#4503 estimating delay in time to kidney failure or death for treatment effects on proteinuria in iga nephropathy

Abstract Background and Aims Reduction in proteinuria is associated with lower risk of kidney failure (KF) in IgA nephropathy (IgAN) (Thompson et al, 2019). In phase 3 randomized controlled trials in IgAN patients, a treatment effect on proteinuria reduction is typically evaluated as a mean percent change in proteinuria from baseline at 6-9 months. In this study, we aim to estimate the delay in time to KF or death associated with treatment effects of 40% and 50% reduction of proteinuria at this timepoint. Method In this study, we used individual patient level data from the UK National Registry of Rare Kidney Disease (RaDaR) IgAN cohort. Adult IgAN patients (n = 535) with a urine protein-creatinine ratio ≥100 mg/mmol (0.88 g/g) ≥6 months from diagnosis (time point defined as baseline) and eGFR ≥30 mL/min at baseline (study population mean = 61 ml/min/1.73 m2 [SD 26]) were included. Predicted risk of KF (eGFR <15 mL/min, initiation of dialysis, transplantation)/doubling serum creatinine/death associated with treatment effects reducing proteinuria by 40% and 50% at 9 months were calculated from IgAN trial level analysis data (Thompson et al, 2019). Accelerated failure time modelling was used to analyse time to KF/death during follow up in the RaDaR IgAN study population, and to estimate the effect that changes in hazard ratio had on median survival time and 5-year survival rates. Weibull, Log-Logistic and Log-Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC. Results Treatment effects reducing proteinuria by 40% and 50% in IgAN patients predict a 59% and 67% lower risk of KF/death, respectively. A 59% reduction in risk, is estimated to extend the median time to KF/death by 6.3 years, from 8.6 years (95% CI 7.8, 9.5) to 14.9 years (95% CI 13.6, 16.4), while the corresponding extension in median time to KF/death estimate for a 67% reduction in risk is 8.5 years (from 8.6 years [95% CI 7.8, 9.5] to 17.1 years [95% CI 15.6, 18.8]) (Figure 1). Five-year KF/death free survival rate increased from 75% to 89% and 91%, for 59% and 67% reduced risk in KF/death, respectively. Conclusion Therapeutic interventions that reduce proteinuria and the risk of KF can confer important and clinically meaningful extensions in the time patients are alive and free from KF.