Urinary Branched-Chain Amino Acid Excretion and Chronic Kidney Disease Progression in Patients With Type 2 Diabetes

Preclinical studies suggest that activating branched-chain amino acid (BCAA) catabolism may improve chronic kidney disease (CKD). In this prospective clinical study, we sought to examine the association between urinary BCAA excretion and risk of CKD progression in patients with type 2 diabetes. Baseline urinary BCAAs were measured by mass spectrometry in 1,868 outpatients with type 2 diabetes. The study outcome was a composite of end-stage kidney disease (estimated glomerular filtration rate <15 mL/min/1.73 m2, dialysis, or death resulting from renal causes) or doubling of serum creatinine. During a median of 7.2 years of follow-up, 203 renal events were identified. One SD increment in urinary valine, leucine, and isoleucine concentration was associated with 1.29-fold (95% CI 1.11–1.51), 1.31-fold (1.11–1.55) and 1.29-fold (1.09–1.53) increased risk, respectively, of the composite renal outcome after adjustment for clinical risk factors. Mediation analysis showed that urinary MCP-1 mediated 57%, 47%, and 58% of the effects of valine, leucine, and isoleucine on the renal outcome, respectively. High levels of urinary BCAAs were also independently associated with an increased risk of CKD progression in the Chronic Renal Insufficiency Cohort in the U.S. Our data suggest that dysregulation of BCAA metabolism in the kidneys may be involved in intrarenal inflammation and drive CKD progression.

Restoration of branched-chain amino acid (BCAA) catabolism improves kidney pathology in animal models, but clinical data on the relationship between urinary BCAA excretion and kidney outcomes are scarce. Are urinary BCAA levels associated with CKD progression independent of clinical risk factors in patients with type 2 diabetes? High levels of urinary BCAAs predicted an increased risk of renal events independent of cardiorenal risk factors, with urinary MCP-1 mediating over 50% of the association. Activating intrarenal BCAA catabolism may potentially improve kidney function in patients with diabetes.