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

Johann Morelle, Celine Marechal, Zanzhe Yu, Huguette Debaix, Tanguy Corre, Mark Lambie, 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 GoffinRalph Crott, Pierre Ripoche, Simon Davies, Olivier Devuyst

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

AQP1 Promoter Variant and Peritoneal Dialysis Variability in ultrafiltration influences prescriptions and outcomes in patients treated with peritoneal dialysis. This study showed that a common variant in AQP1, the gene that encodes the water channel aquaporin-1, was associated with decreased ultrafiltration and an increased risk of death or technique failure among such patients.

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.)

Original languageEnglish
Pages (from-to)1570-1580
Number of pages11
JournalNew England Journal of Medicine
Volume385
Issue number17
DOIs
Publication statusPublished - 21-Oct-2021

Keywords

  • 3.86-PERCENT GLUCOSE
  • EQUILIBRATION TEST
  • ANURIC PATIENTS
  • ULTRAFILTRATION
  • AQUAPORIN-1
  • PERMEABILITY
  • EXPRESSION
  • MANAGEMENT
  • MORTALITY
  • CHANNELS

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