Abstract 3337

Introduction:

Hemolytic uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment. Approximately 10% of the cases are classified as atypical due to the absence of Shiga toxin-producing bacterial infection as a trigger. Compared to typical HUS, atypical HUS (aHUS) has a much poorer prognosis, with up to half of the patients progressing to end-stage renal disease, and a higher mortality. Uncontrolled activation of the complement system plays a role in the pathogenesis of aHUS. More than half of the patients with aHUS have the mutations of genes involved in the alternative pathway of the complement system. Mutations with loss-of-function of regulators (CFH, CFI, MCP and THBD) and gain-of-function of key of complement components (C3 and CFB) have been found to predispose to aHUS. In addition, genomic deletion of CFHR3 and CFHR1 has been linked to a risk of aHUS, sometimes together with the presence of CFH autoantibodies. Although many genetic studies on aHUS have been published in recent years, the Asian data are rare so far. It is important to perform genetic screening in patients with aHUS, because genotype-phenotype correlations have clinical significance in predicting renal recovery and transplant outcome. In this study, we analyzed 10 Japanese aHUS patients and the genotype-phenotype relationship was evaluated.

Patients and Methods:

Ten Japanese patients in Japan-Nara registry of thrombotic microangiopathy (TMA) with aHUS were investigated in this study; eight of them were sporadic and the other two were from one family. Diagnosis of aHUS was made by the simultaneous occurrence of microangiopathic hemolytic anemia, thrombocytopenia, and acute renal failure without association to Shiga toxin. The CFH antigen level was analyzed by a rocket-immunoelectrophoresis method, and hemolytic assay was performed using sheep red blood cells (Sanchez-Corral P, et al. Mol Immunol 2004). Genomic DNA was extracted from peripheral blood leukocytes of patients and their family members. The genetic mutations of 6 candidate genes and the gene deletion in complement factor H (CFH) and CFH-related genes were analyzed.

Results:
(1) Clinical features and laboratory data:

Plasma ADAMTS13 activity was not severely decreased in all patients (29–119% of the normal). The first episode of aHUS occurred at childhood (≤10 yr) in 7 patients. Nine cases had probable triggering events. The plasma C3 level was low in 4 patients. Three patients showed apparent hemolytic activity against the sheep erythrocytes. Five patients had experienced relapses by the most recent follow-up. Five patients progressed to end-stage renal disease and could not be maintained without hemodialysis or peritoneal dialysis.

(2) The result of gene analysis:

We identified 7 causative or potentially causative mutations in 8 of these patients, and these mutations were heterozygous. Three of the mutations, p.R1215Q in CFH, p.I1157T in C3, and p.Y189D in MCP, were identified previously, indicating that these mutations are definitely causative for aHUS. The remaining 4 missense mutations, p.A359V in MCP, p.S562L and p.R425C in C3, and p.T500M in THBD, were novel. We considered them as potentially causative mutations based on the available information, including the PolyPhen-2 prediction, a search of the literature, and the position of the missense mutation in the three-dimensional structure. Two patients, who showed apparently an enhanced hemolytic activity, carried CFH p.R1215Q and 3 other patients carried C3 p.I1157T. One patient had 2 causative mutations in different genes. One patient was a compound heterozygote of the 2 MCP mutations. The patients carrying mutations in CFH or C3 had a high frequency of relapse and a worse prognosis.

Conclusion:

In this study, we identified the cause of aHUS in 8 out of 10 patients. Since the phenotype-genotype correlation of aHUS has clinical significance in predicting renal recovery and transplant outcome, a comprehensively accurate assessment of molecular variation would be necessary as part of the clinical management for aHUS patients. Such an assessment system would facilitate aHUS phenotype- genotype studies in Japan.

Disclosures:

Matsumoto:Alexion Pharma: Membership on an entity's Board of Directors or advisory committees. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

Topics:
atypical hemolytic-uremic syndrome, disease susceptibility, genetics, hemolytic-uremic syndrome, complement system proteins, atypical, kidney failure, chronic, microangiopathic hemolytic anemia, thrombocytopenia, transplantation

Author notes

*

Asterisk with author names denotes non-ASH members.

© 2012 by The American Society of Hematology
2012
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