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

Metabolites in the tricarboxylic acid (TCA) cycle are not only involved in energy metabolism but also play important roles in non-energy production activities. To study whether baseline urine key TCA cycle metabolites (lactate, pyruvate, citrate, α-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). One discovery and one validation nested case-control studies in two independent T2DM cohorts. Subjects with T2DM were recruited and followed in a regional hospital and at a primary care facility. eGFR trajectory (slope) was estimated by linear regression. Progressive CKD was defined as eGFR decline of ≥5 mL/min/1.73 m2 per year. 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. 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.