Cardiac Autonomic Neuropathy and Early Progressive Renal Decline in Patients with Nonmacroalbuminuric Type 1 Diabetes

Abstract

Background and objectives Cardiac autonomic neuropathy predicts future adverse renal outcomes in the general population. This study sought to determine its relationship with early progressive renal decline in type 1 diabetes.Design, setting, participants, & measurements A subset of participants with normoalbuminuria (n=204) or microalbuminuria (n=166) from the First Joslin Kidney Study underwent assessment for cardiac autonomic neuropathy using heart rate variability during baseline visits performed from January 1991 to April 1992. Cardiac autonomic neuropathy was defined as an R-R variation (mean circular resultant) ,20. Participants also had baseline and follow-up measurement of eGFR. Early progressive renal decline was evaluated according to two definitions: early GFR loss (slope of eGFR estimated by cystatin C ,23.3%/year) and incident advanced CKD (stage $3, defined by eGFR [calculated by Modification of Diet in Renal Disease method] ,60 ml/min per 1.73 m 2 ). Association with baseline cardiac autonomic neuropathy was assessed by adjusted logistic regression and Cox proportional hazards.Results Among the 370 participants, 47 (13%) had baseline cardiac autonomic neuropathy, 51 (14%) had early GFR loss, and 68 (18%) had incident advanced CKD over a median 14-year follow-up. Early GFR loss occurred in 15 (32%) of the 47 patients with baseline autonomic neuropathy and in 32 (10%) of the 323 without baseline autonomic neuropathy (P,0.001). Baseline autonomic neuropathy was strongly associated with odds of early GFR loss (adjusted odds ratio, 4.09; 95% confidence interval, 1.65 to 10.12; P=0.002). Incident advanced CKD was observed in 22 (47%) of those with baseline autonomic neuropathy and 46 (14%) of those without baseline autonomic neuropathy (P,0.001). Autonomic neuropathy was independently associated with incident advanced CKD (adjusted hazard ratio, 2.76; 95% confidence interval, 1.44 to 5.30; P=0.002).Conclusions Cardiac autonomic neuropathy was a strong independent predictor of the long-term risk of early progressive renal decline in type 1 diabetes. Future research should explore the mechanisms by which autonomic neuropathy may be associated with renal function loss.

Cardiovascular autonomic neuropathy associates with nephropathy lesions in American Indians with type 2 diabetes

“…A subset of the First Joslin Kidney Study, which included 204 normoalbuminuric patients with type 1 diabetes and 166 with microalbuminuria, underwent a baseline CAN assessment and were followed for a median of 14 years. CAN was strongly associated with both early GFR loss, defined by a loss of cystatin C clearance of more than 3.3%/year, and advanced CKD, defined by eGFR <60 ml/min/1.73m 2 (7). Similar associations have been reported in patients with type 2 diabetes.…”

“…DN is the leading cause of end-stage renal disease worldwide (2, 3), and its interrelationship with CAN remains unclear. Persons with either type 1 or type 2 diabetes who also have CAN have a faster rate of renal function decline than those who do not (4–7), suggesting an association between these complications (4–13) which may be attributable to CAN-induced changes in renal hemodynamics (7, 9, 11, 12). The structural underpinnings of this relationship have not been assessed.…”

Nonblood/Urine Biomarker of Progression of Kidney Disease in Diabetes Mellitus

“…In this issue of CJASN, Orlov et al Although this study uses data from another study on type 1 diabetes and Orlov et al (6) performed an excellent analysis to examine their hypothesis, there are some issues that are worth careful attention. The First Joslin Kidney Study of the Natural History of Microalbuminuria used heart rate variability (HRV) to assess autonomic dysfunction.…”

“…Orlov et al (6) report that patients with autonomic neuropathy were older, had longer uncontrolled diabetes, had higher urinary albumin excretion, and had lower eGFR at baseline. The majority of patients with longstanding diabetes are more likely than their newly diagnosed counterparts to be on a longer list of medications, including a/b-blockers or diuretics, which can potentially impair autonomic nervous system function.…”

“…At the moment, the answers to these questions and several others remain uncertain. The strength of the study by Orlov et al (6) is that it introduces a pathophysiologic concept for future clinical experiments. This study suggests a need for well designed clinical trials to examine the role of autonomic dysfunction in diabetic nephropathy, especially when the evidence of sympathetic overflow in hypertension and insulin resistance is strong (6).…”