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

CHAPTER 32. Microvascular and Macrovascular Diseases of the Kidney

Abbas A. Kanso   Nada M. Abou Hassan   Kamal F. Badr



Microvascular Diseases, 1147



Hemolytic-Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, 1147



Systemic Sclerosis, 1153



Radiation Nephritis, 1155



Atheroembolic Renal Disease, 1157



Renal Involvement in Sickle Cell Disease, 1159



Macrovascular Diseases, 1162



Acute Occlusion of the Renal Artery, 1162



Renal Artery Aneurysms, 1164



Renal Vein Thrombosis, 1165

Microvascular Diseases

The kidney is involved in a number of discreet clinico-pathologic conditions that affect systemic and renal microvasculature. Certain of these entities are characterized by primary injury to endothelial cells, such as the spectrum of hemolytic-uremic syndrome (HUS)–thrombotic thrombocytopenic purpura (TTP) and radiation nephritis. In others, the microvasculature of the kidney is involved in autoimmune disorders, such as systemic sclerosis (scleroderma). The renal microcirculation can also be affected in sickle cell disease, to which the kidney is particularly susceptible because of the low oxygen tension attained in the deep vessels of the renal medulla as a result of countercurrent transfer of oxygen along the vasa recta. The smaller renal arteries and arterioles can also be the site of thromboembolic injury from cholesterol-containing material dislodged from the walls of the large vessels. These conditions are considered jointly in this chapter.

Taken as a group, diseases that cause transient or permanent occlusion of renal microvasculature uniformly result in disruption of glomerular perfusion, and hence of the glomerular filtration rate, thereby constituting a serious threat to systemic homeostasis. Early recognition and aggressive management of these disorders is therefore crucial for the long-term preservation of renal function.


Thrombotic microangiopathy (TMA) represents a group of disorders with common pathological features including alteration in the microvascula-ture with detachment and swelling of the endothelium, deposition of amorphous material in the subendothelial space, and luminal platelets aggregation leading to microthrombosis. Laboratory features include thrombocytopenia, hemolytic anemia, and schistocytes. Among TMAs hemolytic uremic syndrome and thrombotic thrombocytopenic purpura are the most prominent diseases.[1]

Given the overlap in clinical manifestations, the two syndromes were considered as a continuum of a single disease entity. Newly identified pathophysiologic mechanisms, however, have allowed differentiation of the two syndromes on a molecular basis ( Table 32-1 ).[1]

TABLE 32-1   -- New Classification of Thrombotic Thrombocytopenic Purpura and Hemolytic Uremic Syndrome

Thrombotic Thrombocytopenic Purpura

Hemolytic Uremic Syndrome

Hereditary deficiency of ADAMTS 13

Schulman-Upshaw syndrome

D+HUS (classic HUS)

Shiga-toxin associated HUS

Inhibitors of ADAMTS 13

Drug induced Others

D-HUS (familial HUS)

Factor H deficiency and complement activation


D+HUS, diarrhea associated HUS; D-HUS, non-diarrhea associated HUS; HUS, hemolytic uremic syndrome.




Clinical Features

A report by Moschcowitz[2] in 1925 described a 16-year-old girl who developed fever, anemia, petechiae, renal failure, and neurologic impairment and the term TTP was used to describe the syndrome. TTP is usually a sporadic disease, with an incidence of approximately 3% to 7% of cases per 1 million population.[2] It is more common in women (female:male ratio, 3:2 to 5:2) and in whites (white:black ratio, 3:1). Although the peak incidence is in the third and fourth decades of life, TTP can affect any age group.[2]

Thrombotic thrombocytopenic purpura classically presents with the pentad of thrombocytopenia, microangiopathic hemolytic anemia, fever, neurological and renal dysfunction.[2] Thrombocytopenia is essential for the diagnosis;[3]most patients present with values below 5.109/l8.[2] Purpura is minor and can be absent. Retinal hemorrhages can be present; however, bleeding is rare.[2] Neurological symptoms can be seen in over 90% of patients during the entire course of the disease. Central nervous system involvement mainly represents thrombo-occlusive disease of the grey matter, but can also include headache, cranial nerve palsies, confusion, stupor, and coma. These features are transient but recurrent. Up to half of patients who present with neurological involvement may be left with sequelae. Renal insufficiency is less common than initially described. One group has reported 25% of patients to have creatinine clearance less than 40 ml/min. Low-grade fever is present in one quarter of patients at diagnosis, but can often be seen as a consequence of plasma exchange. Less common manifestations include acute abdomen, pancreatitis, and sudden death.[2] The term HUS was introduced in 1955 by Gasser and co-workers[4] in their description of an acute fatal syndrome in children characterized by hemolytic anemia, thrombocytopenia, and severe renal failure. In children, HUS is commonly associated with infection of shiga-like toxin producing E. coli. It is characterized by bloody diarrhea in 90% that starts 2 to 12 days after the ingestion of the contaminated vehicle. Usually patients are afebrile.[4] Renal failure occurs in 50% to 70% of cases.[5] Non-shiga-toxin associated HUS comprises 5% to 10% of all cases.[5] It can be familial or sporadic and has a poor outcome; 50% progress to end-stage renal disease (ESRD) and 25% may die in the acute phase.[6] Neurological symptoms and fever can occur in 30%. Pulmonary, cardiac, and gastrointestinal manifestations can also occur.[4]

Because TTP can sometimes involve severe renal disease and HUS can involve extra renal manifestations, the two can be difficult to distinguish on clinical grounds only.[7]

Laboratory Findings

The hallmark laboratory finding, essential for the diagnosis of HUS/TTP, is microangiopathic hemolytic anemia.[2] Reticulocyte counts are uniformly elevated. The peripheral smear reveals increased schistocytes number, with polychromasia and, often, nucleated RBC. The latter may represent not only a compensatory response, but also damage to the marrow-blood barrier resulting from intramedullary vascular occlusion.[2] Other indicators of intravascular hemolysis include elevated lactate dehydrogenase (LDH), increased indirect bilirubin, and low haptoglobin level.[2] The Coombs test is negative.[2] Moderate leukocytosis may accompany the hemolytic anemia. Thrombocytopenia is uniformly present in HUS/TTP. It may be severe, but is usually less so in patients with severe renal failure.[8] The presence of giant platelets in the peripheral smear or reduced platelet survival time (or both) are consistent with peripheral consumption.[9] In children, the duration of thrombocytopenia is variable and does not correlate with the course of renal disease.[10] Bone marrow biopsy specimens usually show erythroid hyperplasia and an in-creased number of megakaryocytes. Prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen level, and co-agulation factors are normal, thus differentiating HUS/TTP from disseminated intravascular coagulation (DIC). Mild fibrinolysis with minimal elevation in fibrin degradation products, however, may be observed.[6] Diagnostic central nervous system studies in HUS/TTP have not been extensively evaluated. Punctate lesions in the white matter were detected by magnetic resonance imaging (MRI), but not by computed tomography (CT), in two patients with classic TTP presentation.[11]

Renal Involvement

Evidence of renal involvement is present in the majority of patients with HUS/TTP.[12] Microscopic hematuria and subnephrotic proteinuria are the most consistent findings. Male sex, hypertension, prolonged anuria, and hemoglobin levels greater than 10 g/L at onset are associated with a higher risk of renal sequelae in children.[13] In a retrospective study of 216 patients with a clinical picture of TTP, hematuria was detected in 78% and proteinuria in 75% of the patients.[14] Sterile pyuria and casts were present in 31% and 24% of the patients, respectively.[14] Gross hematuria is rare.[14]


The characteristic lesion in HUS/TTP is thrombotic micro-angiopathy.[1] Microthrombi have been demonstrated in arterioles and capillaries of the kidney, brain, skin, pancreas, heart, spleen, and adrenals.[15] In TTP, microthrombi are composed predominantly of platelet aggregates and a thin layer of fibrin.[15] The platelet thrombi stain strongly for von Willebrand factor (VWF), which has been implicated in the pathogenesis of TTP (see later discussion). In contrast, immunohistochemical studies on microthrombi in HUS showed prominent fibrin.[15] Subendothelial hyaline deposits and endothelial cell swelling also contribute to the occlusion of the lumens of arterioles and capillaries.[15] Venules rarely are affected, and vasculitis usually is absent.[16]

Three patterns of renal lesions have been described in HUS/TTP: glomerular, arterial, and a combination of both. In younger children, the pathology is confined mainly to the glomeruli. On light microscopy, it is characterized by thickening of capillary walls, endothelial cell swelling, and narrowing or obliteration of capillary lumens. Widening of the subendothelial space may result in a double contour or double-track appearance of the glomerular capillary walls. Clumps of red blood cells, platelets, or thrombi may be seen in the glomerular capillaries. Widening of the mesangium may be present without evidence of mesangial cell proliferation. [17] [18] [19] [20] Arterial involvement in children with HUS usually is minimal. In older children and in adults, significant arterial changes coexist with glomerular lesions. Thrombi are present in the interlobular arteries, which also demonstrate intimal edema and myointimal cell proliferation. This process may result in arterial fibroplasia. [18] [19] [20]

The glomerular lesions in these patients are ischemic in origin. The glomerular capillary walls are wrinkled, the glomerular tuft may be atrophied, and the Bowman capsule is thickened. In some patients, the glomerular changes described in younger children coexist with the pattern of arterial injury.[21] Acute cortical or tubular necrosis may occur in patients with HUS/TTP.

Immunofluorescence studies performed on renal biopsy specimens of patients with HUS/TTP invariably demonstrate fibrinogen along the glomerular capillary walls and in the arterial thrombi. Granular deposits of C3 and immunoglobulin M (IgM) may be observed in the vessel walls and in glomeruli. Electron microscopic studies demonstrate swelling of the glomerular endothelial cells and detachment from the glomerular basement membrane. [20] [22]

Electron-lucent, “fluffy” material fills the space between the glomerular basement membrane and the detached endothelium. The basement membrane itself remains intact. Similar findings are present in arteries and arterioles.[23]


Hemolytic Uremic Syndrome

Two forms of HUS have been described; diarrhea associated HUS (D+HUS), the most common form of HUS in children, is associated with infection by shiga-toxin producing E. coli O157:H7 and has an excellent prognosis. In contrast, non-shiga-toxin associated HUS and D-HUS have a poor prognosis and are often relapsing.[24]


Most cases are sporadic or occur in small clusters.[24] E. coli O157:H7 is the predominant cause of HUS in the world. Transmission can occur through contaminated food such as ground beef, unpasteurized milk, and salami, lettuce, or through municipal water, airborne transmission, and person-to-person contact.

Most E. coli O157:H7 infections and HUS occur in summer and autumn.[4] In the northern hemisphere there is a rough correlation between distance from the equator and frequency of HUS and rates of isolation of E. coli O157:H7. In the United States the incidence of E. coli O157:H7 is greater among rural than urban population.[4]

Stool culture on sorbitol-MacConkey agar, accompanied with a shiga-toxin detection assay is the ideal detection method of E. coli O157:H7.

Hemolytic uremic syndrome can follow non O15:H7 shiga-toxin producing E. coli (STEC) infections and such infections are almost certainly undetected. Diarrhea starts 2 to 12 days after ingestion of the vehicle; it is bloody in 90% of cases. Most patients, however, are afebrile. Abdominal pain is severe. White blood cells are found in 50% of examined fecal samples. The risk of developing HUS in a child younger than 10 years of age is 15%. Thrombocytopenia is the first abnormality in all patients and hemolysis usually precedes azotemia.[4]


D-HUS typically affects adults, but can occur at any age,[25] in sporadic or familial forms. It is non infective and usually precipitated by drugs or pregnancy.[26] Several studies have demonstrated genetic predisposition in atypical HUS, involving two regulatory proteins of the complement alternative pathway: Factor H (FH) and membrane co-factor protein (MCP or CD46).[25]

A study by Aldo and colleagues showed that mutations in FH, a plasma protein that inhibits the activation of the alternative pathway of complement leading to low C3 levels, are frequent in patients with D-HUS, and common polymorphisms of FH may contribute to D-HUS. In this study, no TTP patients carried this mutations.[24] However, two-thirds of patients with D-HUS has no FH mutation despite decreased C3 concentrations.[24] A study by Noris and co-workers[27] found MCP gene mutations in two related patients with a familial history of HUS. MCP may be a second putative candidate gene for D-HUS.[27]

A recent study involving 48 children with recurrent atypical HUS detected anti-FH antibodies in 3 of those children, by ELISA using coated purified human FH.[25] In this study the plasma FH activity was decreased with normal FH antigenic levels and gene analysis. This is the first report to demonstrate that HUS can occur in the setting of autoimmune disease secondary to auto antibodies that lead to acquired FH deficiency.[25]

Thrombotic Thrombocytopenic Purpura and ADAMTS 13

ADAMTS 13 is a member of the recently recognized ADAMTS (a disintegrin with thrombospondin type 1 motifs) zinc metalloprotease family. This protease cleaves VWF and prevents VWF-platelets interaction. A severe deficiency of ADAMTS13 has been described in patients with TTP,[28] and two forms have been identified.

Inhibitors to ADAMTS 13

In patients with sporadic TTP the deficiency appears to be auto-immune. IgG molecules isolated from patients with TTP suppress ADAMTS 13 activity in normal plasma.[28]

Hereditary Deficiency of ADAMTS 13

Schulman-Upshaw syndrome is characterized by thrombocytopenia and microangiopathic hemolysis developing soon after birth responding to plasma infusion. During the neonatal period, patients are treated with blood transfusion for anemia or whole blood exchange for jaundice. Most patients require subsequently plasma infusion every 2 to 4 weeks. Relapse are triggered by fever, infection, pregnancy, or surgery.[28]

Drug-induced HUS/TTP is well recognized.[29] It was most commonly diagnosed in patients receiving chemotherapeutic agents, the majority of whom were treated with mitomycin C. HUS occurred in 5% to 15% of patients who had received a cumulative dose of 20 mg/m2 to 30 mg/m2 or greater. The onset of hemolytic anemia and renal failure is usually sudden, and the mortality rate is high despite supportive therapy. Treatment with plasma exchange, steroids, immunosuppressive agents, and staphylococcal protein A immunoadsorption, however, was successful in some cases.[29] HUS/TTP has also been reported after chemotherapy with other agents ( Table 32-2 ). Thrombotic microangiopathy, unrelated to chemotherapy, has been described in conjunction with vascular tumors, acute promyelocytic leukemia, and prostatic, gastric, and pancreatic carcinomas.[30] Ticlopidine, an antiplatelet agent, was associated with the development of TTP with an estimated incidence of 1 case per 1600 to 9000 patients treated. An immune-mediated mechanism was suggested by the acute onset and the absence of dose toxicity pattern.[29]Clopidogrel, a new antiplatelet drug that has achieved widespread clinical acceptance because it has a more favorable safety profile than ticlopidine, has also been associated with the disease, and 11 cases were reported recently.[29]Cyclosporine-induced TMA was first reported following bone marrow transplantatiom, but is more commonly in patients receiving renal and other solid organs transplants. In renal allograft recipients, cyclosporine-induced HUS occurs during the first week after transplantation, as drug toxicity is dose related. Renal failure reverses with the cessation or decreasing the dose of cyclosporine.[29]

TABLE 32-2   -- Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura: Causes and Associations



Infectious agents






Escherichia coli O157:H7 (verotoxin-producing)



Shigella dysenteriae type I



Salmonella typhi



Streptococcus pneumoniae



Campylobacter jejuni



Yersinia pseudotuberculosis



Pseudomonas species






Mycobacterium tuberculosis






Togavirus (rubella)









Influenza virus



Epstein-Barr virus









Human immunodeficiency virus





















Mitomycin C









Cytosine arabinoside



Methyl CCNU















Oral contraceptives
























Carbon monoxide



Bee sting





















Malignant neoplasm






Systemic lupus erythematosus



Polyarteritis nodosa



Primary glomerulopathies




Paradoxically, cyclosporine has been used successfully to treat other drug-induced TMA (tacrolimus and clopidogrel) and some idiopathic cases.[29] HUS/TTP may occur after bone marrow transplantation independent of prior radiation or cyclosporine therapy. The incidence of TTP-HUS following hematopoeitic stem cell transplantation varies between 0.5% and 76% in different transplant series, mainly because of lack of uniform definition. The toxicity committee of Blood and Marrow Transplant Clinical Trials Network recommends it be renamed “post transplantation TMA”.[31] Tacrolimus (FK-506)-induced HUS/TTP is reported in 1% to 3% of treated patients, and it is more frequently diagnosed during the first year after transplantation.[29]

Thrombotic microangiopathy associated with interferon has been reported in patients with CML, hairy cell leukemia, and hepatitis. The association is not clearly established and it may represent a rare side effect.[29] Other drugs[32]and toxins[33] less commonly associated with HUS/TTP are listed in Table 32-1 .

Thrombotic thrombocytopenic purpura is commonly associated with pregnancy. Approximately 10% to 25% of patients with TTP are women who are either pregnant or in the postpartum period.[34] The greatest risk is near term and during post partum. This is also the time for thrombotic events, and the occurrence of preeclampsia, eclampsia, and HELLP syndrome, which may be difficult to distinguish from TTP-HUS. Decreased activity of ADAMTS13 that occurs during late pregnancy may be an additional risk factor. However, the risk of recurrence in subsequent pregnancies is unpredictable.[35]

Other diseases associated with HUS/TTP, such as pri-mary glomerular and autoimmune disorders, are listed in Table 32-2 .

Thrombotic thrombocytopenic purpura syndrome has been reported in patients with acquired immunodeficiency syndrome (AIDS).[36] The predominant presenting features are those of TTP, although some patients presented with HUS. HUS has been reported as the initial presentation of HIV infection.[37]


Endothelial Injury

Many of the infectious agents and drugs implicated in the etiology of HUS/TTP are toxic to the vascular endothelium. The shiga-like toxins, which include the verocytotoxins produced by E. coli O157:H7, inhibit eukaryotic protein synthesis and directly damage human vascular endothelial cells.[4] The glycolipid receptor for verotoxins is present on the membranes of renal endothelial, mesangial, and tubular epithelial cells. Shiga toxin has been identified bound to renal sections taken after death from infected children who died from HUS, and cellular differences in expression of glycolipid receptor might underlie organ specific response to circulating shiga toxin.[4]

Plasma of patients with HUS shows increased activity of plasminogen-activator inhibitor 1 (PAI-1), increased fibrin and thrombin generation as manifested by high concentrations of D-dimers and prothrombin fragments 1 + 2 respectively.[4]

Chandler and colleagues[38] found that these coagulation abnormalities precede azotemia and might represent an opportunity for preventing the thrombotic cascade early in the course of the disease, by thrombin inhibition and thus halting the progression to renal failure. In this study, prothrombotic abnormalities were more severe in patients who developed HUS than in those in whom the illness resolved spontaneously, and thus may represent prognostic parameters. However, given the extensive overlap between the two groups these parameters should be used with caution.[38]

In addition to blocking protein synthesis and inducing apoptosis in human renal cells and tissues, shiga toxin has additional effects on endothelial and other eukaryotic cells.[4] A new experiment showed that sublethal doses of shiga toxin, with minimal effect on protein synthesis lead to increased mRNA expression and protein synthesis of IL-8, monocyte chemo attractant protein-1, and cell adhesion molecules, preceded by activation of NF-κb. Shiga toxin alters endothelial cell adhesion properties and metabolism, enabling leukocyte-dependent inflammation. This inflammation activates endothelial cells that lose thromboresistance properties leading to microvascular thrombosis.[5]

Complement Activation

Recent genetic studies have shown that mutations in factor H, membrane cofactor proteins and factor I, regulatory proteins of the alternative complement pathway predispose to non-shiga-toxin associated HUS.[5]

Role of factor H: FH serves as a cofactor for C3b-cleaving enzyme factor I in the degradation of newly formed C3b molecules and controlling the formation and stability of C3b convertase. By depositing at the surface of human glomerular endothelial cells and kidney glomerular membrane, rich in polyanionic molecules FH is protective against complement attack.[5]

The diagnosis of factor H-associated HUS can not be excluded based on normal factor H and C3 levels because mutations cause reduced ability of FH to interact with polyanions and surface bound C3b although it may be normally translated and secreted.[5]

Role of Membrane Co-factor Protein

Membrane co-factor protein is a widely expressed transmembrane protein,[5] which plays a major role in regulating glomerular C3 activation. In the presence of stimuli that activate the complement system, reduced levels of MCP may lead to microvascular damage.[5]

Local Thrombosis and Fibrin Deposition

Microthrombi of fibrin and platelets found in the glomerular capillaries of patients with HUS/TTP constitute the pathognomonic histologic lesion.[3]

Reduced fibrinolytic capacity of the vessel wall has been proposed in the pathophysiology of TTP.[39]

Platelets and Von Willebrand Factor

After its secretion, VWF undergoes proteolytic cleavage by ADAMTS13. This protease was recently purified and its gene cloned. The susceptibility of VWF for cleavage by ADAMTS13 is increased by shear stress. Studies using atomic force microscopy demonstrated that shear stress unfolded the conformation of VWF from a globular configuration to an elongated from, thereby exposing its cleavage sites to ADAMTS13.[28] The conformational response to shear stress is size dependent; the large multimers but not the small ones exhibit increased activity in response to shear stress. ADAMTS13, by cleaving the unfolded forms of VWF, prevents intravascular thrombosis ( Fig. 32-1 ).[28]



FIGURE 32-1  Scheme depicting the role of shear stress and ADAMTS13 in regulating the interaction between VWF and platelets. A, A large VWF multimer is unfolded by shear stress on an injured vessel wall, forming the substrate for supporting platelet rolling, adhesion, and aggregation, a critical step for hemostasis under the high shear stress conditions in the capillaries and arterioles. B, In the circulation, ADMTS13 cleaves VWF whenever its cleavage sites are exposed by shear stress. This process prevents the VWF from becoming fully unfolded. In the process, smaller multimers are generated. C, In the absence of ADAMTS13, VWF becomes unfolded, causing the formation of platelet thrombi in the arterioles and capillaries. Deficiency of ADAMTS13 results in a decrease in the cleavage of VWF and the appearance of ultra-large multimers. The conformation of ultra-large and large VWF multimers is responsive to shear stress; therefore, the process of VWF-platelet binding in the absence of ADAMTS13 provides an explanation of why both large and ultra-large forms of VWF are depleted in thrombotic thrombocytopenic purpura (TTP) when thrombocytopenia is severe (<20 to 30 × 109/L).  (From Tsai HM: Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. J Am Soc Nephrol 14:1072–1081, 2003.)




In 1982 Moake and co-workers reported the presence of unusually large VWF multimers (ULVWF) in plasma of four patients with chronic relapsing TTP during remission. They hypothesized that the lack of a “depolymerase” was responsible for the persistence of these multimers.[39]

Furlan and colleagues report a deficiency of ADAMTS13 in four patients with chronic relapsing TTP. In 1998 IgG auto-antibodies inhibiting ADAMTS13 in normal plasma were found in a patient with severe TTP. Two separate retrospective studies demonstrated that the majority of patients with acute sporadic TTP had sever deficiency of ADAMTS13 due to the presence of IgG antibodies that disappeared in most of the patients during remission.[39]

The Role of ADAMTS13 in Other Thrombotic Microangiopathies

A study by Tsai and colleagues concluded that children with typical HUS had normal or mildly decreased ADAMTS13 activity level, whereas severe deficiency <0.1U/ml was found in patients with TTP.[28] In HUS patients, VWF antigens are elevated and the largest polymers are decreased during acute illness. This pattern returns to normal with clinical improvement, but persists in patients with progressive renal disease. No abnormalities in VWF-cleaving protease have been found in children with diarrhea-induced HUS. Moreover, a decrease in VWF size was accompanied by an increase in VWF proteolytic fragments, presumably caused by enhanced proteolysis from abnormal shear stress in the microcirculation.[28]

Prognosis and Treatment

If HUS/TTP is left untreated, the mortality rate approaches 90%. With the use of plasma exchange or plasma infusion therapy 60% to 90% of the patients survive the acute episodes. In HUS the mortality rate is less than 10% among young patients with shiga-toxin-associated HUS, but it approaches 90% among the elderly.[28]

Several prognostic factors have been postulated to predict the outcome for patients with HUS/TTP. Younger children who present during the summer with the “typical” diarrheal prodrome have a better prognosis than older children with HUS that occurs in the colder months of the year and is not heralded by diarrhea.[18] A high blood PMN count at the time of onset of the disease in children is associated with a higher probability of a poor outcome.[40] A meta-analysis of 3476 patients with 4.4-year mean follow-up period showed that a higher severity of acute illness particularly central nervous system symptoms, and the need for hemodialysis, are associated with a worse prognosis. This study[40] showed that death or ESRD occurred in 12% of patients. Increases in CRP and cytokines levels (IL6, IL10, IL1) were associated with poor prognosis. Early recognition and treatment were associated with better prognosis. One study showed a worse prognosis with HUS during winter.[40] The degree of renal dysfunction and the severity of vascular lesions on biopsy specimens are also indicators of poor outcome in HUS/TTP.[40]

Management of Shiga-toxin-associated Hemolytic Uremic Syndrome

The main challenge in treating patients with HUS is to maintain renal perfusion while avoiding fluid overload. Although a normal volume is important in the face of diarrhea, vomiting, poor oral intake, and hypoalbuminemia, fluids should be restricted at the first indication of HTN or cardiopulmonary overload.[4] Diuretics rarely avert anuria and dialysis is more effective. Vasodilators are preferable for management of HTN.

Antibiotics should not be administered to patients with possible shiga toxin producing E.coli infection. A prospective study showed that children infected with E. coli O157:H7 who received antibiotics had a higher rate of HUS. In adults antibiotics may increase the risk of HUS.[4]

Neurological complications are major cause of mortality and morbidity. Irritability, confusion, and lethargy can be caused by ischemia, direct toxicity of shiga toxin, or cerebral microvascular thrombi. Stroke, coma, and seizures occur in 10%. Brain imaging should be considered to identify organic complications. Cardiac dysfunction can occur. Congestive heart failure is more common in adults. Elevated troponin I should be attributed to ischemia and not to azotemia. Respiratory distress syndrome can occur as well. Intestinal complications consist of necrosis and perforation. Refractory acidosis even with dialysis suggests ischemia or necrotic bowel.[4] Blood transfusion to correct the anemia should be given during dialysis. Platelets transfusion exacerbates thrombosis and is discouraged.

Among the therapeutic modalities used to treat patients with, plasma exchange (plasmapheresis combined with fresh-frozen plasma replacement) is currently the treatment of choice for both children and adults with HUS/TTP. Response rates vary between 60% and 80%.[41] Although significant benefit has also been observed with plasma infusion alone, one randomized prospective trial demonstrated that plasma exchange is more effective than plasma infusion for the treatment of TTP. After a 6-month follow-up period, patients treated with plasma exchange had a 78% response rate and a 22% mortality rate, compared with 49% and 37%, respectively, among patients receiving plasma infusions only.[39] Plasmapheresis could have the advantage of removing the recently identified inhibitory autoantibodies against VWF protease from the circulation and supplying larger amounts of the protease enzyme.[39]No unanimous protocol has been established regarding the frequency and duration of plasma exchange. Usually plasma exchange is performed once a day and replaces one plasma volume (40 mL/kg).[42] For patients with poor initial response to treatment, plasma exchange may be intensified by using a more frequent regimen (e.g., twice daily).[39]

There has been controversy regarding the usefulness of plasma exchange therapy in patients with TTP without severe ADAMTS13 deficiency.[39] In a prospective analysis, mortality rate was 15% in patients with TTP and ADAMTS13 activity below 5%, in contrast to 59% in patients with other TMA (pregnancy, drug or stem cell mediated), none of whom had ADAMTS13 activity below 5%.[1] Multiple studies have shown that assays of ADAMTS13 activity and inhibitors, in addition to clinical categories may be useful for predicting the response and outcome of patients with TTP. [26] [43]

Patients with non-shiga-toxin associated HUS may respond to plasma treatment. Plasma exchange may be better than plasma infusion for removal of toxic substances and increasing platelets count. Some success has been achieved using repetitive plasma substitution for factor H deficiency.[5] Plasma exchange should be performed daily until remission is achieved, remission being normalization of platelet count, or resolution of neurologic symptoms, or both.[44] Hemoglobin level, percent schistocytosis, reticulocyte count, and renal indices do not appear to be determinants of initial response to therapy, because they may be abnormal for an undefined period after remission.[45]Continuation of plasma exchange for several sessions after remission has been advocated to prevent relapses.[45] TTP relapses occur between 1 and 140 months (median, 20 months) after the initial episode in as many as 40% of the patients.[46]

Corticosteroids have been used in addition to plasma therapy for management of TTP. In view of recent data concerning auto-antibody induced ADAMTS13 deficiency, a pathophysiologic basis seems to explain therapeutic strategies: plasma exchange may remove antibodies, FFPs replace lacking proteases, and corticosteroids suppress immunity.[39]

Patients with persistent low levels of inhibitors to ADAMTS13 may develop frequent relapses that require long-term plasma exchange. In such patients, anti-platelet agents, vincristine, cyclophosphamide, staphylococcal protein A columns, or high-dose immunoglobulins have been used with variable success.[39] Although platelet thrombi are invariably present in the thrombotic antipathies, therapy with aspirin and dipyridamole have proved ineffective. Fibrinolytic therapy with either streptokinase or urokinase is ineffective and increases the risk of bleeding.[4]

The role of splenectomy has never been studied in a controlled fashion. It is reserved however for patients with relapse and best performed during remission. Benefit from splenectomy is mainly due to removal of antibody producing B cells, though other mechanisms may be present.[39]

A literature review demonstrated a significant advantage in durable remission rates for patients treated with combination of total plasma exchange and vincristine as initial therapy compared to patients treated with total plasma exchange without vincristine.[47]

Rituximab, a monoclonal anti cd20 antibody, showed promising results in decreasing inhibitor titers and induc-ing long-term remission in patients with refractory TTP.[28] Cancer- and/or chemotherapy-induced HUS/TTP carries a poor prognosis despite treatment. Snyder and co-workers[48] reported improved survival in this group of patients using extracorporeal immunoadsorption with protein A columns to remove circulating immune complexes. Patients whose malignant neoplasms were in complete or partial remission at the time of development of HUS/TTP had a significantly higher estimated 1-year survival rate (74%), compared with a historical control group of patients receiving other treatments (22%).

Management of Renal Failure in Hemolytic-Uremic Syndrome and Thrombotic Thrombocytopenic Purpura

Severe renal insufficiency resulting from HUS/TTP often requires dialysis. Renal transplantation has also been performed. Kidney transplantation is safe and effective for D+HUS patients who have progressed to ESRD, with recurrence rates of 0% to 10%.

In D-HUS 1-year graft survival rate is less than 30% with 50% recurrence in the grafted organ. For patients with factor H mutation, recurrence rate is between 30% and 100%, because FH is synthesized in the liver and concomitant liver and kidney transplantation should be performed to correct the disease.[28]


Clinical Features

Systemic sclerosis is a rare disease, with a reported incidence of about 20 new cases per 1 million population in the United States.[49] It characteristically affects women between the ages of 30 and 60 years of age.[49] The overall incidence in females is four times that in males and the female-to-male ratio increases to 10:1 during the childbearing years.[49] Children and younger men rarely are affected. Although there is no overall racial predilection, young black women have a higher incidence of systemic sclerosis than do young white women.[49]

Involvement of the skin and subcutaneous tissue is the predominant feature of systemic sclerosis. This explains the use of the traditional term scleroderma to describe the disease. In the diffuse cutaneous, or classic, form of the disease, thickening of the skin is observed on the face, trunk, and distal and proximal extremities. This phase is followed by sclerosis, which leads to a taut, shiny appearance of the skin and tapering of the fingertips (sclerodactyly). Rapid progression of the cutaneous induration with extension into the underlying tendon sheaths and joints is a harbinger of visceral involvement.[50] Among other extrarenal manifestations of systemic sclerosis, [51] [52] Raynaud phenomenon is the most prevalent (93% to 97% of patients) and is usually the first symptom in patients with limited cutaneous disease. Telangiectasias on the skin of the face and upper torso are commonly present in patients with either diffuse or limited cutaneous sclerosis. Arthralgias or arthritis occurs in most patients. Myopathy presenting as muscle atrophy and fibrosis occurs in approximately 20% of these patients and usually involves the shoulder and pelvic girdle muscles.[53] Esophageal hypomotility or diminished tone of the lower esophageal sphincter (or both) is also present in of systemic sclerosis cases. Diffuse pulmonary fibrosis occurs in 45% of the patients, causing restrictive lung disease. Myocardial fibroses in systemic sclerosis manifest as conduction disturbances and, occasionally, refractory congestive heart failure.[54]

Laboratory Findings

Autoantibodies are detected in 95% of patients with systemic sclerosis, with ANA being the most common. There are at least seven scleroderma specific antibodies, and there is a correlation between the type of disease and the antibodies present.[55] Only 5% of patients with positive anticentromere antibodies have systemic disease, whereas 71% of patients with antibodies to DNA topoisomerase (anti-Scl-70) have diffuse disease.[55] The type of antibodies correlates as well with the organs involved; anti-RNA POL3 antibodies have been strongly associated with Scleroderma renal disease.[55]

Renal Involvement

Kidney involvement in systemic sclerosis manifests as a slowly progressing chronic renal disease or as scleroderma renal crisis (SRC), which is characterized by malignant hypertension and acute azotemia.[52] The two presentations are not mutually exclusive. In addition, there have been reports of patients with scleroderma developing RPGN. [56] [57]

Based on autopsy studies, the incidence of renal disease in systemic sclerosis approaches 80%.[58] Clinical indicators of chronic renal involvement in systemic sclerosis include proteinuria, hypertension, and decreased glomerular filtration rate (GFR). The proteinuria is usually subnephrotic and occurs in 15% to 36% of the patients.[59] Hypertension is present in 24%, and elevated BUN in 19%[59]; 15% of patients who have diffuse scleroderma have a creatinine above 1.3 mg/dL at some point in their illness, without evidence of renal crisis.[50] Patients with diffuse scleroderma without renal crisis rarely have significant increases in serum creatinine or proteinuria that cannot be explained by other etiologies.[60] Renal manifestations rarely antedate the other features of systemic sclerosis.

Scleroderma renal crisis is defined by the sudden onset of accelerated or malignant arterial hypertension, followed by rapidly progressive oliguric renal failure[52]; 90% of patients have a blood pressure above 150/90 mm Hg and 30% have a diastolic blood pressure above 120Hg. In the 10% of patients with normal blood pressure, there is usually an elevation from an already low baseline blood pressure.[50] Ten percent of patients with scleroderma in general, and 25% of those with diffuse scleroderma develop SRC; 75% of cases take place in the first 4 years of the disease.[50] Patients with the diffuse cutaneous form are at much higher risk for development of SRC than are those with limited cutaneous systemic sclerosis, and so are black patients compared with white patients.[50] Nevertheless, several patients with limited or absent skin manifestations were reported to have SRC with poor or fatal outcomes. [61] [62]

The symptomatology is predominantly that of accelerated/malignant hypertension. [52] [63] Presenting complaints include severe headaches, blurring of vision, encephalopathy, convulsions, and acute left ventricular failure. Grade III or IV retinopathy is present in most of the cases. Oliguria and a rapidly rising serum creatinine concentration follow shortly thereafter. [52] [63] Proteinuria is universal but is rarely nephrotic. The urinalysis reveals microscopic hematuria and granular casts. Plasma renin activity is markedly elevated during SRC, but it is unclear whether this is a primary phenomenon or a result of renal ischemia. [59] [63] SRC progresses rapidly to severe renal failure that requires dialysis. Before the advent of angiotensin-converting enzyme (ACE) inhibitors, the major-ity of patients died from hypertensive complications within 1 to 3 months. [59] [63] Renal function may recover spontaneously even after 18 months of dialysis.[50] Other clinical manifestations of SRC include microangiopathic hemolytic anemia with thrombocytopenia, which also occurs in association with other forms of malignant hypertension. [64] [65]

No reliable predictors of the advent of SRC exist. The prior presence of proteinuria, renal insufficiency, or hypertension in a patient with diffuse systemic sclerosis does not necessarily portend progression to SRC.[50] A rise in plasma renin activity does not seem to herald the onset of SRC, either.[63] A higher frequency of SRC and hypertension has been noted among blacks with systemic sclerosis.[63] It is not clear, however, whether this observation is simply a reflection of the overall increased incidence of essential and malignant hypertension in the black population.


Autopsy studies demonstrate renal histopathologic changes in the majority of patients with systemic sclerosis in whom SRC has not developed. Subintimal proliferation and luminal narrowing of small-sized and medium-sized arteries in the kidney is the most prominent finding. The arterial changes coexist with varying degrees of tubule atrophy, interstitial fibrosis, and glomerular obsolescence. These histopathologic findings have been described in patients with systemic sclerosis even before the onset of hypertension.[59]

Arterial changes also characterize the SRC kidney. [58] [59] Microscopically, small-sized and medium-sized arteries (inter-lobular and arcuate arteries in the renal cortex) show intimal edema and intimal cell proliferation. Accumulation of mucoid substance composed of glycoproteins and mucopolysaccharides may separate the endothelium from the internal elastic lamina. Myointimal cells, absent from normal arteries, possibly participate in the intimal thickening seen in systemic sclerosis. The common end point of these vascular changes is luminal narrowing and subsequent tissue ischemia ( Fig. 32-2 ). The presence of adventitial and periadventitial fibrosis differentiates the renovascular lesions of systemic sclerosis from those of other forms of malignant hypertension.[58] The typical lesion in smaller renal arteries and afferent arterioles in systemic sclerosis is fibrinoid necrosis. Interestingly, these changes can be seen in patients who do not have hypertension or SRC.[58] Lymphocytes and inflammatory cells are typically absent from the vascular lesions.



FIGURE 32-2  Latex injection of postmortem normal kidney (left) and kidney from a patient with scleroderma renal crisis (right). Note obstruction to flow at the level of the medium-sized interlobular arteries.



Glomerular pathology in SRC is probably ischemic in origin and consists of basement membrane thickening, obliteration of the capillary loops, and glomerulosclerosis. Hyperplasia of the juxtaglomerular apparatus has been observed but is not specific for SRC. Tubule epithelial degeneration and scattered interstitial fibrosis are also present. Immunofluorescence findings are generally nonspecific and may reveal IgM, complement, and fibrin deposits in small renal arteries. In a few cases, ANAs have been eluted from renal biopsy tissue.[50]



Abnormal vasomotor control is a dominant feature of systemic sclerosis, as evidenced by the presence of Raynaud phenomenon in the vast majority of the patients.[50] In addition to vasospasm of the digital arteries, a cold stimulus has been shown to decrease renal,[59] coronary,[66] and pulmonary perfusion.[67] The cause of abnormal vasomotor control is not known. Increased circulating levels of catecholamines do not seem to be a significant mediator of Raynaud phenomenon.[68] Renin and angiotensin II (AII) levels in systemic sclerosis increase after cold exposure and could possibly contribute to arterial vasospasm.[50] In addition to the juxtaglomerular apparatus, vascular smooth muscle cells produce renin. In a vessel “primed” by renin-angiotensin, severe vasospasm can be precipitated by cold exposure, physical stress, caffeine, or nicotine.[52] Knock and co-workers[69] demonstrated significantly increased endothelin-binding density in microvessels of skin from patients with systemic sclerosis and primary Raynaud phenomenon, compared with normal controls.

Increased Collagen Production

Fibroblast secretion of collagen, the main extracellular matrix component of connective tissue, is markedly increased in systemic sclerosis.[70] Several investigators have provided evidence that transforming growth factor-β (TGF-β) can mediate increased collagen production in systemic sclerosis. [71] [72] [73] Gabrielli and associates[73] demonstrated increased immunostaining for TGF-β in the vascular endothelium and dermal fibroblasts of patients with systemic sclerosis. Impaired production of interferon-γ (IFN-γ) by T lymphocytes isolated from patients with systemic sclerosis and fibrosing alveolitis has been observed.[74] This defect could contribute to fibrosis, because IFN-γ is known to suppress collagen synthesis by fibroblasts.[75] Other investigators have provided evidence of the production of abnormal collagen in patients with systemic sclerosis.[76] Douvas[76] demonstrated that Scl-70 (DNA topoisomerase I) binds to collagen genes from scleroderma tissue, but not to genes from normal tissue. The pathogenetic significance of this observation is unclear.

Endothelial Cell Abnormalities

Damage to the endothelial cell has been postulated to be a primary event in the pathogenesis of systemic sclerosis.[50] Cytotoxicity of patient serum to cultured endothelial cells has been demonstrated.[77] It is possible that platelet aggregation at the site of endothelial denudement could lead to the release of platelet-derived growth factor (PDGF) and TGF-β. Both cytokines are mitogenic to smooth muscle cells and fibroblasts, in addition to stimulating collagen production. Theoretically, this would account for the subintimal cell proliferation and the fibrosis seen in systemic sclerosis. Increased PDGF levels and circulating platelet aggregates have been demonstrated in patients with systemic sclerosis.[78] Antiplatelet therapy, however, failed to provide any clinical benefit.[52]

Immunologic Mediators

Although several antinuclear autoantibodies have been detected in patients with systemic sclerosis, their contribution to the disease process is not established. Indirect evidence of immunologic mechanisms in systemic sclerosis has been reported.[79] γ-δ T lymphocytes, activated helper T cells, tissue macrophages, mast cells, and fibroblasts are activated,[80] leading to increased production of extracellular matrix proteins, fibronectin, and proteoglycans.[80]Cytokines such as IL-1, IL-2, IL-8, TNF-α, PDGF, TGF-β, IFN-γ, and endothelin are increased.[80] Moreover, intercellular adhesion molecules and soluble IL-2 receptors have been demonstrated in patients. [79] [81] [82] [83] [84]Fibroblasts cultured from the skin of patients with systemic sclerosis produce much higher levels of IL-6 than normal fibroblasts do and may contribute to T cell activation.[85] IL-6 and PDGF-A were shown to be elevated through the action of endogenous IL-1α in fibroblasts from patients with systemic sclerosis.[86] It is unclear whether these immunologic changes constitute primary events in systemic sclerosis or are epiphenomena.


Because of its clinical similarities to chronic graft-versus-host disease and its occurrence more often after childbearing years in women, scleroderma has been proposed as a variant of such a disease. Studies have demonstrated increased frequency of persistent fetal cells among women with scleroderma and a history of pregnancy and the presence of fetal cells in the involved skin of such patients. [87] [88] [89] These associations, however, do not necessarily prove causality.[90]

Pathogenesis of Scleroderma Renal Crisis

It is postulated that SRC is caused by a Raynaud-like phenomenon in the kidney.[63] Severe vasospasm leads to cortical ischemia and enhanced production of renin and AII, which in turn perpetuate renal vasoconstriction. Hormonal changes (pregnancy), physical and emotional stress, or cold temperature[59] may trigger the Raynaud-like arterial vasospasm. The role of the renin-angiotensin system in perpetuating renal ischemia is underscored by the significant benefit of ACE inhibitors in treating SRC (see later discussion).

Management of Renal Complications

The one form of therapy that appears to have made a major difference in the prognosis of SRC is aggressive management of hypertension with ACE inhibitors. [50] [63] The 1-year survival rate was approximately 10% before ACE inhibitors compared with a 5-year survival of 65% after use of ACE inhibitors.[50] Progression to severe renal failure that required dialysis was observed in only half of the patients treated with ACE inhibitors. This suggests that ACE inhibition can forestall progression of SRC in some, but not all, of the patients.[91] A prospective cohort study on short-term and long-term outcomes of SRC in 154 patients who received ACE inhibitors showed that 61% of the patients had good outcomes (no dialysis or temporary dialysis), with a survival rate at 8 years of 80% to 85%, similar to that of patients with diffuse scleroderma without SRC.[92] Diuretics are best avoided because of their ability to stimulate renin release.[52]

Outcomes of the clinical experience with the use of angiotensin receptor blockers (ARBs) have been variable[50] and somehow disappointing. There are several reports in the failure of ARBs as a replacement for ACE inhibitors and as an add-on therapy. [50] [93]

For patients with SRC who progress to severe renal insufficiency despite antihypertensive treatment, dialysis becomes a necessity. Both peritoneal dialysis and hemodialysis have been employed.[94] The End-Stage Renal Disease (ESRD) Network report on 311 patients with systemic sclerosis-induced ESRD dialyzed between 1983 and 1985[94] and revealed a 33% survival rate at 3 years. In a more recent report, more than half of patients with SRC who initially required dialysis and were treated aggressively with ACE inhibitors were able to discontinue dialysis 3 to 18 months later, suggesting that patients should continue to take ACE inhibitors even after beginning dialysis, in the hope of being able to discontinue it later.[92] Interestingly, Raynaud phenomenon of the hands and Raynaud-type vasospasm of peritoneal blood vessels (manifesting as decreased peritoneal clearance) was observed in systemic sclerosis patients using unheated peritoneal dialysate fluid. Four of 18 patients did not have adequate clearance to undergo peritoneal dialysis.[92]

Renal transplantation for systemic SRC-induced ESRD has been performed successfully.[94] A decrease in graft and overall survival has been observed in patients undergoing renal transplant for scleroderma kidney disease compared to those for diabetes and analgesic nephropathy.[95] Recurrence of systemic sclerosis in the transplanted kidney can occur,[96] particularly in patients with aggressive scleroderma disease process.[96]

The various agents used for treatment of the nonrenal complications of systemic sclerosis are reviewed elsewhere. High-dose or low-dose D-penicillamine therapy does not affect the incidence of SRC or overall mortality.[97]

There is a significant association between antecedent high-dose corticosteroid therapy and the development of SRC. In addition, the use of even low-dose corticosteroids has been associated with onset of SRC.[98]


Clinical Features

The long-term consequences of renal irradiation in excess of 2500 rad can be divided into five clinical syndromes. Acute radiation nephritis occurs in approximately 40% of patients after a latency period of 6 to 12 months. It is characterized clinically by abrupt onset of hypertension, headache, vomiting, fatigue, and edema. Clinically patients manifest arteriolar-venous nicking on funduscopic exam, normochromic normocytic anemia, microscopic hematuria, proteinuria, urinary casts, and elevated b2 microglobulins. Decreased creatinine clearance and elevated blood urea nitrogen may accompany these symptoms.[99]

With medical management these manifestations may resolve with mild or no residual, or they may progress to ESRD, or to malignant hypertension.[99] Chronic radiation nephritis has a latency period that varies between 18 months and years after the initial insult. It is insidious in onset and is characterized by hypertension, proteinuria, and gradual loss of renal function.[99] The third syndrome manifests 5 to 19 years after exposure to radiation as benign proteinuria with normal renal function.[99] A fourth group of patients exhibits only hypertension 2 to 5 years later and may have variable proteinuria.[99] Late malignant hypertension arises 18 months to 11 years after irradiation in patients with either chronic radiation nephritis or benign hypertension.[99] High-renin hypertension resulting from irradiation of one kidney has been described, 18 months after irradiation. Removal of the affected kidney reversed the hypertension.[99] Irradiation to one kidney and ipsilateral renal artery may produce renovascular hypertension, mostly in infants and children.

A syndrome of renal insufficiency analogous to acute radiation nephritis has been observed in bone marrow transplantation (BMT) patients who were treated with total-body irradiation (TBI). BMT nephropathy is different from AKI/ARF that occurs after BMT. The latter occurs in 25% or more of BMT patients within 30 days after BMT. It is associated with neutropenia, antibiotics, sepsis, and liver failure.[100] However, this early renal failure is not related to the development of radiation nephropathy a few months later[100] but to TBI given before BMT is administered in 9 fractions over 3 days, a schedule that does not permit enough time for repair of radiation injury to the kidneys. It is usually preceded by chemotherapy for the treatment of primary cancer and concurrent cytotoxic chemotherapy as part pf pre-BMT “conditioning”. This may explain why injury occurs below the threshold of 2500 rads in BMT nephropathy.[100] Cohen and colleagues described two clinical patterns of BMT nephropathy; acute and chronic.[100]

Acute BMT nephropathy presents with an HUS-like picture, with severe hypertension, peripheral edema, microangiopathic hemolytic anemia, and thrombocytopenia. Renal function decreases progressively with significant proteinuria and microscopic hematuria with or without casts. Kidney function uncommonly recovers and mortality rate ranges between 50% and 75%.[101]

Chronic BMT nephropathy presents with mild to moderate HTN and less severe hemolytic anemia. However, in all patients anemia is out of proportion with the level of renal failure. Kidney function decreases slowly with a biphasic pattern in most patients. A steady decrease in the first 12 to 24 months is followed by a period of stabilization, but no recovery.[101] Also present is proteinuria greater than 1 g/day and microscopic hematuria with or without casts. A period of 8 years is generally necessary for chronic renal failure to occur post BMT, a similar to chronic radiation nephropathy.[101] In a long-term study of 103 adult survivors of BMT, Lawton and associates[116] reported late renal dysfunction in 14 patients. Renal biopsies performed on seven of these patients revealed changes consistent with those of acute radiation nephritis (see later discussion). All of the affected patients had received 1400 rad TBI prior to BMT, whereas none of the patients receiving lower doses of irradiation developed late hypertension or decreased GFR. Chemotherapy administered as part of the preparative regimen could potentiate the effects of irradiation on the kidneys.[99] Actinomycin potentiated the effects of irradiation on many tissues (gut, lung, and skin); on the kidney its role is controversial. Cisplatin and BCNU they are toxic mainly when radiation precedes platinum. The effect of Doxorubicin was demonstrated on rat models.[101] The incidence of radiation nephritis after TBI and BMT in children is higher than that observed in adults (approaching 45%) and may be related to lower radiation tolerance.[101]Radiographic studies may aid in the diagnosis of acute radiation nephritis. CT with contrast enhancement demonstrates sharply demarcated, dense, persistent nephrograms corresponding to the irradiated areas.[102] Increased uptake of technetium-99m dimercaptosuccinic acid (99mTc-DMSA) in the damaged areas of the kidneys is also observed after renal irradiation. Quantitative 99mTc-DMSA has been shown to be an indicator of proximal tubular function.[103] It is more sensitive than biochemical tests in assessing radiation-induced renal injury as shown in a prospective 5-year follow-up period of cancer patients irradiated with different doses and volumes for a variety of abdominal malignancies.[103] 99mTc-DMSA is valid as long as the GFR is not severely reduced.


Inflammatory cells are rarely observed in the renal parenchyma, so the term nephritis is actually a misnomer and the term radiation nephropathy was proposed.[99] Early and late changes following renal irradiation were described by White. Early changes include atypia, endothelial microvascular damage as observed on light microscopy, with mild endothelial cell swelling and basement membrane splitting in the glomerular capillaries. Electron microscopic examination revealed marked subendothelial expansion with deposition of basement membrane-like material adjacent to the endothelial cells. The endothelial cell lining was absent in some capillary loops.[99] Immunofluorescence studies were negative. Similar glomerular endothelial injury was observed in kidney biopsy specimens from patients who developed renal insufficiency and hypertension after TBI and BMT.[104] Some of these biopsies also revealed arteriolar intimal thickening and tubule atrophy. Glomerular capillary endothelial cell loss and mesangiolysis is observed within weeks after irradiation.[105] It appears that the endothelial injury resolves but mesangial lesions progress. Late changes include reduction in total renal mass, with prominent and sclerosed interlobar and arcuate arteries, glomerular capillary loop occlusion and hyalinization, with progressive tubular atrophy,[99] increased mesangial matrix, mesangial sclerosis, and, finally, glomerulosclerosis.[105]


Most of the theories proposed are based on murines studies. Philips and colleagues suggested that tubular cellular damage is responsible for renal toxicity from radiation. Galstein, Fejardo, and Brown demonstrated glomerular thrombosis and suggested this site as the target of toxicity from radiation. Hoopes and colleagues suggested that radiation damage has multiple target sites with different time of expression. They demonstrated in their studies that initial functional survival depends on the extent and repair of parenchymal damage. Early vessel wall changes are temporary and that damage to perivascular connective tissue is the dose-limiting toxicity for late effects.[99]

High doses of radiation in TBI or in the presence of radiomimetic chemotherapeutic drugs can cause double-stranded DNA breaks.[101] Renal tubular epithelium is sensitive to radiation. Cell death causes a compensatory proliferation of others. Recently early apoptosis early after 5 Gy single-dose TBI was demonstrated in rat, as was late proliferative responses.[100] Renal endothelial cells are susceptible to radiation injury, leading to DNA damage, and oxygen radical generation. Microthrombi form in damaged endothelium, culminating in an HUS-like picture.[101]

Multiple studies on treatment of experimental radiation nephropathy demonstrated the role of the rennin-angiotensin system in the pathogenesis.

Cohen and co-workers[106] demonstrated that AII infusion from 4 to 8 weeks after TBI caused greater azotemia than irradiation alone or irradiation and AII infusion from 0 to 4 weeks post TBI. This suggested that vascular injury that occurs from 4 to 8 weeks in the form of arteriolar fibrinoid necrosis may determine later outcome. In young animals radiation nephropathy may be attenuated by the administration of captopril from 3.5 weeks to 9.5 weeks after irradiation.[107]

Depressed generation of prostacyclin by endothelial cells in irradiated rabbit aorta or after stimulation by PDGF suggested the role of the clotting system. Oikawa and colleagues demonstrated an increase in renal plasminogen-activator inhibitor mRNA in a 12 Gy single-dose radiation nephropathy model, and its attenuation by ACE inhibitor or angiotensin blocker.[100]

Increases in TGF-β at 50 and 63 days after irradiation in a study done on rats,[107] and the elimination of the rise by an AT1 receptor blocker suggest a role for TGF-β.

A role of chronic oxidative stress in the pathogenesis of radiation nephropathy has been suggested.[108]


Aggressive management of hypertension in patients with radiation nephritis may slow the progression of disease. Evidence in experimental animals suggests that ACE inhibitors may have a renoprotective effect on radiation nephritis independent of their antihypertensive action.[109] In fact, a marked reduction of glomerular, tubule, vascular, and interstitial damage was observed in ACE inhibitor-treated rats after irradiation.[110] Moreover, therapy with ACE inhibitors may be effective in limiting radiation-induced renal injury, even if given for a short course of 3 to 10 weeks, after irradiation of experimental animals.[111] There is evidence that AII receptor antagonists alone are helpful for prophylaxis against radiation nephropathy.[112] In irradiated rats, the protective effect of ACE inhibitors and AII receptor blockers occurs in the absence of increased activity of the renin-angiotensin system (RAS), suggesting that normal activity of the RAS may be deleterious to the irradiated kidney.[113] Data in rats suggest that radiation nephropathy is ameliorated by post radiation treatment with corticosteroids.[114] This regimen appears to be as effective as ACE inhibitors alone. The same study suggested that there may be an additive effect when ACE inhibitors and corticosteroids are combined.[114] Hypertension due to unilateral disease may respond to nephrectomy.[99] Radiation-induced renovascular hypertension may require angioplasty or surgical repair.[99] Uncontrolled hypertension in patients with radiation nephritis who progress to ESRD warrants bilateral nephrectomies.[115] Because radiation nephritis is generally an irreversible process, preventive measures should be observed during the administration of radiation therapy. These include selective shielding of the kidneys and the use of minimum effective doses of fractionated radiation when possible.[116] The use of radioprotectors such as glutathione or cysteine concomitant with irradiation is still in the experimental phase.[117]


Atheroembolic renal disease is part of a systemic syndrome of cholesterol crystal embolization. Renal damage results from embolization of cholesterol crystals from atherosclerotic plaques present in large arteries, such as the aorta (Fig. 32-3 ), to small arteries in the renal vasculature. Atheroembolic renal disease is an increasingly common and often underdiagnosed cause of renal insufficiency in the elderly.[118] Autopsy studies reveal an incidence of 0.1% to 3.3%. The incidence increases among patients with aortic aneurysm and those who undergo surgical procedures involving the abdominal aorta. [119] [120] Male gender, older age, hypertension, and diabetes mellitus are important predisposing factors. [121] [122] Patients with cholesterol embolization syndrome often have a history of ischemic cardiovascular disease, aortic aneurysm, cerebrovascular disease, congestive heart failure, or renal insufficiency. [122] [123] A significant association between renal artery stenosis and atheroembolic renal disease has also been reported. [119] [122] At least one of the precipitating factors, which include vascular surgery, arteriography, angioplasty, anticoagulation, and thrombolytic therapy, can be identified in the majority of patients. [122] [124] [125] [126] Arteriographic procedures constitute the most common intervention reported to incite cholesterol embolization.[123] The most common of these is coronary angiography, which has a rate of cholesterol embolism of 0.1%[122] to 1.4%.[127] An estimated 15% of patients with atheroembolism do not have any of the known risk factors.[123]



FIGURE 32-3  Severe atherosclerosis of the aorta, a usual source of distal atheroemboli.  (Courtesy of Ismail Khalil, MD, FACS. Chief, Division of Vascular Surgery, American University of Beirut Medical Center.)


Clinical Features

The mode of onset of clinical manifestations varies greatly. It may be sudden, few days after a precipitating factor, or insidious, over weeks or months.[119] General systemic manifestations occur in fewer than half of the patients and include fever, myalgias, headaches, and weight loss.[123] The rate of cutaneous manifestations such as livedo reticularis, “purple” toes, and toe gangrene varies from 35% to 90% ( Fig. 32-4 ). The higher incidence of cutaneous lesions was reported in two series and was probably due to closer monitoring. [119] [128] Cutaneous symptoms constitute the most common extrarenal findings and may herald renal involvement.[119] Other parts of the body, such as the eyes, musculoskeletal system, nervous system, and abdominal organs can be targets of cholesterol crystal emboli.[119] An autopsy review of 121 cases of AED noted the kidney to be the most commonly involved internal organ, with 75% of the cases showing evidence of cholesterol emboli ( Table 32-3 ).



FIGURE 32-4  Peripheral manifestations of atheroembolic disease. A, Mottling of both feet (livedo reticularis). B, Violaceous mottling (“purple toe syndrome”) of the right foot in a patient with atheroembolic disease.  (Courtesy of Ismail Khalil, MD, FACS. Chief, Division of Vascular Surgery, American University of Beirut Medical Center.)


TABLE 32-3   -- Location of Cholesterol Emboli Found at Autopsy on Patients with Atheroembolic Disease

Organs Involved (%)

Vidt305 (N = 173[*])

Thadhani[132] (N = 33)









Gastrointestinal tract





















Bone marrow




Vasa vasorum






Urinary bladder


Coronary arteries





Table courtesy of D.G. Vidt.305



Of these 173 patients, autopsy was the sole means of diagnosis in 153; in the other 20 patients, cholesterol embolization was diagnosed before death and confirmed on autopsy.

To enter this study, all patients had to have AKI/ARF due to atheroembolic disease.


In other series, the kidneys are affected in approximately 50% of patients. [123] [129] Accelerated or labile hypertension, the most common manifestation, is present in 48% of patients.[129] Malignant hypertension has been described. The most frequent course is subacute, and the deterioration of renal function takes place in a stepwise fashion.[119] However, renal failure can be acute and oliguric. [119] [129] The need for dialysis among patients with renal atheroembolism varies from 30% to 40% in some series [124] [129] to 61% in others.[128] Renal infarction secondary to cholesterol embolization is rare. Cholesterol embolic disease in renal allografts has been reported. [130] [131]Cholesterol emboli can be of donor as well as of recipient origin. In 10 of 15 cases of biopsy-proven cholesterol emboli to renal allografts, atheroemboli were believed to originate from the donor arteries, with poor prognosis for the graft.[119]

A high degree of suspicion is required to diagnose atheroembolic renal disease.[119] The differential diagnosis includes systemic vasculitis, subacute bacterial endocarditis, polymyositis, myoglobinuric renal failure, drug-induced interstitial nephritis, and renal artery thrombosis or thromboembolism.[118] The time course of decline in renal function may aid in the diagnosis of atheroembolic renal disease. Renal failure due to procedure-induced atheroembolic renal disease is characterized by a decline in renal function over 3 to 8 weeks. Radiocontrast-induced nephropathy, conversely, usually manifests earlier and often resolves within 2 to 3 weeks after appropriate intervention.[132]Histologic demonstration of cholesterol crystals in small arteries and arterioles of target organs is the most definitive method of diagnosing atheroembolic renal disease. Kidney, muscle, and skin biopsy specimens are the most likely to yield a positive diagnosis. [123] [129]

Laboratory Findings

Renal involvement in the cholesterol crystal embolization syndrome is manifested by increased serum creatinine and BUN levels. [123] [129] At the time of diagnosis, as many as 25% of patients have a serum creatinine concentration higher than 5 mg/dL, and in about 80% it is higher than 2 mg/dL.[123] Although the urinary sediment is usually abnormal, it is nondiagnostic.[119] Non-nephrotic range proteinuria is present in more than half of patients. [119] [123]However, nephrotic range proteinuria has been reported.[133] Granular and hyaline casts occur in approximately 40% of cases, whereas microscopic hematuria or pyuria are observed in fewer than 30%.[123] Eosinophiluria was observed in one third of patients with renal biopsy proven atheroembolic renal disease.[134]

Several studies have noted eosinophilia in cholesterol crystal embolic disease, [119] [121] [124] [129] and in most large series this finding was present in up to 60% to 80% of patients. [119] [123] [128] It is usually transient, although persistent eosinophilia has been reported. [129] [135] Increased erythrocyte sedimentation rate, leukocytosis, and anemia are also commonly present. Hypocomplementemia has been described in many series [129] [136] whereas it was not found in others. [119] [122] [128] When present, it is usually transient. Autoantibodies to neutrophil cytoplasmic antigens (ANCA) have been found in few cases,[137] but not in large series.[119] The significance of these findings and their role in the inflammatory component of the disease are yet to be defined.


The pathologic hallmark of atheroembolic renal disease is the demonstration of cholesterol crystals in the renal microvasculature. The renal vessels most commonly involved are the arcuate, interlobular, and terminal arterioles, which are approximately 150 nm to 200 nm in diameter.[119] Histologic examination of the occluded vessels reveals biconvex, needle-shaped clefts of cholesterol crystals present in the lumen ( Fig. 32-5 ). Cholesterol crystals are birefringent under polarized light. The subsequent intravascular inflammatory reaction has been studied in experimental models of atheroembolism and in human biopsy and autopsy samples.[119] The early phase is characterized by a variable PMN and eosinophil infiltrate, followed by the appearance of macrophages and multinucleated giant cells in the lumens of affected vessels within 24 to 48 hours after atheroembolism. In the chronic phase, tissue ischemia is perpetuated by marked endothelial proliferation, intimal thickening, concentric fibrosis of the vessel wall, and persistence of cholesterol crystals and giant cells in the lumens of affected arteries. Hyalinization of glomeruli, atrophy of renal tubules, and multiple wedge-shaped infarcts in the kidney result in reduced kidney size.[119]



FIGURE 32-5  A, Atheroemboli lodged in an interlobular artery of a kidney obtained postmortem. The elongated clefts are actually voids where cholesterol crystals were located before fixation and staining. Note the exuberant intimal thickening and the cellular proliferation, which completely occlude the lumen.  (Courtesy of W. Margaretten.) B, Electron-microscopical view showing needle-like clefts from atheroemboli to afferent arterioles. (From Polu KR, Wolf M: Clinical problem-solving. Needle in a haystack. N Engl J Med 354:68–73, 2006.)





Atheroembolic renal disease is associated with high morbidity and mortality. A 64% to 81% mortality rate has been reported in the literature. [123] [129] In other series, the survival rate was much higher.[128] Compared to older literature, recent studies showed that only 33% of patients died in the first year of follow-up[122] and 82% of patients survived their first year.[124] Most patients die because of cardiovascular causes.[122] The most significant morbidity associated with atheroembolic renal disease is severe renal insufficiency that requires dialysis. Patients who develop ESRD have a twofold increase in mortality.[122]

Among patients who develop renal cholesterol emboli, those who had baseline chronic renal impairment, a longstanding history of hypertension, or were not on statin therapy are at a higher risk of developing ESRD.[122] One third to one half of patients who are started on hemodialysis recover sufficient renal function to stop dialysis. [122] [129] A history of intermittent claudications was found to be a predictor for non-recovery of renal function.[122]


No effective therapy for atheroembolic renal disease has been reported. Unsuccessful medical treatments that have been attempted include plasma expanders, vasodilators, sympathetic blockade, and anticoagulants. [119] [123]Anticoagulants should be avoided because of the risk of precipitating more atheroembolization. [123] [129] In fact, withdrawal of anticoagulation may be beneficial. Surgical excision of atheromatous plaques in the suprarenal region of the aorta is not advocated because of significant postoperative mortality, worsening renal function, and lower limb loss.[138]

Despite high mortality and the absence of effective therapy, several reports have shown a more favorable clinical outcome in patients with atheroembolic renal disease. [121] [139] In many cases, kidney function improved significantly even after a prolonged period of renal insufficiency. [122] [139] Cholesterol-lowering agents have been reported to lead to improved outcome. [124] [140] The use of steroids in the management of renal cholesterol emboli disease is controversial.[119] Despite reported negative results, [120] [123] there are reports of favorable outcomes in both high doses [141] [142] and in low doses. [143] [144]

Meticulous care and “aggressive” therapeutic protocols in patients with multivisceral cholesterol embolism and ARF resulted in 1-year survival rate higher than that previously reported. The regimen was characterized by immediate withdrawal of anticoagulants, postponement of aortic procedures, control of blood pressure (lower than 140/80 mm Hg), control of heart failure, dialysis therapy, and adequate nutritional support. [119] [128] This patient-tailored supportive approach should form the basis of treatment in patients with renal cholesterol emboli.


Clinical Manifestations

Sickle cell anemia, and occasionally the heterozygous forms of sickle cell disease, can lead to multiple renal abnormalities, which include tubular, medullary, and glomerular dysfunction or a combination of these. Gross hematuria is one of the most prevalent features of sickle cell anemia, sickle cell trait (Hb-AS disease), and Hb-SC disease.[145] The hematuria is usually painless and self-limited.[146] A total of 15% to 36% of patients with sickle cell disease develop renal papillary necrosis,[145] which could manifest as an episode of gross hematuria or as a silent finding. Papillary necrosis occurs in both the homozygous and the heterozygous forms of sickle cell disease and is best diagnosed by intravenous pyelography ( Fig. 32-6 ). Microscopic hematuria is present in most patients with sickle cell anemia. The origin of blood is more commonly the left kidney, but either kidney may be involved.[145]



FIGURE 32-6  Renal papillary necrosis with various forms of cavitation in a 33-year-old man with sickle cell hemoglobinopathy and hematuria. Kidneys are normal size and smooth in contour. Central cavitation is present in many papillae, particularly in right interpolar areas (arrows).  (From Davidson AJ, Hartman DS: Radiology of the Kidney and Urinary Tract, 2nd ed. Philadelphia, WB Saunders, 1994, p 184.)


Proteinuria is also a common finding in patients with sickle cell.[145] It occurs in 20% to 30% of patients with sickle cell disease and more commonly in homozygous Hb-SS than in heterozygous Hb-SA, with Hb-SC in between.[146] Proteinuria can either be in the nephrotic or non-nephrotic range. Nephrotic patients have a poorer prognosis and tend to progress to renal failure.[146]

Powars and colleagues[147] reported that chronic renal failure develops in 4.2% of patients with sickle cell anemia and 2.4% of those with Hb-SC disease, with the age of onset in the third and fourth decades of life respectively. The prevalence of renal failure in sickle cell patients has been reported to be as high as 18%.[148] Progression of anemia, hypertension, proteinuria, nephrotic syndrome, and microscopic hematuria are predictors of chronic renal failure.[147] [148] It is important to note , however, that the GFR in most children with Hb-SS is either normal or increased, with an eventual decrease with age.[146] Progression to ESRD occurs within 2 years in 50% of affected patients,[149] and survival time is approximately 4 years, even with dialysis therapy.[147] The cause of progressive renal failure in patients with sickle cell disease is not entirely clear. Although ARF is uncommon, it has been reported in the setting of sickle cell pain crisis. Frequently, concomitant infection or rhabdomyolysis is detected with renal failure.[146] Less often, renal vein thrombosis and intravascular hemolysis have been reported as causes of acute renal insufficiency in patients with sickle cell disease.[150]

An inability to maximally concentrate the urine is a consistent finding in homozygous and heterozygous forms of sickle cell disease, and this results from sickling in the medullary microcirculation, with resultant medullary ischemia. This abnormality is reversible with multiple transfusions for children less than 15 years of age, but it becomes irreversible later in life.[148] Patients with sickle cell anemia are capable of diluting their urine normally. Another renal defect seen in patients with sickle cell disease, particularly those with the Hb-SS or Hb-SC phenotype, is an incomplete form of distal renal tubule acidosis characterized by the inability to achieve minimal urinary pH during acid loading because of impairment of titratable acid excretion. This defect, however, is not severe enough to cause systemic acidosis. Patients with sickle cell trait (Hb-AS) do not have evidence of impaired urinary acidification. Other tubule defects in sickle cell anemia include mild impairment of K+ excretion that does not lead to clinical hyperkalemia.[146] Fractional excretion of creatinine is increased, which necessitates the use of inulin clearance to measure GFR accurately.[148] However, Herrera and colleagues[151] demonstrated an impaired tubular secretion of creatinine in SCA patients with normal GFR. In addition, there is increased PO43- reabsorption in the proximal tubule that could account for the hyperphosphatemia observed in SCA patients.[148]

Renal medullary carcinoma has been associated with hemoglobinopathies. It is mostly found in heterozygous Hb-AS patients[152] and is a very aggressive tumor with poor prognosis.[153]


In 1923, Sydenstricker and colleagues described enlarged glomeruli distended with blood in the kidneys of patients with sickle cell disease. Necrosis and pigmentation of tubular cells was also observed.[145] Medullary lesions are the most prominent finding in the kidneys of these patients. Edema, focal scarring, interstitial fibrosis, and tubule atrophy are observed. Cortical infarction has also been reported in patients with sickle cell disease or sickle cell trait.[145]In Hb-SS patients without renal insufficiency, renal pathology includes glomerular hypertrophy characterized by open, dilated glomerular capillary loops.[154] Enlarged glomeruli are most commonly found in the juxtamedullary region of the kidney. In patients with proteinuria and mild renal insufficiency, Falk and co-workers[155] reported glomerular hypertrophy and focal segmental glomerulosclerosis. FSGS is thought to be the most common cause of renal failure in sickle cell disease.[156] In a study of 240 adult patients with sickle cell anemia and the nephrotic syndrome, Bakir and associates[149] reported the presence of mesangial expansion and glomerular basement membrane duplication by electron microscopy. Effacement of epithelial cell foot processes was also observed. These changes suggest hyperfiltration injury and often are referred to in these patients as sickle cell glomerulopathy. Membranoproliferative pathology was observed in some sickle cell anemia patients, the majority of whom had no immune deposits. [145] [156]


The underlying biologic defect in sickle cell disease is a single amino acid substitution of valine for glutamic acid at the sixth position in the hemoglobin beta-chain. This alteration leads to aggregation of deoxygenated sickle cell hemoglobin (Hb-SS) molecules, resulting in deformation of the shape and decreased flexibility of red blood cells.[157] Hb-SS polymer formation is promoted by higher degrees of deoxygenation, increased intracellular hemoglobin concentration, and the absence of hemoglobin F.[157] As red blood cells from sickle cell patients flow through arterioles and capillaries, Hb-SS polymerization may occur. However, the transit time of red blood cells in the microcirculation is usually shorter than the time required for polymerization of sickle hemoglobin. Therefore, factors that increase the microcirculatory transit time may lead to vaso-occlusion in sickle cell disease. Increased adherence of Hb-SS erythrocytes to the vascular endothelium has been described. Gee and Platt[158] found that sickle reticulocytes adhere to the endothelium via vascular cell adhesion molecule-1 (VCAM-1). Kumar and co-workers[159] reported that increased sickle erythrocyte adherence to the endothelium involves α4b1-integrin receptors. α4b1-integrins on the cell surface of RBC's bind to both fibronectin and VCAM-1 on endothelial cells. This is induced by the presence of inflammatory cytokines such as TNF-a.[146] Platelet activation has also been suggested to play a role in sickle cell-mediated vaso-occlusion.[160] Thrombospondin from activated platelets promotes sickle erythrocyte adherence to the microvascular endothelium.[160] Increased concentration of intracellular sickle hemoglobin may promote polymerization and trigger the sickling process. Drugs that induce hyponatremia may lead to osmotic swelling of erythrocytes and decrease intracellular sickle hemoglobin concentration. The studies of Brugnara and colleagues[161] indicate that there is a reduction of red blood cell dehydration in patients with sickle cell disease treated with the antifungal clotrimazole. It has been suggested that hemoglobin F acts as an inhibitor of the polymerization of deoxyhemoglobin S. Platt and co-workers[162] showed that there is an inverse correlation between the frequency of pain crises and hemoglobin F concentration. Certain drugs, such as 5-azacitidine, hydroxyurea, and sodium phenylbutyrate, have been found to increase the hemoglobin F concentration in patients with sickle cell anemia. [146] [163]

The pathogenesis of medullary renal lesions in sickle cell disease is attributed largely to microvascular occlusion by erythrocytes that carry the mutant hemoglobin beta-chain. Erythrocytes passing through the vessels of the inner renal medulla and the renal papillae are most vulnerable to sickling because of the high osmolality of the blood, which leads to cell shrinkage and increased hemoglobin concentration. The pathogenesis of sickle cell glomerulopathy is generally attributed to hyperfiltration. In children with sickle cell disease, renal function is characterized by glomerular hyperperfusion. Later in life, the GFR often declines, despite persistent high renal blood flow rates.[146]Guasch and associates [164] [165] described a distinct pattern of glomerular dysfunction in patients with sickle cell anemia that consists of a generalized increase in permeability to dextrans secondary to increased pore radius in the glomerular basement membrane. With progression to chronic renal failure, the number of pores is reduced and a size-selectivity defect occurs.[164] This abnormality may account for the proteinuria observed in patients with sickle cell glomerulopathy. Schmitt and colleagues[166] found that in early dysfunction the ultrafiltration coefficient is increased.

Hypoxia and decreased blood flow with secondary increase in endothelin-1 (ET-1) secretion have been suggested in the pathogenesis of sickle nephropathy. [167] [168] In addition, the roles of nitric oxide (NO) and the activation of NO synthase have been studied in the mechanism of glomerular hyperfiltration,[169] and in ischemia/reperfusion-mediated apoptosis of cells.[170]

Genetic studies of sickle cell anemia have suggested that the coinheritance of microdeletions in one of the four α-globin genes (a-thalassemia) may be renoprotective, because they are associated with a lower prevalence of macro-albuminuria and lower mean arterial pressure, compared with intact α-globin genes.[171] Mechanisms such as mesangial phagocytosis of sickle cells, immune complex glomerulopathy due to autoantigens released from ischemic tubules, iron deposits, and endothelial damage have been proposed.[148]


The management of patients with sickle cell disease is targeted at limiting sickle cell crises and end-organ damage. Factors that trigger sickling, such as infection and dehydration, should be treated aggressively. Exposure to hypoxia, cold, or medications that may induce sickle cell crisis should be avoided. Treatment options include transfusion therapy and, more recently, BMT.[172] Interestingly, multiple transfusions may restore urinary concentrating capacity in very young children with sickle cell anemia.[148] Novel approaches that target pathogenetic mechanisms have been proposed. The use of hydroxyurea in patients with sickle cell anemia aims at increasing the formation of Hb-F instead of Hb-SS. It produces a safe reduction in acute sickling crisis and it allows normal growth and development.[146] It is not known whether a reduction in the frequency of sickle cell crises translates to a lower incidence of renal disease. ACE inhibitors such as captopril or enalapril reduce the albuminuria observed in patients with sickle cell disease. [146] [148] [155] [173] The effect of these agents as well as that of angiotensin receptor blockers (ARBs) on the rate of progression of sickle cell glomerulopathy remains to be studied.[145]

Patients with sickle cell disease who reach ESRD have a 60% survival rate at 2 years after the administration of renal replacement therapy. Dialysis is the most common form of renal replacement therapy employed. Kidney transplantation as a possible alternative to dialysis has been attempted with reported success. However, most patients experience further episodes of pain crises after renal transplantation.[145] Moreover, sickle cell nephropathy may recur after transplantation.[145] Follow-up of allograft recipients showed a lower 3-year graft and patient survival in SCD patients compared to other patients with ESRD. [95] [174] Nevertheless, there is a trend toward better patient survival with renal transplantation compared with maintenance hemodialysis, suggesting that these encouraging results should be taken into consideration when offering renal replacement therapy to patients with end-stage sickle cell nephropathy. [175] [176]

There is no room for the use of NSAIDs or steroids in the management or prevention of sickle cell nephropathy.[145]

Macrovascular Diseases


Nontraumatic Renal Artery Thrombosis

Nontraumatic renal artery thrombosis is a rare condition that is usually difficult to suspect and diagnose acutely. Arterial thrombi are composed of platelets with relatively little fibrin, as opposed to the high thrombin content of venous thrombi.[177]

Atherosclerosis is an example of endothelial damage that predisposes to thrombus formation; in addition, renal artery thrombosis has been reported in the setting of renal artery aneurysm, fibrinoid dysplasia, and aortic dissection,[178] as well as in the presence of endothelial injury secondary to use of substances such as cocaine.[179] Infectious and inflammatory states are also known to predispose to renal artery thrombosis, with cases reported in patients with polyarteritis nodosa,[180] Takayasu arteritis,[181] and Behçet disease.[182]

Although inherited hypercoagulable states are classically associated with venous rather than arterial thrombosis,[183] acquired hypercoagulable states can lead to arterial thrombosis. Antiphospholipid syndrome is reported to lead to renal artery thrombosis, [184] [185] [186] [187] [188] whether it is primary or secondary to SLE. [184] [187] Heparin-induced thrombocytopenia has also been associated with renal artery thrombosis, with both unfractionated and low molecular weight heparins. [189] [190] Other hypercoagulable states associated with renal artery thrombosis are Factor V Leiden mutation,[191] antithrombin,[192] MTHFR, [193] [194] hyperhomocysteinemia,[194] and nephrotic syndrome.[195]

Renal allograft vascular thrombosis is a serious complication of kidney transplantation that ultimately leads to graft loss, with a reported incidence of 0.8% to 6%,[196] and a lower incidence of 0.5% in live donor renal transplants.[197] This may explain one third to one half of cases of early graft loss.[198] Transplant recipients who have been found to have higher rates of renal artery thrombosis are pediatric patients, patients with preoperative hypercoagulable states, and those who were on peritoneal dialysis prior to transplantation.[197] The type of fluid used for perfusion[199] and the pro-coagulant effects of OKT3 and cyclosporine A have also been associated with thrombotic sequelae.[197] Bakir and colleagues[196] found that having a right donor kidney, history of venous thrombosis, diabetic nephropathy in the recipient, technical surgical problems, and perioperative hemodynamic status are independent risk factors for primary renal graft thrombosis. In addition, APS may explain renal artery thrombotic events in kidney transplant recipients.[200] The use of cyclosporine A[201] and OKT3[202] has been associated with renal artery thrombosis.[201] Cyclosporine can cause microangiopathic hemolytic anemia with renal failure. Although tacrolimus was believed to have a lower risk of HUS,[203] it has been associated with development of microangiopathy and renal artery thrombosis as well.[204]

Thromboembolism of the Renal Artery

Acute renal artery thromboembolism is a serious medical condition that requires prompt diagnosis and treatment. The heart is the main source of peripheral thromboemboli including those to the renal arteries.[205] Atrial fibrillation is known to increase the risk of peripheral thromboemboli. Men and women with atrial fibrillation have a fourfold and almost sevenfold risk of developing peripheral thromboemboli respectively compared to those without atrial fibrillation.[206] However, renal thromboemboli constitute only 2% of peripheral emboli secondary to atrial fibrillation.[206] Myocardial infarction and heart failure may predispose to the formation of thromboemboli. Valvular heart disease, bacterial endocarditis, heart tumors, and dilated cardiomyopathy are other predisposing factors.[207] Paradoxical emboli have also been described.[208]

The aorta can be a source of renal artery thromboemboli, and more so following endovascular repair of aortic aneurysms.[209] The rate of renal infarcts after such a procedure is about 9%.[209] Endovascular revascularization of renal artery stenosis may be complicated by distal emboli as well.[210] However, the use of angioplasty and stenting with distal protection baskets may decrease the rate of complications.[211]

The clinical presentation of renal artery thromboembolism is variable and depends on the extent of renal injury and on the overall clinical picture.[211] Although anuria is characteristic of bilateral renal artery and solitary kidney renal artery involvement, it has been reported in unilateral renal artery thromboembolism, probably because of reflex vasospasm of the contralateral kidney.[212] A high degree of suspicion is a prerequisite for diagnosis.[205] The patient usually presents with unexplained abdominal pain,[205] gross hematuria,[177] abdominal or flank tenderness, fever, and hypertension.[177] There may be signs of involvement of other end organs by thromboembolic events, or recent cardiac events, such as atrial fibrillation or myocardial infarction. Most patients have an elevated serum LDH and hematuria. [208] [213] Serum aspartate aminotransferase and alanine aminotransferase may be mildly elevated. [177] [207] Urinary sodium excretion may be low,[214] and leukocytosis is common.

Although angiography is considered the gold standard for diagnosis, its use is reserved for situations where intervention is contemplated. Less invasive techniques are used for rapid diagnosis. Contrast-enhanced CT scan readily demonstrates the absence of enhancement in the affected renal tissue[215] although there is concern about further damage to the kidney with the use of iodinated contrast material. Contrast-enhanced three-dimensional magnetic resonance angiography displays sharp images of the renal arteries and of perfusion abnormalities.[216] Isotopic flow scans, typically with a technetium 99m (99mTc)-labeled agent such as dimethylenetriamine pentaacetic acid (DTPA), show absent or markedly reduced perfusion of the affected kidney.[177] Although the use of power Doppler techniques and contrast agents can reduce the number of false negative results,[217] the quality of these studies is operator dependent.[177]

Pathology of Renal Infarction

Renal infarction is an infrequent clinical diagnosis, but it is not an uncommon autopsy finding.[177] Renal infarctions occur when the main renal artery, branch artery, or interlobar and arcuate arteries are occluded acutely. Infarction may also result from renal vein occlusion, but this is much less likely than infarction from arterial occlusions.[218]

The gross appearance of the infarct depends on the size of the occluded artery, the age of the infarct, and the presence of infection. In the first hour, the infarct is red and pyramidal in shape; within hours, the infarcted area becomes gray and has a narrow red rim of congested parenchyma. The necrotic area is eventually replaced by collagen. The area shrinks, forming a V-shaped scar with the wide base toward the surface of the kidney. Infarctions involve only the renal cortex; the medulla usually is spared.[177] The scarring can give the kidney an irregular, bumpy surface.

The microscopic picture of sterile infarctions is the classic image of coagulative necrosis. The initial findings of marked congestion are followed by cytoplasmic and nuclear degenerative changes and gradual loss of viable cytologic structure. The cytoplasm becomes homogeneous and eosinophilic, and the nuclei undergo condensation and karyorrhexis. Surrounding this necrotic area is a transitional zone of sublethal injury with findings similar to those of acute tubular necrosis. This peripheral area becomes infiltrated with polymorphonuclear leukocytes. The central necrotic area becomes smaller and eventually collapses, being replaced by a collagenous scar.[218]

Therapy for Acute Occlusive Renal Arterial Disease

The human kidney is believed to tolerate absence of blood flow for 60 to 90 minutes. [207] [219] The presence of adequate collateral circulation from lumbar, suprarenal, or ureteral vessels may allow the kidney a longer ischemia time.[219] The duration and the extent of ischemia are major determinants of the prognosis of an ischemic kidney.[177]

Treatment options for an acutely occluded renal artery are surgical embolectomy, percutaneous interventional techniques, and intraarterial thrombolysis.[219] Despite the restoration of kidney function in up to 64% of patients with surgical interventions,[220] the mortality rate ranges between 15% and 20%. [220] [221] The outcome of surgical embolectomy has been reported to be worse regarding kidney function.[222] The use of intraarterial thrombolytic agents has been associated with a high rate of renal artery recanalization[223]; however, the success of the procedure does not always translate into recovery of renal function.[223] Patients who sustain complete occlusions or receive delayed treatment have a generally worse prognosis. Nevertheless, there are several case reports that describe favorable outcomes with intraarterial thrombolysis even in cases of prolonged ischemia (20 to 72 hours) and in renal transplant patients.[177] Successful results have also been reported with the use of systemic thrombolysis.[224] Percutaneous aspiration thrombolectomy[221] and rheolytic thrombectomy [221] [225] [226] have been performed with some success.

Traumatic Renal Artery Thrombosis

Renal artery thrombosis is an uncommon sequelae of blunt abdominal trauma. Motor vehicle accidents are the main cause of this injury.[227] Ever since it was first described by Von Recklinghausen in 1861,[228] there have been 200 to 300 reported cases in the literature.[227] Renal vessels can be affected by stretch injury, contusion, or avulsion, all of which may lead to thrombosis.[227] The left renal artery is slightly more affected than the right, but bilateral injury may be present as well. [227] [229] Patients with traumatic renal artery thrombosis are usually critically ill and have other associated injuries, most commonly abdominal. The prognosis is poor with mortality rate reaching 44%.[230]

Clinically, patients present with history of major trauma, have flank and abdominal pain, nausea, vomiting, and fever. They may develop severe hypertension. Patients with bilateral renal artery thrombosis or thrombosis of a solitary functioning kidney develop anuria.[177] Hematuria is present in the majority, but it may be absent in about one fourth of patients.[227] Mild proteinuria is often present.[231] Elevation of serum lactate dehydrogenase in particular, but also creatinine phosphokinase, serum transaminases, and alkaline phosphatase, may be noted.[177]

Computed tomography is the preferred diagnostic modality in patients with suspected renal artery thrombosis. It has the advantage of speed, accuracy, and the ability to detect other associated injuries. [227] [232] Patients with renal artery thrombosis usually have absent parenchymal enhancement in the affected kidney. There is also abrupt termination of the renal artery just beyond its origin.[215] There might be enhancement of the cortex due to perfusion from peripheral and collateral arteries, is referred to as the rim sign on CT.[233] The gold standard for diagnosis of renal artery injury is renal artery angiography that shows intimal flaps with partial stenosis or complete occlusion.[227]Angiography has the advantage of detecting the location of the injury with high accuracy; however, angiography is not usually necessary for confirmation if the CT is diagnostic.[215] There is a concern about contrast-induced nephropathy with the use of iodinated contrast material in patients with renal injury or renal failure. Ultrasonography has been shown to be unreliable in demonstrating vascular lesions of the kidney after blunt abdominal trauma.[234]

With current digital subtraction technology, angiography can be performed using very little iodinated contrast material, and carbon dioxide or gadolinium (or one of its derivatives) can be substituted to further decrease the dose of contrast agent.[177] This decreases concerns of contrast-induced renal failure (RF) in unstable patients who are considered to be at high risk for this complication. If a trauma patient is too unstable to undergo these diagnostic procedures, a simple intravenous bolus injection of contrast material followed by a “one-shot” excretory urogram may furnish valuable information to the surgeon preoperatively. A normal urogram would exclude the presence of major trauma to that kidney.[177]

Ischemia time is a major determinant of the outcome of revascularization in patients with traumatic renal artery thrombosis; 80% of renal artery revascularizations performed within 12 hours are successful. The success rate decreases with time, reaching zero for revascularizations performed after more than 18 hours.[235] However, there are case reports of late successful revascularizations. [236] [237] Other determinants of the outcome are the extent of renal injury, the presence of collateral circulation, the technical difficulties of the surgical procedure, and the injury to other organs.[177]

A significant number of patients who had successful surgical revascularization develop hypertension.[238] Many of them eventually require nephrectomy.[239] The outcome of surgical revascularization in patients with unilateral traumatic renal artery thrombosis may not be better than observation and medical management. [177] [239] Nevertheless, revascularization is indicated in patients with bilateral renal arteries thrombosis and in patients with solitary kidney.[239] Late revascularization may be considered if the kidney size is normal on imaging studies and if preserved glomerular architecture is noted on renal biopsy.[236]

Several surgical procedures can be performed for the repair of a renal pedicle injury including thrombectomy, resection of the injured arterial segment, and replacement with a venous or graft bypass, and autotransplantation with ex vivo repair of the vascular lesions. [177] [240] [241] Endovascular stent placements for traumatic intimal tears have been described.[242] Nephrectomy is required at times to control renal hemorrhage.[177]


Large autopsy studies suggest the incidence of renal artery aneurysms (RAAs) to be 0.01% in the general population.[177] In patients undergoing renal arteriography primarily for the evaluation of renovascular hypertension, RAAs are observed in 1%.[177] Many RAAs remain asymptomatic. However, the clinical concerns of RAAs are their potential to rupture, thrombose, causing distal embolization, or lead to renovascular hypertension. Intrarenal aneurysms may erode into adjacent veins to produce arteriovenous fistulae.[177]

Renal artery aneurysms are classified as saccular, fusiform, dissecting, or intrarenal. They may be located anywhere along the vascular tree, but most of them are found at the bifurcation of the renal artery or in the first-order branch arteries.[243]

Saccular aneurysms, the most common type, constitute 60% to 90%. They are diagnosed typically at about 50 years of age, but can be seen from 13 to 78 years of age. In approximately 20% of cases, RAAs are bilateral. Renal artery stenosis may be associated.

Renal artery aneurysms are sometimes attributed to atherosclerosis, but marked atherosclerotic changes are found in only 16%, and may be secondary.[243]

Fusiform aneurysms are often seen in medial fibromuscular dysplasia and usually arise distal to a focal stenotic segment, giving the image of a poststenotic dilatation. [244] [245] Occasionally, several small aneurysms in sequence give the “string of beads” appearance seen in fibromuscular dysplasia. Fusiform aneurysms are typically found in young hypertensive patients who undergo renal angiography for the evaluation of renovascular hypertension. As with fibromuscular dysplasia, fusiform aneurysms are more common in women.

Renal artery aneurysms have been described in polyarteritis nodosa,[246] Takayasu arteritis, [247] [248] Behçet disease,[182] the Ehlers-Danlos syndrome,[248] and mycotic aneurysms.[249]

Intraparenchymal renal aneurysms make up 10% to 15% of RAAs, and are frequently multiple. They may be congenital, post-traumatic (e.g., after renal biopsy), or associated with polyarteritis nodosa.

Clinical Manifestations of Renal Artery Aneurysms

Many patients with RAAs are asymptomatic and are diagnosed as part of a workup for renovascular hypertension. Occasionally, such patients have flank pain. Flank pain should raise the concern of an expanding aneurysm, rupture and hemorrhage, thrombosis or thromboemboli with impending renal infarction, or dissection. Most RAA patients have hypertension.[177]

Rupture of RAA, a potentially catastrophic event, may present with vascular collapse and hemorrhagic shock. Aneurysm size is a factor in the potential for rupture. Rupture of RAAs, less than 2.0 cm in diameter, is low. Large aneurysms, especially those larger than 4.0 cm in diameter, have a greater tendency to rupture and usually require surgical intervention.[250]

Pregnant women constitute a disproportionate number of cases of RAA rupture. In a review of 43 cases of rupture, 18 (42%) occurred in pregnant women.[251] Most of these occurred during the last trimester of pregnancy, but rupture and hemorrhage also occurred earlier in pregnancy and during the postpartum period.[252] Renal artery rupture during pregnancy has also been described in a renal transplant recipient.[253] Many of the pregnant women who suffered RAA rupture did not have hypertension before or during their pregnancy. The reason for the increased incidence of rupture in pregnancy is not certain. Pathogenic considerations include increased renal blood flow particularly during the last trimester, the effect of female hormones on the vasculature, and increased intra-abdominal pressure.[177] Emergency nephrectomy is usually required in this setting to control the hemorrhage. In recent years, maternal mortality has decreased to 6% and fetal mortality to 25% if the pregnancy had reached the third trimester.[250] If rupture occurred before the third trimester, fetal mortality approached 100%.

The clinical presentation of rupture of a RAA includes flank pain, vascular collapse, and shock. Abdominal distention or a flank mass may be detected. Hematuria may be a helpful finding in some patients, but its absence does not exclude the diagnosis. Renal angiography and MRA will diagnose RAA; CT and radionuclide scanning may be useful screening techniques.

Various authors have attempted to provide criteria for elective surgical intervention in RAA. [177] [220] [243] [254] [255] There is considerable uncertainty inherent in these criteria. A conservative approach, based on the previous discussion, would incorporate a number of factors in deciding about elective surgical intervention. First is the absolute size of the aneurysm. Many authorities agree that an aneurysm larger than 4.0 cm in diameter should be resected, and one less than 2.0 cm in diameter can be safely followed with periodic imaging studies. There is uncertainty about the mid-sized aneurysms, those between 2.1 and 4.0 cm. It may be prudent to recommend repair of RAAs greater than 3.0 cm in diameter in patients with surgical risks if there is reasonable certainty that nephrectomy will not be required.[255] Besides large size of the aneurysm, other factors are considered in the choice for elective surgical intervention ( Table 32-4 ).[177]

TABLE 32-4   -- Indications for Surgery in Renal Artery Aneurysm

Large size (see text)

Aneurysms with lobulations

Aneurysm showing expansion on follow-up

Aneurysms causing clinical signs and symptoms

Aneurysms of any size in young women of childbearing age

Aneurysm in a solitary kidney with the potential for embolization or dissection

Renovascular hypertension




Several surgical techniques for treatment of RAAs have been described, but the most commonly used approach is in situ aneurysmectomy and revascularization. Henke and colleagues[243] used this technique in all but one of their 168 RAA repairs. When carefully done, this surgery carries the least risk of damage to the kidney and ureter. Given the technically demanding nature of RAA surgery, this intervention should be performed by surgeons with demonstrated expertise in renal artery reconstructive procedures. Even with the vast experience of Henke's group, almost 5% of their patients had to undergo unplanned nephrectomy because of technical complications encountered during attempted revascularization.

Catheter-based interventions of stent grafts and embolization techniques using microcoils and Gelfoam have been used to treat RAAs as an alternative to surgery.

Dissecting Aneurysms of the Renal Artery

Dissecting aneurysms of the renal artery are uncommon, and can cause acute or chronic occlusion of the artery. Acute dissections may manifest in an explosive manner, with malignant hypertension, flank pain, and renal infarction. Chronic dissection most commonly manifests as renovascular hypertension.[244] Acute dissection can occur spontaneously, and can be precipitated by strenuous physical activity or trauma.[256] Fibromuscular dysplasia and atherosclerosis are common predisposing factors that lead to intimal tears, medial necrosis of the artery wall, and dissection. Iatrogenic dissection due to angiographic procedures may occur from trauma induced by guide wires, catheters, or angioplasty balloons.[177] Dissections have also been found as incidental autopsy findings, apparently without clinical symptoms during life.[177]

Renal artery dissections are about three times more common in men, and there is a predilection toward involvement of the right side. Approximately 20% to 30% are bilateral. Dissection is most common in 40- to 60-year-olds, although younger patients with fibromuscular dysplasia may be affected.

With acute dissection, patients may present with new-onset, accelerated, or worsening hypertension. [257] [258] Flank pain is frequent, and headache may occur, perhaps as a result of hypertension. In some cases, especially with lesions that develop from an angiographic procedure, the patient may be asymptomatic except for worsening hypertension. Mild proteinuria may be detected, and hematuria is noted in only 20% to 35% of the patients.[256] Impaired renal function with serum creatinine greater than 1.5 mg/dL is present in only 9% and 33% of patients in two series. [256] [259] Selective angiography is necessary for the diagnosis. Dissection on arteriography appears as an abrupt narrowing of the arterial lumen, which is caused by the unfilled false lumen. Less commonly, both true and false lumens fill with contrast material, giving the appearance of a double lumen separated by an intimal flap. [177] [256]

The clinical outcome appears to be variable. Some patients have persistent severe renovascular hypertension that may be resistant to medical therapy. These patients may benefit from revascularization or nephrectomy if they suffered renal infarction, and many show improvement or complete resolution of hypertension after these procedures. [258] [259] Endovascular interventions have also been reported.[259]

Appropriate therapy depends on the severity of the hypertension and its response to therapy. Edwards and colleagues[256] noted adequate responses to medical manage-ment in the majority of patients. Others have emphasized the importance of vascular reconstruction, which may require autotransplantation. [260] [261]


Renal vein thrombosis (RVT) was first described by Hunter.[262] Rayer was the first to make its association with nephrotic syndrome.[263] Though uncommon, it can be seen in a variety of clinical settings such as tumors, aneurysm, or abscesses resulting in direct compression, or from hypovolemic or hypercoagulable states.[264] In adults, RVT is most commonly associated with nephrotic syndrome.

Renal vein thrombosis is the most common form of thromboembolisms in neonates[265] and is a common cause of graft loss in kidney transplants.[266]

A high index of suspicion is essential for the diagnosis of RVT because the clinical presentation can be subtle.[264]


The incidence of RVT in the adult population is difficult to establish. The overall incidence in nephrotic syndrome ranges from 5% to 62%,[267] and is highest in patients affected with membranous nephropathy or membranoproliferative glomerulonephritis.[268]

Llach and colleagues[269] found that among 151 patients with nephritic syndrome, 33 (22%) developed RVT. Biopsy findings showed membranous nephropathy in 20 patients, membranoproliferative glomerulonephritis in 6 patients, and lipoid nephrosis in 2 patients.[264]

A study of 64 nephrotic patients by Robert and co-workers[270] showed that the most important predictive factor for the occurrence of embolism was the presence of membranous nephropathy (MN), such as 33% of patients with MN developed thrombosis and 50% of patients with thrombosis had MN.

Other etiological factors include amyloidosis, oral contraceptives, steroids administration, and genetic procoagulant defects.[271] RVT can occur secondary to trauma (blunt, surgical),[272] neoplasms (hypernephroma, Wilms tumor), extrinsic compression (retroperitoneal tumors, pregnancy, lymphoma), arterial diagnostic puncture,[272] placement of central catheters,[273] and functional states of hypoperfusion such as congestive heart failure,[272] hypovolemia, a cause of RVT in neonates, has also been reported in adults. Morrissey and colleagues[272] reported a case of bilateral RVT in a previously healthy 22-year-old man resulting in moderate proteinuria without underlying glomerular pathology and with normal coagulation profile. The RVT was preceded by 3 days history of nausea and vomiting as the only precipitating event. Treatment with fibrinolytics followed by heparin was successful.[272]

Renal vein thrombosis triggered by hypovolemia was also suggested in other studies. [270] [274] Steroids aggravate hypercoagulable states by increasing factor VIII and other serum proteins and by decreasing fibrinolytic activity.[275]Historically, the advent of steroid therapy coincided with an increase in thromboembolic complications.[276] Cheng and co-workers[277] reported that steroid therapy was associated with a higher incidence of RVT.

The use of oral contraceptives has been implicated as a cause of RVT, and may unmask underlying hypercoagulable disorder. [271] [278] [279]

Acute RVT has been noted with increasing frequency in the transplanted kidney, [280] [281] which unlike the native kidney has a single drainage system. In this setting, RVT may be accompanied by thrombosis of extrarenal sites.[196]Recently, Bakir and associates[196] reviewed 558 consecutive cadaveric kidney transplants, and noted a 6% incidence of RVT, which accounted for one third of all early (90 days) graft failures. RVT usually leads to permanent damage of the graft within hours. Predisposing factors are OKT3 and cyclosporine therapy. [280] [282] Cyclosporine may predispose to vascular thrombosis by exacerbating hypercoagulability.[283]

Neonatal RVT accounts for 15% to 20% of systemic thromboembolic events in neonates and results in significant long-term morbidity.[284] Maternal and patient risk factors for RVT are presented in Table 32-5 .

TABLE 32-5   -- Maternal and Patient Risk Factors for Renal Vein Thrombosis

Maternal Risk Factors

Patient Risk Factors

Fetal distress: 26%

Respiratory distress: 30%

Diabetes, traumatic birth: 17%

Cardiac disease, diarrhea/dehydration, hypotension, polycythemia, factor V Leiden heterozygosity: 13%

Steroids, preeclampsia: 13%

Femoral/umbilical catheter, protein C deficiency, twin-twin transfusion: 4%

Polyhydramnios, amphetamine, protein C deficiency: 4%

No patient risk factors: 26%

No maternal risk factors: 35%


From Zigman A, Yazbeck S, Emil S, Nguyen L: Renal vein thrombosis: A 10-year review. J Pediatr Surg 35:1540–1542, 2000.





Multiple hemostatic abnormalities have been described in patients with nephrotic syndrome ( Table 32-6 ).[268] These abnormalities vary in intensity proportionally with the degree of albuminuria and hypoalbuminemia.[268]

TABLE 32-6   -- Major Contributing Factors to the Hypercoagulable State in the Nephrotic Syndrome

Low zymogen factors: factor IX, factor XI

Increased procoagulatory cofactors: factor V, factor VIII

Increased fibrinogen levels

Decreased coagulation inhibitors: antithrombin III (but protein C and protein S increased)

Altered fibrinolytic system (a2-antiplasmin increased, plasminogen decreased)

Increased platelet reactivity


Increased release reaction in vitro (adenosine diphosphate, thrombin, collagen, arachidonic acid, epinephrine)

Increased factor IV and β-thromboglobulin in vivo

Altered endothelial-cell function

From Orth SR, Ritz E: The nephrotic syndrome. N Engl J Med 338:1202–1211, 1998.




Coagulation Factor Abnormalities

Plasma levels of several coagulation factors (fibrinogen, fibronectin, factor V, factor VIII, and factor XIII) are elevated in patients with nephrotic syndrome.[285]

Robert and colleagues[270] showed no correlation between elevated levels of factor VIII and the occurrence of thromboembolic events. Indeed, the high plasma levels of the factors V, F VIII, F XIII, fibrinogen, and fibronectin result from increased hepatic synthesis secondary to decreased oncotic pressure and contracted intravascular distribution.[268]

Prothrombin complex factors including factors II, F VII, F IX, and FX are within normal range in most nephrotic patients.[268]

Factor XII level I is decreased in nephrotic patients probably secondary to intravascular consumption.[268] Linear deposits of factor XII have been observed in glomeruli from nephrotic patients with membranous nephropathy.[268]

Elevated fibrinogen level has been found to be the most constant plasma coagulation disorder in patients with nephrotic syndrome.[285] A fibrinogen level >600 mg/dl is found in most series.[286] Significant correlations were found between plasma levels of fibrinogen, alpha-2 macroglobulin, and cholesterol, which are inversely correlated with the severity of hypoalbuminemia.[268]

Anticoagulants Proteins

Loss of small molecular weight proteins in nephrotic patients[264] results in low to normal levels of antithrombin III (AT III), low free protein S, high protein C, high alpha-2 macroglobulin, and normal tissue factor pathway inhibitor.[268]

Angiotensin III is an important anticoagulant factor. It is a serine protease synthesized in the liver and endothelial cells, has the same molecular weight as albumin, and is lost in urine in the same manner.[275] It inactivates thrombin and to a lesser extent factors X, IX, Xi, XII, and kallilrein.[287] AT III functions also as a heparin cofactor necessary for heparin anticoagulant activity.[288] Up to 80% of patients with nephrosis have low levels of AT III.[287]Urinary levels are increased and both levels correlate with decreased serum albumin level. Reduced AT III level is counterbalanced by high plasma level of other thrombin inhibitors such as alpha-2 macroglobulin and heparin cofactor II.[289] However, TE events can occur in patients with nephrotic syndrome and normal level of AT III.[287] Robert and colleagues[270] and Panicucci and co-workers[264] found that low AT III level is a poor predictor of the risk of thrombosis in nephrotic patients. Protein C activity is generally normal in nephrotic patients. However, recent studies have implicated protein S as a contributing factor in thrombotic diathesis. [287] [290]


Thrombocytosis has been found in a number of nephrotic adults and children, and platelet hyperaggregability may also be a thrombotic risk factor in nephrotic patients. [270] [291]

Hypoalbuminemia results in higher availability of arachidonic acid for the synthesis of the proaggregant thromboxane A2 within platelets. Platelets activation may also be enhanced by high levels of cholesterol, fibrinogen, and VWF, also by thrombin and immune complexes.[268]


Nephrotic syndrome represents a state of depressed systemic fibrinolysis.[268] Hypoalbuminemia decreases plasminogen binding to fibrin and high fibrinogen levels also interfere with the binding of plasminogen to fibrin. Levels of fibrinolysis inhibitors such as plasminogen-activator inhibitor-1 are elevated as are those of alpha-2 macroglobulin and lipoprotein (a). [268] [292] α-2-antiplasmin level has been found to be more elevated in nephrotic patients with RVT than in those without. This high level could be a result rather than a cause of the thrombosis.[268]

Laboratory Evidence of Coagulation Activation in Nephrotic Syndrome

Hemostatic molecular markers in nephrotic syndrome were studied and provide conflicting evidence for accelerated in vivo thrombin generation. [268] [293] [294]

Recent studies suggest that clotting activation in nephrotic syndrome takes place within renal parenchyma.[268] Immune electron microscopy investigations revealed electron-dense products of fibrin-related antigen and VWF in the endothelium, subendothelium, and mesangium in renal biopsy specimen of nephrotic patients.[268] Immunohistochemical investigations demonstrated the deposition of coagulation-fibrinolysis proteins and the occurrence of platelet products within glomeruli. Biopsy specimens from nephrotic patients with membranous nephropathy showed intra-capillary glomerular deposits of fibrin, intravenular thrombi, and RVT, supporting the view that coagulation at the level of renal parenchyma constitutes the initiation of the coagulation process leading to RVT.[268]

In summary, coagulation disorders in nephrotic syndrome arise from two principal mechanisms[295]: (1) urinary loss of AT III, plasminogen, a2-antiplasmin, and free protein S, and hypoalbuminemia favoring platelets hyperaggregability, alterations in fibrinolytic system, and increased synthesis of procoagulant proteins and (2) activation of glomerular hemostatic mechanisms with intraglomerular thrombin formation ( Fig. 32-7 ).



FIGURE 32-7  Schematic representation of pathogenetic factors leading to renal vein thrombosis in nephrotic syndrome.



Clinical Presentation

Two modes of clinical presentation of RVT have been described. Acute presentation seen in young patients with a short history of nephrotic syndrome manifests with acute flank pain, macroscopic hematuria, and loss of renal function.[264] This presentation occurs in 10% of nephrotic patients at the onset of RVT.[274] It can mimic symptoms of renal colic or pyelonephritis.[271] The physician should have a high index of suspicion especially in patients with predisposing risk factors for hypercoagulability. In these cases imaging reveals an enlarged kidney and pyelocaliceal irregularities.[264]

Chronic RVT is more common in nephrotic patients. These patients are usually older,[264] have little or no accompanying symptoms except for peripheral edema, increase in proteinuria, and gradual decline in renal function.[272]They also have greater incidence of pulmonary emboli and other thromboembolic events.[264]

The degree and rapidity of venous occlusion usually determines the clinical presentation of RVT and most patients fall somewhere between the acute and chronic form of presentation.[264]

Diagnosis of Renal Vein Thrombosis

The radiologic manifestations of acute RVT are well defined and characteristic. In contrast those of chronic RVT may be subtle. Experimentally, with complete occlusion of the renal vein, the kidney increases rapidly in size within the first 24 hours , reaching a peak within 1 week after renal vein occlusion. Thereafter, there is a progressive decrease in renal size over the next 2 months, resulting in a small, atrophic kidney. A progressive decrease in the caliber and length of the renal artery occurs after the occlusion.[177]

Doppler ultrasonography can visualize the actual venous flow, increased blood velocity, and turbulence in a narrowed vein, or complete cessation of the flow if the lumen is totally occluded. Ultrasonography with Doppler color flow should be the initial noninvasive diagnostic study.

However, sonography is highly operator dependent, and has a low specificity (56%) despite a high sensitivity (85%) in experienced hands.[296]

Intrarenal arterial Doppler sonography, though sensitive for the diagnosis of RVT in transplanted kidneys is neither sensitive nor specific for the diagnosis of RVT in native kidneys.[297]

Clinically, renal ultrasound initially reveals an enlarged kidney. Often the renal pelvis can be visualized, and usually is stretched, distorted, and blurred. This may be the result of severe interstitial edema and swelling of the pelvicaliceal system. At this stage, the radiographic appearance has been compared to that observed in polycystic kidney disease, and on occasion it has led to this mistaken diagnosis. The acute symptomatology of RVT in association with this radiologic appearance establishes the diagnosis. Ureteral edema may progress to the point at which the collecting system is completely obliterated.[177]

A characteristic radiographic finding of RVT is notching of the ureter, which usually occurs when collateral veins in close relation to the ureters become tortuous as they dilate to form an alternative drainage route. Originally, the notching of the ureters was interpreted as representing mucosal edema; however, more detailed radiographic studies showed indentation of the ureters by the collateral venous circulation. Notching of the ureter is a very infrequent finding in nephrotic patients with RVT and usually occurs only in a minority of patients with chronic rather than acute RVT.[269] Retrograde pyelography may demonstrate a rectangular, linear mucosal pattern with irregular renal pelvic outlines.

Inferior venacavography with selective catheterization of the renal vein establishes the diagnosis of RVT. If the inferior vena cava is patent and free of filling defects, and if a good streaming of unopacified renal blood is demonstrated to wash out contrast from the vena cava, a diagnosis of RVT is unlikely. The Valsalva maneuver is useful during venacavography; when the intra-abdominal pressure is increased, the transit of contrast agent and blood from the inferior vena cava is slowed, the proximal part of the main renal vein may be opacified, and the patency of the lumen or even the outline of the thrombus may be demonstrated.[177] On occasion, a lack of washout in the area of the renal vein may be suggestive of RVT. Partial defects in the area of the renal vein, characteristic of renal venous thrombus extending into the inferior vena cava, may be demonstrated. In the presence of complete inferior vena cava obstruction below the renal vein, it is desirable to demonstrate the proximal extent of the thrombus, and this can readily be accomplished by transbrachial catheterization with passage of the catheter into the inferior vena cava via the subclavian vein.[177]

Often the inferior venacavogram is not diagnostic, and selective catheterization of the renal vein must be performed. A normal renal venogram demonstrates the entire intralobular venous system to the level of the arcuate vein. In general, the use of epinephrine for better visualization of the smaller vessels is not necessary. However, in the presence of normal renal blood flow, all contrast material is washed out of the renal vein within 3 seconds or less, and occasionally only the main renal vein and major branches are visualized. In this situation there may be uncertainty about thrombi in major or smaller branches. Then the use of intrarenal arterial epinephrine, by decreasing blood flow, enhances retrograde venous filling and allows later visualization of the smaller intrarenal veins. An abnormal renal venogram usually demonstrates a thrombus within the lumen as a filling defect surrounded by contrast material ( Fig. 32-8 ). In the presence of partial thrombosis, extensive collateral circulation can be demonstrated. The presence of such collaterals usually reflects the chronicity of the RVT and may explain the lack of renal functional deterioration.[177]



FIGURE 32-8  Left renal venography from a patient with renal venous thrombosis. Note the arrows indicating filling defects, which reflect accumulation of thrombotic material surrounded by contrast material. There is complete obstruction of the main renal vein as well as of collateral circulation.  (Courtesy of Dr. Llach.)


Renal arteriography may be useful in patients being evaluated for RVT associated with renal trauma or tumor because of the common involvement of the renal artery phase; deviation and stretching of the interlobular arteries are usually observed in these conditions. In the nephrographic phase, the medullary pyramids are more densely opacified than the cortex, and instead of presenting the usual triangular appearance, they appear to bulge and sometimes are even ovoid in appearance.[177]

Both contrast enhanced CT and MRI have been used for the diagnosis of RVT. Both are less invasive than venography; CT utilizes ionizing radiation and iodinated contrast agent, and hence MRI has significant advantages over CT.[296]

Because MRI produces highly contrasting images of flowing blood, vascular walls, and surrounding tissues, vascular patency may be best determined by this technique. However, low signal from the renal veins and pseudofilling defects due to slow mimicking thrombus makes interpretation of image difficult.[296]

Gadolinium enhanced MRI can overcome the limitation of poor signal from the renal vessels, and by performing a delayed second scan the venous anatomy is well demonstrated, and occult renal artery stenosis can also be disclosed.[296]

Clinical Course and Treatment

Recurrent thromboembolic phenomena, most often pulmonary embolism, are the most common cause of death in nephrotic patients with RVT.[177]

The main prognostic factors are initial renal function and type of nephropathy. Patients with membranous nephropathy had significantly better renal function and a lower mortality rate than did patients with other nephropathies. Initial renal insufficiency was significantly associated with a poor prognosis.[177] In infants, marked improvement in survival has been achieved over the past 35 years. Non-operative treatment including supportive therapy and anticoagulation has shown satisfactory survival rates.[298] Nonetheless there is still high rate of renal atrophy and long-term hypertension (17%) that highlights the need for long-term surveillance.

The rationale from the treatment of RVT is to preserve renal function and prevent thromboembolic complications. Anticoagulation is the mainstay of therapy,[264] and is intended to prevent further propagation of the thrombus and thromboembolic complications, while permitting recanalization of occluded vessels.[267]

Thrombolytics provide the possibility of more rapid and complete resolution than anticoagulants at the expense of a higher risk of bleeding.[264]

The relative efficacy of anticoagulation versus fibrinolytics in the treatment of RVT is not well defined. [264] [299]

Thrombolytic therapy is likely warranted in patients with bilateral RVT, extension into inferior vena cava, pulmonary embolism, AKI/ARF, or severe flank pain.[264]

Choice of systemic versus local administration depends on the evaluation of risk and benefit factors. Systemic administration is safe and effective if no obvious contraindications exist, and avoids the need for invasive procedures.[300] Anticoagulation is indicated in nephrotic patients who experience a thromboembolic event. Heparin should be given, although its effect may be attenuated in the presence of low ATIII levels. ATIII deficiency in nephrotic patients is not severe as such to cause heparin resistance.[275] If ATIII level are extremely low, fresh frozen plasma or ATIII concentrates can be administered.[287]

Following heparin, oral vitamin K antagonists should be used. The optimal duration of warfarin therapy is unknown, but given the risk of recurrence, it is reasonable to maintain anticoagulation as long as the patient is nephrotic and has significant hypoalbuminemia.[301] Treatment with heparin warrants monitoring of the anticoagulation response and is associated with some complications such as thrombocytopenia and osteoporosis.[274] Low molecular weight heparin (LMWH) has been suggested as alternative in the treatment of RVT. [274] [302] Prophylactic anticoagulation has been examined by decision analysis.[303]

A Markov-based decision analysis model[295] found that the number of fatal emboli prevented by prophylactic anticoagulation exceeds that of fatal bleeding in nephrotic patients with idiopathic membranous nephropathy. However, no controlled clinical trials have been performed yet to study the efficacy of prophylactic anticoagulation in decreasing vascular events in nephrotic patients with no previous thromboembolism.[268]

Because platelet function is increased in nephrotic patients, anti-platelet, particularly low-dose aspirin are a rational choice, but no controlled studies are available yet.[303]

A retrospective study[266] to assess the influence of Baby Aspirin on the incidence of RVT in cadaveric and living-related renal transplant recipient receiving cyclosporine-based triple immunosuppression showed that, though not abolished, the incidence of RVT decreased significantly with the addition of low-dose aspirin.

Amplatz thrombectomy device (ATD), a new recirculation device developed to mechanically macerate the thrombus, used in massive pulmonary embolism, deep venous thrombosis, and acute occlusions of the femoral arteries, provides an alternative option for the treatment of RVT associated with AKI/ARF. Further studies are still needed to assess its efficacy in RVT.[267]

Although marked improvement in renal function has been occasionally observed after surgical thrombectomy, the majority of patients do not improve with surgery. This modality of therapy may be theoretically useful in patients with acute bilateral RVT who are not otherwise expected to survive the acute episode, especially if recurrent pulmonary emboli occur despite anticoagulation therapy.[177]


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