Poor glycemic control in diabetes and the risk of incident chronic kidney disease even in the absence of albuminuria and retinopathy: Atherosclerosis Risk in Communities (ARIC) Study

Abstract

Background: Diabetic nephropathy is the leading cause of kidney failure in the United States. The extent to which an elevated glycated hemoglobin (HbA(1c)) concentration is associated with increased risk of chronic kidney disease (CKD) in the absence of albuminuria and retinopathy, the hallmarks of diabetic nephropathy, is uncertain.

Methods: Glycated hemoglobin concentration was measured in 1871 adults with diabetes mellitus followed up for 11 years in the Atherosclerosis Risk in Communities (ARIC) Study. Incident CKD was defined as an estimated glomerular filtration rate less than 60 mL/min/1.73 m(2) after 6 years of follow-up or a kidney disease-related hospitalization. We categorized HbA(1c) concentrations into 4 clinically relevant categories. Albuminuria and retinopathy were measured midway through follow-up.

Results: Higher HbA(1c) concentrations were strongly associated with risk of CKD in models adjusted for demographic data, baseline glomerular filtration rate, and cardiovascular risk factors. Compared with HbA(1c) concentrations less than 6%, HbA(1c) concentrations of 6% to 7%, 7% to 8%, and greater than 8% were associated with adjusted relative hazard ratios (95% confidence intervals) of 1.4 (0.97-1.91), 2.5 (1.70-3.66), and 3.7 (2.76-4.90), respectively. Risk of CKD was higher in individuals with albuminuria and retinopathy, and the association between HbA(1c) concentration and incident CKD was observed even in participants without either abnormality: adjusted relative hazards, 1.46 (95% confidence intervals, 0.80-2.65), 1.17 (0.43-3.19), and 3.51 (1.67-7.40), respectively; P(trend) = .004.

Conclusions: We observed a positive association between HbA(1c) concentration and incident CKD that was strong, graded, independent of traditional risk factors, and present even in the absence of albuminuria and retinopathy. Hyperglycemia is an important indicator of risk of both diabetic nephropathy with albuminuria or retinopathy and of less specific forms of CKD.

Figure 1. Kaplan-Meier Survival Estimates for HbA1c by Category

Figure 2. Adjusted Incidence Rates (IR) of CKD by HbA1c

Incidence rates (and 95% confidence intervals (shaded area) of CKD by HbA1c concentration. The curve represents minimally adjusted incidence rates based on a Poisson regression model including a fourth-order polynomial for HbA1c, adjusted to the incidence rate for a 60 year old white male with a baseline eGFR of 90 mL/min/1.73 m². The histogram represents the frequency distribution of HbA1c in the study sample.

Figure 3. Adjusted Incidence Rates (IR) of CKD by HbA1c and Microvascular Complication Status

Incidence rates of CKD by HbA1c concentration stratified by albuminuria and retinopathy status. The curves represent minimally adjusted incidence rates based on Poisson regression models including a fourth-order polynomial for HbA1c, adjusted to the incidence rate for a 60 year old white male with a baseline eGFR of 90 mL/min/1.73 m² within each stratum. HbA1c values were capped at an upper limit equivalent to the stratum-specific 95^th percentile. The histogram represents the frequency distribution of HbA1c in the study sample.