Atypical Hemolytic Uremic Syndrome in Children and Adults With the Hot Spot C3 Gene Variant p.Arg161Trp

Abstract

Introduction: The gain-of-function variant C3 p.Arg161Trp is found in a quarter of Dutch patients with complement-mediated atypical hemolytic uremic syndrome (CaHUS). In this study, we describe the clinical phenotype of C3 p.Arg161Trp–associated CaHUS. Methods: Dutch patients with CaHUS with the C3 p.Arg161Trp variant, identified before October 2023, were included in this retrospective, observational study. Results: A total of 37 patients (11 children and 26 adults) were included, with onset before and after availability of eculizumab. Presentation at onset differed between children and adults, specifically in platelet count (21 vs. 79 x 109/L, P = 0.036), lactate dehydrogenase (2644 vs. 1260 U/L, P = 0.026), estimated glomerular filtration rate (eGFR) (48 vs. 15 ml/min per 1.73 m2, P < 0.001), red-colored urine (90 vs. 24%, P = 0.001), and jaundice (50 vs. 10%, P = 0.022). None of the children developed end-stage kidney disease (ESKD) within a year after disease onset, in contrast to 11 of 26 adults. Ten children initially showed full recovery, of which 1 had received eculizumab. In adults, kidney function recovery occurred more often in those treated with eculizumab (88%, n = 7/8), compared with adults not treated with eculizumab (44%, n = 8/18). Relapse rate in the native kidneys of children and adults was high, 82% and 86%, respectively. The median (range) time between disease onset and relapse was 1.9 (0.3–17.6) years. Conclusion: The clinical phenotype of C3 p.Arg161Trp–associated CaHUS has significant heterogeneity, with differences in presentation and outcomes between children and adults. Children present with more profound hemolysis but milder acute kidney injury (AKI). Furthermore, C3 p.Arg161Trp is linked to a high risk of relapse.