COMPLEMENT GENETIC ALTERATIONS IN HEMOLYTIC UREMIC SYNDROMES

Hemolytic uremic syndrome is the most frequent cause of acute renal failure of children. The disease most often manifests with a diarrhea prodrome (D+HUS) that follows an infection by E.coli bacteria that produce a potent toxin and usually has a favorable outcome. Mini-epidemics of D+HUS have been recorded all over the world, usually associated with assumption of contaminated food (meat, fruit or fish) or water. There are however rare cases (D-HUS), mostly familial, not preceded by diarrhea, which have a poor prognosis, with death or renal failure in the majority of cases. It has been recently shown that the genetic defects leading to D-HUS involve the regulation of the alternative pathway of complement, an inflammatory cascade that mediates body defense toward infections. Mutations in the gene encoding for factor H (HF) have been found in a subgroup of patients with D-HUS. In this project we will screen a great number of patients to clarify the incidence of HF mutations in D-HUS and to provide genetic counseling. The latter service will be crucial for D-HUS patients in need of a kidney transplant since patients with HF mutations invariably experience disease recurrence on the transplanted kidney. Thus kidney transplant should be avoided in these patients unless HF abnormality is corrected. We have preliminary data in a boy with D-HUS and a HF mutation, that combined kidney and liver transplants -the liver is the major source of HF- prevent HUS recurrence. A second aim will be to evaluate the effects of mutations found in HUS patients on HF function, to clarify the role of HF defects in the pathogenesis of HUS. Since a consistent number of patients with D-HUS do not have HF mutations, we will also search for abnormalities in other complement regulatory genes. Finally we will also investigate the role of genetic predisposition in the more common D+HUS, based on findings that only 10% of children experiencing E.coli infection develop HUS.