Cardiovascular Autonomic Neuropathy and Uric Acid in Subjects with Type 1 Diabetes—Preventing Early Renal Loss (PERL) in Type 1 Diabetes Trial

Abstract

Elevated serum uric acid (SUA), an established risk factor for diabetic nephropathy (DN) may also be a risk factor for cardiovascular autonomic neuropathy (CAN). We evaluated the cross-sectional association between CAN and SUA levels in subjects with type 1 diabetes (T1D), mild to moderate chronic kidney disease (CKD) and a SUA ≥4.5 mg/dl enrolled in the ongoing PERL trial that is evaluating the effect of SUA lowering by allopurinol on kidney function decline, specifically iohexol plasma disappearance glomerular filtration rate (iGFR). Also measured are estimated GFR (eGFR) and albumin excretion rates (AER). Measures of baseline CAN included resting heart rate, standard deviation of normal RR interval (SDNN), and QTi (Bazzett formula) derived from resting ECG recordings (RR interval extracted from digital ECG images by ECGSCAN software). Four hundred ninety seven PERL participants had valid baseline CAN and renal function data (age 51 ± 11 years, 68% male, T1D duration 35 ± 12 years, HbA1c 8±1%). Subjects in the highest tertile of serum UA levels had worse measures of renal function (iGFR 60 ± 16 vs. 74 ± 60 ml/min/1.73 m2, eGFR 65.7 ± 18.1 vs. 82.7 ± 17.2 ml/min/1.73 m2, AER 370 ± 783 vs. 1181 ± 475 mcg/mg creatinine) compared to those in the lowest tertile. SDNN correlated negatively with SUA levels (r = -0.11, P = 0.0093). In a multiple linear regression model, lower SDNN was associated with higher SUA levels independent of age, gender, BMI, blood pressure, and HbA1c (β = -0.061, SE= 0.021, P = 0.0049), but this association was no longer significant when adjusted for iGFR (β = -0.0184, SE= 0.024, P = 0.46). In summary, elevated SUA was significantly associated with CAN in subjects with T1D independent of some traditional cardiovascular risk factors. This relationship operated, at least in part, through the inverse association of SUA levels with renal function. Disclosure M. Jaiswal: None. A. Doria: Research Support; Self; Sanofi-Aventis. M. Mauer: None. R. Pop-Busui: Research Support; Self; AstraZeneca.