Proteinuria and risk of kidney failure in US adults with Immunoglobulin A nephropathy

Abstract Purpose Proteinuria is a key predictor of kidney failure in Immunoglobulin A nephropathy (IgAN) patients, but few real-world studies establishing this association have been conducted in the United States (US). This study evaluated the association between time-averaged proteinuria (TA-P) and risk of kidney failure in patients with IgAN in the US, including TA-P levels of < 0.5 g/day and below. Methods This retrospective cohort study used integrated administrative claims from the Komodo Research Data and electronic medical record data from Norstella (January 2016–2026). Adults (≥ 18 years) with IgAN diagnosis, ≥ 3 proteinuria measurements, and no kidney failure before the index date (the day after the third proteinuria measurement) were included. TA-P was calculated as the area under the curve of serial proteinuria measurements divided by the duration of observation. Primary TA-P categories were < 0.5, 0.5-1.0, 1.0-1.5, and ≥ 1.5 g/day; additional analyses used a more granular stratification of TA-P < 0.5 g/day (< 0.3 g/day and 0.3–0.5 g/day). The composite study outcome was kidney failure (chronic kidney disease stage 5, sustained eGFR < 15 mL/min/1.73 m 2 , dialysis, or kidney transplantation). Associations between TA-P and kidney failure were assessed using Cox proportional hazards models adjusted for baseline characteristics such as demographics, race/ethnicity, hypertension, diabetes, hematuria, and eGFR. Results A total of 1820 patients with IgAN were included in the study (median age 46.8 years; 51.4% male). The mean follow-up was 33.2 months with a maximum follow-up of 108 months. Compared with TA- P < 0.5 g/day, adjusted hazard ratios (HRs) for kidney failure were 1.83 (95% confidence interval [CI], 1.38–2.41) for TA-P 0.5–1.0 g/day; 2.16 (95% CI, 1.44–3.22) for TA-P 1.0–1.5 g/day; and 3.14 (95% CI, 2.16–4.56) for TA-P ≥ 1.5 g/day. Compared with TA-P < 0.3 g/day, adjusted HRs were 1.71 (95% CI, 1.17–2.50) for TA-P 0.3–0.5 g/day; 2.17 (95% CI, 1.59–2.95) for TA-P 0.5–1.0 g/day; 2.56 (95% CI, 1.67–3.91) for TA-P 1.0–1.5 g/day; and 3.71 (95% CI, 2.49–5.52) for TA-P ≥ 1.5 g/day. Conclusions Lower TA-P was associated with progressively reduced risk of kidney failure in adults with IgAN in the US. After adjusting for demographics and clinical characteristics, the risk was significantly lower at TA-P < 0.3 g/day even when compared with TA-P levels of 0.3–0.5 g/day. This underscores the importance of achieving and maintaining proteinuria levels below the threshold of 0.5 g/day and ideally < 0.3 g/day to delay kidney failure, consistent with KDIGO recommended treatment goals.