Hemolytic-Uremic Syndromes

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64 Hemolytic-Uremic Syndromes

Christopher LaRosa, Kevin E.C. Meyers

Hemolytic-uremic syndromes (HUS) are clinical conditions characterized by acute kidney injury, thrombocytopenia, and microangiopathic hemolytic anemia with evidence of intravascular red blood cell (RBC) destruction demonstrated by fragmented cells (schistocytes) on blood smear. The kidney injury can manifest as hematuria, proteinuria, or azotemia, which can occur individually or in combination. HUS has clinical overlap with thrombotic thrombocytopenic purpura (TTP), a syndrome known to occur as a pentad that includes the HUS triad in addition to fever and neurologic abnormalities. TTP was first described by Moschcowitz in 1924 in a 16-year-old girl with fever, anemia, heart failure, and stroke; HUS was described by von Gasser in 1955 as a case series of five children with nonimmune (Coombs-negative) hemolytic anemia, thrombocytopenia, and small vessel renal thrombi. Generally, whereas neurologic features predominate in TTP, renal injury is a major component of HUS. The classification of these syndromes has become increasingly complex in view of the fact that multiple distinct underlying pathogenic mechanisms result in a similar disease phenotype. More precise etiologic definitions allows for a better understanding of associated clinical features and prognosis as well as rational treatment approaches.

Etiology and Pathogenesis

Broadly defined, HUS and TTP are syndromes whose pathologic correlate is thrombotic microangiopathy (TMA). TMA describes the microvascular occlusion that occurs most frequently within capillaries and arterioles (Figure 64-1). It is seen histologically as thrombi, endothelial cell swelling, luminal narrowing, and fibrinoid necrosis of the vessel wall. TMA results from dysfunction of the endothelial cell–platelet interface and can originate from various underlying mechanisms, which form the basis for an etiologic classification. HUS can result from infectious causes, genetic causes, or medication-related causes or in association with secondary discrete pathologic entities. TTP results from a deficiency of von Willebrand factor-cleaving protease, (vWF-cp), which can be either acquired because of the presence of an autoantibody or congenital resulting from a mutation in the ADAMTS13 gene.

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Figure 64-1 Thrombotic disorders: hemolytic-uremic syndrome.

The majority of childhood cases of HUS occur after a prodromal diarrheal illness. For this reason, it has been termed D+ or “typical” HUS, in contrast to the less common forms of HUS not associated with a diarrheal prodrome, known as D- or “atypical” HUS. A more precise classification for D+ HUS is Shiga toxin–associated HUS (Stx HUS), which is known to cause 90% of all HUS cases in children. As the name suggests, Stx HUS occurs as a result of Shiga toxin–producing organisms. The most common of these is Shiga toxin–producing Escherichia coli (STEC), also known as verocytotoxin-producing E. coli, so-called for their ability to lyse vero cells, a primate kidney cell line with epithelial characteristics. And of these, the most common serotype is O157 : H7, which expresses somatic (O) antigen 157 and flagellar (H) antigen 7. Stx HUS can occur at any age but primarily affects children younger than 5 years of age; the peak incidence is between the ages of 6 months and 4 years. It occurs both sporadically and in the form of epidemic outbreaks, most commonly during the summer and autumn months and largely in rural areas. The disease has an annual incidence of two to three per 100,000 children younger than 5 years of age in North America and Western Europe. The incidence decreases among older children. In countries such as Uruguay and Argentina, STEC infections are endemic and cause HUS in about 10.5 per 100,000 children per year.

The primary reservoir for STEC is cattle. Environmental sources of the infection include undercooked beef or poultry, deer jerky, unpasteurized milk or other dairy products, unpasteurized apple cider, fruits, vegetables, and contaminated municipal or swimming water. Additionally, STEC infection can be acquired as zoonoses from petting zoos, from human-to-human contact, or from urinary tract infection with the organism. Testing of stool may confirm Stx-producing organisms in up to two-thirds of cases, but the environmental source is rarely discovered in sporadic cases.

HUS not associated with enteropathic STEC (NStx) encompasses a disease group with heterogeneous etiologies. NStx HUS accounts for about 10% of all cases of HUS in children. Of this group, the most common cause is Streptococcus pneumoniae-associated HUS (pneumococcal HUS), accounting for about 40% of children with NStx HUS. Pneumococcal HUS has an estimated incidence of 0.4% to 0.6%, although the possibility that this underestimates the true incidence is noted by an overall lack of recognition of the disease.

Shiga Toxin–Associated Hemolytic-Uremic Syndrome

The most common causative organism of Stx-HUS is enterohemorrhagic E. coli (EHEC). Among the EHEC that cause HUS, serotype O157 : H7 is predominant, accounting for 70% of cases in North America and Western Europe. There are several known STEC that are non-O157 strains (e.g., O111 : H8, O103 : H2, O121, O145, O26, and O113). Shigella dysenteriae type 1-associated HUS occurs more frequently in developing countries in Asia and Africa but rarely in industrialized countries. Other organisms such as Aeromonas spp. and Citrobacter freundii have been known to cause Stx HUS. E. coli O157 : H7 infection can be confirmed by plating a stool sample on sorbitol-MacConkey agar. The O157 : H7 strains cannot ferment sorbitol during an overnight incubation and appear as translucent colonies. The organism can be further confirmed by rapid assays that allow detection of Shiga toxin in the stool, including non-O157 serotypes. It is generally recommended to test stool samples by sorbitol-MacConkey agar as a first screening. The potential to detect the organism is higher in the first 6 days after onset of diarrhea.

Shiga toxin is a potent exotoxin that functions as the virulence factor in STEC. All members of the Stx family share some degree of sequence homology, the protein products of which have common structures that include an enzymatically active A subunit linked to a pentameric B subunit (A1B5). The STEC can elaborate at least four plasmid-encoded Shiga-toxins: Stx1, Stx2, Stx2c, and Stx2d (Stx is used interchangeably with the term VT). Stx1 is nearly identical to the classic Shiga toxin, and Stx2 shares 60% homology with classic Shiga toxin. The Stx may be expressed individually or in combination with two or three different Shiga-toxins. The Stx2 gene is carried by most E. coli O157 : H7, and its expression individually causes more severe disease than Stx1 or the combination of Stx1 and Stx2.

Stx is responsible for the endothelial toxicity of HUS-causing STEC, giving rise to the pathologic hallmark of TMA. It is produced in the bowel and translocated into circulation, where it can localize to the glomeruli, gastrointestinal tract, pancreas, and various other host tissues by a mechanism that has yet to be fully understood. Central to enterocyte entry and subsequent toxemia, the Stx B subunit binds to a cell surface terminal carbohydrate moiety of the globotriaosylceramide receptor (Gb3). The Gb3 receptor is a key determinant for cell sensitivity to Stx, and along with enterocytes and other cell types is present on glomerular endothelial cells, thereby targeting the toxin to the renal microvasculature. In the intestine, binding of Stx to Gb3 commences a sequence of events beginning with receptor-mediated endocytosis. Stx can follow several different pathways: (1) it can be delivered intact to the intestinal submucosa and circulation via transcytosis; (2) it can induce direct cytotoxicity by trafficking to the cell endoplasmic reticulum via the Golgi apparatus in a process known as retrograde transport; or (3) it can, in lower concentrations, alter gene and protein expression of the cell without inducing cell death. Transcytosis of toxin to the intestinal microvascular circulation is thought to give rise to the characteristic intestinal lesion that has the clinical–pathologic manifestation of bowel wall edema, thrombosis, and hemorrhage. Neutrophils localize to the intestinal mucosa during STEC infection, where they are thought to transport Stx to extraintestinal sites. They are known to bind Stx by a distinct receptor with a lower affinity than Gb3. The toxin is therefore not endocytosed, which allows it to be freely unloaded at various target sites (Figure 64-2).

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Figure 64-2 Effects of Shiga toxin on enteric cells and endothelial cells.

The cytopathic effects of Stx result when the A subunit becomes enzymatically active within the host cell by proteolytic cleavage and in turn cleaves its target adenine residue (A4324) on the 28S rRNA of the 60S ribosomal subunit. This action blocks binding of the aminoacyl-tRNA to the subunit with resultant protein synthesis inhibition and cell death. Alternatively, subinhibitory concentrations of toxin are known to alter gene expression in the host cells. Stx has been found to increase expression of prothrombotic and inflammatory genes that affect the properties of endothelial cells. Various cell types undergo toxin-mediated increase in cytokine and chemokine production. For example, subinhibitory toxin concentrations cause endothelial cells to upregulate interleukin-8 (IL-8) and monocyte chemotactic protein-1 (MCP-1) as well as endothelin-1 and tissue factor. The effector functions of these molecules result in leukocyte migration or adhesion, vasoconstriction, and a procoagulant cellular milieu. Additionally, monocytes increase cytokine production of tumor necrosis factor-α and IL-1β, factors known to sensitize host cells to toxin via upregulation of Gb3.

A major virulence cofactor of pathogenic STEC is the ability of the organism to exploit the host enterocyte by secreting its own bacterial receptor into the cell such that it is expressed on its apical surface, in turn allowing firm attachment of the organism along the intestinal mucosal surface. This receptor incorporation occurs through a macromolecular complex called the type 3 secretion system, which results in cytoskeletal changes with associated loss of normal villous architecture, giving rise to a characteristic “attaching and effacing” lesion on the host cell. The genetic locus responsible for this process is found on what are known as pathogenicity islands of the bacterial chromosome. The genes encode the machinery of the type 3 secretion system as well as intimin, expressed on the bacterial cell surface, and the intimin receptor, which is translocated into the host cell for surface expression.

Pneumococcal Hemolytic-Uremic Syndrome

Infection with S. pneumoniae occurs in the form of bacteremia, pneumonia, empyema, and meningitis. Young children are particularly at risk. The prevalence of HUS associated with invasive pneumococcus peaks before age 2 years. The precise events leading to HUS in children with pneumococcal disease are unclear, but it is thought that the Thomson-Friedenreich (TF) antigen contributes to its pathogenesis. Human cells carry the TF antigen on their cell surfaces. The epitope is recognized by preformed circulating IgM antibody. However, this epitope is normally masked by neuraminic (sialic) acid from the cell glycocalyx. Neuraminidase, produced by various microbial pathogens, including pneumococcus, influenza A virus, and Capnocytophaga canimorsus, is released during infection and cleaves the N-acetyl-neuraminic acid from the surface of cells, thereby exposing the TF crypantigen. It is thought that exposure of the TF antigen on RBCs, platelets, and glomerular endothelium during the course of pneumococcal infection leads to a sequence of events that result in HUS. Although tempting to link the pathogenesis of pneumococcal HUS to recognition of exposed TF by anti-TF IgM antibody, this IgM is a cold antibody and as such is unlikely to cause RBC polyagglutination and hemolysis in vivo. Additionally, some children with invasive pneumococcal disease without HUS have evidence of TF antigen. Therefore, the mechanism of HUS in those with pneumococcal disease awaits further clarification.

Genetic Forms of Hemolytic-Uremic Syndrome

The genetic forms account for fewer than 3% of all HUS cases. They include mutations in various regulatory components of the complement cascade. Additionally, mutations causing a deficiency of specific proteins necessary for the intracellular metabolism of vitamin B12 are known to cause HUS. Forms of TTP also have a genetic basis associated with mutations in the ADAMTS13 gene.

Complement component C3 was first noted in 1974 to be reduced in the serum of patients and relatives with inherited forms of NStx HUS. Low serum C3 can also occur with infection-related forms of HUS as a result of C3 consumption in the microvasculature. The low C3 in inherited HUS is persistent and reflects abnormalities that give rise to hyperactivation of the complement cascade. The complement cascade is a key component of the innate immune system comprising groups of plasma and membrane-bound zymogen proteins that follow one of three activation pathways: classical, lectin, or alternative. These pathways converge with the generation of C3 convertase enzymes that convert C3 into C3a and C3b (see Figure 64-2). C3b is necessary for opsonization and generation of C5 convertase, which in turn is necessary for chemotaxis (C5a) and the generation of a membrane attack complex (C5b). This process is tightly regulated by specific regulatory proteins to prevent nonspecific destruction of host cells (Figure 64-3).

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Figure 64-3 Complement pathways and regulatory proteins.

Mutations of at least four complement proteins are associated with NStx HUS. The mutations lead to deficiencies in complement factor H (fH), factor I (fI), or membrane cofactor protein (MCP), or they cause a gain in function of factor B. Factor H mutations segregate to chromosome 1q32, known to be the locus for genes encoding the family of complement regulatory proteins. The mutations are seen in both autosomal dominant and autosomal recessive HUS. The 150 kDa fH is synthesized mainly in the liver and binds polyanionic sites on RBCs and vascular endothelium, thereby increasing its affinity for C3b. Factor H competes with factor B for binding to newly formed C3b, and when successful, it acts as a cofactor for factor I–mediated cleavage and degradation of C3b. It is thought that the polyanion-rich glomerular endothelium and basement membrane protect these components from complement attack. Clinical effects of fH deficiency are speculated to occur as a result of endothelial injury related to downstream effects of unregulated C3 convertase activity. Both homozygote and heterozygote fH deficiency persons can develop HUS. In homozygote persons, laboratory values generally reveal low serum C3, fH, factor B, and CH50 concentrations. HUS usually presents in infancy or early childhood. Heterozygote carriers may have normal complement profiles and may present later in life after exposure to a trigger that directly or indirectly causes complement activation. These include infection, systemic disease, drugs, and pregnancy. There are isolated case reports of acquired NStx HUS in children with antibodies to fH.

Deficiency of MCP is implicated in HUS by virtue of its role as a transmembrane cofactor for factor I–mediated cleavage of C3b and C4b that deposits on the host cell surface. It is speculated that fH and MCP reinforce each other in the control of complement regulation on host cells. Factor I deficiency has been identified in small numbers of patients with NStx HUS. Similarly, a gain-of-function mutation has been identified in several families with NStx HUS and is thought to either increase formation or stabilize the alternative pathway C3 convertase (C3bBb).

Thrombotic Thrombocytopenic Purpura

Platelet adhesion and aggregation require the presence of vWF, which is produced by endothelial cells and platelets as large multimeric units. The vWF-cp is a liver-derived metalloproteinase that cleaves the multimers to vWF dimers. Inherited TTP results from autosomal recessive transmission of mutations affecting the ADAMTS 13 gene on chromosome 9q34, which encodes vWF-cp. The result is enhanced platelet adhesion due to vWF multimers. In acquired TTP, this process occurs because of the presence of autoantibodies (or “inhibitors”) to the vWF-cp. Antiplatelet agents ticlopidine and clopidogrel have been known to cause TTP with vWF metalloproteinase autoantibodies.

Secondary Hemolytic-Uremic Syndrome

HUS is known to occur secondarily in a variety of conditions, including autoimmune diseases such as systemic lupus erythematosus and antiphospholipid syndrome, HIV, adenocarcinomas, after hematopoietic stem cell transplantation, after solid organ transplantation; it may also be associated with pregnancy or use of medication. A complete discussion of these rare forms of HUS is beyond the scope of this chapter but can be found in a recent publication by Copelovitch and Kaplan.

Common Renal Pathology

The common “endotheliopathy” that results from various etiologic forms of HUS produces the histopathologic lesion of glomerular TMA (Figure 64-4). Thrombosis affects the glomerular capillaries and can extend proximally into the afferent arterioles, even rarely into interlobular arteries. Extensive thrombosis into the arteries may produce shrunken, ischemic glomeruli or cortical infarct, which can be responsible for severe hypertension. More commonly, the glomeruli have thickened capillary walls, luminal obstruction or thrombosis, and endothelial cell swelling. The glomeruli may appear large. In more severe cases of HUS, patchy cortical necrosis can be seen. Occasionally, necrosis can be more diffuse and affect the entire superficial cortex. It is important to note that whereas fibrin- and RBC-rich thrombi are seen in Stx and pneumococcal HUS, platelet thrombi are seen in TTP. In TTP, the platelet-dominant thrombi affect the heart, pancreas, kidney, adrenal glands, and central nervous system (CNS) in order of increasing severity. A renal biopsy is rarely necessary in the diagnosis of HUS or TTP.

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Figure 64-4 Hemolytic-uremic syndrome (intravascular coagulation and thrombotic microangiopathy).

Clinical Presentation

There are several well-documented risk factors for the development of Stx-HUS—extremes of age (presumably from lack of antibody against Stx), the presence of Stx2, severe enteritis, fever during enteritis prodrome, leukocytosis, and female gender. Additionally, the use of antibiotics or antimotility agents is discouraged because they are thought to worsen disease.

The clinical spectrum of STEC infection ranges from possible asymptomatic infection to hemorrhagic colitis without HUS to postdiarrheal HUS. Generally, nonbloody diarrhea with abdominal pain, vomiting, and fever occurs 3 days after ingestion of STEC. In 90% of patients, bloody diarrhea then develops 1 to 3 days after these initial symptoms. At this time, leukocytosis may be present, and colonic edema and hemorrhage may be demonstrated as “thumbprinting” on barium enema study. The majority of patients with positive stool cultures for E. coli O157 : H7 will have bloody diarrhea. HUS develops in about 15% of those patients, usually manifesting 6 days after the onset of diarrhea. In 85%, there is spontaneous symptomatic resolution without features of HUS. A clue to the diagnosis is a history of decreasing urine volume in a well-hydrated or volume-resuscitated child with diarrhea. Oligoanuria typically occurs 4 to 7 days after diarrheal onset followed by hematologic abnormalities. Similar to Stx disease, pneumococcal HUS typically develops 1 week after onset of symptoms.

Hematologic Features

The anemia of HUS results from microangiopathic or peroxidative injury. It manifests with hemoglobin generally lower than 8 g/dL and a blood smear with schistocytes, some appearing as helmet cells. As expected, intravascular hemolysis produces laboratory changes, including elevated lactate dehydrogenase, reticulocytosis, unconjugated hyperbilirubinemia, and decreased haptoglobin. The hemolysis in HUS is nonimmune, and Coombs’ testing results are negative except in pneumococcal HUS, in which direct Coombs’ testing results are positive because of exposed TF antigen on the cell surface of erythrocytes. In Stx HUS, hemolytic anemia requires RBC transfusion in up to 75% of patients and may recur in the first few weeks. Thrombocytopenia (usually <50,000/µL) may last up to 2 weeks. In most cases, there are no purpura or active bleeding, and coagulation study results are normal. Pneumococcal HUS features longer durations of thrombocytopenia and greater requirement for blood product transfusions than Stx HUS. There is no correlation between severity of anemia or thrombocytopenia and renal injury.

Renal Features

The extent of acute kidney injury in HUS is variable and ranges from urinary abnormalities with mild renal insufficiency to oligo-anuric renal failure. Some patients have nonoliguric renal failure. The thrombotic glomerular injury in HUS generally causes a reduction in glomerular filtration rate (GFR) accompanied by an increased serum creatinine; biochemical abnormalities; and microscopic or macroscopic hematuria, occasionally with RBC casts. Hyperkalemia uncommonly occurs as a result of reduced GFR, hemolysis, and transcellular shifts from metabolic acidosis. In Stx HUS, this may be insidious in onset because of an initial hypokalemia resulting from gastrointestinal losses. Additionally, stool losses of bicarbonate and albumin (protein-losing enteropathy) may exacerbate metabolic acidosis and hypoalbuminemia. Reduced GFR with oliguria can lead to intravascular volume expansion, especially in the context of blood product transfusions. This may manifest as edema, hypertension, pulmonary venous congestion, and congestive heart failure.

Up to 50% of children with Stx HUS will require acute renal replacement therapy (RRT), but there is an overall favorable chance for renal recovery, and many experience a diuresis phase during recovery. Mortality in Stx HUS is about 3% to 5% and is particularly associated with CNS involvement. Chronic or late sequelae can occur in up to 25% of persons after the acute phase of Stx HUS. These include hypertension, proteinuria, and chronic renal insufficiency. An increased severity of acute illness, specifically a need for RRT, longer duration of oligoanuria, and the presence of CNS symptoms, are associated with worse outcomes. Recurrence of Stx HUS is rare, and posttransplant recurrence is not reported.

In contrast to Stx HUS, pneumococcal HUS results in a greater duration of oligoanuria, with 75% of children requiring RRT. The progression to end-stage renal failure (ESRF) is two to three times higher in pneumococcal HUS (10%), and overall mortality rates are higher (12%). Poor prognosis is especially seen in those with pneumococcal meningitis, in whom the development of HUS is associated with a disproportionately high rate of mortality.

Extrarenal Features

Stx HUS manifests with acute hemorrhagic colitis, which may be complicated by toxic megacolon, bowel wall necrosis, perforation, intussusception, or even frank gangrene of the colon. Hepatomegaly is common, and elevated transaminases can be present. Gallbladder hydrops can occur. The pancreas can be affected by Shiga toxin, causing pancreatitis or insulin-dependent diabetes mellitus secondary to islet cell necrosis and destruction.

Cardiopulmonary disease occurs in about 10% of patients. It may occur because of volume overload. Additionally cardiomyopathy, myocarditis, aneurysms, microthrombi, ischemia with troponin I elevation, pulmonary congestion, and respiratory failure with ARDS can occur in Stx-HUS.

CNS disease can present in about 25% in the form of reduced level of consciousness, tremors, twitching, irritability, seizures, stroke, and coma. Symptoms can result from accelerated hypertension related to volume overload, especially in association with blood product infusions. Hyponatremia and hypocalcemia may also contribute to CNS findings. Shiga toxin–mediated injury is thought to cause encephalopathy. CNS disease in Stx-HUS is associated with poor prognosis. Similarly, pneumococcal meningitis with associated HUS is associated with mortality, and CNS neuraminidase activity with TF antigen exposure is implicated in this finding.

Differential Diagnosis

HUS is marked by hemolytic anemia with fragmented erythrocytes on blood smear, a platelet count lower than 150 −× 103/µL, and acute renal injury. This may be difficult to distinguish from disseminated intravascular coagulation (DIC) that occurs in the context of a systemic inflammatory response to infection. DIC has clinical overlap with the HUS triad, and HUS can be misdiagnosed as DIC, especially in pneumococcal HUS. Distinguishing features include coagulation profiles: fibrinogen and prothrombin time and partial thromboplastin time are usually normal or slightly elevated in patients with HUS. Also in contrast to DIC, active bleeding is unusual in HUS. Definitive diagnosis can be made by renal biopsy showing TMA. However, biopsy is rarely necessary in HUS and is often precluded by thrombocytopenia.

Management

There are no targeted therapies for either Stx or pneumococcal HUS. Both conditions require supportive care with a high level of vigilance. Fluid status should be determined to ensure adequate perfusion without precipitating volume overload. Weight, urine volume, and blood pressure should be assessed frequently. About 50% of patients with Stx HUS develop oligoanuric renal failure and require dialysis. An increase in serum creatinine, elevated blood pressure, and decreasing urine output require prompt fluid restriction and planning for administration of dialysis. Dialysis indications are similar to those in other conditions: volume overload with hypertension or cardiopulmonary compromise, severe acidosis, or hyperkalemia. It is crucial to plan for and initiate dialysis early in the course of HUS because packed RBC transfusion is often required (80%) when hemoglobin drops to 6 to 7 g/dL or with evidence of cardiorespiratory compromise, and transfusion can precipitate hyperkalemia or accelerated hypertension in the setting of oligoanuria. Platelet transfusion should be avoided unless active hemorrhage occurs or surgical interventions are required. An important consideration specific to pneumococcal HUS is the need to provide washed blood products if transfusion is required. This is because of the possible risk that preformed anti-TF antibodies are delivered with unwashed products.

In Stx HUS, antimotility agents delay gastrointestinal clearance of Stx and should be avoided, as should be antibiotics, some of which are known to promote release of Stx from STEC.

A number of therapies remain unproven in Stx HUS but continue to be used by some clinicians. Known ineffective therapies include plasma exchange or plasmapheresis, corticosteroids, anticoagulants, thrombolytics, antiplatelet agents, high-dose furosemide, intravenous immunoglobulin (IVIG), and oral toxin binders such as Synsorb Pk. Plasma exchange is also ineffective in pneumococcal HUS.

Plasma therapy is considered a first-line treatment to supply deficient proteins implicated in genetic forms of HUS (fH, fI) and TTP (vWF-cp). Plasma exchange allows removal of antibodies in acquired TTP and is thought to remove potentially injurious molecules in genetic forms of HUS. Inherited HUS has a relapsing or progressive course. Failure to induce remission with plasma therapy in inherited HUS generally results in progression to ESRF. Other therapies (steroids, IVIG) have been attempted without benefit. Renal transplantation is associated with high risk of recurrence in genetic HUS (50%). Graft failure is nearly inevitable in those with recurrence (>90%) and does not typically respond to plasma exchange. Combined liver–kidney transplants are recommended in high-risk patients to allow for correction of the genetic defect. Currently, monoclonal antibody therapy that blocks cleavage of C5 has been used successfully in patients with genetic HUS.

Suggested Readings

Constantinescu AR, Bitzan M, Weiss L, et al. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43:976-982.

Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol. 2008;23:1951-1956.

Copelovitch L, Kaplan BS. The thrombotic microangiopathies. Pediatr Nephrol. 2008;23:1761-1767.

Loirat C, Taylor CM. Hemolytic uremic syndrome. In: Avner E, Harmon W, Niaudet P, editors. Pediatric Nephrology. ed 5. Philadelphia, Lippincott: Williams & Wilkins; 2004:887-915.

Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:1035-1050.

Tarr PI, Gordon CA, Chandler WL. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet. 2005;365:1073-1086.

Trachtman H, Kaplan B. Hemolytic uremic syndrome: Stx-HUS. In: Kaplan B, Meyers K, editors. Pediatric Nephrology and Urology: The Requisites. Philadelphia: Elsevier Mosby; 2005:203-208.

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