Proteinuria, eGFR Decline, and the Pathway to Kidney Failure in Alport Syndrome

Alport syndrome is a genetic disorder caused by pathogenic variants in COL4A3 , COL4A4 , or COL4A5 , which encode the α3, α4, and α5 chains of type IV collagen. These chains form the collagen α3α4α5(IV) network required for basement membrane function in the kidney, inner ear, and eye. In the kidney, impaired production, assembly, or localization of the α3α4α5 network leads to abnormal glomerular basement membrane (GBM) composition, podocyte dysfunction, proteinuria, glomerulosclerosis, progressive loss of filtration capacity, and kidney failure. End point selection for clinical trials in Alport syndrome requires measures that report disease activity and predict meaningful clinical benefit in trials of feasible size and duration. Proteinuria arises from early stages of Alport pathogenesis: abnormal GBM permeability, podocyte foot-process effacement, podocyte detachment, and glomerulosclerosis. eGFR decline is a later readout of cumulative nephron loss and progression toward kidney failure. This review examines the evidence linking proteinuria and eGFR decline to kidney failure in Alport syndrome, focusing on two contributors to proteinuria: 1) podocyte dysfunction with foot-process effacement, which may be partially modifiable, and 2) proteinuria associated with podocyte loss and glomerulosclerosis, which is less likely to be reversible. The relative contribution of these components may vary with genotype, sex, age, and disease duration. Biopsy-based markers, such as collagen α3α4α5(IV) localization, GBM ultrastructure, podocyte foot-process width, glomerulosclerosis, and tubulointerstitial fibrosis, provide staging information along the disease pathway. The current role of these biopsy markers is strongest for target engagement and pathway modification, because quantitative relationships between changes in these markers and kidney failure risk remain incompletely defined. An end point framework for Alport syndrome should account for genotype, sex, age, baseline proteinuria, baseline eGFR, disease duration, and the expected nonlinear trajectories of proteinuria and eGFR decline.