The association between extracellular fluid volume and sympathetic nervous system activity in patients with chronic kidney disease

Chronic kidney disease (CKD) is associated with hypervolemia and sympathetic nervous system (SNS) overactivity that both contribute to heightened cardiovascular risk. Classically, extracellular fluid volume (ECFV) is inversely related to SNS activity, whereby increased ECFV suppresses SNS activation. However, ECFV and SNS activity could be concomitantly elevated if there is failure to suppress SNS activity or if SNS activity plays a contributory role in ECFV expansion. Therefore, we examined the clinical determinants of increased ECFV, the association between ECFV and SNS activity, and whether kidney function accounts for this relationship in CKD. In this cross-sectional study, patients with stage II-IV CKD (62 ± 12 yr, 67% men, 90% with hypertension, <i>n</i> = 104) underwent an assessment of ECFV via extracellular water/total body water ratio, using multifrequency bioimpedance, and a subset had SNS activity via muscle sympathetic nerve activity (MSNA, <i>n</i> = 39). We examined linear associations between ECFV and clinical factors, including MSNA, and group comparisons of MSNA across ECFV tertiles. Multivariable regression analyses were used to assess the relative contribution of kidney function [i.e., estimated glomerular filtration rate (eGFR)] and MSNA to ECFV. ECFV was inversely associated with eGFR and positively associated with age, systolic blood pressure, and pulse pressure (<i>P</i> < 0.05 for all). MSNA was different across ECFV tertiles (<i>P</i> = 0.009), with higher MSNA in <i>tertiles 2</i> and <i>3</i> compared with <i>tertile 1</i> (41 ± 14 and 35 ± 12 vs. 26 ± 9 bursts/min, <i>P</i> = 0.002 and 0.081, respectively), even after adjusting for eGFR, age, sex, and antihypertensive medications. MSNA (<i>r</i> = -0.376, <i>P</i> = 0.018) was inversely associated with eGFR. In multivariable models, eGFR remained a significant predictor of ECFV (β = -0.341, <i>P</i> = 0.045), whereas MSNA showed no independent association with ECFV (β = 0.124, <i>P</i> = 0.457). An inverse relationship between ECFV and SNS activity is not observed in stage II-IV CKD; rather, MSNA is higher in patients with higher ECFV. These findings suggest that the sympathoexcitatory effects of reduced kidney function may override the sympathoinhibitory effects of increased ECFV in CKD.<b>NEW & NOTEWORTHY</b> Patients with chronic kidney disease (CKD) face high cardiovascular risk from both fluid overload and heightened sympathetic nervous activity. In healthy individuals, fluid expansion suppresses sympathetic tone; however, this inverse relationship was absent in our cohort with CKD stage II-IV. Using direct intraneural recordings and validated volume measures, we found that extracellular fluid and muscle sympathetic nerve activity increased in parallel, highlighting disrupted volume-autonomic interplay and underscoring the need to better understand neurogenic contributions to fluid dysregulation in CKD.