Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease.

Abstract

Introduction

Urine tricarboxylic acid (TCA) cycle organic anions (OAs) are elevated in diabetes and may be biomarkers for diabetic kidney disease (DKD) progression.

Objectives

We assessed associations of 10 urine TCA cycle OAs with estimated glomerular filtration rate (eGFR) and eGFR slope.

Methods

This study is ancillary to the Simultaneous Risk Factor Control Using Telehealth to SlOw Progression of Diabetic Kidney Disease (STOP-DKD) Trial-a randomized trial of pharmacist-led medication and behavior management in 281 patients with early to moderate DKD at Duke from 2014 to 2015. We used linear mixed models to assess associations of urine TCA cycle OAs with outcomes and modelled TCA cycle OAs as: (1) the average of z-scores for each OA; and (2) principal component (PC) scores derived by principal component analysis (PCA). Untargeted urine metabolomics were added for additional discovery.

Results

Among 132 participants with 24 h urine samples (50% men; 58% Black; mean age 64 years [SD 9]; mean eGFR 74 ml/min/1.73m2 [SD 21] and median urine albumin-to-creatinine [UACR] 20 mg/g [IQR 8-95]), PCA identified 3 OA metabolite PCs. Malate, fumarate, pyruvate, α-ketoglutarate, lactate, succinate and citrate/isocitrate loaded positively on PC1; methylsuccinate, ethylmalonate and succinate loaded positively on PC2; and methylmalonate, ethylmalonate and citrate/isocitrate loaded negatively on PC3. Over a median follow-up of 1.8 years (IQR, 1.2 to 2.2), higher average OA z-score was strongly associated with higher eGFR after covariate adjustment (p = 0.01), but not with eGFR slope (p = 0.9). Higher PC3, but not other PCs, was associated with lower eGFR (p < 0.001). Conditional random forests and smooth clipped absolute deviation models confirmed methylmalonate, citrate/isocitrate, and ethylmalonate, and added lactate as top ranked metabolites in models of baseline eGFR (R-squared 0.32 and 0.33, respectively). Untargeted urine metabolites confirmed association of urine TCA cycle OAs with kidney function.

Conclusion

Thus, lower urine TCA cycle OAs, most notably lower methylmalonate, ethylmalonate and citrate/isocitrate, are potential indicators of kidney impairment in early stage DKD.

Department

Description

Provenance

Citation

Published Version (Please cite this version)

10.1007/s11306-021-01858-4

Publication Info

Lunyera, Joseph, Clarissa J Diamantidis, Hayden B Bosworth, Uptal D Patel, James Bain, Michael J Muehlbauer, Olga Ilkayeva, Maggie Nguyen, et al. (2021). Urine tricarboxylic acid cycle signatures of early-stage diabetic kidney disease. Metabolomics : Official journal of the Metabolomic Society, 18(1). p. 5. 10.1007/s11306-021-01858-4 Retrieved from https://hdl.handle.net/10161/29630.

This is constructed from limited available data and may be imprecise. To cite this article, please review & use the official citation provided by the journal.

Scholars@Duke

Diamantidis

Clarissa Jonas Diamantidis

Adjunct Associate Professor of Medicine
Patel

Uptal Dinesh Patel

Adjunct Professor in the Department of Medicine

Uptal Patel, MD is an Adjunct Professor interested in population health with a broad range of clinical and research experience. As an adult and pediatric nephrologist with training in health services and epidemiology, his work seeks to improve population health for patients with  kidney diseases through improvements in prevention, diagnosis and treatment.

Prior efforts focused on four inter-related areas that are essential to improving kidney health: i) reducing the progression of chronic kidney disease by improving its detection and management, particularly by leveraging technology to facilitate engagement and self-management; ii) elucidating the inter-relationships between kidney disease and cardiovascular disease, which together amplify the risk of death; iii) improving the evidence in nephrology through comparative effectiveness research, including clinical trials, observational studies, and meta-analyses; and iv) promoting more optimal clinical health policy for all patients with kidney disease. These inter-disciplinary projects have been funded by a variety of public and private sources including the Robert Wood Johnson Foundation, Veterans Affairs, National Institutes of Health, Agency for Healthcare Research & Quality, Food and Drug Administration, Centers for Medicare & Medicaid Services, Renal Physicians Association, and the American Society of Nephrology. 

Current efforts seek to advance novel therapies for kidney diseases through early clinical development that he leads at AstraZeneca.

Bain

James R. Bain

Professor in Medicine
Ilkayeva

Olga Ilkayeva

Assistant Professor in Medicine

Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.

Shah

Svati Hasmukh Shah

Ursula Geller Distinguished Professor of Research in Cardiovascular Diseases
Scialla

Julia Jarrard Scialla

Adjunct Associate Professor in the Department of Medicine

Dr. Scialla is an Associate Professor of Medicine in Nephrology at Duke University and a faculty member at the Duke Clinical Research Institute.  Dr. Scialla trained in Internal Medicine, Nephrology, and Clinical Epidemiology at the Johns Hopkins University School of Medicine and the Johns Hopkins Bloomberg School of Public Health.  Her research focuses on chronic kidney disease (CKD) epidemiology and prevention, with an emphasis on the role of metabolic complications and nutrition. Current studies are focused on treatment and prevention of abnormal phosphate homeostasis, acid-base physiology, diabetic and other forms of kidney disease, and outcomes in end-stage kidney disease. 

Dr. Scialla’s work engages a number of study designs including prospective cohort studies, observational comparative effectiveness studies, and patient-oriented physiologic studies. She has worked closely with multiple chronic disease cohorts including the Chronic Renal Insufficiency Cohort (CRIC) Study, the African American Study of Kidney Disease and Hypertension (AASK), the Jackson Heart Study (JHS), and secondary analyses in clinical trials. Studies in electronic health records (EHR) and registries have engaged dialysis EHR data, the United States Renal Data System, and public registries, such as the National Health and Nutrition Examination Survey. Physiologic studies include the Acid Base Complication in CKD Study, secondary analyses in the DASH Mechanism Study, and the newly launched MURDOCK Kidney Health Study.


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