Rare but Relevant Kidney Disorders

The spectrum of predisposing factors to atypical hemolytic uremic syndrome (aHUS) is widening. This syndrome includes cases of HUS that are not linked to Shiga toxin–producing bacteria. Approximately half of the patients with aHUS have mutations in genes that regulate complement system: Either loss-of-function mutations in genes that encode inhibitors of the alternative pathway of the complement system (e.g., factor H or I, CFH or CFI, membrane co-factor protein, factor H–related proteins, C4b-binding protein) or gain-of-function mutations of genes that encode factor B and C3. Antibodies against CFH have been observed in 2 to 10% of patients. Thrombomodulin is a ubiquitous transmembrane endothelial cell glycoprotein that suppresses clot formation, inhibits fibrinolysis, interferes with inflammation, and inactivates some complement-derived anaphylatoxins. Delvaeye et al. studied 152 patients who had aHUS and were recruited from the International Registry of Recurrent and Familial HUS/Thrombotic Thrombocytopenic Purpura and 380 control subjects. They sequenced the entire coding region of the thrombomodulin gene (THBD), which lacks introns. Six heterozygous mutations of THBD were identified in seven (4.6%) unrelated patients. Two of them belonged to families with aHUS. In one of these families, four heterozygous carriers (including adults) were asymptomatic. As in complement defects, the THBD mutation is not sufficient by itself to cause HUS. Low serum C3 levels were measured in four patients. The disease was evident during childhood, from 6 mo to 15 yr of age. Three of seven patients progressed to ESRD. Four had recurrent aHUS. One patient developed a first episode of aHUS after kidney transplantation at 15 yr of age. Further studies will indicate whether there is a risk for recurrence of aHUS after kidney transplantation. In vitro studies on cultured cells showed that thrombomodulin provides protection against complement activation. In addition, thrombomodulin binds to C3 and CFH and negatively regulates complement by accelerating CFI-mediated inactivation of C3b in the presence of co-factors CFH and C4b. Cultured cells that express THBD variants that are associated with aHUS had diminished capacity to inactivate C3b and to activate procarboxypeptidase B and thus were less protected from activated complement. In patients with aHUS, genetic testing should include several genes that encode proteins that regulate complement system, including thrombomodulin.