Brenner and Rector's The Kidney, 8th ed.

CHAPTER 31. Secondary Glomerular Disease

Gerald B. Appel   Jai Radhakrishnan   Vivette D'Agati

  

 

Systemic Lupus Erythematosus, 1067

  

 

Antiphospholipid Antibody Syndrome, 1080

  

 

Mixed Connective Tissue Disease, 1082

  

 

Wegener Granulomatosis, 1083

  

 

Microscopic Polyangiitis and Polyarteritis Nodosa, 1087

  

 

Churg-Strauss Syndrome (Allergic Granulomatosis), 1091

  

 

Glomerular Involvement in Other Vasculitides (Temporal Arteritis, Takayasu Disease, Lymphomatoid Arteritis), 1093

  

 

Henoch-Schönlein Purpura, 1094

  

 

Anti-Glomerular Basement Membrane Disease and Goodpasture Syndrome, 1097

  

 

Sjögren Syndrome, 1100

  

 

Sarcoidosis, 1100

  

 

Amyloidosis, 1100

  

 

Waldenström Macroglobulinemia, 1107

  

 

Mixed Cryoglobulinemia, 1108

  

 

Hereditary Nephritis Including Alport Syndrome, 1110

  

 

Thin Basement Membrane Nephropathy, 1112

  

 

Nail-Patella Syndrome (Hereditary Osteo-Onychodysplasia), 1112

  

 

Fabry Disease (Angiokeratoma Corporis Diffusum Universale), 1114

  

 

Sickle Cell Nephropathy, 1115

  

 

Lipodystrophy, 1116

  

 

Lecithin-Cholesterol Acyltransferase (LCAT) Deficiency, 1117

  

 

Lipoprotein Glomerulopathy, 1118

  

 

Glomerular Involvement with Bacterial Infections, 1118

  

 

Glomerular Involvement with Parasitic Diseases, 1119

  

 

Glomerular Involvement with Viral Infections, 1120

  

 

Glomerular Disease Associated with Drugs, 1126

SYSTEMIC LUPUS ERYTHEMATOSUS

Lupus nephritis (LN) is a frequent and potentially serious complication of systemic lupus erythematosus (SLE). [1] [2] [3] [4] [5] [6] Serious kidney disease influences morbidity and mortality both directly and indirectly through complications of therapy. Recent studies have more clearly defined the spectrum of clinical, prognostic and renal histopathologic findings in SLE. Treatment trials have focused on the benefits of a variety of immunosuppressive regimens both in severe proliferative LN and membranous lupus. The new histopathologic, epidemiologic, and clinical data have led to further large controlled randomized trials to define the optimal treatment for LN.

Epidemiology

The incidence and prevalence of SLE depend on the population studied and the diagnostic criteria for defining SLE. Females greatly outnumber males by 8-13:1. [3] [7] [8] However, males with SLE have the same incidence of renal disease as do females. [7] [8] Younger adults outnumber older individuals with over 85% of patients younger than 55 years of age. SLE is more likely to be associated with severe nephritis in children, and is less likely in the elderly.[2] [3] [4] [8] SLE appears to be more common and certainly is associated with more severe renal involvement in the African American population although the precise roles of biologic-genetic versus socioeconomic factors have not been clearly defined. [7] [8] [10] [11] [12] [13] Thus, the overall incidence of SLE ranges from 1.8 to 7.6 cases per 100,000 with a prevalence of from 4 to 250 cases per 100,000. [7] [8] [14] The incidence of renal involvement is even more variable depending on the populations studied as well as the diagnostic criteria for kidney disease and whether involvement is defined by renal biopsy or clinical findings. Approximately 25% to 50% of unselected lupus patients will have clinical renal disease at onset whereas as many as 60% of adults with SLE will develop renal disease during their course. [3] [4] [5] [7] [8]

Although the etiology of SLE remains unknown, certain genetic, hormonal, and environmental factors clearly influence the course and severity of disease expression. A genetic predisposition for the development of SLE is supported by a high concordance rate in monozygotic twins, the significant percentage of relatives of patients with the disease who develop SLE (5%–12%), the higher frequency of certain HLA genotypes (e.g., HLA-B8, DR2, DR3, and DQW1), and the higher frequency of SLE in populations with deficiencies of certain complement components (e.g., C1q, C2, and C4 deficiency).[8] Inherited abnormalities of Fc receptors may also influence the incidence and severity of renal disease in SLE.[14] A multiplicity of genes appears to be involved in the abnormalities related to SLE. Evidence for a predisposing role for hormonal factors includes the strong predominance of females in the childbearing age and the increased incidence of SLE in post-menopausal females given estrogen.[14] There is also more severe and earlier disease in female murine models of SLE (F1 NZB/NZW), which is ameliorated by oophorectomy or androgen therapy. Environmental factors other than estrogens may also affect the occurrence and expression of SLE. Although alterations of the immune system induced by viral or bacterial antigens have been proposed, their role in SLE induction remains far from clear.[15] However, exposure to sunlight, UV radiation, and certain medications can all predispose to the development of SLE.

The diagnosis of SLE is often clinically established by the presence of certain clinical and laboratory features defined by the 1997 modified American Rheumatism Association criteria.[16] Development of 4 of the 11 criteria over a lifetime gives a 96% sensitivity and specificity for SLE. The criteria include malar rash, discoid lupus, dermal disease, photosensitivity, oral or nasal ulcerations, non-deforming arthritis, serositis including pleuritis and pericarditis, and central nervous system disease such as seizures or psychoses. Hematologic involvement is manifested by anemia, leukopenia, lymphopenia or thrombocytopenia, and immunologic markers of disease including a positive anti-DNA antibody, anti-Sm antibody, and test for antiphospholipid antibodies or by a positive ANA. The last remaining criterion is renal involvement defined for these purposes as persistent proteinuria exceeding 500 mg daily (or 3+ on the dipstick) or the presence of cellular casts (consisting of erythrocyte, hemoglobin, granular, tubular, or mixed casts). Although the criteria were not designed for diagnosis in individual patients, they are useful to follow the evolution and treatment response of patients with SLE. Because some patients, especially those with mesangial or membranous glomerular lesions, will present with clinical renal disease before they have fulfilled 4 of the 11 ARA criteria for SLE, the diagnosis of SLE remains a clinical diagnosis with histopathologic findings supporting or confirming the presumed diagnosis.[17]

Pathogenesis

Although numerous immunologic abnormalities have been noted in patients with SLE, it is unclear which factors are directly related to the pathogenesis of the disease itself and which factors are epiphenomena.[15] SLE is a disease in which abnormalities of immune regulation lead to a loss of self-tolerance and subsequent autoimmune responses. [16] [19] [20] [21] SLE has been associated with a decreased number of cytotoxic and suppressor T cells, increased helper (CD4+) T cells, polyclonal activation of B cells, defective B cell tolerance, dysfunctional T cell signaling, and abnormal Th1 and Th2 cytokine production. [8] [22] [23] [24] Some of these abnormalities contribute to the activation and clonal expansion of CD4+ T cells, which via cytokine release cause activation of autoreactive B cells leading to their proliferation and differentiation into cells that produce an excess of antibodies against nuclear antigens. [8] [16] Ultimately unique idiotypic autoantibodies are produced by clones of B cells leading to high levels of antibodies directed against nuclear antigens such as ANA, DNA, Sm, RNA, Ro, La, and other nuclear antigens.[16] [25] [26] The formation of circulating immune complexes and their deposition with complement activation is important for certain patterns of glomerular damage. Immune complexes are also detectable in the skin at the dermal-epidermal junction, in the choroid plexus, pericardium, and pleural spaces. The propensity of these immune complexes to cause disease depends not only on size and charge, but also on the rate of clearance by Fc receptors in the liver and spleen.

Glomerular involvement in SLE has often been considered a human prototype of classic chronic immune complex-induced glomerulonephritis as defined in experimental models.[26] The chronic deposition of circulating immune complexes plays a major role in the mesangial and the proliferative patterns of LN. Size, charge, and avidity of the immune complexes influence their localization within the glomerulus. The clearing ability of the mesangium and local hemodynamic factors may also play a role.[27] In diffuse proliferative LN the deposited complexes consist of nuclear antigens (e.g., DNA) and high affinity complement fixing IgG antibodies. [8] [27] Cationic histones bind to glomerular basement membrane (GBM) as well and may facilitate antinuclear antibody localization. [8] [27] Once deposited, the complement cascade is activated leading to complement mediated damage, activation of procoagulant factors, leukocyte infiltration, release of proteolytic enzymes, and various cytokines regulating glomerular cellular proliferation and matrix synthesis. Other patients may have a different mechanism of immune complex mediated damage. The initiating event may be the local binding of nuclear or other antigens to glomerular sites particularly the subepithelial regions of the GBM, followed by in situ immune complex formation. Glomerular and vascular damage may be potentiated by hypertension and coagulation abnormalities. The presence of anti-phospholipid antibodies, directed against a phospholipid-beta2 glycoprotein complex, and their attendant alterations in endothelial and platelet function, including reduced production of prostacyclin and other endothelial anticoagulant factors, activation of plasminogen, inhibition of protein C or S, and enhanced platelet aggregation, can also potentiate glomerular and vascular lesions.

Pathology of Lupus Nephritis

The histopathology of LN is extremely pleomorphic. [1] [2] [3] [4] [5] [8] This diversity of disease expression is evident when comparing adjacent glomeruli in a single biopsy or comparing biopsy findings among different patients. Moreover, the lesions have the capacity to transform from one pattern to another spontaneously or with therapy. Initial attempts to classify biopsies were hindered by the variable expression of the disease, its ability to transform, and the lack of well-defined clinical-pathologic correlation. Early classifications of LN divided glomerular changes into mild and severe forms. [2] [27] The World Health Organization Classification (WHO), used for almost 30 years,[28]combined light microscopic (LM) findings with the immunofluorescence (IF) and electron microscopic (EM) findings to present an accurate and precise classification system. Although it greatly advanced the study of clinical pathologic correlations, provided valuable prognostic information, and has also allowed the development of controlled collaborative clinical trials of LN, it still had limitations. In 2003 a new classification schema of LN, the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification, addressed these limitations. [30] [31] This classification is now widely used by nephrologists, pathologists, and rheumatologists ( Table 31-1 ). Although it still divides the biopsies of SLE patients into six classes akin to the older WHO classification, it should provide better data from clinical pathologic correlations and more prognostic information to the clinician.

TABLE 31-1   -- International Society of Nephrology/Renal Pathology Society (2003) Classification of Lupus Nephritis

Class I

Minimal mesangial LN

Class II

Mesangial proliferative LN

Class III

  

 

Focal LN* (<50% of glomeruli)

  

 

III (A): Active lesions

  

 

III (A/C): Active and chronic lesions

  

 

III (C): Chronic lesions

Class IV

  

 

Diffuse LN* (≥50% of glomeruli)

  

 

Diffuse segmental (IV-S) or global (IV-γ) LN

  

 

IV (A): Active lesions

  

 

IV (A/C): Active and chronic lesions

  

 

IV (C): Chronic lesions

Class V[†]

Membranous LN

Class VI

Advanced sclerosing LN (≥90% globally sclerosed glomeruli without residual activity)

 

LN, lupus nephritis.

 

Class V may occur in combination with III or IV in which case both will be diagnosed.

 

International Society of Nephrology (ISN) Class I denotes normal glomeruli by light microscopy but with mesangial immune deposits by IF and EM. Even patients without clinical renal disease often have mesangial immune deposits when studied carefully by the more sensitive techniques of IF and EM. [2] [18]

International Society of Nephrology Class II is defined on LM by pure mesangial hypercellularity, with mesangial immune deposits on IF and EM (Figs. 31-1, 31-2, and 31-3 [1] [2] [3]). [2] [8] [32] [33] Mesangial hypercellularity is defined as greater than three cells in mesangial regions distant from the vascular pole in 3 mm-thick sections. There may be rare minute subendothelial or subepithelial deposits visible by IF or EM, but not by LM.

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FIGURE 31-1  Lupus nephritis class II: There is mild global mesangial hypercellularity (Periodic acid-Schiff, ×400).

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FIGURE 31-2  Lupus nephritis class II: Immunofluorescence photomicrograph showing deposits of C3 restricted to the glomerular mesangium (×400).

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FIGURE 31-3  Lupus nephritis class II: Electron micrograph showing abundant mesangial electron-dense deposits (×12,000).

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International Society of Nephrology Class III, focal lupus nephritis, is defined as focal segmental and/or global endocapillary and/or extracapillary glomerulonephritis affecting less than 50% of the total glomeruli sampled. There is usually focal segmental endocapillary proliferation including mesangial cells and endothelial cells, with infiltrating mononuclear and polymorphonuclear leukocytes (Figs. 31-4, 31-5, and 31-6 [4] [5] [6]). [2] [8] [34] Class III biopsies may have active (proliferative), inactive (sclerosing), or active and inactive lesions subclassified as A, C, or A/C respectively. Active lesions may display fibrinoid necrosis, nuclear pyknosis or karyorrhexis, and rupture of the glomerular basement membrane (GBM). Hematoxylin bodies, consisting of swollen basophilic nuclear material acted upon by anti-nuclear antibodies, are occasionally found in association with necrotizing lesions. Subendothelial immune deposits may be visible by LM as “wire loop” thickenings of the glomerular capillary walls or large intraluminal masses, so-called “hyaline thrombi”. Segmental scarring involving less than 50% of the glomeruli qualifies for an ISN Class III C lesion. In Class III biopsies, some glomeruli adjacent to those with severe histologic changes may show only mesangial changes or no abnormality by LM. In Class III, diffuse mesangial and focal and segmental subendothelial immune deposits are typically identified by IF and EM. The segmental subendothelial deposits are usually present in the distribution of the segmental endocapillary proliferative lesions.

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FIGURE 31-4  Lupus nephritis class III: There is focal segmental endocapillary proliferation (Jones methenamine silver, ×100).

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FIGURE 31-5  Lupus nephritis class III: The glomerular endocapillary proliferation is discretely segmental with necrotizing features and an early cellular crescent (Jones methenamine silver, ×400).

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FIGURE 31-6  Lupus nephritis class III: Electron micrograph showing deposits in the mesangium as well as involving the peripheral capillary wall in subendothelial (double arrow) and subepithelial (single arrow) locations (×4900).

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International Society of Nephrology Class IV, diffuse proliferative LN, have glomeruli with qualitatively similar endocapillary glomerular proliferation as in Class III biopsies, but the proliferation involves more than 50% of the glomeruli (Figs. 31-7, 31-8, and 31-9 [7] [8] [9]). [2] [3] [4] [8] [18] [27] [33] [35] [36] The ISN Classification subdivides lupus nephritis Class IV into diffuse segmental versus diffuse global proliferation to facilitate future studies addressing possible differences in outcome and pathogenesis between these subgroups. Class IV-S is used if more than 50% of affected glomeruli have segmental lesions, whereas Class IV-G is used if more than 50% of affected glomeruli have global lesions. All the active features described earlier for Class III (including fibrinoid necrosis, leukocyte infiltration, wire loop deposits, hyaline thrombi, and hematoxylin bodies) may be encountered in Class IV lupus nephritis. In general, there is more extensive peripheral capillary wall subendothelial immune deposition in Class IV biopsies and extracapillary proliferation in the form of crescents is not uncommon. Some patients with ISN Class IV lesions have features similar to idiopathic membranoproliferative (mesangiocapillary glomerulonephritis) with mesangial interposition along the peripheral capillary walls and double contours of the GBMs.

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FIGURE 31-7  Lupus nephritis class IV: There is global endocapillary proliferation with infiltrating neutrophils and segmental wire loop deposits (Hematoxylin-eosin, ×320).

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FIGURE 31-8  Lupus nephritis class IV: Immunofluorescence photomicrograph showing global deposits of IgG in the mesangial regions and outlining the subendothelial aspect of the peripheral glomerular capillary walls (×600).

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FIGURE 31-9  Lupus nephritis class IV: Electron micrograph showing a large subendothelial electron-dense deposit as well as a few small subepithelial deposits (arrow) (×1200).

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International Society of Nephrology Class V is defined by regular subepithelial immune deposits producing a membranous pattern (Figs. 31-10, 31-11, and 31-12 [10] [11] [12]). [2] [8] [27] [33] [37] [38] [39] The co-existence of mesangial immune deposits and mesangial hypercellularity in most cases helps to distinguish membranous LN from idiopathic membranous glomerulopathy.[39] Early membranous lupus nephropathy Class V may have no identifiable abnormalities by LM. In well-developed membranous glomerulonephritis, there is typically thickening of the glomerular capillary walls and “spike” formation. When the membranous alterations are accompanied by additional focal or diffuse proliferative lesions and subendothelial immune complex deposition they are classified as V + III and V + IV. Because sparse subepithelial deposits may also be encountered in other classes (III or IV) of LN, a diagnosis of pure lupus membranous LN should be reserved only for those cases in which the membranous pattern predominates.

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FIGURE 31-10  Lupus nephritis class V: There is diffuse uniform thickening of glomerular basement membranes accompanied by mild segmental mesangial hypercellularity (Hematoxylin-eosin, ×320).

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FIGURE 31-11  Lupus nephritis class V: Silver stain highlights uniform glomerular basement membrane spikes projecting from the glomerular basement membranes (Jones methenamine silver, ×800).

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FIGURE 31-12  Lupus nephritis class V: Electron micrograph showing numerous subepithelial electron-dense deposits as well as mesangial deposits (×5000).

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International Society of Nephrology Class VI is advanced sclerosing lupus nephritis or end-stage LN and is reserved for those biopsies with over 90% of the glomeruli sclerotic. There are no active lesions and it may be difficult in such biopsies to even establish the diagnosis of LN without the identification of residual glomerular immune deposits by IF and EM.

Immunofluorescence

In LN immune deposits can be found in all renal compartments, the glomeruli, tubules, interstitium, and blood vessels. [2] [8] [27] [39] IgG is almost universally present, with co-deposits of IgM and IgA in most specimens. Both C3 and C1q are commonly identified. [2] [8] [27] The presence of all three immunoglobulins, IgG, IgA, and IgM, along with the two complement components, C1q and C3, is known as “full house” staining (after the poker hand!) and is highly suggestive of lupus nephritis, as is strong C1q staining.

Staining for fibrin-fibrinogen is common in the distribution of crescents and segmental necrotizing lesions. In biopsies of patients with lupus the “tissue ANA”,[39] nuclear staining of renal epithelial cells in sections stained with fluoresceinated antisera to human IgG is a frequent finding in all classes. It results from the binding of patient's own ANA to nuclei that have been exposed in the course of cryostat sectioning.

Electron Microscopy

The distribution of glomerular, tubulointerstitial, and vascular deposits seen by EM correlates closely with the pattern observed by IF. [2] [3] [4] [5] [6] [8] [27] Deposits are typically electron-dense and granular. Some deposits exhibit a fingerprint substructure composed of curvilinear parallel arrays measuring 10nm to 15nm in diameter. [2] [4] [27] Tubulo-reticular inclusions (TRIs), intracellular branching tubular structures measuring 24 nm in diameter located within dilated cisternae of the endoplasmic reticulum of glomerular and vascular endothelial cells, are commonly observed in SLE biopsies. [2] [4] [27] TRI's are inducible upon exposure to α-interferon (so-called “interferon footprints”) and are also present in biopsies of HIV-infected patients and those with other viral infections.[40]

Other Histopathologic Features

Some investigators have also found it useful to grade biopsies for features of activity (potentially reversible lesions) and chronicity (irreversible lesions).[41] The system of activity and chronicity indices developed at the NIH is widely used. For activity index, the biopsy is graded on a scale of 0 to 3+ for each of six histologic features including endocapillary proliferation, glomerular leukocyte infiltration, wire loop deposits, fibrinoid necrosis and karyorrhexis, cellular crescents, and interstitial inflammation. The severe lesions of crescents and fibrinoid necrosis are assigned double weight. The sum of the individual components yields a total histologic activity index score of from 0 to 24. Likewise, a Chronicity Index of 0 to 12 is derived from the sum of glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis, each graded on a scale of 0 to 3+. Studies at the NIH correlated with both a high Activity Index (>12) and especially a high Chronicity Index (>4) with a poor 10-year renal survival. [2] [8] [28] [42] However, in several other large studies neither the activity Index nor the Chronicity Index correlated well with long-term prognosis. [18] [43] [44] These studies have included both patients with all WHO classes as well as those with predominantly severe Class IV patients. Other studies from the NIH have shown that a combination of elevated Activity Index (>7) and Chronicity Index (>3) adds prognostic information about the long-term outcome of the patients.[41] Moreover, in these studies the combination of cellular crescents and interstitial fibrosis also predicted a poor outcome. A major beneficial value of calculating an Activity and Chronicity Index is in the comparison of sequential biopsies in individual patients. This provides useful information about the efficacy of therapy and the relative degree of reversible versus irreversible lesions. [45] [46]

Some patients with SLE have major changes in the tubulointerstitial compartment. [47] [48] [49] [50] [51] Active tubulointerstitial lesions include edema and inflammatory infiltrates including T lymphocytes (both CD4 and CD8 positive cells), monocytes, and plasma cells.[50] Tubulointerstitial immune deposits of immunoglobulin or complement (or both) may be present along the basement membranes of tubules and interstitial capillaries. Severe acute interstitial changes and tubulo-interstitial immune deposits are most commonly found in patients with active proliferative Class III and IV LN. The degree of interstitial inflammation does not correlate well with the presence or quantity of tubulo-interstitial immune deposits. [47] [49] Interstitial fibrosis or tubular atrophy (or both) are commonly encountered in the more chronic phases of LN. A recent study of over 150 LN patients documents a strong inverse correlation between the degree of tubular damage and renal survival. In addition renal survival was higher for patients with less expression on their renal biopsy of the adhesion molecule ICAM-I. [48] [50]

Vascular lesions are not included in the formulation of either the ISN classification or the NIH Activity or Chronicity Indices despite their frequent occurrence and clinical significance. [52] [53] [54] The most frequent vascular lesion is simple vascular immune deposition, most common in patients with active Class III and IV biopsies. The vessels may show no abnormalities by LM, but by IF and EM there are granular immune deposits in the media and intima of small arteries and arterioles. Non-inflammatory necrotizing vasculopathy, most common in arterioles in active Class IV LN, is a fibrinoid necrotizing lesion without leukocyte infiltration that severely narrows or occludes the arteriolar lumen. True inflammatory vasculitis resembling polyangiitis is extremely rare in biopsies from SLE patients. It may be limited to the kidney or be part of a more generalized systemic vasculitis. [53] [54] Thrombotic microangiopathy involving vessels and glomeruli may be associated with anticardiolipin/anti-phospholipid antibody or hemolytic uremic syndrome-thrombocytopenic purpura (HUS-TTP)-like syndrome due to autoantibody to the Von Willebrand factor cleaving protease. [53] [54]

A number of other renal diseases have been documented on biopsy in SLE patients including minimal change disease, focal glomerulosclerosis, and HIV-associated-like lesions. [55] [56] [57] In some, the relationship between SLE and the second disease suggests this is not a coincidental occurrence but related to the interaction of the disease processes.

Clinical Manifestations

Although SLE predominantly affects young females, the clinical manifestations are similar in both sexes and in adults and children. [3] [7] [8] SLE is a pleomorphic multisystem disease that can affect virtually any organ system. Organ systems commonly involved include the kidneys, joints, serosal surfaces including pleura and pericardium, central nervous system, and skin. In addition, involvement of other organ systems including cardiac, hepatic, pulmonary, hematopoietic, and gastrointestinal is not infrequent.

The clinical manifestations of kidney involvement in SLE are as varied as the extrarenal manifestations of the disease. Renal involvement often develops concurrently or shortly following the onset of SLE and may follow a protracted course with periods of remissions and exacerbations. Clinical renal involvement usually correlates well with the degree of glomerular involvement in SLE. However, some patients may have severe vascular or tubulointerstitial disease leading to major clinical manifestations despite a benign pattern of glomerular involvement. [47] [53] [54] Although the clinical features of renal involvement in relation to the histologic findings on renal biopsy have not clearly been defined for the new ISN/ RPS classification, they are very likely to be similar to the correlations of the older WHO classification.

Patients with Class I biopsies often have no, or at most mild, evidence of clinical renal disease. Likewise, most patients with disease confined to the mesangial regions of the glomeruli (Class II) have mild or minimal clinical renal findings. [1] [2] [3] [4] [5] [6] [32] [33] They may have a high anti-DNA antibody titer and low serum complement, but urinary sediment is inactive, hypertension is infrequent, proteinuria is usually less than 1 g daily, and the serum creatinine and GFR are usually normal. Nephrotic range proteinuria is extremely rare and may represent a concurrence of minimal change disease with LN when present.[55]

Class III, focal proliferative LN, is often associated with active lupus serologies, although the degree of serologic activity does not necessarily correlate with the severity or extent of the histologic damage. [18] [32] [34] Hypertension and active urinary sediment are commonly present. Proteinuria is often more than 1 g daily, and as many as one quarter to one third of patients with focal LN will have the nephrotic syndrome at presentation. Many patients will have an elevated serum creatinine at presentation. Patients with less extensive glomerular involvement by the focal proliferative process and those with fewer necrotizing features and those without crescents are more likely to be normotensive and have preserved renal function.

Most treatment trials deal largely with patients with ISN Class IV, diffuse proliferative disease, which typically presents with the most active and severe clinical features. These patients often have high anti-DNA antibody titers, low serum complement levels, and very active urinary sediment, with erythrocytes, red cell, and other casts on urinalysis. [1] [2] [3] [4] [5] [6] [8] [18] [32] [35] [36] Virtually all have proteinuria and as many as half of the patients will have the nephrotic syndrome. Likewise, hypertension and renal dysfunction are typical, and even when the serum creatinine appears normal, the GFR is usually depressed.

Patients with lupus membranous nephropathy, ISN Class V, typically present with proteinuria, edema, and other manifestations of the nephrotic syndrome. [1] [3] [4] [8] [18] [37] [38] [39] However, as many as 40% will have less than 3 g proteinuria daily, and 16% to 20% less than 1 g of proteinuria at biopsy. Up to 60% of membranous patients will have a low serum complement and an elevated anti-DNA antibody titer.[17] Likewise, active urine sediment, hypertension, and renal dysfunction may all occur in patients with pure membranous lupus without superimposed proliferative lesions. Patients with lupus membranous nephropathy may present with heavy proteinuria or what appears to be idiopathic nephrotic syndrome before developing other clinical and laboratory manifestations of SLE. [8] [18] [35] As with idiopathic membranous nephropathy, patients with lupus membranous nephropathy are predisposed to developing thrombotic complications such as renal vein thrombosis and pulmonary emboli. [53] [54] Patients with mixed membranous and proliferative patterns on biopsy have clinical features that reflect both components of their renal disease.

End-stage LN, ISN Class VI, is usually the result of “burnt out” LN of long duration. [1] [2] [3] [4] [5] [6] [8] [27] It is often the end result of years of lupus flares alternating with periods of inactivity. Much of the renal histologic damage may represent non-immunologic progression of disease in remaining glomeruli as a result of reduced number of functioning nephrons. Although the lesions are sclerosing and fibrotic without activity on biopsy, patients may still have microhematuria and proteinuria. Virtually all such patients have both hypertension and a decreased GFR. Levels of anti-DNA antibodies and serum complement levels have usually normalized by the time these patients reach stage VI lesions.

“Silent LN” [8] [58] has been described in patients without clinical evidence of renal involvement despite the presence of proliferative LN on renal biopsy. Some investigators consider a patient to have “silent lupus nephritis” if there are active biopsy lesions without active urinary sediment, proteinuria, or a depressed GFR, whereas others require negative lupus serologies as well. Although silent LN is well described in some studies, others have been unable to find even isolated examples. [8] [18] [27] Thus, “silent LN” certainly appears to be a rare phenomenon. Moreover, it is highly likely that even patients with true “silent disease” will manifest clinical renal involvement shortly into their course.

Serologic Tests

Abnormal autoantibody production is the hallmark of SLE. The presence of antibodies directed against nuclear antigens (ANA) and especially against DNA (anti-DNA) antibodies are included in the ARA's diagnostic criteria for SLE, and are commonly used to monitor the course of patients with SLE. Autoantibodies may have wide range of cross-reactivity and autoantibodies of unrelated SLE patients may share idiotypes. [8] [25] [59] ANA's are a highly sensitive screen for SLE, being found in more than 90% of untreated patients, but they are not specific for SLE and occur in many other rheumatologic diseases as well as a variety of infectious diseases including HIV infection. [8] [25] It is unclear how well a particular pattern of ANA fluorescence (e.g., homogeneous, speckled, nucleolar, rim) correlates with any specific rheumatologic disease or with the presence of renal disease. In FANA-negative patients antibodies against nuclear antigens can often be detected by other techniques such as radioimmunoassay. The titer of the ANA does not correlate well with the presence of the severity of renal involvement in SLE. [3] [8] [25]

Autoantibodies directed against double stranded DNA (ant-dsDNA) are a more specific but less sensitive marker of SLE and are found an almost three fourths of untreated patients with active SLE.[24] These antibodies may be detected by a number of techniques including the Farr radioimmunoassay, and an immunofluorescence test directed against the DNA in the kinetoplast of the single celled organism Crithidia luciliae, and by ELISA.[24] Anti-ds DNA IgG antibodies of high avidity that fix complement have correlated best with the presence of renal disease [3] [8] [28] and such anti-dsDNA anti-bodies have been found in the immune glomerular deposits of animal models and humans with LN. [28] [60] High anti-dsDNA antibody titers correlate well with clinical activity. Anti-single stranded DNA antibodies (anti-ssDNA) are commonly found in patients with SLE as well as in many other collagen-vascular diseases and do not correlate well with clinical lupus activity.

A variety of other autoantibodies directed against ribonucleic antigens are commonly present in lupus patients. These include anti-Sm and anti-nRNP against extracted nuclear antigen (ENA).[24] Anti-Sm antibodies, although very specific for SLE are found in only about 25% of lupus patients. The prognostic value of anti-Sm antibodies is not clear. In some studies, patients who are anti-Sm-positive have had a greater incidence of renal and CNS disease or more cutaneous vasculitis, cardiopulmonary disease, and a worse prognosis. Anti-nRNP antibodies, found in over one third of SLE patients, are also present in many rheumatologic diseases other than SLE, particularly mixed connective tissue disease (MCTD). [25] [61] AntiRo/SAA antibodies are directed against the protein complex of a cytoplasmic RNA and are present in 25% to 30% of SLE patients. Anti-La/SSB autoantibodies are directed against a nuclear RNP antigen distinct from ENA and are present in from 5% to 15% of lupus patients. Neither are specific for SLE and both are found in other collagen disease especially Sjögren syndrome. Maternal anti-Ro antibodies are related to lupus in the newborn with its associated cardiac conduction abnormalities.[61] Anti-Ro antibodies are also associated with a unique dermal form of lupus with psoriaform features, with SLE patients who are homozygous C2 deficient, and with a vasculitic disease associated with CNS involvement and cutaneous ulcers.[62] In addition, lupus patients may develop antibodies directed against histones, endothelial cells, antiphospholipids, and neutrophil cytoplasmic antigens (ANCA). [65] [66] [67] [68]

Levels of total hemolytic complement (CH50) and complement components are usually decreased during active SLE and especially active renal disease. [3] [4] [8] Levels of C4 and C3 often decline before a clinical flare of active lupus. [8] [59] Serial monitoring of complement levels, with a decline in levels predicting a flare, is considered more useful clinically than an isolated depressed C3 or C4 value. [3] [8] Likewise, normalization of depressed serum complement levels is often associated with improved renal outcome.[68] Levels of total complement and C3 levels may be decreased in the absence of active clinical or renal disease in patients with extensive dermatologic involvement by SLE. Isolated complement deficiency states (including C1r, C1s, C2, C4, C5, and C8) have been associated with SLE and such patients may have depressed total complement levels despite inactive disease.[69]

Other immunologic tests commonly found in lupus patients include elevated levels of circulating immune complexes (CIC), a positive lupus band test, and the presence of cryoglobulins. None of these tests has been shown to clearly correlate with lupus activity and in specific LN. [8] [71] In patients with both SLE and isolated discoid lupus, immune complex deposits containing IgG antibody and complement are found along the dermal epidermal junction of involved skin lesions. [3] [8] [72] In clinically uninvolved skin the presence of granular deposits in this location has been found only in systemic disease. However, the specificity and sensitiv-ity of this test is debated, it requires immunofluorescence of the dermal biopsy, and its correlation with clinical lupus activity or renal disease is unproven.[8] Mixed IgG-IgM cryoglobulins containing anti-DNA antibodies, DNA, and fibronectin may be found in patients with SLE and active renal disease. Patients with SLE commonly have a false positive VDRL due to the presence of antiphospholipid antibodies.[72]

Monitoring Clinical Disease

It is important in the treatment of patients with lupus to be able to predict clinical and renal relapses and prevent their occurrence through the judicious use of immunosuppressive agents. Serial measurements of many serologic tests for clinical activity (including complement components, autoantibodies, sedimentation rate, C-reactive protein, circulating immune complexes, and recently levels of cytokines and interleukins) have been used to predict flares of lupus activity. Although there is controversy regarding the value of a declining C3 and C4 level and a rising anti-DNA antibody titer in predicting a clinical flare of SLE or active renal disease, [3] [8] [68] clearly these are the most widely used serologic tests to monitor SLE activity. Serum levels of anti-ds DNA typically rise and serum complement levels typically fall as the clinical activity of SLE increases and usually before clinical renal deterioration. In patients with active renal involvement the urinalysis frequently reveals dysmorphic erythrocytes, rbc casts, and other formed elements. An increase in proteinuria from levels of less than 1 g daily to over this amount and certainly from low levels to nephrotic levels is a clear indication of either increased activity or a change in renal histologic class. [8] [18]

Drug-Induced Lupus

A variety of medications may induce a lupus-like syndrome or exacerbate an underlying predisposition to SLE. Although a number of drugs have produced this entity, those metabolized by acetylation such as procainamide and hydralazine are common causes. [74] [75] This occurs more commonly in patients with a genetic decrease in hepatic N-acyltransferase who are slow acetylators.[75] Procainamide-induced SLE may be mediated by its metabolite procainamide hydroxylamine as opposed to the active metabolite N-acetylprocainamide, which does not produce an SLE-like syndrome. [74] [75] [76] Diltiazem, minocycline, penicillamine, isoniazid, methyldopa, chlorpromazine, and practolol are other drugs that have all clearly produced a drug-related lupus syndrome. [74] [75] [77] [78] A number of other drugs that are possibly but not conclusively associated with this syndrome include phenytoin, quinidine, antithyroid drugs, sulfonamides, lithium, b blockers, nitrofurantoin, PAS, captopril, glyburide, hydrochlorothiazide, alfa interferon, carbamazepine, sulfasalazine, and rifampin. [79] [80] Clinical manifestations of drug-induced lupus include fever, rash, myalgias, arthralgias and arthritis, and serositis. CNS and renal involvement are relatively uncommon in drug-induced disease. [81] [82] Although elevated anti-DNA antibodies and depressed serum complement levels are unusual in drug-induced lupus, antihistone autoantibodies are present in more than 95% of patients.[73] These are usually formed against a complex of the histone dimer H2A-H2B and DNA and other histone components.[74] [83] Antihistone antibodies are also present in the vast majority of idiopathic, non-drug-related SLE patients, but they are directed primarily against different histone antigens (H1 and H2B).[73] The diagnosis of drug-related SLE depends on documenting the offending agent and achieving a remission with withdrawal of the drug. The presence of antihistone antibodies in the absence of anti-DNA antibodies and other serologic markers for SLE is also indicative of drug-induced disease.[73] The primary treatment consists of discontinuing the offending drug, although NSAIDs and corticosteroids may be effective in suppressing the serositis and constitutional symptoms of the disease.

Pregnancy and Systemic Lupus Erythematosus

Because SLE occurs so commonly in women of childbearing age, the issue of pregnancy arises often in the care of this population. Independent but related issues are the fate of the mother both in terms of flares of lupus activity and progression of renal disease and the fate of the fetus. It is unclear whether flares of lupus activity occur more commonly during pregnancy or shortly after delivery. [84] [85] [86] [87] Some controlled studies found no increased in lupus flares in pregnant patients over non pregnant controls. [84] [85] [86] [87] Patients who were clinically inactive at the time of pregnancy were especially unlikely to experience an exacerbation of SLE. However, in two retrospective studies, in 37 and 68 patients, flares of lupus activity including renal involvement occurred in over 50% of the pregnancies. [86] [87] This was significantly increased over the rate after delivery and in non pregnant lupus patients. Because the numbers of patients studied are small, it is unclear whether there is an increased risk of exacerbation of SLE during pregnancy. Women with quiescent disease, however, will fare the best.[83]

Pregnancy in patients with LN has also been associated with worsening of renal function. [88] [89] This is less likely to occur in patients who have been in remission for at least 6 months. Patients with hypertension are likely to have higher levels and those who have proteinuria are likely to have increased levels during pregnancy. Patients with elevated serum creatinines are most likely to suffer worsening of renal function and to be at highest risk for fetal loss. Both high-dose corticosteroids and azathioprine have been used in pregnant lupus patients, but cyclophosphamide is contraindicated due to its teratogenicity and newer agents such as mycophenolate and rituximab are not recommended, making the treatment of severe LN more difficult.

The rate of fetal loss in all SLE patients in most series is 20% to 40% and may approach 50% in some series. [85] [87] [89] [90] [91] Although fetal mortality is increased in SLE patients with renal disease, it may be decreasing in the modern treatment era. [85] [86] [88] [89] Patients with anticardiolipin antibodies, hypertension, or heavy proteinuria are at higher risk for fetal loss.[84] One review of 10 studies in over 550 women with SLE found fetal death in between 38% and 59% of all pregnant SLE patients with antiphospholipid antibodies as opposed to 16% to 20% of those without antibodies.[91]

Dialysis and Transplantation

The percentage of patients with severe LN who progress to end-stage renal disease (ESRD) varies from 5% to 50% depending on the population studied, the length of follow-up, and the response to therapy. [8] [18] [45] [58] [93] [94] [95] [96] Many with progressive renal failure have a resolution of their extrarenal manifestations of disease and serologic activity. [97] [98] [99] With duration of dialysis the incidence of clinically active patients declines further, decreasing in one study from 55% at the onset of dialysis to less than 10% at the fifth year and 0% by the tenth year of dialysis.[97] Although ESRD has been described as an immunosuppressed state it is unclear precisely what mechanisms underlie this immune suppression of dialysis and ESRD. Patients with ESRD due to LN have increased mortality during the early months of dialysis due to infectious complications as a result of their immunosuppressive treatment.[97] [99] [100] Long-term survival for SLE patients on chronic hemodialysis or continuous ambulatory peritoneal dialysis is similar to other patients with ESRD with most common cause of long-term death being cardiovascular. [98] [99] [100]

In general, most renal transplant programs allow patients with active SLE to undergo a period of dialysis for from 3 to 12 months to allow clinical and serologic disease activity to become quiescent.[97] Allograft survival rates in patients with ESRD due to LN are comparable to the rest of the ESRD population. [8] [99] [100] [101] [102] [103] The rate of recurrent SLE in the allo-graft has been low in most series (<4%) [97] [98] [101] although in several recent reports a higher recurrence rate has been noted.[102] The low recurrence rate is in part due to the immune suppressant action of ESRD prior to transplantation and in part the immunosuppressive regimens used to prevent allograft rejection. Lupus patients with an antiphospholipid antibody may benefit from anticoagulation therapy during the post transplant period. [104] [105]

Course and Prognosis of Lupus Nephritis

The course of patients with LN is extremely varied with from less than 5% to over 60% of patients developing progressive renal failure. [1] [5] [8] [18] [34] [45] [93] [94] [95] [96] [106] This course is defined by the initial pattern and severity of renal involvement as modified by therapy, exacerbations of the disease, and complications of treatment. The prognosis has clearly improved in recent decades with wider and more judicious use of new immunosuppressives. Most studies have found additional prognostic value of renal biopsy over clinical data in SLE populations. [107] [108] [109]

Patients with lesions limited to the renal mesangium generally have an excellent course and prognosis. [1] [2] [3] [4] [5] [6] [8] Those who do not transform into other patterns are unlikely to develop progressive renal failure and mortality is generally due to extrarenal manifestations and complications of therapy. It is unknown why some patients will progress to more serious renal disease whereas others do not over a lifetime. Patients with focal proliferative disease have an extremely varied course. Those with mild proliferation in a small percentage of glomeruli respond well to therapy and less than 5% progress to renal failure over 5 years of follow-up. [1] [2] [3] [4] [5] [6] [8] [18] [110] [111] Patients with more proliferation, those with necrotizing features, and those with crescent formation have a prognosis more akin to patients with Class IV diffuse proliferative disease. Some Class III patients will transform or evolve to Class IV over time. In one study, patients with “severe” Class III lesions actually had a lower remission rate and renal survival than patients with Class IV lesions.[111] This emphasizes the different patterns within the designation focal proliferative lupus nephritis among investigators in the older WHO classification. Clearly patients with very active segmental proliferative and necrotizing lesions fare worse than those with global milder proliferative lesions in only some of the glomeruli.

Patients with diffuse proliferative disease have the least favorable prognosis in most series. [1] [2] [3] [4] [5] [6] [8] [18] Nevertheless, the prognosis for this group has markedly improved. Five-year renal survival rates, commonly less than 50% in the past are now over 90% in some series of patients treated with modern immunosuppressive agents. [8] [36] [111] [113] In recent trials from NIH the risk of doubling the serum creatinine, a surrogate marker for progressive renal disease, at 5 years in diffuse proliferative lupus treated with cyclophosphamide containing regimens ranged from 35% to less than 5%. [94] [95] [113] Groups with a better prognosis received more intensive regimens of therapy. In an Italian study of diffuse proliferative disease survival was 77% at 10 years and over 90% if extrarenal deaths were excluded.[35] In a recent U.S. study of 89 patients with diffuse prolifera-tive disease, renal survival was 89% at 1 year and 71% at 5 years.[10] It is unclear whether the improved survival in these recent series is largely due to improved therapy with immunosuppressive medications, or better supportive care and clinical use of these medications.

In the past some studies have found age, gender, and race to be as important prognostic variables as clinical features in patient and renal survival in SLE [1] [4] [6] [8] [17] [109] [114] [115] [116]; however, a consistent finding is that African Americans have a greater frequency of LN and a worse renal and overall prognosis. [1] [4] [8] [17] [111] [114] [117] This worse prognosis appears to relate to both biologic/genetic factors and to socioeconomic ones. [10] [11] [17] In a study from NIH of 65 patients with severe LN, clinical features at study entry associated with progressive renal failure included age, black race, hematocrit less than 26%, and serum creatinine greater than 2.4 mg/dl.[41] Patients with combined severe activity and chronicity (Activity Index >7 plus Chronicity Index >3 on renal biopsy) as well as those with the combination of cellular crescents and interstitial fibrosis also had a worse prognosis. In another U.S. study of 89 patients with diffuse proliferative LN, none of the following features impacted on renal survival: age, gender, SLE duration, uncontrolled hypertension, or any individual histologic variable.[10] Entry serum creatinine over 3.0 mg/dl, combined activity and chronicity on the biopsy, and black race did predict a poor outcome. Renal survival for the white patients was 95% at 5 years but only 58% for the black patients at 5 years. In a study of over 125 LN patients with WHO Class III or IV from New York both racial and socioeconomic factors influenced the poor outcome in African Americans.[116] African Americans and Hispanics had a worse renal prognosis. In the Hispanics this was entirely related to socioeconomic factors whereas in the blacks both socioeconomic and genetic biologic factors appeared to be involved in the adverse outcome.[116] An evaluation of 203 patients from the Miami area confirms a worse renal outcome in both African Americans and Hispanics related to both biologic factors and more aggressive disease as well as economic factors.[117]

A more rapid renal remission and more complete remission have been related to improved long-term prognosis. [119] [120] Renal flares during the course of SLE also may predict a poor renal outcome. [106] [121] [122] Relapses of severe LN occur in up to 50% of patients over 5 to 10 years of follow-up and usually respond less well and more slowly to repeated course of cytotoxics. [8] [106] [123] [124] [125] A retrospective analysis of 70 Italian patients in which over half had diffuse proliferative disease found excellent patient survival (100% at 10 years and 86% at 20 years) as well as preserved renal function with probability of not doubling the serum creatinine at 10 years to be 85% and at 20 years to be 72%.[105] Most patients in this study were white and this may be associated with the excellent long-term prognosis. Multivariate analysis in the Italian study showed males, those more anemic, and especially those with flare ups of disease to have a worse outcome. Patients with renal flares of any type had 6.8 times the risk of renal failure, and those with flares with rapid rises in the creatinine had 27 times the chance of doubling their serum creatinine. Another Italian study of 91 patients with diffuse proliferative lupus nephritis showed over 50% having a renal flare that correlated with a younger age at biopsy (<30 years old), higher activity index, and karyorrhexis on biopsy.[120] The number of flares, nephritic flares, and flares with increased proteinuria correlated with a doubling of the serum creatinine. The role of relapses in predicting progressive disease has been documented by others as well, although relapse does not invariably predict a bad outcome.[125]

Although an elevated anti-DNA antibody titer and low serum complement levels have in some studies predicted progressive renal disease, they may normalize with therapy and in most prognostic studies they have not correlated with long-term prognosis. [8] [11] [18] [93] [106] In several studies anemia has been a poor prognostic finding regardless of the underlying etiology. [42] [106] Severe hypertension has also been related to renal prognosis in some studies, but not others.[17] Renal dysfunction as noted by an elevated serum creatinine or decreased GFR or by heavy proteinuria and the nephrotic syndrome are indicative of a poor renal prognosis in the vast majority of series. [1] [2] [3] [4] [5] [6] [7] [8] [117] Not all studies have found an elevation of the initial serum creatinine to predict a poor prognosis long-term and in some the initial serum creatinine only predicted short-term renal survival over years, not long-term renal prognosis.[10] Other renal features such as duration of nephritis and rate of decline of GFR may also predict prognosis. [93] [111]

Finally, histologic features such as class, the degree of activity and chronicity, and the severity of tubulointerstitial damage on biopsy have also been predictive of prognosis. In a number of studies the pattern of renal involvement, especially when using the ISN or older WHO classification, has been a useful guide to prognosis. [1] [2] [3] [4] [5] [6] [8] [18] [31] [56] In early clinical trials at the NIH, patients with severe proliferative LN who had higher Activity Index or Chronicity Index were more likely to have a progressive course to renal failure.[110] Other studies with different referral populations could not confirm that an elevated activity or chronicity index predicted a poor prognosis. [2] [4] [8] [18] [27] [43] [93] Although there is disagreement about the role of individual indices, the contribution of chronic scarring to a poor long-term outcome has been confirmed by many studies. [50] [93] [121] [126] [127] Some studies have found the initial renal biopsy to have little predicative value in terms of long-term outcome, but features on a repeat biopsy at 6 months to be a strong predictor of doubling the serum creatinine or progression to ESRD. [48] [128]These features at 6 months include ongoing inflammation with cellular crescents and macrophages in the tubular lumens, persistent immune deposits (especially C3) on IF, and persistent subendothelial and mesangial deposits. More recent studies by this group suggest that reversal of interstitial fibrosis and glomerular segmental scarring along with remission of initial inflammation and immune deposition is an important favorable prognostic finding on the 6-month biopsy.[125] Thus, chronic changes on biopsy are not always cumulative and immutable and their reversal may be crucial in preventing ESRD when new acute lesions develop.

The natural history of membranous lupus is unclear. In early studies with short follow-up, the course of membranous lupus appeared far better than that of patients with active proliferative lesions.[32] Subsequent studies with longer follow-up suggested a worse outcome for some patients especially those with persistent nephrotic syndrome.[17] Recent retrospective studies with long-term follow-up show 5-year renal survival rates largely depend on whether patients have true pure membranous lesions (pure Class V) or superimposed proliferative lesions either in a focal segmental (Class III + V) or diffuse distribution (IV + V). [38] [39] One U.S. study found the 10-year survival rate was 72% for patients with pure membranous lesions but only 20% to 48% for those with superimposed proliferative lesions.[37] Black race, elevated serum creatinine, higher degrees of proteinuria, hypertension, and transformation to another WHO pattern all portended a worse outcome. [1] [4] The poor survival in blacks with membranous lupus nephropathy may explain the excellent results in retrospective Italian studies, which are largely white. One such Italian study found the 10-year survival of membranous patients to be 93%.[38] Even in this Italian population survival was far better than in patients with superimposed proliferative lesions (Classes III + V or IV + V). Thus, at least in part the variability of prognosis in older studies can be explained by the differences in racial background, underlying histology of the membranous lesions, as well as differences in therapy.

Management of Lupus Nephritis

The treatment of many patients with severe LN remains controversial. [1] [3] [6] [7] [8] Although recent controlled randomized studies have better defined the course and therapy for these patients, the most effective and least toxic regimen for any given patient is often less clear cut. Although some newer therapies may offer clear short-term benefits, it is unclear whether they prevent chronic renal failure at 5 and 10 years later. Moreover, as patient survival improves it is crucial to find regimens that have equivalent efficacy but less side effects and toxicity.

Patients with Class I and Class II biopsies have an excel-lent renal prognosis and need no therapy directed at the kidney. Transformation to another histologic class is usually heralded by increasing proteinuria and urinary sediment activity.[30] At this point repeat renal biopsy may serve as a guide to therapy.[8] There is no general consensus on the treatment of patients with focal proliferative LN, Class III lesions. This is, in part, due to the spectrum of disease that occurs in Class III. Patients with only mild or moderate proliferative lesions involving a few glomeruli, with no necrotizing features and no crescent formation, have a good prognosis and will often respond to a short course of high-dose corticosteroid therapy. Patients with severe segmental lesions and with necrotizing features and crescent formation usually require more vigorous therapy similar to patients with diffuse proliferative LN.

Patients with diffuse proliferative disease, Class IV lesions, require aggressive treatment to avoid irreversible renal damage and progression to ESRD. [1] [2] [3] [4] [5] [6] [8] The precise form of immunosuppressive regimen is still debated and may include high-dose daily or alternate day corticosteroids, azathioprine, intravenous pulse methylprednisolone, oral or intravenous cyclophosphamide, cyclosporine, mycophenolate mofetil, and rituximab. There is also data in the literature on other less well-studied therapies such as ancrod treatment, total lymphoid irradiation, thromboxane inhibitors, intravenous gamma-globulin, tolerance-inducing molecules (e.g., LJP 394), blockers of lymphocyte co-stimulation, and total marrow ablation with stem cell rescue therapy. Only a few of the latter therapies have been examined in well-designed long-term studies. No current regimen of immunosuppressives is without major potential side effects and no agent is universally effective. Thus, newer therapeutic agents are being developed, not only to manage active disease or to prevent flare ups of LN, but also to minimize the side effects of current regimens. The concept of more vigorous initial treatment, an induction phase, followed by more prolonged lower dose therapy, a maintenance phase of treatment, is widely accepted.[8]

Prednisone has been used for almost 50 years to treat LN. Despite the lack of controlled trials, higher doses of corticosteroids appeared more effective than low-dose therapy (<30 mg Prednisone daily) in retrospective studies. [1] [3] [4] [5] [6] [8] Even the high-dose corticosteroids given in early studies were in doses far lower than in modern regimens. Initial use of high-dose corticosteroid treatment for severe LN, reserving other immunosuppressives agents only for those patients who fail to respond to several months of therapy or who have evidence of rapid clinical progression of disease, is still utilized by some clinicians especially for limited focal proliferative disease. However, for severe proliferative LN, either Class III or Class IV, most clinicians institute corticosteroids along with other immunosuppressives.[8] Some have utilized regimens of 1 mg/kg/day of prednisone converting to 2 mg/kg/day on alternate days after 4 to 6 weeks of treatment. Others prefer to start with pulses of IV Solu-Medrol (see later).

Controlled randomized trials at the NIH and elsewhere have helped clarify the role of cyclophosphamide in the management of severe LN. [45] [94] [95] [113] [129] [130] In one trial, patients were randomly assigned to treatment regimens of high-dose corticosteroids for 6 months, or oral cyclophosphamide, oral azathioprine, combined oral azathioprine plus cyclophosphamide, or every third month intravenous cyclophosphamide all given with low-dose corticosteroids.[112] Evaluation at 120 months of follow-up showed a significant improvement in renal survival in the intravenous cyclophosphamide group versus the steroid group. At longer follow-up to 200 months, the renal survival of the azathioprine group was now statistically no better than that of the corticosteroid group.[112] Thus, the cyclophosphamide groups seemed most successful in preventing renal failure. Because side effects appeared least severe in the intravenous cyclophosphamide group, subsequent protocols at NIH have utilized regimens of the drug intravenously. Recent trials use monthly pulses of intravenous cyclophosphamide for 6 consecutive months as opposed to every third monthly regimens. [10] [45] [94] [95] [123] [129] [130]

There have been few randomized trials using pulse methyl prednisolone therapy for severe LN. [94] [95] Initial trials of pulse methylprednisolone in patients with diffuse proliferative disease and a rising serum creatinine showed favorable results utilizing a regimen of three consecutive daily one gram pulses. [1] [8] Subsequent reports and uncontrolled trials used a variety of immunosuppressive regimens with the pulse steroids with favorable results. Two NIH trials have found pulse corticosteroids to be less effective than intravenous cyclophosphamide in preventing progressive renal failure. [94] [95] [131] In one diffuse proliferative LN patients were randomized to receive either monthly pulse methylprednisolone (1 g/m2) or one of two cyclophosphamide regimens.[94] At 60 months, 48% of the pulse steroid treated patients doubled their serum creatinine in comparison to only 25% of the cyclophosphamide groups.

A number of other groups have confirmed the benefits and response rate of intravenous cyclophosphamide regimens in severe LN. [45] [123] [129] [130] [160] In a meta-analysis of 19 prospective controlled trials in 440 patients with severe LN treated with oral prednisone, azathioprine, oral cyclophosphamide, or intravenous cyclophosphamide, other immunosuppressive agents were more effective than prednisone for reducing both total mortality and ESRD.[131]In most patients treated with intravenous cyclophosphamide side effects such as hemorrhagic cystitis, alopecia, and so far tumors have been infrequent. [1] [3] [4] [5] [6] [8] Exceptions are menstrual irregularities and premature menopause, which is most common in women over 25 years of age who have received IV cyclophosphamide for over 6 months treatment.[132] The dose of IV cyclophosphamide must be reduced in patients with significant renal impairment and adjusted for some removal by hemodialysis in ESRD patients. MESNA therapy has been beneficial in reducing bladder complications from the toxic metabolite of cyclophosphamide, acrolein.[133] Not all investigators feel the promising results obtained with intravenous cyclophosphamide can be attributed to the immunosuppression alone, but rather to improved medical management of hypertension, and the metabolic and infectious complications of SLE as well.[134]

A controlled randomized trial at NIH of 1 year of monthly doses of intravenous methylprednisolone versus monthly intravenous cyclophosphamide for 6 months and then every third month doses, versus the combination of both therapies found the remission rate was highest with the combined treatment regimen (85%) as opposed to cyclophosphamide alone (62%) and methylprednisolone alone (29%).[93] Mortality was low and similar in all groups. Although the combined regimen was the most effective, it also appeared to have the greatest incidence of short-term adverse side effects. Longer follow-up of this same population indicates that over time drug toxicity was not different between the cytotoxic group and the combined cytotoxic-methylprednisolone group.[130] Side effects included premature menopause (56% cyclophosphamide versus 56% combined), aseptic necrosis (28% cyclophosphamide versus 30% combined), Herpes zoster (28% cyclophosphamide versus 25% combined), and major infections (33% cyclophosphamide versus 45% combined). It is likely through higher sustained remissions and fewer long-term relapses less patients required repeated treatments in the combined cyclophosphamide steroid treated group. Moreover, the long-term efficacy was greatest for the combination therapy group especially in terms of renal outcomes. Thus, for many patients combined Solu-Medrol pulses and intravenous cyclophosphamide pulses together became a standard therapy for severe LN despite problems with side effects.

Mycophenolate mofetil (MMF) has proven to be an effective immunosuppressive in transplant patients and has replaced azathioprine in many transplant centers. It is a reversible inhibitor of inosine monophosphate dehydrogenase and blocks B and T cell proliferation, inhibits antibody formation, and decreases expression of adhesion molecules among other effects. MMF has been effective in treating animal models of LN. [136] [137] [138] Initially evaluated in small nonrandomized trials in LN patients either intolerant or resistant to intravenous cyclophosphamide therapy, MMF has now been shown to have benefits in efficacy and in reduction of complications of therapy when compared to standard treatment regimens in a number of well-performed randomized trials. [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] In one 6-month Chinese trial of over 40 patients randomized to either MMF or IV pulse cyclophosphamide for induction therapy of severe LN,[141] proteinuria and microhematuria decreased more in the MMF patients than in the cytotoxic group, with renal impairment pre and post therapy, activity index on biopsy pre and post therapy, and serologic improvement equivalent. MMF was better tolerated with fewer gastrointestinal side effects and fewer infections. In another randomized controlled trial of 42 LN patients given either prednisone plus oral MMF or a regimen of prednisone plus cyclophosphamide orally for 6 months followed by oral azathioprine for another 6 months both drugs proved to be similar in efficacy.[142] Of the MMF group 81% achieved complete remission and 14% partial remission versus 76% complete and 14% partial remission for the cyclophosphamide-azathioprine group. Treatment failures, relapses post therapy, discontinuations of therapy, mortality, and time to remission were similar. Although these results were very promising the initial study was short term and in a Chinese populations with unclear applicability to the U.S. population and especially to African Americans.[143] Longer follow-up of these patients with the addition of 22 more patients showed the MMF to have comparable efficacy to the cyclophosphamide with no significant difference in complete or partial remissions, doubling of baseline creatinine, or relapses. Significantly fewer MMF patients developed severe infections, leukopenia, or amenorrhea, and all deaths and ESRD were in the cyclophosphamide group.[144] Thus, in this population, at long-term follow-up induction treatment of severe LN with MMF was as effective as oral cyclophosphamide but with fewer side effects.

A recent U.S. study compared MMF to IV cyclophosphamide for induction therapy for 140 patients with severe Class III and IV LN.[145] The LN patients, including over 50% blacks, had heavy proteinuria and active urinary sediment. They were randomized to either receive standard monthly pulses of IV cyclophosphamide 0.5–1 g/m2 for 6 months or oral MMF 2 to 3 g/day. Although this was designed as an equivalency study to test the hypothesis of equal efficacy between treatments but superior toxicity profile, the MMF proved superior in an intention-to-treat analysis in both complete and complete and partial remissions. Side effect profile also appeared better with MMF. At 3-year follow-up there was a trend to less renal failure and mortality favoring the MMF. Thus, in a patient population at high risk for poor renal outcomes, MMF proved superior to IV cyclophosphamide. It should be stressed that the mean entry serum creatinine of both arms of this study was only slightly greater than 1 mg/dl and it is unknown whether patients with severe depressions of the GFR or with severe histologic damage on biopsy will respond as well. An ongoing international multicenter randomized controlled trial will compare MMF to IV cyclophosphamide for induction therapy in over 370 enrolled LN patients (The Aspreva Lupus Management Trial/ALMS trial).[146]

Although these trials focused on the induction of remis-sion in severe LN patients, other trials have looked at maintenance of remission and prevention of activation of disease. The Euro Lupus Nephritis Trial, a multicenter prospective trial of 90 patients with severe LN compared low-dose versus “conventional” high-dose IV cyclophosphamide for both induction and remission.[147] Patients were randomized to either a standard high dose regimen of 6 monthly IV pulses of 0.5 to 1 g/m2 cyclophosphamide followed by 2 quarterly pulses or only 500 mg IV every 2 weeks for a total of 6 doses both followed by oral azathioprine (AZA) as maintenance therapy. At long-term follow-up (over 40 months) there were no statistically significant differences in treatment failures, renal remissions, or renal flares, but twice as many infections occurred in the high-dose group. Although this trial may have included some patients with milder renal disease (mean creatinine 1–1.3 mg/dl; mean proteinuria 2.5–3.5 g/day for both groups), and may be applicable only to a white population, nevertheless, it supports the use of shorter duration and lower total dose cyclophosphamide for induction therapy for some patients and confirms the benefit of azathioprine maintenance. Longer follow-up of the same population to 73 months confirms these data and suggests that early response to therapy is predictive of a good long-term outcome.[148]

A randomized controlled trial from Miami examined LN patients who had successfully completed induction of remission with 4 to 7 monthly pulses of IV cyclophosphamide and were then randomized to either continued every third month IV cyclophosphamide, oral azathioprine, or oral MMF. [5] [150] The 54 LN patients randomized were largely composed of blacks and Hispanics (50% black) and included many patients with the nephrotic syndrome (64%), renal dysfunction, and severe proliferative LN on biopsy (81% Class IV); 87% achieved remission following cyclophosphamide therapy. Fewer patients in the azathioprine and the mycophenolate group reached the primary end points of death and chronic renal failure compared to the cyclophosphamide group. The cumulative probability of remaining relapse free was higher with MMF (78%) and azathioprine (58%) compared with cyclophosphamide (43%), and there was increased mortality in patients given continued IV cyclophosphamide. Complications of therapy were all reduced in the MMF and azathioprine groups including days of hospitalization, amenorrhea, and infections. Thus, maintenance therapy with either MMF or azathioprine was superior to IV cyclophosphamide with less toxicity. An ongoing trial by the European Working Party on SLE compares MMF to azathioprine as remission maintaining treatment for severe LN (MAINTAIN Nephritis Trial).

A number of other commonly used immunosuppressive agents have been used in small studies in LN patients. Low dose cyclosporine (4–6 mg/kg/day) has been used usually in combination with other immunosuppressive agents in over 100 SLE patients.[150] One uncontrolled trial of SLE patients with disease resistant to other therapies described 26 patients with LN who received 2 years of cyclosporine plus tapering corticosteroids.[151] The patients experienced improvement in lupus serology, clinical activity, proteinuria, and renal histology without any increase in serum creatinine over the 2 years of treatment. Others have found that cyclosporine along with low-dose corticosteroids is not satisfactory therapy for severe proliferative disease with decreases in the dose of cyclosporine (e.g., for rises in the serum creatinine) leading to flares of disease activity.[150] Tacrolimus, widely used in solid organ transplantation, has been compared successfully to standard cyclophosphamide therapy in a number of small trials in LN patients. In one study of 48 severe LN patients, 59% of tacrolimus-treated patients experienced a complete remission versus 32% of IV cyclophosphamide-treated patients.[152]

Rituximab, a chimeric monoclonal antibody directed against the B7 antigen on B lymphocytes, depletes CD20 B cells through multiple mechanisms including complement-dependent cell lysis, FcRg dependent antibody dependent cell mediated cytotoxicity, and induction of apoptosis. Rituximab has been utilized with varying success in many immunologic and autoimmune diseases including a variety of primary glomerular diseases. In LN it has been used in over 100 patients mostly in case reports and open-labeled uncontrolled trials. [154] [155] Although it is difficult to draw conclusions based on these studies, it clearly has been successful in some patients with both severe and refractory LN. A typical trial included 10 patients with focal or diffuse proliferative LN who received 4 weekly infusions of rituximab (375 mg/m2) with oral prednisolone.[153] Eight patients achieved a partial remission and five patients subsequently developed complete remissions of their LN. Complete remission was sustained in four of five patients at 12 months. Rituximab has been used with repeated administration up to three cycles in some patients with severe LN.[155] Of the initial 15 resistant LN patients treated by the Columbia Nephrology group with IV rituximab for resistant disease, half had a beneficial response in terms of reductions of proteinuria and improvement in GFR. A current multicenter prospective randomized placebo controlled trial compares the combination of rituximab and MMF to MMF alone for induction and maintenance therapy in 140 patients with severe LN.[156]

Other therapies used in LN include plasmapheresis, total lymphoid irradiation, ancrod, thromboxane antagonists, tolerance molecules, marrow ablation with stem cell rescue, use of blockers of co-stimulatory molecules, and IV gamma-globulin. All are still experimental since none has of yet undergone large successful controlled clinical trials.

There are isolated cases or small series of LN patients who have experienced improvement of severe clinical and histologic renal disease with plasmapheresis in combination with a number of other treatments. A large multicenter controlled trial of 86 patients with severe LN randomized to standard therapy or standard therapy plus plasmapheresis found no benefit in the plasmapheresis group beyond a more rapid lowering of anti-DNA antibody titers.[157]There was no difference in clinical remission, progression to renal failure, or patient survival. Likewise, plasmapheresis synchronized to IV cyclophosphamide pulse therapy has not proven effective.[158] At present plasmapheresis is not standard therapy and should be reserved for only certain patients with LN as those with severe pulmonary hemorrhage failing other therapy, patients with a TTP-like syndrome, patients with anticardiolipin antibodies and a clotting episode who cannot be anticoagulated due to hemorrhage, etc.[159]

Intravenous immune globulin has been used successfully in a number of immunologic disease, including a number of SLE patients to treat thrombocytopenia as well as LN. [161] [162] In one series of nine patients with LN resistant to standard therapy, IVIG therapy resulted in clinical and histologic improvement.[161] However, other studies have not found success with IVIG and its role remains unclear. The one controlled trial included only 14 patients but did show stabilization of the plasma creatinine, creatinine clear-ance, and proteinuria when IVGG was used as maintenance therapy after successful induction of remission with IV cyclophosphamide.[162]

T lymphocytes activation requires two signals.[163] The first occurs when the antigen is presented to the T cell receptor (TCR) in the context of MHC class II molecules on antigen presenting cells and the second by the interaction of costimulatory molecules on T lymphocytes and antigen presenting cells. Disruption of costimulatory signals interrupts the (auto)immune response. In murine lupus models an important role for CD40:CD40L and CD28:B7 costimulatory molecules has been established. However, two clinical trials using different humanized antiCD40L monoclonal antibodies (BG9588 and IDEC-131) in LN patients have not been successful. [165] [166] [167] A study using BG9588 (riplizumab) showed improved renal function and lupus serology, but was terminated prematurely due to thromboembolic complications. A second trial with IDEC-131, although showing no major safety concerns, did not show clinical efficacy in human SLE. Another costimulatory pathway is mediated through the interaction of CD28-CD80/86. CTLA4 antagonizes CD28 dependent costimulation.[1] CTLA-4 Ig, a fusion molecule that combines the extracellular domain of human CTLA4 with the constant region (Fc) of the human IgG1 heavy chain, interrupts the CD28-CD80/86 interaction. Two preparations, Abatacept and Belatacept (LEA29Y), are being evaluated. However, clinical trials using these monoclonal antibodies in lupus are only in an early stage.

One new agent that has been evaluated in large multicenter blinded trials is a designer molecule directed at inducing tolerance and preventing anti-DNA antibody formation. [168] [169] LJP 340 (Riquent, Abetimus sodium) has been developed as a tolerogen to block B cell antibody formation by binding to immunoglobulin receptors on B cells. In animal models it decreases antiDNA antibody titers, lupus renal histopathologic manifestations, proteinuria, and renal dysfunction in lupus prone animals.[167] In an initial trial of over 230 patients treated for over 76 weeks it did not prove more effective than placebo in preventing flares of the disease and decreasing ant-ds DNA anti body levels. However, in the subgroup of 189 patients whose anti-DNA antibodies had a high affinity to the molecule it significantly reduced renal flares, the concurrent need for high-dose corticosteroid use, and major clinical SLE flares.[168] In a subsequent randomized trial the drug failed to reduce flares at a rate greater than placebo. It is of interest that the renal flare rate was much lower both in the treatment and placebo groups showing the benefits of modern maintenance background therapy.

Total lymphoid irradiation, similar to that used in management of Hodgkin disease, has been used in one series of LN patients.[169] The long-term results of therapy do not appear advantageous enough to warrant such potentially aggressive regimen. Because there may be evidence of microthromboses of the glomerular capillaries in severe LN, ancrod or pit-viper venom has been used in one series of patients with severe LN.[170] Again, the results in terms of preventing progressive disease were not impressive. In a short-term trial in a small group of patients with lupus, an intravenous thromboxane antagonist led to an improvement in GFR and renal blood flow.[171] However, it is doubtful that oral therapy will produce complete enough blockade of thromboxane synthesis to sustain improved function in patients clinically. Other agents under preliminary investigation that have successfully been used in lupus prone animal models include an antibody directed against the fifth component of complement to block the membrane attack complex (antiC5 antibody), and blockers of inflammatory mediators such as gamma interferon. [173] [174]Immunoablative therapy with high-dose cyclophosphamide with and without stem cell transplantation has been used successfully in a limited number of SLE patients with only a short period of follow-up. [175] [176] [177]

For patients with Class V, membranous lupus nephropathy, there have been conflicting data regarding the course, prognosis, and response to treatment. [1] [8] The degree of superimposed proliferative lesions greatly influences outcome in Class V patients, and it is unclear if older trials really only included true membranous patients. Some patients with pure membranous lupus nephropathy will have a prolonged course of asymptomatic proteinuria or the nephrotic syndrome yet little progression to renal failure over time. Others with active serology, severe nephrotic syndrome, and a progressive course will more clearly benefit from therapy. Early trials reported low response rates and inconsistent response rates with oral corticosteroids.[36] Excellent long-term results with intensive immunosuppressive regimens from Italian studies and others raise questions of whether the results are related to the therapeutic intervention or to the population studied and better supportive treatments.[38] A retrospective Italian trial found better remission with a regimen of chlorambucil and methylprednisolone over that with corticosteroids alone.[177] In a small nonrandomized trial of cyclosporine in membranous lupus there was an excellent remission rate of the nephrotic syndrome with mean proteinuria decreasing from 6 to 1 g to 2 g daily by 6 months.[45] At long-term follow-up and re biopsy there was no evidence of cyclosporine-induced renal damage, but two patients had developed superimposed proliferative lesions over time. An NIH trial of 42 patients with membranous lupus nephropathy and the nephrotic syndrome comparing cyclosporine, prednisone, and intravenous cyclophosphamide found superior remission rates for the cyclosporine and cyclophosphamide regimens but a trend toward more relapses when the cyclosporine was withdrawn.[178] A study of 38 patients with pure membranous LN evaluated long-term treatment with prednisone plus azathioprine.[179] At 12 months 67% of the patients had experienced a complete remission and 22% a partial remission. At 3 years only 12% had relapsed, at 5 years only 16%, and at 90 months only 19% relapsed. At the end of follow-up no patients had doubled their serum creatinine. Clearly in this population a regimen of steroids plus azathioprine was highly effective.

The response of patients with membranous LN to MMF has been varied. In one series of 18 patients with different classes of LN treated with MMF, all four treatment failures were in those with membranous LN.[180] Others in small trials have reported more favorable results. [182] [183] [184] In the randomized multicenter study of 140 LN patients, 27 had pure membranous lupus nephropathy. Analysis of all membranous patients who completed the study showed no difference in rates of partial or complete remission, changes in SCr, serum albumin, urinary protein excretion, or serologies between the MMF and IV cyclophosphamide groups at follow-up.[184] Based on this limited data management of MLN should be based on severity of disease. Patients with pure MLN and a good renal prognosis (subnephrotic levels of proteinuria and preserved GFR) may benefit from a short course of cyclosporine with low-dose corticosteroids along with inhibitors of the renin-angiotensin system and statins. For those at higher risk of progressive disease (e.g., blacks, those who are fully nephrotic) options include cyclosporine, monthly IV pulses of cyclophosphamide, MMF, or azathioprine plus corticosteroids. Patients with mixed membranous nephropathy and proliferative disease are treated in the same way as those with proliferative disease alone.

As effective and safer therapies for LN have evolved, greater attention has been directed at other causes of morbidity and mortality in this population. Lupus patients have accelerated atherogenesis and a disproportionate rate of coronary vascular disease leading to a high mortality many years after the onset of their LN.[185] The high cardiovascular risk rate has been attributed to concurrent hypertension, hyperlipidemia, nephrotic syndrome, prolonged corticosteroid use, antiphospholipid antibody syndrome, and in some, the added vascular risks of CKD. [187] [188] Despite limited data on therapeutic interventions in this population, aggressive management of modifiable cardiovascular risk factors may alter the morbidity and mortality of this population. Extrapolating from other CKD populations, closely monitored BP control (<130/80), the use of ACEI and/or ARBs, and correction of dyslipidemia with statins are reasonable in all LN patients. In addition, use of calcium, vitamin D supplements, and bisphosphonates to prevent glucocorticoid-induced osteoporosis may be useful.

Some form of antiphospholipid antibodies are present in 25% to 75% of lupus patients. Because most do not experience thrombotic complications, it is clear most require no special attention directed to the prevention of large vessel and microvascular thromboses. [189] [190] [191] In SLE patients with evidence of a clinical thrombotic event most investigators use chronic anticoagulation with Coumadin as long as the antibody remains present in high titer. Although the standard practice has been not to anticoagulate other patients, in one recent series of over 100 SLE patients over one fourth had antiphospholipid antibodies, of whom almost 80% had a thrombotic event. The antibody positive patients also had a greater incidence of chronic renal failure than the antibody negative patients.[91] (See Anticardiolipin antibodies and glomerulonephritis in following section.)

ANTIPHOSPHOLIPID ANTIBODY SYNDROME

The presence of antiphospholipid (APL) antibodies may be associated with glomerular disease, large vessel renal involvement, as well as coagulation problems in dialysis and renal transplant patients. [189] [190] [191] [193] Patients with the antiphospholipid syndrome have arterial and venous thromoboses and an increased risk of fetal loss associated with a variety of antibodies directed against plasma proteins bound to phospholipids including anticardiolipin antibodies, antibodies causing a false positive VDRL, the lupus anticoagulant, and antibodies directed against beta2 glycoprotein 1.[193] Specific criteria for a definitive diagnosis of APL antibody syndrome have recently been developed and include at least one of the following clinical features and at least one of the following laboratory findings. Clinical criteria include either one or more episodes of venous, arterial, or small vessel thrombosis and/or morbidity with pregnancy, whereas laboratory criteria include the presence of aPL (on two or more occasions at least 12 weeks apart and no more than 5 years prior to clinical manifestations) as demonstrated by one or more of the following: IgG and/or IgM anticardiolipin antibody in moderate or high titer, antibodies to β2-glycoprotein 1 of IgG or IgM isotype at high titer, or lupus anticoagulant activity. [195] [196] In some studies the presence of specific beta2glycoprotein 1 antibodies has been correlated with the presence of anticardiolipin antibodies and an increased risk of thrombotic events in patients with antiphospholipid syndrome. [197] [198] Catastrophic APL syndrome occurs when there is rapid thromboses in multiple organ systems. [199] [200] Antiphospholipid antibodies have been associated with increased endothelial production of adhesion molecules such as VCAM 1, and may contribute to atherosclerosis by binding to oxidized LDL.[200] The pathogenesis of the thrombotic tendency in patients with antiphospholipid antibodies remains to be elucidated, but may involve a combination of dysregulation of coagulation, platelet activation, and endothelial injury. [189] [191] [193]

Thirty percent to 50% of patients with APL antibodies have the primary APL syndrome in which there is no associated autoimmune disease. [189] [191] [193] A number of commonly used tests are available to confirm the suspicion of APL syndrome including the “lupus anticoagulant”, anticardiolipin antibodies, or broader APL antibodies (against cardiolipin, phosphatidylserine, and other phospholipids) by an ELISA assay. APL antibodies have also been found in from 25% to 75% of SLE patients, although most of these patients never experience the clinical features of the APL syndrome. [189] [191] [193] In an analysis of 29 published series comprising over 1000 SLE patients, 34% were positive for the lupus anticoagulant and 44% for anticardiolipin antibodies.[201] Although some studies have not found a high incidence of thrombotic events in SLE patients positive for antiphospholipid antibodies, others with longer follow-up generally have correlated their presence with a higher thrombotic event rate. [203] [204] A recent European study of almost 575 patients with SLE found the prevalence of IgG anticardiolipin antibodies to be 23% and for IgM 14%.[204] Patients with IgG antibodies had a clear association with thrombocytopenia and thromboses. A recent multicenter European analysis of 1000 SLE patients found thromboses in 7% of patients over 5 years. Patients with IgG anticardiolipin antibodies again had a higher incidence of thromboses, as did those with a lupus anticoagulant.[205] APL antibodies are also found in up to 2% of normal individuals and in those with a variety of infections and drug reactions, but these are not usually associated with the clinical spectrum of the APL syndrome.[206] HIV-infected patients and those infected with hepatitis C have much higher frequencies of anticardiolipin antibodies but no antibodies to beta2-glycoprotein 1, and usually do not have manifestations of the antiphospholipid syndrome. [208] [209] [210]

The clinical features of the APL syndrome relate to thrombotic events and consequent ischemia. In one series of 1000 APL syndrome patients the most common features were deep vein thrombosis 32%, thrombocytopenia 22%, livedo reticularis 20%, stroke 13%, pulmonary embolism 9%, and fetal loss 9%.[210] Patients may also experience pulmonary hypertension, memory impairment and other neurologic manifestations and fever, malaise, and constitutional symptoms. [189] [190] [191] [192] [193]

Renal involvement occurs in as many as 25% of patients with primary APL syndrome. [189] [190] [191] [192] [193] The renal pathology of APL syndrome is characterized by thrombosis of blood vessels ranging from the glomerular capillaries to the main renal artery and vein. [189] [190] [191] [211] [212] Lesions involving the arteries and arterioles often have both a thrombotic component and a reactive or proliferative one with intimal mucoid thickening, subendothelial fibrosis, and medial hyperplasia ( Fig. 31-13 ). [211] [212] Inflammatory vasculitis has been identified rarely. Interstitial fibrosis and cortical atrophy may occur due to tissue ischemia.[211] Glomerular lesions include glomerular capillary thrombosis with associated mesangiolysis, mesangial interposition and duplication of glomerular basement membrane, and electron lucent, fluffy, subendothelial deposits resembling other forms of glomerular thrombotic microangiopathy such as HUS-TTP.

000284

000519

FIGURE 31-13  Anti-phospholipid antibody syndrome: Organizing recanalized thrombi narrow the lumens of two interlobular arteries. The adja-cent glomerulus displays ischemic retraction of its tuft (Hematoxylin-eosin, ×200).

000519

 

A recent study retrospectively evaluated renal biopsies from 81 patients with aPL.[212] APL syndrome nephropathy existed in almost 40% of APL-positive patients versus only 4% of patients without aPL and was associated with both lupus anticoagulant and anticardiolipin antibodies. Among APL-positive SLE patients, APS nephropathy was found in two thirds of those with APL syndrome and in one third of those without APL syndrome. Although patients with APL nephropathy had a higher frequency of hypertension and elevated serum creatinine levels at biopsy in this series, they did not have a higher frequency of renal insufficiency, end-stage renal disease, or death at follow-up.[212] This is in contrast to another recent series of over 100 lupus patients that found the presence of APL antibodies to be associated with both thrombotic events and a greater progression to renal failure.[191] Some renal biopsies have been misclassified as focal segmental glomerulosclerosis, membranous nephropathy, and membranoproliferative GN when they truly display a thrombotic microangiopathy.[213] However, a recent study reports patients with a number of glomerular histologic patterns on light microscopic including membranous nephropathy, minimal change/focal sclerosis, mesangial proliferative GN, and pauci immune rapidly progressive GN to have classic APL syndrome.[214]

The most frequent clinical renal features are proteinuria, at times in the nephrotic range, active urinary sediment, hypertension, and progressive renal dysfunction. [189] [191] [211] Some patients present with acute deterioration of renal function.[213] With major renal arterial involvement there may be renal infarction, and renal vein thrombosis may be silent or present with sudden flank pain and a decrease in renal function. Renal artery stenosis has been reported with and without malignant hypertension in both SLE patients and others with antiphospholipid antibody syndrome. [216] [217] [218] [219] In SLE, APL antibodies have been associated with a history of systemic thromboses, neurologic disorders, and thrombocytopenia. [189] [191] [193] [202] Although only about 10% of biopsied lupus patients have glomerular microthromboses as their major histopathologic finding, nevertheless, therapy of this glomerular lesion clearly differs from that of immune complex mediated glomerulonephritis.[52] One study of 114 biopsied SLE patients found vasoocclusive lesions in one third of biopsies, which both correlated with hypertension and an increased serum creatinine level.[219] In SLE features that correlate well with high titers of IgG APL antibodies are thrombocytopenia, the presence of a false positive VDRL for syphilis (FTA negative), and a prolonged APTT. [189] [190] [191] [193] [220] Neither the titer of anti-DNA antibodies nor the serum complement levels correlate well with the APL antibody levels. In SLE, in general, high titers of IgG ACL antibody correlate well with risk of thromboses. However, not all studies have been able to correlate the presence of anticardiolipin or specific APL antibodies with thrombotic events in SLE patients. For example, in one study of 114 biopsied patients renal thrombi were related to anti lupus antibodies but not anticardiolipin antibodies.[219] The clinical features of APL syndrome in SLE patients are identical to the in primary APL syndrome. One recent study documents the prevalence of APL antibodies in 26% of 111 LN patients observed a mean of 173 months. Of the APL antibody positive patients 79% developed a thrombotic event or fetal loss and the presence of antibodies was strongly correlated with the developed of progressive chronic kidney disease.[191] Studies in ESRD patients have shown a high prevalence of APL antibodies in patients on hemodialysis (10%–30%). [221] [222] Studies in patients with renal insufficiency and patients on peritoneal dialysis have shown a much lower incidence of APL antibodies.[188] Studies have found antiphospholipid antibodies to be present in 31% of hemodialysis patients with a varying prevalence of the lupus anticoagulant and anticardiolipin antibodies. [221] [222] In general, there has been no association with age, gender, or duration of the dialysis. One cross-sectional study of hemodialysis patients found 22% of 74 patients with arteriovenous grafts had a raised titer of IgG anticardiolipin antibody versus only 6% of 17 patients with arteriovenous fistulas.[221] There was a significant increase in the odds of having two or more episodes of AV graft thrombosis in patients with raised ACLP titer. Whether AV grafts induce ACLN antibodies or whether patients with ACLN antibodies require AV grafts remains unclear.[222] In a study of 230 hemodialyzed patients titers of IgG anticardiolipin antibodies were elevated in 26% of the patients as opposed to elevated titers of IgM antibodies in only 4%, and elevated titers of both antibodies in 3%.[223] The mean time to AV graft failure was significantly shorter in the group with elevated IgG antibodies but there was no difference in AV fistula clotting between those with and without high IgG antibody titers. The use of Coumadin increased graft survival in patients with elevated IgG anticardiolipin levels.

The presence of APL antibodies may also damage the renal allograft. In several studies 20% to 60% of SLE patients with APL antibodies who received renal transplants had evidence of related problems with venous thromboses, pulmonary emboli, or persistent thrombocytopenia. [225] [226] [227] [228] In one large study of non-SLE patients 28% of 178 transplant patients had antiphospholipid antibodies that were associated with a threefold to fourfold increased risk of arterial and venous thromboses.[225] However, a recent study of 337 renal transplant recipients found the 18% who were IgG or IgM ACL antibody positive (even after correction for the effects of anticoagulation) had no greater allograft loss or reduction in GFR over time than did patients who were ACL antibody negative.[228] Although most hepatitis C virus positive patients with antiphospholipid antibodies do not have evidence of increased thromboses and the antiphospholipid syndrome, HCV-positive renal transplant patients with anticardiolipin antibodies appear to have a higher risk of thrombotic microangiopathy in the allograft.[229] In many of these transplant studies treatment with anticoagulation has proven successful in preventing recurrent thromboses and graft loss. [225] [227] [228]

Treatment

The optimal treatment of patients with APL antibodies or the APL syndrome (or both) remains to be defined. [189] [190] [191] Many patients with SLE with APL antibodies do not experience thrombotic events and do not require anticoagulation or other special therapy. Higher titers of IgG APL antibody have been related to a greater incidence of thrombotic events. [205] [206] In patients without evidence of the APL syndrome, and no thrombotic events, some are treated only with daily aspirin therapy. In patients with the full APL syndrome either primary or secondary to SLE high-dose anticoagulation has proven more effective than either no therapy, aspirin, or low-dose anticoagulation in preventing recurrent thromboses. [189] [193] [231] A retrospective analysis of 147 patients with the APL syndrome and documented prior thromboses (62 primary disease and 66 SLE and 19 lupus-like syndrome) recorded 186 recurrent thrombotic events in 69% of the patients.[230] The median time between the initial thrombosis and the first recurrence was 12 months but with a huge range (0.5 to 144 months). Treatment with warfarin to produce an INR >3 was significantly more effective than treatment with low-dose warfarin (INR <3) or treatment with aspirin alone. The highest rate of thrombosis (1.3 per patient-year) occurred in patients in the 6 months after discontinuing anticoagulation with Coumadin. Bleeding complications occurred in 29 of the 147 patients but were severe in only 7 patients. The role of immunosuppressive agents has been uncertain in treating this syndrome. [189] [193] [207] [232]Thus, in SLE patients the anti-DNA antibody titer and the serum complement may normalize in response to immunosuppressive medication without a significant change in a high titer of IgG APL antibody.[231] In pregnant patients with antiphospholipid syndrome heparin and low-dose aspirin have been successful in several studies but prednisone use has not. [233] [234] [235] In rare patients who cannot tolerate anticoagulation due to recent bleeding, who have thromboembolic events despite adequate anticoagulation, or who are pregnant, plasmapheresis with corticosteroids and other immunosuppressives have been used with some success. [236] [237] Use of other treatments such as intravenous gammaglobulin and hydroxychloroquine remains anecdotal. [238] [239]

MIXED CONNECTIVE TISSUE DISEASE

Mixed connective tissue disease (MCTD), first described in 1972, is defined by a combination of clinical and serologic features. [240] [241] [242] Patients with MCTD share many overlapping features with patients with SLE, scleroderma, and polymyositis. [241] [242] [243] [244] [245] They also typically have distinct serologic findings with a very high ANA titer, often with a speckled pattern, and antibodies directed against a specific ribonuclease sensitive extractable nuclear antigen (ENA), U1 RNP. [241] [242] [243] [244] [245] MCTD is far more common in females than males with a 16:1 sex ratio. Genetic predisposition to MCTD has been linked to HLA-DR4 and DR 2 genotypes.[245]Not all patients with clinical features of the syndrome have a positive ENA, and not all patients with a positive ENA have the clinical features of MCTD. [243] [245] Moreover, because some patients fulfill diagnostic criteria for other connective tissue diseases, investigators have questioned whether MCTD is a distinct syndrome. The term “undifferentiated autoimmune rheumatic and connective tissue disorder” or overlap syndrome is sometimes used because many patients with features of MCTD will eventually develop into SLE, scleroderma, or rheumatoid arthritis. [243] [244] [245] [246] [247]

In the early stages of MCTD patients do not usually manifest overlapping features of other connective tissue disorders, but rather nonspecific symptoms such as malaise, fatigue, myalgias, arthralgias, and low-grade fever. Over time systemic clinical features of MCTD similar to those found in each of the various rheumatologic connective tissue disease often appear. These include arthralgias and in some deforming arthritis, myalgias and myositis, Raynaud phenomenon, swollen hands and fingers, restrictive pulmonary disease and pulmonary hypertension, esophageal dysmotility, pericarditis and myocarditis, serositis, oral and nasal ulcers, digital ulcers and gangrene, discoid lupus-like lesions, malar rash, alopecia, photosensitivity, and lymphadenopathy. [242] [243] [244] [245] [247] [248] [249] [250] However, patients with MCTD and especially those documented to have anti-U1RNP antibodies, infrequently have major CNS disease or severe proliferative glomerulonephritis. [242] [243] [244] [245] [247] [248] [249] [250] Low-grade anemia, lymphocytopenia, and hypergammaglobulinemia are all common in MCTD.

The most widely used serologic test to confirm a diagnosis of MCTD is the ENA with anti-U1RNP antibodies. [243] [244] [245] [251] The diagnosis of MCTD is even firmer in those patients with IgG antibodies against an antigenic component of U1RNP, the 68kD protein. [251] [252] Antibodies to other nuclear antigens have been found in MCTD and some correlate better with some clinical features of specific rheumatologic diseases. [242] [243] [244] [245] [247]Thus antibodies to Ku and anti-Jo-1 correlate with individual clinical spectrums of overlapping rheumatologic disease. Antibodies against dsDNA, Sm antigen, and Ro are infrequently positive in MCTD, but up to 70% of patients will have a positive rheumatoid factor.[242] Antiphospholipid antibodies are found less frequently than in SLE.

In initial studies of patients with MCTD renal disease was infrequent. [243] [244] [245] In subsequent studies the incidence of involvement has varied from 10% to 26% of adults and from 33% to 50% of children with MCTD. [243] [244] [245] [247] [249] Many patients may have mild or minimal clinical manifestations with only microhematuria and less than 500 mg proteinuria daily. However, heavier proteinuria and the nephrotic syndrome occur. [249] [253] Other patients will have severe hypertension and acute renal failure reminiscent of “scleroderma renal crisis”. [249] [254] Although the titer of anti-RNP does not correlate with renal involvement, the presence of serologic markers typical of active SLE, high anti-dsDNA antibody titers, anti-Sm antibody are more common with renal disease. [243] [244] [245] Low serum complement levels have not always correlated with the presence of renal involvement.[248] Children with MCTD more often have glomerular involvement even though many will not have clinical or urinary findings suggestive of renal involvement.[254] Hypocomplementemia in these children is often associated with a membranous or mixed pattern of GN.

The pathology of MCTD is pleomorphic with the glomerular lesions resembling the spectrum found in SLE and vascular lesions resembling those found in scleroderma. Glomerular disease is most common and is usually superimposed on a background of mesangial deposits and mesangial hypercellularity as in SLE. [249] [253] [255] [256] [257] [258] [259] As many as 30% of cases have mesangial deposits of IgG and C3. Other patients have focal proliferative glomerulonephritis with both mesangial and subendothelial deposits, but glomerular fibrinoid necrosis and crescent formation is rare. The most common pattern of glomerular involvement is that of membranous nephropathy reported in up to 35% of cases [249] [253] [255] [256] [257] [258] with typical granular capillary wall staining for IgG, C3, and at times IgA and IgM. Some patients, especially children, will have a mixed pattern of membranous plus mesangial proliferative GN.[254] Patients may evolve or transform from one pattern of glomerular involvement to another in a fashion similar to SLE patients. By ultrastructural analysis findings similar to those in SLE have been reported including endothelial tubulo-reticular inclusions, deposits with “fingerprint” substructure, and tubular basement membrane deposits. [249] [258] In one review of 100 biopsied patients with MCTD 12% had normal biopsies, 35% mesangial lesions, 10% proliferative lesions, and 36% membranous nephropathy.[257] In addition 15% to 25% of patients had interstitial disease and vascular lesions. In autopsy series in which two thirds of patients had clinical renal disease a similar distribution of glomerular lesions with a predominance of membranous features was found.[258] Other renal pathology findings in MCTD include secondary renal amyloidosis,[259]vascular sclerosis ranging from intimal sclerosis to medial hyperplasia,[248] and vascular lesions resembling those in scleroderma kidney with involvement of the interlobular arteries by intimal mucoid edema and fibrous sclerosis.

Therapy of MCTD with corticosteroid is effective in treating the inflammatory features of joint disease and serositis. [243] [244] [245] [249] There are no controlled treatment trials in patients with MCTD. Steroids are less effective in treating sclerodermatous features such as cutaneous disease, esophageal involvement, Raynaud phenomenon, and especially pulmonary hypertension, which has been treated with CCB's, ACE inhibitors, prolonged immunosuppression, or IV prostacyclin.[260] IV immunoglobulin has been used as in SLE patients with decreased platelets, hemolytic anemia, and erythema skin disease.[261] Glomerular involvement can vary as in SLE and treatment is generally directed at the glomerular lesion in a similar fashion to treating active LN.

Originally MCTD was felt to have a good prognosis with little mortality and few patients developing clear cut other connective tissue disorders. The longer patients with MCTD are observed the greater percentage who evolve more clearly into a specific connective tissue disorder. [243] [244] [245] [247] In some series almost half of the patients with a short dura-tion of follow-up were still felt to have true MCTD, but in those with longer follow-up the percentage had dropped to 15% or less. [243] [244] [245] [247] [249] Most patients evolve toward a picture of either SLE or systemic sclerosis, but some develop prominent features of rheumatoid arthritis.[248] Mortality rates have been found to range from 15% to 30% at 10 to 12 years with patients with more clinical features of scleroderma and polymyositis having a worse prognosis. [243] [244] [245] [249] The leading causes of mortality in MCTD are pulmonary hypertension, myocarditis, and renovascular hypertension with cerebral hemorrhage. [243] [244] [245] Patients with IgG anticardiolipin antibodies may be at greater risk. Other causes include vascular lesions of the coronary and other vessels, hypertensive scleroderma crisis, and chronic renal failure. Clearly the view of MCTD as a benign disorder is incor-rect, and it is a disease with significant morbidity and mortality.

WEGENER GRANULOMATOSIS

Wegener granulomatosis is usually classified together with a number of other small vessel vasculitides including microscopic polyangiitis and Churg-Strauss syndrome.[262] There is often considerable overlap in the clinical, histologic, and laboratory features of these entities, all may by associated with anti-neutrophil cytoplasmic antibodies (ANCA), and the treatment for all is often similar involving potent immunosuppressives. Wegener granulomatosis has been traditionally defined by the triad of systemic vasculitis associated with necrotizing, granulomatous inflammation of the upper and lower respiratory tracts, and glomerulonephritis.[263] Subsequent descriptions of “limited” upper respiratory tract disease, of multiorgan system involvement, and of the nature and potential pathogenesis of the serologic marker of ANCA have enhanced our understanding of this disease. [265] [266] [267] [268] [269] Even in the pre-ANCA era these criteria yielded a sensitivity of 88% and a specificity of 92%. Clearly adding ANCA to the diagnostic criteria increases these percentages. [270] [271] [272]

Wegener granulomatosis has a slight male predominance and although it may occur at any age of life has a peak incidence in the fourth to sixth decade of life. [264] [268] [273] [274] Pauciimmune rapidly progressive glomerulonephritis (including Wegener and microscopic polyangiitis) are the most common forms of crescentic glomerulonephritis at all ages, and especially in the elderly.[274] Most reported patients have been white, although with use of newer serologic tests such as the ANCA patients of all races are being diagnosed.[275] The occurrence of Wegener granulomatosis in more than one family member has rarely been noted.[276] Although certain HLA frequencies such as HLA DR2, HLA B7, and HLA DR1 and DR1-DQW1 have been reported more commonly in Wegener patients, the data is far from conclusive about a genetic profile of the disease.[277]

Pathology

The classic histopathologic finding in Wegener granulomatosis is a focal segmental necrotizing and crescentic glomerulonephritis ( Fig. 31-14 ). [268] [279] Although the percentage of affected glomeruli can vary widely, the necrotizing changes are usually segmental in nature. [268] [279] [280] Unaffected glomeruli typically appear normal. Global proliferation and necrotizing glomerular tuft involvement may be more common in more severe disease when greater numbers of glomeruli are affected. “Intracapillary thrombosis” with deposition of eosinophilic “fibrinoid” material is common in early lesions together with endothelial cell swelling, infiltration by polymorphonuclear leukocytes, and pyknosis or karyorrhexis (nuclear dust). [268] [279] [280] In areas of active necrotizing glomerular lesions “gaps” may be present in the GBM and crescents typically overlie the segmental lesions. Crescents vary from segmental to circumferential. They may be associated with destruction of Bowman capsule.[280] Granulomatous crescents containing epithelioid histiocytes and giant cells may involve from less than 15% to over 50% of cases; the finding of large numbers of them is more typical of Wegener granulomatosis and C-ANCA positive patients than other vasculitides. Chronic segmental or global glomerulosclerosis with fibrous crescents often occur side by side with more active glomerular lesions in the same biopsy. Although there is much overlap in the histologic findings in patients who have microscopic polyangiitis and Wegener granulomatosis, some differences have been noted. Patients with microscopic polyangiitis are more likely to have a greater degree and severity of glomerulosclerosis, interstitial fibrosis, and tubular atrophy on initial biopsy.[281] Likewise, these findings are all more extensive in patients who are myeloperoxidase-ANCA positive (MPO) rather than anti-proteinase 3 (PR3) ANCA positive.[281]

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FIGURE 31-14  Wegener granulomatosis: A typical glomerulus displays segmental fibrinoid necrosis with rupture of glomerular basement membrane, fibrin extravasation into the urinary space, and an overlying segmental cellular crescent (Jones methenamine silver, ×500).

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The vasculitis in Wegener granulomatosis may affect small and medium sized renal arteries, veins, and capillaries [268] [279] [280] The vasculitis, which is focal in nature, has been reported in 5% to 10% of biopsies of Wegener patients. [264] [267] [268] [283] It is more commonly found at autopsy with larger tissue samples and where serial sectioning and a directed search for the lesions have been performed. The necrotizing arteritis consists of endothelial cell swelling and denudation, intimal fibrin deposition, and mononuclear and polymorphonuclear leukocytes infiltration of the vessel wall with mural necrosis ( Fig. 31-15 ). The vasculitis may be associated with granuloma formation. Tubules show areas of focal tubular degenerative and regenerative changes, and cortical infarcts may be found. [263] [268] Interstitial inflammatory infiltrates of lymphocytes, monocytes, plasma cells, and polymorphonuclear leukocytes associated with edema are common. Granulomas with giant cells have been noted in interstitium of the cortex and medulla in from 3% to 20% of cases.[272] Papillary necrosis, which is usually bilateral and affects most papillae, has been reported is as many as one-fifth of Wegener patients and may be related to impaired papillary blood supply due to medullary capillaritis.[283] Biopsy of extrarenal tissue may show necrotizing and granulomatous inflammation or evidence of vasculitis. [267] [268] [269] [270] [271] [272] [273] [274] [275] [276] [277] [278] [279]

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FIGURE 31-15  Wegener granulomatosis: An interlobular artery displays necrotizing vasculitis with intimal fibrin deposition and transmural inflammation by neutrophils and lymphocytes (Hematoxylin-eosin, ×375).

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Immunopathologic Features

There is no glomerular immune staining in most cases of Wegener granulomatosis. Although some reports have described the localization of various immunoglobulins and complement components in the glomerular tuft and vasculature, this likely represents non-immunologic trapping in areas of necrosis and sclerosis. Most reports describe only focal low intensity IF staining, a pattern referred to as “pauci-immune”. [264] [265] [266] [267] [268] [279]Positivity for fibrin/fibrinogen is common in the distribution of the necrotizing glomerular lesions, crescents, and vasculitic lesions. Reports of immunofluorescent staining in pulmonary vasculature, sinus tissue, and alveolar tissue have all been inconsistent.

Electron Microscopy

By electron microscopy glomeruli affected by necrotizing lesions often show areas of intraluminal and subendothelial fibrin deposition associated with endothelial necrosis and gaps in the GBM through which fibrin and leukocytes extravasate into Bowman space. [264] [265] [266] [267] [268] [279] There may be subendothelial accumulation of electron lucent “fluffy” material associated with intravascular coagulation. True electron-dense immune type deposits are not usually identified and when present are sparse and ill defined. [264] [265] [266] [267] [268] [279] Thus, Wegener granulomatosis like polyarteritis fits into the category of “pauci-immune” glomerulonephritides. Electron microscopy of the vessels in Wegener granulomatosis may show swelling and denudation of endothelial cells, and subendothelial accumulation of fibrin, platelets, and amorphous electron-dense material, but no typical immune-type electron-dense deposits.

Pathogenesis

Although the pathogenesis of Wegener granulomatosis remains unknown, abnormalities of both humoral and cell mediated immunity have been noted. [267] [268] The disease shares many morphologic features of the type IV hypersensitivity reaction, an immunologic response resulting from interaction of sensitized lymphocytes with specific antigens leading to the release of lymphokines, macrophage accumulation, and activation and transformation to epithelioid histiocytes and giant cells. Vasculitis in other systems (such as the cutaneous necrotizing vasculitis) suggests additional mechanisms of vessel injury mediated by polymorphonuclear leukocytes or ANCA-induced neutrophil degranulation, an Arthus reaction (type II reaction) or immune complex injury similar to the model of acute serum sickness (type III reaction).

Recent in vitro and animal experiments strongly support a role for ANCA in the pathogenesis of the disease. [285] [286] In RAG-2 mice, transfer of anti-MPO IgG causes glomerulonephritis with necrosis and crescent formation that appears identical to human ANCA-associated glomerulonephritis by LM and IF.[286] This can occur in the absence of antigen-specific T lymphocytes strongly suggesting a pathogenetic role for the antibodies themselves. In humans, neonatal microscopic polyangiitis with pulmonary hemorrhage and renal disease has occurred secondary to the transfer of maternal MPO-ANCA.[287] However, there is still support for cell mediated mechanisms of tissue injury with a predominance of CD 4-positive T lymphocytes and monocytes in the inflammatory respiratory tract infiltrates, defects in delayed hypersensitivity, a rise in soluble markers of T cell activation as soluble interleukin-2 receptor and CD 30, impaired lymphocyte blastogenesis, and T cell response to protease 3. [269] [289] [290] [291] [292]

With prominent respiratory tract involvement it is logical to envision an inhaled pathogen or environmental allergen as the initiator of the disease process. Nevertheless, no specific microbes or antigenic substances has been identified. Again ANCA antibodies have been proposed as promoters of the vasculitic process rather than just markers of the disease process. The expression of granule proteins on the surface of neutrophils and monocytes allows for the interaction with ANCA leading to a respiratory burst in the cell, degranulation and local release of damaging and chemoattractant products, and neutrophil apoptosis. [267] [268] [269] [293] [294] Chemoattractant products and the activated cells result in damage to the endothelium. In the presence of ANCA, neutrophils exhibit exaggerated adhesion and transmigration through endothelium.[294] A spectrum of glomerular and vascular disease reaction is seen depending on antigen expression, host leukocyte activation, circulating and local cytokines and chemokines, the condition of the endothelium, and the nature of T and B cell interactions. [267] [268] [269] [293] The membranes of leukocytes from Wegener patients may be primed with PR 3 molecules on their surfaces ripe for activation of the disease process. [269] [294] [296] [297] This might explain the exacerbations of disease activity associ-ated with respiratory infections causing the cytokine release that leads to neutrophil and monocyte priming, as well as the potential benefits of therapy with trimethoprim sulfamethoxazole. [298] [299]

Clinical and Laboratory Features

Patients with Wegener granulomatosis may present with an indolent slowly progressive involvement of the respiratory tract and mild renal findings or with fulminant acute glomerulonephritis leading to the necessity for dialysis. In the past there was often a several month period between onset of symptoms and the establishment of the diagnosis. [264] [273] Despite greater awareness of disease symptoms, the more rapid use of renal biopsy and the use of ANCA assays, diagnosis is still often delayed. Most patients will have constitutional symptoms including fever, weakness, and malaise at presentation. [264] [265] [266] [267] [268] [273] [300] From 70% to 80% of patients will have upper respiratory findings at presentation and even more will develop this over time. [264] [265] [266] [267] [268] [273] [300] There may be rhinitis, purulent or bloody nasal discharge and crusting, and sinusitis. [264] [265] [266] [267] [268] [273] Sinus involvement demonstrated by radiographs or by CT scanning typically involves the maxillary sinus and less commonly the sphenoid, ethmoid, and frontal sinuses. [264] [273] There may be opacification, air fluid levels, mass lesion, or rarely bony erosions. Upper respiratory tract involvement can also be manifest by tinnitus and hearing loss, otic discharge and earache, and perforation of the tympanic membrane, hoarseness and throat pain. [264] [265] [266] [267] [268] [273] Chronic sequelae of the upper respiratory disease include deafness, chronic sinusitis with repeated secondary infections and nasal septal collapse with saddle nose deformity.

Lower respiratory tract disease, found at presentation in up to 75% of patients eventually develops in most pa-tients. [264] [265] [266] [267] [268] [273] Symptoms include cough often with sputum production, dyspnea on exertion and shortness of breath, alveolar hemorrhage and hemoptysis, and pleuritic pain. [301] [302] Chest radiographs and CT scans may reveal single or multiple nodules some with areas of cavitation, alveolar infiltrates and interstitial changes, and less commonly small pleural effusions and atelectatic areas. Chest radiograph or CT scan may document lower respiratory tract disease in the absence of pulmonary symptoms or clinical findings.[272] Airflow obstruction and a reduced carbon monoxide diffusing capacity are typically present.[302]

Wegener granulomatosis is a multisystem disease with many organs involved by the vasculitic process and its sequelae. [264] [265] [266] [267] [268] [273] Cutaneous involvement, present in 15% to over 50% of patients, may occur with a variety of macular lesions, papules, nodules, or purpura usually on the lower extremities. Patients may also present with rheumatologic involvement with arthralgias of large and small joints as well as non-deforming arthritis of the knees and ankles or more rarely a myopathy or myositis. Up to 65% of patients have ophthalmologic disease manifested by conjunctivitis, episcleritis and uveitis, optic nerve vasculitis, or proptosis due to retro-orbital inflammation. Nervous system involvement is most typically manifested as a mononeuritis multiplex, but may involve cranial nerves or the central nervous system. Other organs involved include the liver, parotids, thyroid, gall bladder, and the heart. [264] [265] [266] [267] [268] [273]

Abnormal laboratory tests in Wegener granulomatosis include a normochromic, normocytic anemia, a mild leukocytosis, and a mild thrombocytosis. [264] [268] [273] Eosinophilia is uncommon and there have been no abnormalities of circulating lymphocytes subsets in the disease.[273] Non-specific markers of an inflammatory disease process such as an elevated sedimentation rate, C-reactive protein levels, and rheumatoid factor tests are often positive and correlate with the general disease activity. Other serologic tests including those for ANA, serum complement levels, and cryoglobulins are normal or negative.[263] CIC are found in a variable percentage of patients, but relation to disease activity is debated. Likewise elevated levels of IgA or IgE have been reported but are of unclear significance. [265] [266] [267] [268] [273]

The vast majority of patients with active Wegener granulomatosis will be positive for ANCA by a variety of assays. ANCA has been detected in from 88% to 96% of these patients. [265] [266] [267] [268] [269] [270] In general patients with granulomatous lesions are more likely to be C-ANCA positive with antibody directed against a serine proteinase of the neutrophilic granules. Protease 3 is a 228 amino acid serine proteinase found in azurophilic granules of neutrophils and the lysosomes of monocytes. [265] [266] [267] [268] [269] [270] However, many patients fitting the clinical and histologic definition of Wegener granulomatosis will be P-ANCA positive with antibodies directed against myeloperoxidase, a highly cationic 140kD dimer located in a similar distribution to proteinases. [265] [266] [267] [268] [269] [270] In a recent study of 89 patients from China who fulfilled clinical and histopathologic criteria for Wegener granulomatosus according to the Chapel Hill Consensus Conference, 61% were -MPO ANCA positive and only 38% PR3 ANCA positive.[275] Although the specificity of C-ANCA for Wegener granulomatosis has been as high as 98% to 99% by different assays, the sensitivity may be low in certain populations with inactive disease or limited disease. [265] [266] [267] [268] [269] [270] [304] False positive C-ANCA tests have been reported in patients with certain infections (e.g., HIV, tuberculosis, subacute bacterial endocarditis), neoplastic disease, and drug-induced conditions. [305] [306] Although there has been debate whether the ANCA levels parallel the clinical and histologic activity of the disease, many patients will normalize their ANCA titer during periods of quiescence. [265] [266] [267] [268] [269] [307] Nevertheless approximately 40% of patients in remission will have positive tests for C-ANCA. [307] [308] A subsequent rise in ANCA titer from low titer has been suggested as predictive of renal and systemic flares. [265] [266] [267] [268] [269] [307] [309] [310] [311]

Renal Findings

Renal findings in Wegener granulomatosis are extremely variable and usually occur along with other systemic manifestations. [264] [265] [266] [267] [268] [269] [273] [300] Most patients have evidence of clinical renal disease at presentation, and from 50% to 95% of patients with Wegener granulomatosis will eventually develop clinical evidence of renal involvement. There is typically mild proteinuria and urinary sediment findings often with microscopic hematuria, and red cell casts present. Patients with more severe glomerular involvement often have a decrease in GFR and greater levels of proteinuria, but the nephrotic syndrome is uncommon. The level of proteinu-ria may be high in those without severe renal insuffici-ency and may actually increase during therapy as the GFR improves. [273] [274] [275] [276] [277] [278] [279] [280] [281] [282] [283] [284] [285] [286] [287] [288] [289] [290] [291] [292] [293] [294] [295] [296] [297] [298] [299] [300] The degree of renal failure and serum creatinine do not always correlate well with the percent of glomerular necrotizing lesions, the percent of glomerular crescent formation, or the presence of interstitial granulomas or vasculitis. The incidence of both acute oliguric renal failure and significant hypertension varies among reports but is higher in reports from renal centers. Intravenous pyelograms are typically normal, and by angiography aneurysms are not usually present. [264] [265] [266] [267] [268] [269]

In addition to glomerular and vascular lesions, other renal conditions associated with Wegener granulomatosis have included pyelonephritis and hydronephrosis due to vasculitis causing ureteral stenosis, papillary necrosis, perirenal hematoma from arterial aneurysm rupture, and lymphoreticular malignancies with neoplastic infiltration of the renal parenchyma in patients treated with immunosuppression.[311]

Course and Treatment

The course of the active glomerulonephritis is typical of rapidly progressive glomerulonephritis with progression to renal failure over days to months. [264] [265] [266] [267] [268] [269] [273] Patients with severe necrotizing granulomatous glomerulonephritis are more likely to develop renal failure, and patients with more global glomerulosclerosis are more likely to develop ESRD.[312] One study found greater glomerulosclerosis and interstitial fibrosis to predict a poor renal outcome, but greater numbers of active crescents actually predicted a better outcome.[313] Even with immunosuppressive therapy, a significant number of patients will eventually progress over the long term to renal failure.[313]

The introduction of effective cytotoxic immunosuppressive therapy has dramatically changed the course of Wegener granulomatosis. Initial studies of untreated patients and even those utilizing corticosteroids alone documented survivals of 20% to 60% at 1 year.[263] Although corticosteroids lead to some clinical improvement there has been documentation of the progression of both renal and extrarenal lesions during corticosteroid therapy. [264] [265] [266] [267] [268] [269] Although other immunosuppressive agents have been used, and despite few controlled trials, cyclophosphamide has become the treatment of choice for Wegener granulomatosis. [264] [265] [266] [267] [268] [269] [315]Long-term survival with cyclophosphamide-based regimens range from 87% at 8 years to 64% at 10 years in different series. [264] [265] [266] [267] [268] [269] [316] Using a regimen of combined cyclophosphamide (1.5–2 mg/kg/day) and corticosteroids investigators at the NIH achieved remissions in 85% to 90% of 133 Wegener patients.[263] Most patients were converted to every other day steroid usage in several months and were able to discontinue steroid use by 1 year. Although one half of the patients eventually relapsed many patients remained in long-term remission off immunosuppressives. Similar results have been found by other investigators using cyclophosphamide-based regimens.[266] [267] [268] [269] [306] [315] [316] Complete remissions of renal and extrarenal symptoms including severe pulmonary disease, and renal failure requiring dialysis have been well described. [266] [267] [268] [269] [315] [316] [317] [318] Over 50% of dialysis-dependent patients will be able to discontinue dialysis and remain stable for periods up to a number of years. Although resistance to therapy is well documented, some patients are documented as treatment failures due to non-compliance, intercurrent infection requiring decreased treatment, or inadequate duration of therapy. Other immunosuppressives appear less effective in inducing an initial remission in Wegener granulomatosis and cyclophosphamide has been effective in patients who have failed treatment with azathioprine or chlorambucil.

Because there are few randomized controlled trials the optimal dose, duration of treatment, route of administration, and concomitant therapy to be given with cyclophosphamide remain unclear. Although cyclophosphamide is usually administered with corticosteroids initially as the patient responds to treatment the dose of the steroids are often tapered or changed to alternate day therapy.[263] Some regimens have included administration of intravenous high-dose “pulse” corticosteroids initially and others have used plasmapheresis as well in critically ill patients. [317] [318] [319] [320] A typical regimen for induction therapy for severe Wegener granulomatosis might include IV pulse methylprednisolone 7 mg/kg for 3 days followed by daily oral prednisone 1 mg/kg for the first month with subsequent tapering of the dose along with either IV or oral cyclophosphamide given for approximately 6 months. Doses can be adjusted for leucopenia and other side effects as well for treatment response. Several studies have evaluated the role of pulse IV cyclophosphamide versus oral cyclophosphamide in ANCA positive small vessel vasculitis. [265] [321] [322] [323] In one study of 50 patients with Wegener granulomatosis randomly assigned to either 2 years of IV or oral cyclophosphamide, remissions at 6 months occurred in 89% of the IV group versus 78% of the oral group.[322] At the end of the study remissions occurred in 67% of the IV group and 57% of the oral group, but relapses were more common in the IV group (60% versus 13%). In a meta-analysis of 11 non-randomized studies including over 200 ANCA-associated vasculitis patients, complete remissions occurred in over 60% of patients and partial remissions in another 15%.[323] IV pulse cyclophosphamide was more likely to induce remission and less likely to cause infection than oral cyclophosphamide. The rate of relapse, although not statistically significant, was greater in the IV pulse group. It is unclear how frequent the initial intravenous “pulses” of cyclophosphamide should be given, with some investigators using monthly doses and others starting with smaller doses every 2 to 3 weeks. Despite these uncertainties, it is clear that early application of an intensive immunosuppressive regimen can prevent long-term morbidity and end organ damage. Because the total dose of the cyclophosphamide is far less in patients receiving pulsed IV therapy, many prefer to use it as a less toxic regimen and try to enhance maintenance therapy to avoid relapse.

In several studies the addition of plasmapheresis to cyclophosphamide-based regimens did not improve outcome. [314] [317] [318] [319] [320] However, there appears to be a role for plasmapheresis in certain patients with severe renal failure, those with pulmonary hemorrhage, those with coexistent anti-GBM antibodies, and those failing all other therapeutic agents. [314] [317] [318] [319] [320] In one study of 20 ANCA positive small vessel vasculitis patients with massive pulmonary hemorrhage treated with methylprednisolone, IV cyclophosphamide, and plasmapheresis all 20 patients had resolution of their pulmonary hemorrhage with this regimen.[326] Likewise a review of 88 patients with ANCA-positive renal vasculitis in seven series in the literature showed a benefit in renal survival with plasmapheresis added (67%) over standard steroid and cyclophosphamide therapy (40%).[327] Unpublished preliminary results of a trial of over 150 patients with ANCA-positive glomerulonephritis with a marked elevation of the serum creatinine treated with either induction therapy with plasma exchange plus oral prednisone plus oral cyclophosphamide versus pulsed methylprednisolone plus oral steroids plus oral cyclophosphamide showed an advantage for the plasma exchange group.[327] The addition of etanercept to a standard induction regimen for Wegener granulomatosis was evaluated in 174 patients and provided no additional benefit in terms of sustained remissions, or time to achieve remission.[328] Disease flares and adverse events were common in both treatment groups and solid tumors developed in six patients in the etanercept group. A small number of uncontrolled trials have evaluated rituximab, a chimeric monoclonal antibody directed against CD-19 and CD20 B cells, with sustained remissions in most of the patients studied.[329] Likewise, a study of Alemtuzumab, an anti-CD52 monoclonal antibody, in 70 patients gave a remission rate of 83% but this was associated with a high rate of relapse, infection, and mortality.[327] The use of infliximab a TNF-α blocker in four uncontrolled trials was associated with a 80% remission rate but a high rate of infectious complications.[330] Relapse rates from 20% to 50% have been reported often when infectious complications have led to a discontinuation of immunosuppressive therapy. [306] [310] [315] [332] Predictors of relapse in a cohort of 350 patients with ANCA-positive vasculitis included C-ANCA or PR 3 positivity, lung involvement, upper respiratory involvement as opposed to factors not predicting relapse such as age, gender, race, and a clinical diagnosis of Wegener granulomatosis rather than microscopic polyangiitis or renal limited vasculitis.[332] Most relapses respond to another course of cyclophosphamide therapy.[314] In patients whose ANCA level has declined during remission, a major rise in titer may predict a relapse although ANCA levels and clinical disease activity do not always correlate well. Although some studies have found unacceptably high relapse rates with intravenous cyclophosphamide, others have found patients to respond equally well to this regimen as to oral cyclophosphamide. [269] [315] [324] [325] [326]Clearly IV cyclophosphamide appears to have fewer side effects than oral cyclophosphamide but a higher risk of relapses.

Because of the potential for multiple severe complications with cyclophosphamide therapy (e.g., infections, infertility, hemorrhagic cystitis, and an increased risk of long-term malignancy once an initial remission has been achieved) some patients have been switched to less toxic immunosuppressives such as azathioprine, low-dose methotrexate, or mycophenolate mofetil. [334] [335] [336] A recent study of 155 patients with ANCA-positive vasculitis treated patients with cyclophosphamide and steroids to induce a remission and then randomized patients to either oral azathioprine or continued cyclophosphamide therapy.[336] Of the 155 patients 144 entered remission and were randomized. There was no difference in the relapse rate of 10 vs. 11 patients in the two groups or in the adverse event rate. Relapse rates were lower in patients with microscopic polyangiitis than in the Wegener group. Cyclosporine has also been used in small numbers of patients successfully. [337] [338] Infections of the respiratory tract may be associated with flares of disease activity in patients with Wegener granulomatosis. Prophylactic use of trimethoprim-sulfamethoxazole may reduce the incidence of respiratory infections and in some studies prevent activation of the disease process.[338] Methotrexate has been evaluated in an uncontrolled trial of over 40 patients with remission in 80% of patients and reasonable evidence of real improvement or stabilization long term. [340] [341] Other agents being evaluated in Wegener granulomatosis include IV gammaglobulin, the chemotherapeutic agent etoposide, and humanized monoclonal antibodies directed at T cells. [342] [343] [344] [345] [346] [347] Supportive measures such as sinus drainage procedures, hearing aids, and correc-tive surgery for nasal septal collapse may be helpful in individuals with chronic sequelae of upper respiratory involvement. [264] [265] [266] [267] [268]

Dialysis and transplantation have been performed in increasing numbers of Wegener patients. [337] [348] [349] [350] [351] [352] [353] [354] [355] Some patients' disease activity diminishes with onset of renal failure, but others still require intensive immunosuppres-sion and relapses have been reported after onset of ESRD. Fatality rates may be high in the ESRD population due to slow recognition of relapses of the vasculitic process in the presence of dialysis. Most patients receiving allografts have been maintained on prednisone and cyclosporine or tacrolimus with or without mycophenolate. [337] [348] [349] [350] [351] [352] [353] Recurrent active glomerulonephritis in the allograft occurs in 15% to 20% of patients[345] and may respond to cyclophosphamide therapy. [337] [349] [350] [351] There is no evidence that regimens including mycophenolate mofetil or tacrolimus have advantages over older immunosuppressive regimens in preventing recurrences of Wegener activity. There is only limited experience with sirolimus.[354]

MICROSCOPIC POLYANGIITIS AND POLYARTERITIS NODOSA

Polyarteritis was first described by Rokitansky in 1852 and the term “periarteritis nodosa” was first used by Kussmaul and Maier in 1866.[355] The disease has been divided into a “classic” pattern with a systemic necrotizing vasculitis primarily affecting muscular arteries, often at branch points, producing lesions of varying ages with focal aneurysm formation and a “microscopic” polyangiitis with a necrotizing inflammation of small arteries, veins, and capillaries involving multiple viscera, including lung and dermis and producing lesions of similar age, usually without aneurysms. There are some patients with overlapping features of both patterns.[356] Moreover, many patients with both presentations of polyarteritis may have anti-neutrophil cytoplasmic antibodies along with pauci-immune segmental necrotizing and crescentic glomerulonephritis similar to patients with isolated pauci-immune idiopathic rapidly progressive glomerulonephritis and Wegener granulomatosis.[357] At present ANCA-positive microscopic polyangiitis should be considered as part of the spectrum of ANCA-associated vasculitides ranging from renal-limited idiopathic RPGN, to multisystem diseases including Wegener granulomatosis, Churg-Strauss syndrome, and other vasculitides. [358] [359] [360]

The incidence of renal disease associated with vasculitis has been increasing in a number of series.[360] While in part this may be due to wider use of serologic tests such as the ANCA and wider use of renal biopsy in older individuals, many investigators feel the absolute incidence has increased. In one large series ANCA-associated crescentic glomerulonephritis made up almost 10% of all glomerular diseases diagnosed by renal biopsy in a 2-year period.[361] Polyarteritis is more common in males than females (sex ratio 2.5:1) and occurs most often in the fifth and sixth decades of life although it has been reported in all age groups. There are rare reports of familial incidence of necrotizing vasculitis, and an increased frequency of certain HLA haplotypes (e.g., All, B35) has been reported.[362]

Clinically, the prevalence of renal disease in polyangiitis varies from 64% to 76% in unselected series and virtually 100% in nephrology-based series. [364] [365] [366] Moreover, the prevalence of pathologic renal involvement may exceed that of clinically evident renal disease. Although a number of diseases have been associated with glomerular disease and a systemic and/or renal vasculitis, true idiopathic polyarteritis is a primary vasculitis. “Secondary” vasculitis associated with cryoglobulinemia, systemic lupus, and Henoch-Schönlein purpura is usually readily distinguished. Likewise, vasculitis and glomerulonephritis similar to that seen in microscopic polyarteritis have been noted in relapsing polychondritis. [367] [368] ANCA-positive polyangiitis has been associated with use of oral anti-thyroid medication propylthiouracil.[368] Classic polyarteritis has been associated with drug abuse with amphetamines and other illicit drugs, but it is unclear how many of these patients had associated viral infectious hepatitis.[369] Patients with both anti-GBM antibodies and ANCA have been described, [371] [372] [373] some of whom have a prominent systemic vasculitis. (See section on Goodpasture syndrome.) The most common associated illness to be found in patients with classic polyarteritis is hepatitis B infection. The incidence ranges from 0% to 30% to 55% of different series but is probably less than 10% of all cases.[373] It is unclear how many of these patients have had concomitant hepatitis C infection. Hairy cell leukemia has also been reported in association with polyarteritis.[374]

Pathology

Classic (Macroscopic) Polyangiitis

In classic polyarteritis the glomeruli are usually unaffected. Some glomeruli may show ischemic collapse of the tuft and sclerosis of Bowman capsule. Some patients with large vessel vasculitis may also have a focal necrotizing glomerulonephritis with or without crescents identical to that seen in microscopic polyarteritis and idiopathic pauci-immune RPGN. [312] [376] Whether these represent overlap with microscopic polyangiitis awaits further clarification about pathogenesis. The vasculitis in classic polyarteritis affects the medium size to large arteries (i.e., those of subarcuate, arcuate, and interlobar caliber) in a segmental distribution often producing lesions of different ages, including acute, healing, and chronic lesions. [362] [376] There are areas of involvement interspersed with normal areas of the vessel and even in the involved portions the vessel wall has eccentric inflammation in only some parts of its circumference. In areas of active vasculitis there is an inflammation of the vessel wall involving the intima alone, the intima and media, or all three layers of the vessel wall. Inflammatory infiltrates are composed of lymphocytes, polymorphonuclear leukocytes, monocytes, and occasionally eosinophils. Lesions are often necrotizing with mural fibrin deposition and rupture of the elastic membranes. These areas of necrosis may lead to aneurysm formation particularly in larger arteries (i.e., arcuate, interlobar), which can be associated with rupture and hemorrhage into the renal parenchyma. Superimposed thrombosis with luminal occlusion is not uncommon. In the healing phase, the vascular inflammation subsides and the vessel wall is thickened by concentric cellular proliferation of myointimal cells separated by a loose ground substance. Localized destruction of elastic lamellae is demonstrable with elastic stains. Eventually the media is replaced by areas of broad fibrous scars. There may be almost total occlusion of the vessel lumen by intimal fibroplasia with areas of concentric reduplication and discontinuity of the internal elastic membrane. Wedge-shaped, macroscopic cortical infarcts are common in “classic” polyarteritis and are usually caused by thrombotic occlusion of vasculitic lesions.[361] In more chronic biopsies there is tubular atrophy and interstitial fibrosis.

Microscopic Polyangiitis

Patients with microscopic polyangiitis infrequently have true arteritis identified on renal biopsy. The frequency ranges from 11% to 22% with predominant involvement of interlobular arteries and arterioles rather than larger vessels as in “classic” polyarteritis.[361] Involvement is circumferential, lesions are of the same age, and aneurysm formation is rare. The acute vasculitis may resemble that of the classic form histologically or it may be granulomatous with the vessel media expanded by infiltrating mononuclear and polymorphonuclear leukocytes, epithelioid cells, and focal giant cells. In the same vessel features of granulomatous and necrotizing vasculitis may co-exist. In later stages of the disease there may be narrowing of the lumens of small arteries due to concentric intimal fibroplasia and elastic reduplication, but medial scarring is less frequent and severe than in the classic form of periarteritis. In microscopic polyangiitis there is often a diffuse interstitial inflammatory cell infiltrate with plasma cells, lymphocytes, and polymorphonuclear leukocytes especially around glomeruli and vessels. In some biopsies this contains large numbers of eosinophils, in others inflammatory cells penetrate the tubular basement membrane causing tubulitis.[376] In more chronic stages there is patchy tubular atrophy and interstitial fibrosis that parallels the glomerular and vascular damage.

In microscopic polyangiitis the most prominent histologic finding is typically a focal segmental necrotizing glomerulonephritis with crescents affecting from few to many glomeruli ( Fig. 31-16 ). [362] [377] There is focal destruction of the glomerular basement membrane associated with polymorphonuclear infiltration, karyorrhexis, and deposition of fibrin within the tuft and adjacent Bowman space. The tuft may show a variable degree of hypercellularity. Crescents characteristically overlie areas of segmental tuft necrosis and may be segmental or circumferential. Both cellular and fibrous crescents often appear in the same biopsy. Some crescents are voluminous with a “sunburst” appearance due to massive circumferential destruction of Bowman capsule. In the chronic or healing phase of the disease there is segmental and global glomerulosclerosis with focal fibrous crescents. A recent study documents differences between biopsies of patients with microscopic polyangiitis and Wegener granulomatosis. Biopsies from patients with polyangiitis are more likely to show glomerulosclerosis, interstitial fibrosis, and tubular atrophy. This is also true of P(MPO)-ANCA-positive patients. This suggests a more prolonged, less fulminant course of these patients' renal disease than in patients with Wegener granulomatosis.

000301

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FIGURE 31-16  Microscopic polyarteritis (polyangiitis): There are diffuse crescents with focal segmental necrosis of the glomerular tuft (Jones methenamine silver, ×125).

000519

 

Immunofluorescent and Electron Microscopic Findings

In most cases the glomeruli show no or only weak immune staining by IF consistent with the designation “pauci-immune” glomerulonephritis. [362] [377] A review of a number of large series reported positivity for one or another immunoglobulin in from 3% to 35% of cases with great heterogeneity and variability of intensity.[361] Fibrinogen was most commonly present in glomeruli, followed by C3 and then by IgG and Clq.[376] The pattern is felt to be consistent with “nonspecific trapping” in areas of glomerular necrosis and sclerosis rather than immune complex deposition. Vascular staining is similar.

By electron microscopy the glomeruli in most patients with either macroscopic or microscopic polyarteritis have no electron-dense deposits. [366] [377] [378] Patients may have sparse irregular deposits in various glomerular locations. Glomeruli may show endothelial swelling, subendothelial accumulation of “fluffy” electron lucent material, and subendothelial and intracapillary fibrin deposition and occasional fibrin-platelet thrombi. Through gaps in the GBM, fibrin tactoids and neutrophils may exude into Bowman space associated with epithelial crescents. In the chronic phase glomeruli develop segmental or global glomerulosclerosis with fibrous crescents. Vascular changes have included swelling and focal degeneration of the endothelium, separation of the endothelium from its basement membrane with subendothelial fibrin deposition, and with severe damage intraluminal fibrin, platelet thrombi, erythrocyte sludging, severe subendothelial fibrin deposition, edema and inflammatory infiltration of the intima and media by leukocytes. [362] [377] [378] As in the glomeruli, no electron-dense deposits are found in the vessels. In biopsies with chronic changes there may be expansion of the vessel intima by concentric layers of elastic tissue, fibrillar collagen and non fibrillar basement membrane material, and scarring of the media.

Pathology of Extrarenal Systemic Disease

Autopsy studies in polyarteritis describe the kidneys as being the most commonly affected organ (65%) followed by the liver (54%), peri adrenal tissue (41%), pancreas (39%), and less commonly muscle and brain. [362] [377] [379] It is unclear what percent of patients with microscopic polyangiitis have pulmonary involvement due to overlap in classification with Wegener granulomatosis and Churg-Strauss syndrome. When biopsied other tissues giving high yields for diagnosing the vasculitis of polyarteritis include the testes, the sural nerve, skin, rectum, and skeletal muscle.

Pathogenesis

The vasculitis of polyarteritis may be mediated by a number of diverse pathogenetic factors including humoral vascular immune deposits, cellular immunity, endothelial cytopathic factors, and anti-neutrophilic cytoplasmic antibody. An immune complex (IC) pathogenesis of vasculitis is suggested by experiments of acute serum sickness in which an acute glomerulonephritis is produced along with a systemic vasculitis resembling polyarteritis.[361] The vasculitis can be largely prevented by complement or neutrophile depletion. The experimental Arthus reaction can also induce a vasculitis resulting from in situ vascular immune complex formation with vessel injury preventable by neutrophil or complement depletion.[379] MRL-1 mice develop an immune complex glomerulonephritis with necrotizing vasculitis similar to polyarteritis nodosa[380] in association with high levels of circulating immune complexes, predominantly autoantibodies containing anti-DNA. Viral infection of the muscle cells of the vessel media by murine leukemia virus is also associated with a necrotizing vasculitis and lupus-like syndrome with vascular deposits of immunoglobulin and complement.[381] However, glomerular and vascular immune deposits are rarely found in human polyarteritis despite significant levels of CIC's.

Two models of cell mediated vasculitis have been produced experimentally in mice.[382] There is no evidence in these models for vascular immune deposits and some have a granulomatous form of vasculitis similar to that of polyarteritis in multiple organs. In Kawasaki vasculitis IgM anti-endothelial antibodies directed against endothelial surface antigens inducible by cytokines have been found.[383] Likewise, several viral infections in humans are capable of inducing direct cytopathic injury to arterial endothelium.[361]

ANCA may play a pathogenetic role in ANCA-associated microscopic polyangiitis and glomerulonephritis in a manner similar to Wegener granulomatosis (see section on Wegener granulomatosis). There may be initial priming of the neutrophil with cytokines and other mediators of inflammation, perhaps in response to infection, leading to expression of ANCA antigens on cell surfaces. These antigens can then react with circulating ANCAs. Myeloperoxidase is expressed on neutrophil cell surfaces following neutrophil priming with tumor necrosis factor and ANCAs have been demonstrated to stimulate a respiratory burst, with release of reactive oxygen species by primed neutrophils and monocytes, as well as degranulation of activated neutrophils and monocytes. Prior infection may set in motion the priming mechanisms that eventuate in vasculitis and in vitro evidence supports injury to endothelial cells by primed neutrophils exposed to ANCA. The induction of ANCA-positive microscopic polyangiitis associated with use of the antithyroid drug propylthiouracil suggests a pathogenetic role for ANCA as well. [369] [385] Although ANCA develop in relation to many different antigens in these patients (e.g., elastase, cathepsin G, lactoferrin), it is those patients with high titers of specific anti-MPO antibodies characteristics (e.g., high avidity and complement binding) who develop the disease.

Clinical Features

The clinical features of polyarteritis are quite variable depending on the population studied and the diagnostic criteria used for the disease. Because both the classic and microscopic forms of the disease share many clinical find-ings they are often included together despite the marked differences in pathology. Many patients with ANCA-positive idiopathic pauci-immune rapidly progressive glomerulonephritis will have evidence of extrarenal symptoms. If these patients are included in the spectrum of polyarteritis the clinical presentation and features will also differ from older series.[385]

The most common clinical findings relate to constitutional symptoms of fever, weight loss, and malaise.[386] Gastrointestinal involvement may include nausea, vomiting, abdominal pain, gastrointestinal bleeding, bowel infarcts, and perforations. [362] [388] [389] Liver involvement may be associated with hepatitis B or C, and vasculitis of the mesenteric vessels, hepatic arteries, and of the gall bladder leading to cholecystitis have all been found. [362] [388] [389]Patients may develop heart failure, coronary artery ischemia with angina or myocardial infarction, and less commonly pericarditis and conduction abnormalities.[361] Disease of the nervous system may be central, with seizures and cerebro-vascular accidents, or related to peripheral nerves, with mononeuritis multiple and peripheral neuropathies. [362] [390] [392] Patients may develop muscle weakness, myalgias or myositis, and arthralgias but frank arthritis is less common. [362] [393] Clinical findings also may relate to disease in the gonads, salivary glands, pancreas, adrenal, ureter, breast, and eyes. [362] [394] In general, with the exception of liver manifestations and arthralgias, there is little difference between the clinical findings of patients who are hepatitis B positive or negative. Patients with cutaneous disease may present with “palpable purpura” with a leukocytoclastic angiitis on biopsy, or with petechiae, nodules, papules, livedo reticularis, and skin ulcerations. [362] [395] The extent of pulmonary involvement is variable depending on the criteria for classification of polyarteritis versus other vasculitic disease such as Wegener granulomatosis and Churg-Strauss syndrome.[361]

There are a number of differences in the presentation of patients with the classic pattern and the microscopic form of polyarteritis.[361] In the classic form patients typically have findings related to visceral organ infarction and ischemia, and abdominal, cardiac, and neurologic findings are prominent. In the microscopic form cutaneous disease and pulmonary findings are more frequent. Patients with idiopathic focal segmental necrotizing glomerulonephritis and ANCA-positive rapidly progressive glomerulonephritis have similar clinical findings and presentations regardless of whether vasculitis has been documented on renal biopsy.[386] Likewise the extrarenal findings in patients with ANCA positive rapidly progressive glomerulonephritis have been similar whether the patients are P-ANCA or C-ANCA positive.[386]

Laboratory Tests

Laboratory tests in patients with polyarteritis include an elevated erythrocyte sedimentation rate in almost all patients and anemia, leukocytosis, and thrombocytosis present in over two thirds. [362] [386] Eosinophilia is found in from 10% to 40%, being higher in patients with the microscopic form of PAN and in those overlapping with Churg-Strauss syndrome. Most patients have negative tests for anti-nuclear antibodies and normal serum complement values. Tests for circulating immune complexes and rheumatoid factor are often positive.[395] Although cryoglobulins have often been reported to be positive in many patients it is unclear what percent have had associated hepatitis infection.[361] The incidence of hepatitis B antigenemia has been variable ranging from 0% to as many as 40% in some series weighted heavily for classic polyarteritis. It is usually positive in less than 10% of unselected patients.[362] [396]

The widespread use of accurate assays for ANCA have facilitated the clinical diagnosis of polyangiitis. There is considerable clinical overlap between patients with polyarteritis, Wegener granulomatosis, and Churg-Strauss, and all have high rates of ANCA positivity. Although C-ANCA positive patients are more likely to have biopsy proven necrotizing vasculitis or granulomatous inflammation of the sinuses or lower respiratory tract there is a large overlap in the clinical manifestations between C-ANCA positive and P-ANCA positive patients. Patients with classic polyarteritis are usually ANCA negative. ANCA titers vary considerable among patients with similar clinical manifestation and the role of the titre in predicting flares of the disease is not fully defined. Some patients will retain high ANCA levels despite clinical remission and some patients are positive for anti-GBM antibodies as well as ANCA (see section on Wegener granulomatosis).

Renal Findings

Although the kidney is typically the organ most commonly involved in polyarteritis, the pattern may vary considerably. [362] [397] In the microscopic form of the disease vasculitis and glomerulonephritis relate to the clinical findings, whereas in the classic pattern renal ischemia and infarction due to larger vessel disease predominate. Hypertension is common in polyarteritis and is found initially in up to one half of patients.[361] Hypertension may be mild or severe, and if not present initially can develop at any time during the course of the disease.[397] Presenting symptoms related to kidney disease are uncommon in “classic” polyarteritis with the exception of hypertension but may include hemorrhage from a renal artery aneurysm, flank pain, and gross hematuria. Oliguric acute renal failure is uncommon as are symptoms related to the nephrotic syndrome.[397]

Most patients will have laboratory evidence of their renal involvement at presentation. The majority of cases of microscopic polyangiitis and some of classic polyarteritis have urinary sediment changes with microscopic hematuria and often red blood cell casts.[361] Proteinuria is found in most patients but the nephrotic syndrome is rarely present. A decreased GFR is present in up to half of the patients in unselected series, and more in those selected for renal involvement. Severe renal insufficiency may be found at presentation in some patients. These renal findings are similar to those found in patients with ANCA-positive idiopathic RPGN, whether or not associated with systemic involvement.[385] In microscopic polyarteritis the severity of the clinical renal findings generally correlates with the degree of glomerular involvement akin to patients with Wegener granulomatosis. Patients with normal serum creatinines or creatinine clearances are likely to have normal glomeruli on biopsy or only ischemic glomerular changes, whereas patients with reduced or deteriorating renal function are more likely to exhibit severe segmental necrotizing glomerulonephritis or diffuse proliferative features. [362] [366] [399] Extensive crescent formation correlates with oliguria, severe renal failure, and a residual decrease in GFR after therapy. [362] [377]

Angiographic examination of the vasculature for evidence of polyarteritis is far more likely to be positive in patients with the classic pattern. Angiograms reveal multiple rounded, saccular aneurysms of medium-sized vessels in about 70% of cases as well as thromboses, stenoses, and other luminal irregularities. [362] [388] [399] Aneurysms most commonly involve the hepatic, splanchnic, and renal vessels, are usually bilateral, multiple, and vary in size from 1 mm to 12 mm.[398] There is no way to clinically predict the presence of aneurysms.[398] Vasculitic changes and even aneurysms can heal with time as documented by angiography usually in correlation with the clinical response of the patient. [388] [399] Similar aneurysms have been documented in Wegener granulomatosis, SLE, TTP, bacterial endocarditis, and Churg-Strauss syndrome.

Prognosis and Treatment

In retrospective studies of untreated patients with polyarteritis survival has been dismal with 5-year survival less than 15%.[361] Many patients had a fulminant course with a high early mortality due to the acute vasculitic process. A poor prognosis has been found in the elderly, those with a delay in diagnosis, with gastrointestinal tract catastrophes such as bowel infarction and hemorrhage, and with severe renal disease. Hypertension has been variably found to adversely affect the prognosis or have no effect on it. Renal prognosis has been reported to be adversely affected by increased activity on the biopsy, more crescents, severity of endocapillary proliferation, and glomerulosclerosis.[361] Early mortality in polyarteritis relates to the active vasculitis leading to renal failure, gastrointestinal hemorrhage or acute cardiovascular events whereas late mortality has been attributed to chronic vascular changes with chronic renal failure, and heart disease with congestive heart failure.[363] Survival has not been different in a series of over 150 patients with focal segmental necrotizing glomerulonephritis either alone or with associated arteritis.[396]

Corticosteroid use improved the survival of polyarteritis patients significantly with 5-year survivals of approximately 50%.[361] Nevertheless some patients achieve only partial remissions of the disease with continued activity leading to long-term morbidity and mortality. The addition of cytotoxic immunosuppressives to corticosteroid regimens has greatly improved the survival with 5-year survival rate increased to well over 80%. Although a number of immunosuppressives including azathioprine, busulfan, methotrexate, 6-mercaptopurine, and antithymocyte globulin have all been used successfully, many feel cyclophosphamide is the most effective agent.[399] Initial therapy of polyarteritis usually consists of high doses of cyclophosphamide (e.g., 1–2 mg/kg/day), adjusted to avoid leukopenia, commonly given along with high doses of corticosteroids (e.g., 60 mg Prednisone/day). The steroid dose is then tapered over time. Successful treatment can lead to complete inactivity of the vasculitic process and reversal of even severe renal failure requiring dialytic support. Other regimens have used various combinations of pulse methylprednisolone, plasma exchange, and intravenous cyclophosphamide with good short-term results. These regimens are discussed extensively in the section on Wegener granulomatosis because many treatment studies included all ANCA-positive vasculitis patients together. One trial of intravenous versus oral cyclophosphamide along with corticosteroids in ANCA-positive patients with microscopic polyarteritis nodosa or Wegener granulomatosis found equivalent efficacy and less side effects with the intravenous regimen. ANCA-positive patients with rapidly progressive glomerulonephritis many of which fit the definition of microscopic polyangiitis have responded well to regimens of oral corticosteroids and bolus intravenous methylprednisolone, with either bolus intravenous cyclophosphamide, or oral cyclophosphamide. The frequency of administration of the intravenous cyclophosphamide has varied from monthly to every 2 to 3 weeks at doses ranging from 0.5 to 1 g/m2, whereas pulse methylprednisolone has been given at daily doses of 500 mg or up to 7 mg/kg body weight for several days. Although the benefits of oral versus IV cyclophosphamide have been debated, they are discussed under Wegener granulomatosus. A recent large multicenter prospective randomized trial comparing oral to IV cyclophosphamide in 144 ANCA-positive polyangiitis patients for induction therapy found no difference in efficacy, BVAS score, or serum creatinine between the two regimens. Even patients with dialysis requiring renal failure may respond to these regimens. Although controlled trials have shown ambiguous results regarding the benefit of adding plasmapheresis to standard regimens in ANCA-positive polyangiitis, it may benefit a subset of patients with severe glomerulonephritis requiring dialysis, or those with pulmonary hemorrhage. Even patients with a good response to therapy may suffer residual glomerular damage and progress long term to end-stage renal disease. Thus, aggressive, vigorous early therapy to turn off the disease process is felt to be crucial in preventing residual organ damage. [402] [403] [404] Therapeutic intervention in addition to immunosuppressive therapy includes control of hypertension, and measures to prevent non-immunologic glomerular disease progression such as use of anti-hypertensives that blockade the renin-angiotensin system, and use of low protein diets in some patients. Alpha interferon and other anti-viral agents have been used in the management of polyarteritis associated with hepatitis B infection and Hairy cell leukemia. [405] [406]

For patients with ESRD, immunosuppressive therapy should be continued for 6 months to 1 year after the disease appears inactive. Although transplantation has been performed in only a limited number of patients with polyarteritis, by extrapolation of results from populations with ANCA positive rapidly progressive glomerulonephritis and Wegener granulomatosis, most patients should do well on standard immunosuppressive regimens; the risk of recurrence remains in the 15% to 20% range.

CHURG-STRAUSS SYNDROME (ALLERGIC GRANULOMATOSIS)

Churg-Strauss syndrome, or allergic granulomatosis and angiitis, is a rare systemic disease characterized by vasculitis, asthma, organ infiltration by eosinophils, and peripheral eosinophilia. [407] [408] Churg and Strauss first fully described the syndrome in 1951.[361] Although there may be some overlap with other vasculitic and allergic processes such as polyarteritis nodosa, Wegener granulomatosis and microscopic polyangiitis, Loeffler syndrome, and chronic eosinophilic pneumonitis, the clinical and pathologic features of “Churg-Strauss syndrome” are distinct. [410] [411]

Churg-Strauss syndrome is an uncommon disease with only several hundred cases reported in the literature. In a review of almost 185,000 asthmatic patients taking medications only 21 cases of Churg-Strauss syndrome were identified.[411] The low incidence may reflect under recognition and there might also be a higher disease incidence if a looser definition of the disease was applied with only some clinical and histopathologic features required for defining the diagnosis. A more inclusive definition includes (1) asthma, (2) peripheral blood eosinophilia, and (3) systemic vasculitis involving two or more extrapulmonary organs. Using this definition, many cases described as other vasculitic syndromes in asthmatics would fit the definition of Churg-Strauss syndrome.

There is no gender predominance in Churg-Strauss syndrome, and although the disease has been reported at all ages, the mean age of diagnosis is about 50 years old. [407] [408] [409] [410] [411] The clinical renal involvement in Churg-Strauss syndrome is clearly less prevalent than morphological renal involvement. However, a recent series from one center reports a high incidence of clinical renal disease.[413] In autopsy series, the kidney is affected in over one half of patients, whereas clinical renal disease has been described in from 25% to over 90% of patients. [407] [408] [409] [410] [411] [414]

A number of studies document the rare occurrence of Churg-Strauss syndrome in steroid-dependent asthmatics taking leukotriene receptor antagonists (montelukast, zafirlukast, pranlukast). [415] [416] [417] [418] [419] [420] [421] This may represent unmasking of the vasculitic syndrome as the leukotriene receptor antagonist permits steroid withdrawal because similar cases have been reported in “asthmatics” with a change from oral to inhaled steroids. [419] [420]Rarely, substitution of a leukotriene receptor antagonist for inhaled steroids has led to Churg-Strauss syndrome.[420] Other investigators have not been able to find evidence to support a pathogenic role for leukotriene receptor antagonists in the development of the disease.[421]

Pathology

Renal biopsies in Churg-Strauss syndrome vary from normal kidney tissue to severe glomerulonephritis, vasculitis, and interstitial inflammation. [362] [407] [408] [409] [413] [414] [423] [424] There may be a focal segmental necrotizing glomerulonephritis sometimes with small crescents. In most cases the glomerulonephritis is mild, affects only several glomeruli, and involves the tuft segmentally. The glomerulonephritis may, however, be diffuse and global with severe necrotizing features and crescents. Rarely there is only mesangial hypercellularity without endocapillary proliferation or necrosis. In autopsy studies vasculitis was found in the kidney in over one half of the original cases studied by Churg and Strauss and it has been noted on renal biopsy as well.[361] It may involve any size artery from arterioles to arcuates and histologically may vary from fibrinoid necrotizing to granulomatous. Although resembling other forms of vasculitis, the arteritis is characterized by eosinophilic granulocytes within the arterial wall and in the surrounding connective tissue ( Fig. 31-17 ). Destruction of elastic membrane, aneurysms, and luminal thrombosis with recanalization may occur as may epithelioid cells and multinucleated giant cells in the media, adventitia, and perivascular connective tissue. Active and healed lesions may co-exist. Less commonly, venules and small veins of interlobular size may be affected, often with granulomatous features and in close association with adjacent interstitial granulomatous inflammation. The tubulointerstitial region is involved by an inflammatory infiltrate containing eosinophils and some lymphocytes, plasma cells, and polymorphonuclear leukocytes in association with interstitial edema. [362] [414] In some cases there are interstitial granulomas composed of a core of eosinophilic or basophilic necrotic material surrounded by a rim of radially oriented macrophages, giant cells of the Langhans type, and numerous eosinophils. Interstitial nephritis may be present without glomerular pathology.

000384

000519

FIGURE 31-17  Churg-Strauss syndrome: Granulomatous vasculitis involves an arcuate artery. There is granulomatous transmural inflammation with focal giant cells and superimposed luminal thrombosis (Hematoxylin-eosin, ×125).

000519

 

By IF areas of segmental necrosis in the glomeruli may contain IgM, C3, and fibrinogen. [362] [413] [414] A single report describes IgA staining in the glomerulus.[412] Several investigators have described complement in arteries in Churg-Strauss syndrome. The presence of IgE in renal or other tissues has not been adequately investigated.[424] EM of the glomeruli, pulmonary granulomas, venules, and capillaries reveals no electron-dense deposits. [362] [407] [408] [409]

Pathogenesis

Although the pathogenesis of Churg-Strauss syndrome remains unclear, allergic or hypersensitivity mechanisms are supported by the presence of asthma, hypereosinophilia, and elevated plasma levels of IgE. [407] [408] [409] [413] [425] [426] Eosinophils in patients with Churg-Strauss syndrome have prolonged survival due to inhibition of CD95 mediated apoptosis; T cell secretion of eosinophil activating cytokines may play a role as well.[425] Human eosinophil cationic proteins, which are capable of tissue destruction in a variety of hypereosinophilic syndromes, have been found in granulomatous tissue from patients with Churg-Strauss syndrome. [427] [428] Higher serum levels of eosinophil cationic protein (ECP), soluble interleukin-2 receptor (sIl-2R) and soluble thrombomodulin levels have been associated with active disease in Churg-Strauss syndrome.[427] Although a pathogenetic role for immune complex deposition has been suggested, hypocomplementemia and CIC's have rarely been observed and the negative IF and EM findings do not support an immune complex pattern of injury. Cell mediated immunity may be involved in the pathogenesis of the lesions and high helper/suppressor ratios in the peripheral blood during the acute phase of the disease are reported as well as a preponderance of helper T cells in the granulomas of skin biopsies.[361] It is likely that ANCA may play a role akin to that in Wegener granulomatosis and microscopic polyarteritis.

Clinical and Laboratory Features

Patients may have initial constitutional symptoms such as weight loss, fatigue, malaise, and fever. [362] [407] [408] [409] Characteristic extrarenal features include asthma (present in over 95% of cases), an allergic diathesis, allergic rhinitis, and peripheral eosinophilia. [407] [411] [413] Asthmatic disease typically precedes the onset of the vasculitis by years, but it may occur simultaneously. The severity of the asthma does not necessarily parallel the severity of the vasculitis. Many patients subsequently develop eosinophilia in the blood along with eosinophilic infiltrates in multiple organs. This is followed by vasculitis of organs in some patients. This multisystem disease often involves the heart with pericarditis, heart failure, and/or ischemic disease, the gastrointestinal tract with abdominal pain, ulceration, diarrhea, or bowel perforation, and the skin with subcutaneous nodules, petechiae, and/or purpuric lesions. [407] [408] [409] [410] [411] [413] [429] [430] [431] A peripheral neuropathy with mononeuritis multiplex is common, but migrating polyarthralgia or arthritis (or both) occur less frequently.[431] The eye, prostate, and genitourinary tract may be involved. Some patients with Churg-Strauss syndrome have overlapping features with polyarteritis or other vasculitides. [407] [408] [409] [410] [411]

Laboratory evaluation typically reveals anemia, leukocytosis, and an elevated erythrocyte sedimentation rate. [362] [407] [408] [409] [410] [411] Eosinophilia is universally present and may reach 50% of the total peripheral leukocyte count. The degree of eosinophilia and the erythrocyte sedimentation rate may correlate with disease activity as may the level of eosinophilic cationic protein, soluble interleukin-2 receptor, and soluble thrombomodulin levels.[427]Rheumatoid factor is often positive and C-reactive protein levels are increased, whereas serum complement, hepatitis markers, CIC's, ANA, and cryoglobulins are usually negative. [362] [407] [408] [409] [410] [411] Elevated serum IgE levels and IgE-containing CIC's are frequently found. [407] [408] [409] [410] [411] [413] [425] Chest radiograph may show patchy infiltrates, nodules, diffuse interstitial disease, and pleural effusion. [407] [408] [409] [410] [411] [432] [433] Pleural effusions my be exudative and contain large numbers of eosinophils.[433] On angiography visceral aneurysms may be present in patients with both polyarteritis overlap syndromes and classic Churg-Strauss syndrome.

ANCA levels have been elevated in 40% to 80% of Churg-Strauss patients. [422] [429] [435] [436] Most patients are P-ANCA positive with antibody directed against myeloperoxidase, but some are positive for C-ANCA. In one recent analysis of almost 100 patients 35% were ANCA positive by immunofluorescence with a perinuclear pattern and anti-myeloperoxidase specificity in about three quarters.[435] Some investigators have found a good correlation between ANCA positivity and ANCA titers and clinical activity whereas others have not. [422] [429] [436] Clearly in some, ANCA titers may remain positive despite clinical remissions. In Churg-Strauss patients ANCA positivity has been correlated variably with renal involvement, pulmonary disease, peripheral neuropathy, and the presence of vasculitis. [435] [436]

Although the clinical renal findings in Churg-Strauss syndrome are diverse, as opposed to other vasculitides, renal involvement rarely predominates. [362] [407] [408] [409] [410] [411] Microscopic hematuria and mild proteinuria are common, but nephrotic range proteinuria is infrequent. Hypertension is found in up to 75% of patients. In pure Churg-Strauss syndrome, renal failure has been uncommon although it occurs in patients with overlap syndromes. Recent reports, however, suggest a higher incidence of renal involvement and renal failure. [410] [411] [414] [423]

Prognosis, Course, and Treatment

Patients may have several phases of the syndrome over many years. [407] [408] [409] [410] [411] There may be a prodromal phase of asthma or allergic rhinitis followed by a phase of peripheral blood and tissue eosinophilia remitting and relapsing over months to years before development of systemic vasculitis. A shorter duration of asthma prior to onset of vasculitis has been associated with a worse prognosis.[412] The correlation between ANCA levels with the disease activity in Churg-Strauss syndrome has been variable. In general, renal disease is mild with only 7% of one large literature review having renal failure as a cause of death even in untreated patients. [362] [413] [414] Most patients surviving the initial insult usually fare well with survival rates in treated patients approximately 90% at 1 year and 70% at 5 years. [407] [408] [409] [410] [411] [429] Patients with significant cardiac, CNS, gastrointestinal involvement, and those with greater degrees of renal damage have a poor long-term survival.[428] However, cases progressing to severe renal failure and dialysis have certainly been reported. [411] [414] [423]

Corticosteroid therapy is successful in most patients with Churg-Strauss syndrome. [407] [408] [409] [410] [411] Patients respond rapidly to high daily oral prednisone therapy and even relapses respond to retreatment. Extra renal disease often responds as well. Resistant cases may benefit from treatment with other immunosuppressive agents such as azathioprine, methotrexate, cyclophosphamide, or plasma exchange although one meta-analysis could find no benefit from the addition of plasma exchange to other treatments. [407] [408] [409] [410] [411] [436] [437] Pulse intravenous cyclophosphamide has also been used successfully.[437] IV immune globulin has been used successfully in some small groups of patients resistant to other forms of therapy. [439] [440] TNF blocking agents such as infliximab and etanercept have also been useful in some such patients.[434] Alpha interferon has been used to treat successfully several patients resistant to corticosteroids and cyclophosphamide.[440] Although recovery is usually complete, some patients relapse and others have chronic sequelae such as peripheral neuropathy, chronic pulmonary changes, and hypertension. [407] [429]

GLOMERULAR INVOLVEMENT IN OTHER VASCULITIDES (TEMPORAL ARTERITIS, TAKAYASU DISEASE, LYMPHOMATOID ARTERITIS)

Temporal Arteritis

Temporal arteritis or giant cell arteritis is a systemic vasculitis with a characteristic giant cell vasculitis of medium size and large arteries. [442] [443] [444] [445] The disease is slightly more prevalent in females than in males and is the most common form of arteritis in western countries. [442] [443] [444] [445] [446] [447] Temporal arteritis is primarily a disease of the elderly, the average age of onset of symptoms being 72 years, with over 95% of patients exceeding 50 years of age. [446] [447] Extra cranial vascular involvement occurs in from 10% to 15% of patients with giant cell arteritis. [442] [445] [448] Renal manifestations are rare and generally mild, consisting of mild hematuria and proteinuria, without renal functional impairment. [442] [443] [444] [445] Renal failure occurring in patients with temporal arteritis is exceedingly unusual.

There are several reports of a polyarteritis nodosa-like renal involvement occurring in association with temporal arteritis or polymyalgia rheumatica.[448] Some patients are P-ANCA positive and less commonly patients have been C-ANCA positive.[449] The renal pathology has been described as a focal segmental necrotizing glomerulonephritis with focal crescents and vasculitis of the PAN type, primarily affecting small arteries and arterioles. Rarely visceral aneurysms have been demonstrable angiographically. Whether these cases represent true manifestations of temporal arteritis or forms of “overlap” with polyarteritis nodosa is not clear. There is also single report of probable LN occurring in a patient with temporal arteritis.[450] In a report of membranous glomerulopathy occurring in a patient with temporal arteritis, it was not clear whether the association was fortuitous or pathogenetically linked because both the proteinuria and systemic symptoms responded to steroid therapy.[451] Renal amyloidosis has also rarely been noted in patients with temporal arteritis.

The most common renal manifestations of mild proteinuria and microhematuria are present in less than 10% of patients. [443] [444] [445] [448] Erythrocyte casts have been found on urinalysis in some patients and especially those with extracranial large vessel involvement. Renal excretory function is usually unaffected and renal insufficiency is uncommon. Rare cases of renal insufficiency or renal failure (or both) have been attributed to renal arteritis affecting the main renal artery or its intraparenchymal branches. [449] [450] In some cases the pathology has been inadequate to diagnose the precise etiology of the renal failure. The nephrotic syndrome has been reported in a patient with temporal arteritis and membranous glomerulopathy.[451] In this case steroid therapy produced a partial response with reduction in proteinuria from 6.8 to 1.3 grams/day. Hypertension is infrequent and most often mild to moderate when present.

The vasculitis seen in temporal arteritis is characterized by segmental transmural inflammation of medium size and large elastic arteries by a mixed infiltrate of lymphocytes, monocytes, polymorphonuclear leukocytes, scattered eosinophils, and giant cells. [442] [443] [444] [445] Giant cells are quite variable in number and are usually most prominent in the region of the internal and external elastic membrane, with associated gaps in the elastica. Necrosis of the intima and media may occur in the acute phases. In the chronic phase, exuberant intimal fibroplasia may lead to marked narrowing of the arterial lumen.

The management of temporal arteritis with corticosteroids causes rapid and dramatic improvement in general well being, specific symptomatology, and laboratory abnormalities. [442] [443] [444] [445] A number of corticosteroid sparing and secondary immunosuppressives have been used successfully in temporal arteritis. [453] [454] Abnormal urinary sediment changes disappear, and there is resolution of extracranial large vessel involvement. [452] [453] [454] However, once established, visual loss is often permanent, despite resolution of the active disease process. Exacerbation of systemic vasculitis may occur if corticosteroids are tapered too rapidly.

Takayasu Arteritis

Takayasu arteritis is a rare vasculitic disease of unknown pathogenesis characterized by inflammation and stenosis of medium and large arteries, with a predilection for the aortic arch and its branches. [455] [456] [457] [458] The disease most commonly affects young women between the ages of 10 and 40, and Asians are much more commonly affected. [455] [456] [457] [458] Although findings are typically confined to the aortic arch, the subclavian, carotid, and pulmonary arteries, in some cases the abdominal aorta and its branches are affected.[454] The histopathologic findings of the vessels include arteritis with transmural infiltration by lymphocytes, monocytes, polymorphonuclear leukocytes, and in some cases Langhans giant cells. In the chronic phase of the disease, intimal fibroplasia and medial scarring may result in severe vascular stenoses or total luminal obliteration.

Although in the past renal disease was believed to be uncommon, renal involvement is now reported more frequently. [458] [459] [460] [461] [462] [463] This is usually due to an obliterative arteritis of the main renal artery or narrowing of the renal ostia by abdominal aortitis leading to renovascular hypertension. Arteriography is usually used to make the diagnosis of Takayasu arteritis although computerized tomography, MR, and PET scan imaging have been used as well. [455] [464] [465] Laboratory abnormalities reveal mild anemia, elevated erythrocyte sedimentation rate, increased levels of C-reactive protein, and elevated gammaglobulin levels but other serologic tests such as ANA, latex fixation, VDRL, ASLO, and serum complement levels are normal. Some patients have antiendothelial cell antibodies.[465] Hypertension, which may be severe occurs in 40% to 60% of patients and has been attributed to decreased elasticity of the aorta, increased renin secretion due to stenosis of major renal arteries, and other mechanisms. [460] [462] [467] [468] Although mild proteinuria and hematuria are found in some patients, nephrotic range proteinuria is uncommon and should suggest the possibility of secondary renal amyloidosis.[468] The serum creatinine is usually normal, but may be mildly elevated or associated with a high BUN to creatinine ratio suggestive of “pre-renal” azotemia. Progressive renal failure is uncommon. [456] [457] [460]

A mild mesangial proliferative glomerulonephritis may occur in patients with Takayasu arteritis. [459] [461] [469] Mesangial deposits of IgG, IgM, IgA, C3, and C4 have been reported and mesangial electron-dense deposits are found on EM. Most patients have normal renal function and only mild hematuria and proteinuria. Elevated serum levels of IgA have been noted, and some patients have had glomerular involvement typical of IgA nephropathy. [461] [469]Whether this is coincidental or part of the disease process is unclear. One series of patients with Takayasu arteritis had unusual glomerular histopathology with mesangial sclerosis and nodules, as well as mesangiolysis and glomerular microaneurysms resembling diabetic nephropathy.[458] None of these patients had diabetic nephropathy. IF and EM in these cases of “centrolobular mesangiopathy” did not support an immune pathogenesis. There are also rare reports of renal amyloidosis occurring in association with Takayasu arteritis[468] and cases of membranoproliferative glomerulonephritis, crescentic glomerulonephritis, and proliferative glomerulonephritis.[469]

Treatment

In the majority of patients, corticosteroids are effective therapy for the vasculitis and systemic symptoms and further vascular deterioration is suppressed. [455] [456] [457] Other medications including azathioprine, methotrexate, cyclophosphamide, mycophenolate, and anti-TNF therapy have also been used successfully in individuals as have anticoagulants, vasodilators, and acetyl salicylic acid. [471] [472] [473] [474] [475] Residual morbidity and mortality may result from the progressive fibrosis and stenosis of previously inflamed arteries.[475]

Lymphomatoid Granulomatosis

Lymphomatoid granulomatosis is a rare disease that may encompass a spectrum from premalignant disease to frank neoplastic lymphoproliferative disorder.[476] Many cases are now felt to be associated with EB virus B cell lymphomas. Although in a recent review of over 150 cases renal involvement was found on histopathology in almost one third of cases at autopsy, glomerular involvement is unusual. Histologically, there is focal infiltration of the renal interstitium by a polymorphous infiltrate of mature lymphocytes, plasma cells, histiocytes, immunoblasts, and atypical lymphoid cells whereas the glomeruli are spared. Lymphomatoid granulomatosis may cause diagnostic confusion with true vasculitides such as Wegener granulomatosis, allergic granulomatosis, and polyarteritis nodosa.

HENOCH-SCHöNLEIN PURPURA

Henoch-Schönlein purpura (HSP) is a systemic vasculitic syndrome with involvement of the skin and gastrointestinal tract and joints in association with a characteristic glomerulonephritis. [478] [479] [480] [481] In HSP IgA containing immune complexes deposit in the skin, kidney, and other organs in association with an inflammatory reaction of the vessels. In the skin this leads to a leukocytoclastic angiitis with petechiae and purpura. In gastrointestinal tract involvement there may be ulcerations, pain, and bleeding, and in the kidney an immune complex glomerulonephritis is found. [478] [479] [480] [481]

Males are slightly more commonly affected than females, and children are far more frequently affected than adults although the disease can occur at any age. [478] [482] [483] [484] [485] [486] The peak age of patients with HSP is approximately 5 years old as opposed to IgA nephropathy, which has a peak age of 15 to 30 years old. [478] [479] [480] [481] [482] [483] [484] [485] HSP may account for up to 15% of all glomerulonephritis in young children. [478] [479] [480] [481] [482] [483] [484] [485] More severe renal disease occurs in older children and adults.[485] HSP is uncommon in blacks.[487] Familial occurrence has rarely been reported and the frequency of HLA-Bw35 has been reported to be increased in some but not all patients with HSP. [490] [491] About one fourth of patients will have a history of allergy but exacerbations related to a specific allergen are rare. In some cases relapses of the syndrome have occurred after exposure to allergens or the cold and seasonal variations show peak occurrence in the winter months.

Although HSP with classic organ system involvement is readily diagnosed, the syndrome may be confused with other systemic illnesses such as SLE and polyarteritis nodosa, with infectious agents such as meningococcemia, gonococcemia, and Yersinia enterocolitis. Likewise, certain medications and vaccination-related hypersensitivity reactions may mimic this disease as can post-infectious glomerulonephritis, which may have at times systemic manifestations. Although an upper respiratory infection precedes HSP in 30% to 50% of patients, serologic evidence of streptococcal infection is lacking. Abdominal pains may be mistaken for appendicitis, cholecystitis, or another surgical emergency and lead to exploratory laparotomy.

Clinical Findings

The classic tetrad of findings in HSP includes dermal involvement, gastrointestinal disease, joint involvement, and glomerulonephritis, but not all patients will have all organ systems clinically involved. [478] [479] [480] [481]Constitutional symptoms such as fever, malaise, and fatigue and weakness may be associated with active isolated dermal involvement or full-blown systemic diseases. Skin lesions are almost universal in both children and adults with HSP and are commonly found on the lower and upper extremities but may also be on the buttocks or elsewhere. [478] [480] [492] They are characterized by urticarial macular and papular reddish-violaceous lesions that do not blanch. Lesions may be discrete or may coalesce into palpable purpuric lesions associated with lower extremity edema even in the absence of the nephrotic syndrome. New crops of lesions may recur over weeks or months. On skin biopsy there is a leukocytoclastic angiitis with evidence of IgA containing immune complexes along with IgG, C3, properidine but not C4 or C1q.[808] Gastrointestinal manifestations are present in from 25% to 90% of patients and may include colicky pain, nausea and vomiting, melena, and hematochezia. [478] [479] [480] [481] [493] [494] [495] [496] One recent study of over 260 patients found that 58% had abdominal pain and 18% evidence of GI bleeding.[496] In patients with gastrointestinal involvement, endoscopy may reveal purpuric lesions, and rarely patients may develop areas of intussusception or perforation. Rheumatologic involvement is most common in the ankles and knees and less commonly in elbows and wrists, and may consist of arthralgias or frank arthritis with painful, tender effusions. [478] [479] [480] [481] Patients do not develop joint deformities or erosive arthritis. Rarely patients will have evidence of other organ involvement with pulmonary, central nervous system, or ureteritis. [478] [479] [480] [481] [498]

Renal involvement varies from 20% to 100% of patients with HSP depending on the method of detection of renal disease and referral source of the patients. [478] [479] [480] [481] [485] [486] [487] [492] In one recent series of over 260 patients 20% developed renal disease.[498] In studies routinely examining the urine, renal involvement ranges from 40% to 60% of patients.[499] In a series of 250 adults with HSP 32% had renal insufficiency usually with proteinuria (97%) and hematuria (93%).[491] The onset of active renal disease usually follows the onset of the systemic manifestations by days to weeks and is characterized by microscopic hematuria, active urinary sediment, and proteinuria. [478] [480] [488] [492] Gross hematuria is uncommon. Even in children without clinical evidence of renal disease excessive excretion of erythrocytes in the urine has been documented. Some patients with clinical renal involvement will develop the nephrotic syndrome and some will have a nephritic picture. There is no relationship between the severity of extra renal organ involvement and the severity of the renal lesions.

Laboratory Features

In HSP platelet counts and serum complement levels are all usually normal. [478] [479] [480] [481] Rarely slightly low CH50 and properidine levels or evidence of alternate pathway activation of complement is observed. Serum IgA levels are elevated in up to one half of patients especially during active phases of the illness, but do not correlate well with the severity of clinical manifestations or course of the disease. [478] [479] [480] [481] [484] A number of abnormal IgA antibodies have been noted including IgA rheumatoid factor, CIC's with IgA and IgG, IgA anticardiolipin antibodies, IgA fibronectin aggregates, IgA anti-alpha-galactosyl antibodies, and IgA ANCA. [503] [504] [505] [506] [507] [508] [509] [510] [511] The relationship of these to active renal or systemic disease remains to be confirmed although concentrations of IgA and IgG immune complexes, IgA rheumatoid factor, and IgA anti-galactosyl antibodies have been correlated with clinical renal disease manifestations. [504] [505] [506] [510] Some patients have cryoglobulins.

Pathology

Although by LM the renal biopsy findings of HSP resemble those of IgA nephropathy, there are some histopathologic differences. The typical glomerular pathology of HSP is a mesangio-proliferative glomerulonephritis with variable crescent formation. [478] [479] [480] [481] [482] [485] [486] [492] [502] [512] The mesangial changes include both increased mesangial cellularity and matrix expansion that may be focal or diffuse ( Fig. 31-18 ). In severe cases, polymorphonuclear cells and mononuclear cells may also infiltrate the glomerular tufts and there may be necrotizing features. By monoclonal antibody staining increased numbers of monocyte/macrophages and CD4 and CD8 T cells are found. [513] [514] Some cases have a well-developed membranoproliferative pattern with double contours of the GBM. Crescents vary from segmental to circumferential and are initially cellular but later fibrotic in nature ( Fig. 31-19 ). Tubulointerstitial changes of atrophy and interstitial fibrosis are consistent with the degree of glomerular damage. In general, endocapillary and extracapillary proliferation as well as glomerular fibrin deposition are more frequent and severe in HSP than in IgA nephropathy.[481] The histopathologic classification system proposed by the International Study of Kidney Disease of Childhood correlates the glomerular lesions with clinical manifestations as well as prognosis. [485] [502] These categories include Class I with minimal glomerular alterations; Class II with mesangial proliferation only; Class III with either focal (a) or diffuse (b) mesangial proliferation but less than 50% of glomeruli containing crescents or segmental lesions of thrombosis, necrosis, or sclerosis; Class IV with similar mesangial proliferation as IIIa and IIIb but 50% to 75% of glomeruli with crescents; Class V with similar changes and over 75% crescents; and Class VI a “pseudo” membranoproliferative pattern. Although hematuria is common to all groups, and proteinuria of some degree may be found in all, the nephrotic syndrome is present in only 25% of groups I, II, and III. Likewise, groups IIIb, IV, and V tend to have a progressive course toward renal failure.[515] Even by LM deposits may be seen in the mesangial regions and rarely along the capillary walls as well. It is unusual to find the presence of a vasculitis on renal biopsy.

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FIGURE 31-18  Henoch-Schönlein purpura nephritis: An example with global mesangial proliferation and focal infiltrating neutrophils (Hematoxylin-eosin, ×500).

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FIGURE 31-19  Henoch-Schönlein purpura nephritis: There is segmental endocapillary proliferation with an overlying segmental cellular crescent (Periodic acid Schiff, ×475).

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Immunofluorescence and Electron Microscopy

By IF, IgA is the dominant or co-dominant immunoglobulin. Co-deposits of IgG and IgM, C3, and properidine are common. Deposits are typically found in the mesangium, especially involving the paramesangial regions, and may extend into the subendothelial areas ( Fig. 31-20 ). [478] [479] [480] [481] [482] Early classical complement components of C1q and C4 are rarely present. These findings contrast with LN in which IgG usually predominates and C1q is almost always present. The depo-sited IgA is usually IgA1 subclass and may have the J chain indicating its polymeric nature, but secretory piece is not found. [478] [479] [480] [481] [482] [517] [518] Fibrin-related antigens are also commonly present.[515] IgA may be deposited along with C3 and C5 in both involved and uninvolved skin in the small vessels similar to the findings in IgA nephropathy. [519] [520] IgA is also found in vasculitic lesions in the intestinal tract. [494] [495] [496] Similar IgA deposits may also occur in the skin in dermatitis herpetiformis (at the tips of the dermal papillae) and in SLE along with early and late complement components (at the dermal epidermal junction).

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FIGURE 31-20  Henoch-Schönlein purpura nephritis: Immunofluorescence photomicrograph showing intense deposits of IgA distributed throughout the mesangium and also extending into a few peripheral glomerular capillary walls (×600).

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By EM characteristic immune type electron-dense deposits are found predominantly in the mesangial regions, accompanied by increase in mesangial cellularity and matrix. [478] [479] [480] [481] [482] [515] In some capillaries, the deposits extend subendothelially from the adjacent mesangial regions. Occasionally, subepithelial deposits are also present and may resemble the humps of post-streptococcal disease.[515] Immunoelectron microscopy has confirmed the predominance of IgA in association with some C3 and IgG in the deposits.[511] Evidence of coagulation with fibrin and platelets thrombi may be found in capillary lumina. In cases with severe crescent involvement there may be disruption or rupture of the capillary walls.

Pathogenesis

The pathogenesis of HSP remains unknown. It is clearly a systemic immune complex disease with IgA-containing CIC's that are associated with a small vessel vasculitis and capillary damage. [478] [479] [480] [481] The complexes contain polymeric IgA of the IgA1 subclass and late-acting complement components. This composition together with the presence of terminal complement components suggests alternate pathway complement activation. Whether IgA immune complexes trigger this complement activation and the ultimate role of complement participation in the glomerular disease process are unclear. The presence of circulating polymeric IgA complexes, the deposition of IgA in the kidney as well as the skin, intestines and other organs, and recurrence of disease in the allograft all point to the systemic nature of the disease process. [521] [522] [523] Again the precise role of the IgA containing complexes or various IgA containing antibodies in the disease process is unclear because IgA is deposited in some diseases (e.g., celiac disease and chronic liver disease) without major clinical glomerular damage.[523] Complement activation, platelet activation and coagulation, and vasoactive prostanoids, cytokines, and growth factors may all play a role here. Impaired T cell activity has also been implicated in the pathogenesis of HSP.[524] HSP has also been reported in a patient with an IgA monoclonal gammopathy.[525] The relationship of HSP to IgA nephropathy is obscure with some investigators considering the disease separate entities and others describing them as different ends of the same pathogenetic spectrum. [478] [479] [480] [481] Similar renal histologic findings and similar immunologic abnormalities such as circulating IgA levels, IgA fibronectin aggregates, and anti-mesangial cell antibodies suggest a common mechanism of renal injury. [528] [529] IgG autoantibodies against mesangial cells parallel the course of the renal disease. Both IgA nephropathy and HSP have occurred in different members of the same families and in monozygotic twins after adenovirus infection. [489] [527] [530] Infectious agents associated with the occurrence of HSP have included varicella, measles, adenovirus, hepatitis A and/or B, Yersinia, Shigella, mycoplasma, HIV infection, and staphylococci including methicillin resistant organisms, but none has been proven as the etiology of the vasculitic disease. [479] [480] [527] [531] [532] [533] Likewise, HSP has been reported to occur in association with vaccinations, insect bites, cold exposure, and trauma, although an etiologic relation is unproven.[533]

Course, Prognosis, and Treatment

In most patients HSP is a self-limited disease with a good long-term outcome. [478] [479] [480] [481] Patients may have recurrences of the rash, joint symptoms, and gastrointestinal symptoms for months or years, but most patients have a benign short-term and long-term renal course. In general there is a good correlation between the clinical renal presentation and the ultimate prognosis. [478] [479] [480] [481] [485] [492] [502] [516] Patients with focal mesangial involvement and only hematuria and mild proteinuria tend to have an excellent prognosis. In one recent large pediatric study renal survival was 100%.[498] In another series of 150 patients with 50% renal involvement only two patients had residual hematuria and no patient abnormal renal function at 2.5 years.[477] In most series by several years from presentation over half of the patients had no renal abnormalities, less than one fourth sediment abnormalities or proteinuria, only 10% decreased GFR, and less than 10% patients with severe clinical renal involvement at onset had persistent hypertension or declining GFR over a long period of time. A review of over 50 patients observed over 24 years after childhood onset HSP found 7 of 20 with severe HSP at onset with residual renal impairment as adults as opposed to only 2 of 27 patients with mild initial renal disease.[534] In a large series unselected for renal involvement only 2% to 5% of patients will develop ESRD. Long-term renal function may not be as good in adults with HSP. [492] [536] [537] In a series of over 250 adults with HSP observed almost 15 years, 11% developed ESRD, 13% severe renal impairment with a clearance less than 30 ml/min, and 15% moderate renal insufficiency.[491] A poor renal prognosis is predicted by an acute nephritic presentation, older age, and especially by larger amounts of proteinuria and more severe nephrotic syndrome. [536] [538] On renal biopsy, a poor prognosis is predicted by IgA deposits extending from the mesangium out along the peripheral capillary walls, increased interstitial fibrosis, glomerular fibrinoid necrosis, and especially the presence of greater percentage of crescents on renal biopsy. [492] [538] [539] In one large study of over 150 children with HSP those with greater than 50% glomeruli with crescents had at last follow-up over one third of patients with ESRD and another 18% with chronic renal insufficiency.

Repeat biopsies in patients with HSP who have clinically improved show decreased mesangial deposits and hypercellularity. Although complete clinical recovery occurs in 95% of affected children and most adults with HSP over one third of HSP patients who become pregnant have associated hypertension or proteinuria.[501] Mortality in HSP is less than 10% at 10 years.

There is no proven therapy for HSP. [478] [479] [480] [481] Most patients fare well in the short term regardless of lack of any immunosuppressive intervention. Although steroids have been as-sociated with decreased abdominal and rheumatological symptoms they have not been proven to ameliorate the renal lesions in any controlled fashion. [540] [541] [542] [543] [544] One study did find improved long-term renal findings in patients who received a trial of corticosteroids, and pulse intravenous methylprednisolone followed by high-dose corticosteroids has been successful in some studies leading to a low progression to renal failure despite the presence of poor prognostic findings. [540] [544] However, other studies have not found long-term benefit from pulse steroids or oral corticosteroids. Patients with more severe clinical features and especially those with more crescents on biopsy have also been treated with anticoagulants, azathioprine, cyclophosphamide, chlorambucil and other immunosuppressives, and even plasma exchange. [544] [545] [546] [547] [548] [549] [550] [551] Although these reports have shown anecdotal success in reversing the renal progression, controlled trials have not yet shown benefits of using cytotoxic immunosuppressive therapy. [538] [539] IV immune globulin has been used in several patients with the nephrotic syndrome and decreased GFR in an uncontrolled non-randomized but apparently successful fashion.[548]

Clinical renal disease due to HSP has only rarely been reported to recur in the renal allograft. [521] [522] [523] [552] However, as in IgA nephropathy, histologic recurrence is more common than clinical recurrence. Rarely recurrent disease in the allograft occurs along with extrarenal involvement and leads to loss of the allograft. [521] [522] [523] This may be more common in patients who are transplanted either with living related donors or while still active clinically within the first few years of developing ESRD.

ANTI-GLOMERULAR BASEMENT MEMBRANE DISEASE AND GOODPASTURE SYNDROME

Anti-GBM disease is caused by circulating antibodies directed against an antigenic site on type 4 collagen in the GBM. [553] [554] [555] [556] In 1919 Goodpasture described the case of an 18-year-old male who died with an influenza-like illness characterized by pulmonary hemorrhage and a proliferative glomerulonephritis. However, pulmonary hemorrhage can occur in many diseases associated with glomerulonephritis aside from true Goodpasture syndrome including SLE, ANCA positive vasculitides, HSP, MCTD, and with renal vein thrombosis in the nephrotic syndrome. [557] [558] [559] [560] True Goodpasture syndrome should consist of the triad of (1) proliferative, usually crescentic, glomerulonephritis, (2) pulmonary hemorrhage, (3) and the presence of anti-GBM antibodies. [553] [554] [555] [556] In anti-GBM disease the pulmonary hemorrhage may precede, occur concurrently with, or follow the glomerular involvement. [553] [554] [555] [556] [561] [562] Some patients with anti-GBM antibodies and glomerulonephritis and hence “anti-GBM” disease never experience pulmonary involvement and thus do not have true “Goodpasture” syndrome. [555] [556] [561] Documentation of anti-GBM antibody-induced disease may be via renal biopsy, [562] [563] [564] or by establishing the presence of circulating anti-GBM antibodies. Indirect IF although insensitive is specific for the presence of anti-GBM antibodies, and it is positive in more than three fourths of patients.[562] Radioimmunoassay, enzyme-linked immunoabsorbent assay, and immunoblotting for the antibodies are highly specific and sensitive. [555] [556]

Pathogenesis

Anti-GBM autoantibodies react with epitopes on the non-collagenous domain of type IV collagen. [553] [554] [565] [566] [567] [568] This is encoded for by genes in the q35-37 region of chromosome 2. In many cases the primary antigenic site is between amino acids 198 and 237 of the terminal region of the alpha 3 chain of the type IV collagen. [553] [554] [555] This epitope is found in GBM, the basement membrane of alveoli, and several other locations in the body. The structure of the epitope is identical in the glomeruli and the alveolar basement membranes and may require partial denaturation for full exposure to antibody. The alpha 3 chain of type IV collagen is found predominantly in the GBM and alveolar capillary basement membranes, perhaps explaining the limited distribution of disease involvement in Goodpasture syndrome.[554] Eluates of antibody from lung and kidney of patients with Goodpasture syndrome cross react with GBM and the alveolar basement membrane and can produce disease in animal models.[568] Most anti-GBM antibodies belong to the IgG1 subclass and not all fix complement.[569] Antibody reacting with its antigen(s) and perhaps via autoreactive T cells leads to an inflammatory response, the formation of a proliferative glomerulonephritis, breaks in the GBM, and the subsequent extracapillary proliferation or crescent formation. [555] [556] A role for T cells in Goodpasture syndrome is supported by the T cell infiltrates on biopsy, patient T cell proliferation in response to alpha 3 (IV) NC1 domain, the correlation of autoreactive T cells with disease activity, and the role of CD4+CD25+ regulatory cells controlling the autoreactive T cell response. [555] [571] [572] When the anti-GBM antibodies cross react with and cause damage to the basement membrane of pulmonary capillaries the patient will develop pulmonary hemorrhage and hemoptysis. An initial insult to the pulmonary vascular integrity may be required because alveolar capillaries are not normally permeable to passage of anti-GBM antibodies.[572] Exacerbations of disease and especially pulmonary disease with hemoptysis have been related to hydrocarbon fume exposure, cigarette smoking, hair dyes, exposure to metallic dust, D-penicillamine, and cocaine inhalation. [573] [574] [575] [576] [577] [578] [579] [580] Although smokers with anti-GBM disease have a higher incidence of pulmonary hemorrhage, circulating anti-GBM antibody levels are no higher than in patients with disease who are non-smokers. [573] [574]Goodpasture syndrome has occasionally been reported in more than one family member and has rarely occurred in clusters of unrelated patients occasionally at a particular season of the year. [555] [561] Certain HLA types, HLA-DRw15 and DR4 and DRw2 may predispose to the syndrome and perhaps more severe disease. [581] [582] Influenza A2 infection has also been associated with Goodpasture syndrome. Anti-GBM disease can also occur in patients with typical membranous nephropathy and in 5% to 10% of patients receiving allografts for ESRD secondary to Alport hereditary nephritis. [583] [584]

Clinical Features

Glomerulonephritis mediated by anti-GBM antibodies, although reported in hundreds of patients in the literature and well studied immunopathogenetically, is an infrequent pattern of glomerular injury. [553] [554] [555] [556] [561]Although some studies suggested estimates as high as 3% to 5% of all glomerular diseases, most studies reduce this estimate to 1% to 2%. The disease has two peaks of occurrence, the first in younger males and the second in elderly females, but it can occur at any age and in either sex. [553] [554] [555] [556] [561] [574] [585] [586] [587] [588] Anti-GBM disease limited to the kidney may be more common in older patients. Goodpasture syndrome is less common in blacks perhaps due to less frequent occurrence of certain predisposing HLA antigens in this population. [553] [554] [555] [556] [561] [574] [585] [586] [587] [588] An upper respiratory infection precedes the onset of disease in 20% to 60% of cases.[553] [554] [555] [556] [574]

The most common extrarenal findings are by far related to pulmonary involvement. Patients may have cough, dyspnea, and shortness of breath, and hemoptysis may vary from trivial amounts to life-threatening massive amounts associated with exsanguination and suffocation. [555] [556] [557] [574] [586] In almost three fourths of cases pulmonary hemorrhage precedes or is coincident with the glomerular disease. [553] [554] [555] [556] Although some patients have constitutional symptoms with weakness, fatigue, weight loss, chills, and fevers, this is less prominent than in systemic vasculitides; others may have skin rash, hepatosplenomegaly, nausea and vomiting, and arthralgias or arthritic complaints at onset.[554]

The clinical renal presentation may be with an acute nephritic picture with hypertension, edema, hematuria and active urinary sediment, and reduced renal function; however, only 20% of patients are hypertensive at onset. [553] [554] [555] [556] [586] Renal function is usually already reduced at presentation and may deteriorate from normal to dialysis requiring levels in a matter of days to weeks. [553] [554] [555] [556] [586] However, one recent study found over one third of patients to have a normal GFR.[587] There is a good correlation between the serum creatinine level and the percentage of glomeruli involved by severe crescent formation.

Laboratory Findings

Laboratory evaluation in patients with Goodpasture syndrome typically shows active urinary sediment with red cells and red cell casts. [555] [556] [586] Proteinuria although commonly present is usually not in the nephrotic range perhaps secondary to the reduction in GFR commonly present. Serologic tests such as ASLO, ANA, serum complement levels, rheumatoid factor, cryoglobulins, and CIC's are all either negative or normal. [555] [556] [586] [587] [588]Circulating anti-GBM antibodies are present in over 90% of patients although the antibody titer does not always correlate well with the manifestations or course of either the pulmonary or renal disease. [553] [555] [556] [589] Most patients have a decrease in serum antibody titer with time. From 10% to 38% of patients will have both positive anti-GBM antibodies and ANCA tests usually directed against myeloperoxidase but occasionally against serine proteinase. [555] [587] [590] [591] [592] [593] The anti-GBM antibodies in patients who are ANCA positive have the same antigenic specificity as in patients who are ANCA negative.[592] The ANCA titers are also similar in patients with and without coexistent anti-GBM antibodies. Some studies suggest that the course of patients double positive for anti-GBM antibodies and ANCA parallels that of patients with anti-GBM antibody disease with a much poorer renal prognosis for patients with severe renal failure than ANCA-positive patients.[593] Some patients have a clinical systemic vasculitis with purpura and arthralgias and arthritis—findings rarely seen in isolated Goodpasture syndrome without coexistent ANCA. [587] [590] [591] In Goodpasture syndrome a microcytic, hypochromic anemia is common even without overt pulmonary hemorrhage. Other patients may have a leukocytosis. Iron deposition in the lungs may be documented by either Fe59 scanning or by pulmonary lavage or expectorated sputum showing hemosiderin laden macrophages. In patients with pulmonary involvement chest radiograph is abnormal in over 75% and typically shows infiltrates corresponding to areas of pulmonary hemorrhage, but it may also demonstrate atelectasis, pulmonary edema, and areas of coexistent pneumonia. [553] [554] [555] [556] Hypoxemia and an increased arterial alveolar gradient is present in severe cases.

Pathology

By LM patients with mild clinical involvement often have a focal, segmental proliferative glomerulonephritis. [553] [555] [556] [589] This is typically associated with areas of segmental necrosis and overlying small crescents.[588]However, the most common biopsy picture is diffuse crescentic glomerulonephritis involving over 50% of glomeruli, with exuberant circumferential crescents ( Fig. 31-21 ). [555] [595] The underlying tuft is compressed but displays focal necrotizing features. Disruption and destruction of portions of the GBM and the basement membrane of Bowman capsule may be seen on silver stain.[594] Early crescents are formed by proliferating epithelial cells and infiltrating T lymphocytes, monocytes, and polymorphonuclear leukocytes, whereas older ones are composed predominantly of spindled fibroblast-like cells, with few if any infiltrating leukocytes. [595] [596] An associated tubulointerstitial nephritis with inflammatory cell infiltration and edema is commonly found. Multinucleated giant cells may be present in the crescents or tubulointerstitial regions. Some patients have necrotizing vasculitis of small arteries and arterioles. This is particularly common in those with associated ANCA seropositivity. In biopsies taken later in the course of the glomerulonephritis there is progressive global and segmental sclerosis and interstitial fibrosis. Pulmonary histology reveals intra-alveolar hemorrhage with widening and disruption of the alveolar septa and hemosiderin laden macrophages. [553] [554] [555] [556]

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FIGURE 31-21  Goodpasture disease: There is diffuse crescentic glomerulonephritis with large circumferential cellular crescents and severe compression of the glomerular tuft (Periodic acid Schiff, ×80).

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The IF findings define the disease process in Goodpasture syndrome and differentiate it from pauci-immune and immune complex-mediated forms of crescentic glomerulonephritis that may have similar light microscopic features. The diagnostic finding is an intense and diffuse linear staining for IgG, especially IgG1 and IgG4, involving GBM's ( Fig. 31-22 ). [570] [597] [598] Rarely have IgM or IgA been identified in a linear distribution.[595] C3 deposits are found in a more finely granular GBM distribution in many patients. C1q is typically absent. Linear IF staining with IgG may also be found along the tubular basement membranes in some but not all cases. Fibrin-related antigens are commonly present within the crescents and segmental necrotizing lesions. In the lungs, similar linear deposition of IgG occurs along the alveolar capillary walls.[554]

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FIGURE 31-22  Goodpasture disease: Immunofluorescence photomicrograph showing linear glomerular basement membrane deposits of IgG. Some of the glomerular basement membranes are discontinuous, indicating sites of rupture (×800).

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Electron microscopic analysis of glomeruli in patients with Goodpasture syndrome typically does not reveal any immune type electron-dense deposits. Some rare reports of such deposits may represent partially degraded products of coagulation.[597] There may be widening of the subendothelial space by a semi lucent zone containing fibrin-like material, and gaps in the GBM and in Bowman capsule are commonly present.[595] Rare patients have co-existent membranous glomerulopathy with typical findings by light microscopy, IF, and EM.[582] EM of pulmonary tissue may demonstrate hyperplasia of pneumocytes and alveolar basement membrane thickening.

Course, Treatment, and Prognosis

The course of untreated Goodpasture syndrome is one of progressive renal dysfunction leading to uremia. [553] [554] [555] [556] [586] Early studies reported almost all patients with the disease dying from either pulmonary hemorrhage or progressive renal failure. Recent studies have shown a marked decrease in mortality to less than 10% probably related to improved supportive care and more rapid diagnosis and treatment. [555] [598] [599] Some patients have one or more relapses of the pulmonary disease. [600] [601] Spontaneous remission of the renal involvement is rare although with therapy many patients will have a stable course and some dramatic improvement of their renal function. [553] [554] [555] [556] [598] [599] If treatment is started early in the course of the disease patients may regain considerable kidney function. The plasma creatinine correlates fairly well with the degree of crescentic involvement of the glomeruli, and if the plasma creatinine is markedly elevated and the patient requires dialysis, most go on to develop ESRD. [555] [556] [598] A recent study from China in over 100 patients with anti-GBM antibodies noted a poorer prognosis in patients with creatinines over 600 mmol/L, oligo-anuria at presentation, over 85% crescents on biopsy, and renal involvement before pulmonary hemorrhage.

Anti-GBM disease is an uncommon disease with no large randomized studies defining the benefits of any given therapy. Pulmonary hemorrhage and clinical lung involvement has abated with high-dose oral or intravenous corticosteroid therapy. [553] [554] [555] [556] [599] Frequently with resolution of pulmonary disease, patients are left with few clinical sequelae or respiratory symptoms. Renal involvement appears less responsive to corticosteroid alone. Plasmapheresis may have a dramatic effect in reversing pulmonary hemorrhage and renal disease when used early in the course in combination with immunosuppressants. [555] [598] [602] [603] [604] Plasmapheresis removes the circulating anti-GBM antibodies whereas immunosuppressive therapy prevents new antibody formation and controls the ongoing inflammatory response. One review of uncontrolled trials found that 40% of patients had stabilized or improved renal function with plasmapheresis.[603] Patients with severe renal failure who are already on dialysis or who have serum creatinines greater than 8 mg/dl are less likely to respond to therapy, but some have recovered. [555] [598] [603] [604] One recent series of patients who were positive for both anti-GBM antibodies and ANCA behaved similar to those with anti-GBM antibodies alone with a 1-year renal survival of 73% in those with a plasma creatinine less than 500 mmoles/L and 0% in those on dialysis.[593] In other series dialysis-dependent patients who are both anti-GBM antibody and ANCA positive are still more likely to recover than patients who are dialysis dependent with only anti-GBM antibody positivity. [587] [590] [591] [592] One therapy for Goodpasture syndrome includes a combination of prednisone (1 mg/kg/day) or IV pulse methylprednisolone (30 mg/kg/day or 1000 mg/day) for several days followed by high-dose oral therapy along with plasmapheresis and cyclophosphamide (2 mg/kg/day). Although daily plasmapheresis is usually maintained for weeks, its frequency can be determined by the rapidity of clinical response. Exacerbations of disease may occur with intercurrent infections.[600] Immunosuppressive therapy is usually continued for 6 to 12 months with a tapering regimen to allow spontaneous cessation of autoantibody production. Some patients with early disappearance of circulating anti-GBM antibodies may respond to shorter therapy or tolerate change to less toxic immunosuppressives such as azathioprine. [555] [556] [586] There is limited data on other immunosuppressive regimens such as cyclosporine, and experimental protocols such as using blockade of CD28-B7 T cell costimulatory pathways in Goodpasture syndrome. [605] [606] Immunoadsorption has also been used to remove the anti-GBM antibodies in Goodpasture syndrome.[606] Even in patients with initial improvement of renal function, some with severe crescentic glomerular involvement will progress to renal failure over time perhaps related to non-immunologic progression of disease. The incidence of ESRD in patients with significant glomerular involvement is over 50% and the renal outcome is usually progressively downhill unless vigorous prompt therapy is instituted.

Anti-GBM mediated renal disease may recur in the renal allograft. [608] [609] [610] [611] As with a number of other forms of glomerulonephritis evidence of histologic recurrence (i.e., linear staining for IgG along GBM's) is far higher than clinical involvement and may be as high as 50%. The low recurrence rate reported in transplants recently probably reflects a combination of waiting sufficient time to document the absence of anti-GBM antibodies, the use of immunosuppressives and plasmapheresis to remove current antibody, and the “one-shot” nature of the disease. [612] [613] Patients with recurrence typically have hematuria and proteinuria. Graft loss secondary to recurrent disease is rare. Patients should not be transplanted during the acute phase of their illness when autoantibody levels are high, and prophylactic pretransplant immunosuppression has been recommended for those receiving allografts from living related donors. Although patients with resolving pulmonary disease may have residual diminished gas exchange, most pulmonary function tests return to normal and do not limit the renal transplant process.[613]

SJöGREN SYNDROME

Sjögren syndrome is characterized by a chronic inflammatory cell infiltration of the exocrine salivary and lacrimal glands and is associated with the “sicca complex” of xerostomia and xerophthalmia. [615] [616] [617] [618] Although this may occur as isolated exocrine gland involvement, patients may have involvement by a systemic inflammatory disease of the kidneys, lungs, esophagus, thyroid, stomach, and pancreas. [615] [616] [617] [618] Other patients have manifestations of a collagen vascular disease most commonly rheumatoid arthritis, and less frequently SLE, scleroderma, polymyositis, or MCTD. Still other patients will have different immunologic disorders such as chronic active hepatitis, primary biliary cirrhosis, Crohn disease, and fibrosing alveolitis or develop lymphoma or Waldenström macroglobulinemia. Serologic abnormalities are common in Sjögren syndrome and include hypergammaglobulinemia, rheumatoid factor, cryoglobulins, a homogeneous or speckled pattern ANA, anti-Ro/SSA and anti-La/SSB, but serum complement levels are generally normal unless the patient has associated SLE. [615] [616] [617] [618]

The major clinical renal manifestations of patients with Sjögren syndrome usually relate to tubulointerstitial involvement of the kidneys with tubular defects such as a distal RTA, impaired concentrating ability, hypercalciuria, and less frequently proximal tubular defects. [615] [616] [617] [618] [619] [620] [621] [622] Most patients do not have clinical evidence of glomerular disease and have relatively negative urinalysis with only mild elevations of the serum creatinine. In one recent analysis of over 470 patients with primary Sjögren syndrome observed for a mean of 10 years only 20 patients (4%) developed overt renal disease.[618] Ten patients had interstitial nephritis on biopsy, eight patients glomerular lesions, and two both lesions. In those infrequent patients with glomerular lesions, hematuria, proteinuria, and renal insufficiency are found. Some patients will develop the full nephrotic syndrome whereas others may develop renal vasculitis with prominent hypertension and renal insufficiency.

In most cases the renal pathology shows prominent tubulointerstitial nephritis with sparing of the glomeruli. [615] [616] [617] [618] [619] [622] There is a chronic active interstitial inflammation by a predominantly lymphocytic infiltrate occasionally with granuloma formation and with variable interstitial fibrosis and tubular atrophy. By IF, there may be no detectable deposits. However, in some cases tubular basement membrane deposits of IgG and C3 have been described. A nonspecific glomerulosclerosis with mesangial sclerosis, GBM thickening and wrinkling is found in those with chronic and severe tubulointerstitial damage. Infrequently patients will have an immune complex mediated glomerular involvement. [616] [617] [622] [623] [624] [625] [626] [627] [628] In one recent series of biopsied patients with primary Sjögren syndrome, patients had either mesangial proliferative glomerulonephritis or membranoproliferative glomerulonephritis, usually associated with cryoglobulins, on biopsy.[618] In other series patients may have associated features of SLE. As in SLE, the spectrum of glomerular involvement ranges from mesangial proliferative[625] to focal proliferative,[621] diffuse proliferative, [626] [627] and membranous nephropathy. A membranoproliferative pattern of proliferative glomerulonephritis has been reported in patients with associated cryoglobulinemia. [625] [628]By IF and EM, immune deposits have been localized in the various patterns to the mesangial region or the subendothelial or subepithelial aspect of the GBM as in SLE. Some patients with Sjögren syndrome have a necrotizing arteritis of the kidney occasionally with extra renal involvement.[628] Most patients with severe tubulointerstitial disease and Sjögren syndrome respond to treatment with corticosteroids. [616] [630] Patients with immune complex glomerulonephritis and Sjögren syndrome are generally treated in a similar fashion to those with SLE, and those with vasculitis generally receive cytotoxic therapy similar to other necrotizing vasculitides.[615]

SARCOIDOSIS

Most manifestations of sarcoidosis are not related to the kidney.[630] The most common renal findings are interstitial nephritis (typically granulomatous), nephrolithiasis, and tubular functional abnormalities. [632] [633] Glomerular disease is infrequent and may be the coincidental expression of two unrelated disease processes in one individual rather than secondary to the sarcoidosis itself. A variety of glomerular lesions have been described in patients with sarcoidosis including minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA nephropathy, membranoproliferative glomerulonephritis, and proliferative and crescentic glomerulonephritis. [632] [633] [634] [635] [636] [637] [638] [639] [640] [641] [642] [643] ANCA-positive crescentic glomerulonephritis has also been reported.[643] The IF and EM features conform to the various histologic patterns. Some patients have granulomatous renal interstitial nephritis in addition to the glomerular lesions, whereas others have only extrarenal histologic documentation of the sarcoidosis. The clinical presentation of glomerular disease in sarcoidosis is usually that of proteinuria, active urinary sediment at times, and most commonly the nephrotic syndrome. Patients have been treated with various forms of immunosuppres-sion including steroids depending on their glomerular lesions. [634] [635] [636] [637] [638] [639] [640] [641] [642] [643] [644]

AMYLOIDOSIS

Amyloidosis comprises a diverse group of systemic and local diseases characterized by the extracellular deposition of fibrils in various organs. [645] [646] [647] Although the precursor proteins vary, all share an antiparallel beta pleated sheet configuration on X-ray diffraction leading to their amyloidogenic properties and unique staining characteristics. [645] [646] [647] All amyloid fibrils bind Congo red (leading to characteristic apple green birefringence under polarized light) and thioflavin T, and have a characteristic ultrastructural appearance. All types of amyloid contain a 25Kd glycoprotein, serum amyloid P component (SAP), a member of the pentraxin family that includes C-reactive protein. Amyloid deposits may also contain restricted subsets of heparin and dermatan sulfated glycosaminoglycans (GAGS) and proteoglycans non covalently linked to the amyloid fibrils.[647] Amyloid fibrils may be composed of many different proteins, but only some proteins produce deposition in the kidney. In AL amyloidosis, the deposited fibrils are derived from the variable portion of immunoglobulin light chains produced by a clonal population of plasma cells. [645] [646] [647] AA amyloid is due to the deposition of serum amyloid A protein in chronic inflammatory states.[644] Forms of hereditary amyloid involving the kidney include mutations in transthyretin, fibrinogen A chain, apolipoprotein A1, lysozyme, apolipoprotein AII, cyclostatin C, and gelosin. [647] [649] [650] [651] These include two predominantly neuropathic forms and forms related to deposition of a fibrinogen fragment or a fragment of an apolipoprotein variant.[650]

The pathogenesis of amyloidosis remains unclear. [652] [653] [654] [655] [656] Because diverse proteins may produce amyloid, co-factors such as amyloid P component may have an important role in the pathogenesis of tissue deposition. These may act by promoting fibrillogenesis, stabilization of the fibrils, binding to matrix proteins, or affect the metabolism and proteolysis of formed fibrils. It is also possible that cofactors are deposited after fibrillogenesis. [647] [651] [652] [653] [654] [655] [656] It is unclear what factors allow some proteins to aggregate into amyloid fibrils. Amyloid fibrils generally resist biodegradation and accumulate in the tissues resulting in organ dysfunction. However, amyloid deposits have been shown to exist in a dynamic state and have been shown to regress by radiolabeled SAP scintography.[656] Patients with secondary amyloidosis have levels of circulating SAA protein no greater than those patients with inflammatory diseases who do not have amyloid deposition. Therefore, some additional unknown stimulus is required for amyloid fibrils to form and precipitate. In AL amyloid biochemical characteristics of the light chain, such as an aberrant amino acid composition at certain sites, appear important in determining amyloid formation. [655] [656] This may account for the reproducibility of a given form of renal disease (cast nephropathy versus amyloid) in animal models infused with monoclonal light chains from affected patients.[657] Certain light chains may also form high molecular weight aggregates in vitro.[658] Macrophage dependent generation of pre amyloid fragments with chemical properties allowing aggregation may also play a role.[658] Amyloid P component may prevent degradation of amyloid fibrils once formed. [660] [661]

AL and AA Amyloidosis

In AL amyloidosis, fibrils are composed of the N terminal amino acid residues of the variable region of an immunoglobulin light chain. Lambda light chains predominate over kappa in AL amyloidosis, and there is an increased incidence of monoclonal lambda type VI.[661] Although the diagnosis of AL amyloidosis may be suspected on clinical grounds, confirmation requires biopsy documentation. Organ involvement is quite variable, and the absence of other organ involvement does not exclude amyloidosis as a cause of major renal disease. [645] [646] The kidneys are the most common major organ involved by AL amyloid and most patients will eventually have renal amyloid on autopsy.[662] In patients over the age of 60 years old as many as 10% to 20% of patients with presumed idiopathic nephrotic syndrome will have amyloidosis on renal biopsy.[663] Multiple myeloma occurs in up to 20% of primary amyloidosis cases. Amyloidosis should be suspected in all patients with circulating serum monoclonal M proteins, and approximately 90% of primary amyloid patients will have a paraprotein spike in the serum or urine by immunofixation.

The incidence of AL amyloid is about 8 per million annually but varies greatly in different locations.[664] Most patients with AL amyloidosis are over 50 years old (median age 59-63) and less than 1% are under 40 years old. Men are affected twice as often as women. [645] [646] [663] Presenting symptoms include weight loss, fatigue, light-headedness, shortness of breath, peripheral edema, pain due to peripheral neuropathy, and purpura. Patients may have hepatosplenomegaly, macroglossia, or rarely enlarged lymph nodes. Multisystem organ involvement is typical with most commonly affected organs being the kidney (50%), heart (40%), and peripheral nerves (up to 25%). [645] [646] [663]

Amyloidosis due to the deposition of AA protein occurs in chronic inflammatory diseases. AA amyloid is composed of the amino terminal end of the acute phase reactant serum amyloid A protein (SAA). [645] [646] [647] [648] [654] [666] SAA is produced in the liver and circulates in association with high density lipoprotein (HDL). AA amyloid is commonly found in rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, quadriplegics with chronic urinary infections and decubitus ulcers, chronic heroin addicts who inject drugs subcutaneously, bronchiectasis, and occasionally in poorly treated osteomyelitis. [645] [654] [667] [668] [669] [670] In an autopsy study of 150 addicts 14% of subcutaneous and 26% of those with chronic suppurative infections had renal amyloidosis.[669] This form of amyloid typically occurs in older addicts with a long history of substance abuse who have exhausted sites of intravenous access and resorted to skin popping.

The diagnosis of amyloid is usually established by tissue biopsy of an affected organ. [645] [646] [647] [648] [649] [671] Liver and kidney biopsy are positive in as many as 90% of clinically affected cases. A diagnosis may be made with less invasive techniques with fat pad aspirate (60%–90%), rectal biopsy (50%–80%), bone marrow aspirate (30%–50%), gingival biopsy (60%), or dermal biopsy (50%) in selected series. [671] [672] [673] [674] Serum amyloid P whole body scintigraphy, following injection of radiolabeled SAP, may allow the noninvasive diagnosis of amyloidosis as well as allowing quantification of the extent of organ system involvement and non-invasive assessment of the therapeutic response to treatment.[674] This test may be positive even when tissue biopsy has been negative and may be more accurate in AA than in AL amyloidosis. In AL amyloidosis detection of an abnormal ratio of free kappa to lambda light chains in the serum is a new technique to detect plasma cell dyscrasias, which has a higher sensitivity than either serum or urinary electrophoretic techniques.[675] This technique also allows assessment of response to therapy by following the level of abnormal free light chain in the serum.[676] Patients with hereditary amyloidosis due to deposition of abnormal transthyretin, apolipoproteins, lysozyme, and other protein may present in a fashion similar to AL amyloid. In one series 10% of 350 cases of hereditary amyloidosis were misdiagnosed as having AL amyloid. [651] [678] Hereditary amyloidosis may present at any age from the second to eighth decade. Although the course is often more prolonged and benign than that of AL amyloid its presentation can be identical. Establishing the correct diagnosis is crucial because the management of hereditary amyloid may include liver transplantation rather than chemotherapy and stem cell transplantation as in AL amyloid.

Clinical manifestations of renal disease depend on the location and extent of amyloid deposition. Renal involvement predominates in AL amyloidosis with one third to one half of patients having renal manifestations at presentation.[645] [646] [647] Most patients have proteinuria, approximately 25% have the nephrotic syndrome at diagnosis, and others present with varying degrees of azotemia. [645] [646] [647] [663] Over time as many as 40% will develop the nephrotic syndrome whereas others have lesser degrees of proteinuria or azotemia. Urinalysis is typically bland but micro hematuria and cellular casts have been reported. Proteinuria is typically nonselective and almost 90% of patients with greater than 1 gram/day urinary protein will have a monoclonal protein in the urine. Hypercholesterolemia is less common than in other forms of the nephrotic syndrome. The amount of glomerular amyloid deposition does not correlate well with the degree of renal dysfunction. [645] [646] Despite the literature suggestion of enlarged kidneys in AL amyloid, by ultrasonography most patients have normal-sized kidneys.[644] Hypertension is found in from 20% to 50% of patients, but many will have orthostatic hypotension either due to peripheral neuropathy, autonomic neuropathy, and/or the nephrotic syndrome. Patients with predominantly vascular involvement may have little proteinuria but renal insufficiency due to decreased renal blood flow. Infrequently patients will have predominantly tubular deposition of amyloid with tubular defects such as distal RTA and nephrogenic diabetes insipidus. [645] [646] [647] [663]

Pathology

In patients with clinical renal disease, the sensitivity of renal biopsy with adequate tissue sampling approaches 100%. [646] [679] [680] [681] [682] Renal biopsy is useful to distinguish primary AL amyloid from AA amyloid, and to rule out involvement by other renal disease in patients with known amyloidosis of other organ systems.

By LM there is a glomerular deposition of amorphous hyaline material that usually begins in the mesangium and extends into the peripheral capillary walls ( Fig. 31-23 ). This material is eosinophilic, weakly PAS positive, and non argyrophilic. In trichrome-stained sections it may appear lavender or grey-blue. Affected glomeruli appear hypocellular and may have a nodular aspect. In the peripheral GBM, amyloid deposits form spicular hair-like projections that resemble the spikes of membranous glomerulopathy ( Fig. 31-24 ). Congo red stain gives an orange staining reaction and the diagnostic apple green birefringence under polarized light ( Fig. 31-25 ). Amyloid deposits stain metachromatically with crystal or methyl violet and fluoresce under ultraviolet light following thioflavin T staining. Amyloid deposition may be confined to the glomeruli or involve other renal components including tubular basement membranes, interstitium, and blood vessels. IF in AL amyloidosis gives strong staining with antisera to the pathogenic light chain, usually lambda ( Fig. 31-26 ). In AA amyloidosis, immunostaining for immunoglobulins and complement components is generally negative, whereas for SAA protein there is strong reactivity by IF or immunoperoxidase staining ( Fig. 31-27 ). Hereditary amyloidoses should stain neither selectively with a single light chain nor for AA protein. Under EM, typical non branching 8nm to 12nm wide fibrils are randomly distributed in the mesangium and along the GBM in the subepithelial, intramembranous, and subendothelial locations ( Fig. 31-28 ). Mild cases may have deposition limited to the mesangium. More severe cases usually have more extensive deposition in the peripheral capillary walls. By EM glomerular capillary wall deposits may form characteristic spike-like projections along the subepithelial aspect of the glomerular capillary wall.

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FIGURE 31-23  Amyloidosis: The glomerular tuft contains segmental deposits of amorphous eosinophilic hyaline material involving the vascular pole and some mesangial regions (Hematoxylin-eosin, ×375).

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FIGURE 31-24  Amyloidosis: The amyloid deposits expand the mesangium and form focal spicular projections through the glomerular capillary walls, resembling spikes (arrows) (Jones methenamine silver, ×800).

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FIGURE 31-25  Amyloidosis: Congo red stain of a glomerulus that is largely replaced by amyloid demonstrates the characteristic birefringence under polarized light (×450).

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FIGURE 31-26  Amyloidosis: Immunofluorescence photomicrograph showing glomerular staining for lambda light chain in the distribution of the glomerular amyloid deposits in a patient with AL amyloidosis and plasma cell dyscrasia (×600).

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FIGURE 31-27  Amyloidosis: Immunoperoxidase staining for SAA protein outlines the glomeruli and arteries of a patient with secondary AA amyloidosis (×125).

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FIGURE 31-28  Amyloidosis: Electron micrograph showing extensive infiltration of the glomerular basement membrane by 10-nm fibrils that project toward the urinary space (×8000).

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Course, Prognosis, and Treatment

The prognosis of patients with AL amyloidosis in the past has been poor with some series having a median survival of less than 2 years. [645] [646] The baseline serum creatinine at diagnosis and the degree of proteinuria are predictive of the progression to ESRD. The median time from diagnosis to onset dialysis is 14 months, and from dialysis to death only 8 months in some series. [646] [663] Recent data suggests improved survival in at least some amyloid patients. Factors associated with decreased patient survival include evidence of cardiac involvement, lambda versus kappa proteinuria, renal dysfunction with an elevated serum creatinine, and interstitial fibrosis on renal biopsy. [663] [683] Cardiac involvement with associated heart failure and arrhythmias is the primary cause of death in amyloidosis followed by renal disease. [684] [685]

The optimal treatment for AL amyloid differs dependent on age, organ systems involved, and overall health of the patient. [645] [646] [647] [648] A number of treatment strategies focus on methods to decrease the production of monoclonal light chains akin to myeloma therapy using chemotherapeutic drugs such as melphalan and prednisone, cyclophosphamide, or VAD therapy. In some patients there has been evidence of resolution of proteinuria, stabilization of renal function, improvement of symptoms, and occasionally evidence of decreased organ involvement such as decreased hepatosplenomegaly.[685] In a review of 153 AL amyloid patients treated with melphalan and prednisone only 18% of the patients had a regression of organ manifestations of amyloidosis with responders having a 5-year survival of 78% versus only 7% in the non-responders.[686] Patients with renal amyloidosis fared best with 25% having a 50% resolution in nephrotic range proteinuria and stable or improved GFR. Colchicine was used to manage AL amyloidosis in the past.[687] Most trials have demonstrated a clear benefit of chemotherapeutic options over colchicine, and even the addition of colchicine to these regimens provided only a small benefit. [689] [690] A study compared therapy with melphalan, prednisone, and colchicine therapy to colchicine alone in 100 consecutive patients seen between 1987 and 1992.[688] The group receiving combined chemotherapy plus colchicine had less long-term mortality than the colchicine group.

Another study of 220 AL amyloid patients randomized to colchicine, melphalan plus prednisone, or all three drugs found a median survival of 8.5 months for the colchicine group as opposed to 17 to 18 months for the other groups.[689] Eighteen percent of the chemotherapy groups had a 50% decrease in proteinuria as opposed to 6% of the colchicine group. However, renal failure developed in a similar percentage, 14% to 21% of each of the three groups. Thus, current therapy focuses on chemotherapy. A recent prospective trial in over 100 patients compared an intensive regimen with five agents (vincristine, BCNU, melphalan, cyclophosphamide, and prednisone) to melphalan and prednisone alone. This showed no survival advantage for the intensive treatment group over the standard therapy.[690]

Other therapies for primary amyloid used experimentally to treat small numbers of patients include dimethyl sulfoxide, 4′-iodo-4′-deoxydoxorubicin, fludarabine, vitamin E, and interferon alpha-2. [645] [692] [693] [694] [695] None has proven efficacy at this time. High-dose dexamethasone therapy has been suggested to have benefits in isolated patients, but in a trial of 25 patients it yielded only a 12% response rate and a 14-month mean survival time.[695] Recent reports using high-dose melphalan followed by allogeneic bone marrow transplant or stem cell transplant have given promising results. [697] [698] [699] [700] [701]

The use of high-dose chemotherapy followed by peripheral blood stem cell transplantation has led to resolution of the nephrotic syndrome and biopsy proven improvement of amyloid organ involvement in isolated cases. [698] [699] [700] [701] [702] Although there was a high mortality in early reports (20% in the first 3 months), 60% of the survivors had a complete hematologic response and at 2 years over two thirds of the patients were alive.[697] Of those patients with renal involvement all survived and two thirds had a 50% decrease in proteinuria without a worsening of GFR. One retrospective study analyzed 65 AL amyloid patients with over 1 g daily proteinuria treated with dose-intensive ablative chemotherapy followed by autologous blood stem-cell transplantation.[702] Three fourths of the patients survived the first year and among those a good renal response was found in 36% at 1 year and 52% at 2 years. Patients with a complete hematologic response were more likely to have a good renal response and patient survival was superior in patients with less than three organ systems involved, younger patients, and those able to tolerate higher doses of the ablative therapy. Toxicities included mucositis, edema, elevated liver function tests, pulmonary edema, gastrointestinal bleeding, and in 23% transient acute renal failure. Thus, for younger patients with predominantly renal involvement stem cell transplantation is currently a reasonable alternative therapy for AL amyloid. Subsequent studies from other centers have supported stem cell transplantation as a beneficial therapy for some patients with AL amyloid.[703] Even patients with ESRD due to amyloidosis may undergo this form of therapy with results no different from non-ESRD patients with AL amyloidosis.[704]

Regardless of whether chemotherapy or marrow transplant is used, the treatment of amyloid patients with nephrotic syndrome involves supportive care. This may include judicious use of diuretics and salt restriction in those with edema, treatment of orthostatic hypotension with compression stockings, fludrocortisone, and in some midodrine, an oral alpha adrenergic agonist. [645] [706]

The management of AA amyloid focuses on the management of the underlying inflammatory disease process. This has included surgical debridement of inflammatory tissue, antibiotic therapy of infectious processes, and anti-inflammatory medications and immunosuppressive agents in rheumatoid arthritis and inflammatory bowel disease. Therapy may lead to stabilization of renal function, reduction in proteinuria, and partial resolution of amyloid deposits. Prognosis may be good if the underlying disease can be controlled and there is not already extensive amyloid deposition. Alkylating agents have been used to control AA amyloidosis secondary to rheumatologic diseases in a number of studies with evidence of increased GFR and decreased proteinuria, with prolonged renal survival. [707] [708] Similar results have been achieved with other immunosuppressive agents with improvement in proteinuria, prolonged survival compared with controls, and in several cases regression of amyloid deposits on repeat biopsy.[644]

In familial Mediterranean fever, an autosomal recessive disease primarily found in Sephardic Jews, Turks, Armenians, and Arabs, there are recurrent attacks of fever and serositis associated with the development of AA amyloidosis in up to 90% of untreated patients.[708] Colchicine has long been used successfully to prevent the febrile attacks and was effective in preventing the development of proteinuria and stabilizing proteinuria in other patients.[708]However, renal function did deteriorate in all patients with the nephrotic syndrome at presentation. A retrospective analysis of FMF patients with milder renal clinical involvement and at least 5 years' follow-up concluded that high doses of colchicine were more effective in preventing renal dysfunction, and that patients with lower levels of serum creatinine at presentation responded better to therapy.[708] Once the serum creatinine level was elevated, however, increasing the dose of colchicine did not seem to prevent progression to ESRD. Secondary amyloidosis seen in drug abusers with suppurative skin lesions secondary to subcutaneous injection of drugs has occasionally responded to colchicine therapy, although most investigators feel the key to improvement appears to be management of the underlying infections and cessation of skin popping. [670] [710]

A recent multicenter randomized controlled trial compared a GAG mimetic, used to inhibit the binding between heparin sulfate, perlecan, and the amyloid fibril protein and thus block fibrillogenesis, to placebo in 183 patients with AA amyloid. Although the specified end point of the study was not achieved, the GAG mimetic did reduce the risk of doubling the serum creatinine by 54% and halved the risk of a 50% decrease in creatinine clearance.[710] This study clearly shows the need for newer therapies for amyloidosis and the value of controlled trials in studying these agents.[710] Several promising experimental therapies for managing amyloid include using anti-amyloid antibodies, and the use of an inhibitor of the binding of amyloid P component to amyloid fibrils.[647]

End-Stage Renal Disease in Amyloidosis

In most series the median survival of amyloid patients with ESRD is less than 1 year with the primary cause of death being complications of cardiac amyloid. [712] [713] However, for patients who survive the first month of ESRD replacement therapy the survival rate is over 50% at 2 years and 30% at 5 years.[712] This is still 20% lower than an age-matched general ESRD population. There appears to be no survival advantage to the use of a specific dialytic technique such as peritoneal dialysis or hemodialysis.[712] Experience with renal transplantation is largely in patients with AA amyloid and is limited in AL amyloid. [714] [715] One series on transplantation in amyloid included 45 patients (with 42 with AA amyloid) and found an overall low patient survival, particularly in the early posttransplant period in older patients due to infectious and cardiovascular complications.[713] Graft survival, however, was not decreased despite rates of recurrence of amyloidosis in the allograft as high as 20% to 33%. [714] [715] [716]

Fibrillary Glomerulonephritis and Immunotactoid Glomerulonephritis

Patients with glomerular lesions may have fibrillar deposi-tion differing in size from that of amyloid and without the typical staining properties of amyloid. [645] [717] [718] [719] [720] [721] In the past similar patients were reported as having Congo red-negative amyloid, amyloid-like glomerulopathy, and non-amyloidotic fibrillary glomerulopathy. Many investigators have subdivided these patients into two major groups depending on clinical associations and fibril size. In fibrillary GN the fibrils are approximately 16nm to 24nm (mean 20nm) in diameter and in immunotactoid GN there are larger microtubules of 30nm to 50nm in diameter. It has been suggested that the fibrils represent a slow-acting cryoprecipitate of polyclonal or monoclonal immunoglobulin.[721] A third rare form of fibrillary renal disease is fibronectin glomerulopathy in which the glomeruli are involved with massive deposition of fibronectin.[723] [724] [725]

Although some would choose to classify both fibrillary GN and immunotactoid GN as a single disease entity, most clinicians and nephropathologists would divide them into distinct disorders. [645] [717] [718] [719] [720] [721] Almost 90% of cases have the smaller 20nM fibrils of fibrillary glomerulopathy. [717] [718] [719] [720] [721] Fibrillary GN occurs mostly in adults, in both sexes, in all age groups, and most commonly in whites. It is usually an isolated renal entity. Patients with immunotactoid GN tend to be older, may have a less rapidly progressive course, and in all series are more likely to have an associated lymphoproliferative disease often with a circulating paraprotein. [717] [718] [719] [720] [721] Patients with both disease usually have proteinuria, and most have hypertension and hematuria. About 70% have the nephrotic syndrome at biopsy, but this may represent a bias in biopsy selection. At presentation renal insufficiency is common and most patients progress to ESRD. The course to ESRD appears to be more rapid than in patients with renal amyloidosis, particularly in older patients, those with an elevated serum creatinine, and those with crescentic lesions on biopsy. Fibronectin GN is a familial disease with probable autosomal dominant inheritance that presents with proteinuria and hematuria usually in adolescents and eventually progresses to the nephrotic syndrome and slow deteriorating renal function. [723] [724] [725]

The diagnosis of all of these fibrillary diseases is made solely on renal biopsy. [717] [718] [719] [720] [721] [726] LM findings in fibrillary glomerulonephritis are highly variable and include mesangial proliferation, mesangial expansion by amorphous amyloid-like material, membranous, membranoproliferative, and crescentic glomerulonephritis ( Fig. 31-29 ). In immunotactoid glomerulonephritis, glomerular lesions are often nodular and sclerosing whereas others are proliferative or membranous ( Fig. 31-30 ). The pathognomonic findings are seen on EM and consist of non branching fibrils of 16nm to 24nm in diameter in fibrillary glomerulopathy (as opposed to 8nm–12nm for amyloid) (Fig. 31-31 ) and hollow microtubules of 30nm to 50nm in immunotactoid glomerulonephritis ( Fig. 31-32 ). In fibrillary glomerulonephritis, fibrils are arranged randomly in the mesangial matrix and GBMs. By contrast the microtubules of immunotactoid glomerulopathy are often arranged in parallel stacks. The fibrils and microtubules do not stain with Congo red or thioflavin T. In fibrillary GN, IF is almost always positive for IgG ( Fig. 31-33 ) (especially subclass IgG4), C3, and both kappa and lambda chains. [717] [718] [719] [720] [721] [726] Staining for IgM, IgA, and C1 has been reported in a minority of cases. In immunotactoid glomerulonephritis, the immunoglobulin deposits are often monoclonal. In both diseases the fibril-related deposits are usually limited to the glomerulus. In fibronectin GN the fibrils may be admixed with more granular glomerular electron-dense deposits. [723] [724] [725]Rare patients with fibrillary glomerulopathy have been reported to have extrarenal deposits involving alveolar capillaries, and in the case of immunotactoid GN, the bone marrow. [727] [728]

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FIGURE 31-29  Fibrillary glomerulonephritis: The mesangium is mildly expanded and the capillary basement membranes appear thickened with segmental double contours (Periodic acid Schiff, ×300).

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FIGURE 31-30  Immunotactoid glomerulopathy: There is lobular expansion of the glomerular tuft by abundant mesangial deposits of silver-negative material. Segmental extension of deposits into the subendothelial aspect of some glomerular capillaries is also seen (Jones methenamine silver, ×500).

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FIGURE 31-31  Fibrillary glomerulonephritis: Electron micrograph showing the characteristic randomly oriented fibrils, measuring 16–20nm within the glomerular basement membrane. The foot processes are effaced (×8,000).

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FIGURE 31-32  Immunotactoid glomerulopathy: Electron micrograph showing abundant mesangial deposits of tubulo-fibrillar structures measuring approximately 35nm in diameter (×10,000).

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FIGURE 31-33  Fibrillary glomerulonephritis: Immunofluorescence photomicrograph showing smudgy deposits of IgG throughout the mesangium, with segmental extension into the peripheral glomerular capillary walls (×800).

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No proven therapy for fibrillary GN is known. Some clinicians choose to treat the LM pattern observed on renal biopsy (e.g., membranous, crescentic GN) and ignore the presence of the precipitated fibrils. [645] [717] Prednisone, cyclophosphamide, and colchicine have not led to consistent benefit in most patients. [645] [717] [718] However, in some patients with crescentic GN, cyclophosphamide and corticosteroid therapy has led to a dramatic improvement of GFR and proteinuria with some patients being able to discontinue dialytic support. Cyclosporine has also been used successfully in some patients with fibrillary GN and a membranous pattern on light microscopy.[644] In patients with associated with CLL, treatment with chemotherapy has been associated with improved renal function and decreased proteinuria. [645] [717] Dialysis and transplantation have been performed in fibrillary GN but there is a recurrence of disease in one half of patients. [717] [729] [730] [731]

Monoclonal Immunoglobulin Deposition Disease

Monoclonal immunoglobulin deposition disease (MIDD), which includes light chain deposition disease (LCDD), light and heavy chain deposition disease (LCDD/HCDD), and heavy chain deposition disease (HCDD), is a systemic disease caused by the overproduction and extracellular deposition of a monoclonal immunoglobulin protein. [732] [733] [734] [735] [736] LCDD is by far the most common pattern. As opposed to amyloidosis, in LCDD the deposits in approximately 80% of cases are composed of kappa rather than lambda light chains. [732] [733] [734] [735] [736] [737] [738] [739] The deposits are also granular in nature, do not form fibrils or beta pleated sheets, do not bind Congo red stain or thioflavine-T, and are not associated with amyloid P protein. [732] [733] [734] [735] [736] [737] [738] [739] In amyloid the fibrils are usually derived from the variable region of the light chains, whereas in LCDD it is usually the constant region of the immunoglobulin light chain that is deposited. This may explain the far brighter IF staining for light chains found in LCDD as opposed to amyloidosis. The pathogenesis of the glomerulosclerosis in LCDD is not entirely clear but mesangial cells from patients with LCDD produce transforming growth factor-β, which acting as an autacoid in turn promotes these cells to produce matrix proteins such as type IV collagen, laminin, and fibronectin.[739]

Patients with LCDD are generally over 45 years old. [732] [733] [734] [735] [736] [737] [738] [739] [740] Many such patients develop frank myeloma and others clearly have a lymphoplasmacytic B cell disease such as lymphoma or Waldenström macroglobulinemia. [735] [736] [737] [738] Even in such patients without an overt plasma cell dyscrasia, it is exces-sive production of abnormal monoclonal light chains that produce the disease. As in amyloidosis, the clinical features vary with the location and extent of organ deposition of the monoclonal protein. Patients typically have cardiac, neural, hepatic, and renal involvement, but other organs such as the skin, spleen, thyroid, adrenal, and gastrointestinal tract may be involved. [732] [733] [734] [735] [736] [737] [738] [739] [740] Patients with renal involvement usually have significant glomerular involvement and thus present with proteinuria, with the nephrotic syndrome in up to one half. This is often accompanied by hypertension and renal insufficiency. Some patients may have greater tubulointerstitial involvement and less proteinuria along with renal insufficiency.[737]

The glomerular pattern by LM is usually nodular sclerosing with mesangial nodules of acellular eosinophilic material resembling the nodular glomerulosclerosis seen in diabetic glomerulosclerosis ( Fig. 31-34 ). [732] [733] [734] [735] [736] [737] [738] [739] [740] [741] Glomerular capillary microaneurysms may also be found.[741] Some glomeruli have associated membranoproliferative features. In LCDD the nodules are more strongly PAS positive and less argyrophilic than in diabetes. [732] [743] Unlike diabetic glomerulosclerosis the GBMs in LCDD are not usually thickened by LM. Other glomeruli may be entirely normal or have only mild mesangialsclerosis. IF is usually diagnostic with a monoclonal light chain (kappa in 80%) staining in a diffuse linear pattern along the GBMs, in the nodules, and along the tubular basement membranes and vessel walls ( Fig. 31-35 ). [732] [733] [734] [735] [736] [737] [738] [739] Staining for complement components is usually negative. By EM deposition of a finely granular punctate electron-dense material occurs along the lamina rara interna of the GBM in the mesangium and along tubular and vascular basement membranes. [732] [733] [734] [735] [736] [737] [738] [739] [743]

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FIGURE 31-34  Light chain deposition disease: There is nodular glomerulosclerosis with marked global expansion of the mesangium by intensely PAS-positive material, but without appreciable thickening of the glomerular capillary walls (Periodic acid Schiff, ×375).

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FIGURE 31-35  Light chain deposition disease: Immunofluorescence photomicrograph showing linear staining for kappa light chain involving glomerular and tubular basement membranes, the mesangial nodules, Bowman capsule, and vessel walls (×250).

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The prognosis for patients with LCDD is uncertain and appears to be better than that for AL amyloidosis. As in amyloidosis death is often attributed to cardiac disease and heart failure or infectious complications. [732] [733] [734] [735] [736] [737] [738] [739] [741] In one recent large series of 63 patients 65% of patients developed myeloma.[735] Of the total 63 patients 36 developed uremia and 37 died. Predictors of worse renal outcome included increased age and elevated serum creatinine at presentation. Predictors of worse patient survival included increased age, occurrence of frank myeloma, and extrarenal deposition of light chains. Treatment with melphalan and prednisone, as in amyloid, has led to stabilized or improved renal function in LCDD. However, this therapy is not successful in patients with significant renal dysfunction and a plasma creatinine above 4 mg/dl at initiation of treatment.[740] Patient survival is about 90% at 1 year and 70% at 5 years, with renal survival 67% and 37% at 1 and 5 years.[740] Patients with LCDD and associated cast nephropathy have a worse renal and patient survival. Marrow or stem cell transplantation may be the optimal treatment for many patients with LCDD in the future. [732] [736] Although there is little data on dialysis and transplantation in LCDD, patients appear to fare as well as those with amyloidosis. Recurrences in the renal transplant have been reported [732] [738] [741] [744] [745] [746] and one recent trial of seven patients with LCDD who received renal transplants found recurrences in five of seven in a mean time of less than 1 year.[746] Thus, suppression of the abnormal paraprotein producing cel clone is crucial prior to renal transplantation.

In some patients with a plasma cell dyscrasia either both light and heavy immunoglobulin chains (LCDD/HCDD) or truncated heavy chains alone (HCDD) are deposited in the tissue ( Fig. 31-36 ). [732] [733] [737] [748] [749] The clinical features are similar to those of LCDD and amyloidosis. [732] [749] Most patients are middle age or older although at least one patient has been 35 years of age. They present with renal insufficiency, proteinuria, hypertension, and often the nephrotic syndrome. In most patients a monoclonal protein is detected in the serum or urine. In contrast to amyloid and LCDD, HCDD often manifests hypocomplementemia.[748] All patients with HCDD have a deletion of the CH1 domain of the heavy chain, which causes it to be secreted prematurely from the plasma cell. [749] [750] [751] [752] The characteristic light microscopic finding in HCDD is a nodular sclerosing glomerulopathy at times with crescents. [732] [749] The diagnosis is made by IF with linear positivity for the heavy chain of immunoglobulin (usually gamma) and negativity for both kappa and lambda light chains.[748] The distribution is diffuse involving glomerular, tubular, and vascular basement membranes. Treatment has been similar to LCDD, and most patients have progressed to renal failure. Recurrence in the renal transplant has been documented with eventual loss of the allograft.[731]

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FIGURE 31-36  Heavy chain deposition disease: Electron micrograph showing band-like finely granular electron-dense deposits involving the glomerular basement membrane, with greatest intensity along the inner aspect (×5000).

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Glomerular Disease in Myeloma and Benign Gammopathies

Patients with plasma cell dyscrasia may develop pathology in the tubulo-interstitial, glomerular, and vascular compartments.[752] Glomerular and vascular lesions are usually restricted to those patients with associated AL amyloidosis or monoclonal light or heavy chain deposition disease (or both)(see Amyloid and MIDD). In myeloma cast nephropathy, there are severe tubulo-interstitial lesions. The glomeruli are usually spared and appear normal by LM or have only mild GBM thickening or minor amounts of mesangial matrix deposition without mesangial hypercellularity. Recently patients with a proliferative glomerulonephritis resembling immune complex glomerulonephritis have been described in patients with plasma cell disorders.[753] These patients presented with renal insufficiency and proteinuria with many having the nephrotic syndrome, but no evidence of cryoglobulinemia. On biopsy all had granular electron-dense deposits in the mesangial, subendothelial, and subepithelial sites, but by IF these were restricted to a single monoclonal gamma subclass and light chain isotype (e.g., IgG1kappa or IgG2lambda). No patient developed overt myeloma or lymphoma during the follow-up period. In rare cases intracellular glomerular crystals within the podocytes have been noted, sometimes in association with tubular epithelial crystalline deposits. [755] [756]Pamidronate-associated focal sclerosis has been noted in myeloma[756] as have crescentic glomerulonephritis and membranoproliferative glomerulonephritis have been reported rarely, particularly in patients with associated cryoglobulinemia.

Monoclonal gammopathies of undetermined significance (MGUS), also known as benign gammopathies, are premalignant plasma cell disorders that occur in 3.2% of the population over 50 years of age.[757] The prevalence of MGUS increases with age from 5% of those over 70 years old to 7.5% of those 85 years of age or older. Patients with benign monoclonal gammopathies have an abnormal circulating immunoglobulin and abnormal clonal proliferation of plasma cells producing this protein without evidence of myeloma, amyloidosis, Waldenström macroglobulinemia, or other dysproteinemia.[757] Only a small percentage of these patients will progress to myeloma or other clinically relevant plasma cell dyscrasia. Clinical renal disease is uncommon in patients with true benign monoclonal gammopathy and only some patients will have mild proteinuria or hematuria.[752]

The literature on the pathology of this disorder is complicated by the fact that not all patients have had IF or EM evaluation making it possible that some actually had amyloidosis, light chain deposition disease, or cryoglobulinemia. By LM most patients with benign monoclonal gammopathies have had mild or focal proliferative glomerular lesions.[752] Some patients have a more severe and diffuse proliferative glomerulonephritis with invading polymorphonuclear cells and macrophages whereas others have been reported to have membranoproliferative picture, membranous or minimal change pattern. Few biopsies have been examined by IF but those studied with a proliferative glomerulonephritis have glomerular immunoglobulin deposits corresponding to the circulating monoclonal immunoglobulin. Other patients have had deposits of IgG, and IgM and C3. By EM patients with minimal change and membranous nephropathy have had findings similar to patients without a monoclonal paraproteinemia. Other patients have had fibrillar deposits along the GBM or crystalline deposits in endothelial cells. Some have a rapidly progressive glomerulonephritis. [759] [760] Again it is unclear if these patients have had a coexistent cryoglobulinemia or other disorder.

WALDENSTRöM MACROGLOBULINEMIA

Waldenström macroglobulinemia is a syndrome in which patients have an abnormal circulating monoclonal IgM protein in association with a B cell lymphoproliferative disorder involving small lymphocytes. [761] [762] [763] [764] This slowly progressive disorder occurs in older patients (median age 60 with a slight male predominance) who present with fatigue, weight loss, bleeding, visual disturbances, peripheral neuropathy, and with hepatosplenomegaly, lymphadenopathy, anemia, and often hyperviscosity syndrome. [761] [762] [763] [764] Renal involvement is uncommon, but glomerular lesions are found in some patients. [765] [766] Renal involvement is usually manifested by microscopic hematuria and proteinuria, which may be nephrotic or at lower levels. In some cases it is due to excreted light chains. Patients may have enlarged kidneys. The pathology seen in Waldenström macroglobulinemia is varied. [765] [766] Some patients will have invasion of the renal parenchyma by neoplastic lymphoplasmacytic cells. Acute renal failure associated with intraglomerular occlusive thrombi of the IgM paraprotein has also been reported. These cases have large eosinophilic, amorphous, PAS positive, deposits occluding the glomerular capillary loops with little or no glomerular hypercellularity ( Fig. 31-37 ). By IF these glomerular “thrombi” stain for IgM and a single light chain, consistent with monoclonal IgM deposits, but complement components are usually negative. By EM the deposits contain non-amyloid fibrillar or amorphous electron-dense material.[766] Some patients develop membranoproliferative glomerulonephritis with an associated Type 1 or Type 2 cryoglobulinemia ( Fig. 31-38 ). Cases of LCDD have also been reported. At times intratubular casts similar to those of myeloma cast nephropathy may be present. Amyloid has been found in a number of patients with Waldenström macroglobulinemia. Management of Waldenström macroglobulinemia is directed against the lymphoproliferative disease with alkylating agents, melphalan, and prednisone, and at times plasmapheresis for hyperviscosity signs and symptoms as well as newer therapies including fludarabine, cladribine, α-interferon, and Rituximab, and marrow transplantation. [768] [769] [770]

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FIGURE 31-37  Waldenström macroglobulinemia: Large Aprotein thrombi corresponding to the monoclonal IgM deposits fill the glomerular capillary lumina, with minimal associated glomerular hypercellularity (Jones methenamine silver, ×600).

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FIGURE 31-38  Waldenström macroglobulinemia: An example with cryoglobulinemic glomerulonephritis showing the characteristic intraluminal deposits, infiltrating leukocytes, and double contoured glomerular basement membranes (Jones methenamine silver, ×600).

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MIXED CRYOGLOBULINEMIA

Cryoglobulinemia refers to a pathologic condition caused by the production of circulating immunoglobulins that precipitate upon cooling and resolubilize on warming. [771] [772] [773] [774] Cryoglobulinemia is associated with a variety of infections, especially hepatitis C virus (see later) as well as collagen-vascular disease, and lymphoproliferative diseases. Cryoglobulins have been divided into three major groups based on the nature of the circulating immunoglobulins. [771] [772] [773] In type I cryoglobulinemia the cryoglobulin is a single monoclonal immunoglobulin often found associated with Waldenström macroglobulinemia or myeloma.[773] Both Type II and Type III cryoglobulinemia are defined as mixed cryoglobulins, containing a least two immunoglobulins. In Type II a monoclonal immunoglobulin (IgM kappa in over 90%) is directed against polyclonal IgG and has rheumatoid factor activity.[774] In Type III the antiglobulin is polyclonal in nature with both polyclonal IgG and IgM in most cases. The majority of patients with Type II and III mixed cryoglobulins have now been clearly shown to have HCVirus infection. [776] [777] To establish a diagnosis of cryoglobulinemia, the offending cryoglobulins or the characteristic renal tissue involvement must be demonstrated. Hypocomplementemia, especially of the early components Clq-C4, is a characteristic and often helpful finding.

In the past in 30% of all mixed cryoglobulinemias there was no clear etiology and the name essential mixed cryoglobulinemia was appropriate. [771] [772] [777] [778] [779] The disease was uncommon but not rare, and it occurred predominantly in adult females. Systemic manifestation of mixed cryoglobulinemia included weakness, malaise, Raynaud phenomena, arthralgias-arthritis, hepato-splenomegaly with abnormal liver function tests in two thirds to three quarters of patients, peripheral neuropathy, and purpuric-vasculitic skin lesions. [771] [772] [773] [774] [775] [777] [778] Low levels of total complement and especially C4 levels are common.

Renal disease occurs at presentation in less than one fourth of patients, but develops in as many as 50% over time. [771] [772] [773] [776] [777] [778] In up to one quarter to one third of patients an acute nephritic picture with hematuria, hypertension, proteinuria, and acute renal insufficiency develops. An oliguric rapidly progressive GN picture is present only rarely. About 20% of patients present with the nephrotic syndrome. The majority of patients with renal disease have a slow indolent renal course characterized by proteinuria, hypertension, hematuria, and renal insufficiency.

Many studies of Type II cryoglobulinemia have shown evidence of hepatitis B infection or other viral infections (e.g., Epstein-Barr virus). [780] [781] However, recent studies have clearly documented HCV as a major cause of cryoglobulin production in most patients previously felt to have essential mixed cryoglobulinemia. [776] [782] [783] [784] Antibodies to HCV antigens have been documented in the serum and HCV RNA and anti-HCV antibodies are enriched in the cryoglobulins of these patients. [776] [782] [783] [784] [785] [786] This is true even for patients with normal levels of aminotransferases and no clinical evidence of hepatitis. HCV antigens have also been localized by immunohistochemistry in the glomerular deposits.[783]

In cryoglobulinemia immunoglobulin complexes deposit in the glomeruli and small and medium-sized arteries binding complement and inciting a proliferative response. [776] [778] The serum cryoglobulin has been clearly shown to participate in the formation of the glomerular immune complex. In vitro studies have shown that IgM kappa rheumatoid factor from patients with Type II cryoglobulinemia are much more likely to bind to cellular fibronectin (a component of the glomerular mesangium) than IgM from patients with Waldenström's, normal controls, or IgM containing rheumatoid factor from rheumatoid arthritis patients.[786] The particular physicochemical characteristics of the variable region of the immunoglobulin cryoglobulin may be important in the localization of the renal deposits.

Although by LM the glomerular lesions of cryoglobulinemia may show a variety of proliferative and sclerosing features ( Fig. 31-39 ), certain features help to distinguish the proliferative GN of essential mixed cryoglobulinemia from other proliferative glomerulonephritides. [771] [774] [775] [783] These include massive exudation of monocytes and to a lesser degree polymorphonuclear leukocytes; amorphous eosinophilic PAS positive, Congo red negative deposits on the inner side of the glomerular capillary wall and sometimes filling the lumens; membranoproliferative features with double contoured GBMs and interposition of deposits, mesangial cells, and monocytes; and the rarity of extracapillary proliferation despite the intense intracapillary proliferation. The glomerular lesions may be accompanied by an acute vasculitis of small- or medium-sized vessels. The monocytes of patients with active cryoglobulinemia and associated nephritis have been shown to phagocytose cryoglobulins but to be unable to catabolize them. By IF ( Fig. 31-40 ), the glomeruli in Type II or Type III cryoglobulinemia contain deposits of both IgM as well as IgG with C3 and frequently C1q in the distribution of subendothelial and mesangial deposits and the intracapillary “thrombi”. By EM ( Fig. 31-41 ), deposits present in the subendothelial position or filling the capillary lumens, often appear as either amorphous electron-dense deposits or organized deposits of curvilinear parallel fibrils that appear tubular in cross section and have a diameter of 20nM to 35nM. [771] [773] [787] [788]

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FIGURE 31-39  Cryoglobulinemia: There is global endocapillary proliferative glomerulonephritis with membranoproliferative features and focal intraluminal cryoglobulin deposits, forming Athrombi (Periodic acid Schiff, ×375).

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FIGURE 31-40  Cryoglobulinemia: Immunofluorescence photomicrograph showing deposits of IgM corresponding to the large glomerular intracapillary deposits, with more finely granular subendothelial deposits outlining the glomerular capillary walls (×900).

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FIGURE 31-41  Cryoglobulinemia: Electron micrograph showing organized subendothelial deposits with an annular-tubular substructure. These curvilinear tubular structures measure approximately 30nm in diameter (×30,000).

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Some patients with mixed cryoglobulinemia will have a partial or total remission of their disease whereas most have episodic exacerbations of their systemic and renal disease. [771] [783] Before the association of mixed cryoglobulinemia and HCV was discovered, many patients were treated successfully with prednisone and cytotoxic agents such as cyclophosphamide and chlorambucil. [771] [773] None was used in a controlled fashion. In patients with severe renal disease, in those with digital necrosis from the cryoglobulins, and in those with life-threatening organ involvement, plasmapheresis has also been used in combination with steroids and cytotoxics. [779] [790] [783]Currently most patients with HCV-associated cryoglobulinemia are treated with antiviral agents. [791] [792] (See section on Hepatitis C Virus.) Aggressive immunosuppressive therapy carries the risk of promoting HCV replication in HCV-infected patients and of lymphoma in others. Most patients with cryoglobulinemia in the past did not die of renal disease, but rather of cardiac or other systemic disease and infectious complications.[789] Rituximab has recently been used successfully for management of Type II mixed cryoglobulinemia in patients with and without evidence of HCV infection.[792] Dialysis and transplantation in cryoglobulinemia have been used, but recurrences in the allograft have been reported. [794] [795] [796]

HEREDITARY NEPHRITIS INCLUDING ALPORT SYNDROME

Alport syndrome is an inherited (usually X-linked) disorder with characteristic glomerular pathology, frequently associated with hearing loss and ocular abnormalities. Guthrie first reported a family with recurrent hematuria.[796]Alport reported additional observations on this family, the occurrence of deafness associated with hematuria, and the observation that affected males died of uremia whereas affected females lived to an old age.[797] Since then, several hundred unrelated kindreds exhibiting hereditary nephritis, with and without deafness, have been described, representing a wide variety of geographic and ethnic groups. [799] [800] [801] [802] [803] [804] [805] Alport syndrome accounts for 2.5% of children and 0.3% of adults with end-stage renal disease in the United States.[805]

Clinical Features

The disease usually manifests in children or young adults. [803] [804] [807] Males have persistent microscopic hematuria, with episodic gross hematuria, which may be exacerbated by respiratory infections or exercise. There may be flank pain or abdominal discomfort accompanying these episodes. Proteinuria is usually mild at first and increases progressively with age. The nephrotic syndrome has also been described.[807] Hypertension is a late manifestation. Slowly progressive renal failure is common in males. End-stage renal disease usually occurs in males between the ages of 16 and 35. In some kindred, the course may be more delayed with renal failure occurring between 45 and 65 years of age. In most females, the disease is mild and only partially expressed, however, some females have experienced renal failure.[808] In the European Community Alport Syndrome Concerted Action (ECASCA) cohort, hematuria was observed in 95% of carriers and consistently absent in the others. Proteinuria, hearing loss, and ocular defects developed in 75%, 28%, and 15%, respectively.[809] This variability in disease severity in females can be explained by the degree of random inactivation of the mutated versus wild-type X chromosome due to Lyonization.

High-frequency sensorineural deafness occurs in 30% to 50% of patients. Hearing impairment is always accompanied by renal involvement. The severity of hearing loss is variable and there is no relation between the severity of hearing loss and of the renal disease. Based on brain stem auditory evoked responses, the site of the aural lesion is in the cochlea. [811] [812] Families with hereditary nephritis, but without sensorineural hearing loss have been described. [812] [813]

Ocular abnormalities occur in 15% to 30% of patients.[813] Anterior lenticonus, which is the protrusion of the central portion of the lens into the anterior capsule, is virtually pathognomonic of Alport syndrome. Other ocular abnormalities include keratoconus, spherophakia, myopia, retinal flecks, cataracts, retinitis pigmentosa, and amaurosis. [803] [804] [815] Other variants of Alport syndrome, now known to be distinct entities, include the association of hereditary nephritis with thrombocytopathia (mega thrombocytopenia), so-called Epstein syndrome, [816] [817] diffuse leiomyomatosis,[817] ichthyosis and hyperprolinuria,[818] and Fechtner syndrome (nephritis, macrothrombocytopenia, Döhle-like leukocyte inclusions, deafness, and cataract).[819]

Pathology

The LM appearance of biopsies is non-specific.[820] The diagnosis rests on the EM findings. By LM most biopsies have glomerular and tubulointerstitial lesions. In the early stages (<5 years of age), the kidney biopsy may be normal or nearly normal.[821] The only abnormality may be the presence of superficially located fetal glomeruli involving 5% to 30% of the glomeruli or interstitial foam cells. [823] [824] In the older child (5–10 years of age), mesangial and capillary wall lesions may be visible. These consist of segmental to diffuse mesangial cell proliferation, matrix increase, and thickening of the glomerular capillary wall.[824] Special stains such as Jones methenamine silver or periodic acid Schiff may reveal thickening and lamellation of the GBM. Segmentally or globally sclerosed glomeruli may be present. Tubulointerstitial changes may include interstitial fibrosis, tubular atrophy, focal tubular basement membrane thickening, and interstitial foam cells. The glomerular and tubular lesions progress over time. A pattern of focal segmental and global glomerulosclerosis with hyalinosis is common in advanced cases, especially those with nephrotic-range proteinuria. Tubulointerstitial lesions progress from focal to diffuse involvement. [823] [826]

By IF many specimens are negative [823] [827] but some may have nonspecific granular deposits of C3 and IgM within the mesangium and vascular pole and along the glomerular capillary wall in a segmental or global distribution.[804] [812] The finding in rare cases of nonspecifically trapped immune deposits within the lamellated glomerular basement membranes may lead to an erroneous diagnosis of immune complex GN.[827] With segmental sclerosis, subendothelial deposits of IgM, C3, properdin, and C4 are found. [804] [823] The GBM of males with Alport syndrome frequently lacks reactivity with sera from patients with anti-GBM antibody disease, or with monoclonal antibodies directed against the Goodpasture epitope. [829] [830] This abnormality can help in diagnosing equivocal cases where the electron microscopic findings are not specific.[820]

In the mature kidney, collagen IV is composed of heterotrimers made up of six possible alpha chains. Chains composed of α1, α1, α2 are distributed in all renal basement membranes. Collagen IV chains composed of α3, α4, α5 are present in mature GBM and some distal TBM. Chains of α5, α5, α6 are distributed in Bowman capsule and collecting duct TBM, as well as in epidermal basement membrane. Commercially available antisera to the subunits of collagen IV reveal preservation of the α1 and α2 subunits but loss of immunoreactivity for the α3, α4 and α5-subunits from the GBM of affected males with X-linked disease. In addition, there is loss of α5 staining from Bowman capsule, distal tubular basement membranes and skin in affected males with X-linked disease. Females are chimeras with segmental loss of α5 in glomerular and epidermal basement membranes due to random inactivation of the mutated X chromosome in podocytes and basal keratinocytes. Patients with autosomal recessive forms of Alport disease typically lack the α3, α4, and α5 subunits in GBM but retain α5 immunoreactivity in Bowman capsule, collecting ducts, and skin (where α5 forms a heterotrimer with α6). Thus, absence of α5 staining in skin biopsies is highly specific for the diagnosis of X-linked Alport syndrome.[830]

On EM the earliest change is thinning of the GBM (which is not specific for hereditary nephritis and can occur in thin basement membrane disease).[831] The cardinal ultrastructural abnormality is the variable thickening, thinning, basket weaving, and lamellation of the GBM ( Fig. 31-42 ). These abnormalities may also be seen in some patients without a family history of nephritis[832]; these patients may be offspring of asymptomatic carriers, or may represent new mutations. The endothelial cells are intact, and foot process effacement may be seen overlying the altered capillary walls. The mesangium may be normal in early cases, but with time, matrix and cells increase and mesangial interposition into the capillary wall may be observed. [804] [827] In males, the number of glomeruli showing lamellation increases from about 30% by age 10 to over 90% by age 30. In females with mild disease, less than 30% of the glomeruli may be affected.[833]

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FIGURE 31-42  Alport disease: Electron micrograph showing a thickened, lamellated glomerular basement membrane with the characteristic split and splintered appearance (×4000).

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The specificity of the GBM findings has been questioned.[834] Foci of lamina densa lamellation and splitting have been seen in 6% to 15% of unselected renal biopsies. These changes also may be seen focally in other glomerulopathies. Thus clinical correlation and immunofluorescence examination are essential when the ultrastructural features suggest Alport syndrome. Although diffuse thickening and splitting of the GBM strongly suggests Alport syndrome, not all Alport kindreds show these characteristic features. Thick, thin, normal, and nonspecific changes have also been described.

Pathogenesis and Genetics of Hereditary Nephritis

There are three genetic forms of hereditary nephritis. In the majority of cases, the disease is transmitted via an X-linked inheritance (i.e., father-to-son transmission does not occur, and women tend to be carriers because of Lyonization). Autosomal dominant and recessive inheritance have also been described, as has sporadic occurrence. [801] [803] [836] The frequency of the Alport gene has been estimated to be 1:5000 in Utah[836] and 1:10,000 in the United States.[837]

Hereditary nephritis is caused by defects in type IV collagen. Six genes for type IV collagen have been characterized. Mutations in the COL4A5 gene (encoding the α-5 subunit of collagen type IV) on the X chromosome are responsible for the more frequent X-linked form of hereditary nephritis.[838] The identified mutations include deletions, insertions, substitutions, and duplications. [839] [840] [841] [842] [843] However, there are other abnormalities that are not encoded by the COL4A5 gene. Other Type IV collagen peptides are abnormally distributed. The α1 and α2 peptides that are normally confined to the mesangial and subendothelial regions, become distributed throughout the full thickness of the GBM in hereditary nephritis. With progressive glomerular obsolescence, these peptide chains disappear, with an increase in collagen V and VI.[843] Moreover, the basement membranes of these patients do not react with anti-GBM antibodies. This implies that the NC1 domain of the α3 subunit of type IV collagen is not incorporated normally into the GBM, probably because the α5 subunit is required for normal assembly of the minor alpha chains of collagen IV into heterotrimers.[844] Cationic antigenic components are also absent.[845] The reason why these GBM abnormalities occur is not known, but may be due to alteration in the incorporation of other collagens into the GBM.[846]

Genetic screening is difficult because of the large number of mutations and the lack of hot spots on the genomic sequence involved.[847] Autosomal recessive and autosomal dominant hereditary nephritis have been shown to involve the α-3 or α-4 chains. The genes for these proteins are encoded on chromosome 2. An abnormality of any of these chains could impair the integrity of the basement membranes in the glomerulus and cochlea, leading to similar clinical findings.

Recently, the minor causes of familial hematuria, the Fechtner and Epstein syndromes, along with two other genetic conditions featuring macrothrombocytes (Sebastian syndrome and May-Hegglin anomaly), were shown to result from heterozygous mutations in the gene MYH9, which encodes nonmuscle myosin heavy chain IIA (NMMHC-IIA).[848]

Course and Treatment

Recurrent hematuria and proteinuria may be present for many years followed by the insidious onset of renal failure. Virtually all affected males reach ESRD but there is considerable interkindred variability in the rate of progression. The rate of progression within male members of an affected family is usually but not always relatively constant. [804] [850] [851] The presence of gross hematuria in childhood, nephrotic syndrome, sensorineural deafness, anterior lenticonus, and diffuse GBM thickening are indicative of an unfavorable outcome in females.[808] A European Community Alport Syndrome Concerted Action (ECASCA) has been established to define the AS phenotype and to determine genotype-phenotype correlations. A report on 401 male patients belonging to the 195 families with COL4A5 mutation showed a 90% probability rate of progression to end-stage renal failure by age 30 years in patients with large deletions, nonsense mutations, or frameshift mutations. The same risk was of 50% and 70%, respectively, in patients with missense or splice site mutations. The risk of developing hearing loss before 30 years of age was approximately 60% in patients with missense mutations, compared with 90% for the other types of mutations.[804] Female carriers with the COL4A5 mutation generally have less severe disease. In the ECASCA cohort described earlier, the probability of developing ESRD before the age of 40 years was 12%, in females versus 90%, in males. The risk of progression to end-stage renal disease appears to increase after the age of 60 years in women. Risk factors for renal failure in women included the development and progressive increase in proteinuria, and the occurrence of a hearing defect.

There is no proven therapy for Alport syndrome. Proteinuria-reduction strategies, such as aggressive control of hypertension and use of angiotensin-converting enzyme inhibitors (ACEI) might slow the rate of progression in patients with hereditary nephritis.[851] A small number of patients showed apparent stabilization when treated long term with cyclosporine.[852] However, the potential for calcineurin inhibitor toxicity exists.

Renal replacement therapy (either dialysis or transplantation) may be performed in patients with hereditary nephritis. Allograft and patient survival were comparable to survival rates in the UNOS database.[853] In approximately 2% to 4% of male patients receiving a renal transplant, anti-GBM antibody disease may develop.[854] These antibodies are directed against the Goodpasture antigen in the α-3 chain. This antigen, which presumably does not exist in the kidney in patients with hereditary nephritis, is present in normal kidneys and is thus recognized as foreign. [856] [857] A profile of these patients has been compiled.[820] The patients are usually male, always deaf, and likely to have reached end-stage renal disease before the age of 30. There is a suggestion that certain mutations in the COL4A5 gene, such as deletions (which account for 11%–12% of Alport cases), may predispose patients to the development of allograft anti-GBM nephritis.[856] In 75% of cases, the onset of anti-GBM nephritis occurs within the first year after transplantation, and 76% of the allografts were lost.

THIN BASEMENT MEMBRANE NEPHROPATHY

Thin basement membrane nephropathy (TBMN) (also known as benign familial hematuria and thin GBM nephropathy) describes a condition that differs from Alport disease in its generally benign course and lack of progression. The typical finding on renal pathology is diffuse thinning of the glomerular basement membranes (GBM). However, thin GBM may be found in other conditions as well (including early Alport disease and IgA nephropathy).[857] The true incidence of TBMN disease is unknown; reports evaluating patients with isolated hematuria suggest that 20% to 25% of such patients have thin GBM disease. [859] [860] [861]

Clinical Features

Patients usually present in childhood with microhematuria. Hematuria is usually persistent but may be intermittent in some patients. Episodic gross hematuria may occur particularly with upper respiratory infections. [862] [863]Patients do not typically have overt proteinuria, but when present, this may suggest progression of disease. [859] [864]

Pathology

Renal biopsies typically show no histologic abnormalities with the exception of focal erythrocyte casts. By IF, no glomerular deposits of immunoglobulins or complement are found. By EM, there is diffuse and relatively uniform thinning of the GBM ( Fig. 31-43 ). The normal thickness of the GBM is age and gender dependent. Vogler and colleagues[864] have defined normal ranges for children: at birth 169 ± 30nm, at 2 years of age 245 ± 49nm, at 11 years 285 ± 39nm. Steffes and associates[865] have defined normal ranges for adults 373 ± 42 (males) 326 ± 45nm (females). Each laboratory should attempt to establish its own normals for GBM thickness. A cutoff value of 250nm has been reported by some authors, [867] [868] [869] whereas other groups have used a cutoff of 330nm.[863] There is often accentuation of the lamina rara interna and externa. Focal GBM gaps may be identified ultrastructurally. Immunostaining for the alpha subunits of collagen IV reveal a normal distribution in the GBM.

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FIGURE 31-43  Thin basement membrane disease: By electron microscopy, the glomerular basement membranes are diffusely and uniformly thinned, measuring less than 200nm in thickness (×2500).

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Pathogenesis

About 40% of TBMN disease has been linked to mutations of the COL4A3 and COL4A4 genes.[869] In most kindreds with TBMN, the disorder appears to be transmitted in an autosomal dominant pattern. In a few families with several affected children and apparently unaffected parents suggests a recessive mode of inheritance or that one parent was an asymptomatic carrier. [861] [862] [871] There appears to be a reduction or loss of the subepithelial portion of the basement membrane, which apparently contains normal amounts of type IV collagen.[871]

Differential Diagnosis of Familial Hematurias

Type IV collagen defects can cause both TBMN and Alport syndrome. Patients with TBMN can be considered carriers of autosomal recessive Alport syndrome. [873] [874] With advances in molecular biology and immunopathology, hereditary forms of hematuria have been better characterized. Table 31-2 shows a summary of the clinical, pathologic, and genetic aspects of the various forms of hereditary nephritis.[874] Because GBM thinning may be seen in early cases of Alport syndrome, immunohistochemical analysis of α3, α4, and α5-subunits should be undertaken (because genetic tests are not practical). Table 31-3 shows the typical immunostaining patterns in the kidney and skin basement membranes.


TABLE 31-2   -- Classification of Familial Hematurias

 

Locus

Progressive Nephropathy

Deafness

Ocular Changes

GBM Changes

Hematologic Features

Type IV collagen disorders

Alport syndrome

 X-linked

COL4A5

+

+

+

Thickening

No

 X-linked + diffuse leiomyomatosis

COL4A5 + COL4A6

+

+

No

Thickening

No

Autosomal recessive

COL4A3 or COL4A4

+

+

+

Thickening

No

Autosomal dominant

COL4A3 or COL4A4

+

+

No

Thickening

No

Thin hasement membrane nephropathy[*]

COL4A3 or COL4A4

No

No

No

Thinning

No

Non-collagen disorders

Fechtner syndrome

MYH9

+

+

+

Thickening

Thrombocytopenia May-Hegglin

Epstein syndrome

MYH9

+

+

+

Thickening

Thrombocytopenia

From Kashtan CE: Familial hematurias: What we know and what we don't. Pediatr Nephrol 20(8):1027–1035, 2005.

*

Some families with thin basement membrane disease have mutations at loci other than the type IV collagen genes.

 

 


TABLE 31-3   -- Immunostaining Patterns for α5 in Kidney and Epidermal 3 Basement Membranes

 

Glomerular Basement Membrane

Bowman Capsule

Epidermal Basement Membrane

Normal

Present/Normal

Present/Normal

Present/Normal

X-linked Alport Males

Absent

Absent

Absent

X-linked Alport Female carriers

Present/Mosaic

Present/Mosaic

Present/Mosaic

Autosomal recessive Alport

Absent

Present/Normal

Present/Normal

Thin Basement Membrane Disease

Present/Normal

Present/Normal

Present/Normal

 

 

 

NAIL-PATELLA SYNDROME (HEREDITARY OSTEO-ONYCHODYSPLASIA)

Nail-patella syndrome (NPS) is an autosomal dominant condition affecting tissues of both ectodermal and mesodermal origin, manifested as symmetrical nail, skeletal, ocular, and renal anomalies.

Clinical Features

The classical tetrad of anomalies of the nails, elbows and knees, and iliac horns was described by Mino and colleagues in 1948.[875] Nail dysplasia and patellar aplasia or hypoplasia are essential features for the diagnosis of NPS. The presence of triangular nail lunulae is a pathognomonic sign for NPS. Other skeletal abnormalities include dysplasia of the elbow joints, posterior iliac horns, and foot deformities. Various ocular anomalies have sporadically been found in NPS patients, including microcornea, sclerocornea, congenital cataract, iris processes, pigmentation of the inner margin of the iris, and congenital glaucoma.[876]

Renal involvement is variable, being present in up to 38% of patients. Renal manifestations first appear in children and young adults and may include proteinuria, hematuria, hypertension, or edema. The nephrotic syndrome and progressive renal failure may occasionally occur. The course is generally benign with renal failure being a late feature. [878] [879] Congenital malformations of the urinary tract and nephrolithiasis are also more frequent in these patients.

Pathology

The findings on LM are nonspecific and include focal and segmental glomerular sclerosis, segmental thickening of the glomerular capillary wall, and mild mesangial hypercellularity.[879] IF microscopy is nonspecific and IgM and C3 have been observed in sclerosed segments. Ultrastructural studies show a thickened basement membrane that contains irregular lucencies, imparting a “moth-eaten” appearance ( Fig. 31-44A ). The presence of intramembranous fibrils with the periodicity of collagen is revealed by phosphotungstic acid stains in electron microscopic sections, corresponding to the distribution of the intramembranous lucencies ( Fig. 31-44B ). These must be distinguished from the occasional collagen fibrils that can accumulate nonspecifically in the sclero-tic mesangium in a variety of sclerosing glomerular conditions.[879]

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FIGURE 31-44  Nail-Patella syndrome. A, Routine electron micrograph showing thickening of a glomerular basement membrane with focal irregular internal lucencies (×15,000). B, Phosphotungstic acid-stained electron micrograph demonstrating the characteristic banded collagen fibrils within the rarefied segments of glomerular basement membrane (×15,000).

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Pathogenesis

The genetic locus for this syndrome appears to be on chromosome 9, in linkage with ABO and the locus for adenylate kinase. [881] [882] Features reminiscent of nail patella syndrome have been produced in mice with targeted disruption of the LIM-homeodomain protein Lmx1b. Lmx1b plays a central role in dorso-ventral patterning of the vertebrate limb. The authors also showed that LMX1B mapped to the NPS locus and that three NPS patients carried de novo heterozygous mutations in this gene.[882] This finding has been confirmed in other kindreds with NPS.[883]

Treatment

There is no treatment for this condition; occasional patients with renal failure have been successfully transplanted.[884]

FABRY DISEASE (ANGIOKERATOMA CORPORIS DIFFUSUM UNIVERSALE)

Fabry disease[885] is an X-linked inborn error of glycosphingolipid metabolism involving a lysosomal enzyme, α-galactosidase A (also known as ceramide trihexosidase). The enzyme deficiency leads to the accumulation of globotriaosylceramide (ceramide trihexoside) and related neutral glycosphingolipids leading to multisystem involvement and dysfunction. Clinical guidelines for the diagnosis and treatment of Fabry disease have recently been published.[886]

Clinical Features

Fabry disease has been reported in all ethnic groups, and the estimated incidence in males is 1 in 40,000 to 1 in 60,000. In male hemizygotes, the initial clinical presentation usually begins in childhood with episodic pain in the extremities and acroparesthesias. Renal involvement is common in male hemizygotes and is occasional in female heterozygotes. The disease presents with hematuria and proteinuria, which often progresses to nephrotic levels. In men, progressive renal failure generally develops by the fifth decade. In the United States, Fabry disease accounted for 0.02% of patients who began renal replacement therapy between 1995 and 1998.[887]

The skin is commonly involved with reddish-purple macules (angiokeratomas) typically found on the abdomen, buttocks, hips, genitalia, and upper thighs. Other findings include palmar erythema, conjunctival and oral mucous membrane telangiectasia, and subungual splinter hemorrhages. The nervous system is involved with peripheral and autonomic neuropathy. Premature arterial disease of coronary vessels leads to myocardial ischemia and arrhythmias at a young age. Similarly, cerebrovascular involvement leads to early onset of strokes. In the heart, valvular disease and hypertrophic cardiomyopathy have also been reported. Corneal opacities are seen in virtually all hemizygotes and most heterozygotes. Posterior capsular cataracts, edema of retina and eyelids, tortuous retinal and conjunctival vessels may also been seen in the eye. Generalized lymphadenopathy, hepatosplenomegaly, aseptic necrosis of femoral and humeral heads, myopathy, hypoalbuminemia, and hypogammaglobulinemia have been reported.

In carrier females, clinical manifestations may range from asymptomatic to severe disease similar to male hemizygotes. Up to one third of female carriers have been reported to have significant disease manifestations.[888]

Pathology

Glycosphingolipid accumulation begins early in life[889] and the major renal site of accumulation is the podocyte (visceral epithelial cells). By LM, these cells are enlarged with numerous clear, uniform vacuoles in the cytoplasm causing a foamy appearance ( Fig. 31-45 ). These vacuoles can be shown to contain lipids when fat stains (such as Oil Red-O) are used, or when viewed under the polarizing microscope where they exhibit a double refractile appearance before being processed with lipid solvents. All renal cells may accumulate the lipid. These include (in addition to podocytes) parietal epithelial cells, glomerular endothelial cells, mesangial cells, interstitial capillary endothelial cells, distal convoluted tubule cells, and to a lesser extent, cells of the loops of Henle, and proximal tubular cells. Indeed, vascular endothelial cells are involved in virtually every organ and tissue.[890] In the kidney, the myocytes and endothelial cells of arteries are commonly involved. In heterozygotes, similar changes are present but with less severity.[891] Characteristic findings are noted on EM ( Fig. 31-46 ). The major finding is large numbers of “myelin figures” or “zebra bodies” within the cytoplasm of the podocytes, and to a variable extent, in other renal cell types. These intracytoplasmic vacuoles consist of single membrane-bound dense bodies with a concentric whorled or multilamellar appearance. Glomerular podocytes exhibit variable foot process effacement. The GBMs are initially normal, but with progression of disease, there may be thickening and collapse of the GBM, focal and segmental glomerular sclerosis, with accompanying tubular atrophy and interstitial fibrosis.[892] Findings on IF microscopy are usually negative except in areas of segmental sclerosis, where IgM and complement may be demonstrated. Orange autofluorescence corresponding to the lipid inclusions may be found in podocytes and other renal cells.

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FIGURE 31-45  Fabry disease: By light microscopy, the visceral epithelial cells are markedly enlarged with foamy-appearing cytoplasm (Trichrome, ×800).

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FIGURE 31-46  Fabry disease: Electron micrograph showing abundant whorled myelin figures within the cytoplasm of the podocytes. A few similar inclusions are also identified within the glomerular endothelial cells (×2000).

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Pathogenesis

The entire gene for α-galactosidase has been sequenced.[893] Specific molecular defects vary from family to family, and include rearrangements, deletions, and point mutations.[894] Deficiency of the enzyme leads to accumulation of globotriaosylceramide especially in the vascular endothelium, with subsequent ischemic organ dysfunction. Patients with blood groups B and AB have earlier and more severe symptoms, likely related to accumulation of the terminal α-galactose substance occurring during the synthesis of the B antigen on red blood cell membranes.[895] Globosyltriaosylceramide accumulation in podocytes may lead to proteinuria and renal dysfunction, but functional abnormalities are not always noted, especially in female heterozygotes. A gene-knockout mouse model of Fabry disease has been produced, which shows the characteristic changes.[896]

Diagnosis

The diagnosis in affected males can be established by measuring levels of α-galactosidase-A in plasma or peripheral blood leukocytes. Hemizygotes have almost no measurable enzyme activity. Female carriers may have enzyme levels in the low to normal range; to diagnose female carriers, the specific mutation in the family must be demonstrated.[886] The measurement of urinary ceramide digalactoside and trihexoside levels may also be of use to identify the carrier state. Prenatal diagnosis can be made by measuring amniocyte enzyme levels in amniotic fluid.

Treatment

Two randomized, controlled trials have shown that recombinant human α-galactosidase-A replacement therapy is safe and can improved clinical parameters. In one short-term study α-galactosidase-A treatment was associated with improved neuropathic pain, decreased mesangial widening, and improved creatinine clearance.[897] In the second study, repeat renal biopsies showed decreased microvascular endothelial deposits of globotriaosylceramide. [891] [899] [900] [901] Clinical guidelines for the management of Fabry disease have recently been published: enzyme replacement therapy should be administered as early as possible in all males with Fabry disease (including those with end-stage renal disease) and female carriers with substantial disease manifestations.[886]

The European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Registry has reported outcomes on patients with Fabry disease. Since 1985, 4 to 13 new patients per year have commenced renal replacement therapy in Europe. Patient survival on dialysis was 41% at 5 years; cardiovascular complications (48%) and cachexia (17%) were the main causes of death. Graft survival at 3 years in 33 patients was not inferior to that of other nephropathies (72% versus 69%), and patient survival after transplantation was comparable to that of patients under 55 years of age.[899] In the U.S. population, survival of Fabry patients was lower than non-diabetic renal failure patients.[887]

Long-term allograft function in patients with Fabry disease has been reported. Glycosphingolipid deposits do recur in allografts, but have not been reported to cause graft failure.[900] It is likely that enzyme therapy will benefit patients on dialysis and those who have been transplanted.

SICKLE CELL NEPHROPATHY

Renal disease associated with sickle cell disease includes gross hematuria, papillary necrosis, nephrotic syndrome, renal infarction, inability to concentrate urine, renal medullary carcinoma, and pyelonephritis. [904] [905] Microscopic or gross hematuria is likely the result of microinfarcts in the renal medulla. Glomerular lesions however, are less commonly encountered and may be seen in patients with HbSS, HbSC, and sickle cell-thalessemia.[903]

Clinical Features

In one study, the prevalence of proteinuria (>1+ on a dipstick) in SS disease was 26%.[903] The majority of proteinuric patients had less than 3 g/d and an elevated serum creatinine levels was present in 7% of patients. In another study, 4.2% with SS disease, and 2.4% with sickle C disease developed renal failure. The median age of disease onset for these patients was 23.1 and 49.9 years, respectively. Survival time for patients with SS anemia after the diagnosis of renal failure, despite dialysis, was 4 years, and the median age at the time of death was 27 years. The risk for renal failure was increased in patients with the Central African Republic beta s-gene cluster haplotype, hypertension, proteinuria, and severe anemia.[904] The course of SS renal disease is progressive; in one series, 18% of patients with SS disease progressed to ESRD.[905]

Pathology

Two patterns of glomerular lesions may be seen in patients with SS-associated glomerulopathy. Immune-mediated glomerulonephritis with a membranoproliferative pattern exhibits mesangial proliferation with mild to moderate capillary wall thickening due to GBM reduplication and mesangial interposition ( Fig. 31-47 ). Some of these patients also exhibit features of chronic thrombotic microangiopathy, with narrow double contours of the GBM and mesangiolysis. A pattern of membranous glomerulonephritis has also been described. On IF microscopy, irregular granular deposits of IgG and C3 have been reported in association with membranous or mesangiocapillary findings on LM.[906] Ultrastructural studies show granular dense deposits in the mesangial and subepithelial area. Some cases have no detectable deposits, but subendothelial accumulation of electron lucent “fluff” resembling the changes in chronic thrombotic microangiopathies may be seen. Mild mesangial proliferation and peripheral mesangial interposition is frequently seen. Sickled erythrocytes containing para crystalline inclusions may be identified within glomerular capillaries. [909] [910] [911] [912] [913]

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FIGURE 31-47  Sickle cell disease: An example of sickle cell glomerulopathy with membranoproliferative features. There are double contours of the glomerular basement membrane associated with segmental mesangiolysis (Jones methenamine silver, ×500).

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In the second form of sickle glomerulopathy, focal and segmental glomerulosclerosis is seen associated with glomerulomegaly ( Fig. 31-48 ). Two patterns of FSGS may be observed: a “collapsing” pattern and an “expansive” pattern. [904] [906] [914] [915] [916] On IF nonspecific IgM and C3 are seen in sclerosed segments. In all these forms, there may be prominent intracapillary erythrocyte sickling and congestion.

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FIGURE 31-48  Sickle cell disease: An example with focal segmental glomerulosclerosis. The nonsclerotic glomerular capillaries are congested with sickled erythrocytes (Hematoxylin-eosin, ×500).

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Pathogenesis

The mechanism(s) for glomerular abnormalities in SS patients is not fully understood. One theory proposes that mesangial cells are activated by the presence of fragmented RBCs in glomerular capillaries. This activation of mesangial cells promotes synthesis of matrix proteins and GBM reduplication.[914] In another study, renal tubular epithelial antigens and complement components were detected in a granular pattern along the GBM; the authors hypothesized that glomerulonephritis was mediated by glomerular deposition of immune complexes containing renal tubular epithelial antigen and antibody to renal tubular epithelial antigen (the antigen possibly released after tubular damage secondary to decreased oxygenation and hemodynamic alterations related to SS disease).[906]

In patients with the FSGS pattern, it is proposed that the collapsing pattern represents an initial but progressive obliteration of the glomerular capillary bed by red blood cell sickling, which cannot be compensated by further glomerular hypertrophy. Hemodynamic glomerular injury then supervenes from the sustained or increasing hyperfiltration in a diminishing capillary bed, manifesting morphologically as the expansive pattern of sclerosis. [906] [914]The role of reactive oxygen species in producing chronic vascular endothelial injury has also been suggested.[915]

Treatment

The management of renal disease has generally not been satisfactory. Treatment of patients with SS nephropathy with angiotensin-converting enzyme inhibitors reduces the degree of proteinuria. [906] [919] However, their effectiveness in preserving renal function remains to be established.

SS nephropathy accounts for 0.1% of ESRD patients in the United States.[917] Renal transplantation has been performed in SS patients. One-year graft survival in SS patients was similar to other transplanted patients; however, long-term renal outcome was worse, as was short-term and long-term mortality.[918] Transplanted sickle patients commonly experience SS crises. [922] [923] Recurrent SS nephropathy has been reported in the transplanted kidney. [915] [924]

LIPODYSTROPHY

Lipodystrophies are rare diseases in which there is loss of fat, which may be localized to the upper part of the body in partial lipodystrophy (PLD) or more diffuse in generalized lipodystrophy (GLD). [925] [926] PLD is commonly associated with Type II mesangiocapillary (membranoproliferative glomerulonephritis).

Partial lipodystrophy most often presents in girls between ages 5 and 15 years. In addition to the loss of fat, the lipodystrophies are associated with a wide variety of metabolic and systemic abnormalities. Hyperinsulinism, insulin resistance, and diabetes are common. Other metabolic abnormalities include hyperlipidemia, hyperproteinemia, and euthyroid hypermetabolism. Clinical findings may include tall stature, muscular hypertrophy, hirsutism, macroglossia, abdominal distension, subcutaneous nodules, acanthosis nigricans, hepatomegaly, cirrhosis, clitoral or penile enlargement, febrile adenopathy, cerebral atrophy, cerebral ventricular dilatation, hemiplegia, mental retardation, and cardiomegaly. [925] [926] Renal disease occurs in 20% to 50% of patients with PLD, [925] [926] and PLD occurs in 10% of patients with membranoproliferative glomerulonephritis (MPGN) Type II. [927] [928] Patients are noted to have asymptomatic proteinuria and microhematuria, but the nephrotic syndrome is occasionally present. [929] [930] Diminished C3 levels in association with the C3 nephritic (C3NeF) is the most prominent serologic abnormality. The course of glomerular disease is fairly rapid progression to ESRD and the prognosis of PLD is determined mainly by renal disease.[923]

In GLD, the nephrotic syndrome, non-nephrotic proteinuria, and hypertension have been reported.[922] In a recent report, 88% of these patients had albumin excretion greater than 30 mg/24h, 60% had albuminuria (>300 mg/24h), and 20% had nephrotic-range proteinuria greater than 3500 mg/24h.[928]

Pathology

Partial lipodystrophy is frequently associated with mesangiocapillary (membranoproliferative) glomerulonephritis Type II or dense deposit disease. [929] [930] [932] [933] Patients with type III MPGN[931] and minimal change disease[932] have also been reported. Focal and segmental glomerulosclerosis, membranoproliferative glomerulonephritis, and diabetic glomerulosclerosis have been reported in patients with GLD.[928]

Pathogenesis and Treatment

The pathogenesis of PLD and GLD is poorly understood. It is unlikely that one unifying link will be found given the differences in epidemiology, genetics, and clinical features. Acquired forms of lipodystrophy are believed to be autoimmune disorders. Most patients with PLD possess an IgG autoantibody, C3 nephritic factor (C3NeF), which binds to and stabilizes the alternate pathway convertase, C3 convertase-C3bBb. In the presence of C3NeF, C3bBb becomes resistant to its regulatory proteins H and I. Although the majority of patients with partial dystrophy have low serum C3, not all patients will exhibit nephritis.[930] Recombinant leptin appears to decrease the proteinuria in some patients with GLD.[928] There is no effective therapy for PLD, and although renal transplantation is the treatment of choice when ESRD ensues, recurrence in transplants has been reported. [926] [932] [936]

LECITHIN-CHOLESTEROL ACYLTRANSFERASE (LCAT) DEFICIENCY

Gjone and Norum reported a familial disorder characterized by proteinuria, anemia, hyperlipidemia, and corneal opacity. [937] [938] Most of the initial patients were of Scandinavian origin; subsequent reports have been from other countries. [939] [940]

Clinical Features

The triad of anemia, nephrotic syndrome, and corneal opacities suggests this disorder. Renal disease is a universal finding with albuminuria noted early in life. Proteinuria increases in severity during the fourth and fifth decades, often with development of the nephrotic syndrome. The latter is accompanied by hypertension and progressive renal failure. Most patients are mildly anemic with target cells and poikilocytes on the peripheral smear. There is evidence of low-grade hemolysis. During childhood, corneal opacities appear as grayish spots over the cornea accompanied by a lipoid arcus. Visual acuity is unimpaired. Atherosclerotic events are accelerated in these patients. [937] [941] [942] [943] [944]

Pathology

Abnormalities are found mainly in the glomeruli, but arteries and arterioles may also be affected. [937] [938] [943] [945] By light microscopy ( Fig. 31-49 ), the glomerular capillary walls are thickened and there is mesangial expansion. Basement membranes are irregular and often appear to contain vacuoles, resembling stage 3 membranous alterations. Double contouring of capillary walls is occasionally present. Similar vacuoles in the mesangium impart a honeycomb appearance. There is no associated glomerular hypercellularity. By immunofluorescence microscopy, there is typically negative staining for all immunoglobulin and complement components. On electron microscopy (Fig. 31-50 ), the vacuolated areas seen by light microscopy correspond to extracellular irregular lucent zones (lacunae) in the mesangial matrix and GBM containing lipid inclusions. These inclusions contain rounded, small, dense structures, either solid or with a lamellar substructure.

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FIGURE 31-49  Lecithin-Cholesterol Acyltransferase (LCAT) deficiency: The glomerular basement membranes and mesangium have a vacuolated appearance, resembling stage 3 membranous glomerulopathy (Jones methenamine silver, ×800).

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FIGURE 31-50  Lecithin-Cholesterol Acyltransferase (LCAT) deficiency: Electron micrograph showing intramembranous lacunae with rounded structures containing an electron-dense membranous core and electron lucent periphery (×5000).

000519

 

Pathogenesis

The disorder is inherited in an autosomal recessive pattern. Patients have little or no LCAT activity in their blood circulation because of mutations in the LCAT gene. [946] [947] LCAT is an enzyme that circulates in the blood primarily bound to high-density lipoprotein and catalyzes the formation of cholesteryl esters via the hydrolysis and transfer of the sn-2 fatty acid from phosphatidylcholine to the 3-hydroxyl group of cholesterol. Thus patients with LCAT deficiency have high levels of phosphatidylcholine and unesterified cholesterol, with corresponding low levels of lysophosphatidylcholine and cholesteryl ester in the blood. An abnormal lipoprotein, lipoprotein-X (Lp-X) is present in patients' plasma. Lp-X is thought to arise from the surface of chylomicron remnants that are not further metabolized due to the absence of active LCAT. Accumulation of lipid component occurs in both intra- and extracellular sites. Damage to the GBM occurs from these lipids resulting in proteinuria. Endothelial damage and resulting vascular insufficiency may contribute to renal insufficiency. It has been proposed that Lp-X stimulates mesangial cells, leading to the production of MCP-1 (monocyte chemoattractant protein-1), promoting monocyte infiltration, foam cell formation, and progressive glomerulosclerosis in a manner similar to atherosclerosis.[945]

Diagnosis

In patients suspected of having LCAT deficiency, measurements of plasma enzyme should be performed. The enzyme levels and activity vary among kindreds[939]; thus enzyme measurements should include activity as well as mass. Other abnormalities of lipids frequently accompany LCAT deficiency. The plasma is turbid, total cholesterol varies, triglycerides are increased, HDL is reduced, and all fractions contain higher amounts of cholesterol.

Treatment

A low lipid diet or lipid lowering drugs have not shown to be of benefit.[940] Plasma infusions may provide reversal of erythrocytic abnormalities, but long-term benefits have yet to be demonstrated.[946] The lesions may recur in the allograft but renal function is adequately preserved.[947]

LIPOPROTEIN GLOMERULOPATHY

Lipoprotein glomerulopathy (LPG) is a newly recognized glomerular characterized by dysbetalipoproteinemia, lipid deposition in the kidney leading to glomerulosclerosis and renal failure. The majority of patients have been from Japan. [951] [952]

The histologic hallmark of LPG is the presence of lami-nated thrombi consisting of lipids within the lumina of dilated glomerular capillaries. The pathogenesis of LGP is unknown, but the presence of thrombi consisting of lipoproteins raised the possibility that LPG might be related to a primary abnormality in lipid metabolism.[950] Indeed Type III hyperlipidemia (elevated LDL and high apo-E levels) have been reported in Japanese patients, associated with apo-E variants. [952] [954] [955] [956] [957] [958] Furthermore, LPG-like deposits were detected in apo-E deficient mice transfected with apo-E (Sendai), one of the apo-E variants associated with LPG. Abnormal apo-E has not been found in the single European patient with this disease.[956]

There is no uniformly effective therapy for LPG; however, intensive lipid-lowering therapy has been reported to be effective in one patient with LPG.[957] Recurrence of lesions of LPG have occurred in renal allografts. [961] [962]

GLOMERULAR INVOLVEMENT WITH BACTERIAL INFECTIONS

Infectious Endocarditis

The natural history of endocarditis-associated glomerulonephritis has changed significantly in parallel with the changing epidemiology of infectious endocarditis (IE) and the advent of antibiotics. In the pre-antibiotic era, Streptococcus viridans was the most common organism and glomerulonephritis occurred in between 50% to 80% of cases.[960] During that era, glomerulonephritis was less common in association with acute endocarditis. [964] [965]With the use of prophylactic antibiotics in patients with valvular heart disease, and an increase in intravenous drug use, Staphylococcus aureus has replaced S. viridans as the primary pathogen. Glomerulonephritis in these patients with acute IE occurs as commonly as in subacute endocarditis. [963] [966] [967] [968] The incidence of glomerulonephritis with endocarditis with S. aureus ranges from 22% to 78% [966] [969] being higher in those series consisting predominantly of intravenous drug users. [969] [970]

Clinical Features

Renal complications of IE include infarcts, abscesses, and glomerulonephritis (all of which may coexist). In focal glomerulonephritis, mild asymptomatic urinary abnormalities including hematuria, pyuria, and albuminuria may be noted. Infrequently, with severe focal glomerulonephritis, renal insufficiency or uremia may be present. Renal dysfunction, micro or gross hematuria and the nephrotic-range proteinuria may be present with diffuse glomerulonephritis. [963] [966] [971] Rapidly progressive renal failure with crescents has been reported. [963] [972] Rarely, patients may present with vasculitic features (including purpura).[970] Although hypocomplementemia is frequent, it is neither invariable (occurring in 60% to 90% of patients with glomerulonephritis), nor specific for renal involvement. [968] [969] The majority of patients demonstrate activation of the classical pathway. [969] [974]Alternate pathway activation has been described in some cases of S. aureus endocarditis.[966] The degree of complement activation correlates with the severity of renal impairment[966] and the complement levels normalize with successful therapy of the infection. Circulating immune complexes have been found in the serum in up to 90% of patients. [974] [975] Mixed cryoglobulins and rheumatoid factor may also be present in the serum of patients. [968] [976]ANCA positivity has been occasionally reported in biopsy-proven immune complex glomerulonephritis associated with IE.[974] Anti-GBM antibody in eluates from diseased glomeruli has been reported.[975]

Pathology

On light microscopy, focal and segmental endocapillary proliferative glomerulonephritis with focal crescents is the most typical finding. Some patients may exhibit a more diffuse proliferative glomerulonephritis lesion with or without crescents. [963] [964] [966] [979] [980] IF reveals granular capillary and mesangial deposits of IgG, IgM, and C3. [963] [966] [979] EM shows electron-dense deposits in mesangial, subendothelial, and occasionally subepithelial locations, with varying degrees of mesangial and endocapillary proliferation. [963] [966] [979]

Pathogenesis

The diffuse deposition of immunoglobulin, the depression of complement and electron-dense deposits supports an immune complex mechanism for the production of this form of glomerulonephritis. The demonstration of specific antibody in kidney eluates and the detection of bacterial antigen in the deposits further supported this view. Both S. aureus[978] and hemolytic Streptococcus[979] antigens have been identified.

Treatment

With the initiation of antibiotic therapy, the manifestations of glomerulonephritis begin to subside. Rarely, microhematuria and proteinuria may persist for years.[960] Plasmapheresis and corticosteroids have been reported to promote renal recovery in some patients with renal failure. [972] [983] However, this approach should be taken cautiously because of the risk of promoting infectious aspects of the disease while ameliorating the immunologic manifestations.

Shunt Nephritis

Ventriculovascular (ventriculoatrial, ventriculojugular) shunts use for the management of hydrocephalus used to be colonized commonly with microorganisms, particularly Staph. albus (75%).[981] Less often, other bacteria (e.g., Propionibacterium acnes) have been implicated.[982] Ventriculo-peritoneal shunts are more resistant to infection. However, glomerulonephritis has been reported with these shunts as well.[983] Infected peritoneovenous (LeVeen) shunts also have been associated occasionally with glomerulonephritis.[984]

Patients commonly present with fever. Anemia, hepatosplenomegaly, purpura, arthralgias, and lymphadenopathy are found on examination. Renal manifestations include hematuria (microscopic or gross), proteinuria (nephrotic syndrome in 30% of patients), azotemia, and hypertension. Laboratory abnormalities include presence of rheumatoid factor, cryoimmunoglobulins, elevated sedimentation rate and C-reactive protein levels, hypocomplementemia, and presence of circulating immune complexes. [988] [989] Shunt nephritis usually presents within a few months of shunt placement, but delayed manifestations, as late as 17 years have been reported.[987] By LM, glomeruli exhibit mesangial proliferation or membranoproliferative changes. IF reveals diffuse granular deposits of IgG, IgM, and C3. Electron-dense mesangial and subendothelial deposits are found by EM.[988]

Antibiotic therapy and prompt removal of the infected catheter usually leads to remission of the glomerulonephritis.[989] However, cases progressing to chronic renal failure have been reported.[990] Rarely, patients have elevated proteinase-3-specific ANCA titers, which also improved after removal of the infected shunt, with or without corticosteroid therapy.[991]

Visceral Infection

Visceral infections in the form of abdominal, pulmonary, and retroperitoneal abscesses are known to be associated with glomerulonephritis.[992] The clinical and pathological syndrome resembles infective endocarditis. Beaufils and colleagues reported on 11 patients who had visceral abscesses and in whom acute renal failure developed. Circulating cryoglobulins, decreased serum complement levels, and circulating immune complexes were found in some of these patients. All renal biopsies showed a diffuse proliferative and crescentic glomerulonephritis. The evolution of the glomerulonephritis, documented by serial biopsies, closely paralleled the course of the infection. A complete recovery of renal function occurred in those cases in which a rapid and complete cure of the infection was obtained. For those patients in whom the infection was not cured or in whom therapy was delayed, chronic renal failure also developed.[993]

Other Bacterial Infections and Fungal Infections

Congenital, secondary, and latent forms of syphilis rarely may be complicated by glomerular involvement. Patients are typically nephrotic and proteinuria usually responds to penicillin therapy. [997] [998] [999] [1000] [1001] Membranous nephropathy with varying degrees of proliferation and with granular IgG and C3 deposits is the commonest finding on biopsies. Treponemal antigen and antibody have been eluted from deposits. Rarely minimal change lesions[999]and crescentic glomerulonephritis[1000] or amyloidosis may be seen.

Renal involvement including azotemia, proteinuria, nephrotic syndrome, renal tubular defects, and hematuria is not uncommon in leprosy, especially with the lepra reaction. [1004] [1005] [1006] [1007] [1008] [1009] Rarely, presentation with RPGN can occur[1007] and ESRD.[1008] Mesangial proliferation, diffuse proliferative glomerulonephritis, crescentic glomerulonephritis, membranous nephropathy, membranoproliferative glomerulonephritis, microscopic angiitis, and amyloidosis may all be seen in kidney biopsies. Organisms consistent with M. Leprae have been found in glomeruli.

Aspergillosis has been associated with immune complex-mediated glomerulonephritis.[1009] Membranous nephropathy, membranoproliferative glomerulonephritis, crescentic glomerulonephritis, and amyloidosis have been associated with M. tuberculosis. [1013] [1014] [1015] [1016] Mycoplasma has been reported to be associated with nephrotic syndrome and rapidly progressive glomerulonephritis. Antibiotics do not seem to alter the course of the disease. Mycoplasmal antigen has been reported to be present in glomerular lesions. [1017] [1018] [1019] [1020] [1021] Acute glomerulonephritis with hypocomplementemia has been reported with pneumococcal infections. Proliferative glomerulonephritis with deposition of IgG, IgM, complements C1q, C3, C4, and pneumococcal antigens have been observed in renal biopsies. [1022] [1023] Nocardiosis has been associated with mesangiocapillary glomerulonephritis.[1021] In infections with Brucella, patients may present with hematuria, proteinuria (usually nephrotic), and varying degrees of renal functional impairment. There usually is improvement after antibiotics, but histologic abnormalities, proteinuria, and hypertension may persist. Glomerular mesangial proliferation, focal and segmental endocapillary proliferation, diffuse proliferation, and crescents may be found in renal biopsies. IF may show no deposits, IgG, or occasionally IgA. [1025] [1026] [1027] [1028] [1029] Asymptomatic urinary abnormalities may be seen in up to 80% of patients infected with Leptospira. Patients usually present with acute renal failure due to tubulointerstitial nephritis. Rarely, mesangial or diffuse proliferative glomerulonephritis may be seen. [1030] [1031] From 1% to 4% of patients with typhoid fever secondary to Salmonella experience glomerulonephritis. Asymptomatic urinary abnormalities may be more frequent. Renal manifestations are usually transient and resolve within 2 to 3 weeks. Serum C3 may be depressed. Mesangial proliferation with deposits of IgG, C3, and C4 is the most common finding. IgA nephropathy has also been reported. [1032] [1033] [1034]

GLOMERULAR INVOLVEMENT WITH PARASITIC DISEASES

Malaria

Four strains of malaria parasite cause human disease: Plasmodium vivax, P. falciparum, P. malariae (causing quartan malaria), and P. ovale. Of these, renal involvement has been extensively documented and studied in P. malariae and falciparum. In falciparum malaria, clinically overt glomerular disease is uncommon. Asymptomatic urinary abnormalities may occur with sub-nephrotic proteinuria and hematuria or pyuria. Renal function is usually normal. Renal biopsies show mesangial proliferation or membranoproliferative lesions.[1032] Severe malaria may be manifest with hemoglobinuric acute renal failure.[1033] In quartan malaria with renal involvement, proteinuria is the cardinal manifestation, ranging from mild and transient to florid nephrotic syndrome. Significant hematuria is unusual. Serum complement may be depressed in early stages of the disease. There is progression to end-stage renal failure within 3 to 5 years. Spontaneous remissions may occur, but are rare. Antimalarial treatment fails to improve the renal outcome, and response to steroids is disappointing.[1034] Renal biopsies in Ugandan adults and children with quartan malaria show some form of proliferative glomerulonephritis (diffuse, focal, lobular, or minimal). Membranous nephropathy has also been described in these patients.[1035] However, in Nigerian children, the most common lesion was a localized or diffuse thickening of glomerular capillary walls with focal or generalized double-contouring and segmental sclerosis of the tuft.[1036] IF examination revealed deposits of IgG, IgM, C3, and P. malariae antigen in the glomeruli. By EM electron-dense material has been observed within the irregularly thickened GBM.[1037] Immune complex deposition is thought to mediate quartan malarial nephropathy through deposition of malarial antigens and antibody within the glomerulus. An experimental model in mice using P. berghei supports this hypothesis.[1038] However, late in the course of the disease, these antigens cannot be detected and possibly, non-immune mechanisms lead to persistence of disease.

Schistosomiasis is a visceral parasitic disease caused by the blood flukes of the genus Schistosoma. S. mansoni and S. japonicum cause cirrhosis of the liver and S. hematobium causes cystitis. Glomerular involvement in S. Mansoni includes mesangial proliferation, focal sclerosis, membranoproliferative lesions, crescentic changes, membranous nephropathy, amyloidosis, and eventually end-stage kidneys. [1042] [1043] [1044] Schistosomal antigens have been demonstrated in renal biopsies in such patients.[1042] Treatment with antiparasitic agents does not appear to influence progression of renal disease.[1043] S. hematobium is occasionally associated with the nephrotic syndrome, which may respond to treatment of the parasite.[1039] In some patients with schistosomiasis, renal involvement may be related to concomitant Salmonella infection.[1044]

Leishmaniasis also known as Kala-Azar is caused by Leishmania donovani. Renal involvement in Kala-Azar appears to be mild and reverts with anti-leishmanial treatment. Renal biopsies show glomerular mesangial proliferation or focal endocapillary proliferation. IgG, IgM, C3 may be observed in areas of proliferation. Amyloidosis may also complicate Kala-Azar. [1048] [1049] In Trypanosomiasis, Trypanosome brucei, T. gambiense, and T. rhodesiense cause African sleeping sickness and have rarely been associated with proteinuria.[1047] Filariasis caused by organisms in the genus Onchocerca, Brugia, Loa loa, and Wuchereria. Hematuria, proteinuria (including nephrotic syndrome) has been described. Renal manifestations may appear with management of infection. Renal biopsy findings have included mesangial proliferative glomerulonephritis with C3 deposition, diffuse proliferative glomerulonephritis, and collapsing glomerulopathy with loiasis. [1051] [1052] [1053] [1054] [1055] [1056] Trichinosis is caused by Trichinella spiralis and may be associated with proteinuria and hematuria, which abated after specific treatment. Renal biopsies in patients with trichinosis have shown mesangial proliferative glomerulonephritis with C3 deposition. [1057] [1058] Echinococcus granulosus and E. multilocularis cause hydatid disease or echinococcosis in humans. Mesangiocapillary glomerulonephritis and membranous nephropathy have occasionally been associated with hepatic hydatid cysts. [1059] [1060] Toxoplasmosis may be associated with nephrotic syndrome in infants and rarely, in adults. Mesangial and endothelial proliferation may be found, with deposition of IgG, IgA, IgM, C3, and fibrinogen in areas of proliferation. [1061] [1062] [1063]

GLOMERULAR INVOLVEMENT WITH VIRAL INFECTIONS

Viruses have been postulated to cause glomerular injury by various mechanisms including direct cytopathic effects, the deposition of immune complexes, or by initiation of autoimmune mechanisms.

In a study of previously healthy people with non-streptococcal upper respiratory infections, 4% had erythrocyte casts and glomerulonephritis on biopsy. A reduction in serum complement and serologic evidence of infection with adenovirus, influenza A, or influenza B were observed in some. Initial renal biopsy showed either focal or diffuse mesangial proliferation in all nine, with mesangial C3 deposits in six specimens. Sequential creatinine clearances were reduced in about half these patients during follow-up.[1061]

The nephrotic syndrome has been described with Epstein-Barr virus (EBV) infections.[1062] Renal biopsies in patients with urinary abnormalities have included immune complex-mediated glomerulonephritis with tubulointerstitial nephritis,[1063] minimal glomerular lesions with IgM deposition,[1064] and widespread glomerular mesangiolysis sometimes admixed with segmental mesangial sclerosis.[1065] In addition, the presence of EBV DNA in the glomerulus is thought to worsen glomerular damage in chronic glomerulopathies.[1066] Other viruses have rarely been associated with glomerulonephritis including herpes zoster, mumps, adenovirus, echovirus, Coxsackie virus, and influenza A and B.[1067]

HIV-Related Glomerulopathies

Over 42 million people have been infected with the human immunodeficiency virus (HIV) worldwide, with an estimated 5 million new infections each year.[1068] A variety of glomerular lesions and in particular, a unique form of glomerular damage, HIV-associated nephropathy (HIVAN), have emerged as significant forms of renal disease in HIV-infected patients. [1072] [1073]

HIV-Associated Nephropathy

Clinical Features

In 1984, the first detailed report of a new pattern of sclerosing glomerulopathy in HIV-infected patients was reported.[1071] Subsequent studies mainly from large urban centers confirmed the occurrence and described the features of HIVAN. [1074] [1075] [1076] [1077] [1078] [1079] [1080] [1081] [1082] [1083] [1084] In these largely urban eastcoast centers, the prevalence of HIVAN approached 90% in nephrotic HIV-positive patients in contrast to a prevalence of only 2% in San Francisco where most seropositive patients were white homosexuals. [1085] [1086] [1087]

There is a strong predilection for HIVAN among HIV-infected patients of African Heritage. The black:white ratio among patients with HIVAN is 12:1.[1085] HIVAN is the third leading cause of ESRD among African Americans aged 20 to 64, following only diabetes and hypertension. [1081] [1089] Of HIV-infected adults, who do not use intravenous drugs, with glomerular lesions, 17% of whites had very mild FSGS, 75% diffuse mesangial hyperplasia (DMH), and none severe FSGS in contrast to blacks in whom only 27% had DMH but in whom 55% had severe FSGS. Blacks were also more likely to have more severe clinical renal disease with heavier proteinuria, a higher incidence of the nephrotic syndrome, and greater renal insufficiency. A similar presentation has been found in Los Angeles and Europe. [1090] [1091] Racial factors are important in mutations of HIV receptors, which may in part explain some differences in the racial predisposition to HIV infection and HIVAN. [1092] [1093] [1094] Although intravenous drug use has been the most common risk factor for the HIVAN, the disease has been seen in all groups at risk for AIDS including homosexuals, perinatally acquired disease, heterosexual transmission, and exposure to contaminated blood products.[1069] HIVAN usually occurs in patients with a low CD4 count, but full-blown AIDS is certainly not a prerequisite for the disease. In one New York study the onset of HIVAN was most common in otherwise asymptomatic HIV-infected patients (i.e., 12 of 26 were asymptomatic patients). [1074] [1078] There is no relationship between the development of HIVAN and patient age and duration of HIV infection, or types of opportunistic infections or malignancies.[1069] The prevalence of HIVAN in patients who test positive for HIV is reported to be 3.5% in patients screened in the clinic setting[1092]; the same group reported that HIVAN was found in 6.9% of autopsies in HIV-infected patients.[1093]

The clinical features of HIVAN include presenting features of proteinuria, typically in the nephrotic range (and often massive), and renal insufficiency. Other manifestation of the nephrotic syndrome including edema, hypoalbuminemia, and hypercholesterolemia have been common in some series but less so in others despite the heavy proteinuria. [1072] [1074] [1077] [1078] [1082] [1084] [1097] Likewise, the incidence of hypertension has been variable even in patients with severe renal failure. Some patients, however, present with subnephrotic range proteinuria, and urinary sediment findings of microhematuria and sterile pyuria.[1095] The renal ultrasound in HIVAN show echogenic kidneys with preserved or enlarged size with an average of over 12 cm in spite of the severe renal insufficiency. [1078] [1082] Echogenicity may correlate with the histopathologic tubulo-interstitial changes better than the glomerular changes.[1079]

Pathology

The term HIVAN is reserved for the characteristic LM pattern of focal segmental glomerulosclerosis and related mesangiopathies.[1070] The focal sclerosing features are typically collapsing with retraction of the glomerular capillary walls and luminal occlusion either in a segmental or global distribution ( Fig. 31-51 ). [1073] [1076] [1099] In the acute phase, this occurs without a substantial increase in matrix or hyalinosis. There is striking hypertrophy and hyperplasia of the visceral epithelial cells, which form a cellular crown over the collapsed glomerular lobules ( Fig. 31-52 ). In one study analyzing the expression pattern of podocyte differentiation and proliferation markers, there was disappearance of all podocyte differentiation markers from collapsed glomeruli, associated with cell proliferation suggesting that the podocyte phenotype is dysregulated.[1097] Patients with HIVAN have a higher percentage of glomerular collapse, less hyalinosis, and greater visceral cell swelling than patients with classic idiopathic FSGS or heroin nephropathy even when matched for serum creatinine and degree of proteinuria.[1073] The tubulointerstitial disease is also more severe in HIVAN with tubular degenerative changes and regenerative features, interstitial edema, fibrosis, and inflammation. [1073] [1076] Tubules are often greatly dilated into microcysts containing proteinaceous casts (see Fig. 31-51 ). By IF, IgM and C3 are present; however, by EM, immune deposits are not detected ( Fig. 31-53 ). In almost all biopsies of HIVAN there are numerous tubulo-reticular inclusions (TRI) within the glomerular and vascular endothelial cells ( Fig. 31-54 ). [1072] [1073] [1076] [1099] These 24-nm inter-anastomosing tubular structures are found within the dilated cisternae of the endoplasmic reticulum.

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FIGURE 31-51  HIV-associated nephropathy: Glomeruli have collapsed tufts with capping of the overlying podocytes and dilatation of the urinary space. The tubules are dilated forming microcysts with abundant proteinaceous casts (Periodic acid Schiff, ×125).

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FIGURE 31-52  HIV-associated nephropathy: The characteristic pattern of collapsing glomerular sclerosis is depicted. Glomerular capillary lumina are occluded by wrinkling and retraction of the glomerular capillary walls associated with marked hypertrophy and hyperplasia of the podocytes, forming a pseudocrescent (Periodic acid-Schiff, ×325).

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FIGURE 31-53  HIV-associated nephropathy: Electron micrograph showing wrinkling of glomerular basement membranes with marked podocyte hypertrophy, complete foot process effacement, and numerous intracytoplasmic protein resorption droplets (×2500).

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FIGURE 31-54  HIV-associated nephropathy: Electron micrograph showing a typical tubuloreticular inclusion within the endoplasmic reticulum of a glomerular endothelial cell (×6000).

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Pathogenesis

Recent evidence strongly supports a role for direct HIV-1 infection of renal parenchymal cells. By in-situ hybridization, HIV-1 RNA was detected in renal tubular epithelial cells, glomerular epithelial cells (visceral and parietal), and interstitial leukocytes.[1098] Renal epithelial cells may be an important reservoir for HIV because HIV RNA was found in the kidney of patients with undetectable viral loads in peripheral blood.[1098] Moreover, HIV-infected tubular epithelium can support viral replication, as evidenced by the detection of HIV quasispecies separate from those found in peripheral blood of the same patient.[1099]

A replicative-deficient transgenic mouse model of HIVAN has been developed with lesions identical to HIV nephropathy. [1103] [1104] [1105] It was subsequently demonstrated that the HIV transgene expression is required for development of the HIVAN phenotype.[1103] Thus, viral replication may not be necessary for the development of the disease and it is likely that a viral gene product with direct effects on renal cells is operative.

The lesions of collapsing glomerulopathy are associated with podocyte proliferation and de-differentiation. [1100] [1107] The specific gene(s) responsible for producing these changes are being investigated. The nef gene (which is thought to act by activation of tyrosine kinases) was found to be essential in producing HIV-induced changes in podocyte cultures[1105] and in one murine model of HIVAN.[1106] Recent evidence supports a synergistic role for nef and vpr on podocyte dysfunction and progressive glomerulosclerosis.[1107] Host genes may also play a role in the pathogenesis of HIVAN. The expression of two cyclin-dependent kinase inhibitors (which regulate cell cycle), p27 and p57, were decreased in podocytes from HIVAN biopsies whereas expression of another CDK inhibitor, p21, was increased.[1108]

Course and Treatment

The natural history of HIVAN during the early part of the AIDS epidemic was characterized by rapid progression to end-stage renal disease (ESRD). Case series from the United States that were published during the years that HIVAN was first described demonstrated an almost universal requirement for dialysis within less than 1 year of diagnosis. [1074] [1077] [1078] There are no randomized controlled trials to define the optimal treatment of HIVAN. There are several early case reports and retrospective analyses in which patients with biopsy-documented or presumed HIVAN have experienced either remissions of the nephrotic syndrome or improvement in GFR when treated with AZT or AZT with acyclovir. [1112] [1113] [1114] [1115] Recently, the role of combined antiviral therapies and the use of newer agents in the management of HIVAN have been investigated in small numbers of patients with apparent beneficial effects. [1116] [1117] [1118] Corresponding to the introduction of highly active anti-retroviral therapy (HAART) the rise in new cases of ESRD due to HIVAN slowed markedly.[1116]

There have been a few studies using corticosteroids in HIVAN. In an early study, prednisone was not associated with improvement in children with HIVAN. [1120] [1121] Remissions in HIV-infected children with the minimal change pattern on biopsy treated with steroids have been noted, but not in children with sclerosing or collapsing lesions.[1069] In adults, however, several retrospective studies have shown short-term improvement in clinical parameters.[1122] [1123] [1124]

Three pediatric patients with HIVAN on biopsy had sustained remissions of the nephrotic syndrome when treated with cyclosporine.[1117] They eventually developed opportunistic infections requiring the cyclosporine to be discontinued and subsequently experienced relapses of the nephrotic proteinuria and renal failure.

In isolated patients and in several small trials use of ACE inhibitors has been shown to decrease proteinuria in HIVAN and to slow the progression to renal failure. [1125] [1126] [1127] Serum ACE levels are elevated in HIV patients and ACE inhibitors may prevent proteinuria and glomerulosclerosis by either hemodynamic mechanisms or through modulation of matrix production and mesangial cell proliferation or even by affecting HIV protease activity. [1125] [1126] [1127] Although some of these studies used control groups of untreated HIV patients of similar age, sex, race, and degree of renal insufficiency and proteinuria the studies were not randomized, blinded trials. Nevertheless in each study the ACE-treated group had less proteinuria, less rise in serum creatinine, and less progression to ESRD.

At present the therapy of HIVAN should include use of multiple anti-viral agents as in HIV infected patients without nephropathy. Use of ACE inhibitors or perhaps angiotensin II receptor blockers, with careful attention to hyperkalemia and acute rises in the serum creatinine, may be beneficial. Immunosuppressive therapy with steroids or cyclosporine should be used only in certain patients where the potential benefits of therapy outweigh the risks of further immunocompromise and opportunistic infections.

Several studies have documented favorable outcomes in HIVAN patients who received renal transplants. [1128] [1129] The current consensus is that renal transplantation is no longer a contraindication in HIV-positive patients, and the British HIV Association have published guidelines on this topic.[1127]

Other Glomerular Lesions in Patients with HIV Infection

Although HIVAN is the most common form of glomerulopathy found in HIV-infected patients, other lesions have been reported as well. In one series of over 100 biopsies for glomerular disease in HIV-positive patients, 73% were classic HIVAN, but other lesions included MPGN in 10%, minimal change disease in 6%, amyloid in 3%, lupus-like nephritis in 3%, acute postinfectious glomerulonephritis in 2%, membranous nephropathy 2%, and 1% each of focal and segmental necrotizing glomerulonephritis, thrombotic microangiopathy, IgA nephropathy, and immunotactoid nephropathy.[1070] Collapsing FSGS is most common in urban centers with large black populations, whereas higher rates of immune complex glomerulonephritis are found in other cities and especially European white populations. [1090] [1091] In a study from Paris, immune complex GN was found in over 50% of the white HIV seropositive patients but only 21% of the blacks. [1090] [1091] Likewise in a study from northern Italy of 26 biopsies on HIV-infected patients most cases were of immune complex GN but none of classic HIVAN.[1128]

IgA nephropathy has been reported in a number of series of HIV-infected patients. [1132] [1133] [1134] [1135] [1136] This has occurred in both whites and blacks despite the rarity of typical IgA nephropathy in black populations. The clinical features usually include hematuria, proteinuria, and some renal insufficiency. Cases with leukocytoclastic angiitis of the skin (consistent with Henoch-Schönlein purpura) have also been noted. The histology shows a variety of changes from mesangial proliferative glomerulonephritis to collapsing glomerulosclerosis with mesangial IgA deposits. IgA anti-HIV immune complexes have been eluted from the kidneys of several such patients, and several patients have had circulating immune complexes containing IgA idiotypic antibodies directed against viral proteins, either anti-HIV p24 or HIV gp41.[1132]

Membranoproliferative glomerulonephritis may be the most common pattern of immune complex-mediated glomerulonephritis seen in HIV-infected patients. Two series document a high occurrence in intravenous drug abusers co-infected with HIV and hepatitis C. [1137] [1138] Most patients have had microscopic hematuria, nephrotic-range proteinuria, and renal insufficiency at biopsy. Cryoglobulins are commonly positive, as is hypocomplementemia, and some have had both hepatitis B and hepatitis C infection. The pathology of the glomerulopathy may be similar to idiopathic MPGN Type 1 or Type 3 although some patients also have features of segmental membranous or mesangioproliferative features.

A lupus-like immune complex glomerulonephritis has been reported in a number of patients. [1081] [1139] [1140] [1141] Most of these patients have had positive serology for SLE with positive ANA, anti-DNA, and low complement levels. This contrasts with a low incidence of ANA positivity and almost no anti-DNA positivity in the general HIV-infected population.[1139]

A not-infrequent association in both white and black HIV-infected patients has been thrombotic thrombocytopenic purpura (TTP). Most have been in an advanced stage of HIV infection and had renal involvement with hematuria, proteinuria, and variable renal insufficiency. Other typical findings of TTP such as fever, neurologic symptoms, thrombocytopenia, and microangiopathic hemolytic anemia are often present. There is no known association with E.coli O157:H7 or other agents implicated in the epidemic forms of hemolytic uremic syndrome. Mortality is high even if treated with vigorous therapy (e.g., plasmapheresis, fresh frozen plasma infusion, and corticosteroids).[1140]

Glomerular Manifestations of Liver Disease

Hepatitis B

Hepatitis B antigenemia has been associated with glomerulonephritis for over 30 years. Hepatitis B has a worldwide distribution. In countries where the virus is endemic (sub-Saharan Africa, Southeast Asia, and Eastern Europe) there is vertical transmission from mother to infant and horizontal transmission between siblings. Hepatitis B-associated nephropathy occurs in these children with a 4:1 male preponderance. [1144] [1145] [1146] In the United States and Western Europe where hepatitis B is acquired by parenteral routes or sexually, the nephropathy affects mainly adults and has a different clinical course from the endemic form. [1147] [1148] [1149] However, hepatitis B-associated nephropathy is rare in hepatitis B carriers.[1147] Polyarteritis nodosa has also been associated with hepatitis B.[1148]

Clinical Features

Most patients present with proteinuria or the nephrotic syndrome. In endemic areas, there may not be a preceding history of hepatitis. The majority of patients have normal renal function at time of presentation. There may be urinary erythrocytes but the majority have a bland sediment. Liver disease may be absent (carrier state) or chronic, and clinically mild. Serum aminotransferases may be normal or modestly elevated (between 100–200IU/L). Liver biopsies in these patients often show chronic active hepatitis. Some patients ultimately develop cirrhosis in their biopsies. There is often spontaneous resolution of the carrier state with resolution of renal abnormalities. Spontaneous resolution of HBV-associated nephropathy is particularly common in children from endemic areas. The probability of a spontaneous remission may be as high as 80% after 10 years. [1152] [1153]

Pathology

Most cases of hepatitis B-associated nephropathy manifest membranous nephropathy, although mesangial proliferation and sclerosis have also been reported. [1144] [1145] [1147] [1148] [1149] [1154] [1155] A few patients with membranoproliferative glomerulonephritis have also been described, with mesangial cell interposition, reduplication of the GBM, and subendothelial glomerular deposits. [1147] [1149] [1154] In a few series Type III MPGN have been reported in which there are electron-dense subepithelial deposits in addition to the changes seen in Type I MPGN.[1146] Crescentic glomerulonephritis in association with membranous changes and primary crescentic glomerulonephritis have also been described. [1156] [1157] The glomerular lesions appear to be immune complex-mediated. HBsAg, HBcAg, and HBeAg[1155] have all been demonstrated in glomerular lesions, as has HBV DNA.[1146] [1159]

Treatment

In children with mild endemic form of hepatitis B-associated nephropathy, no treatment other than supportive care is advocated. In patients with progressive renal dysfunction, interferon has been used with mixed results. [1160] [1161] [1162] [1163] Steroids do not significantly improve proteinuria and may potentially enhance viral replication. [1164] [1165] Adenine arabinoside and thymic extract (Thymostimuline) for 6 months have shown to be of some benefit in these cases.[1163] Nucleoside analogs including lamivudine (3TC), adefovir, and lobucavir have also demonstrated clinical utility in treating hepatitis B infection; Lamivudine was shown to reduce proteinuria and lead to a lesser incidence of ESRD in 10 patients with hepatitis B-associated nephropathy.[1164] Preemptive lamivudine therapy in renal transplant recipients has shown improved survival compared to historical controls. [1168] [1169]

Hepatitis C

Renal disease associated with hepatitis C virus (HCV) infection includes membranoproliferative glomerulonephritis with or without associated mixed cryoglobulinemia and membranous glomerulopathy. The membranoproliferative glomerulonephritis is most often type 1, with fewer cases of type 3. [1170] [1171] [1172] Rare cases of diffuse proliferative and exudative glomerulonephritis, polyarteritis, and fibrillary and immunotactoid glomerulopathy have also been described in association with HCV.[1170] Most patients have evidence of liver disease as reflected by elevated plasma transaminase levels. However, transaminase levels are normal in some cases and a history of acute hepatitis is often absent.

Pathogenesis

The pathogenesis of HCV-related nephropathies is immune complex-mediated. HCV-specific proteins have been isolated from glomerular lesions.[1171] The disappearance of viremia in response to interferon (see later) is associated with a diminution of proteinuria; a relapse of viremia is accompanied by rising proteinuria.

Clinical and Pathologic Features

Mixed cryoglobulinemia is associated with hepatitis C virus and may cause a systemic vasculitis; patients may exhibit constitutional systemic symptoms, palpable purpura, peripheral neuropathy, and hypocomplementemia. The renal manifestations include hematuria, proteinuria (often in the nephrotic range), and renal insufficiency. The histologic findings resemble those in idiopathic MPGN type 1 or type 3 (Figs. 31-55 and 31-56 [55] [56]) except for intraluminal protein “thrombi” on light microscopy and the organized annular-tubular substructure of the electron-dense deposits on electron microscopy. Prior to the advent of hepatitis C serological tests, mixed cryoglobulinemia had been considered an idiopathic disease (“essential” mixed cryoglobulinemia). Up to 95% of these patients show signs of HCV infection.[1172] Few patients with thrombotic microangiopathy associated with cryoglobulinemia have been described.[1173] Membranoproliferative glomerulonephritis without associated cryoglobulinemia may occur, but is much less common.[1168]

000235

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FIGURE 31-55  Hepatitis C-associated membranoproliferative glomerulonephritis type 1: The mesangium is expanded by global mesangial hypercellularity associated with numerous double contours of the glomerular basement membranes (Periodic acid Schiff, ×500).

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000590

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FIGURE 31-56  Hepatitis C-associated membranoproliferative glomerulonephritis type 3: There are mixed features of membranoproliferative glomerulonephritis type 1 (with mesangial proliferation and duplication of glomerular basement membrane) and membranous glomerulopathy (with basement membrane spikes) (Jones methenamine silver, ×325).

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Rarely, membranous nephropathy may be associated with HCV infection. Patients present with the nephrotic syndrome or proteinuria. Complement levels tend to normal and neither cryoglobulins nor rheumatoid factors are present in HCV-associated membranous nephropathy.[1174]

Both Type I MPGN (with and without cryoglobulinemia) and membranous nephropathy may recur in the allograft after renal transplantation, sometimes leading to graft loss. [1178] [1179] [1180] [1181] Similar lesions have occurred in native kidneys after liver transplantation in HCV-positive patients. [1182] [1183]

Treatment

A number of reports demonstrating a beneficial response to α-interferon therapy in patients with HCV-induced renal disease. [1177] [1184] [1185] Vasculitic symptoms, viral titers, proteinuria, and in some studies, plasma creatinine improved in 50% to 60% of patients receiving α-interferon for periods up to 1 year. Cessation of interferon therapy, however, was associated with recurrence of viremia and cryoglobulinemia in a majority of patients in these studies. Longer periods of treatment (18 months) show some additional benefit in liver disease, but has not been evaluated in the HCV-induced renal disease.[1183] Interferon therapy may paradoxically exacerbate proteinuria and hematuria that appears to be unrelated to viral antigenic effects.[1184]

Combination therapy with ribavirin and interferon has shown better response rates as initial therapy, and in α- interferon relapses in patients with HCV liver disease. [1188] [1189] [1190] Combination therapy appeared to improve biochemical parameters of renal dysfunction in 20 HCV-GN patients, which was not accompanied by a significant virological response.[1188] Another report on 18 patients showed sustained virologic responses in two thirds of patients which was associated with improvement in renal parameters.[1189] Combination therapy (especially ribavirin) may not be well tolerated in the presence of significant renal dysfunction. Interferon-α treatment of renal transplant patients with HCV has been associated with acute renal failure[1190] and acute humoral rejection.[1191]

Cyclophosphamide treatment has been used successfully in HCV-glomerulonephritis,[1192] even if interferon-resistant.[1193] Cyclophosphamide treatment may be associated with a temporary, reversible increase in viral load and a change of quasispecies.[1194] Fludarabine has been reported to decrease proteinuria in HCV-associated cryoglobulinemic MPGN.[1195] Recently, there have been reports of rituximab-induced remissions of proteinuria in HCV-GN.[1196] In renal transplant patients with HCV-GN, similar improvement in renal parameters have been reported, albeit with a higher incidence of infectious complications.[1197]

Autoimmune Chronic Active Hepatitis

Autoimmune chronic hepatitis is a distinctive progressive necrotic and fibrotic disorder of the liver with clinical or serologic evidence (or both) of a generalized autoimmune disorder.[1198] Two distinct clinical lesions have been associated with this disorder: glomerulonephritis and interstitial nephritis. Patients with the glomerular lesion present with nephrotic syndrome or renal insufficiency. On renal biopsy they have membranous or membranoproliferative glomerulonephritis. In two patients with membranous nephropathy, circulating immune complexes containing U1-RNP (ribonucleoprotein) and IgG have been reported. Eluates from the kidney tissue revealed higher concentrations of anti U1-RNP antibody. It is not known whether immunosuppressive therapy ameliorates the renal disorder.[1198] It is unclear if coexistent hepatitis C infection had been present in many of these patients.

Liver Cirrhosis

Glomerulonephritis is a rare manifestation of liver cirrhosis. Glomerular morphologic abnormalities with IgA deposition have been noted in more than 50% of patients with cirrhosis at both necropsy and biopsy [1202] [1203] although this has also been found in some autopsies of non-cirrhotic kidneys.[1201] Clinically, there may be mild proteinuria or hematuria (or both). There are two patterns on histology: a mesangial sclerosis (“cirrhotic glomerular sclerosis”) or membranoproliferative glomerulonephritis. The latter may be associated with more severe renal symptoms and a depression of serum complement C3 levels.[1202] Again, it is unclear if some patients had co-existent hepatitis C infection. Rarely, HSP with rapidly progressive glomerulonephritis has been described in association with cirrhosis.[1203]

Renal biopsies of patients with cirrhosis on light microscopy show an increase in mesangial matrix with little on no increase in mesangial cellularity, a lesion known as “hepatic glomerulopathy”. Less commonly, the distinctive pathologic findings consist of mesangial proliferative glomerulonephritis with mesangial IgA deposits usually accompanied by complement deposition and less intense IgG and/or IgM. [1202] [1207] [1208] By electron microscopy, the mesangium and subendothelial regions contain lucencies with dense granular and rounded membranous structures consistent with lipid inclusions ( Fig. 31-57 ). Increased serum IgA levels are found in over 90% of cirrhotic patients with glomerular IgA deposition. Other authors have reported IgM as the dominant immunoglobulin.[1200] Cirrhotic glomerulonephritis is usually a clinically silent disease; however, the diagnosis can be suspected by finding proteinuria, or abnormalities of the urine sediment. The pathogenesis may relate to defective hepatic clearance of IgA as well as altered processing or portacaval shunting (or both) of circulating immune complexes.[1206] This theory is bolstered by the finding of increased deposits of IgA in skin and hepatic sinusoids in cirrhotic patients.[1207] Moreover, in patients with non-cirrhotic portal fibrosis who underwent portal-systemic bypass procedures there was an increase in the incidence of clinically overt glomerulonephritis (from 78% to 32%) associated with deposition of IgA after the procedure. In the latter group, there was also a significant incidence of renal failure (50% after 5 years).[1208] Similar findings were noted in children with end-stage liver disease from α-1 antitrypsin deficiency or biliary atresia, which resolved after liver transplantation.[1209]

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FIGURE 31-57  Hepatic glomerulopathy: A paramesangial electron-dense deposit corresponding to IgA is present. In addition, there are irregular lucencies containing dense granular and rounded membranous structures within the mesangial matrix and extending into the subendothelial space (×6000).

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Glomerular Lesions Associated with Neoplasia

The occurrence of glomerular syndromes, both nephrotic and nephritic, may be associated with malignancy, but is rare (<1%). Glomerular disease may be seen with a wide variety of malignancies. Carcinomas of the lung, stomach, breast, and colon are most frequently associated with glomerular lesions. Membranous nephropathy is the most common lesion associated with carcinoma. [1213] [1214] [1215] Patients over the age of 50 presenting with nephrotic syndrome should be reviewed for the presence of a malignancy. [1216] [1217]

Clinical and Pathologic Features

Clinically, the glomerulopathy of neoplasia may be manifested by proteinuria or the nephrotic syndrome, an active urine sediment, and/or diminished glomerular filtration. Significant renal impairment is uncommon, and is usually associated with the proliferative forms of glomerulonephritis. In evaluating an erythrocyte sedimentation rate (ESR) in patients with nephrotic syndrome, it should be noted that most such patients have an ESR above 60 mm/h, with roughly 20% being above 100 mm/h. As a result, an elevated ESR alone in a patient with the nephrotic syndrome (or with end-stage renal disease) is not an indication to evaluate the patient for an occult malignancy or underlying inflammatory disease. [1218] [1219]

Membranous Nephropathy

Membranous nephropathy may be associated with malignancies in 10% to 40% of cases. [1217] [1220] These include carcinoma of bronchus,[1218] breast,[1219] colon, [1223] [1224] stomach, ovary,[1222] kidney,[1223] pancreas,[1224]and prostate, [1228] [1229] as well as testicular seminoma,[1227] parotid adenolymphoma, carcinoid tumor, [1231] [1232] and Hodgkin disease and carotid body tumor.[1230] In some cases of membranous nephropathy associated with malignancy, tumor antigens have been detected within the glomeruli. It is postulated that tumor antigen deposition in the glomerulus is followed by antibody deposition, causing “in situ” immune complex formation, and subsequent complement activation. [1234] [1235] Immune complexes and complement have been found in cancer patients without overt renal disease.[1231] Removal of the tumor may lead to remission of the nephrotic syndrome, which may then recur, following the development of metastasis. In many instances successful treatment of the neoplasm has induced a partial or complete remission of the associated glomerulopathy.

Minimal Change Disease or Focal Glomerulosclerosis

Minimal change disease or focal glomerulosclerosis may occur in association with Hodgkin disease, [1236] [1237] [1238] and, less often, non-Hodgkin lymphoma or leukemia,[1234] and rarely thymoma,[1236] mycosis fungoides,[1237]renal cell carcinoma,[1238] and other solid tumors. [1242] [1243] [1244] Secretion of a lymphokine by abnormal T cells may underlie glomerular injury in these disorders. [1245] [1246]

Secondary amyloidosis has been described with a number of malignancies, particularly renal cell carcinoma, Hodgkin disease, and chronic lymphocytic leukemia. [1] [2] [4] In Hodgkin disease, for example, renal amyloidosis is generally a late event resulting from a chronic inflammatory state; by comparison, minimal change disease most often occurs at the time of initial presentation.[5]

Proliferative Glomerulonephritides and Vasculitides

Both membranoproliferative and rapidly progressive glomerulonephritis have been described in patients with solid tumors and lymphomas, although the etiologic relationship between these conditions is not proven. [1244] [1247] The association is probably strongest for membranoproliferative glomerulonephritis and chronic lymphocytic leukemia and may be associated with circulating cryoglobulins. [1248] [1249] Mesangial proliferation with IgA deposition has been associated with mucosa-associated lymphoid tissue (MALT) lymphoma, which resolved following management of the malignancy with chlorambucil.[1247] Although the association between crescentic glomerulonephritis and vasculitis with tumors may be coincidental, it has been suggested that the malignancy may act as a trigger for the vasculitis. [1251] [1252] [1253] In contrast to the nephrotic states described earlier in which renal function is generally well preserved at presentation and the urine sediment is usually benign, patients with proliferative glomerulonephritis often have an acute decline in renal function and an active urine sediment.

Thrombotic Microangiopathy

Both the hemolytic-uremic syndrome (HUS) and the related disorder thrombotic thrombocytopenic purpura (TTP) can occur in patients with malignancy. An underlying carcinoma of the stomach, pancreas, or prostate may be associated with HUS. More commonly, however, anti-tumor therapy is implicated: mitomycin, the combination of bleomycin and cisplatin, and radiation plus high-dose cyclophosphamide prior to bone marrow transplantation all can lead to the HUS, which may first become apparent months after therapy has been discontinued.[1251] This topic is reviewed elsewhere in this book.

GLOMERULAR DISEASE ASSOCIATED WITH DRUGS

Heroin Nephropathy

In the 1970's, reports began to appear linking heroin abuse to the nephrotic syndrome and renal biopsy findings of focal and segmental glomerulosclerosis. This syndrome was referred to as heroin-associated nephropathy (HAN).[1255] [1256] [1257] [1258] [1259] [1260] Similar lesions were seen in users of intravenous pentazocine (Talwin), and tripelennamine (pyribenzamine) so-called T's and Blues.[1258] This syndrome occurred almost exclusively in blacks; it has been suggested that blacks may have a genetic predisposition for developing HAN. [1262] [1263] The mean age was less than 30 years old with 90% of the patients being males. The duration of drug abuse varied from 6 months to 30 years (mean 6 years) prior to the onset of renal disease. Most patients presented with the nephrotic syndrome. The course of HAN was relentless progression to ESRD over many years in those addicts who continued to use heroin, whereas a regression of abnormalities was seen in patients that were able to stop using the drug. Kidney biopsies of these patients showed lesions of focal segmental and global sclerosis. Nonspecific trapping leads to the deposition of IgM and C3 in areas of sclerosis. There was usually significant interstitial inflammation associated with the glomerular lesion. The pathogenesis of HAN is unknown. Abnormalities of cellular and humoral immunity have been well described in heroin addicts.[1261] It has been suggested that morphine itself could act as an antigen and that contaminants used to “cut” the heroin could contribute to the pathogenesis. Morphine (the active metabolite of heroin) has been shown to stimulate proliferation and sclerosis of mesangial cells and fibroblasts. [1265] [1266] The syndrome of HAN has almost disappeared among drug addicts presenting with renal failure; for example, there has been a sharp decline in incident cases of HAN and there have been no reported cases of HAN-associated ESRD from Brooklyn, New York during the period of 1991 to 1993. [1267] [1268] In part this trend coincides with the rise of HIV infection and HIVAN.

Nonsteroidal Anti-Inflammatory Drugs (NSAID)-Induced Nephropathy

Nonsteroidal anti-inflammatory drugs are being used by approximately 50 million of the general public in the United States at any point in time. Approximately 1% to 3% of patients exposed to NSAIDs will manifest one of the renal abnormalities associated with its use: fluid and electrolyte disturbances, acute renal failure, and nephrotic syndrome with interstitial nephritis and papillary necrosis.[1266] The combination of acute interstitial nephritis and nephrotic syndrome is characteristic of this group of compounds. Essentially all NSAIDS can cause this type of renal disease, [1270] [1271] [1272] including the cyclooxygenase-2 inhibitors. [1273] [1274]

Clinical and Pathologic Features

Minimal-Change Disease with Interstitial Nephritis

The onset of NSAID-induced nephrotic syndrome is usually delayed, with a mean time of onset of 5.4 months (range 2 weeks to 18 months). Patients may present with edema and oliguria. Systemic signs of allergic interstitial nephritis are usually absent. The urine exhibits microhematuria and pyuria. Proteinuria is usually in the nephrotic range. The extent of renal dysfunction may be mild to severe. On LM the findings consist of minimal-change disease with interstitial nephritis. A focal of diffuse interstitial infiltrate consists predominantly of cytotoxic T lymphocytes (also other T cell subsets, B cells, and plasma cells). [1275] [1276] The syndrome usually reverses after discontinuing therapy, and the time to recovery may be between 1 month to 1 year.[1269] Complete remission is usually seen.[1274] Relapse of proteinuria has been reported.[1275] Treatment of the nephrotic syndrome is usually unnecessary because the disorder is self-limiting. However, a short course of corticosteroids may be beneficial in patients in whom no response is seen after several weeks of discontinuation of the drug.[1276] Plasma exchange was reported with being associated with rapid recovery of renal function in two patients.[1277]

Other Patterns

Minimal-change nephrotic syndrome without interstitial disease has been occasionally reported.[1278] Granulomatous interstitial disease without glomerular changes has also been described.[1279] Membranous nephropathy has also been reported in association with NSAID use,[1280] including the newer COX-2 inhibitors.[1271] As in minimal change nephrotic syndrome, there is rapid recovery after drug withdrawal in NSAID-induced membranous nephropathy.

Pathogenesis

The mechanism of NSAID-induced nephrotic syndrome has not been defined. It has been proposed that inhibition of cyclooxygenase by NSAID inhibits prostaglandin synthesis and shunts arachidonic acid pathways towards the production of leukotrienes. These byproducts of arachidonic acid metabolism may promote T lymphocyte activation and enhanced vascular permeability, leading to minimal change disease. [1270] [1271] [1272]

Anti Rheumatoid Arthritis Therapy-Induced Glomerulopathy

Gold Salts and D-Penicillamine

Proteinuria and nephrotic syndrome have been reported to occur in association with both oral and parenteral gold. [1284] [1285] Dermatitis may occur concurrently. Membranous nephropathy, and rarely minimal-change disease have been reported.[1283] A higher incidence of nephropathy has been reported in patients with HLA B8/DR3. [1287] [1288]

Proteinuria in association with membranous nephropathy is the most common lesion reported. Less commonly, minimal-change disease and mesangial proliferative lesions have been reported.[1285] Goodpasture-like syndrome,[1286]minimal-change nephrotic syndrome,[1287] and membranous nephropathy concurrently with vasculitis[1288] have been described rarely. HLA B8/DR3 haplotypes are also associated with penicillamine nephropathy.[1289] Tiopronin and bucillamine (a penicillamine-like compound) have also been associated with the same renal lesions described for penicillamine. [1293] [1294] The onset of proteinuria with gold or penicillamine therapy is usually between 6 to 12 months after starting therapy. Proteinuria usually resolves after withdrawing the offending agent; persistent renal dysfunction is uncommon. [1288] [1292] [1295] Under close supervision, gold and penicillamine has been continued in patients with nephropathy with no obvious adverse effect on renal function.[1293] Anti-TNF alpha agents have been reported to promote the development of lupus-like nephritis and ANCA-associated glomerulonephritis in patients with rheumatoid arthritis.[1294]

Other Medications

Organic mercurial exposure can occur with diuretics, skin lightening creams, gold refining, and industrial exposure. Proteinuria and nephrotic syndrome have been reported. [1298] [1299] [1300] Renal biopsy in such patients has shown membranous nephropathy [1301] [1302] or minimal-change disease.[1300] The nephrotic syndrome has been associated with the anticonvulsants ethosuccimide,[1301] trimethadione,[1302] and paradione.[1303] Diffuse proliferative glomerulonephritis may be seen with mesantoin (mephenytoin).[1304] ANCA-associated vasculitis as well as a lupus-like nephritis has been reported with propylthiouracil. [1308] [1309] [1310] [1311] Captopril has been associated with the development of proteinuria and the nephrotic syndrome due to membranous nephropathy.[1309] Substituting enalapril for captopril has been reported to ameliorate the nephrotic syndrome.[1310] Interferon-α has been associated with interstitial nephritis, minimal-change disease, focal and segmental glomerulosclerosis and acute renal failure, [1314] [1315] thrombotic microangiopathy, [1316] [1317] and crescentic glomerulonephritis.[1315] Mercapto propionyl glycine(2-MPG) used in the management of cystinuria has been associated with membranous glomerulopathy.[1316] Lithium use has been associated with minimal change disease, [1320] [1321] membranous nephropathy,[1319] and focal and segmental glomerulosclerosis. [1323] [1324] The use of high-dose pamidronate in patients with malignancies has been associated with HIV-negative collapsing focal and segmental glomerulosclerosis.[1322]

Miscellaneous Diseases Associated with Glomerular Lesions

Well-documented cases exist of nephrotic syndrome associated with unilateral renal artery stenosis, which improved after correction of the stenosis. The mechanism of proteinuria presumably relates to high levels of angiotensin-II.[1326] [1327] [1328]

Acute silicosis has been associated with a proliferative glomerulonephritis with IgM and C3 deposits, leading to renal failure.[1326] A patient with dense lamellar inclusions in swollen glomerular epithelial cells, similar to those seen in Fabry disease has also been described.[1327]

Membranous nephropathy and membranoproliferative glomerulonephritis[1328] have been described in association with ulcerative colitis.[1329]

Kimura disease and angiolymphoid hyperplasia with eosinophilia (ALHE) produce skin lesions that appear as single or multiple red-brown papules or as subcutaneous nodules with a predilection for the head and neck region. Other associated features include eosinophilia and elevated IgE levels. Both Kimura disease and the similar ALHE are frequently associated with glomerular disease. Mesangial proliferative glomerulonephritis[1330] and minimal change disease[1331] have been described.

Renal complications of Castleman disease (angiofollicular lymph node hyperplasia) are uncommon. The reported cases are very heterogeneous and their renal pathology includes minimal-change disease, mesangial proliferative glomerulonephritis,[1332] membranous nephropathy,[1333] membranoproliferative glomerulonephritis,[1334] crescentic glomerulonephritis,[1335] fibrillary glomerulonephritis,[1336] and amyloidosis.[1337] Serum Il-6 levels appear to be elevated and declines with corticosteroid therapy.[1332] Removal of tumor mass, or management with steroids appears to ameliorate the renal manifestations in some cases.

Angioimmunoblastic lymphadenopathy has been associated with diffuse proliferative glomerulonephritis with necrotizing arteritis, and minimal-change disease. [1237] [1341]

Acknowledgment

The authors thank Dr. Alice Appel for excellent editorial assistance in the completion of this chapter.

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