Comprehensive Approach to Genetic Analysis and Therapy in Patient with Recurrence Atypical Hemolytic Uremic Syndrome

Abstract

Hemolytic uremic syndrome (HUS) is a disorder characterised by thrombotic microangiopathy (TMA) with thrombocytopenia, haemolytic anaemia and renal failure. Two different forms can be described. The typical form is usually associated with food-borne infections with Shiga-like toxin producing Escherichia coli O157:H7 (E. coli O157:H7) causing diarrhea and in approximately 6% end-stage renal failure (ESRD); however, the long-term prognosis is good. Atypical HUS (aHUS), is most frequently seen in children and is not caused by infection with the toxin-producing E. coli. The prognosis is less favourable, up to 50% progress to ESRD. Uncontrolled activation of the complement system is related to the pathogenesis of aHUS, half of which accounts for the mutations of regulatory genes involved in the alternative pathway of the complement cascade including complement factor H (CFH), complement factor I (CFI), membrane cofactor protein (MCP or CD46), complement component 3 (C3), complement factor B (CFB), and thrombomodulin (THBD). Normal plasma levels of complement proteins do not preclude the presence of a mutation in these genes. More importantly, genotype-phenotype correlations of aHUS have clinical significance in predicting renal recovery and transplant outcome. We describe an adult renal transplant recipient who developed recurrent hemolytic uremic syndrome 3 weeks after transplantation. The initial diagnosis before transplantation was diarrheal associated epidemic HUS without Shiga-like toxin. Due to proven episodes of HUS we suspected a possible dysfunctioning complement system which consequently was thoroughly investigated. Directional sequencing of CFH confirmed that the causative mutation inherited from paternal part in CFH has been detected in the patient with aHUS. The missense mutation of CFH is R1215Q localized in the vitally functional area of domain 20. The hemolysis test of sheep erythrocyte with the presentation of CFH purified protein is positive in this patient, which is a proof of dysfunctional CFH. Results of renal transplantation in patients with mutations in either CFH or CFI are dismal, with recurrent disease leading to graft loss in the majority of cases. However the patient with a factor H polymorphism was successfully transplanted with postoperative plasmapheresis and administration of eculizumab. This report reemphasizes the importance of screening patients with atypical hemolytic uremic syndrome for mutations in these genes before renal transplantation and shows the challenges in the management of these patients.