Common Gene Variant May Predict Peritoneal Dialysis Outcomes

A common genetic variant predicted poor outcomes from peritoneal dialysis, suggesting a potential factor for patient selection and treatment, researchers found.

Variants in AQP1, the gene that encodes for a key water transport channel across the peritoneal membrane, were associated with decreased ultrafiltration while on peritoneal dialysis and a 70% increased risk of death or failure of that form of dialysis as well.

The 10-16% of patients with the TT genotype of the rs2075574 variant could be good candidates for precision medicine in dialysis treatment, Johann Morelle, MD, PhD, of the Cliniques Universitaires Saint-Luc in Brussels, Belgium, and colleagues reported in the New England Journal of Medicine.

There haven't been clear reasons why water and solute transport across the peritoneal membrane that this dialysis technique relies on varies so much from patient to patient, the group noted, "and thus strategies to reduce complications and improve outcomes in patients treated with peritoneal dialysis are limited."

However, the team discovered that peritoneal dialysate agent made a difference for these TT carriers.

Among a group of 144 patients who used both types of osmotic agents, TT carriers had reduced ultrafiltration when using glucose dialysate but not when the colloid icodextrin was used. Mouse model experiments confirmed the difference.

"In contrast to glucose-driven crystalloid osmosis, water flow generated by icodextrin is independent of aquaporins," Morelle's group noted.

While these findings need to be confirmed, "it opens up a really interesting new avenue into thinking about individualization of dialysis treatment," commented Steven Fishbane, MD, of the Feinstein Institutes for Medical Research in Manhasset, New York, who was not involved with the study.

Having a prospective predictor of how well someone might respond to peritoneal dialysis to weigh in the decision between dialysis modalities would be "really exciting," he told MedPage Today. But he argued that this single factor shouldn't become something that rules out peritoneal dialysis. "It's not going to be an absolute go/no-go, yes/no but rather tipping the scales a little bit one way or another."

Instead, it could be a driver for more aggressive management of strategies to prevent ultrafiltration failure and transition to hemodialysis, suggested Mala Sachdeva, MD, medical director of the Northwell Health home dialysis program in Great Neck, New York, and also not involved with the study. That might mean getting more diuretics on board and adjusting other medications, closer monitoring of salt and water intake, and even seeking transplantation sooner, she said in an interview.

"From a practical perspective, testing for TT, CT, and CC genotypes would be easy to do with the construction of specific primers to amplify the upstream sequence of AQP1," noted Daniel G. Bichet, MD, of the Université de Montréal, in an editorial accompanying the paper. "From a wider perspective, mapping of the genetic architecture of human traits could lead to personalized kidney therapies."

Genetic testing is being done for other reasons in selected kidney disease patients, like looking for the risk-associated APOL1 variants, but it would likely face cost and insurance barriers, noted Sachdeva.

"What they'll try to do is to turn this into an assay that would be clinically usable without being overly costly," predicted Fishbane.

Morelle and co-authors studied 1,851 peritoneal dialysis patients who had DNA samples and outcomes available in seven cohorts from Belgium, the Netherlands, Spain, the United Kingdom, and China. Of this group, 38% were women, 23% were of Asian descent, and 75% of European descent, and mean age was 54 years.

Genotyping on a group of 433 of these patients with baseline glucose-based peritoneal equilibration tests available turned up the functional AQP1 variant rs2075574 as the only significant association with measures of water transport.

TT carriers of that variant had a lower mean net ultrafiltration level than the 35% to 47% carrying the CC genotype, both in the discovery phase (506 vs 626 ml, P=0.007) and in the subsequent validation phase among 985 patients from three cohorts in the U.K. and China (368 vs 563 ml, P=0.003).

Compared with CC carriers, TT carriers also had both a higher risk of the composite of death or peritoneal dialysis failure (adjusted HR 1.70, 95% CI 1.24-2.33) and greater likelihood of death from any cause (24% vs 15%, P=0.03).

Other studies have also showed increased mortality with similarly reduced baseline ultrafiltration levels in peritoneal dialysis, Morelle's group pointed out. "Furthermore, in patients who are anuric or oliguric and rely on peritoneal ultrafiltration to attain fluid balance, such differences may be critical with regard to whether the patient can maintain adequate nutrition."

Prevalence of TT carriers was similar across the cohorts, with findings independent of race, peritoneal dialysis practices, and changes in solute transport. In the subgroup of patients undergoing maintenance dialysis, the findings were also independent of the duration of dialysis.

Study limitations, the researchers said, included the retrospective design, meaning they were unable to determine causality, and lack of evaluation of volume status.

Further studies should also test whether adaptation of prescriptions for peritoneal dialysis can mitigate the risk of carrying the AQP1 variant, Morelle and co-authors suggested.

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