Validation of Estimated Glomerular Filtration Slope and Proteinuria Reduction as Surrogate Endpoints in IgA Nephropathy: A Weighted Analysis by Corticosteroid Therapy in the Japan IgA Nephropathy Cohort Study (J-IGACS)

BackgroundEstimated glomerular filtration rate (eGFR) slope and proteinuria reduction have been proposed as surrogate endpoints for kidney outcomes in IgA nephropathy (IgAN), but their validity remains under debate. We aimed to evaluate the surrogate potential of these markers in the context of corticosteroid therapy within a large Japanese cohort. MethodsPatients with biopsy-proven IgAN from the Japan IgA Nephropathy Cohort Study (J-IGACS) were analyzed. Patients were categorized based on corticosteroid exposure within 12 months of diagnosis. To minimize confounding, overlap weighting was used to balance baseline characteristics. The primary outcome was a composite kidney endpoint defined as a [&ge;]40 decline in eGFR or the initiation of kidney replacement therapy. Secondary outcomes included 2-year eGFR slope and proteinuria ratio at 1-year. ResultsCorticosteroid therapy was associated with a lower incidence of the composite kidney outcome (15.5 vs. 28.2%, P = 0.007), slower decline in eGFR (-0.30 vs. -2.99 mL/min/1.73 m2/year, P = 0.001), and lower proteinuria ratio (0.521 vs. 0.235, P < 0.001). These associations were consistent with predictions from established meta-regression models that linked changes in surrogate markers to kidney outcomes across diverse kidney diseases including IgAN. ConclusionBoth the eGFR slope and proteinuria ratio demonstrated strong and consistent associations with kidney outcomes in the context of corticosteroid therapy. These findings support their validity as surrogate endpoints for clinical trials and suggest their usefulness for risk stratification and therapeutic monitoring in routine nephrology practice. Lay-SummaryIgA nephropathy (IgAN) is a common kidney disease that can lead to kidney failure over time. To monitor treatment effectiveness, researchers often use early indicators like how quickly kidney function declines (eGFR slope) and changes in protein levels in urine (proteinuria). However, whether these markers truly reflect long-term outcomes remains uncertain. In this study, we analyzed over 1,000 patients with biopsy-confirmed IgAN from a nationwide Japanese cohort. We compared those who received corticosteroid treatment within a year of diagnosis to those who did not. After adjusting for differences between groups, we found that corticosteroid use was linked to better kidney outcomes, slower decline in kidney function, and reduced proteinuria. These results matched predictions from large-scale international studies. Our findings support the use of eGFR slope and proteinuria as reliable surrogate endpoints in clinical trials and everyday care, helping doctors assess treatment response more quickly and accurately.