Predictive Capabilities of Urine Metabolites on Progressive Chronic Kidney Disease in T2D

human kidneys
human kidneys
Investigators examine whether urine metabolites in the tricarboxylic acid cycle can independently predict the risk for CKD progression in individuals with type 2 diabetes.

The pathophysiological pathway leading to progressive chronic kidney disease (CKD) might include the urine tricarboxylic acid cycle metabolite fumarate, according to a study published in The Journal of Clinical Endocrinology and Metabolism.

Researchers of this study analyzed urine tricarboxylic acid cycle metabolites of patients with type 2 diabetes. There were 2 cohorts: one with progressive CKD and one with stable renal function. A decline in estimated glomerular filtration rate of 5 ml/min/1.73m2 or greater over the course of a year was categorized as progressive CKD, and a decline of 2 ml/min/1.73m2 or less was categorized as stable kidney function.

There were 2 independent nested case-controlled phases of this study: the discovery phase (N=387) and the validation phase (N=498). The primary goal of the discovery phase was to evaluate whether certain tricarboxylic acid cycle metabolites could be used to predict progressive CKD. The primary goal of the validation phase was to use estimated glomerular filtration rate to predict kidney function. In both phases, urine tricarboxylic acid cycle metabolites were analyzed by gas chromatography mass spectrometry.

Analysis indicated that urine citrate (P =.001) was significantly lower and lactate (P =.00026), fumarate (P= .000034), and malate (P= .000029) were significantly higher in the progressive chronic kidney disease cohort. Urine fumarate and malate were significantly associated and independently able to predict progressive CKD. When assessing sex differences, fumarate was associated with progressive CKD in both the discovery phase (P =.02) and validation phase (P =.09), while malate was only associated in the discovery phase (P =.03). Fumarate levels at baseline could independently predict progressive chronic kidney disease in men after controlling for covariates (P <.001).

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Future studies need to analyze the specific mechanism between fumarate and progressive CKD and the role of physical activity, cardiovascular diseases, and medications.

Researchers conclude that tricarboxylic acid cycle metabolite differences exist between patients with progressive CKD and stable kidney function, with fumarate and malate having predictive associations. Fumarate has a high predictive association in men.

This study was supported by Singapore National Medical Research Council Center Grant and Khoo Teck Puat hospital STAR Grant.


Liu JJ, Liu S, Gurung RL, et al. Urine tricarboxylic acid (TCA) cycle metabolites predict progressive chronic kidney disease in type 2 diabetes [published online July 27, 2018]. J Clin Endocrinol Metab. doi: 10.1210/jc.2018-00947