瑞士苏黎世大学Olivier Devuyst团队研究了AQP1启动子变异、水转运和腹膜透析结局的相关性。2021年10月20日出版的《新英格兰医学杂志》发表了该成果。

在接受腹膜透析治疗的肾衰竭患者中，超滤的变异性影响处方和结果。AQP1基因的变异可能是导致这种变异性的原因之一。AQP1基因编码原始水通道蛋白-1。

研究组收集了七个队列中1851名接受腹膜透析治疗患者的临床和基因学数据，以确定AQP1变异是否与腹膜超滤以及死亡或技术失败（即转为血液透析）的综合风险相关。他们在细胞、小鼠模型和从人类获得的样本中进行研究，以确定AQP1变异的特征并研究缓解策略。

常见的AQP1启动子变异体rs2075574与腹膜超滤有关。无论是在发现阶段（506±237 mL与626±283 mL）还是在验证阶段（368±603 mL与563±641 mL），rs2075574的TT基因型携带者（10-16%的患者）的平均（±SD）净超滤水平均低于CC基因型携带者（35-47%的患者）。

平均随访944天后，898名患者中有139名（15%）死亡，280名（31%）转入血液透析。TT携带者比CC携带者有更高的死亡或技术失败综合风险，全因死亡风险也更高，分别为24%与15%。在机理研究中，rs2075574风险变异与AQP1启动子活性、水通道蛋白-1表达和葡萄糖驱动的渗透水转运的降低有关。胶体渗透剂的使用减轻了风险变异的影响。

研究结果表明，在接受腹膜透析治疗的患者中，AQP1的一个常见变异与超滤减少和死亡或技术失败风险增加有关。

附：英文原文

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

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

Issue&Volume: 2021-10-20

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.

DOI: 10.1056/NEJMoa2034279

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2034279