Epidemiology, clinical presentation, and pathophysiology of atypical and recurrent hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) includes a heterogeneous group of hemolytic disorders. Among the identified causes of HUS are infections, particularly infections with Shiga toxin-producing ESCHERICHIA COLI (STEC), complement disorders, and disorders interfering with the degradation of von Willebrand factor (VWF). Other causes for atypical HUS include the cobalamin metabolism; pregnancy/hemolysis, elevated liver enzymes, and low platelets syndrome (HELLP); drugs; and other disorders (e.g., systemic diseases appearing as HUS, such as systemic lupus erythematosus and rejection after transplantation). The group not related to STEC is often also called atypical HUS. Most of the occurrences of infectious HUS have only one episode. Recurrent episodes (recurrent HUS) have strong relationships to diseases of the complement system. In these two subgroups the prognosis is poor, with severe renal insufficiency, together with the need for renal replacement therapy. Severe arterial hypertension is common. Treatment options are limited. To better define this group of patients, the European Society for Pediatric Nephrology supported an initiative to develop a European HUS registry. In this registry, 167 patients were acquired; 73 were female (43.8%). The year of onset of the disease ranged from 1974 to 2005. The prevalence of atypical HUS/recurrent HUS can be calculated as 3.3 per million child population (< 18 years). Underlying disorders included factor H, factor I, MCP-1, pneumococci, and von Willebrand factor disturbances. In 33 patients at least one renal transplantation was performed (total, 55 kidneys); 18% were successful and 73% demonstrated recurrence or thrombosis. Treatment options were plasma substitution or plasmapheresis. Despite continued efforts, transplantation is not recommended at present for these patients. Living-related transplantation should be abandoned. New therapeutic strategies are urgently needed.

Terminal complement complex (C5b-9) in children with recurrent hemolytic uremic syndrome.

Recurrent hemolytic uremic syndrome (recHUS) is a heterogeneous group of disorders. The pathogenesis of recHUS is not fully understood. recHUS has a high risk of development of terminal renal insufficiency and other sequelae. Abnormalities in complement factor H or in membrane-bound complement inhibitors with consecutive complement activation can be found in approximately 30 to 50% of the patients. Starting in 2001, we evaluated 42 patients with recHUS from five European countries (Germany, Austria, Hungary, Switzerland, and the Czech Republic). We measured the terminal complement complex (TCC) by an enzyme-linked immunosorbent assay using a neoepitope-specific anti-C9 antibody in 17 patients in plasma (native complement activation), serum (after coagulation), and zymosan-activated serum (Z-serum; after stimulation of coagulation). We compared the results to those of 16 healthy persons. In patients with recHUS (eight males, nine females) with a median age of 10.8 years, the TCC values were higher in plasma (0.57 versus 0.48 microg/mL; P = 0.04) and serum (3.1 versus 2.2 microg/mL) than in those of the control group, with a median age of 28.6 years (six males, 10 females) The TCC values in patients with low C3 compared with patients with normal C3 levels were even higher in plasma and serum, and the ratio was much lower. Children with recHUS have higher concentrations of TCC in plasma and serum. The ratio of Z-serum to serum showed significantly lower values in children with recHUS (96.01 versus 150.3; P = 0.01). These findings indicate a higher grade of complement activation and consumption in recHUS, suggesting that TCC may mediate cell toxicity. This may play an important role in the inferior outcome of these patients. The isolated substitution of factor H, or other complement inhibitors to block TCC formation, may represent useful therapies for these patients.