Urine Tricarboxylic Acid Cycle Metabolites Predict Progressive Chronic Kidney Disease in Type 2 Diabetes

Context: Metabolites in the tricarboxylic acid (TCA) cycle are not only involved in energy metabolism but also play important roles in non-energy production activities. Objective: To study whether baseline urine key TCA cycle metabolites (lactate, pyruvate, citrate, alpha-ketoglutaric acid, succinate, fumarate, and malate) independently predict risk of chronic kidney disease (CKD) progression [fast estimated glomerular filtration rate (eGFR) decline] in individuals with type 2 diabetes mellitus (T2DM). Design: One discovery and one validation nested case-control studies in two independent T2DM cohorts. Setting and Participants: Subjects with T2DM were recruited and followed in a regional hospital and at a primary care facility. Main Outcome Measures: eGFR trajectory (slope) was estimated by linear regression. Progressive CKD was defined as eGFR decline of >= 5 mL/min/1.73 m(2) per year. Results: As compared with those with stable renal function (n = 271), participants who experienced progressive CKD (n = 116) had a lower level of urine citrate but significantly higher levels of lactate, fumarate, and malate levels at baseline. Both fumarate and malate predicted progressive CKD independent of traditional cardio-renal risk factors, including eGFR and albuminuria. Fumarate interacted with sex (P for interaction = 0.03) and independently predicted progressive CKD in male but not female participants. All these findings were reproducible in a validation study (case n = 96, control n = 402). Exploratory analysis suggested that fumarate might partially mediate the effect of oxidative stress on CKD progression. Conclusions: Key TCA cycle metabolites, especially fumarate, may be involved in the pathophysiologic pathway independent of traditional cardio-renal risk factors, leading to CKD progression in patients with T2DM.