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 uremic metabolites associated with impairment in executive function in two cohorts of patients receiving maintenance 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 function with the Trail Making Test Part B and the Digit 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 false-detection rate significance 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 SD increase in 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline, respectively. The association between 4-hydroxyphenylacetate and impaired executive function was replicated in the second cohort (relative risk 1.12; 95% CI, 1.02 to 1.23), whereas the associations for phenylacetylglutamine, hippurate, and prolyl-hydroxyproline did 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.

Keywords: ESRD; cognitive function; dialysis; metabolism.

Figure 1.

Distribution of (A) 4-hydroxyphenylacetate, (B) phenylacetylglutamine, (C) hippurate, and (D) prolyl-hydroxyproline among subjects with (red) and without (black) impaired executive function in the discovery cohort. The beeswarm plots illustrate significantly higher metabolite levels among subjects with versus without impaired executive function.

Figure 2.

Adjusted RR of impaired executive function for subjects with one, two, and three or more elevated metabolites, compared with subjects with no elevated metabolites. The figure illustrates a significantly higher risk for impaired executive function among subjects with two or more elevated metabolites. An elevated metabolite is defined as the highest tertile for each metabolite: 4-hydroxyphenylacetate, phenylacetylglutamine, hippurate, and prolyl-hydroxyproline.