Cardiovascular autonomic neuropathy as predictor of kidney function decline in type 1 and type 2 diabetes

Aims: To assess whether cardiovascular autonomic neuropathy (CAN) is an independent predictor of diabetic kidney disease (DKD) progression in patients with type 1 (T1D) and type 2 diabetes (T2D).

Methods: This is a post hoc analysis from Preventing Early Renal Loss in Diabetes (PERL) and Action to Control Cardiovascular Risk in Diabetes (ACCORD) cohorts including T1D and T2D populations, respectively. Autonomic function was evaluated in both studies using heart rate variability (HRV) indices from ultra-short (10 sec) 12-lead resting ECG recording after overnight fasting. CAN was defined according to fixed HRV cut-off values derived in DCCT/EDIC cohorts (i.e., both SDNN <17.13 ms and RMSSD <24.94 ms). Outcomes of kidney function were: 

• eGFR slope, calculated as the effect of time on eGFR using a linear mixed-effects model;

• rapid kidney function decline, defined as eGFR slope of less than or equal to -5mL/min1,73m2/year;

• ≥40% eGFR loss, calculated using at least two eGFR values during follow-up, or the eGFR at the baseline and eGFR at the end of the follow-up period.

Results: A total of 496 individuals with T1D (88% of PERL cohort) and 7973 individuals with T2D (78% of ACCORD cohort) were included. ACCORD cohort was older, with a shorter disease duration, with higher cardiovascular disease prevalence. According to study design, PERL cohort had lower eGFR values and high prevalence of micro- and macroalbuminuria. At baseline 62.4% with T1D and 65.0% with T2D had CAN, in both groups individuals with CAN had higher HbA1c, lower eGFR and higher prevalence of albuminuria.

Median follow-up period was 3.2 years (IQR 3.1, 3.3) for T1D group and 4.9 years (IQR 4.0, 5.7) in T2D group. In participants with CAN a faster rate of eGFR decline was observed in both cohorts. Using a minimally adjusted analysis, the differences in eGFR slopes between CAN-group and noCAN-group were -1.15 mL/min/1.73 m2/year in PERL (P=4.0 × 10-3) and -0.34 mL/min/1.73 m2/year in ACCORD (P=6.3 × 10-6).

In both cohorts, the association between CAN and kidney function decline was stronger in participants with macroalbuminuria at baseline. In T2D population, no interactions were described between CAN and the use of glitazone or insulin for renal outcomes.

Conclusions: CAN is a strong and independent predictor of renal function decline in both T1D and T2D. These findings could have clinical implications to target and treat diabetic microvascular complications. The nature of this connection is not completely understood but a sympathetic activation may have a central role and drugs acting on sympathetic mechanisms might be a strategy to prevent and manage CAN and renal failure.

Comments. These results based on a large population of well-characterized individuals with T1D and T2D confirm and strengthen previous findings in literature showing the association between CAN and the progression of renal failure in both T1D and T2D. Preventing CAN even in its early and asymptomatic manifestation could represent a challenge for the future to manage also the progression of DKD.

Ilenia D’Ippolito

Reference. Tang Y, Ang L, Jaiswal M, Dillon BR, Esfandiari NH, Shah HS, Spino C, Plunkett C, Perkins BA, Pop-Busui R, Doria A. Cardiovascular Autonomic Neuropathy and Risk of Kidney Function Decline in Type 1 and Type 2 Diabetes: Findings From the PERL and ACCORD Cohorts. Diabetes. 2024 May 1;73(5):751-762. doi: 10.2337/db23-0247. PMID: 37467433; PMCID: PMC11043059.

https://diabetesjournals.org/diabetes/article/73/5/751/153421/Cardiovascular-Autonomic-Neuropathy-and-Risk-of