Urine Tricarboxylic Acid Cycle Metabolites and Risk of End-stage Kidney Disease in Patients With Type 2 Diabetes

Context: Metabolites in the tricarboxylic acid (TCA) pathway have pleiotropic functions. Objective: To study the association between urine TCA cycle metabolites and the risk for chronic kidney disease progression in individuals with type 2 diabetes. Design, setting and participants: A prospective study in a discovery (n = 1826) and a validation (n = 1235) cohort of people with type 2 diabetes in a regional hospital and a primary care facility Exposure and Outcome: Urine lactate, pyruvate, citrate, alpha-ketoglutarate, succinate, fumarate, and malate were measured by mass spectrometry. Chronic kidney disease progression was defined as a composite of sustained estimated glomerular filtration rate below 15 mL/ min/1.73 m², dialysis, renal death, or doubling of serum creatinine. Results: During a median of 9.2 (interquartile range 8.1-9.7) and 4.0 (3.2-5.1) years of follow-up, 213 and 107 renal events were identified. Cox regression suggested that urine lactate, fumarate, and malate were associated with an increased risk (adjusted hazard ratio, [95% CI] 1.63 [1.16-2.28], 1.82 [1.17-2.82], and 1.49 [1.05-2.11], per SD), whereas citrate was associated with a low risk (aHR 0.83 [0.72-0.96] per SD) for the renal outcome after adjustment for cardiorenal risk factors. These findings were reproducible in the validation cohort. Noteworthy, fumarate and citrate were independently associated with the renal outcome after additional adjustment for other metabolites. Conclusion: Urine fumarate and citrate predict the risk for progression to end-stage kidney disease independent of clinical risk factors and other urine metabolites. These 2 metabolites in TCA cycle pathway may play important roles in the pathophysiological network, underpinning progressive loss of kidney function in patients with type 2 diabetes.