Baroreceptor Sensitivity in Individuals with CKD and Heart Failure : Kidney360

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Original Investigation: Chronic Kidney Disease

Baroreceptor Sensitivity in Individuals with CKD and Heart Failure

Charytan, David M.1; Soomro, Qandeel H.1; Caporotondi, Angelo2; Guazzotti, Giampaolo2; Maestri, Roberto3; Pinna, Gian Domenico3; La Rovere, Maria Teresa2

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Kidney360 3(12):p 2027-2035, December 2022. | DOI: 10.34067/KID.0004812022
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Heart failure and CKD commonly coexist (1,2), and the presence of CKD is associated with increased rates of cardiovascular events and all-cause mortality, particularly in more advanced stages of CKD (3,4). However, despite increasing recognition of the strong associations between CKD and heart failure outcomes, the underlying causes of the increased mortality remain incompletely understood.

Although the pathophysiology of cardiorenal syndrome is complex, autonomic nervous system dysfunction is likely to be an important contributor to the progression and high morbidity of cardiovascular disease in the setting of CKD. A robust body of evidence demonstrates that the prevalence of sympathovagal imbalance and elevated sympathetic tone are increased in individuals with significant impairment of kidney function (5–8). Furthermore, sympathetic overdrive without an appropriate increase in vagal tone may drive renin-angiotensin-aldosterone activation, with subsequent sodium retention and pathologic cardiovascular remodeling (9,10). In line with these data, increased muscle sympathetic nerve activity was associated with worse survival in a study of 122 individuals with heart failure (11). Similarly, trials of β-adrenergic receptor blockers have demonstrated significant mortality benefits in the setting of heart failure (12). Finally, reduced sensitivity of the baroreceptor reflex—a negative feedback loop in which arterial stretch reduces sympathetic tone and increases vagal tone, leading to vasodilation, negative inotropy, and reduced heart rate—has been implicated as a potent predictor of mortality in heart failure (13).

These data suggest that changes in autonomic function regulation have the potential to contribute to the high incidence of mortality in patients with combined CKD and heart failure. Nevertheless, data on autonomic function and its association with outcomes in the setting of combined CKD and heart failure are sparse, and we are unaware of any prior analyses describing the association of CKD with baroreceptor sensitivity (BRS) in the setting of heart failure. To understand the joint associations of CKD, BRS, and survival outcomes in heart failure better, we retrospectively analyzed data from a prospectively recruited cohort in which BRS and laboratory parameters were measured in patients with heart failure.

Materials and Methods

Study Patients

Because data on BRS in CKD are limited, we analyzed their association in a historical cohort, which provided a unique opportunity to assess BRS in patients with heart failure and early CKD. We retrospectively analyzed data from a previously recruited cohort study (14). The population under study included 247 individuals in sinus rhythm with moderate to severe heart failure consecutively referred for inpatient evaluation to a single heart failure unit from January 1996 to August 2002 who had been submitted to the assessment of autonomic function. Individuals with insulin-dependent diabetes were excluded from enrollment. At the time of the autonomic evaluation, patients were in a stable clinical condition on optimal therapy, were not undergoing titration of β blockers, and had not had a recent (within 6 months) myocardial infarction or cardiac surgery. All patients gave written informed consent, and the study was approved by the local ethics committee.

BRS Assessment

Subjects were studied in the morning, in the supine position. The experimental protocol comprised: instrumentation (electrocardiogram and noninvasive systolic BP [SBP] by Finapres [Ohmeda, Madison, WI]), patient familiarization, signal stabilization (about 20 minutes), and phenylephrine test (15). The phenylephrine test was carried out by injecting an intravenous bolus of drug (3–4 μg/kg) to raise SBP by 15–30 mm Hg. If necessary, the phenylephrine dose was increased by 50 μg in subsequent injections to reach the target BP increase. The injection was repeated twice after a 10-minute interval. In order to measure BRS, the RR intervals on the electrocardiogram were plotted against the preceding SBP value, and the analysis window was interactively defined as the interval between the beginning and the end of the first significant (>15 mm Hg) increase of SBP after drug injection. The gain of the reflex (in ms/mm Hg) was measured as the slope of the regression line between changes in RR interval (ms) from baseline and corresponding changes in SBP (mm Hg). BRS was calculated as the mean value of computed slopes, with lower values representing more significantly impaired parasympathetic reflexes. BRS was dichotomized as <3 ms/mm Hg or ≥3 ms/mm Hg because this threshold has been associated with outcomes in prior studies and was the threshold used in the original analysis of this dataset (14,15).

Clinical Evaluation, Laboratory Testing, and Follow-Up

Within 1 week of the autonomic evaluation, standard clinical and laboratory examinations, including 2D echocardiography, cardiopulmonary exercise testing, 24-hour Holter recording, and routine blood tests, including the baseline serum creatinine, were performed while the participant was in stable condition with compensated heart failure. SD of the interbeat normal sinus beats (SDNN) was calculated using 24-hour Holter monitor recordings. During follow-up, patients were periodically re-evaluated and hospitalized if clinically unstable. The date and mode of death and information regarding transplantation were investigated; events not occurring in hospitals were ascertained from chart review and/or telephone interview with relatives or the referring physician. Cardiovascular deaths included death from myocardial infarction, arrhythmia, heart failure, or cardiac transplantation. eGFR was assessed using the baseline serum creatinine and the 2009 CKD-Epi equation (16). We categorized CKD as present when CKD stage was ≥3 (eGFR <60 ml/min per 1.73 m2).

Statistical Analyses

Baseline characteristics for continuous variables are reported as the mean±SD or median (interquartile range), according to their distribution. Categorical variables are reported as n (%). To understand the association of BRS with CKD, we modeled BRS as a binary outcome (<3 ms/mm Hg versus ≥3 ms/mm Hg). Exploratory analyses also examined the relationship of eGFR as a continuous variable with BRS as a continuous measure using graphical analyses and univariate correlations.

Logistic regression models were utilized to assess the independence of the association of CKD with BRS. Models were adjusted for demographic factors, medications, and clinical factors potentially associated with cardiovascular death or autonomic and baroreceptor function. We additionally adjusted for indices of volume control and cardiac pump function (ejection fraction and left ventricular end systolic function) with potential association with cardiovascular outcomes and effect on the function of pressure/volume sensitive receptors in the aorta and carotid arch or with overall autonomic function (17–20). Additional covariates considered represented an index of cardiovascular fitness (peak oxygen consumption) (21–23) and the SDNN as a measure of heart rate variability/cardiovascular autonomic function (24). We considered four iterative models: (1) unadjusted; (2) model 1, adjusted for age and sex only; (3) model 2, adjusted for factors in model 1 plus clinical factors, including cause of heart failure, resting SBP, ejection fraction, left ventricular end systolic diameter, use of angiotensin-converting enzyme inhibitors, β blockers, and nitrates; (4) model 3, adjusted for factors in model 2 plus peak oxygen consumption, SDNN, and the presence of nonsustained ventricular tachycardia. To assess associations between the four categories and cardiovascular mortality, we considered the binary categories of CKD and abnormal BRS. Kaplan–Meir survival plots were produced, and the log-rank test was utilized to assess univariate associations. Cox proportional hazards models using the approach above were used to assess independence of associations of the four categories of CKD and BRS with cardiovascular mortality.

To avoid creating unstable model estimates, given the limited number of outcomes in the cohort, only the unadjusted model and models 1 and 2 were used in survival analyses. We additionally analyzed the interaction of the binary classification of CKD with BRS using the same models. An exploratory analysis also examined univariate associates of eGFR as a restricted cubic spline with three knots. A P value of <0.05 was considered statistically significant, and all tests were two-tailed. All statistical analyses were carried out using the SAS/STAT statistical package v9.4 (SAS Institute, Inc., Cary, NC).


Baseline Data

Baseline characteristics are shown in Table 1. There were 68 (28%) patients with CKD and 179 (73%) with preserved kidney function. The median eGFR among individuals with CKD was 52 (IQR 44–56) ml/min per 1.73 m2, with the majority (97%) having stage 3 CKD. One individual each (3%) had stage 4 CKD and stage 5 CKD. Patients with CKD were older than those with preserved kidney function (59 versus 53 years), more likely to have class III or above New York Heart Association heart failure (49% versus 32%), more likely to have ischemic disease as a cause of heart failure (68% versus 44%), and more likely to be using nitrates or amiodarone. Heart rate variability as assessed from the SDNN intervals was not different in those with and without CKD.

Table 1. - Demographic, clinical, and functional characteristics at baseline according to presence or absence of CKD
Characteristic CKD (N=68) Preserved Kidney Function (N=179) P Value
Age (yr) 59 (55–63) 53 (46–57) <0.001
Men (%) 84 85 0.83
NYHA class (%) 0.03
 I–II 51 68
 III–IV 49 32
Cause of heart failure (%): 0.001
 Ischemic 68 44
 Nonischemic 32 56
Baseline RR interval (ms) 853 (785–982) 878 (763–995) 0.68
Resting SBP (mm Hg) 112 (100–123) 110 (100–120) 0.38
Resting DBP (mm Hg) 70 (70–80) 70 (70–80) 0.27
Left ventricular ejection fraction (%) 25 (22–32) 27 (23–33) 0.13
Left ventricular end systolic diameter (mm) 59 (51–65) 59 (50–66) 0.65
Left ventricular end diastolic diameter (mm) 70 (62–72) 70 (65–78) 0.13
Mitral regurgitation 2–3+ (%) 29 28 0.89
Peak VO2 (ml/kg per min) 13 (11–16) 16 (14–19) <0.001
Ventricular premature contractions (n/h) 16 (4–58) 16 (3–59) 0.74
Nonsustained ventricular tachycardia (%) 34 39 0.44
SDNN (ms) 82 (62–107) 91 (64–117) 0.18
BRS (ms/mm Hg) 2.0 (0.5–5.7) 3.6 (1.1–7.8) 0.04
Angiotensin-converting enzyme inhibitor (%) 87 85 0.71
β blocker (%) 37 44 0.33
Diuretics (%) 91 85 0.23
Nitrates (%) 71 47 0.001
Digitalis (%) 65 51 0.05
Amiodarone (%) 43 22 0.001
BUN (mg/dl) 59 (51–79) 45 (38–52) <0.001
Creatinine (mg/dl) 1.44 (1.37–1.60) 1.09 (0.95–1.2) <0.001
eGFR (ml/min per 1.73 m2) 52 (44–56) 75 (67–87) <0.001
Sodium (mEq/L) 140 (138–142) 140 (139–142) 0.21
Potassium (mEq/L) 4.4 (4.3–4.8) 4.3 (4.1–4.6) 0.01
Continuous variables are expressed as median (interquartile range). IQR, interquartile range; NYHA, New York Heart Association; SBP, systolic BP; DBP, diastolic BP; SDNN, SD of normal-to-normal RR intervals; BRS, baroreceptor sensitivity; VO2, volume of oxygen consumption.


Individuals with reduced BRS were markedly different than individuals with preserved BRS (Supplemental Tables 1 and 2). Notably, the use of angiotensin-converting enzyme inhibitors was similar in patients with and without reduced BRS, whereas the proportion of patients using β blockers was markedly lower (P<0.001) in the group with depressed BRS (26%) compared with those with preserved BRS (58%). eGFR was lower in those with depressed BRS (65 [IQR 54–76] ml/min per 1.73 m2) compared with those with preserved BRS (73 [IQR 64–87] ml/min per 1.73 m2; P<0.001). Conversely, median BRS was markedly lower (P=0.04) in those with CKD (2 [IQR 0.5–5.7] ms/mm Hg) compared with those with preserved kidney function (3.6 [IQR 1.7–7.8] ms/mm Hg). Of 68 individuals with CKD, 41 (60%) had depressed BRS compared with 83 of 179 (46%) individuals without CKD (P=0.05).

When examined as continuous variables, BRS and eGFR were modestly but significantly correlated (r=0.24; P<0.001), with BRS decreasing at lower eGFR (Figure 1). The relationship between eGFR and BRS was similar, with eGFR treated as a restricted cubic spline (P=0.01) with no clear inflection points, although the slope appeared to be marginally steeper at lower eGFR (Supplemental Figure 1). As shown in Table 2, the association of eGFR with BRS remained independent in models adjusted for age and sex (model 1) and with additional adjustment for etiology of heart failure (ischemic versus nonischemic), pump function, BP, and standard cardiovascular medications such as angiotensin-converting enzyme inhibitors, β blockers, and nitrates (model 2). Although point estimates were similar (odds ratio=0.98; 95% confidence interval [CI], 0.95 to 1), significance was lost with additional adjustment for maximal oxygen consumption, presence of nonsustained ventricular tachycardia and a measure of heart rate variability (SDNN intervals). Among the other factors in the models, only SBP, left ventricular ejection fraction, and use of β blockers (protective) were significantly associated with BRS in model 2. In model 3, only maximal oxygen consumption (higher levels associated with lower risk) and use of β blockers were independently associated with risk of depressed BRS. In unadjusted analyses, kidney function examined as binary variable (CKD versus no CKD) had a borderline association with depressed BRS (odds ratio=1.76, 95% CI, 1 to 3.1). Adjustment for additional risk factors in models 1–3 iteratively attenuated the strength of the association of CKD and BRS, which was not significant in any of the adjusted models.

Figure 1.:
Scatter plot of baroreceptor sensitivity according to eGFR. BRS, baroreceptor sensitivity.
Table 2. - Crude and adjusted associations of eGFR and CKD with baroreceptor sensitivity <3
eGFR (ml/min per 1.73 m2) CKD (eGFR <60 ml/min per 1.73 m2)
Model Odds Ratio (95% Confidence Interval) P Value Odds Ratio (95% Confidence Interval) P Value
Crude 0.97 (0.96–0.99) <0.001 1.76 (1–3.1) 0.05
Model 1 0.97 (0.95–0.99) <0.001 1.55 (0.84–2.85) 0.16
Model 2 0.98 (0.96–0.99) 0.01 1.38 (0.68–2.81) 0.38
Model 3 0.98 (0.96–1) 0.08 0.98 (0.46–2.07) 0.65
Model 1, adjusted for age and sex. Model 2, model 1 factors plus cause of heart failure, systolic BP, left ventricular ejection fraction, left ventricular systolic diameter, use of angiotensin-converting enzyme inhibitors, use of β blockers, and use of nitrates. Model 3, model 2 factors plus maximum oxygen consumption, heart rate variability as measured by the SD of NN intervals, and presence of nonsustained ventricular tachycardia.

Cardiovascular Survival

Cardiovascular survival during follow-up was not significantly different in patients with and without CKD (Figure 2A; P=0.18). Twenty-six (38%) patients with CKD and 46 (26%) patients with preserved kidney function died due to cardiovascular causes (P=0.05). In contrast, cardiovascular survival was significantly shorter among individuals with depressed BRS than in individuals with preserved BRS (Figure 2B; P≤0.001), with 53 (43%) cardiovascular deaths among 124 patients with depressed BRS compared with 19 (16%) deaths among the 123 individuals with preserved BRS (P<0.001). Cardiovascular mortality occurred in 13 of 96 (14%) patients with preserved kidney function and preserved BRS, 6 of 27 (22%) individuals with CKD and preserved BRS, 33 of 83 (40%) individuals with depressed BRS and preserved kidney function, and 20 of 41 (49%) individuals with CKD and depressed BRS.

Figure 2.:
Time to cardiovascular death according to the presence of CKD or reduced BRS. (A) Time to cardiovascular death according to presence of CKD at baseline. CKD is shown in red and preserved kidney function in blue. (B) Time to cardiovascular death according to baseline BRS. Preserved BRS is shown in blue, and reduced BRS is shown in red.

In crude analyses (Figure 3, Table 3), survival was not different in individuals with CKD and preserved BRS compared with individuals with both preserved kidney function and preserved BRS (P=0.36). However, cardiovascular mortality risk was significantly higher in patients with depressed BRS with CKD (P<0.001) or with reduced BRS with preserved kidney function (P<0.001) compared with those with preserved kidney function and preserved BRS. Similarly, there was no evidence of significant effect modification by the presence of CKD of the association of BRS with cardiovascular mortality (Pinteraction=0.33). Results were similar in crude, age-, and sex-adjusted, and fully adjusted models (model 2), although effect estimates were reduced with additional adjustment. Compared with individuals with preserved BRS and preserved kidney function, individuals with BRS <3 ms/mm and preserved kidney function (hazard ratio [HR]=4.3; 95% CI, 2.18 to 8.48) and those with both BRS<3 ms/mm and CKD (HR=3.29; 95% CI, 1.49 to 7.27) had an increased risk of cardiovascular death. In contrast, the risk of cardiovascular death was not higher in those with CKD but preserved BRS (HR=0.99; 95% CI, 0.35 to 2.8).

Figure 3.:
Cardiovascular mortality-free survival according to combined BRS and CKD categories. P<0.001 for comparison no CKD/normal BRS group with no CKD/reduced BRS group. P=0.36 for comparison of no CKD/normal BRS with CKD/normal BRS. P<0.001 for comparison of no CKD/normal BRS with CKD/reduced BRS group.
Table 3. - Crude and adjusted association with cardiovascular mortality
Unadjusted Model 1 Model 2
CKD/BRS Group Hazard Ratio (95% Confidence Interval) P Value Hazard Ratio (95% Confidence Interval) P Value Hazard Ratio (95% Confidence Interval) P Value
Preserved kidney function/BRS ≥3 ms/mm Ref. Ref. Ref. Ref. Ref. Ref.
Preserved kidney function/BRS <3 ms/mm 6.17 (3.22–11.82) <0.001 5.87 (3.06–11.23) <0.001 4.3 (2.18–8.48) <0.001
CKD/BRS ≥3 ms/mm 1.57 (0.6–4.13) 0.36 1.47 (0.55–3.94) 0.45 0.99 (0.35–2.8) 0.99
CKD/BRS <3 ms/mm 5.53 (2.74–11.17) <0.001 4.68 (2.19–10.02 <0.001 3.29 (1.49–7.27) 0.03
Model 1, adjusted for age and sex. Model 2, model 1 factors plus cause of heart failure, systolic BP, left ventricular ejection fraction, left ventricular systolic diameter, use of angiotensin-converting enzyme inhibitors, and use of nitrates. CKD=0; BRS=preserved is the reference group. BRS, baroreceptor sensitivity; Ref., reference.


In this study, we analyzed the associations of CKD and cardiac BRS with each other and with cardiovascular mortality in a heterogeneous cohort of heart failure subjects. We found that depressed BRS is common in patients with CKD and heart failure compared with those with heart failure and preserved kidney function (60% versus 46%) and that kidney function is independently associated with depressed BRS in models adjusted for key covariates. Although depressed BRS is associated with cardiovascular mortality in those with and without CKD, the presence of CKD did not incrementally worsen the risk of cardiovascular mortality over the effect of depressed BRS alone. In aggregate, our results underscore the central importance of baroreflex dysfunction as a determinant of CV outcomes in individuals with heart failure.

Prior investigations have also suggested a possible relationship between impaired kidney function and reduced cardiac BRS. For instance, in a study involving 55 predialysis, nondiabetic patients with a mean eGFR of 27 ml/min per 1.73 m2, the correlation coefficient for eGFR and BRS was 0.34 (P≤0.05). In addition, in a comparison of moderate (eGFR 15–59 ml/min per 1.73 m2) and severe CKD (eGFR <15 ml/min per 1.73 m2), cardiac BRS was significantly lower with severe CKD (8.7 versus 15.1 ms/mm Hg). However, in adjusted models using eGFR as a continuous variable, the association between eGFR and cardiac BRS was not significant (25). In contrast, in another study of 109 patients with a median eGFR of 23 ml/min per 1.73 m2, reduced kidney function and impaired BRS were significantly associated. However, unlike the current study, that investigation excluded individuals with heart failure (26). Our findings are consistent with these earlier studies in suggesting that reduced kidney function is associated with depressed cardiac BRS. The more modest correlation (r=0.24) observed here likely reflects the fact that the majority of the individuals we studied had mild CKD.

Cardiovascular mortality is high in patients with CKD, and autonomic dysfunction is believed to be an important contributor to the high risk of cardiovascular events (27). We found that risk of cardiovascular mortality in those with CKD and depressed BRS was nearly 2.5-fold higher compared with those with CKD and preserved BRS. In contrast, there was no significant increase in those with CKD but preserved BRS. This suggests that depressed cardiac BRS could be a key mediator of the increased cardiovascular mortality observed in CKD, particularly during the early stages of CKD present in the population we studied. However, we exclusively analyzed individuals with heart failure. Thus, the extent to which our findings are applicable to the population in general is uncertain. The absence of a significant association with cardiovascular mortality in those with CKD and preserved BRS may be attributable to the mild CKD in our cohort. In addition, some associations might be attenuated because the majority of patients were optimized on medications known to improve BRS such as β blockers and angiotensin-converting enzyme inhibitors. Conversely, this may suggest that BRS is a more important determinant of outcome in heart than impaired kidney function, and that individuals with CKD but preserved BRS may be at relatively low risk of adverse outcomes.

The baroreflex arc under autonomic control is crucial for short-term regulation of BP, and impaired BRS is an important prognostic factor for heart failure outcomes. Why BRS might be impaired in CKD and whether the relationship is bidirectional remains uncertain. Limited evidence suggests impairment of BRS in CKD is due to disease of the vascular and neural components forming the baroreflex arc, including vascular remodeling and calcification with increased arterial stiffness, and remodeling of the afferent neurons of the baroreflex (28). In fact, a causal path between CKD and reduced BRS is suggested by improvement of the latter after kidney transplantation, with the underlying mechanisms seemingly related to improving vascular rather than neural health (29). Conversely, the effect of uremia on neural function may be important. Afferent signaling failure can result in unrestrained sympathetic tone, which might be the primary mechanism underlying BRS abnormalities in CKD, although some evidence suggests that later in the course of the CKD, impairment of central processing may also be responsible (30). In contrast, in individuals with diabetes and in the elderly, efferent baroreflex dysfunction predisposing to parasympathetic activation and orthostatic hypotension is common (31).

Our findings suggest that the association between CKD and BRS begins with even a modest reduction in GFR, and even at this stage is likely to be an important contributor to the increased risks of cardiovascular mortality in individuals with CKD and heart failure. Similar inferences may be made from a small study of individuals with resistant hypertension and CKD who underwent baroreflex activation therapy for 6 months. At follow-up, there was significant improvement in proteinuria, albuminuria, and cystatin C with treatment compared with control, despite a nonsignificant improvement in BP (32). These findings suggest that research regarding the distinct contributions of heart failure and CKD to BRS abnormalities could help identify novel therapies to prevent heart failure progression. Therapies such as angiotensin-converting enzyme inhibitors have shown promise because both heart failure and CKD lead to activation of the renin-angiotensin axis, with stimulation of endogenous aldosterone leading to baroreceptor dysfunction (33,34). Similarly, there is emerging evidence that sodium/glucose cotransporter 2 inhibitors improve cardiovascular autonomic dysfunction (35). Our data suggest that changes in BRS may partly mediate the benefit of these established therapies and that measurement of BRS could be used to guide more tailored use of both established and novel therapies. Other innovative therapies more directly targeting the autonomic system such as transcutaneous vagal nerve stimulation and meditation to improve sympathovagal balance might also be worth investigating in select populations with CKD and heart failure.

Several limitations to the present study should be mentioned. First, the overall study population was small, and the majority had well-preserved kidney function. Furthermore, our CKD population was primarily limited to individuals with primarily mild (stage 3) CKD. As only two individuals had stage 4–5 CKD, we can only speculate about whether findings would be similar with more severe CKD. However, previous studies have identified linear associations of BRS with kidney function. Additionally, this was a single-center study of modest sample size of whom >80% of participants were men. Our results should be generalized cautiously, with more study needed in more advanced stages of CKD and in women because an association between sex and BRS has been described (36). Finally, although individuals with overt insulin-dependent diabetes were excluded, data on the presence of less severe diabetes were not collected. This limited ability to assess the interaction of diabetes and CKD on BRS or to disentangle fully the effects of CKD from diabetes.

BRS has been infrequently measured in the setting of CKD, and despite these limitations, our analysis of this unique cohort of patients with heart failure allowed us to parse through some of the complexities of the relationships between depressed BRS and CKD. Several of the key associations identified point in the direction of seeking more conclusive evidence of its role as an important contributor to cardiovascular mortality in the setting of CKD.

In conclusion, we found that CKD and cardiac baroreflex dysfunction are both highly co-prevalent in the heart failure population and that the association of moderate CKD with cardiovascular death was attenuated when BRS was preserved. Impaired BRS appears to be an important contributor to the high incidence of cardiovascular mortality in individuals with combined CKD and heart failure. Additional studies to understand the spectrum of BRS dysfunction better in this setting and its potential as therapeutic index or target are warranted.


D.M. Charytan reports consultancy for Allena Pharmaceuticals, Amgen, AstraZeneca, CSL Behring, Eli Lilly/Boehringer Ingelheim, Fresenius, Gilead, GSK, Janssen PLC Medical, Medtronic, Merck, Nitto Biopharma, Novo Nordisk, Renalytix, and Zogenix; research funding from Amgen, FifthEye (clinical), Gilead, Medtronic (clinical trial support), and NovoNordisk; an advisory or leadership role for the Clinical Journal of the American Society of Nephrology; and other interests or relationships as an expert witness (fees related to proton pump inhibitors). All remaining authors have nothing to disclose.


Q.H. Soomro is supported by an ASN Ben J. Lipps fellowship grant and partly by UL1TR001445.

Author Contributions

A. Caporotondi, D.M. Charytan, G. Guazzotti, M.T. La Rovere, R. Maestri, and G.D. Pinna were responsible for the methodology; A. Caporotondi, D.M. Charytan, M.T. La Rovere, and G.D. Pinna were responsible for conceptualization; A. Caporotondi, G. Guazzotti, M.T. La Rovere, R. Maestri, and G.D. Pinna were responsible for data curation; D.M. Charytan, Q.H. Soomro, G. Guazzotti, M.T. La Rovere, R. Maestri, and G.D. Pinna were responsible for the formal analysis; D.M. Charytan, G.D. Pinna, and Q.H. Soomro were responsible for visualization; D.M. Charytan and Q.H. Soomro wrote the original draft of the manuscript; and all authors were responsible for the investigation and validation, and reviewed and edited the manuscript.

Data Sharing Statement

Partial restrictions to the data and/or materials apply: Data are available from the last author upon request. Restriction on the use of data at the time of consent during the original study preclude deposition.

Supplemental Material

This article contains the following supplemental material online at

Supplemental Figure 1. Scatter plot of baroreceptor sensitivity according to eGFR, with eGFR treated as a restricted cubic spline with three knots.

Supplemental Table 1. Demographic, clinical and functional characteristics according to presence of depressed baroreceptor sensitivity (BRS <3 ms/mm Hg).

Supplemental Table 2. Demographic, clinical and functional characteristics according to CKD and baro-receptor sensitivity.


1. Bagshaw SM, Cruz DN, Aspromonte N, Daliento L, Ronco F, Sheinfeld G, Anker SD, Anand I, Bellomo R, Berl T, Bobek I, Davenport A, Haapio M, Hillege H, House A, Katz N, Maisel A, Mankad S, McCullough P, Mebazaa A, Palazzuoli A, Ponikowski P, Shaw A, Soni S, Vescovo G, Zamperetti N, Zanco P, Ronco C; Acute Dialysis Quality Initiative Consensus Group: Epidemiology of cardio-renal syndromes: Workgroup statements from the 7th ADQI Consensus Conference. Nephrol Dial Transplant 25: 1406–1416, 2010
2. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R: Cardiorenal syndrome. J Am Coll Cardiol 52: 1527–1539, 2008
3. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY: Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med 351: 1296–1305, 2004
4. Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, Collins AJ: Chronic kidney disease and the risk for cardiovascular disease, renal replacement, and death in the United States Medicare population, 1998 to 1999. J Am Soc Nephrol 16: 489–495, 2005
5. Orlov S, Cherney DZ, Pop-Busui R, Lovblom LE, Ficociello LH, Smiles AM, Warram JH, Krolewski AS, Perkins BA: Cardiac autonomic neuropathy and early progressive renal decline in patients with nonmacroalbuminuric type 1 diabetes. Clin J Am Soc Nephrol 10: 1136–1144, 2015
6. Thapa L, Karki P, Sharma SK, Bajaj BK: Cardiovascular autonomic neuropathy in chronic kidney diseases. JNMA J Nepal Med Assoc 49: 121–128, 2010
7. de Oliveira CA, de Brito Junior HL, Bastos MG, de Oliveira FG, Casali TG, Bignoto TC, Fernandes NM, Beraldo AF, de Paula RB: Depressed cardiac autonomic modulation in patients with chronic kidney disease. J Bras Nefrol 36: 155–162, 2014
8. Ligtenberg G, Blankestijn PJ, Oey PL, Klein IH, Dijkhorst-Oei LT, Boomsma F, Wieneke GH, van Huffelen AC, Koomans HA: Reduction of sympathetic hyperactivity by enalapril in patients with chronic renal failure. N Engl J Med 340: 1321–1328, 1999
9. Curtis BM, O’Keefe Jr JH: Autonomic tone as a cardiovascular risk factor: The dangers of chronic fight or flight. Mayo Clin Proc 77: 45–54, 2002
10. Nishi EE, Bergamaschi CT, Campos RR: The crosstalk between the kidney and the central nervous system: The role of renal nerves in blood pressure regulation. Exp Physiol 100: 479–484, 2015
11. Barretto AC, Santos AC, Munhoz R, Rondon MU, Franco FG, Trombetta IC, Roveda F, de Matos LN, Braga AM, Middlekauff HR, Negrão CE: Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol 135: 302–307, 2009
12. Packer M, Coats AJ, Fowler MB, Katus HA, Krum H, Mohacsi P, Rouleau JL, Tendera M, Castaigne A, Roecker EB, Schultz MK, DeMets DL; Carvedilol Prospective Randomized Cumulative Survival Study Group: Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 344: 1651–1658, 2001
13. Osterziel KJ, Hänlein D, Willenbrock R, Eichhorn C, Luft F, Dietz R: Baroreflex sensitivity and cardiovascular mortality in patients with mild to moderate heart failure. Br Heart J 73: 517–522, 1995
14. La Rovere MT, Pinna GD, Maestri R, Robbi E, Caporotondi A, Guazzotti G, Sleight P, Febo O: Prognostic implications of baroreflex sensitivity in heart failure patients in the beta-blocking era. J Am Coll Cardiol 53: 193–199, 2009
15. La Rovere MT, Pinna GD, Raczak G: Baroreflex sensitivity: Measurement and clinical implications. Ann Noninvasive Electrocardiol 13: 191–207, 2008
16. Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro 3rd AF, Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J; CKD EPI: A new equation to estimate glomerular filtration rate. Ann Intern Med 150: 604–612, 2009
17. Connelly TP, Sheldahl LM, Tristani FE, Levandoski SG, Kalkhoff RK, Hoffman MD, Kalbfleisch JH: Effect of increased central blood volume with water immersion on plasma catecholamines during exercise. J Appl Physiol (1985) 69: 651–656, 1990
18. Hinghofer-Szalkay H: Gravity, the hydrostatic indifference concept and the cardiovascular system. Eur J Appl Physiol 111: 163–174, 2011
19. Ito K, Li S, Homma S, Thompson JLP, Buchsbaum R, Matsumoto K, Anker SD, Qian M, Di Tullio MR; WARCEF Investigators: Left ventricular dimensions and cardiovascular outcomes in systolic heart failure: The WARCEF trial. ESC Heart Fail 8: 4997–5009, 2021
20. Debonnaire P, Heyning CMV, Haddad ME, Coussement P, Paelinck B, de Ceuninck M, Timmermans F, De Bock D, Drieghe B, Dujardin K, Vandekerckhove Y, Kedhi E, Claeys M, Van der Heyden J: Left ventricular end-systolic dimension and outcome in patients with heart failure undergoing percutaneous MitraClip valve repair for secondary mitral regurgitation. Am J Cardiol 126: 56–65, 2020
21. Masson GS, Borges JP, da Silva PP, da Nóbrega AC, Tibiriçá E, Lessa MA: Effect of continuous and interval aerobic exercise training on baroreflex sensitivity in heart failure. Auton Neurosci 197: 9–13, 2016
22. Komine H, Sugawara J, Hayashi K, Yoshizawa M, Yokoi T: Regular endurance exercise in young men increases arterial baroreflex sensitivity through neural alteration of baroreflex arc. J Appl Physiol (1985) 106: 1499–1505, 2009
23. Swank AM, Horton J, Fleg JL, Fonarow GC, Keteyian S, Goldberg L, Wolfel G, Handberg EM, Bensimhon D, Illiou MC, Vest M, Ewald G, Blackburn G, Leifer E, Cooper L, Kraus WE; HF-ACTION Investigators: Modest increase in peak VO2 is related to better clinical outcomes in chronic heart failure patients: Results from heart failure and a controlled trial to investigate outcomes of exercise training. Circ Heart Fail 5: 579–585, 2012
24. Ponikowski P, Anker SD, Chua TP, Szelemej R, Piepoli M, Adamopoulos S, Webb-Peploe K, Harrington D, Banasiak W, Wrabec K, Coats AJ: Depressed heart rate variability as an independent predictor of death in chronic congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 79: 1645–1650, 1997
25. Lacy P, Carr SJ, O’Brien D, Fentum B, Williams B, Paul SK, Robinson TG: Reduced glomerular filtration rate in pre-dialysis non-diabetic chronic kidney disease patients is associated with impaired baroreceptor sensitivity and reduced vascular compliance. Clin Sci (Lond) 110: 101–108, 2006
26. Bavanandan S, Ajayi S, Fentum B, Paul SK, Carr SJ, Robinson TG: Cardiac baroreceptor sensitivity: A prognostic marker in predialysis chronic kidney disease patients? Kidney Int 67: 1019–1027, 2005
27. Soomro QH, Charytan DM: Cardiovascular autonomic nervous system dysfunction in chronic kidney disease and end-stage kidney disease: Disruption of the complementary forces. Curr Opin Nephrol Hypertens 30: 198–207, 2021
28. Kaur M, Chandran D, Lal C, Bhowmik D, Jaryal AK, Deepak KK, Agarwal SK: Renal transplantation normalizes baroreflex sensitivity through improvement in central arterial stiffness. Nephrol Dial Transplant 28: 2645–2655, 2013
29. Jha VK, Bhowmik D, Agarwal SK, Kaur M, Jaryal A: Renal transplantation significantly improves autonomic function with normalization of baroreflex sensitivity as early as three-month post-transplantation. Saudi J Kidney Dis Transpl 32: 645–656, 2021
30. Salman IM, Hildreth CM, Ameer OZ, Phillips JK: Differential contribution of afferent and central pathways to the development of baroreflex dysfunction in chronic kidney disease. Hypertension 63: 804–810, 2014
31. Kaufmann H, Norcliffe-Kaufmann L, Palma JA: Baroreflex dysfunction. N Engl J Med 382: 163–178, 2020
32. Wallbach M, Lehnig LY, Schroer C, Hasenfuss G, Müller GA, Wachter R, Koziolek MJ: Impact of baroreflex activation therapy on renal function—A pilot study. Am J Nephrol 40: 371–380, 2014
33. Rangaswami J, Bhalla V, Blair JEA, Chang TI, Costa S, Lentine KL, Lerma EV, Mezue K, Molitch M, Mullens W, Ronco C, Tang WHW, McCullough PA; American Heart Association Council on the Kidney in Cardiovascular Disease and Council on Clinical Cardiology: Cardiorenal syndrome: Classification, pathophysiology, diagnosis, and treatment strategies: A scientific statement from the American Heart Association. Circulation 139: e840–e878, 2019
34. Yee KM, Struthers AD: Endogenous angiotensin II and baroreceptor dysfunction: A comparative study of losartan and enalapril in man. Br J Clin Pharmacol 46: 583–588, 1998
35. Spallone V, Valensi P: SGLT2 inhibitors and the autonomic nervous system in diabetes: A promising challenge to better understand multiple target improvement. Diabetes Metab 47: 101224, 2021
36. Fisher JP, Kim A, Hartwich D, Fadel PJ: New insights into the effects of age and sex on arterial baroreflex function at rest and during dynamic exercise in humans. Auton Neurosci 172: 13–22, 2012

chronic kidney disease; autonomic dysfunction; baroreceptor sensitivity; CKD; heart failure; pressoreceptors

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