Mark Canney1,2,3, Sean J Barbour4,2, Yuyan Zheng2, Rosanna Coppo5, Hong Zhang6, Zhi-Hong Liu7, Keiichi Matsuzaki8, Yusuke Suzuki8, Ritsuko Katafuchi9, Heather N Reich10, Daniel Cattran11. 1. Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada. 2. BC Renal, Provincial Health Services Authority, British Columbia, Canada. 3. Department of Medicine, University of Ottawa and the Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. 4. Division of Nephrology, University of British Columbia, Vancouver, British Columbia, Canada sean.barbour@vch.ca daniel.cattran@uhn.ca. 5. Fondazione Ricerca Molinette, Regina Margherita Hospital, Turin, Italy. 6. Institute of Nephrology, Peking University, Beijing, China. 7. School of Medicine, Nanjing University, Nanjing, China. 8. Faculty of Medicine, Juntendo University, Tokyo, Japan. 9. National Hospital Organization Fukuoka Higashi Medical Center, Fukuoka, Japan. 10. Division of Nephrology, University of Toronto, Toronto, Ontario, Canada. 11. Division of Nephrology, University of Toronto, Toronto, Ontario, Canada sean.barbour@vch.ca daniel.cattran@uhn.ca.
Abstract
BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). RESULTS: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. CONCLUSIONS: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.
BACKGROUND: On the basis of findings of observational studies and a meta-analysis, proteinuria reduction has been proposed as a surrogate outcome in IgA nephropathy. How long a reduction in proteinuria needs to be maintained to mitigate the long-term risk of disease progression is unknown. METHODS: In this retrospective multiethnic cohort of adult patients with IgA nephropathy, we defined proteinuria remission as a ≥25% reduction in proteinuria from the peak value after biopsy, and an absolute reduction in proteinuria to <1 g/d. The exposure of interest was the total duration of first remission, treated as a time-varying covariate using longitudinal proteinuria measurements. We used time-dependent Cox proportional hazards regression models to quantify the association between the duration of remission and the primary outcome (ESKD or a 50% reduction in eGFR). RESULTS: During a median follow-up of 3.9 years, 274 of 1864 patients (14.7%) experienced the primary outcome. The relationship between duration of proteinuria remission and outcome was nonlinear. Each 3 months in sustained remission up to approximately 4 years was associated with an additional 9% reduction in the risk of disease progression (hazard ratio [HR], 0.91; 95% confidence interval [95% CI], 0.89 to 0.93). Thereafter, each additional 3 months in remission was associated with a smaller, nonsignificant risk reduction (HR, 0.99; 95% CI, 0.96 to 1.03). These findings were robust to multivariable adjustment and consistent across clinical and histologic subgroups. CONCLUSIONS: Our findings support the use of proteinuria as a surrogate outcome in IgA nephropathy, but additionally demonstrate the value of quantifying the duration of proteinuria remission when estimating the risk of hard clinical endpoints.
Keywords:
IgA nephropathy; end stage kidney disease; epidemiology and outcomes; glomerular disease; proteinuria; renal function decline; renal pathology
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