Autonomic Modulation with Mindfulness-Based Stress Reduction in Chronic Kidney Disease: A Randomized Controlled Trial

Abstract

Background:

Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that leads to increased cardiovascular disease risk. This study was conducted to evaluate the effects of Mindfulness-Based Stress Reduction (MBSR) on SNS activity in CKD patients.

Method:

Participants with CKD stages III-IV were randomized to the 8-week MBSR program or Health Enhancement Program (HEP; a structurally parallel, active control group). Intraneural measures of SNS activity directed to muscle (MSNA) via microneurography was recorded at rest and during stress maneuvers (mental arithmetic, handgrip exercise and cold pressor test). Data analyses were performed based on the intent-to-treat principle.

Results:

29 participants (64 ±9 years; 86% males) completed the intervention with 17 in MBSR and 12 in HEP. There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post-intervention) interaction in MSNA reactivity to mental stress (p=0.029), with a significant reduction in the mean ΔMSNA over 3 minutes of mental arithmetic at post-intervention (10.3 ± 4.2 to 5.9 ± 5.6 bursts/min, p<0.001; (Hedges’g = −0.858, 95% CI [−1.578, −0.167]), while no change was observed within the HEP group (p=0.818). Reduced ΔMSNA during handgrip exercise was also observed, while ΔMSNA during the cold pressor test and resting MSNA remained unchanged in both groups from baseline to post-intervention.

Conclusions:

In this randomized controlled trial, patients with CKD had a reduction of sympathetic reactivity during mental stress and static handgrip exercise following 8-weeks of MBSR but not after HEP. Our findings demonstrate that mindfulness training is feasible and may have clinically beneficial effects on autonomic function in CKD.

Trial Registration.

ClinicalTrials.gov, NCT 04099992.

Funding.

NIH R01HL135183; R61AT10457; KL2TR002381; VA Merit I01CX001065.

Graphical Abstract

Patients with chronic kidney disease (CKD) stages III-IV were randomized to the 8-week Mindfulness-Based Stress Reduction (MBSR, n=17) program or Health Enhancement Program (HEP; a structurally parallel, active control group, n=12). Muscle sympathetic nerve activity (MSNA) via microneurography was assessed during 3 minutes of mental arithmetic stress at baseline and post-intervention. A reduction of ΔMSNA reactivity to mental stress was observed following 8 weeks of MBSR but not after HEP. This study’s results suggest the feasibility and clinical benefits of MSBR on autonomic function in CKD.

Introduction

Chronic kidney disease (CKD) affects more than 35 million individuals in the United States and is associated with a significantly elevated risk of cardiovascular (CV) disease and mortality by 5-15 fold (Go et al., 2004; Herzog et al., 2011). A primary contributor to heightened CV risk among patients with CKD is the persistent elevation of sympathetic nervous system (SNS) activity (Klein et al., 2003; Neumann et al., 2004; Grassi et al., 2011). Even modest declines in kidney function are associated with substantial increases in both resting SNS activity as well as SNS reactivity that are independently associated with adverse CV events (Neumann et al., 2004; Grassi et al., 2011). Clinical tools to combat SNS overactivation are limited to sympatholytic medications such as beta-blockers, alpha-blockers, and central alpha agonists. However, the use of sympatholytic medications in CKD is clinically limited (Badve et al., 2011; Tomiyama & Yamashina, 2014) due to adverse side effects (Vonend et al., 2003; Bakris et al., 2004; Hundemer et al., 2021) and inferior efficacy in CV risk reduction compared to alternative antihypertensive agents (Bakris et al., 2004; James et al., 2014; Whelton et al., 2018). Therefore, there is a critical need to develop novel therapeutic approaches to safely and effectively counter SNS overactivity to improve clinical outcomes in CKD and other high-risk patient populations characterized by SNS overactivation.

Mindfulness meditation may be one such novel nonpharmacologic strategy to lower SNS activity in individuals with CKD. In particular, mindfulness-based stress reduction (MBSR) is an 8-week structured mindfulness meditation training program that has been extensively studied and has demonstrated beneficial effects on CV outcomes in patient populations (Lengacher et al., 2012; Lakhan & Schofield, 2013; Lengacher et al., 2014). Specifically, some, although not all, studies have shown that MBSR lowers clinic and ambulatory blood pressure (BP) (Barnes et al., 2008; Manikonda et al., 2008; Goldstein et al., 2012; Younge et al., 2015; Scott-Sheldon et al., 2020), and attenuates psychological (Hoge et al., 2013; Creswell et al., 2014) and physiological reactivity to stress (Nyklicek et al., 2013; Hoge et al., 2018; Lindsay et al., 2018; Dutcher et al., 2021). Although the mechanisms underlying the cardioprotective mechanisms of MBSR remain unknown, indirect evidence suggests that MBSR may lower BP by modulating autonomic nervous system activity, particularly by lowering SNS activity (Shapiro et al., 2006; Creswell & Lindsay, 2014; Loucks et al., 2015). Earlier investigations using indirect measures of SNS activity have shown that meditation increases low frequency and high frequency heart rate variability (Ditto et al., 2006; Nijjar et al., 2014; Wang et al., 2022) and lowers plasma norepinephrine levels (Curiati et al., 2005). In addition, our group previously measured direct, intraneural recordings of muscle sympathetic nerve activity (MSNA) via the gold-standard microneurographic technique to demonstrate the first direct evidence that a single session of mindfulness meditation acutely reduces BP and MSNA in patients with CKD (Park et al., 2014). However, there have been no prior studies testing the sustained effects of MBSR on SNS activity and reactivity using direct measures of SNS activity in humans. Therefore, we performed a randomized controlled trial to test the hypothesis that MBSR leads to sustained reductions in both resting MSNA and MSNA reactivity to stress in CKD.

Methods

Ethical Approval

This study was approved by the Emory University Institutional Review Board and the Atlanta VA Health Care System Research and Development Committee and registered with clinicaltrials.gov (NCT 04099992). All study procedures conformed to the standards set forth by the Declaration of Helsinki.

Participants

Individuals with CKD stages III and IV (estimated glomerular filtration rate (eGFR) between 15-59 mL/min/1.73 m²), as defined by the race-free CKD-EPI equation (Inker et al., 2021), were recruited from Emory University clinics and the Atlanta VA Health Care System for participation in this study from September 2019 to Jun 2022.

Eligibility Criteria

All participants had stable renal function (no greater than a decline of eGFR of 1cc/min/1.73m² per month over the prior 3 months). Exclusion criteria included uncontrolled hypertension (BP>160/90mmHg), vascular disease, use of clonidine, clinical evidence of heart failure or active heart disease determined by history, electrocardiogram (ECG) or echocardiogram, ongoing illicit drug use, alcohol use > 2 drinks/day within the past 12 months, diabetic neuropathy, severe anemia (hemoglobin <10mg/dL), and pregnancy or plans to become pregnant. Individuals with prior experience in mindfulness or meditation were excluded from the study.

Study Design and Randomization

This was a single-site, parallel-group, randomized controlled clinical trial. Participants were allocated to MBSR group or a control Health-Enhancement Program (HEP) group in a 3:2 ratio using a computer-generated sequence stratified by stage of CKD (Stage IIIA, IIIB, and IV). While the nature of the interventions did not allow for masking of the MBSR and HEP instructors and participants, all investigators and assessors were masked to study identifiers or group assignment during data analysis. After obtaining written informed consent, baseline measurements and a basic metabolic panel were obtained. All measurements were obtained in a quiet, temperate (21°C) environment, after abstaining from food, caffeine, smoking, and alcohol for at least 12 h, and exercise for at least 24 h. After baseline assessments, participants were randomly assigned to one of two interventions; MBSR and HEP. At the end of the trial, baseline measurements were repeated under identical conditions within 2 weeks following the completion of the final session. Participants were instructed not to change medication regimens, dietary habits, or physical activity levels for the duration of the study.

Study Interventions

Both interventions followed detailed manuals and were administered to small groups (4-6 participants) for 2.5 hours, once per week for eight consecutive weeks. Weekly group sessions as well as a half-day retreat were administered using Zoom© video conferencing. In addition to weekly attendance, participants were assigned 45-minutes of homework 6 days per week.

MBSR intervention

The MBSR intervention was comprised of 8 weeks of 2.5 h sessions held once per week. An additional one-day “retreat” was also required for participants to attend between weeks 7 and 8. A single, fully-certified teacher (M.D.) who had completed the University of Massachusetts MBSR professional training program with more than 15 years of mindfulness practice and teaching experience delivered the formalized program curriculum to participants.

The formal MBSR program focuses on mindfulness by increasing awareness of thoughts, feelings, and sensations from moment to moment, and to more skillfully respond (rather than automatically react) to stressors. Each of the eight weekly sessions includes psychoeducation about mindfulness and stress (including a discussion of habitual behavioral and physiological reactions to stress, and learning to more purposely respond rather than react); experiential mindfulness practice, and a discussion of participants’ experiences with mindfulness practice. Participants learn formal mindfulness practices (e.g., sitting meditation, yoga, body scan, walking meditation, body scan meditation) as well as more informal mindfulness activities such as awareness of breath, thoughts, or emotions, and mindfulness of daily life activities (e.g., eating, breathing, washing dishes). They were encouraged to practice mindfulness in their daily lives. Participants received MP4 downloads on an electronic tablet with guided mindfulness meditation practices, a home practice manual, and weekly handouts with each week’s formal and informal practice assignments. Participants were asked to perform daily home practice of 40-45 minutes of recorded practice and keep a written record of their practice times. A makeup class on a different day was available if a participant missed a class. The half-day retreat session between weeks 7 and 8 sought to further integrate acquired skills and involved guided meditation practice and reflection.

HEP Intervention

An 8-week HEP, a non-meditation intervention was administered as the gold-standard control intervention for MBSR (MacCoon et al., 2012; Eisendrath et al., 2014; Eisendrath et al., 2016). HEP is designed to provide a structurally parallel, active control intervention to MBSR within the same group-based environment, matching for group support, facilitator attention, intervention duration, time spent on at-home practice while omitting any components of mindfulness. The original HEP manual had been developed for use in a non-clinical sample as a control condition for MBSR (MacCoon et al., 2012). Specifically, HEP consists of music therapy, nutritional education, posture and balance movements, walking and stretching instructed by a health educator (a registered dietician) in a group setting for 8 weekly 2.5-hour sessions. Work with all practices with group discussion and exercises during an all-day match the all-day retreat in MBSR. Participants received MP4 downloads on an electronic tablet with recordings of health education topics, a home listening manual, and weekly handouts with each week’s listening assignments, and were asked to listen to these MP4 recordings daily for 40-45 minutes and log their daily adherence. HEP was administered by a clinician with health education experience.

Outcomes and Measurements

The primary outcomes were sympathetic activity quantified as resting MSNA and MSNA reactivity to acute stressors. Secondary outcomes included resting BP and BP reactivity to acute stressors.

Muscle Sympathetic Nerve Activity and Beat-to-Beat Blood Pressure

Multiunit postganglionic MSNA was recorded directly from the peroneal nerve by microneurography, as previously described (Wallin & Fagius, 1988). Participants were placed in a supine position, and the leg was positioned for microneurography. A tungsten microelectrode (tip diameter 5–15 μm, 2.0 ± 0.4 MΩ impedance) (Bioengineering, University of Iowa and FHC, Bowdoin, ME) was inserted into the nerve, and a reference microelectrode was inserted subcutaneously 1–2 cm from the recording electrode. The signals were amplified (total gain: 50,000–100,000), filtered (700-2,000 Hz), rectified, and integrated (time constant 0.1 s) to obtain a mean voltage display of sympathetic nerve activity (Nerve Traffic Analyzer, model 662C-4, University of Iowa, Bioengineering) that was recorded by the LabChart 7 Program (PowerLab 16sp, ADInstruments). Continuous ECG was recorded simultaneously with the neurogram using a bioamp system. Beat-to-beat arterial BP was measured concomitantly using a noninvasive monitoring device that detects digital blood flow via finger cuffs and translates blood flow oscillations into continuous pulse pressure waveforms and beat-to-beat values of BP (Finometer, Finapres Medical Systems, Amsterdam, The Netherlands and CNAP^™, CNSystems Medizintechnik, Graz, Austria) (Jeleazcov et al., 2010). Absolute values of BP were internally calibrated using a concomitant upper arm BP reading and were calibrated at the start and every 15 min throughout the study. The tungsten microelectrode was manipulated to obtain a satisfactory nerve recording that met previously established criteria (Mano et al., 2006). After 10 min of rest, BP, ECG, and MSNA were recorded continuously for 10 min. After 10 minutes of rest, MSNA, beat-to-beat BP, heart rates (HR) and ECG were continuously measured throughout the stress protocols that include mental arithmetic (3 min), handgrip exercise (3 min) and cold pressor test (CPT, 1min), separated by 15 min of rest and followed by 5 minutes of recovery. Detailed stress maneuver protocols are described below.

For MSNA data analysis, MSNA and ECG data were exported from the LabChart data acquisition system to WinCPRS (Absolute Aliens, Turku, Finland) for analysis. R-waves were detected and marked from the continuous ECG recording. MSNA bursts were automatically detected by the program using the following criteria: 3:1 burst-to-noise ratio within a 0.5-s search window, with an average latency in burst occurrence of 1.2–1.4 s from the previous R-wave. After automatic detection, the ECG and MSNA neurograms were visually inspected for accuracy of detection. MSNA was expressed as burst frequency (bursts/min) and burst incidence (bursts/100 heartbeats).

The spontaneous sympathetic baroreflex sensitivity (sBRS; Ensemble, Elucimed, Wellington, New Zealand) and the cardiac baroreflex sensitivity (cBRS; CardioSeries v2.4) were quantified. The spontaneous sBRS was quantified using the method originally described by Kienbaum et al (2001). Briefly, sBRS was measured by shifting the MSNA nerve tracing (~1.2–1.4 s) to account for conduction delay, binning diastolic BP into 3-mmHg increments, and plotting MSNA burst incidence against diastolic BP. The slope of the linear regression analysis (r > 0.7) provided the sBRS for each participant (Sabino-Carvalho et al., 2024). cBRS was assessed using the sequence technique which analyzes progressive changes in systolic BP followed by corresponding changes in RR intervals over three or more heartbeats, as previously described (Sabino-Carvalho et al., 2023). The slope of the SBP-RR interval relationship for all sequences was identified using linear regression analysis (R² ≥ 0.85) and the total cBRS sequences was detected, analyzed and reported.

Resting heart rate variability (HRV) was determined in accordance with the guidelines of the Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology (1996) and was quantified in the time domain as root mean square of the successive differences (RMSSD) using a 5-min segment at baseline.

Resting Blood Pressure

Baseline resting BP was measured after 5 min of rest in a seated position with the arm supported at heart level using an appropriately sized cuff per American College of Cardiology/American Heart Association (ACC/AHA) guidelines (Whelton et al., 2018) using an automated device (Omron, HEM-907XL, Omron Healthcare, Kyoto, Japan). Measurements were taken three times, with each reading separated by a one-minute interval. Mean arterial blood pressure (MAP) was calculated as 2/3 diastolic BP (DBP) + 1/3 systolic BP (SBP).

Intervention Satisfaction

Participants in both groups completed the 8-item Client Satisfaction Questionnaire (CSQ-8) to assess intervention satisfaction (Attkisson & Zwick, 1982) at post-intervention.

Stress Maneuvers

Mental Arithmetic.

Participants were asked to serially subtract a one- or two-digit number from a three- or four-digit number and were urged to do so as quickly and accurately as possible for 3 minutes. An investigator used flash cards with a three- or four-digit number and was urged by two additional study team members in white coats to answer ‘faster’ and ‘get it right’. At the end of mental stress, participants were asked to rate their perceived stress during the mental math trial using a standard five-point scale, ranging from 0 (no stress) to 4 (severe stress). This test is shown to induce mental stress and increase MSNA (Fonkoue et al., 2020) (Park et al., 2017).

Static Handgrip (SHG).

Moderate intensity SHG was performed by squeezing the hand dynamometer at 30% maximal voluntary contraction in a sustained manner for 3 min. The participant was instructed to avoid inadvertent Valsalva and to maintain normal breathing patterns. Moderate SHG elicits an increase in MSNA (Mark et al., 1985) by activating the exercise pressor reflex and central command.

Cold Pressor Test (CPT).

The dominant hand was immersed up to the wrist in an ice water bath (4°C) for 1 min, which was followed by 3 min of recovery. Subjects were instructed to avoid breath holding and to stay as relaxed as possible. The participant was asked to rate the degree of pain during the maneuver on a five-point pain scale, ranging from 0 (no pain) to 4 (severe pain). CPT is a sympatho-excitatory maneuver that is known to evoke an increase in MSNA (Victor et al., 1987).

Statistics

Based on our pilot data, the group difference in MSNA change after MBSR program (vs. a control program) was estimated to be −9.7 ± 5.4 bursts/min. A minimum of 33 in total (20 in MBSR and 13 in a control group) was required to achieve >90 % power at a significance level (α) of 0.05 for the primary outcome (MSNA) after considering the expected 20% dropout rate.

Values are presented as mean ± standard deviation (SD) unless otherwise noted. Data normality was assessed by the Shapiro-Wilk test for continuous variables. Differences in participant characteristics between groups were determined using independent, 2-tailed, t-tests for continuous variables and chi-square tests for categorical variables. When normality was not met, Mann-Whitney U tests were used. The primary analyses were based on the intention-to-treat approach. Repeated ANOVA tests with Group (MBSR vs. HEP) as a between factor and Time (baseline and post-intervention) as a within factor were used to analyze the change in MSNA reactivity during 3 minutes of mental arithmetic and SHG and 1 minute of CPT. In addition, a linear mixed model (LMM) analysis was conducted with Minutes, Group and Time as fixed factors and participants as a random factor to compare the group difference in slope-of-rise in the absolute MSNA change over 3 minutes of mental arithmetic and SHG. Adjustment with potential confounding factors, including sex and the use of antihypertensive medications, was performed. Sensitivity analysis, including within-group analysis and weighting adjustments with group sample sizes, was also conducted. The within-group comparison from baseline to 8 weeks was done using 2-tailed, paired t-tests. Weights were calculated based on the sample proportions of MBSR and HEP groups relative to the intended equal allocation ratio, and weighted repeated ANOVA was conducted. Additionally, effect size values, including partial η² and omega squared (ω²) for the interaction effect and Hedges’ g for within-group comparisons, which are conservative estimates adjusted for small and unbalanced sample sizes, were reported to quantify the magnitude of the observed effects between and within groups. An α <0.05 was considered statistically significant for all analyses. All analyses were performed using SPSS version 26.0 (IBM Corporation, Somers, NY) and R (version 4.0.2, R Foundation for Statistical Computing, Vienna, Austria).

Results

Participants and Intervention Adherence

A total of twenty-nine participants who completed the study intervention were included in this study (Figure 1). No significant differences in baseline demographics, comorbid conditions, medication use or clinical characteristics were observed between the MBSR and HEP groups. Intervention adherence measured by attendance of intervention group sessions, retreats and time spent on total home practice was high in both groups and comparable. CSQ-8 score indicated that participants in both groups were generally satisfied with the intervention (Table 1).

Figure 1.

CONSORT diagram. The diagram depicts patient flow through the randomized clinical trial.

MBSR: Mindfulness-Based Stress Reduction, HEP: Health Enhancement Program, ITT: Intent-to-Treat.

Table 1.

Participant Characteristics and Intervention Adherence

Characteristics	MBSR (n=17)	HEP (n=12)	P-value#
Age (yr)	64.1 ± 8.1	63.3 ± 10.3	0.834
Sex (male, %)	15 (88%)	10 (83%)	0.556
Race
Black	10 (59%)	10 (83%)	0.160
White	7 (41%)	2 (17%)
Height (cm)	176 ± 8	177 ± 11	0.770
Weight (kg)	102 ± 22	94 ± 17	0.322
BMI (kg/m2)	32.9 ± 6.2	30.1 ± 4.8	0.202
Smokers (n,%)	8 (47%)	7 (58%)	0.729
Hypertension (n,%)	14 (82%)	11 (92%)	0.474
Diabetes (n,%)	7 (41%)	7 (58%)	0.362
Antihypertensive medications (n,%)
ACEI/ARB	13 (76%)	9 (75%)	0.927
CCB	9 (53%)	7 (58%)	0.774
Diuretics	9 (53%)	5 (42%)	0.550
β-blockers	4 (24%)	7 (58%)	0.057
α-blockers	5 (29%)	2 (17%)	0.430
Hydralazine	2 (12%)	0 (0%)	0.218
Statin (n,%)	10 (59%)	7 (58%)	0.979
eGFR (ml·min−1·1.73 m−2)	40.7 ± 12.3	46.0 ± 7.4	0.205
Intervention Adherence and Satisfaction
Class Attendance (%)	95 ± 10	94 ± 11	0960
Home Practice (%)	78 ± 23	85 ± 21	0.610
Home Practice (hour)	34 ± 19	43 ± 23	0.212
Retreat Attendance	14/17	8/12	0.349
Satisfaction	28 ± 4 (86 ± 13%)	30 ± 2 (95 ± 6 %)	0.066

Continuous values are expressed as means ± standard deviation.

BMI: Body Mass Index, ACEI: Angiotensin Converting Enzyme Inhibitors, ARB: Angiotensin Receptor Blocker CCB: Calcium Channel Blocker, eGFR: Estimated Glomerular Filtration Rate.

^#indicates p-values for group comparisons by independent t-tests or Mann-Whitney U tests for continuous variables and chi-square tests for categorical variables.

Effect of MBSR on MSNA and Hemodynamics at Rest and During Stress

Resting Outcomes.

Resting MSNA, BP, heart rate, cBRS, sBRS and RMSSD remained unchanged in both groups from pre-intervention baseline levels to post-intervention (Table 2).

Table 2.

Effects of MBSR vs. HEP Intervention on Resting and Reactivity to Mental Arithmetic, Static Handgrip and Cold Pressor Test of Cardiovascular and Sympathetic Parameters at in Patients with Chronic Kidney Disease.

	MBSR (n=17)			HEP (n=12)
	Baseline	8 weeks	Within-group P-value#	Baseline	8 weeks	Within-group P-Value#	Between-group P-Value&	Group x Time P-value*
Resting
SBP (mmHg)	122 ± 11	118 ±16	0.233	123 ± 12	121 ± 11	0.665	0.705	0.772
DBP (mmHg)	75 ± 8	71 ± 13	0.157	73 ± 12	72 ± 9	0.934	0.475	0.322
MAP (mmHg)	91 ± 8	86 ±14	0.161	89 ± 11	88 ± 8	0.787	0.715	0.441
HR (bpm)	72 ± 9	69 ±9	0.101	64 ± 7	66 ± 10	0.397	0.088	0.083
MSNA (bursts/min)	32.8 ± 7.6	33.8 ±8.9	0.382	38.9 ± 9.4	36.2 ± 8.9	0.193	0.276	0.096
MSNA (bursts/100HB)	53.7 ± 15.3	55.8 ± 17.9	0.395	61.3 ± 12.3	59.3 ± 12.6	0.632	0.320	0.372
cBRS (ms/mmHg)	6.0 ± 2.3	7.9 ± 4.2	0.058	9.1 ± 6.0	10.4 ± 6.0	0.329	0.276	0.210
sBRS┼ (bursts/100HB/mmHg)	−1.4 ± 0.7	−1.3 ± 0.5	0.630	−1.6 ± 0.8	−1.4 ± 0.6	0.632	0.613	0.372
RMSSD (ms)	34.6 ± 50.8	28.6 ± 23.6	0.904	31.1 ± 33.0	40.3 ± 37.0	0.701	0.904	0.210
Reactivity to Mental Arithmetic
Δ SBP (mmHg)	6 ± 12	5 ± 6	0.671	9 ± 12	8 ± 7	0.808	0.526	0.914
Δ DBP (mmHg)	4 ± 6	2 ± 15	0.566	5 ± 6	4 ± 11	0.684	0.667	0.805
Δ MAP (mmHg)	5 ± 10	5 ± 5	0.841	8 ± 6	6 ± 4	0.527	0.425	0.787
Δ HR (bpm)	4 ± 4	4 ± 3	0.759	4 ± 6	4 ± 4	0.505	0.854	0.794
Δ MSNA (bursts/min)	10.3 ± 4.2	5.9 ± 5.6	0.012	9.3 ± 4.6	9.5 ± 5.1	0.818	0.554	0.029
Δ MSNA (bursts/100HB)	12.6 ± 8.8	5.7 ± 8.4	<0.001	10.8 ± 9.2	11.8 ± 8.0	0.639	0.585	0.003
Reactivity to SHG
Δ SBP (mmHg)	11 ± 11	11 ± 13	0.929	10 ± 10	6 ± 8	0.277	0.842	0.286
Δ DBP (mmHg)	7 ± 7	9 ± 8	0.451	8 ± 6	6 ± 7	0.529	0.974	0.318
Δ MAP (mmHg)	10 ± 9	10 ± 9	0.973	9 ± 8	7 ± 6	0.353	0.734	0.416
Δ HR (bpm)	5 ± 4	6 ± 5	0.543	6 ± 6	5 ± 4	0.832	0.750	0.623
Δ MSNA (bursts/min)	14.1 ± 6.8	10.1 ± 6.4	0.136	10.8 ± 7.8	11.9 ± 9.1	0.587	0.264	0.155
Δ MSNA (bursts/100HB)	16.2 ± 11.2	8.7 ± 10.3	0.045	9.5 ± 8.5	13.0 ± 12.3	0.253	0.108	0.029
Reactivity to CPT
Δ SBP (mmHg)	7 ± 9	1 ± 16	0.089	11 ± 19	8 ± 12	0.559	0.387	0.641
Δ DBP (mmHg)	8 ± 4	8 ± 9	0.851	14 ± 13	13 ± 11	0.673	0.093	0.837
Δ MAP (mmHg)	9 ± 6	6 ± 12	0.252	15 ± 16	10 ± 9	0.357	0.242	0.764
Δ HR (bpm)	7 ± 4	6 ± 4	0.126	10 ± 10	11 ± 8	0.688	0.422	0.272
Δ MSNA (bursts/min)	13.8 ± 15.4	11.8 ± 5.8	0.600	20.4 ± 16.4	22.1 ± 8.0	0.658	0.364	0.514
Δ MSNA (bursts/100HB)	15.1 ± 22.1	13.4 ± 12.4	0.754	17.6 ± 11.8	23.6 ± 9.2	0.340	0.734	0.503

Values are expressed as mean ± standard deviation.

SBP: Systolic Blood Pressure, DBP: Brachial Diastolic Blood Pressure, MAP: Mean Arterial Blood Pressure, HR: Heart Rate, MSNA: Muscle Sympathetic Nervous Activity, HB: Heart Beats, cBRS: Cardiac Baroreflex Sensitivity, sBRS: Cardiac Baroreflex Sensitivity, RMSSD: Root Mean Square of Successive Differences, SHG: Static Handgrip, CPT: Cold Pressor Test.

^#indicates p-values for within-group comparisons over 8 weeks were tested by paired t-tests.

^&indicates p-values for between-group comparisons at baseline by independent t-tests or Mann-Whitney U tests.

^*indicates p-values for between-group comparisons on the changes over 8 weeks (Group by Time) were tested by repeated ANOVA tests.

^┼: sBRS results were from 13 patients (n=7 in MBSR, n=6 in HEP) that met the analysis criteria, the sBRS regression r value of > 0.7.

Reactivity to Mental Arithmetic.

There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post-intervention) interaction in MSNA reactivity to mental arithmetic stress over 3 minutes (p = 0.029 and 0.003; partial η² = 0.165 and 0.281; ω² = 0.157 and 0.268 for burst frequency and burst incidence, respectively). Specifically, the MBSR group had a significant reduction in the mean change in ΔMSNA over 3 minutes of mental arithmetic at post-intervention (Hedges’ g = −0.858, 95% CI [−1.578, −0.167] and −0.784, 95% CI [−1.49, −0.09] for MSNA burst frequency and incidence respectively), while no change was observed within the HEP group (Hedges’ g = −0.039, 95% CI [−0.76, 0.84] and 0.120, 95% CI [−0.67, 0.92] for MSNA burst frequency and incidence respectively) (Figure 2 A–B). ΔMSNA was lower at the 1^st, 2^nd and 3^rd minute of mental arithmetic within the MBSR group at post-intervention (7.2 ± 5.1 to 2.6 ± 6.3, p=0.017; 11.3 ± 8.9 to 5.8 ± 6.9, p=0.010; 12.5 ± 8.6 to 7.8 ± 5.6, p=0.010 bursts/min respectively; 8.6 ± 6.8 to 1.1 ± 9.4, p=0.004; 13.4 ± 11.2 to 5.8 ± 10.9, p=0.005; 16.2 ± 12.7 to 8.0 ± 7.6, p=0.011 bursts/100 heartbeats respectively), while no such change was observed within the HEP group (p>0.05 for all) (Figure 3 A–D). In addition, LMM analyses revealed a significant decrease in the slope-of-rise of absolute ΔMSNA changes during 3 minutes of mental arithmetic from baseline to post-intervention within the MBSR group, but not in the HEP group (effect sizes for the group difference (MBSR vs. HEP) in the slope change (baseline to post-intervention) of ΔMSNA: −1.46 bursts/min per min; p=0.011 and −2.34 bursts/100 heartbeats per min; p=0.006). Results were similar when adjusted for sex and antihypertensive medication usage, as well as when weighted with group sample sizes (p=0.036 and 0.006 for Group by Time interaction effect on burst frequency and burst incidence, respectively). There was no significant change in the reactivity of BP and heart rate during mental arithmetic in both groups (Figure 3 E–H). The individual reactivity in MSNA, BP and heart rate over 3 minutes of mental arithmetic at baseline and post-intervention in MBSR and HEP groups are shown in Supplemental Figures 1 and 2 respectively. Perceived stress levels during mental arithmetic were comparable between baseline and post-intervention in both groups (2.2 ± 1.2 to 2.2 ± 0.9 in the MBSR and 2.5 ± 1.0 to 2.4 ± 1.3 in the HEP group, p=0.825 for the Group by Time interaction).

Figure 2.

Reactivity of Muscle Sympathetic Nervous Activity (MSNA) Burst Frequency (A) and MSNA Burst Incidence (B) averaged over 3 minutes of Mental Arithmetic from baseline (0 wk) to post-intervention (8 wk) in patients with chronic kidney disease randomized to Mindfulness-Based Stress Reduction (MBSR; N=17) versus Health Enhancement Program (HEP; N=12) groups.

Open circles (∘) depict individual values for each study participant and bar graphs depict the mean and standard deviation values at baseline and post-intervention within each group. P-values denote statistically significant differences in the change from baseline to post-intervention between groups (Group x Time interaction) by repeated ANOVA tests.

* denotes statistically significant within-group difference from baseline to post-intervention by paired t-tests.

Figure 3.

Reactivity in Muscle Sympathetic Nervous Activity (MSNA) Burst Frequency (A, B), MSNA Burst Incidence (C, D), Mean Arterial Blood Pressure (MAP) (E, F) and Heart Rate (HR) (G, H) during each minute of Mental Arithmetic from baseline (0 wk, closed circles) to post-intervention (8 wk, open circles) in patients with chronic kidney disease randomized to Mindfulness-Based Stress Reduction (MBSR; N=17) versus Health Enhancement Program (HEP; N=12) groups.

* denotes a statistically significant Time (baseline vs. post-intervention) by Minute (1^st, 2^nd or 3^rd minute) interaction effect within the MSBR group by repeated ANOVA tests.

Reactivity to Static Handgrip Exercise.

There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post-intervention) interaction in ΔMSNA burst incidence to SHG (p=0.029), with a reduced mean change in ΔMSNA burst incidence over 3 minutes of SHG following MBSR (Hedges’ g = −0.627, 95% CI [−0.084, 1.337], p=0.045), but no change within the HEP group post-intervention (p=0.253) (Table 2). There was no group difference in mean change in ΔMSNA burst frequency, ΔBP and ΔHR over 3 minutes of SHG from baseline to post-intervention in both MBSR and HEP groups (p>0.050 for both, Table 2). LMM analyses showed no significant group difference in the slope-of-rise of absolute ΔMSNA during 3 minutes of SHG from baseline to post-intervention between the MBSR and HEP groups (effect sizes for the group difference for ΔMSNA: −0.67 bursts/min per min; p = 0.360 and −1.57 bursts/100 heartbeats per min; p = 0.133).

Reactivity to Cold Pressor Test.

ΔMSNA, ΔBP and ΔHR to CPT remained unchanged from baseline to post-intervention in both MBSR and HEP groups (Table 2). Perceived pain levels during CPT were comparable between baseline and post-intervention in both groups (2.3 ± 1.3 to 2.0 ± 1.4 in the MBSR and 3.5 ± 0.7 to 2.9 ± 1.0 in the HEP group, p=0.416 for the Group by Time interaction).

The Impact of Baseline MSNA Reactivity on MBSR-Induced Changes

We further examined the linear association of baseline levels of MSNA reactivity during mental arithmetic with MBSR-induced changes in MSNA reactivity within the MBSR group. The magnitude of change in MSNA reactivity was inversely associated with baseline MSNA reactivity (p<0.001, Figure 4A, C) in the MBSR group, while no significant association was found within the HEP group (p>0.050; Figure 4B, D).

Figure 4.

Association between Reactivity in Muscle Sympathetic Nervous activity (MSNA) Burst Frequency and MSNA Burst Incidence during Mental Arithmetic at Baseline (0 wk) and the Change (post-intervention; 8 wk – baseline; 0 wk) in MBSR (A, C respectively, n=17) and in the HEP Group (B, D respectively, n=12) by Pearson correlation tests.

Closed circles (•) depict individual values for each study participant in the MBSR group, while open circles (∘) depict individual values for each study participant in the HEP group.

Discussion

We conducted a randomized controlled trial testing the efficacy of MBSR in lowering SNS overactivity in patients with CKD. By using direct intraneural recordings of SNS activity directed to the muscle via microneurography, we demonstrate a significant reduction in MSNA reactivity during acute mental and exercise stress in CKD patients who were randomized to 8 weeks of MBSR compared to the HEP control intervention. The MBSR intervention was well-accepted with high adherence rates to classes and practice homework, and our results suggest that MBSR may be a feasible adjunct intervention to improve CV risk by modulating autonomic balance in CKD.

MBSR is the most extensively studied meditation intervention in the US, with confirmed psychological and physiological health benefits including improved CV disease risk across different patient populations (Lengacher et al., 2012; Lakhan & Schofield, 2013; Lengacher et al., 2014; Younge et al., 2015; Scott-Sheldon et al., 2020). Mindfulness-based interventions are hypothesized to improve CV health by promoting effective self-emotion regulation through non-judgmental present-moment awareness and a shift in stress appraisal, ultimately reducing the stress-reactivity response (Shapiro et al., 2006; Garland et al., 2015; Loucks et al., 2015). These improvements in coping skills and psychological functioning may be coupled with the normalization of physiological functioning, such as the autonomic nervous system, potentially leading to improved CV outcomes (Creswell & Lindsay, 2014). Despite this concept that autonomic regulation during stress may underlie the CV health benefits of MBSR, limited research has investigated this area, with existing data primarily relying on indirect markers of autonomic function (Ditto et al., 2006; Nijjar et al., 2014; Wang et al., 2022) such as heart rate variability and plasma norepinephrine (Curiati et al., 2005), and largely focusing on resting-state activity. We now provide the first evidence that MBSR may modulate SNS response to acute mental stress in CKD, a patient population at increased CV risk by virtue of chronic SNS overactivation. Our results align with previous evidence demonstrating that MBSR has favorable effects on stress responses on objectively measured stress biomarkers (Nyklicek et al., 2013; Hoge et al., 2018; Lindsay et al., 2018) as well as self-reported stress scales (Hoge et al., 2013; Creswell et al., 2014). Prior work has shown that mindfulness-based interventions may attenuate increases in BP (Nyklicek et al., 2013; Lindsay et al., 2018), neurohormonal (cortisol, adrenocorticotropic hormone) and inflammatory (IL-6, TNF-a) reactivity (Hoge et al., 2018), perceived stress levels (Hoge et al., 2013; Creswell et al., 2014) and functional magnetic resonance imaging-based neural reactivity (Goldin & Gross, 2010; Dutcher et al., 2021) during stressful stimuli. Given heightened physiological responses to stressors have been linked to an increased risk of CV diseases and mortality (Chida & Steptoe, 2010; Weiss et al., 2010; Schultz et al., 2013), our results demonstrating MBSR-driven reductions in SNS stress reactivity have important clinical implications for CV risk management in CKD.

Our data also demonstrate that participants who initially displayed an augmented MSNA response to stress exhibited a more substantial reduction in MSNA reactivity following the MBSR intervention. This pattern of intervention response linked to the initial stress profile was specific to MBSR and not observed within the HEP group; thus, it is unlikely that these findings can be explained by regression toward the mean. These findings are in line with previous reports demonstrating a greater degree of BP reduction with MBSR in those with elevated levels of BP initially (Loucks et al., 2019; Lee et al., 2020). Therefore, our findings suggest that the expected benefits of MBSR on autonomic stress reactivity may vary depending on an individual’s initial stress response patterns, emphasizing the importance of tailored interventions to maximize the clinical utility of MBSR for optimal CV risk management in CKD.

Contrary to our hypothesis, decreased MSNA reactivity was not significantly associated with changes in BP reactivity, nor did resting BP and MSNA change significantly following the MBSR intervention in the present study. Many (Younge et al., 2015; Scott-Sheldon et al., 2020), but not all meta-analyses (Abbott et al., 2014) have demonstrated clinically significant reductions in BP as well as task-driven BP responses after participating in an MBSR intervention in individuals with CV disease. Our previous investigation showed BP and MSNA were acutely attenuated during a mindfulness meditation session that was sustained during the immediate recovery period in CKD patients (Park et al., 2014). However, in the present study, resting BP and MSNA were not altered after the completion of 8 weeks of MBSR, although the time frame and study design were not comparable between the previous and the current studies (i.e., the acute response to 14 minutes of mindfulness meditation vs. the changes over 8 weeks on resting MSNA and responses to a stressor). It is possible that more comprehensive or prolonged practice is needed for sustained improvements in resting MSNA, with downstream improvements in BP profiles in CKD. Alternatively, long-term change in BP stress reactivity may be more closely tied to peripheral vascular (i.e., adrenergic receptor sensitivity) and autonomic feedback (i.e., baroreflex sensitivity) mechanisms rather than changes in central SNS output, or due to other non-adrenergic mechanisms (i.e., inflammatory or renin-angiotensin-aldosterone system (RAAS) pathways). Furthermore, differences in sympathetic transduction could also alter the relationship between MSNA and BP, and should be further investigated in future studies. It should also be noted that the majority of study participants were on anti-hypertensive medications, including RAAS inhibitors (76%), calcium-channel blockers (55%) and beta-blockers (38%), which might have modulated the transduction of SNS activation on peripheral vasculature during an acute stressor to some extent.

We observed discrepant results in MSNA reactivity during different types of stressors following MBSR in CKD. While we observed significant reductions in ΔMSNA burst frequency and incidence during mental arithmetic and a reduction in ΔMSNA burst incidence during static handgrip exercise after MBSR, no significant change in MSNA reactivity was observed during pain stress by cold pressor test. Although the mechanisms underlying these discrepant results are unclear, these differences in autonomic stress reactivity after MBSR may be attributed to the unique physiological mechanisms underlying each stressor. Mental stress increases SNS activity primarily through central neural pathways involving higher brain centers such as the prefrontal cortex, amygdala, and hippocampus (Herman et al., 2003; Ulrich-Lai & Herman, 2009). On the other hand, physical exercise involves a multifaceted interplay of peripheral and central mechanisms that increase SNS activity (Gallagher et al., 2006; Smith et al., 2006). This includes input from metabo- and mechano-receptors in skeletal muscles, baroreflex receptors on the carotid arteries, aortic arch, and pulmonary vessels, and central command signals, all working together to regulate SNS activity (Gallagher et al., 2006; Smith et al., 2006). The cold pressor test primarily increases SNS via nociceptors (pain receptors) on the skin (Burton et al., 2016). These peripheral factors are closely tied to the physiological demands posed by exercise and pain and play a significant role in determining autonomic responses. Mindfulness practice aims to promote emotional self-regulation and reduce stress appraisal, potentially achieved through enhanced regulation of central neural signals. Previous evidence has demonstrated that mindfulness training can reduce CV responses during mental stress tasks (Nyklicek et al., 2013; Lindsay et al., 2018), and induce positive changes in brain regions responsible for processing stress neural signals (Creswell et al., 2007; Modinos et al., 2010; Holzel et al., 2013; Taren et al., 2015). In addition, previous work has shown that CKD patients have exaggerated exercise pressor reflex leading to augmented blood pressure reactivity during handgrip exercise (Park et al., 2013). Therefore, MBSR may have greater effects on SNS activation during mental stress and physical stress, driven by both central and peripheral mechanisms, while its impact on pain stress, mediated largely by peripheral nociceptive pathways, may be less pronounced due to the reduced involvement of central autonomic pathways (Gallagher et al., 2006; Smith et al., 2006; Burton et al., 2016). Additionally, baroreflex sensitivity and its resetting during stress may modulate SNS activity differently across various stressors and contribute to the variability in autonomic responses (Dampney, 2017). Although we assessed resting BRS data, these measures might not fully reflect baroreflex function during distinct stress tasks. Our study was not designed to reveal the different mechanisms and mediating variables behind this dissociation, which may be worthy of further exploration.

Limitations

The majority of participants were Black males which may limit the generalizability of study results to females and other races. Antihypertensive medications such as angiotensin receptor blockers are known to impact sympathetic activity (Ohlstein et al., 1997), and therefore, may have confounded results, although no difference in medication usage was found between groups at baseline, and the primary results remained the same when adjusted for medication use. Furthermore, participants maintained a stable medication regimen throughout the study period. Therefore, MBSR-induced changes in MSNA stress reactivity are likely to represent true intervention effects, and the results of this study can be applicable to the general medicated CKD patients. MSNA burst amplitude (i.e., MSNA total activity) was not quantified due to shifts in baseline during some of the stress maneuvers. The intervention sessions were administered virtually due to COVID-19 restrictions. However, besides the virtual platform, MBSR was administered per standard protocol by a certified MBSR trainer. The nature of the interventions did not allow for masking of the MBSR and HEP instructors and participants. However, analyses of all physiologic data were made in a masked fashion without the investigators’ knowledge of group assignment. In addition, the active control intervention, HEP, was administered in parallel and matched for group setting, instructor attention, intervention duration, time spent on at-home practice while omitting any components of mindfulness. We acknowledge the unequal group sizes in this early phase RCT that prioritized randomization to the active intervention group. A sensitivity analysis demonstrated consistent results, and the effect size measures that are adjusted for small and unbalanced groups (Lakens, 2013; Kroes & Finley, 2023) indicated moderate to large intervention effects in the primary outcomes, supporting the reliability of the observed intervention impact.

Conclusion

In this randomized controlled trial, we evaluated the effects of MBSR on SNS activity and reactivity in CKD and demonstrated a beneficial effect of MBSR on sympathetic reactivity during mental stress and static handgrip exercise. We also observed greater reductions in MSNA reactivity in participants with higher MSNA reactivity at baseline suggesting that MBSR may have greater beneficial effects in patients with higher sympathetic reactivity to stress. Our results highlight the therapeutic potential of MBSR in ameliorating mental stress-induced SNS overactivation in CKD.

Supplementary Material

Supinfo1

Supplemental Figure 1. Mean and Individual Reactivity in Muscle Sympathetic Nervous Activity (MSNA) Burst Frequency (A, B), MSNA Burst Incidence (C, D), Mean Arterial Blood Pressure (MAP) (E, F) and Heart Rate (HR) (G, H) during each minute of Mental Arithmetic from baseline (0 wk) to post-intervention (8 wk) in patients with chronic kidney disease randomized to Mindfulness-Based Stress Reduction (MBSR; N=17). Closed circles represent the means and standard deviations at the Minute.

P-values represent significant levels of within-group comparisons on the changes over 3 minutes by repeated ANOVA tests.

* denotes statistically significant within-group difference from Minute 0 by LSD post-hoc tests.

^# denotes statistically significant within-group difference from Minute 1 by LSD post-hoc tests.

Supinfo2

Supplemental Figure 2. Mean and Individual Reactivity in Muscle Sympathetic Nervous Activity (MSNA) Burst Frequency (A, B), MSNA Burst Incidence (C, D), Mean Arterial Blood Pressure (MAP) (E, F) and Heart Rate (HR) (G, H) during each minute of Mental Arithmetic from baseline (0 wk) to post-intervention (8 wk) in patients with chronic kidney disease randomized to Health Enhancement Program (HEP; N=12). Closed circles represent the means and standard deviations at the Minute.

P-values represent significant levels of within-group comparisons on the changes over 3 minutes by repeated ANOVA tests.

* denotes statistically significant within-group difference from Minute 0 by LSD post-hoc tests.

^# denotes statistically significant within-group difference from Minute 1 by LSD post-hoc tests.

Key Points.

Question:

Does Mindfulness-Based Stress Reduction (MBSR) program reduce sympathetic activity in patients with chronic kidney disease (CKD)?

Finding:

In this randomized controlled trial including 29 patients with CKD, 8 weeks of MBSR decreases sympathetic reactivity to mental stress compared to the control Health Enhancement Program (HEP).

Meaning:

These finding suggest that mindfulness training may have clinically beneficial effects on autonomic function in CKD.

Data Availability Statement

All data supporting the results of the present study are reported in the manuscript.