Proteinuria Reduction as a Surrogate Endpoint for Clinical Study of IgA Nephropathy in Japanese Patients: Data from the J-CKD-DB-Ex

Early reduction in proteinuria has been validated as a surrogate endpoint for IgA nephropathy (IgAN) in Western trials and is used for accelerated drug approval by the U.S. FDA, with new drug receiving approval based on 9-month proteinuria reduction. However, its applicability to Japanese patients remains unclear, given that the incidence, prevalence, clinical course, and prognosis of IgAN differ between Japanese and Western populations. Although these effective drugs are available overseas, they are not yet accessible in Japan, creating a drug lag that disadvantages Japanese patients. Therefore, this study aimed to evaluate the association between early proteinuria reduction and long-term renal outcomes in Japanese patients with IgAN, using real-world data from J-CKD-DB-Ex.

This retrospective observational study used data from J-CKD-DB-Ex, a real-world database of CKD in Japan comprising 21 university hospitals. Adult participants with IgAN (identified using ICD-10 codes), baseline urine protein/creatinine ratio (UPCR) ≥ 0.5 g/gCr, and eGFR ≥ 30 mL/min/1.73 m² were included. Exclusion criteria included patients without eGFR measurements during observation and those using immunosuppressants (excluding corticosteroids). The exposure was a ≥ 30% UPCR reduction at 9 months after the index date (UPCR reduction group), versus participants without such reduction (non-UPCR reduction group). UPCR values obtained within 9-12 months after the index date were used for the second measurement. The primary endpoint was a composite of 40% decline in eGFR from baseline or onset of CKD stage G5 (eGFR < 15 mL/min/1.73 m²). Cox proportional hazard models and linear mixed-effects models evaluated the association between UPCR reduction, renal events, and eGFR slope, adjusted for age, sex, baseline eGFR, baseline UPCR, and RAS inhibitor use.

Among 385 participants (mean observation period 2,040 days), 64% (245 patients) achieved ≥ 30% reductions in UPCR. Baseline characteristics showed mean age 46.7 years, mean eGFR 64.7 mL/min/1.73 m², and mean UPCR 1.8 g/gCr. The UPCR reduction group showed significantly lower cumulative incidence of renal composite events than the non-UPCR reduction group [aHR 0.53 (95% CI: 0.35 - 0.79), p=0.002]. Similarly, the risk was significantly reduced for eGFR <15 mL/min/1.73 m² [aHR 0.16 (95% CI: 0.07 - 0.39), p < 0.001] and 40% eGFR decline [aHR 0.45 (95% CI: 0.30 - 0.68), p < 0.001], respectively. Annual eGFR decline was slower in the UPCR reduction group than that in the non-UPCR group (-1.9 vs -3.4 mL/min/1.73 m²/year). Multivariable regression model presented that greater UPCR reductions were linearly associated with more favorable eGFR slope [β coefficient: -0.01 (95% CI: -0.02, -0.01) per 1% UPCR decrease].

Using the Japanese CKD database J-CKD-DB-Ex, we examined whether early urinary protein reduction, a surrogate endpoint widely adopted in international clinical trials, is appropriate for Japanese patients with IgAN. A reduction of ≥ 30% in urinary protein at 9 months was associated with decreased subsequent renal failure risk and attenuation of eGFR decline. These findings suggest that early proteinuria reduction is a valid surrogate endpoint for renal prognosis in Japanese IgAN populations.