Thrombotic microangiopathy (TMA) refers to injured endothelial cells that are thickened, swollen, or detached mainly from arterioles and capillaries. Platelet and hyaline thrombi causing partial or complete occlusion are integral to the histopathology. TMA is the histologic result of microangiopathic hemolytic anemia (MAHA), which consumes platelets and erythrocytes and is characterized by thrombocytopenia and schistocytes. In the kidney, TMA is characterized by swelling of the endocapillary cells (endotheliosis), fibrin thrombi, platelet plugs, arterial intimal fibrosis, and membranoproliferative changes. In severe cases, the fibrin thrombi may extend into the arteriolar vascular pole producing glomerular collapse and sometimes cortical necrosis. Secondary focal segmental glomerulosclerosis may be seen in individuals who recover from acute TMA. Diseases that present with this lesion include thrombotic thrombocytopenia (TTP), hemolytic-uremia syndrome (HUS), malignanthypertension, scleroderma renal crisis, antiphospholipid syndrome, preeclampsia/HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome, HIV infection, and radiation nephropathy.
Hemolytic-Uremic Syndrome (HUS)/Thrombotic Thrombocytopenic Purpura (TTP)
HUS and TTP are the prototypes of MAHA. Whether they represent a spectrum of the same disease or two distinct entities continues to be debated. Histologically, the diseases are inseparable, but they differ regarding epidemiology and pathophysiology. Typical HUS usually affects children (most under the age of 5) and is preceded by hemorrhagic diarrhea. Typical TTP affects individuals in their thirties and forties. Neurologic symptoms are more common in TTP and have significant morbidity and mortality rates if not treated with plasma exchange, while plasma exchange is ineffective in most HUS. The argument is strengthened with the discovery of a disintegrin and metalloproteinase with a thrombospondin type 1 motif member 13 (ADAMTS13), a von Willebrand factor (vWF) cleaving protease that is either absent or inactive in TTP but not in HUS. However, neurologic symptoms can occur in HUS, and low ADAMTS13 activity has been identified in HUS cases. Furthermore, plasma infusion/exchange is effective in some HUS. As a result, the distinction between the two is blurred, and they are often identified simply as HUS/TTP.
There are at least four variants of HUS. The most common is D+ HUS referring to its association with bacterial gastroenteritis. This typically affects young children (<5 years), but adults are also susceptible. More than 80% of cases are preceded within a week by diarrhea, often bloody. Gastrointestinal symptoms include abdominal pain, cramping, and vomiting. Fever is typically absent. Neurologic symptoms are common and may include lethargy, encephalopathy, seizures, and even cerebral infarction. The pathogenic agent linked to D+ HUS is the shiga toxin, also referred to as verotoxin. This toxin is produced by certain strains of Escherichia coli and Shigella dysenteriae. In the United States and Europe, the most common shiga-toxigenic E. coli (STEC) strain is the 0157:H7. Other strains such as 0157/H−, 0111:H−, 026:H11/H−, and 0145:H28 can also produce shiga toxin. Once shiga toxin enters the circulation, it binds to neutrophils and preferentially localizes in the kidney, where it causes damage to the endothelial cells. This results in platelet aggregation, which initiates the microangiopathic process. Another bacterium associated with HUS is Streptococcus pneumoniae. This bacterium produces a neuraminidase that cleaves the N-acetyl neuraminic acid moieties that cover the Thomsen-Friedenreich antigen on platelets and endothelial cells. Exposure of this normally cryptic antigen to preformed IgM results in severe MAHA.
Another variant produces atypical HUS (aHUS), caused by congenital complement dysregulation rather than a toxin. These patients have low C3 levels, a characteristic of alternative pathway activation. The most common cause is a deficiency of factor H, which has been linked to families with aHUS. Factor H competes with factor B to prevent the formation of C3b,Bb and acts as a cofactor for factor I, which proteolytically degrades C3b. More than 70 mutations of the factor H gene have been identified. Most are missense mutations that produce normal levels of factor H with abnormalities mainly in the C-terminus region, which affect its binding to C3b. Other mutations result in low or complete absence of the protein. Deficiencies in other complement regulatory proteins such as factor I, factor B, membrane cofactor protein or MCP (CD46), C3, complement factor H–related protein 1 (CFHR1), CFHR3, and CFHR5 have also been described. Finally, an autoimmune variant of HUS has been discovered. Deficient for CHFR protein and factor H autoantibody–positive (DEAP), HUS occurs when an autoantibody is formed against factor H. DEAP-HUS is often associated with a deletion of an 84-kb fragment of the chromosome that encodes for CFHR1 and CFHR3. The autoantibody blocks the binding of factor H to C3b and surface-bound C3 convertase.
Thrombotic Thrombocytopenic Purpura
Traditionally TTP is characterized by the pentad (hemolytic anemia, thrombocytopenia, neurologic symptoms, fever, and renal failure). Classic TTP is differentiated from HUS by neurologic involvement. However, in practice, differentiation between TTP and HUS is unreliable due to overlap in clinical manifestations. TTP has been linked with the absence or marked decreased activity in the metalloprotease ADAMTS13 specific for vWF, although this is not universally present. Even complete absence of ADAMTS13 alone does not produce TTP. Most often, an additional trigger (such as infection, surgery, pancreatitis, or pregnancy) initiates clinical TTP.
Data from the Oklahoma TTP/HUS Registry reveal an incidence rate of 11.3 per 106 patients. The median age of the patients was 40 years. Higher frequency was noted among blacks, with an incidence more than nine times higher than non-blacks. Women have nearly three times the incidence, similar to the demographics for systemic lupus erythematosus. If untreated, TTP has a mortality rate exceeding 90%. Even with modern therapy, 20% of the patients die within the first month from complications of microvascular thrombosis.
Several subtypes of TTP have been described. The classic form is acquired or idiopathic TTP, which usually follows an infection, malignancy, or an intense inflammatory reaction such as pancreatitis. This variant typically occurs with deficiency of ADAMTS13 or its activity and is the result of an autoantibody. The autoantibody (IgG or IgM) can either increase clearance of ADAMTS13 or inhibit its activity. A hereditary form with congenital deficiency of ADAMTS13 is seen in patients with Upshaw-Schulman characterized by MAHA and thrombocytopenia. TTP in these patients can start within the first weeks of life, but in others, may not start until several years of age. Environmental and genetic factors are thought to influence the development of TTP. Plasma transfusion is effective as a prevention and treatment during the TTP episodes.
Drug-induced TTP/TMA is a recognized complication of chemotherapeutic agents, immunosuppressive agents, antiplatelet agents, and quinine. Two mechanisms are responsible for drug-induced TMA. With chemotherapeutic agents (mitomycin C, gemcitabine, etc.) and immunosuppressive agents (cyclosporine, tacrolimus, and sirolimus), endothelial damage is the main cause of the MAHA. This process is usually dose-dependent. Alternatively, drugs can induce autoantibodies that produce TMA. Suppression of ADAMTS13 activity and formation of an autoantibody has been detected in patients exposed to ticlopidine. Quinine appears to induce autoantibodies against granulocytes, lymphocytes, endothelial cells, and platelet glycoprotein IbB/IX or IIb/IIIa complexes but not to ADAMTS13. Quinine-associated TTP is more common in women. Autoantibody-associated TTP can occur after a single dose in patients who had previous exposure to the drug. Most patients developing TTP from clopidogrel do not have either autoantibodies or decreased ADAMTS13 activity. Drugs that inhibit vascular endothelial growth factor (VEGF) sometimes produce TMA. The mechanism is not fully understood.
Treatment of HUS/TTP should be based on the pathophysiologic pathways that are identified. Autoantibody-mediated TTP and DEAP HUS should be treated with plasma exchange or plasmapheresis. In addition to removing the autoantibodies, plasma exchange replaces ADAMTS13. Twice-daily plasma exchanges, vincristine, and rituximab occasionally have been found to be effective in refractory cases. Plasma infusion is usually sufficient for congenital TTP such as Upshaw-Schulman syndrome. Plasma exchange should be considered if larger volumes of plasma are necessary. TTP secondary to drug-induced autoantibodies responds well to plasma exchange, while drugs that cause endothelial damage may not. D+ HUS should be treated with supportive measures. Plasma exchange has not been found to be effective. Antimotility agents and antibiotics increase the incidence of HUS and should be avoided. Conversely, plasma infusion/exchange may be beneficial in aHUS by repleting complement regulatory proteins. Antibiotics and washed red cells should be given in neuraminidase-associated HUS. Plasma and whole blood should be avoided since they contain IgM, which would exacerbate the MAHA. The coexistence of factor H and ADAMTS13 deficiency can exacerbate TTP and make it less responsive to plasma infusion, illustrating the complexity of managing these disorders.
Transplantation-Associated Thrombotic Microangiopathy (TA-TMA)
TA-TMA can develop after hematopoietic stem cell transplantation (HSCT) with an incidence of 8.2%. Etiologic factors include conditioning regimens, immunosuppression, infections, and graft-versus-host disease. Other risk factors include female sex, age, and human leukocyte antigen (HLA)-mismatched donor grafts. TA-TMA usually occurs within the first 100 days after HSCT. Table 286-3 lists definitions of TA-TMA currently used for clinical trials. A firm diagnosis may be difficult because thrombocytopenia, anemia, and renal insufficiency are common in the posttransplant period. TA-TMA carries a high mortality rate (75% within 3 months). Plasma exchange is beneficial in less than 50% of patients, most of whom have more than 5% ADAMTS13 activity. Calciuria inhibitors should be discontinued, and substitution with daclizumab [antibody to the interleukin 2 (IL-2) receptor] is recommended. Treatment with rituximab and defibrotide may also be helpful.
Table 286-3 Criteria for Establishing Microangiopathic Kidney Injury Associated with Hematopoietic Stem Cell Transplantation
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Table 286-3 Criteria for Establishing Microangiopathic Kidney Injury Associated with Hematopoietic Stem Cell Transplantation
|International Working Group||Blood and Marrow Transplant Clinical Trials Network Toxicity Committee|
|> 4% schistocytes in the blood||RBC fragmentation and at least 2 schistocytes per high-power field|
|De novo, prolonged, or progressive thrombocytopenia||Concurrent increase in LDH above baseline|
|A sudden and persistent increase in LDH||Negative direct and indirect Coombs test|
|Decrease in hemoglobin or increased RBC transfusion requirement||Concurrent renal and/or neurologic dysfunction without other explanations|
|Decrease in haptoglobin concentration|
TMA is mainly a complication encountered before widespread use of highly active retroviral therapy for HIV. It is seen in patients with advanced AIDS and low CD4 count, although it occasionally can be the first manifestation of HIV infection. The presence of MAHA thrombocytopenia and renal failure are suggestive, but renal biopsy is required to establish the diagnosis since HIV is associated with several other renal diseases. The median platelet count is 77,000/μL with a range of 10,000 to 160,000/μL, which may prohibit a renal biopsy in some patients. Cytomegalovirus (CMV) coinfection may also be a risk factor. The mechanism of injury is unclear, but HIV may induce apoptosis in endothelial cells. Plasma exchange is effective and is recommended in conjunction with antiviral therapy.
Radiation can produce microangiopathic injury after either local or total body irradiation. The kidney is one of the most radiosensitive organs, and injury can result with as little as 4–5 Gy exposure. It is characterized by renal insufficiency, proteinuria, and hypertension usually presenting 6 months or longer after radiation exposure. Renal biopsy reveals classic TMA in the kidney with damage to glomerular, tubular, and vascular cells. Systemic evidence for MAHA is rare. Because of its high incidence after allogeneic HSCT, it is often referred to as bone marrow transplant (BMT) nephropathy. No specific therapy is available, although some evidence supports treatment with renin-angiotensin system blockade.
Scleroderma (Progressive Systemic Sclerosis)
Scleroderma commonly affects the kidney, with 52% of subjects with widespread scleroderma having renal involvement sometime during the follow-up period. Of these, 19% were due to scleroderma renal crisis (SRC). Other renal manifestations in scleroderma include transient (prerenal) or medication-related forms of acute kidney injury [e.g., d-penicillamine, nonsteroidal anti-inflammatory drugs (NSAIDs), or cyclosporine]. SRC occurs in patients with diffuse systemic sclerosis (12 vs. 2% in limited systemic sclerosis). SRC is the most severe manifestation, characterized by accelerated hypertension, a rapid decline in renal function, nephrotic proteinuria, and hematuria. Retinopathy and encephalopathy may accompany the hypertension. Salt and water retention with microvascular injury can lead to pulmonary edema. Other manifestations include myocarditis, pericarditis, and arrhythmias, which denote an especially poor prognosis. Although MAHA is present in over half of the patients, coagulopathy is rare.
The renal lesion in SRC is characterized by arcuate artery intimal and medial proliferation with luminal narrowing. This lesion is described as onionskinning and can be accompanied by glomerular collapse due to reduced blood flow. Histologically it is indistinguishable from malignanthypertension. Fibrinoid necrosis and thrombosis are common. Before the availability of angiotensin-converting enzyme (ACE) inhibitors, the mortality rate for SRC at 1 month was greater than 90%. Introduction of renin-angiotensin system blockade has lowered the mortality rate to 30% at 3 years. Nearly two-thirds of patients with SRC require dialysis support. Half of those needing dialysis as a result of SRC will recover renal function (median time = 1 year). Glomerulonephritis and vasculitis associated with antineutrophil cytoplasmic antibodies (ANCAs) and systemic lupus erythematosus have been described in patients with scleroderma. An association has been found with antinuclear antibodies' (ANAs) speckled pattern and anti-RNA polymerase antibodies (I and III). Anti-U3-RNP may identify young patients at risk for SRC. Anticentromere antibody (ACA), however, is a negative predictor of SRC. Because of the overlap between SRC and other autoimmune disorders, a renal biopsy is recommended for patients with atypical renal involvement, especially if hypertension is absent.
Treatment with ACE inhibition is the first-line therapy unless contraindicated. The goal of therapy is to reduce systolic blood pressure by 20 mmHg and diastolic by 10 mmHg every 24 hours until blood pressure is normalized. Additional antihypertensive therapy may be added once the ACE inhibition is maximized. Both ACE inhibitors and angiotensin II receptor antagonists are effective, although published data show that treatment is superior with ACE inhibitors. ACE inhibition alone does not prevent SRC, although it reduces the role of hypertension. Intravenous iloprost has been used in Europe for blood pressure management and improvement of renal perfusion. Kidney transplantation is not recommended for 2 years after the start of dialysis, since delayed recovery may occur.
Antiphospholipid Syndrome (APS)
Antiphospholipid syndrome (Chap. 320) can be either primary or secondary to systemic lupus erythematosus. It is characterized by systemic thrombosis (arterial and venous) and fetal morbidity mediated by antiphospholipid antibodies (aPLs). The aPLs are mainly anticardiolipin (aCL) antibodies, which can be IgG, IgM, or IgA, lupus anticoagulant (LA), and anti-β-2 glycoprotein I antibodies (antiβ2GPI). Patients with both aCL and antiβ2GPI appear to have the highest risk of thrombosis. The vascular compartment within the kidney is the main site of renal involvement. Arteriosclerosis is commonly present in the arcuate and intralobular arteries. In the intralobular arteries, fibrous intimal hyperplasia characterized by intimal thickening secondary to intense myofibroblastic intimal cellular proliferation with extracellular matrix deposition is frequently seen along with onionskinning. Arterial and arteriolar fibrous and fibrocellular occlusions are present in over two-thirds of the biopsies. Cortical necrosis and focal cortical atrophy may result from vascular occlusion. TMA is commonly present in the renal biopsies, although signs of MAHA and platelet consumption are usually absent. TMA is especially common in the catastrophic variant of APS. In patients with secondary antiphospholipid syndrome (APS), other glomerulopathies may be present including membranous nephropathy, minimal change disease, focal segmental glomerulosclerosis, and pauci-immune crescentic glomerulonephritis.
Large vessels can be involved in APS and may form the proximal nidus near the ostium for thrombosis of the renal artery. Renal vein thrombosis can occur and should be suspected in patients with lupus anticoagulant LA who develop nephrotic range proteinuria. Progression to end-stage renal disease can occur, and thrombosis may form in the vascular access and the renal allografts. Hypertension is common. Treatment entails lifelong anticoagulation. Glucocorticoids may be beneficial in accelerated hypertension. Immunosuppression and plasma exchange may be helpful for catastrophic episodes of APS, but themselves do not reduce recurrent thrombosis.
HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome is a dangerous complication of pregnancy. Occurring in 0.5–0.9% of all pregnancies and 10–20% of cases with severe preeclampsia, it has a mortality rate that ranges between 7.4 and 34%. Most commonly occurring in the third trimester, 10% of cases occur before week 27 and 30% postpartum. Although most consider HELLP to be a severe form of preeclampsia, nearly 20% are not preceded by preeclampsia. HELLP patients have increased inflammatory markers [C-reactive protein (CRP), IL-1Ra, and IL-6] as compared to preeclampsia alone.
Renal failure occurs in half of patients with HELLP, although the etiology is not well understood. Limited data suggest renal failure is the result of a combination of preeclampsia and acute tubular necrosis from HELLP. Renal histologic findings are those of TMA with endothelial cell swelling and occlusion of the capillary lumens, but luminal thrombi are typically absent. However, thrombi become more common in severe eclampsia and HELLP. Although renal failure is common, the organ that defines this syndrome is the liver. Subcapsular hepatic hematomas sometimes produce spontaneous rupture of the liver and can be a life-threatening complication. Neurologic complications such as strokes, cerebral infarcts, cerebral and brainstem hemorrhage, and cerebral edema are other major potentially life-threatening complications. Nonfatal complications include placental abruption, permanent vision loss due to Purtscher-like (hemorrhagic and vasoocclusive vasculopathy) retinopathy, pulmonary edema, bleeding, and fetal demise.
The HELLP syndrome shares many features with other forms of MAHA. Distinguishing the specific disorders is complicated by the fact that both aHUS and TTP flares can be triggered by pregnancy. Patients with antiphospholipid syndrome have a higher risk of HELLP. A history of episodes of MAHA before pregnancy is helpful. Serum levels of ADAMTS13 activity is reduced (30–60%) in HELLP but not to the levels seen in TTP (<5%). Some authors suggest using LDH to AST ratio for diagnosis. Patients with HELLP and preeclampsia have an LDH to AST ratio of 13 to 1 versus 29 to 1 in patients without preeclampsia. Other markers such as antithrombin III (decreased in HELLP but not in TTP) and d-dimer (elevated in HELLP but not in TTP) may aid in the diagnosis. HELLP syndrome resolves spontaneously in most cases after delivery, although a portion of HELLP occurs postpartum. Glucocorticoids may decrease inflammatory markers, although two randomized, controlled trials failed to confirm beneficial effects. Plasma exchange should be considered if the hemolysis is refractory to glucocorticoids and/or delivery, especially if TTP had not been ruled out.
Renal complications in sickle cell disease (SCD) result from occlusion of the vasa recta in the renal medulla. The low partial pressure of oxygen and high osmolarity predispose to hemoglobin S polymerization and erythrocyte sickling. Sequelae include hyposthenuria, hematuria, and papillary necrosis. The kidney responds by increasing blood flow and GFR mediated by prostaglandins. This dependence on prostaglandins may explain why patients with SCD experience greater reduction of GFR by NSAIDs than others. The glomeruli are typically enlarged. Intracapillary fragmentation and phagocytosis of sickled erythrocytes are thought to be responsible for the membranoproliferative glomerulonephritis-like lesion, and focal segmental glomerulosclerosis is sometimes seen. Proteinuria is present in 20–30% of the patients, and nephrotic range proteinuria is associated with renal failure. ACE inhibitors reduce proteinuria, although data are lacking on prevention of renal failure. Patients with SCD are also more prone to acute renal failure. The cause is thought to reflect microvascular occlusion associated with nontraumatic rhabdomyolysis, high fever, infection, and generalized sickling. Chronic kidney disease is present in 12–20% of patients. Despite the frequency of renal disease, hypertension is uncommon in patients with SCD.