Antiphospholipid Antibody Syndrome. Rare Diseases of the Immune System

9. Antiphospholipid Syndrome (APS) and the Renal Involvement

Nicoletta Mezzina  and Renato Alberto Sinico 

(1)

Clinical Immunology and Renal Unit, Azienda Ospedaliera Ospedale San Carlo Borromeo/Università Statale di Milano, Via Pio II, 3/Via Festa del Perdono, Milan, 20100, Italy

(2)

Clinical Immunology Unit and Renal Unit, Azienda Ospedaliera Ospedale San Carlo Borromeo, Via Pio II, 3, Milan, 20100, Italy

Nicoletta Mezzina

Email: nicoletta.mezzina@unimi.it

Renato Alberto Sinico (Corresponding author)

Email: renatoalberto.sinico@fastwebnet.it

Keywords

Antiphospholipid syndrome (APS) nephropathyGlomerulonephritisThrombotic microangiopathy (TMA)HypertensionProteinuria

9.1 Introduction

Even if hypertension (the most frequent clinical sign of APS renal involvement) has been described as a part of the spectrum of APS manifestations since the first publication on this syndrome [1], APS kidney involvement was probably underestimated and not well characterized until recently.

A possible explanation is that several manifestations of renal involvement (hypertension, haematuria, and proteinuria) were often neglected and that renal biopsy was rarely performed due to the frequent occurrence of thrombocytopenia and the use of anticoagulants among APS patients.

For these reasons the true prevalence of renal involvement in APS is difficult to establish. In the few retrospective studies on large cohorts of APS patients, a prevalence of approximately 9–10 % is reported [23], but it could be speculated that it might be higher.

Renal involvement in APS is characterized by noninflammatory occlusion/thrombosis of renal vessels (arterial and venous) ranging in size from large vessels to intrarenal microvasculature. Indeed, a large spectrum of vascular manifestations have been described in association with antiphospholipid antibodies, such as renal artery stenosis/thrombosis, renal infarction, renal vein thrombosis, and a small-vessel vaso-occlusive nephropathy recently defined as “APS nephropathy” [45]. In addition to vaso-occlusive abnormalities, other kinds of renal lesions such as glomerulonephritis have been reported in primary APS (PAPS) [26]. This heterogeneity of renal involvement could be explained by the presence of different underlying pathogenetic mechanisms.

From a clinical point of view, the most frequent signs and laboratory characteristics of APS renal involvement include hypertension, hematuria, acute renal failure, and progressive chronic renal insufficiency with mild to nephrotic range proteinuria. APS can also cause end-stage renal disease (rare) and allograft vascular thrombosis [7].

This chapter reviews the range of renal abnormalities associated with APS, their diagnosis and treatment options.

9.2 Renal Artery Lesions

Renal artery involvement is well known and has been described in either SLE-related APS and primary APS (PAPS).

In 1990, Ostuni et al. [8] reported for the first time the occurrence of renal artery thrombosis and hypertension in a 13-year-old girl with high titers of aCL (anticardiolipin Ab). More recently, in 2003 Sangle et al. [9] showed how aPL-positive hypertensive patients, compared to young hypertensive controls and healthy individuals, had more frequently renal artery lesions detected by magnetic resonance renal angiography (26 vs. 8 %, p < 0.001).

The defining characteristic of artery involvement associated with aPL is renal artery stenotic lesions which had two different patterns with some unique features: smooth well delineated and often noncritical stenosis distal to the ostium of the renal artery and, a less frequent pattern, similar to atherosclerotic lesion, characterized by stenosis proximal to the ostium, occasionally involving the aorta [9].

These occlusive lesions can be uni- or bilateral and their pathogenesis can be related with in situ thrombosis of the renal artery or emboli from heart valve lesions [9]. Moreover, it has been suggested that aPL leads to accelerated atherosclerosis as well as to increased endothelin levels with consequent vasoconstriction. Additional observations have suggested cross-reactivity between aPL and antibodies to Apo A-I, HDL, and oxidized LDL, which could indicate a possible link between thrombotic and atherosclerotic complications [10].

9.2.1 Clinical Manifestations and Diagnosis

The most common clinical manifestation of renal artery thrombosis is the onset of severe hypertension or a worsening of a preexisting systemic hypertension, sometimes associated with pain in the renal area, hematuria, or renal failure [59]. This lesion can also lead to renal infarction, resulting from partial or total occlusion of renal artery or infrarenal aorta, or to ischemic acute renal failure, or to the slowly progressive ischemic chronic renal insufficiency.

Imaging techniques, for example, renal Doppler ultrasound as a first-line procedure followed, if necessary, by computed tomography (CT), renal angiography, renal scintigraphy, and gadolinium enhancement magnetic resonance angiography, should be used for the diagnosis and the evaluation of the extension of these lesions [11].

9.2.2 Treatment

For all aPL-positive patient, as general recommendations, it is important to control risk factors for atherosclerosis, such as obesity, smoking, hypertension, diabetes, and hyperlipidemia. The oral contraceptive pill and hormone replacement therapy should be avoided, given their association with thromboembolic events [7].

Regarding drugs therapy, a successful management with antihypertensive drugs, antiplatelet drugs, or anticoagulants has been reported. After the initial heparin treatment, the current recommendation for secondary thromboprophylaxis in APS patients is lifelong warfarin, because of the risk of recurrent events. But the intensity of anticoagulation is controversial because in randomized controlled trials (RCT), aimed at finding the appropriate INR levels for secondary thrombosis prevention, only a small proportion of the involved patients had arterial events. Although target INR levels of 2.0–3.0 should be enough for APS patients with vein thrombosis, for patients with renal artery thrombosis, an addition of antiplatelet agents to warfarin (target INR 2.0–3.0) or adoption of higher INR target ranges of 3.0–4.0 may be required [12].

Thrombolysis or transluminal balloon angioplasty with or without stenting has also been described [13] and may be considered. For severe lesions not amenable to angioplasty and stenting, surgical intervention is suggested [14].

9.3 Renal Vein Thrombosis

Thrombosis of the inferior vein cava and the main and/or minor renal veins has been described in patients with primary APS as well as SLE-related APS.

In 1993, Asherson et al. [15] reported for the first time the association of aPL and renal vein thrombosis in patients with SLE and positive lupus anticoagulant (LA).

Indeed this manifestation has been especially associated with LA positivity and occurs more frequently in APS patients with SLE than in those without SLE [11]. These associations suggest that aPL could play a role in renal vein thrombosis pathogenesis; however, other procoagulant conditions, such as trauma, extrinsic compression, pregnancy, oral contraceptive, and especially nephrotic syndrome, have to be ruled out in any cases of renal thrombosis in APS patients.

9.3.1 Clinical Manifestations and Diagnosis

The clinical manifestation depends on the extent of the renal thrombosis, but it is usually represented by nephrotic range proteinuria. Renal failure may also occur, especially in cases of bilateral thrombosis.

Consequently, if any patient with persistently positive aPL suddenly develops heavy proteinuria or presents an exacerbation of a previously stable proteinuria, careful doppler studies of the renal vasculature should be considered in order to rule out renal vein thrombosis [16].

9.3.2 Treatment

As assumed for arterial lesions, the control of risk factors for atherosclerosis is indicated in patients with venous renal thrombosis, and a lifelong thromboprophylaxis with warfarin (target INR 2.0–3.0) is mandatory for the high risk of recurrence. An adoption of higher INR target (3.0–4.0) or addition of antiplatelet agents may be required in recurrent cases [12].

9.4 Intrarenal Vascular Lesions “APS Nephropathy”

As it was previously stated, even if thrombosis may take place at any vascular site of the renal vasculature, the intrarenal lesions of APS were poorly recognized until recently.

The term “APS nephropathy” was coined in the near 1999 by Nochy et al. who first described in a systematic way the clinical and histopathologic lesions on renal biopsy of 16 cases of primary APS (PAPS). The patients had small-vessel acute thrombosis (thrombotic microangiopathy, TMA) associated with chronic vascular lesions such as fibrous intimal hyperplasia (FIH) or occlusion of intrarenal arteries and arterioles, organizing thrombi with or without recanalization, or focal cortical atrophy (FCA) [5] (Table 9.1).

Table 9.1

Histologic characteristics of APS nephropathy

Acute lesions

Chronic lesions

Thrombotic microangiopathy (TMA)

Arterial fibrous intimal hyperplasia (FIH) or arterial occlusion by organized thrombi with or without recanalization

 

Focal cortical atrophy (FCA)

 

Tubular thyroidization

APS nephropathy was also observed in SLE-related APS patients, independently of lupus nephritis, and in catastrophic APS (especially thrombotic microangiopathy) [17].

Thrombotic microangiopathy (TMA) in APS patients is the best-known feature of APS nephropathy as it was observed previously also by other authors [1819], and it is histopathologically characterized by the absence of inflammatory cells and of vascular immune deposits and by the presence of fibrin thrombi in glomeruli and in the entire intrarenal vascular circulation. Immunofluorescence studies reveal that fibrin is the main constituent of thrombi in the absence of immunoglobulins. These lesions resemble the histological picture of the other thrombotic microangiopathies such as thrombocytopenic purpura and hemolytic uremic syndrome. TMA represents the most important vascular lesion threatening the renal prognosis in SLE-related APS [20], and it is the predominant renal lesion seen in catastrophic APS [17].

Fibrous intimal hyperplasia (FIH) is characterized by an intense myofibroblastic intimal cellular proliferation which reduces the arteriolar lumen. The intima tends to be much more cellular than that seen in typical arteriosclerosis of aging, assuming an onion-skin arrangement in biopsy cross sections. Sometimes the lumina could be obstructed by fibrous tissue and permeated with endothelialized channels indicative of recanalizing thromboses (organizing thrombi).

Focal cortical atrophy (FCA) involves the superficial cortex under the renal capsule, forming foci or triangles that led to retraction of the tissue, with a sharp border with the rest of the normal cortex, and it is accompanied by a depression of the contour of the remaining renal capsule.

In these atrophic areas all elements of the renal parenchyma are altered as a part of the ensemble of lesions comprising FCA: the glomeruli appear either small and sclerotic or large but virtually lacking the glomerular tuft, the tubules are atrophic and packed with eosinophilic casts, resembling thyroid tissue (tubular thyroidization), and the arterioles are occluded by fibrin microthrombi or by fibrous tissue.

The presence of identical lesions of FIH and tubular thyroidization in surgical nephrectomies performed for renal artery stenosis (in order to reduce hypertension secondary to unilateral stenosis) led to speculate that tissue ischemia and the activation of the renin-angiotensin system are possible causes of those lesions in APS [5].

9.4.1 Clinical Manifestations and Diagnosis

Clinical presentation of APS nephropathy can vary widely ranging from arterial hypertension, which is the prominent and sometimes the only clinical sign suggestive of nephropathy, to sudden acute renal failure or to mild and progressive chronic renal insufficiency with different levels of proteinuria. Lupus anticoagulant (LA) positivity seems to be more frequently present among APS patients with an intrarenal involvement (2).

In all APS patients with clinical and laboratory findings that suggest renal involvement (new onset of hypertension, proteinuria, hematuria, or renal insufficiency), renal biopsy should be performed [21].

On the other hand, every time it is found in a biopsy section, a combination of any two of three elements which represents a constellation more or less characteristic of APS (TMA, FIH, or FCA), the pathologist should be alerted to the possibility of PAPS diagnosis which has to be clinically confirmed [5].

Moreover, in patients with biopsy-proven APS nephropathy lesions and persistently positive aPL, the diagnosis of APS should be considered even without thrombotic events or pregnancy morbidity [21].

9.4.2 Treatment

Since no evidence-based recommendations are available, the optimum management of patients with only intrarenal vascular lesions (APS nephropathy), alone or in combination with SLE nephropathy, is unknown.

Several empirical therapeutic approaches have been used, ranging from the pharmacological management of hypertension, associated with aspirin and/or oral anticoagulants, with steroids, and in some cases with additional immunosuppressive treatment.

Pons-Estel et al. [7] on the basis of their personal experience recommend starting anticoagulation with an INR target of 2.0–3.0 (as for any other patient with thrombotic APS) and adding antiplatelet agents or increasing target INR levels to 3.0–4.0 if no improvement is achieved.

In other recent studies, a stabilization of renal function and proteinuria by use of rituximab is reported. These studies proposed that rituximab might have a function in the treatment of persistently aPL-positive patients with non-criteria manifestations of APS, by reducing the production of autoantibodies [2223].

9.5 Glomerular Disease

Besides the vaso-occlusive abnormalities of the intrarenal arteries and glomerular capillaries, other types of histological lesions have been also described in primary APS patients with renal involvement. These lesions include membranous glomerulonephritis (the most frequent), IgA nephropathy, pauci-immune crescentic glomerulonephritis, mesangial C3 nephropathies, vasculitis, and minimal change disease/focal segmental glomerulosclerosis [6224].

Glomerulonephritis in PAPS can’t be ascribed to thrombosis; instead other mechanisms such as immune complex deposition seem to be implicated. PAPS is considered a systemic autoimmune disease, and it has been described a number of different circulating autoantibodies and a different degree of complement reduction especially among patients who had PAPS with nephropathy.

The autoantibodies positivity, such as antinucleosome (anti-NSC) ab, and complement reduction found in renal PAPS support the idea of heterogeneity of renal involvement and suggest the presence of a continuum between SLE and PAPS.

As expected, anti-NCS antibodies are more frequently detected in PAPS with lupus-like disease, and patients with MN or proliferative glomerulonephritis, especially when C1q deposits and hypocomplementemia are present, should be considered at high risk for developing SLE. So a careful monitoring is mandatory in these patients [2].

9.5.1 Clinical Manifestations and Diagnosis

The clinical presentation is not different from APS nephropathy, with only a more frequent presence of nephrotic range proteinuria. As it was stated before, renal biopsy should be performed every time a renal APS involvement is suspected.

Moreover, a complete nephrologic workup should be performed especially in these kinds of patients, in which a differential diagnosis is very important to classify and treat them correctly.

9.5.2 Treatment

Since no evidence-based recommendations are available, several different therapeutic approaches have been used in these cases. The treatments usually consist in steroids, also IV pulses, associated with different immunosuppressive drugs, on the basis of the scheduled treatments for the same but not APS-related glomerulonephritis.

9.6 ESRD and Renal Transplantation

ESRD is a rare complication of primary APS. This was clearly revealed in different prospective and retrospective studies in which only few PAPS patients developed ESRD [225]. Instead, several studies have revealed that there is a higher incidence of aPL positivity among patients with ESRD and on dialysis, than that found in the general population [2627]. This association of ESRD and aPL is irrespective of age, sex, type of dialysis membrane, drug treatment, and chronic B and C hepatitis. Possible causes include bioincompatibility problems as dialysis membranes, trauma to blood passing through the hemodialysis circuit, and induction by microbial agents or their products, for example, endotoxins present in the dialysate. However, it is still uncertain if these antibodies are truly pathogenic in ESRD patients or are just an epiphenomenon.

Moreover, evidence suggests that aPL-positive patients undergoing renal transplantation are at increased risk of renal and systemic vascular thrombosis and graft failure. For this reason, recently the somministration of perioperative immunosuppressives, given in addition to anticoagulation, has been proposed for aPL-positive patients undergoing renal transplantation [28].

In Table 9.2 the main reports from the literature concerning renal involvement in primary antiphospholipid syndrome are summarized.

Table 9.2

Main reports on renal involvement in primary antiphospholipid syndrome (PAPS)

Author, year

Type of study

n° of patients

Result

D’Agati et al. (1990) [18]

Biopsy-documented report

3 patients:

In all pts:

 1 with PAPS

 Active lesions → TMA involving arterioles and glomerular capillaries

 1 with SLE-APS

 Renal thrombosis not associated with active endocapillary proliferative lupus nephritis

 1 with lupus-like syndrome

Amigo et al. (1992) [19]

Case series

20 patients with PAPS:

In all pts:

 5 with renal involvement → renal biopsy performed

 Active lesions → TMA involving both arterioles and glomerular capillaries

Levy et al. (1996) [24]

Case report

1 patient with PAPS and MN at renal biopsy

Peripheral blood lymphocytes from the patient transferred to a SCID mice, which developed renal lesion consistent with the human MN → role of aPL as possible inducers of renal damage

Nochy et al. (1999) [5]

Biopsy case series

16 patients with PAPS and renal manifestations undergone renal biopsy

“APS nephropathy”

Active lesions → TMA in 5 cases (31 %)

Chronic lesions → FCA in 10 cases (62 %) and FIH in 12 cases (75 %)

Fakhouri et al. (2003) [6]

Biopsy case series

29 biopsies performed in patients with PAPS

“APS nephropathy” (TMA + FCA + FIH) in 20 cases

Glomerular diseases in 9 cases:

 MN in 3 cases

 MCD/FSGS in 3 cases

 Mesangial C3 nephropathy in 2 cases

 Pauci-immune crescentic GN in 1 case

Tektonidou et al. (2008) [17]

Biopsy case series

37 patients with biopsy-proven renal involvement:

“APS nephropathy”

 6 with CAPS

Acute lesions (TMA)

 8 with CAPS

 CAPS: all patients (100 %)

 23 with SLE-APS

 PAPS: in 3 of 8 (37.5 %) patients

 SLE-APS: 8 of 23 (35 %) patients

Chronic lesions (FIH and FCA)

 Similar frequencies (66 % and 50, respectively) in all 3 groups

Sinico et al. (2010) [2]

Retrospective study on PAPS patients

160 patients with PAPS:

“APS nephropathy” in 4 patients:

 14 (8.7 %) patients with renal manifestations → in 10 pts was performed a renal biopsy

 Acute lesions (TMA) in 2 cases

 Chronic lesions (FCA + FIH) in 2 cases

Glomerular diseases in 10 patients:

 MN in 4 cases

 Proliferative GN in 2 cases

SLE systemic lupus erythematosus, TMA thrombotic microangiopathy, MN membranous nephropathy, aPL antiphospholipid antibodies, FCA focal cortical atrophy, FIH fibrous intimal hyperplasia, MCD/FSGS minimal change disease/focal segmental glomerular sclerosis, GN glomerulonephritis, CAPS catastrophic antiphospholipid syndrome

APS and the renal involvement: key points

1. Probably underestimated

2. Hypertension, microscopic hematuria and proteinuria: most common clinical signs

3. New onset or worsening of hypertension and/or pain in the renal area suggest renal artery thrombosis/stenosis

4. New onset or worsening of proteinuria and/or pain in the renal area may be due to renal vein thrombosis

5. Positive LA is more closely associated with APS renal involvement

6. APS nephropathy: acute lesions (TMA) + chronic lesions (FCA, FIH)

7. Kidney biopsy crucial for diagnosis and management

8. APS as allograft rejection cause (higher RR in positive aCL patients)

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