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

Abstract

Historically, the majority of patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS) progress to end-stage kidney disease (ESKD). Single-arm trials of eculizumab with a short follow-up suggested efficacy. We prove, for the first time to our knowledge, in a genotype matched CaHUS cohort that the 5-year cumulative estimate of ESKD-free survival improved from 39.5% in a control cohort to 85.5% in the eculizumab-treated cohort (hazard ratio, 4.95; 95% confidence interval [CI], 2.75-8.90; P = .000; number needed to treat, 2.17 [95% CI, 1.81-2.73]). The outcome of eculizumab treatment is associated with the underlying genotype. Lower serum creatinine, lower platelet count, lower blood pressure, and younger age at presentation as well as shorter time between presentation and the first dose of eculizumab were associated with estimated glomerular filtration rate >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 patients with a pathogenic mutation and 1 per 10.8 person years for those with a variant of uncertain significance. No relapses were 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 demonstrated that biallelic pathogenic mutations in RNA-processing genes, including EXOSC3, encoding an essential part of the RNA exosome, cause eculizumab nonresponsive aHUS. Recessive HSD11B2 mutations causing apparent mineralocorticoid excess may also present with thrombotic microangiopathy.

Graphical abstract

Figure 1.

Patient selection. All individuals referred to the NRCTC with suspected aHUS were considered for study entry. Individuals referred between 1995 and 2012 (before the approval of eculizumab) and those not treated with eculizumab were retrospectively identified. Those with a pathogenic mutation in a gene associated with aHUS or a positive factor H autoantibody were included in the control cohort. Individuals referred to the National Service between 2013 and July 2019 with suspected aHUS who received eculizumab for native kidney disease were prospectively identified and included in the treated cohort. Recipients who had undergone kidney transplantation were excluded. Individuals referred after 2013 but who did not receive eculizumab, were included in the control cohort. THBD and VTN mutations have been reported in aHUS but were not detected in our cohort, and the PLG susceptibility variant c.1481C>T was identified in 1 individual who had compound heterozygous DGKE mutations. ^«Twenty-two individuals were treated with eculizumab between 2010 and 2012, before regulatory approval, either as part of a clinical trial or on compassionate grounds. ^¥Excluding individuals treated preemptively during kidney transplantation or posttransplantation. In addition to eculizumab, treatment could have comprised supportive management, renal replacement therapy, and plasma exchange. ^¢Management determined by the treating physician could have comprised supportive management, renal replacement therapy, and plasma exchange. ^¤Of the 40 individuals, 24 recovered renal function, 15 developed/presented with ESKD, and 1 died. See supplemental Table 1 for genetic and clinical details. ^ꬸFor survival analysis, 17 individuals were analyzed in the control CaHUS group until the point at which they received eculizumab for relapse and were then analyzed in the treated CaHUS group. CFH, n = 8; CD46, n = 7; C3, n = 1; combined, n = 1. ^‡For 2 individuals (nmd) in the treated CaHUS cohort and 13 individuals in the control CaHUS cohort (CFH, n = 5; CFHR1 hybrid, n = 1; CFI, n = 1; CD46, n = 4; C3, n = 1; and FHAA, n = 1), survival data were not available. ^¶Thrombotic thrombocytopenic purpura is excluded before treatment with eculizumab: treatment is not commenced if ADAMTS13 <10%. Other secondary TMAs may be identifiable before the initial decision to commence eculizumab based on clinical history or initial laboratory testing: disseminated intravascular coagulation; malignancy-associated TMA; bone marrow transplantation–associated TMA; de novo TMA after solid organ transplantation; and drug-induced TMA. Some secondary TMAs may not be identified until further genetic or serological tests or kidney biopsies are available: Shiga toxin HUS (STEC-HUS); pneumococcal HUS; HIV; cobalamin C deficiency TMA; glomerular disease–associated TMA; and autoimmune disease–associated TMA. ^#No complement mutations and no FHAA were identified in any of those with a secondary cause identified. ^§PLG screened only for the susceptibility variant c.1481C>T rs4252128; identified in 1 individual (with compound heterozygous DGKE mutations). ^ꬸOther diagnoses, n = 4: renal biopsy specimen showed severe chronic damage, no TMA detected with a renal biopsy specimen; renal biopsy specimen showed acute tubular necrosis; no TMA detected with a renal biopsy specimen; died before definitive diagnosis made. ∗Analysis of variants in July 2020 classified those with definitive evidence of functional significance as pathogenic and those without as VUS. GN, glomerulonephritis; IgA, immunoglobulin A; PNH, paroxysmal nocturnal hemoglobinuria.

Figure 2.

Five-year cumulative estimates (Kaplan-Meier) of end-stage kidney disease–free survival. HRs and 95% CIs calculated using the Cox proportional hazard regression model, P values calculated using the log-rank test, and the NNT are shown where appropriate. (A) Treated vs control, CaHUS with mutation or FHAA. (B) Children vs adults, CaHUS with mutation or FHAA. (C) Control group based on the mutation type. (D) Treated group, based on the mutation type. (E) Treated vs control, individuals with CFH mutation subgroup. (F) Treated vs control, individuals with CD46 mutation subgroup.

Figure 2.

Five-year cumulative estimates (Kaplan-Meier) of end-stage kidney disease–free survival. HRs and 95% CIs calculated using the Cox proportional hazard regression model, P values calculated using the log-rank test, and the NNT are shown where appropriate. (A) Treated vs control, CaHUS with mutation or FHAA. (B) Children vs adults, CaHUS with mutation or FHAA. (C) Control group based on the mutation type. (D) Treated group, based on the mutation type. (E) Treated vs control, individuals with CFH mutation subgroup. (F) Treated vs control, individuals with CD46 mutation subgroup.

Figure 3.

Hematological and renal responses to eculizumab. (A) Renal function 6 months after eculizumab commenced in the treated CaHUS cohort compared with that at presentation. Not available for 6 individuals; 4 individuals died. (B) Hematological response to eculizumab, defined by the number of days from the first dose of eculizumab to platelet normalization (>150 × 10⁹/L). Median, interquartile range, 1.5× interquartile range, and outliers are shown. There were no statistically significant differences between the mutation types. Three extreme outliers are not shown in the chart: 70 and 90 days (CFH) and 96 days (CD46). Twenty-nine percent already had normal platelets at the time of the first eculizumab dose. In 11 individuals, the platelet count did not normalize; 8 out of 11 had no mutation detected, 2 had VUS (1 had hypersplenism), and 1 had FHAA (and von Willebrand Disease). Of the 17 individuals with a response time of >2 weeks (range, 15-96 days), 3 had a CFH mutation, 1 had a CFI mutation, 2 had a CD46 mutation, 3 had a C3 mutation, 1 had FHAA, 4 had a VUS, and 3 had no mutation detected; 4 out of 17 developed ESKD, 2 of whom died. Fifty-eight percent received plasma exchange before the first dose of eculizumab (supplemental Figure 8B). The subgroup analysis of hematological response in those who received eculizumab but not plasma exchange is shown in supplemental Figure 8C, the median time to platelet normalization in individuals with CaHUS was 5 days. (C) Renal response to eculizumab in the treated CaHUS cohort. Changes in creatinine as a percentage of creatinine in patients with CaHUS (this includes only those who recovered renal function and not those who remained dialysis-dependent) at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 12 months after commencing eculizumab treatment. The complete data set is available for n = 101. Solid circles with a connecting line, mean; bars, 95% CI; x, median. A Wilcoxon Signed Ranks Test demonstrated that there was a statistically significant difference in the mean change in creatinine between all the time points recorded (P value shown). (D) Renal response to eculizumab in the CaHUS cohort. The mean change in creatinine as a percentage of creatinine in patients with CaHUS by mutation type (this includes only those who recovered renal function, not those who remained dialysis-dependent) at 1 week, 2 weeks, 1 month, 3 months, 6 months, and 12 months after commencing eculizumab treatment. (E) Recovery from dialysis dependency in the CaHUS cohort. The proportion of patients with CaHUS on dialysis in the first year after commencing eculizumab. At presentation, 66.7% received dialysis, and at 6 months, 65.7% became dialysis-independent, with 22.9% remaining on dialysis. (F) Recovery from dialysis dependency in the CaHUS cohort. The proportion of patients with CaHUS on dialysis for the first year after commencing eculizumab according to mutation type.

Figure 4.

Eculizumab withdrawal. Reasons for restarting eculizumab in patients with functioning kidneys in whom it was stopped but restarted. Individuals who entered the SETS clinical trial are excluded. For 49 individuals with CaHUS who stopped eculizumab because of patient or clinician choice, the median time to relapse following eculizumab withdrawal was 244 days (range, 104-1095 days). ∞Two patients with CFH pathogenic mutations were noncompliant with eculizumab and died because of refusal to undergo dialysis. ^¥One patient with CD46 VUS who moved overseas. ^¤Three patients with no mutation detected were lost to the follow-up. ^ˆOne individual with pancreatitis and a pathogenic CD46 mutation had no renal involvement but no hematological improvement. Nmd, no mutation detected.