Proteinuria Trajectory and Disease Progression in Children and Adults with IgA Nephropathy/Vasculitis

Background: Identifying patients with IgA Nephropathy at risk for disease progression is critical for clinical decision making, risk-based patient counseling, and optimal enrollment of clinical trials. Methods: Patients with IgA Nephropathy (IgAN) and IgA Vasculitis with Nephritis (IgAVN) were enrolled in CureGN, a multi-center observational cohort study. Children and adults were analyzed separately in four cohorts 1) full, 2) incident, 3) prevalent, and 4) histology. Groups were defined using latent class trajectory modeling using proteinuria measurements over two years. Linear mixed models were used to calculate predicted estimated glomerular filtration rate (eGFR) slope. In adults, Cox proportional hazard models were used to model time to kidney failure or 40% eGFR decline as a function of proteinuria trajectory group. Results: Of 919 individuals with IgAN/IgAVN enrolled into CureGN, 368 adults and 234 children were included in the analysis. In the full adult cohort, Group 1 had the lowest levels of proteinuria (IQR 0.1-0.4 g/g), while Groups 2 and 3 had intermediate and higher levels of proteinuria (IQR 0.5-1.5 and IQR 1.8-4.1 g/g, respectively). Average predicted time to eGFR less than 15 ml/min/1.73 m 2 was >90, 16, and 8 years and >90, 67, 11 years for proteinuria trajectory groups 1, 2, and 3, in the full adult and pediatric cohorts, respectively. In adults, adjusting for age, eGFR at enrollment, immunosuppression exposure, and hypertension, Group 3 membership was associated with 3.13 (95% CI 1.84-5.33), 1.98 (95% CI 0.97-4.06), and 3.36 (95% CI 1.59-7.13) times higher hazard of progressing to a composite outcome compared to Group 2 membership in the full, prevalent and histology cohorts, respectively, but not associated with progression in the incident cohort. Conclusions: Proteinuria trajectory is a major predictor of disease progression in patients with IgA nephropathy.