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

Abstract

OBJECTIVE To evaluate the association of a multicomponent advanced glycation end product (AGE) 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 Action to Control Cardiovascular Risk in Diabetes (ACCORD) (n = 1,150) and 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 estimated glomerular filtration rate (eGFR) (30% RFL in 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 HbA1c and other risk factors in ACCORD, the AGE score was associated with reduction in eGFR (β-estimate −0.66 mL/min ⋅ 1.73m2 per year; P = 0.001), 30% RFL (hazard ratio 1.42 [95% CI 1.13–1.78]; P = 0.003), 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) (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.

The Role of Advanced Glycation End Products and Its Soluble Receptor in Kidney Diseases

“…Although glycated hemoglobin (HbA1c), an Amadori rearrangement product formed by hemoglobin binding to glucose in red blood cells, has been demonstrated to be a reliable prognostic marker in the general diabetic population, it may not be effective in diabetes patients with chronic renal impairment [ 82 ]. Table 3 gives an overview of human studies investigating the role of AGEs and sRAGE in DN [ 6 , 34 , 35 , 36 , 83 , 84 , 85 , 86 , 87 ].…”

“…Even in individuals with normal kidney function (eGFR > 90 mL/min 1.73 m 2 ), there was a link between a higher AGE score and a higher likelihood of poor renal outcomes. Because they are related with two separate renal outcomes, the deterioration of both proteinuria and creatinine clearance, plasma AGEs have a wide pathophysiologic relationship with acute kidney problems [ 6 ].…”

“…N 6 -carboxymethyl- l -lysine (CML), N 6 -carboxyethyl- l -lysine (CEL), S-carboxymethyl- l -cysteine (CMC), S-(1-carboxyethyl)- l -cysteine (CEC), methylglyoxal-derived hydroimidazolone (MG-H1), furosine, and pentosidine are the most routinely detected AGEs [ 1 , 4 , 5 ]. Intracellular proteolysis of AGE-modified proteins results in the formation of AGE-free adducts that are discharged into the circulation and can contribute to systemic consequences [ 6 ]. AGEs have a role in the detrimental legacy effect of long-term inadequate glycemic management on microvascular diabetic complications in people with diabetes mellitus (DM) [ 7 , 8 ].…”

“…Elevated circulating AGEs are caused by both increased production in disorders linked with high levels of inflammation and oxidative stress, as well as impaired renal clearance, as in chronic kidney disease (CKD) [ 32 ]. In line with the major involvement of the kidneys in the clearance of circulating AGE-free adducts, serum AGE levels are inversely related to the estimated glomerular filtration rate (eGFR) [ 6 , 33 , 34 , 35 , 36 ].…”

AKI-to-CKD transition is a potential mechanism for non-albuminuric diabetic kidney disease

“…It has been shown that renal function correlates more with the degree of tubulointerstitial injury than that of the glomerular lesions in patients with DKD 1 . A large body of evidence indicates that hyperglycemia and advanced glycation end products in diabetes contribute to tubular epithelial cell injury 17 – 19 . Proteinuria, caused by diabetic glomerulopathy, also contributes to tubular cell injury and fibrosis development 20 .…”