Advanced Glycation End Products Predict Loss of Renal Function and High-Risk Chronic Kidney Disease in Type 2 Diabetes

Objective: To evaluate the association of a multicomponent advanced glycation endproducts (AGEs) panel with decline in kidney function and its utility in predicting renal function loss (RFL) when added to routine clinical measures in type 2 diabetes.

Research Design and Methods: Carboxymethyl and carboxyethyl lysine, and methylglyoxal, 3-deoxyglucosone and glyoxal hydroimidazolones were measured in baseline serum and plasma samples, respectively, from the Action to Control Cardiovascular Risk in Diabetes (ACCORD, n=1,150) and the Veterans Affairs Diabetes Trial (VADT, n=447) participants. A composite AGE-score was calculated from individual AGE z-scores. The primary outcome was a sustained 30% decline in eGFR (30% RFL, both cohorts). Secondary outcomes (in ACCORD) were 40% RFL, macroalbuminuria, and high-risk chronic kidney disease (hrCKD).

Results: After adjustment for baseline and follow-up HbA_1c and other risk factors in ACCORD, the AGE score was associated with reduction in eGFR (beta-estimate -0.66 ml/min∙1.73m² per year, p=0.001), a 30% RFL (hazard ratio 1.42 [95%CI: 1.13-1.78], p=0.003), a 40% RFL (1.40 [1.13-1.74], p=0.003), macroalbuminuria (1.53 [1.13-2.06], p=0.006), and hrCKD (1.88 [1.37-2.57), p<0.0001). AGE-score improved net-reclassification (NRI) and relative integrated discrimination (IDI) for 30% RFL (NRI 23%, p=0.02 and relative IDI 7%, p=0.009). In VADT, the AGE-score calculated by the ACCORD-derived coefficients was associated with 30% RFL (1.37 [1.03-1.82), p=0.03) and improved NRI (24%, p=0.03) but not IDI (p=0.18).

Conclusions: These data provide further support for a causal role of AGEs in diabetic nephropathy independently of glycemic control and suggest utility of the composite AGE panel in predicting long-term decline in renal function.