title: 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.
authors.affiliation: Geriatric Research and Education Clinical Center, Palo Alto Veterans Administration Health Care System, Palo Alto, California; mktamura@stanford.edu.|Division of Nephrology, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Manjula
authors.initials: M
authors.lastname: Kurella Tamura
authors.affiliation: Division of Nephrology, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Chertow
authors.affiliation: Division of Nephrology, University of California Davis School of Medicine, Davis, California.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Depner
authors.affiliation: David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California; and.
authors.forename: Allen R
authors.initials: AR
authors.lastname: Nissenson
authors.affiliation: Division of Nephrology, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schiller
authors.affiliation: Division of Nephrology, University of California San Diego, San Diego, California.
authors.forename: Ravindra L
authors.initials: RL
authors.lastname: Mehta
authors.affiliation: Division of Nephrology, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Sai
authors.initials: S
authors.lastname: Liu
authors.affiliation: Geriatric Research and Education Clinical Center, Palo Alto Veterans Administration Health Care System, Palo Alto, California.|Division of Nephrology, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Tammy L
authors.initials: TL
authors.lastname: Sirich
mesh_terms: D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism*; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic / Q000150:complications / Q000378:metabolism* / Q000628:therapy*; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D006435:Renal Dialysis
keywords: ESRD; cognitive function; dialysis; metabolism