Quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy

Canney, M.; Barbour, S. J.; Zheng, Y.; Coppo, R.; Zhang, H.; Liu, Z. -H.; Matsuzaki, K.; Suzuki, Y.; Katafuchi, R.; Reich, H. N.; Cattran, D.; Russo, M. L.; Troyanov, S.; Cook, H. T.; Roberts, I.; Tesar, V.; Maixnerova, D.; Lundberg, S.; Gesualdo, L.; Emma, F.; Fuiano, L.; Beltrame, G.; Rollino, C.; Amore, A.; Camilla, R.; Peruzzi, L.; Praga, M.; Feriozzi, S.; Polci, R.; Segoloni, G.; Colla, L.; Pani, A.; Piras, D.; Angioi, A.; Cancarini, G.; Ravera, S.; Durlik, M.; Moggia, E.; Ballarin, J.; Di Giulio, S.; Pugliese, F.; Serriello, I.; Caliskan, Y.; Sever, M.; Kilicaslan, I.; Locatelli, F.; Del Vecchio, L.; Wetzels, J. F. M.; Peters, H.; Berg, U.; Carvalho, F.; da Costa Ferreira, A. C.; Maggio, M.; Wiecek, A.; Ots-Rosenberg, M.; Magistroni, R.; Topaloglu, R.; Bilginer, Y.; D'Amico, M.; Stangou, M.; Giacchino, F.; Goumenos, D.; Kalliakmani, P.; Gerolymos, M.; Galesic, K.; Geddes, C.; Siamopoulos, K.; Balafa, O.; Galliani, M.; Stratta, P.; Quaglia, M.; Bergia, R.; Cravero, R.; Salvadori, M.; Cirami, L.; Fellstrom, B.; Kloster Smerud, H.; Ferrario, F.; Stellato, T.; Egido, J.; Martin, C.; Floege, J.; Eitner, F.; Lupo, A.; Bernich, P.; Mene, P.; Morosetti, M.; van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Boria Grinyo, J. M.; Cusinato, S.; Benozzi, L.; Savoldi, S.; Licata, C.; Mizerska-Wasiak, M.; Martina, G.; Messuerotti, A.; Dal Canton, A.; Esposito, C.; Migotto, C.; Triolo, G.; Mariano, F.; Pozzi, C.; Boero, R.; Bellur, S.; Mazzucco, G.; Giannakakis, C.; Honsova, E.; Sundelin, B.; Di Palma, A. M.; Gutierrez, E.; Asunis, A. M.; Barratt, J.; Tardanico, R.; Perkowska-Ptasinska, A.; Arce Terroba, J.; Fortunato, M.; Pantzaki, A.; Ozluk, Y.; Steenbergen, E.; Soderberg, M.; Riispere, Z.; Furci, L.; Orhan, D.; Kipgen, D.; Casartelli, D.; Galesic Ljubanovic, D.; Gakiopoulou, H.; Bertoni, E.; Cannata Ortiz, P.; Karkoszka, H.; Groene, H. J.; Stoppacciaro, A.; Bajema, I.; Bruijn, J.; Fulladosa Oliveras, X.; Maldyk, J.; Ioachim, E.; Bavbek, N.; Cook, T.; Alpers, C.; Feehally, J.; Berthoux, F.; Bonsib, S.; D'Agati, V.; D'Amico, G.; Emancipator, S.; Emmal, F.; Fervenza, F.; Florquin, S.; Fogo, A.; Groene, H.; Haas, M.; Hill, P.; Hogg, R.; Hsu, S.; Hunley, T.; Hladunewich,; Jennette, C.; Joh, K.; Julian, B.; Kawamura, T.; Lai, F.; Leung, C.; Li, L.; Li, P.; Liu, Z.; Massat, A.; Mackinnon, B.; Mezzano, S.; Schena, F.; Tomino, Y.; Walker, P.; Wang, H.; Weening, J.; Yoshikawa, N.; Zeng, C. -H.; Shi, S.; Nogi, C.; Suzuki, H.; Koike, K.; Hirano, K.; Yokoo, T.; Hanai, M.; Fukami, K.; Takahashi, K.; Yuzawa, Y.; Niwa, M.; Yasuda, Y.; Maruyama, S.; Ichikawa, D.; Suzuki, T.; Shirai, S.; Fukuda, A.; Fujimoto, S.; Trimarchi, H.

doi:10.1681/ASN.2020030349

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.

Quantifying duration of proteinuria remission and association with clinical outcome in IgA nephropathy / Canney, M.; Barbour, S. J.; Zheng, Y.; Coppo, R.; Zhang, H.; Liu, Z. -H.; Matsuzaki, K.; Suzuki, Y.; Katafuchi, R.; Reich, H. N.; Cattran, D.; Russo, M. L.; Troyanov, S.; Cook, H. T.; Roberts, I.; Tesar, V.; Maixnerova, D.; Lundberg, S.; Gesualdo, L.; Emma, F.; Fuiano, L.; Beltrame, G.; Rollino, C.; Amore, A.; Camilla, R.; Peruzzi, L.; Praga, M.; Feriozzi, S.; Polci, R.; Segoloni, G.; Colla, L.; Pani, A.; Piras, D.; Angioi, A.; Cancarini, G.; Ravera, S.; Durlik, M.; Moggia, E.; Ballarin, J.; Di Giulio, S.; Pugliese, F.; Serriello, I.; Caliskan, Y.; Sever, M.; Kilicaslan, I.; Locatelli, F.; Del Vecchio, L.; Wetzels, J. F. M.; Peters, H.; Berg, U.; Carvalho, F.; da Costa Ferreira, A. C.; Maggio, M.; Wiecek, A.; Ots-Rosenberg, M.; Magistroni, R.; Topaloglu, R.; Bilginer, Y.; D'Amico, M.; Stangou, M.; Giacchino, F.; Goumenos, D.; Kalliakmani, P.; Gerolymos, M.; Galesic, K.; Geddes, C.; Siamopoulos, K.; Balafa, O.; Galliani, M.; Stratta, P.; Quaglia, M.; Bergia, R.; Cravero, R.; Salvadori, M.; Cirami, L.; Fellstrom, B.; Kloster Smerud, H.; Ferrario, F.; Stellato, T.; Egido, J.; Martin, C.; Floege, J.; Eitner, F.; Lupo, A.; Bernich, P.; Mene, P.; Morosetti, M.; van Kooten, C.; Rabelink, T.; Reinders, M. E. J.; Boria Grinyo, J. M.; Cusinato, S.; Benozzi, L.; Savoldi, S.; Licata, C.; Mizerska-Wasiak, M.; Martina, G.; Messuerotti, A.; Dal Canton, A.; Esposito, C.; Migotto, C.; Triolo, G.; Mariano, F.; Pozzi, C.; Boero, R.; Bellur, S.; Mazzucco, G.; Giannakakis, C.; Honsova, E.; Sundelin, B.; Di Palma, A. M.; Gutierrez, E.; Asunis, A. M.; Barratt, J.; Tardanico, R.; Perkowska-Ptasinska, A.; Arce Terroba, J.; Fortunato, M.; Pantzaki, A.; Ozluk, Y.; Steenbergen, E.; Soderberg, M.; Riispere, Z.; Furci, L.; Orhan, D.; Kipgen, D.; Casartelli, D.; Galesic Ljubanovic, D.; Gakiopoulou, H.; Bertoni, E.; Cannata Ortiz, P.; Karkoszka, H.; Groene, H. J.; Stoppacciaro, A.; Bajema, I.; Bruijn, J.; Fulladosa Oliveras, X.; Maldyk, J.; Ioachim, E.; Bavbek, N.; Cook, T.; Alpers, C.; Feehally, J.; Berthoux, F.; Bonsib, S.; D'Agati, V.; D'Amico, G.; Emancipator, S.; Emmal, F.; Fervenza, F.; Florquin, S.; Fogo, A.; Groene, H.; Haas, M.; Hill, P.; Hogg, R.; Hsu, S.; Hunley, T.; Hladunewich, ; Jennette, C.; Joh, K.; Julian, B.; Kawamura, T.; Lai, F.; Leung, C.; Li, L.; Li, P.; Liu, Z.; Massat, A.; Mackinnon, B.; Mezzano, S.; Schena, F.; Tomino, Y.; Walker, P.; Wang, H.; Weening, J.; Yoshikawa, N.; Zeng, C. -H.; Shi, S.; Nogi, C.; Suzuki, H.; Koike, K.; Hirano, K.; Yokoo, T.; Hanai, M.; Fukami, K.; Takahashi, K.; Yuzawa, Y.; Niwa, M.; Yasuda, Y.; Maruyama, S.; Ichikawa, D.; Suzuki, T.; Shirai, S.; Fukuda, A.; Fujimoto, S.; Trimarchi, H.. - In: JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY. - ISSN 1046-6673. - 32:2(2021), pp. 436-447. [10.1681/ASN.2020030349]