TY - JOUR
T1 - AQP1 promoter variant, water transport, and outcomes in peritoneal dialysis
AU - Morelle, Johann
AU - Marechal, C. line
AU - Yu, Zanzhe
AU - Debaix, Huguette
AU - Corre, Tanguy
AU - Lambie, Mark
AU - Verduijn, Marion
AU - Dekker, Friedo
AU - Bovy, Philippe
AU - Evenepoel, Pieter
AU - Bammens, Bert
AU - Selgas, Rafael
AU - Bajo, Maria A.
AU - Coester, Annemieke M.
AU - Sow, Amadou
AU - Hautem, Nicolas
AU - Struijk, Dirk G.
AU - Krediet, Raymond T.
AU - Balligand, Jean-Luc
AU - Goffin, Eric
AU - Crott, Ralph
AU - Ripoche, Pierre
AU - Davies, Simon
AU - Devuyst, Olivier
N1 - Funding Information: Supported in part by grants from the Swiss National Science Foundation (310030_189044), the University Research Priority Program Innovative Therapies in Rare Diseases of the University of Zurich, and the Swiss National Centers of Competence in Research Kidney Control of Homeostasis (all to Dr. Devuyst); grants from Fonds de la Recherche Scientifique (40000157 and 4003771), Fondation Saint-Luc, and Fonds de Recherche Clinique des Cliniques Universitaires Saint-Luc (all to Dr. Morelle); a Concerted Research Action grant (ARC16-21/074, to Drs. Bal-ligand and Devuyst); and a grant from the Walloon Excellence in Lifesciences and Biotechnology (WELBIO) Institute (to Dr. Balli-gand). Dr. Balligand is a WELBIO established investigator. Dr. Sow is supported by a Research Fund of the UCLouvain Medical School. Dr. Yu is supported by a Dorothy Hodgkin Postgraduate Award and an award from the Shanghai Pujiang Program (16PJ1405900). Drs. Morelle, Davies, and Devuyst are beneficiaries of the IMPROVE-PD (Identification and Management of Patients at Risk — Outcome and Vascular Events in Peritoneal Dialysis) project funded by the European Union Horizon 2020 program under a Marie Skłodowska-Curie grant agreement (812699). The PD-CRAFT study was supported by a grant from the National Institute for Health Research (PB-PG-0610-22456). The Stoke-on-Trent study was supported in part by the North Staffordshire Medical Institute. NECOSAD was supported by the Dutch Kidney Foundation. Publisher Copyright: Copyright © 2021 Massachusetts Medical Society.
PY - 2021/10/21
Y1 - 2021/10/21
N2 - BACKGROUND Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1, the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability. METHODS We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies. RESULTS The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (±SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506±237 ml vs. 626±283 ml, P=0.007) and in the validation phase (368±603 ml vs. 563±641 ml, P=0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P=0.001), as well as a higher risk of death from any cause (24% vs. 15%, P=0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant. CONCLUSIONS A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis.
AB - BACKGROUND Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in AQP1, the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability. METHODS We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether AQP1 variants were associated with peritoneal ultrafiltration and with a risk of the composite of death or technique failure (i.e., transfer to hemodialysis). We performed studies in cells, mouse models, and samples obtained from humans to characterize an AQP1 variant and investigate mitigation strategies. RESULTS The common AQP1 promoter variant rs2075574 was associated with peritoneal ultrafiltration. Carriers of the TT genotype at rs2075574 (10 to 16% of patients) had a lower mean (±SD) net ultrafiltration level than carriers of the CC genotype (35 to 47% of patients), both in the discovery phase (506±237 ml vs. 626±283 ml, P=0.007) and in the validation phase (368±603 ml vs. 563±641 ml, P=0.003). After a mean follow-up of 944 days, 139 of 898 patients (15%) had died and 280 (31%) had been transferred to hemodialysis. TT carriers had a higher risk of the composite of death or technique failure than CC carriers (adjusted hazard ratio, 1.70; 95% confidence interval [CI], 1.24 to 2.33; P=0.001), as well as a higher risk of death from any cause (24% vs. 15%, P=0.03). In mechanistic studies, the rs2075574 risk variant was associated with decreases in AQP1 promoter activity, aquaporin-1 expression, and glucose-driven osmotic water transport. The use of a colloid osmotic agent mitigated the effects of the risk variant. CONCLUSIONS A common variant in AQP1 was associated with decreased ultrafiltration and an increased risk of death or technique failure among patients treated with peritoneal dialysis.
UR - http://www.scopus.com/inward/record.url?scp=85118103875&partnerID=8YFLogxK
U2 - https://doi.org/10.1056/NEJMoa2034279
DO - https://doi.org/10.1056/NEJMoa2034279
M3 - Article
C2 - 34670044
SN - 0028-4793
VL - 385
SP - 1570
EP - 1580
JO - New England journal of medicine
JF - New England journal of medicine
IS - 17
ER -