Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults

Abstract

Background and objectives: Atypical hemolytic uremic syndrome (aHUS) is a rare complement-mediated kidney disease that was first recognized in children but also affects adults. This study assessed the disease presentation and outcome in a nationwide cohort of patients with aHUS according to the age at onset and the underlying complement abnormalities.

Design, setting, participants, & measurements: A total of 214 patients with aHUS were enrolled between 2000 and 2008 and screened for mutations in the six susceptibility factors for aHUS and for anti-factor H antibodies.

Results: Onset of aHUS occurred as frequently during adulthood (58.4%) as during childhood (41.6%). The percentages of patients who developed the disease were 23%, 40%, 70%, and 98% by age 2, 18, 40, and 60 years, respectively. Mortality was higher in children than in adults (6.7% versus 0.8% at 1 year) (P=0.02), but progression to ESRD after the first aHUS episode was more frequent in adults (46% versus 16%; P<0.001). Sixty-one percent of patients had mutations in their complement genes. The renal outcome was not significantly different in adults regardless of genetic background. Only membrane cofactor protein (MCP) and undetermined aHUS were less severe in children than adults. The frequency of relapse after 1 year was 92% in children with MCP-associated HUS and approximately 30% in all other subgroups.

Conclusion: Mortality rate was higher in children than adults with aHUS, but renal prognosis was worse in adults than children. In children, the prognosis strongly depends on the genetic background.

Figure 1.

Summary of the 85 mutations in the CFH, MCP, CFI, CFB, and C3 genes identified in the national French cohort of 214 patients with atypical hemolytic uremic syndrome (aHUS). The nucleotide and amino acid numbering refers to the translation start site (A in ATG is +1), as recommended by the Human Genome Variation Society. The genetic changes reported here were not found in any control, and none is reported in the single nucleotide polymorphism (SNP) databases with the exception of the ultra-rare SNPs G119R, H183R, G261D, I416L, and P553S. For CFH, CFI, and MCP genes: Type I mutations (protein level below the normal range) are located above the schematic representations of the genes, and type II mutations (normal protein level) are indicated below. Among the type II mutations, four were detected in the CFH N-terminal short consensus repeats 1–3, including three in the C3b binding site (Q81P, M162V, and A161S) and one (R53C) affecting an exposed residue on the opposite surface short consensus repeat 1, which, although not in contact with C3, could affect the local protein conformation. ^aMutations in the CFH gene associated with a complex CFH rearrangement identified using multiplex ligation–dependent probe amplification. ^bMutations found in 4 patients associated with THBD genetic changes: A43T(n=3) and P501L (n=1). *Mutations found in familial forms (but not exclusively). **The two mutations that did not segregate with the disease (i.e., they were found in one family member with aHUS but not in another member of the family also with aHUS). Bold characters indicate 13 mutations identified in two or more unrelated patients, suggesting that they may represent mutational hot spots. Among these mutations, two variants, G261D and I416L in the CFI gene, are rare SNPs. CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; MCP, membrane cofactor protein; THBD, thrombomodulin.

Figure 2.

Cumulative Kaplan-Meier estimates of the rates of patients without ESRD or death according to the age at onset. Overall, the renal survival was significantly better in patients with early onset than in those with late onset. aHUS, atypical hemolytic uremic syndrome.

Figure 3.

Percentage of the patients who developed atypical hemolytic uremic syndrome at a given age according to the complement genetic abnormality. The percentages of patients who developed the disease were 23%, 40%, 70%, and 98% by age 2, 18, 40, and 60 years, respectively. CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; MCP, membrane cofactor protein; THBD, thrombomodulin.

Figure 4.

Cumulative Kaplan-Meier estimates of the rates of patients without ESRD or death according to the age at onset in patients with CFH, MCP, CFI, or C3 mutations or no mutation identified and no anti-CFH antibodies. *CFH mutations: only children with heterozygous mutations are taken into account for this figure. CFB, complement factor B; CFH, complement factor H; CFI, complement factor I; MCP, membrane cofactor protein; THBD, thrombomodulin.