Metabolic profiling of impaired cognitive function in patients receiving dialysis

Abstract

Retention of uremic metabolites is a proposed cause of cognitive impairment in patients with ESRD. We used metabolic profiling to identify and validate uremicmetabolites associated with impairment in executive function in two cohorts of patients receivingmaintenance dialysis.We performed metabolic profiling using liquid chromatography/mass spectrometry applied to predialysis plasma samples from a discovery cohort of 141 patients and an independent replication cohort of 180 patients participating in a trial of frequent hemodialysis.We assessed executive functionwith the TrailMaking Test Part B and theDigit Symbol Substitution test. Impaired executive function was defined as a score $2 SDs below normative values. Four metabolites-4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline-were associated with impaired executive function at the falsedetectionratesignificance threshold.After adjustment for demographic and clinical characteristics, the associations remained statistically significant: relative risk 1.16 (95%confidence interval [95%CI], 1.03 to 1.32), 1.39 (95%CI, 1.13 to 1.71), 1.24 (95%CI, 1.03 to 1.50), and 1.20 (95%CI, 1.05 to 1.38) for each SDincrease in 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline, respectively. The association between 4-hydroxyphenylacetateand impaired executive functionwas replicated in the second cohort (relative risk1.12; 95% CI, 1.02 to1.23),whereas the associations for phenylacetylglutamine, hippurate, andprolyl-hydroxyprolinedid not reach statistical significance in this cohort. In summary, four metabolites related to phenylalanine, benzoate, and glutamate metabolism may be markers of cognitive impairment in patients receiving maintenance dialysis.