Validation of Estimated Glomerular Filtration Slope and Proteinuria Reduction as Surrogate Endpoints in IgA Nephropathy: A post-hoc Analysis from the J-IGACS

Background Estimated 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.

Patients 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 ≥40 decline in eGFR or the initiation of kidney replacement therapy. Secondary outcomes included 2-year eGFR slope and proteinuria ratio at 1-year.

Corticosteroid 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.

Both 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-Summary IgA 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. Competing Interest Statement YS has received consulting fees from Otsuka Pharmaceutical (Visterra), Novartis, Chinook Therapeutics, ARGENX, BioCryst, Alexion Pharmaceuticals, Renalys, Alpine, and George Clinical. YS has also received honoraria for lectures, presentations, manuscript writing, or educational events from Kyowa Kirin, Novartis, Mitsubishi Tanabe, Otsuka Pharmaceutical, Daiichi Sankyo, AstraZeneca, Boehringer Ingelheim, and Chinook Therapeutics. Funding Statement This study was partly supported by a Grant-in-Aid for Progressive Renal Diseases Research, Research on Rare and Intractable Disease, from the Ministry of Health, Labour and Welfare of Japan. This research was supported by the Japan Agency for Medical Research and Development under grant JP19ek0109261. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the ethics review board of the Jikei University School of Medicine (approval no. 37-069 [12706]). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Footnotes Minor title change. Updated COI disclosure. Data availability statement All data produced in the present study are available upon reasonable request to the authors.