Elevated lipoxygenase and cytochrome P450 products predict progression of chronic kidney disease
Year: 2018
Type: article
Abstract: BACKGROUND: The clinical relevance of arachidonic acid (AA) metabolites in chronic kidney disease (CKD) progression is poorly understood. We aimed to compare the concentrations of 85 enzymatic pathway products of AA metabolism in patients with CKD who progressed to end-stage kidney disease (ESKD) versus patients who did not in a subcohort of Chronic Renal Insufficiency Cohort (CRIC) and to estimate the risk of CKD progression and major cardiovascular events by levels of AA metabolites and their link to enzymatic metabolic pathways. METHODS: A total 123 patients in the CRIC study who progressed to ESKD were frequency matched with 177 nonprogressors and serum eicosanoids were quantified by mass spectrometry. We applied serum collected at patients' Year 1 visit and outcome of progression to ESKD was ascertained over the next 10 years. We used logistic regression models for risk estimation. RESULTS: Baseline 15-hydroxyeicosatetraenoate (HETE) and 20-HETE levels were significantly elevated in progressors (false discovery rate Q ≤ 0.026). The median 20-HETE level was 7.6 pmol/mL [interquartile range (IQR) 4.2-14.5] in progressors and 5.4 pmol/mL (IQR 2.8-9.4) in nonprogressors (P < 0.001). In an adjusted model, only 20-HETE independently predicted CKD progression. Each 1 standard deviation increase in 20-HETE was independently associated with 1.45-fold higher odds of progression (95% confidence interval 1.07-1.95; P = 0.017). Principal components of lipoxygenase (LOX) and cytochrome P450 (CYP450) pathways were independently associated with CKD progression. CONCLUSIONS: We found higher odds of CKD progression associated with higher 20-HETE, LOX and CYP450 metabolic pathways. These alterations precede CKD progression and may serve as targets for interventions aimed at halting progression.
DOI: 10.1093/ndt/gfy232
Authors: Farsad Afshinnia, Lixia Zeng, Jaeman Byun, Stefanie Wernisch, Rajat Deo, Jing Chen, Lee Hamm, Edgar R Miller, Eugene P Rhee, Michael J Fischer, Kumar Sharma, Harold I Feldman, George Michailidis, Subramaniam Pennathur, the CRIC Study Investigators, Lawrence J Appel, Alan S Go, Jiang He, John W Kusek, James P Lash, Panduranga S Rao, Mahboob Rahman, Raymond R Townsend
Language: English
Subfield: Biochemistry
Domain: Life Sciences
Open Access status: green
Funders: University of Pennsylvania, University of Michigan, Tulane University, Johns Hopkins University, University of Illinois System, National Institutes of Health, University of Illinois at Urbana-Champaign, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Advancing Translational Sciences
Awards: G1251546689, Clinical and Translational Science Institute, Integrated Systems Biology Approach to Diabetic Microvascular Complications, Hispanic Chronic Renal Insufficiency Cohort(CRIC) Study, Continuation of the Chronic Renal Insufficiency Cohort (CRIC) Study, Michigan Regional Comprehensive Metabolomics Resource Core (MRC2), GENERAL CLINICAL RESEARCH CENTER, General Clinical Research Center, University of Michigan O'Brien Kidney Translational Core Center, G4053391054, Center for Clinical and Translational Science, Michigan Institute for Clinical and Health Research (MCHR), Prognostic Biomarkers in Chronic Kidney Disease, Institute for Clinical and Translational Research, Institutional Clinical and Translational Science Award, Clinical and Translational Science Award, Clinical and Translational Science Collaborative of Cleveland, G8660623442, Clinical and Translational Science Collaborative of Cleveland, G9000097295, Michigan Diabetes Research Center (MDRC), Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases, A pilot trial of an intervention to support initial type 2 diabetes selfmanagement among younger adults with children., Prospective renal insufficiency cohort evaluation: PRICE, Chronic Renal Insufficiency Cohort (CRIC) Study Clinical Center, Michigan Nutrition Obesity Research Center, Continuation of the Chronic Renal Insufficiency Cohort (CRIC), Continuation of the University of Illinois Chicago CRIC Clinical Center, Louisiana Clinical and Translational Science Center, Limited Competition for the Continuation of the Chronic Renal Insufficiency Cohort (CRIC) Hopkins Clinical Center, Tulane Clinical Center for Chronic Renal Insufficiency Cohort Study, Chronic Renal Insufficiency Cohort Limited competition continuation, Chronic Renal Insufficiency Cohort (CRIC) Study, Spatial Multi-Omics to Profile Metabolic Pathways for Kidney Disease
OpenAlex ID: W2884885188