GFR decline predicts total mortality and mediates the effect of tryptophan metabolism on death risk in type 2 diabetes

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Context The independent role of glomerular filtration rate (GFR) decline in shaping the risk of mortality in people with type 2 diabetes has only been partially addressed. Objective The objective of the study was 2-fold: (1) to investigate the association between all-cause mortality and eGFR changes over time; (2) to understand whether renal dysfunction mediates the effect of tryptophan metabolism on death risk. Methods Prospective study with an average follow-up of 14.8 years at a research hospital. The aggregate Gargano Mortality Study included 962 patients with type 2 diabetes who had at least 3 eGFR recordings and at least 1.5 years of follow-up. This was an observational study, with no interventions. Rate of all-cause mortality was measured. Results Age- and sex-adjusted annual incident rate of mortality was 2.75 events per 100 person-years. The median annual rate of decline of eGFR was 1.3 mL/min per 1.73 m2 per year (range −3.7; 7.8). The decline of kidney function was strongly and independently associated with the risk of death. Serum kynurenine to tryptophan ratio (KTR) was associated with both eGFR decline and all-cause mortality. Causal mediation analysis showed that 24.3% of the association between KTR and mortality was mediated by eGFR decline. Conclusion In patients with type 2 diabetes, eGFR decline is independently associated with the risk of all-cause mortality and mediates a significant proportion of the association between tryptophan metabolism and death.