Kidney Failure: Common Gene Variant Associated with Decreased Ultrafiltration Portends Poor Outcome with Peritoneal Dialysis

A common variant of a gene that facilitates water transport across cell membranes was associated with decreased ultrafiltration and an increased risk of death or failure of peritoneal dialysis in patients on peritoneal dialysis for end-stage renal disease (ESRD), a cohort study found.

In a study involving 1,851 patients treated with peritoneal dialysis, the common promoter sequence of aquaporin-1 (AQP1), referred to as rs2075574, was found to determine quantitative differences in peritoneal ultrafiltration, in which defective ultrafiltration was found in carriers of the TT genotype at rs2075574 compared with carriers of the CC genotype, Johann Morelle, MD, PhD, Cliniques Universitaires Saint-Luc, UCLovain, Brussels, Belgium, and colleagues reported in The New England Journal of Medicine.

TT carriers also had a 70% higher risk of death or the need to transfer to hemodialysis than CC carriers at an adjusted hazard ratio (HR) of 1.70 (95% CI, 1.24-2.33; P=0.001), investigators added.

This finding was linked to the roughly 200-mL lower daily net ultrafiltration level in TT carriers, which was possibly associated with fluid overload.

“We should consider whether peritoneal dialysis should be initiated in patients with the TT genotype, given the implications of a lower level of peritoneal water transport in those patients,” Daniel Bichet, MD, University of Montreal, Montreal, Quebec, observed in an editorial accompanying the study.

“We should also consider whether a different prescription should be used in patients with the TT genotype [and f]rom a wider perspective, mapping of the genetic architecture of human traits could lead to personalized kidney therapies,” he suggested.

Bichet also suggested that testing for the different genotypes would be easy to do provided specific primers could be constructed to amplify the upstream sequences of AQP1.

Morelle and colleagues recruited patients from 7 georgraphic/institutional cohorts: Belgium (n=277), the Netherlands AMC (Amsterdam University Medical Center) cohort (n=81) and NECOSAD (Netherlands Cooperative Study on the Adequacy of Dialysis) cohort (n=344), Spain (n=156), the United Kingdom Stoke-on-Trent cohort (n=130) and PD-CRAFT (Peritoneal Dialysis Competitive Risk Analysis for Long-Term Outcomes) study cohort (n=483), and China (n=380).

Clinical and genetic data from all 7 cohorts studied were collected in order to determine whether AQP1 variants were associated with peritoneal ultrafiltration as well as the composite endpoint of death or transfer to hemodialysis in patients initially treated with peritoneal dialysis.

Studies were done in cells, mouse models, and samples from patients to characterize the AQP1 variant and investigate mitigation strategies, the authors explained.

The mean age across all cohorts was 54 years, and three-quarters of the patients were of European descent.

“Results for net ultrafiltration and sodium sieving, which are both measures of water transport, varied widely across individual patients,” Morelle and colleagues noted.

On the other hand, among the AQP1 variants analyzed, only the rs2075574 variant was significantly associated with measures of water transport, they added.

For example, patients with the TT genotype at rs2075574 had a significantly lower net ultrafiltration level at 506 mL compared with patients with the CC genotype whose net ultrafiltration level was 626 mL (P=0.007).

Levels of sodium sieving were also significantly lower among patients with the TT genotype compared with those with the CC genotype, despite having a similar peritoneal solute transfer rate and similar clinical characteristics.

“Patients with the TT genotype had a lower daily net ultrafiltration level than patients with the CC genotype,” investigators pointed out—at 368 mL compared with 563 mL, respectively (P=0.003), although the rs2075574 variant was not associated with residual urine volume, as investigators noted.

As was observed in patients with the TT genotype at rs2075574, there was also about a 50% decrease in aquaporin-1 expression in the peritoneal membrane of AQP1 positive/negative mice even in the absence of structural changes.

In contrast, water transport was similar in AQP1 positive-negative mice as well as in AQP1 positive/positive littermates with the use of icodextrin, suggesting that there is a potential value for using colloid osmotic agents for the treatment of patients with a deleterious AQP1 genotype.

As the authors pointed out, water removal is critical to the efficacy of dialysis.

Given this, they tested whether there was an association between the AQP1 genotype at rs2075574 and outcomes in peritoneal dialysis patients.

Out of 898 patients available for analysis, almost half at 47% had died or had experienced peritoneal dialysis failure after a mean follow-up of 944 days.

Patients with the TT genotype also had a higher risk of the composite endpoint of death or technique failure at 58% compared with 42% of patients with the CC genotype (P=0.01) as well as a higher risk of death from any cause at 24% compared with 15%, respectively (P=0.03), study authors added.

“The trend toward worse outcomes in patients with the TT genotype was consistent across subgroups and cohorts,” they observed, although women were less likely to have the same poor outcomes associated with the TT genotype than men.

Findings were also independent of race, peritoneal dialysis practices and changes in solute transport, they added.

As the authors suggested, these deleterious effects on ultrafiltration are clinically relevant.

“Fluid overload is a substantial contributor to death among patients treated with peritoneal dialysis, regardless of whether death occurs suddenly or after a debilitation period characterized by frequent hospital admissions,” they observed.

Moreover, the association between the AQP1 genotype at rs2075574 and peritoneal ultrafiltration was seen both in patients starting dialysis as well as in patients undergoing maintenance dialysis.

However, in both patients with the TT genotype as well as in Aqp1 positive/negative mice, the effect of decreased aquaporin-1 expression on peritoneal water transport was only observed with the use of glucose as an osmotic agent and not with the use of icodextrin.

This data suggest that the use of colloid osmotic agents may mitigate the deleterious effect of the TT genotype on water transport, they reaffirmed.

1. A common variant of a gene that facilitates water transport across cell membranes was associated with decreased ultrafiltration and an increased risk of death and technique failure in peritoneal dialysis patients.

2. Consideration should be given as to whether or not to initiate peritoneal dialysis in carriers of this common gene variant given the toxic potential for fluid overload.

Pam Harrison, Contributing Writer, BreakingMED™

Cat ID: 127

Topic ID: 81,127,730,127,192,925