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

Methods: We conducted an ancillary study 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 2014-2015. In this study, we used linear mixed models to assess associations of 10 urine TCA cycle OAs with estimated glomerular filtration rate (eGFR) and eGFR decline. TCA cycle OAs were measured in 24h urine samples by targeted MS and modeled as: (1) the average of z-scores for each OAs; and (2) factor scores derived by principal component analysis (PCA). We extended follow-up for eGFR to mid-2019 using electronic health records.

Results: Among 132 participants (50% men; 58% Black; mean age 64 years [SD 9]; median eGFR 72 ml/min/1.73m2 [IQR 59-89] and urine albumin-to-creatinine [UACR] 25 mg/g [IQR 9-81]), PCA identified 3 OA metabolite factors (F). Fumarate, malate, α-ketoglutarate, citrate, lactate, and pyruvate loaded positively on F1; succinate, pyruvate, and lactate loaded negatively on F2; and methylsuccinate, ethylmalonate, and methylmalonate loaded positively on F3. Over a median follow-up of 1 year [IQR 1.3], higher average OA z score, F1, and F3 were each strongly associated with higher baseline eGFR after adjustment for age, sex, race, and log(UACR) at baseline (all p<0.01). Higher F2, but not other scores, was associated with faster eGFR decline (p=0.05).

Conclusion: Lower urine TCA cycle OAs, most notably a factor comprising lower succinate, pyruvate and lactate, are potential biomarkers for faster DKD progression.


J. Lunyera: None. M. Nguyen: None. C.J. Diamantidis: None. H.B. Bosworth: Board Member; Self; Preventric Diagnostic. Consultant; Self; Abbott, Medicines Company, Novartis Pharmaceuticals Corporation. Research Support; Self; improved patient outcomes, Novo Nordisk Foundation, Otsuka Pharmaceutical Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pharma foundation, Proteus Digital Health, Proteus Digital Health, Sanofi. U.D. Patel: Board Member; Self; Goldfinch Bio. Employee; Self; Gilead Sciences, Inc. C.A. Davenport: None. J.R. Bain: None. M. Muehlbauer: None. O. Ilkayeva: None. S.H. Shah: Research Support; Self; AstraZeneca, Verily Life Sciences LLC. J. Scialla: Advisory Panel; Self; Tricida. Other Relationship; Self; GlaxoSmithKline plc., Sanofi.


National Institute of Diabetes and Digestive and Kidney Diseases (DK076169)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at