Association of Prediabetes With CKD Progression and Adverse Cardiovascular Outcomes: An Analysis of the CRIC Study

Abstract

Purpose: Despite our understanding of diabetes as an established risk factor for progressive kidney disease and cardiac complications, the prognostic significance of prediabetes in patients with chronic kidney disease (CKD) remains largely unknown.

Methods: Participants of the Chronic Renal Insufficiency Cohort (CRIC) were categorized as having normoglycemia, prediabetes, or diabetes according to fasting plasma glucose, glycated hemoglobin A1c (HbA1c), and treatment with antidiabetic drugs at baseline. Unadjusted and adjusted proportional hazards models were fit to estimate the association of prediabetes and diabetes (versus normoglycemia) with: (1) composite renal outcome (end-stage renal disease, 50% decline in estimated glomerular filtration rate to ≤ 15 mL/min/1.73 m2, or doubling of urine protein-to-creatinine ratio to ≥ 0.22 g/g creatinine); (2) composite cardiovascular (CV) outcome (congestive heart failure, myocardial infarction or stroke); and (3) all-cause mortality.

Results: Of the 3701 individuals analyzed, 945 were normoglycemic, 847 had prediabetes and 1909 had diabetes. The median follow-up was 7.5 years. Prediabetes was not associated with the composite renal outcome (adjusted hazard ratio [aHR] 1.13; 95% confidence interval [CI], 0.96-1.32; P = 0.14), but was associated with proteinuria progression (aHR 1.23; 95% CI, 1.03-1.47; P = 0.02). Prediabetes was associated with a higher risk of the composite CV outcome (aHR 1.38; 95% CI, 1.05-1.82; P = 0.02) and a trend towards all-cause mortality (aHR 1.28; 95% CI, 0.99-1.66; P = 0.07). Participants with diabetes had an increased risk of the composite renal outcome, the composite CV outcome, and all-cause mortality.

Conclusions: In individuals with CKD, prediabetes was not associated with composite renal outcome, but was associated with an increased risk of proteinuria progression and adverse CV outcomes.

Keywords: all-cause mortality; cardiovascular outcomes; chronic kidney disease; diabetes; prediabetes; renal outcomes.

Figure 1.

Kaplan-Meier curves for composite renal outcome (A), composite CV outcome (B), and all-cause mortality (C) in participants with normoglycemia, prediabetes, or diabetes. Composite renal outcome: development of ESRD (renal transplantation or dialysis initiation), a 50% decline in baseline eGFR (CKD-EPI equation) to ≤ 15 mL/min/1.73 m², or doubling of urine protein to creatinine ratio to ≥ 0.22 g/g creatinine. Composite CV outcome: CHF, MI, or stroke. P values were calculated with the use of log-rank tests. Abbreviations: CHF, congestive heart failure; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MI, myocardial infarction.

Figure 2.

Composite renal outcome and composite CV outcome or all-cause mortality according to baseline fasting plasma glucose and HbA1c levels. Composite renal outcome: development of ESRD (renal transplantation or dialysis initiation), a 50% decline in baseline eGFR (CKD-EPI equation) to ≤ 15 mL/min/1.73 m², or doubling of urine protein to creatinine ratio to ≥ 0.22 g/g creatinine. Composite CV outcome: CHF, MI, or stroke. Model 2: age, sex, race/ethnicity, body mass index, antiplatelet therapy, lipid lowering therapy, systolic blood pressure at baseline, coronary artery disease (defined as prior MI or prior coronary revascularization), peripheral vascular disease, congestive heart failure, hematocrit, baseline eGFR, serum albumin and 24-hour urine protein. Dashed lines indicate the upper and lower 95% CI for the regression line (solid black line). Vertical dashed lines indicate the cutoffs for transition from normoglycemia to prediabetes range and to diabetes range. Prediabetes range is shaded in gray. Abbreviations: CHF, congestive heart failure; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; MI, myocardial infarction.