Urine TCA-Cycle Organic Anions in Diabetic Kidney Disease
Kidney disease occurs in ~25% of patients with diabetes with few strategies to slow progression. Prior work suggests that lower metabolic production of fixed acids in the form of organic anions (OAs) may be a modifiable risk factor for progression of diabetic kidney disease (DKD) and a novel target for secondary prevention. OAs are net produced when the conjugate base of an endogenously produced organic acid is lost from the body in the urine, such as loss of lactate, ketones, and intermediates from the tricarboxylic acid (TCA) cycle. We hypothesize that increased urinary losses of OAs drive favorable changes in kidney energetics in an effort to restore intermediates of the TCA cycle. Specifically, higher OA production will stimulate fatty acid oxidation and branched-chain amino acid (BCAA) metabolism, and inhibit unfavorable pathways that “off-load” excess intermediates, such as gluconeogenesis. The rate at which the kidney reabsorbs and metabolizes OAs is regulated by acid-base status; thus, these changes could be reversed by simple alkali interventions and lead to new treatment strategies for DKD prevention. In this study, we will use samples and data from the prospective Simultaneous Risk Factor Control Using Telehealth to Slow Progression of DKD (STOP-DKD) Study to: (1) characterize OA production in patients with DKD using targeted gas chromatography/mass spectrometry (GC/MS) of 24 hour urine collections to measure TCA-cycle related OAs and selected OAs in plasma (i.e., lactate and ketones); (2) define associations of OA production with dysregulated systemic lipid, glucose, and BCAA metabolism, and (3) generate preliminary evidence of an association of OA production and DKD progression over 12 month follow up. This pilot study will lay the foundation for larger, fully-powered studies evaluating urine TCA cycle-related OAs as modifiable risk factors for DKD progression in the next phase of this research.

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