Urinary Metabolites in Tryptophan-Kynurenine Pathway and Risk of CKD Progression in Patients With Type 2 Diabetes.

RATIONALE &

OBJECTIVE

Tryptophan-kynurenine pathway is integral for energy metabolism and immune-inflammation regulation. We sought to study the associations between urinary metabolites in tryptophan-kynurenine pathway and risk of chronic kidney disease (CKD) progression in patients with type 2 diabetes.

STUDY

DESIGN

Prospective cohort study.

SETTING &

PARTICIPANTS

1,892 participants with type 2 diabetes from Southeast Asia were included in the primary analysis; 951 Chronic Renal Insufficiency Cohort (CRIC) participants with diabetes at baseline were included in the validation study.

EXPOSURES: Urinary tryptophan, kynurenine, 3-hydroxykynurenine, kynurenic acid, xanthurenic acid and kynurenine-to-tryptophan ratio (KTR).

OUTCOMES: CKD progression defined as a composite of incident end stage kidney disease (sustained eGFR < 15 ml/min/1.73m2, maintenance dialysis, renal death) or doubling of serum creatinine concentration.

ANALYTICAL APPROACH: Cause-specific hazard regression.

RESULTS

A total of 224 CKD progression events were identified over a median follow-up of 7.2 years. Each one SD increase in the concentration of urinary kynurenine, 3-hydroxykynurenine, kynurenic acid, and KTR was associated with 1.60 [95% CI 1.16-2.22], 1.64 [1.17-2.31], 1.47 [1.10-1.97] and 1.97 [1.43-2.71] fold higher risk of CKD progression, respectively, after adjustment for known clinical risk factors. These associations were more pronounced in participants with prevalent CKD (eGFR <60 ml/min/1.73m2) compared to those with preserved eGFR. Each one SD increase in urinary tryptophan and kynurenine concentrations was independently associated with 1.60 [1.24-2.06] and 1.35 [1.05-1.73] fold higher risk of CKD progression, respectively, in CRIC participants with diabetes.

LIMITATIONS: Observational study with unmeasured confounding.

CONCLUSIONS

Higher concentrations of urinary metabolites in the tryptophan-kynurenine pathway were associated with higher risk of CKD progression in patients with type 2 diabetes. Future studies are warranted to elucidate the biological mechanisms linking the tryptophan-kynurenine pathway and progression of kidney disease.