Background and objectives: Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Most childhood cases are caused by Shiga toxin-producing bacteria. The other form, atypical HUS (aHUS), accounts for 10% of cases and has a poor prognosis. Genetic complement abnormalities have been found in aHUS.Design, setting, participants, and measurements: We screened 273 consecutive patients with aHUS for complement abnormalities and studied their role in predicting clinical phenotype and response to treatment. We compared mutation frequencies and localization and clinical outcome in familial (82) and sporadic (191) cases.Results: In >70% of sporadic and familial cases, gene mutations, disease-associated factor H (CFH) polymorphisms, or anti-CFH autoantibodies were found. Either mutations or CFH polymorphisms were also found in the majority of patients with secondary aHUS, suggesting a genetic predisposition. Familial cases showed a higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases. Patients with CFH or THBD (thrombomodulin) mutations had the earliest onset and highest mortality. Membrane-cofactor protein (MCP) mutations were associated with the best prognosis. Plasma therapy induced remission in 55 to 80% of episodes in patients with CFH, C3, or THBD mutations or autoantibodies, whereas patients with CFI (factor I) mutations were poor responders. aHUS recurred frequently after kidney transplantation except for patients with MCP mutations.Conclusions: Results underline the need of genetic screening for all susceptibility factors as part of clinical management of aHUS and for identification of patients who could safely benefit from kidney transplant.

he hemolytic-uremic syndrome is characterized by nonimmune hemolytic anemia, thrombocytopenia, and renal impairment. 1 The disorder occurs most frequently in children under the age of 5 years, with an annual incidence of 6.1 cases per 100,000 children under 5 years, as compared with an overall incidence of 1 to 2 cases per 100,000. The presentation is generally heralded by diarrhea, which is often bloody. 2,3 Most cases (including more than 90% of those in children) are secondary to infection with Escherichia coli serotypes O157:H7, O111:H8, O103:H2, O123, O26, or others, 1 which produce Shiga-like toxin (Stx), and several other bacteria, such as Streptococcus pneumoniae. 4 Approximately 10% of cases of the hemolytic-uremic syndrome are classified as atypical, since they are not caused by either Stx-producing bacteria or streptococci. 1,5 Atypical hemolytic-uremic syndrome has a poor prognosis, with death rates as high as 25% 5 and progression to end-stage renal disease in half the patients. 1,4 Research has linked atypical hemolytic-uremic syndrome to uncontrolled activation of the complement system. This article reviews current concepts about the pathobiology of this syndrome and its diagnosis and management. The His t ol ogic Lesion The lesions of Stx-related hemolytic-uremic syndrome, which are indistinguishable from those of its atypical form on the basis of standard histologic analysis, are characterized by thickening of arterioles and capillaries, endothelial swelling and detachment, and subendothelial accumulation of proteins and cell debris (Fig. 1). 6,7 The subendothelial space is widened, and platelet thrombi obstruct vessel lumina. Hemolysis occurs, and fragmented or distorted erythrocytes are evident in blood smears. Lesions typically affect the kidney (mainly glomeruli and arterioles), although the brain, heart, lungs, gastrointestinal tract, and pancreas all may be involved. Cl a ssific ation of Dise a se Familial Form Less than 20% of cases of atypical hemolytic-uremic syndrome are familial (Table 1). Patients with the familial form of the disease have a poor prognosis, with a rate of either end-stage renal disease or death of 50 to 80%. In 1965, a combination of hemolytic anemia and azotemia was described in concordant monozygous twins. 8 Since that time, familial atypical hemolytic-uremic syndrome has been reported in children and, infrequently, in adults. Both autosomal dominant and recessive patterns of inheritance have been reported. 9 Sporadic Form Atypical hemolytic-uremic syndrome that develops in patients who do not have a family history of the disease is classified as sporadic. Triggers for the sporadic form

Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy with manifestations of hemolytic anemia, thrombocytopenia, and renal impairment. Genetic studies have shown that mutations in complement regulatory proteins predispose to non-Shiga toxin-associated HUS (non-Stx-HUS). We undertook genetic analysis on membrane cofactor protein (MCP), complement factor H (CFH), and factor I (IF) in 156 patients with non-Stx-HUS. Fourteen, 11, and 5 new mutational events were found in MCP, CFH, and IF, respectively. Mutation frequencies were 12.8%, 30.1%, and 4.5% for MCP, CFH, and IF, respectively. MCP mutations resulted in either reduced protein expression or impaired C3b binding capability. MCPmutated patients had a better prognosis than CFH-mutated and nonmutated patients. In MCP-mutated patients, plasma treatment did not impact the outcome significantly: remission was achieved in around 90% of both plasma-treated and plasma-untreated acute episodes. Kidney transplantation outcome was favorable in patients with MCP mutations, whereas the outcome was poor in patients with CFH and IF mutations due to disease recurrence. This study documents that the presentation, the response to therapy, and the outcome of the disease are influenced by the genotype. Hopefully this will translate into improved management and therapy of patients and will provide the way to design tailored treatments. (Blood.

SummaryComplement is an important component of the innate immune system that is crucial for defense from microbial infections and for clearance of immune complexes and injured cells. In normal conditions complement is tightly controlled by a number of fluid-phase and cell surface proteins to avoid injury to autologous tissues. When complement is hyperactivated, as occurs in autoimmune diseases or in subjects with dysfunctional regulatory proteins, it drives a severe inflammatory response in numerous organs. The kidney appears to be particularly vulnerable to complement-mediated inflammatory injury. Injury may derive from deposition of circulating active complement fragments in glomeruli, but complement locally produced and activated in the kidney also may have a role. Many kidney disorders have been linked to abnormal complement activation, including immune-complex–mediated glomerulonephritis and rare genetic kidney diseases, but also tubulointerstitial injury associated with progressive proteinuric diseases or ischemia-reperfusion.