Quantifying associations of genotype, proteinuria and eGFR with long-term kidney outcomes in Alport Syndrome using data from the UK National Registry of Rare Kidney Diseases (RaDaR).

Abstract Background Alport Syndrome (AS), caused by pathogenic variants in type IV collagen genes COL4A3/4/5, is a leading monogenic cause of Kidney Failure (KF). Clinical course varies widely, and disease specific predictors of progression relevant to clinical care and trial design remain incompletely defined. Methods In this retrospective cohort study of individuals with AS in the UK National Registry of Rare Kidney Diseases, patients were classified as having AS or heterozygous genotypes and followed to assess proteinuria progression, eGFR slope and kidney survival. Proteinuria and eGFR trajectories were analysed using mixed effects regression models; kidney survival using Kaplan Meier analysis. Results Among 1032 participants (median follow up 11.6 years; 47% female), 475 (46%) had AS genotypes (Male XLAS or autosomal recessive AS). eGFR decline accelerated with advancing CKD stage across all genotypes (p<0.001). Proteinuria increased as eGFR declined and occurred earlier in AS genotypes. After reaching proteinuria thresholds of more than 1.0 and 3.0g/g, kidney survival over the subsequent 5 years did not differ significantly between genotypes (logrank p=0.14, p=0.17, respectively), although modest differences emerged over longer follow-up. Across eGFR thresholds (90, 60, and 45mL/min/1.73m2), higher proteinuria was associated with shorter time to KF; for example, at eGFR 45mL/min/1.73m2, median time to KF was 3.0 years (IQR, 1.6-5.4) for above-median vs 6.5 years (5.1-not estimable) for below-median proteinuria (p<0.0001). Almost all patients who reached KF had developed proteinuria of more than 0.3g/g. Conclusion In this national cohort, eGFR decline accelerated with CKD stage and proteinuria was strongly associated with progression to KF across genotypes. The non linearity of eGFR decline may inform its interpretation in clinical practice and use as a trial endpoint. Once comparable proteinuria levels were reached, differences in outcomes by genotype were attenuated, supporting proteinuria as a key prognostic marker and strengthening rationale for its use as a surrogate endpoint in AS clinical trials