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AQP1 Promoter Variant, Water Transport, and Outcomes in Peritoneal Dialysis.

Morelle, Johann; Marechal, Céline; Yu, Zanzhe; Debaix, Huguette; Corre, Tanguy; Lambie, Mark; Verduijn, Marion; Dekker, Friedo; Bovy, Philippe; Evenepoel, Pieter; Bammens, Bert; Selgas, Rafael; Bajo, Maria A.; Coester, Annemieke M.; Sow, Amadou; Hautem, Nicolas; Struijk, Dirk G.; Krediet, Raymond T.; Balligand, Jean-Luc; Goffin, Eric; Crott, Ralph; Ripoche, Pierre; Davies, Simon; Devuyst, Olivier

Authors

Johann Morelle

Céline Marechal

Zanzhe Yu

Huguette Debaix

Tanguy Corre

Marion Verduijn

Friedo Dekker

Philippe Bovy

Pieter Evenepoel

Bert Bammens

Rafael Selgas

Maria A. Bajo

Annemieke M. Coester

Amadou Sow

Nicolas Hautem

Dirk G. Struijk

Raymond T. Krediet

Jean-Luc Balligand

Eric Goffin

Ralph Crott

Pierre Ripoche

Olivier Devuyst



Abstract

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. (Funded by the Swiss National Science Foundation and others.).

Journal Article Type Article
Acceptance Date Oct 21, 2021
Publication Date Oct 21, 2021
Journal New England Journal of Medicine
Print ISSN 0028-4793
Publisher Massachusetts Medical Society
Peer Reviewed Peer Reviewed
Volume 385
Pages 1570 - 1580
DOI https://doi.org/10.1056/NEJMoa2034279
Publisher URL https://www.nejm.org/doi/10.1056/NEJMoa2034279

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