Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study

Historically the majority of patients with complement mediated atypical haemolytic uraemic syndrome (CaHUS) progressed to end stage kidney disease (ESKD). Single arm trials of eculizumab with short follow-up suggested efficacy. We prove for the first time in a genotyped matched CaHUS cohort that the five-year cumulative estimate of ESKD free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab treated cohort; HR 4.95 (95% CI 2.75-8.90), p=0.000, number needed to treat 2.17 (95% CI 1.81-2.73). Outcome following eculizumab is associated with underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure and younger age at presentation, as well as shorter time between presentation and first dose of eculizumab were associated with eGFR >60 ml/min at 6 months in multivariate analysis. The rate of meningococcal infection in the treated cohort was 550 times greater than the background rate in the general population. The relapse rate upon eculizumab withdrawal was 1 per 9.5 person years for those with a pathogenic mutation and 1 per 10.8 person for those with a variant of uncertain significance. There were no relapses recorded in 67.3 person years off eculizumab in those with no rare genetic variants. Eculizumab was restarted in 6 individuals with functioning kidneys in whom it had been stopped with no individual progressing to ESKD. We demonstrate that biallelic pathogenic mutations in RNA processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab non-responsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with a thrombotic microangiopathy.