Atypical Hemolytic Uremic Syndrome (aHUS): Mutations in components of complement and their impact on the clinical course

Hemolytic uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal impairment, and is the most common cause of acute renal failure in childhood. Most cases occur secondary to infection with Shiga toxin-producing bacteria. About 10% of HUS patients are classified as atypical (aHUS) with a generally poorer prognosis. Genetic complement abnormalities play a major role in aHUS and lead to uncontrolled overactivation of the alternative complement pathway. While the glomerular vasculature of the kidney is the main target, about 20% of patients additionally show extrarenal involvement (CNS or multivisceral). There is increasing evidence for a multiple-hit scenario in aHUS with complex inheritance, i. e. mutations in genes encoding complement regulatory proteins or complement activators predispose to aHUS rather than being causative per se. Genetic testing of CFH, CFI, MCP, THBD, CFB and C3 is indicated in all patients with aHUS, even if plasma levels are normal. Genotype-phenotype correlations make genetic testing an essential part of clinical management; the kind of genetic predisposition often determines the prognosis after the initial HUS episode and after renal transplantation. While patients with CFH mutations usually have the worst prognosis, the outcome of patients with MCP mutations is relatively good. Early intensive plasmatherapy should be started as early as possible and appears to have a beneficial effect, except in MCP-mutated patients. Here we present our molecular findings and an efficient genetic testing approach in patients with aHUS. Our data corroborate that many patients carry an alteration in more than one gene which may aggravate the clinical phenotype in line with a mutational load model. Thus, genetic testing for all susceptibility factors is necessary. Its complexity makes interpretation challenging and requires an interdisciplinary approach in diagnostics and treatment of patients with aHUS.

atypical hemolytic uremic syndrome (aHUS) - complement system - end stage renal disease (ESRD) - genotype-phenotype correlations - oligogenic inheritance - mutational load theory