From the Division of Nephrology, Cliniques Universitaires Saint-Luc (J.M., E.G., O.D.), and Institut de Recherche Expérimentale et Clinique (J.M., C.M., H.D., A.S., N.H., J.-L.B., E.G., O.D.) and Institut de Recherche Santé et Société, Faculty of Public Health (R.C.), UCLouvain, Brussels, the Division of Nephrology, Clinique Saint-Joseph, Liege (P.B.), and the Department of Microbiology, Immunology, and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven (P.E., B.B.), and the Department of Nephrology, Dialysis, and Renal Transplantation, University Hospitals Leuven (P.E., B.B.), Leuven - all in Belgium; the Department of Nephrology, Shanghai Jiao Tong University School of Medicine and Renji Hospital, Shanghai, China (Z.Y.); the Faculty of Medicine and Health Sciences, Keele University, Keele, United Kingdom (Z.Y., M.L., S.D.); the Institute of Physiology, University of Zurich, Zurich (H.D., O.D.), and the Center for Primary Care and Public Health (Unisanté), University of Lausanne, Lausanne (T.C.) - both in Switzerland; the Department of Clinical Epidemiology, Leiden University Medical Center, Leiden (M.V., F.D.), the Division of Nephrology, Department of Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam (A.M.C., D.G.S., R.T.K.), and the Department of Surgery, University Medical Center Groningen, Groningen (A.M.C.) - all in the Netherlands; the Division of Nephrology, Hospital Universitario La Paz, and Instituto de Investigación Sanitaria La Paz, Red de Investigación Renal, Universidad Autonoma, Madrid (R.S., M.A.B.); and Institut National de la Transfusion Sanguine, Paris (P.R.).
N Engl J Med. 2021 Oct 21;385(17):1570-1580. doi: 10.1056/NEJMoa2034279.
Variability in ultrafiltration influences prescriptions and outcomes in patients with kidney failure who are treated with peritoneal dialysis. Variants in , the gene that encodes the archetypal water channel aquaporin-1, may contribute to that variability.
We gathered clinical and genetic data from 1851 patients treated with peritoneal dialysis in seven cohorts to determine whether 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 variant and investigate mitigation strategies.
The common 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 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.
A common variant in 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.).
超滤变异影响接受腹膜透析治疗的肾衰竭患者的处方和结局。编码典型水通道蛋白 aquaporin-1 的 基因的变体可能导致这种变异。
我们从七个队列中接受腹膜透析治疗的 1851 名患者收集临床和遗传数据，以确定 变体是否与腹膜超滤以及死亡或技术失败（即转为血液透析）复合风险相关。我们在细胞、小鼠模型和从人类获得的样本中进行了研究，以描述一个 变体并研究缓解策略。
常见的 启动子变体 rs2075574 与腹膜超滤有关。rs2075574 的 TT 基因型（10-16%的患者）携带者的平均（±SD）净超滤水平低于 CC 基因型（35-47%的患者）携带者，在发现阶段（506±237ml 与 626±283ml，P=0.007）和验证阶段（368±603ml 与 563±641ml，P=0.003）均如此。在平均随访 944 天后，898 名患者中有 139 名（15%）死亡，280 名（31%）转为血液透析。TT 携带者的死亡或技术失败复合风险高于 CC 携带者（调整后的危险比，1.70；95%置信区间[CI]，1.24 至 2.33；P=0.001），以及任何原因导致的死亡风险更高（24%比 15%，P=0.03）。在机制研究中，rs2075574 风险变体与 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降低有关。胶体渗透压剂的使用减轻了风险变体的影响。
接受腹膜透析治疗的患者中， 中的常见变体与超滤减少和死亡或技术失败风险增加相关。（由瑞士国家科学基金会等资助）。
