MO246ESTIMATING DELAY IN TIME TO ESKD FOR TREATMENT EFFECTS ON PROTEINURIA IN IGA NEPHROPATHY AND FSGS*

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Abstract Background and Aims Reduction in proteinuria is associated with lower risk of end-stage kidney disease (ESKD) in IgA nephropathy (Thompson et al, 2019) and focal segmental glomerulosclerosis (FSGS) (Troost et al, 2017). Sparsentan, a dual endothelin receptor and angiotensin II receptor antagonist, is in phase 3 clinical trials in IgA nephropathy (PROTECT) and FSGS (DUPLEX), that are powered to detect a treatment benefit on proteinuria-based endpoints versus standard of care angiotensin receptor blockade (irbesartan). In this study, we aim to estimate the delay in time to ESKD conferred by the hypothesized treatment effect of sparsentan on proteinuria in these phase 3 trials; for PROTECT, a 30% reduction in urine protein to creatine ratio (UP/C) vs irbesartan in IgA nephropathy patients, and for DUPLEX, 30% more patients achieving the new FSGS Partial Remission Endpoint (UP/C <1.5 g/g associated with a 40% reduction in UP/C) versus irbesartan. Methods We analysed individual patient level data from two UK registries: the first is provided by Leicester General Hospital, UK and consists of IgAN patients, and the second is the UK National Registry of Rare Kidney Disease (RaDaR) Nephrotic Syndrome cohort, with access provided by the University of Bristol, UK, including FSGS patients. IgAN patients with urine total protein value ≥1.0 g/day or UP/C ≥1.0 g/g and eGFR >30 mL/min at the initiation of renin-angiotensin system blockade (RASB) were identified, as were patients with primary or genetic FSGS with UP/C ≥1.5 g/g and eGFR ≥30 mL/min. The time to ESKD (eGFR <15 mL/min, initiation of dialysis, transplantation) or death from any cause over the patient follow-up period was analysed using accelerated failure time modelling; Weibull, Log Logistic and Log Normal distributions were applied with the fitted survivor function reported from the model with the lowest AIC. The time gained for a given reduction in risk in ESKD/death and 5-year survival was estimated under proportional hazards. Results A 30% reduction in proteinuria in IgAN patients confers a 50% lower risk of ESKD, extending the median time to ESKD by 10.7 years, from 12.4 to 23.1 years; 5-year ESKD free survival rate is also increased, from 77.7% to 88.1%. Similarly, ongoing analysis in FSGS patients indicates 30% more patients achieving the FSGS Partial Remission Endpoint confers lower risk for ESKD and increase in 5-year ESKD free survival. Conclusion The data from the Leicester General Hospital, UK and RaDaR provide invaluable insight into the longer-term natural history of IgAN and FSGS patients and time to ESKD. Therapeutic interventions that reduce proteinuria and the risk of ESKD can confer important and clinically meaningful extensions in the time patients are alive and free from ESKD.