Genetic Variation and Ultrafiltration with Peritoneal Dialysis

Key Points There is a large person-to-person variability in ultrafiltration with peritoneal dialysis at the time of starting treatment. In this international cohort study, heritability of peritoneal ultrafiltration with peritoneal dialysis was estimated at 50%. In genome-wide association study, two single-nucleotide variants reached genome-wide significance—rs72631501 in CRK intron with European ancestry and rs1416265, intergenic, with South Asian ancestry. Background There is a large person-to-person variability in ultrafiltration volume with peritoneal dialysis (PD), most of which cannot be accounted for by demographic and clinical differences. In this article, we tested the hypothesis that common genetic variants are associated with peritoneal ultrafiltration and explored one mechanistic pathway identified by genetic studies. Methods We generated estimates of heritability and undertook genome-wide and gene-wise association studies, adjusted for peritoneal solute transfer rate, to test associations of genetic variation with ultrafiltration on peritoneal equilibration test conducted at PD initiation in 2723 participants in the international Biological Determinants of PD (Bio-PD) study. We used a mouse model of PD to study the mechanistic basis for the association of PTGES gene with peritoneal ultrafiltration. Results The peritoneal equilibration test was conducted at a median of 61 (interquartile range, 38–118) days from PD start with a median 4-hour ultrafiltration volume of 250 (interquartile range, 25–465) ml. The heritability of peritoneal ultrafiltration was estimated to be 50% ( P = 0.001). In single-nucleotide variant–wise multiancestry genome-wide association study using TRACTOR software, one single-nucleotide variant reached genome-wide significance in participants with European local ancestry (rs72631501, CRK intron, P = 2.6×10 −8 ) and one in participants with South Asian local ancestry (rs1416265, intergenic, P = 4.2×10 −8 ). Gene-wise analyses showed significant association of 21 genes at false discovery rates (FDRs) <0.10 in the European strata, notably PTGES (FDR=0.053), SLC24A3 (FDR=0.0003), and CRK (FDR=0.04). SLC24A3 remained significant (FDR=0.03) in meta-analysis of the four ancestry strata. Using single-cell RNA sequencing, PTGES localized in peritoneal adipocytes. In a mouse PD model, pharmacologic modulation of prostaglandin E synthase altered dialysate PGE2 levels with changes in adipocyte volume, peritoneal small solute transfer rate, and ultrafiltration volume. Conclusions Common genetic variants accounted for a substantial proportion of the variability in peritoneal ultrafiltration with potential associations with 21 genes, including CRK , PTGES , and SLC24A3 . Functional studies substantiated a potential role for prostaglandin E synthase/prostaglandin E2 in regulating peritoneal ultrafiltration. Clinical Trial registry name and registration number: ClinicalTrials.gov, NCT02694068.