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



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


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


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.


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.


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





Published Version (Please cite this version)


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.

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Clarissa Jonas Diamantidis

Adjunct Associate Professor of Medicine

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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