Association of Urinary N-Acetyl--D-Glucosaminidase with Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Mellitus without Nephropathy

Background: Cardiovascular autonomic neuropathy (CAN) is a common microvascular complication of diabetes and related to albuminuria in diabetic nephropathy (DN). Urinary N-acetyl-beta-D-glucosaminidase (uNAG) is a renal tubular injury marker which has been reported as an early marker of DN even in patients with normoalbuminuria. This study evaluated whether uNAG is associated with the presence and severity of CAN in patients with type 1 diabetes mellitus (T1DM) without nephropathy. Methods: This cross-sectional study comprised 247 subjects with T1DM without chronic kidney disease and albuminuria who had results for both uNAG and autonomic function tests within 3 months. The presence of CAN was assessed by age-dependent reference values for four autonomic function tests. Total CAN score was assessed as the sum of the partial points of five cardiovascular reflex tests and was used to estimate the severity of CAN. The correlations between uNAG and heart rate variability (HRV) parameters were analyzed. Results: The association between log-uNAG and presence of CAN was significant in a multivariate logistic regression model (adjusted odds ratio, 2.39; 95% confidence interval [CI], 1.08 to 5.28; P=0.031). Total CAN score was positively associated with logu-NAG (beta=0.261, P=0.026) in the multivariate linear regression model. Log-uNAG was inversely correlated with frequency-domain and time-domain indices of HRV. Conclusion: This study verified the association of uNAG with presence and severity of CAN and changes in HRV in T1DM patients without nephropathy. The potential role of uNAG should be further assessed for high-risk patients for CAN in T1DM patients without nephropathy.