Association between heart rate fragmentation and kidney function decline in MESA: evidence consistent with parasympathetic degradation

The contribution of sympathetic overactivity to the pathogenesis of chronic kidney disease (CKD) is well established; in contrast, the role of the parasympathetic system in renal homeostasis remains less well understood. Studies in animal models suggest that parasympathetic activity may influence kidney function by buffering sympathetic tone, activating the cholinergic anti-inflammatory pathway, and modulating cardiovascular (CV) function. We investigated whether a novel noninvasive marker of parasympathetic function, heart rate fragmentation (HRF), was associated with <i>1</i>) the likelihood of prevalent CKD and <i>2</i>) longitudinal changes in estimated glomerular filtration rate (eGFR) over ∼5 yr. The analytical cohort included 1,388 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) (mean age: 66.8 ± 8.5 yr; 44.5% male) with polysomnographic ECG recordings. Higher HRF, indicative of reduced parasympathetic function, was associated with <i>1</i>) an increased likelihood of prevalent CKD (rate ratio: 1.15 [95% confidence interval (CI): 1.04; 1.27], per 1-SD increase in HRF) and <i>2</i>) a steeper decline in eGFR (-0.86 [95% CI: -1.43; -0.28] mL/min/1.73 m², per 1-SD increase in HRF), independent of major comorbidities, including age, hypertension, diabetes, and baseline CKD status. Stratified analyses in lower- and higher-risk subgroups yielded consistent results. These findings support a role for parasympathetic activity in renal homeostasis and suggest that HRF may serve as a noninvasive biomarker of risk for <i>1</i>) early renal function decline in lower-risk populations and <i>2</i>) accelerated decline in the general and higher-risk populations. HRF may also be useful for evaluating interventions targeting renal neuroautonomics, such as vagal stimulation or renal sympathetic denervation.<b>NEW & NOTEWORTHY</b> This study identifies reduced cardiac parasympathetic activity, measured by heart rate fragmentation (HRF), as a potential contributor to accelerated renal function decline in a community-based population. The findings suggest a mechanistic link between vagal dysfunction and kidney deterioration. From a translational perspective, the results support the utility of HRF-a noninvasive, repeatable measure-for renal disease risk stratification and monitoring of autonomic-targeted interventions.