Clin Res Cardiol DOI 10.1007/s00392-015-0832-5
ORIGINAL PAPER
Effects of renal sympathetic denervation on urinary sodium excretion in patients with resistant hypertension Janine Po¨ss • Sebastian Ewen • Roland E. Schmieder • Sonja Muhler • Oliver Vonend • Christian Ott • Dominik Linz • Ju¨rgen Geisel • Lars C. Rump Markus Schlaich • Michael Bo¨hm • Felix Mahfoud
•
Received: 12 October 2014 / Accepted: 19 February 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Background Sympathetic overactivity increases sodium retention and contributes to the pathophysiology of hypertension. Renal sympathetic denervation lowers blood pressure and reduces sympathetic activity in certain patients with resistant hypertension. Methods and results This study aimed to assess the effect of renal denervation on urinary sodium excretion. 24-h urinary sodium excretion was estimated at baseline and after 6 months using the Kawasaki formula in 137 patients
J. Po¨ss and S. Ewen contributed equally. J. Po¨ss (&) S. Ewen S. Muhler D. Linz M. Bo¨hm F. Mahfoud (&) Klinik fu¨r Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universita¨tsklinikum des Saarlandes, Kirrberger Str., Geb. 40, 66421 Homburg/Saar, Germany e-mail: [email protected] F. Mahfoud e-mail: [email protected] R. E. Schmieder C. Ott Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universita¨tsklinikum Erlangen, Erlangen, Germany O. Vonend L. C. Rump Klinik fu¨r Nephrologie, Universita¨tsklinikum Du¨sseldorf, Du¨sseldorf, Germany J. Geisel Klinische Chemie und Laboratoriumsmedizin, Universita¨tsklinikum des Saarlandes, Homburg/Saar, Germany M. Schlaich Neurovascular Hypertension and Kidney Disease Laboratories, Baker IDI Heart and Diabetes Institute, Alfred Hospital, Melbourne, Australia
with resistant hypertension undergoing renal denervation. Sodium excretion was adjusted for cystatin C GFR and fractional sodium excretion was assessed. Mean office systolic blood pressure at baseline was 171 ± 2 mmHg despite an intake of 5.2 ± 0.1 antihypertensive drugs. Six months after renal denervation, systolic and diastolic BP decreased by 18 ± 2 mmHg (p \ 0.0001) and 10 ± 1 mmHg (p \ 0.001). 90 patients (65.7 %) had SBP reductions C10 mmHg (responders). After 6 months, 24-h UNa increased by 13 % compared to baseline (236 ± 9 vs. 268 ± 9 mmol/day, p \ 0.003). This increase was most pronounced in patients with less response in BP. These findings were paralleled by a significant increase in fractional sodium excretion (1.19 ± 0.11 vs. 1.64 ± 0.14 %, p \ 0.0001) and were observed independently of the intake of antihypertensive drugs affecting sodium balance, such as mineralocorticoid receptor antagonists or diuretics. Conclusion RDN lowered BP and increased estimated UNa and fractional sodium excretion in patients with resistant hypertension independently of renal function and antihypertensive therapy. Keywords Resistant hypertension Renal sympathetic denervation 24-h sodium excretion Fractional sodium excretion Kawasaki formula
Introduction Hypertension is the major cardiovascular risk factor accounting for most deaths worldwide [1]. Renal sympathetic nerve activity is involved in the development and progression of hypertension [2]. Predominant mechanisms include increased urinary sodium retention via activation of a1B-adrenoceptors and increased renin release via
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stimulation of b1-adrenoceptors [2]. Sodium plays an important pathophysiological role in hypertension as it elevates blood pressure (BP) by expanding the plasma volume, reducing the effects of vasodilatory agents and interacting with components of the sympathetic nervous system [3]. Beyond its impact on BP, sodium exerts direct harmful cardiovascular effects such as increasing the risk of stroke [4], left ventricular hypertrophy [5] and arterial stiffness [6]. There are experimental data indicating that renal denervation (RDN) can increase sodium excretion on a short-term basis of several weeks [2]. Catheter-based RDN has been documented to effectively reduce BP and sympathetic nerve activity in patients with resistant hypertension [7–12]. The exact mechanisms by which RDN results in BP reduction are not yet fully understood, but are likely to include a progressive reduction in total peripheral resistance, reduced activity of the renin–angiotensin system and favorable alterations of water and salt handling. This prospective study aimed to investigate the effects of RDN on urinary sodium excretion and its relationship to the achieved BP reduction 6 months after RDN in 137 patients with resistant hypertension treated in three different specialized centers.
Methods
medically required. At the 6-month follow-up, patients were classified, based on their office BP, into a responder group (SBP reduction C10 mmHg) and a non-responder group (SBP reduction \10 mmHg). Renal sympathetic denervation procedure All patients underwent bilateral RDN. The RDN procedure was performed via femoral access with a special radiofrequency catheter (SymplicityTM Catheter System, Ardian/Medtronic Inc., California, USA) inserted percutaneously and advanced to the distal segment of the renal artery under fluoroscopy. A detailed description of the procedure has been published elsewhere [16]. All RDN procedures were performed by experienced interventionalists between February 2011 and October 2012 with subsequent follow-up of 6 months (FU). Based on their office SBP at 6-month FU, patients were classified into a responder group (SBP reduction C10 mmHg) and a nonresponder group (SBP reduction \10 mmHg). Office BP readings were taken in a seated position with an automatic oscillometric Omron HEM-705 monitor (Omron Healthcare, Vernon Hills, IL, USA) after 5 min of rest according to the Standard Joint National Committee VII Guidelines [17]. At baseline, BP was measured at each arm and the arm with the higher BP was used for all subsequent readings. Averages of the triplicate measures were calculated and used for analysis.
Studied patients Measurement of renin and aldosterone concentrations The study included 137 patients undergoing RDN in three different hypertension centers of excellence (Universita¨tsklinikum des Saarlandes, Homburg/Saar; Universita¨tsklinikum Erlangen; Universita¨tsklinikum Du¨sseldorf). Patients were aged C18 years with an office SBP above goal (C140 mmHg) despite the use of at least three antihypertensive agents of different classes, including a diuretic at the maximum or highest tolerated dose [13]. Patients with GFR \15 ml/min/1.73 m2 and patients on hemodialysis were excluded. The measurements were performed as an extension to the Symplicity protocols (NCT00664638, NCT00888433, and NCT01888315). The study was approved by the local ethic committees in accordance with the Declaration of Helsinki. Only patients with stable antihypertensive drug regimen were included and patients with known, treatable secondary causes of hypertension were excluded [14, 15]. All patients underwent a complete history and physical examination, assessment of vital signs, and review of medication. Patients were interviewed whether they had taken their complete medication at defined doses. Patients and physicians were instructed not to change antihypertensive medication during the study period except when
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Renin plasma concentrations were assessed by chemiluminescent immunoassay (Diasorin LIAISONÒ). Aldosterone concentrations were measured by ELISA (IBL). Estimation of 24-h sodium excretion 24-h urinary sodium excretion (UNa) was estimated at baseline and after 6 months from a fasting morning urine sample using the Kawasaki formula [18]. This equation is based on patient’s gender, age, body weight, height, as well as sodium and creatinine concentrations in the spot urine sample [19] and has been shown to provide a reliable estimation of 24-h sodium excretion in patients taking antihypertensive drugs [20]. The effect of RDN on kidney function was analyzed in all patients with impaired renal function either at baseline or after 6 months according to the KDOQI criteria (by cystatin C GFR \90 ml/min) [21]. To minimize interference induced by renal dysfunction, UNa was adjusted for cystatin C GFR. Furthermore, fractional sodium excretion (FENa), defined as the percentage of the sodium filtered by the kidney that is excreted in the urine, was assessed [22].
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Statistical analysis
Sodium excretion
Data are presented as mean ± standard error of the mean (SEM) unless otherwise specified. Statistical comparisons for continuous variables were made with paired student’s t test, ANOVA or Wilcoxon rank sum test, when appropriate. Categorical variables were compared by a Pearson Chi-square test or Wilcoxon rank sum test. Significance tests were two-tailed with p \ 0.05 considered significant. All statistical analyses were calculated using the SPSS statistical software (version 20.0, SPSS Inc., Chicago, Illinois).
Mean estimated urinary sodium excretion at baseline using the Kawasaki formula was 236 ± 9 mmol/day. After 6 months, urinary sodium excretion was increased by 13 % to 268 ± 9 (p = 0.003). This was paralleled by a significant increase in fractional sodium excretion (1.19 ± 0.11 at baseline vs. 1.64 ± 0.14 % after 6 months, p \ 0.001) (Fig. 1a–c).
Results A total of 137 patients with resistant hypertension (mean age of 63 ± 1 years) were included. The patients’ baseline characteristics are depicted in Table 1. Despite an average intake of 5.2 ± 0.1 antihypertensive drugs, average office SBP/DBP was 171 ± 2/93 ± 1 mmHg with a heart rate (HR) of 70 ± 1 bpm. RDN was performed in all patients without procedural complications. Six months after RDN, SBP was reduced by 18 ± 2 mmHg (p \ 0.001) and DBP by 10 ± 1 mmHg (p \ 0.001), respectively, and HR was reduced by 3 ± 1 bpm (p = 0.008). 90 patients (65.7 %) had SBP reductions C10 mmHg and, thus were classified as responders. We did not observe significant changes in kidney function measured by cystatin C GFR (Table 2).
Influence of antihypertensive medication Patients and physicians were instructed not to change antihypertensive medication during the study period. However, antihypertensive drug regimen was reduced in 11 patients (8 %) due to confirmed blood pressure levels below respective target BP or the development of symptomatic hypotension. Antihypertensive treatment was increased in 11 patients (8 %) who remained above target BP during FU. Censoring for these post-procedural medication changes did not affect the observed results regarding the increase in sodium excretion after RDN, making a relevant influence of treatment intensification unlikely. To further exclude a bias induced by antihypertensive medication, a sub-analysis was performed investigating sodium excretion in patients according to the intake of agents with relevant effects on urinary sodium excretion, namely diuretics and mineralocorticoid receptor antagonists (MRA). Herein, 115 patients (84 %) were treated with diuretics and 23 patients (17 %) with MRA, respectively. Notably, neither sodium excretion at baseline nor the observed increase after 6 months was different in patients taking MRA or diuretics (Fig. 2a, b).
Table 1 Baseline characteristics of all (n = 137) patients All patients n = 137
Renin and aldosterone
Age (years) Male
63 ± 1 86 (63 %)
BMI (kg/m2)
30.4 ± 0.4
In a subgroup of patients (n = 66), renin and aldosterone plasma concentrations were measured. RDN did not significantly change plasma renin (baseline: 95 ± 33 pg/ml, 6-month FU: 92 ± 32 pg/ml; p = 0.669) or aldosterone concentrations (baseline: 138 ± 8 pg/ml, 6-month FU: 150 ± 8 pg/ml; p = 0.06), although there was a trend towards an increase in aldosterone within 6 months after treatment. No differences in aldosterone concentrations were found after stratification of the patients in tertiles according to the extent of sodium excretion after RDN precluding a counter-regulatory effect of aldosterone.
Office SBP (mmHg)
171 ± 2
Office DBP (mmHg)
93 ± 1
Coronary artery disease
30 (22 %)
Hypercholesterolemia
60 (44 %)
Type 2 diabetes
53 (39 %)
Number of antihypertensive drugs
5.2 ± 0.1
ACE inhibitors/ARBs
125 (91 %)
Beta-blockers
109 (80 %)
Calcium-channel blockers
105 (77 %)
Diuretics
115 (84 %)
Aldosterone receptor antagonists
23 (17 %)
Sympatholytics
72 (53 %)
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, ACE angiotensin-converting enzyme, ARB angiotensin receptor blocker
Sodium excretion and blood pressure reduction There was no correlation between sodium excretion and BP lowering after RDN (r = 0.101, p = 0.246). To further investigate the relationship between sodium excretion and BP reduction, patients were stratified in tertiles according
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Clin Res Cardiol Table 2 Changes of important parameters from baseline to 6-month follow-up
SBP systolic blood pressure, DBP diastolic blood pressure, GFR glomerular filtration rate, KDOQI kidney disease outcomes quality initiative
All patients Baseline
6-month FU
n
p values
Office SBP (mmHg)
171 ± 2
153 ± 2
137
\0.001
Office DBP (mmHg)
93 ± 1
83 ± 2
137
\0.001
Office heart rate (bpm)
70 ± 1
67 ± 1
137
0.008
Number of antihypertensive drugs
5.2 ± 0.1
5.2 ± 0.1
137
0.947
Decrease (number of patients)
11
137
Increase (number of patients)
11
137
Plasma aldosterone (pg/ml)
138 ± 8
150 ± 8
67
0.06
Plasma renin (pg/ml)
95 ± 33
92 ± 32
67
0.669
Cystatin C GFR (mL/min/1.73 m2)
72 ± 3
69 ± 3
78
0.062
KDOQI 1 (GFR C90 mL/min/1.73 m2)
21
20
27 97 ± 5
24 85 ± 5
2
KDOQI 4–5 (GFR \30 mL/min/1.73 m ) Urine creatinine (mg/dl)
0.567 137
0.567 0.037
Fig. 1 Urinary sodium excretion before and 6 months after RDN. a Estimated sodium excretion estimated by the Kawasaki formula. b Fractional sodium excretion. BL baseline, 6 months, FU 6-month follow-up
Fig. 2 Estimated sodium excretion by the Kawasaki formula stratified according to the intake of— a mineralocorticoid receptor antagonists (MRA) and b diuretics
to SBP reduction after 6 months. Interestingly, the most pronounced increase in sodium excretion was observed in patients within the lowest tertile of SBP reduction (\10 mmHg), (Fig. 3a). Non-responders (SBP reduction \10 mmHg) were characterized by a larger increase in sodium excretion compared to responders, Fig. 3b. Notably, this relationship was not found between HR and sodium excretion.
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Discussion Catheter-based RDN offers a novel approach to selectively interrupt renal sympathetic fibers and effectively reduce BP in certain patients with uncontrolled hypertension. However, the exact mechanisms by which RDN causes BP lowering are unknown. The results of the present study show an increased sodium excretion in patients with
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Fig. 3 Increase in sodium excretion according to SBP reduction stratified—a by tertiles and b by responder state
resistant hypertension after RDN, even after adjustment for kidney function and consideration of concomitant diuretic and antihypertensive therapy. Abundant evidence indicates the crucial role of sympathetic activation in the pathogenesis of hypertension [23]. Experimental studies showed that targeted stimulation of renal sympathetic nerves decreases sodium excretion and increases renal tubular sodium reabsorption [2]. However, these effects were noted acutely in experimental settings. The effect of sympathetic activation on renal sodium homeostasis is mainly mediated by two neuroeffectors in the kidney: (1) stimulation of a1B-adrenoceptors directly increases renal tubular sodium retention by renal tubular epithelial cells and (2) activation of juxtaglomerular cells induced by b1-adrenoceptors leading to an increased renin release with subsequent aldosterone synthesis and release which, in turn, increases sodium retention [2]. Numerous studies show an adverse effect of a surfeit of sodium on arterial pressure [24, 25]. Patients with resistant hypertension show increased salt sensitivity, exhibiting a considerably larger degree of BP reduction after dietary salt restriction than general hypertensive populations [26]. International guidelines recommend a salt restriction to 5–6 g per day (class IA recommendation) [13]. RDN can lower sympathetic nervous system activity and both office and 24-h BP in patients with resistant hypertension [10, 11, 14]. Experimentally, surgical and chemical RDN increased sodium excretion by decreasing tubular sodium reabsorption acutely [2]. Interestingly, the present study shows a significantly increased estimated sodium excretion after RDN. This finding needs interpretation in light of the fact that sodium excretion was estimated 6 months after RDN and not directly following the procedure. The magnitude of sodium excretion did not correlate with the BP lowering post RDN and non-responders were characterized by a larger increase in sodium excretion compared to responders. These results suggest that the increase in sodium excretion might at least partly reflect an
increased sodium intake after RDN. Furthermore, the findings raise the question whether dietary sodium restriction or intensified diuretic therapy might potentiate the BP-lowering effect of RDN, especially in non-responders. Interestingly, a subgroup analysis of the Symplicity HTN-3 trial showed a trend towards an increased blood pressurelowering effect of RDN in patients with aldosterone antagonist treatment at baseline. The underlying mechanism is unknown but besides others might include an increased sodium excretion induced by aldosterone blockers [27]. It has been suggested that RDN affects renin and aldosterone concentrations by reducing renal b1-adrenoceptor activation. However, in our study, no significant differences in renin or aldosterone levels after RDN were observed and consecutively, the aldosterone/renin ratio remained unchanged. Furthermore, no counter-regulatory increase in aldosterone was documented in patients with the highest compared to the lowest tertile of sodium excretion. These findings have to be interpreted with caution as the intake of antihypertensive drugs (especially MRA, ARB/ACE inhibitors, beta-blockers, renin inhibitors) might affect components of the RAS system. RDN did not significantly decrease kidney function measured by cystatin C GFR (Table 2) [28]. Herein, a slight, non-significant trend towards a reduction in cystatin C GFR by 3 ml/min (from 72 ± 3 ml/min at baseline to 69 ± 3 ml/min; p = 0.062) was observed. In addition, fractional sodium excretion (FeNa) was measured. FeNa was significantly increased by 72 % after RDN and remained in a physiologic range (according to the current definitions), making a relevant renal tubular damage at baseline or after RDN unlikely. Since the dose of diuretics was kept unchanged in all included patients throughout the study period, the observed increase in FeNa cannot be explained by a change of diuretic therapy. These findings indicate that the observed increase in urinary sodium excretion is unrelated to renal dysfunction. This is in line with the results of earlier experimental studies showing that modulation of
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renal sympathetic nerves influenced sodium excretion without affecting GFR [2]. Another relevant factor influencing sodium excretion is the intake of antihypertensive and diuretic drugs. The Kawasaki formula (used herein to estimate the 24-h urinary sodium excretion) has been validated in patients on antihypertensive therapy [20]. To further address this issue, we stratified the patients according to the intake of diuretics and MRA, known to impact natriuresis. Notably, there were no differences in baseline or 6-month sodium excretion in patients treated with diuretics or MRA compared to those not receiving these agents. Our study might have some limitations. Due to the lack of a control group and/or a sham procedure, a potential bias with regard to blood pressure and sodium excretion cannot be excluded. 24-h urine collection was not performed. However, the approximation of 24-h sodium excretion as done herein has been validated in patients with hypertension and represents a reliable method to estimate sodium excretion [20]. Importantly, daily sodium intake was not assessed, precluding further investigation of the sodium balance and the above-mentioned issue whether BP nonresponse to RDN is related to a compensatory increased sodium intake. This issue should be investigated in further studies. Furthermore, sodium excretion was assessed after 6 months and not directly after RDN or after a shorter period of time, which would also be interesting.
Conclusion In this study, a significant increase in urinary sodium excretion was observed 6 months after RDN in patients with resistant hypertension. This effect remained apparent after consideration of antihypertensive drug therapy. Further trials are needed to answer the questions to which extent this effect is attributable to a natriuretic effect of RDN or rather a compensatory increased sodium intake and, in the latter case, whether a dietary sodium restriction or an increased diuretic therapy might potentiate the blood pressure-lowering effect of RDN. Acknowledgments The institution (Universita¨tsklinikum des Saarlandes) has received scientific support from Medtronic/Ardian (Mountain View, California, US). MB is supported by Deutsche Forschungsgemeinschaft (Bonn, Germany; KFO 196). SE, OV and FM are supported by Deutsche Hochdruckliga (Heidelberg, Germany). FM and MB are supported by Deutsche Gesellschaft fu¨r Kardiologie (Du¨sseldorf, Germany). Conflict of interest RES, MB and FM were investigators of Symplicity HTN-1 and HTN-2 trial. OV, RES, MB and FM have received speaker honorarium and consultancy fees from Medtronic/Ardian (Mountain View, California, US), St. Jude Medical (Eschborn, Germany).
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ORIGINAL PAPER
Effects of renal sympathetic denervation on urinary sodium excretion in patients with resistant hypertension Janine Po¨ss • Sebastian Ewen • Roland E. Schmieder • Sonja Muhler • Oliver Vonend • Christian Ott • Dominik Linz • Ju¨rgen Geisel • Lars C. Rump Markus Schlaich • Michael Bo¨hm • Felix Mahfoud
•
Received: 12 October 2014 / Accepted: 19 February 2015 Ó Springer-Verlag Berlin Heidelberg 2015
Abstract Background Sympathetic overactivity increases sodium retention and contributes to the pathophysiology of hypertension. Renal sympathetic denervation lowers blood pressure and reduces sympathetic activity in certain patients with resistant hypertension. Methods and results This study aimed to assess the effect of renal denervation on urinary sodium excretion. 24-h urinary sodium excretion was estimated at baseline and after 6 months using the Kawasaki formula in 137 patients
J. Po¨ss and S. Ewen contributed equally. J. Po¨ss (&) S. Ewen S. Muhler D. Linz M. Bo¨hm F. Mahfoud (&) Klinik fu¨r Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universita¨tsklinikum des Saarlandes, Kirrberger Str., Geb. 40, 66421 Homburg/Saar, Germany e-mail: [email protected] F. Mahfoud e-mail: [email protected] R. E. Schmieder C. Ott Medizinische Klinik 4, Nephrologie und Hypertensiologie, Universita¨tsklinikum Erlangen, Erlangen, Germany O. Vonend L. C. Rump Klinik fu¨r Nephrologie, Universita¨tsklinikum Du¨sseldorf, Du¨sseldorf, Germany J. Geisel Klinische Chemie und Laboratoriumsmedizin, Universita¨tsklinikum des Saarlandes, Homburg/Saar, Germany M. Schlaich Neurovascular Hypertension and Kidney Disease Laboratories, Baker IDI Heart and Diabetes Institute, Alfred Hospital, Melbourne, Australia
with resistant hypertension undergoing renal denervation. Sodium excretion was adjusted for cystatin C GFR and fractional sodium excretion was assessed. Mean office systolic blood pressure at baseline was 171 ± 2 mmHg despite an intake of 5.2 ± 0.1 antihypertensive drugs. Six months after renal denervation, systolic and diastolic BP decreased by 18 ± 2 mmHg (p \ 0.0001) and 10 ± 1 mmHg (p \ 0.001). 90 patients (65.7 %) had SBP reductions C10 mmHg (responders). After 6 months, 24-h UNa increased by 13 % compared to baseline (236 ± 9 vs. 268 ± 9 mmol/day, p \ 0.003). This increase was most pronounced in patients with less response in BP. These findings were paralleled by a significant increase in fractional sodium excretion (1.19 ± 0.11 vs. 1.64 ± 0.14 %, p \ 0.0001) and were observed independently of the intake of antihypertensive drugs affecting sodium balance, such as mineralocorticoid receptor antagonists or diuretics. Conclusion RDN lowered BP and increased estimated UNa and fractional sodium excretion in patients with resistant hypertension independently of renal function and antihypertensive therapy. Keywords Resistant hypertension Renal sympathetic denervation 24-h sodium excretion Fractional sodium excretion Kawasaki formula
Introduction Hypertension is the major cardiovascular risk factor accounting for most deaths worldwide [1]. Renal sympathetic nerve activity is involved in the development and progression of hypertension [2]. Predominant mechanisms include increased urinary sodium retention via activation of a1B-adrenoceptors and increased renin release via
123
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stimulation of b1-adrenoceptors [2]. Sodium plays an important pathophysiological role in hypertension as it elevates blood pressure (BP) by expanding the plasma volume, reducing the effects of vasodilatory agents and interacting with components of the sympathetic nervous system [3]. Beyond its impact on BP, sodium exerts direct harmful cardiovascular effects such as increasing the risk of stroke [4], left ventricular hypertrophy [5] and arterial stiffness [6]. There are experimental data indicating that renal denervation (RDN) can increase sodium excretion on a short-term basis of several weeks [2]. Catheter-based RDN has been documented to effectively reduce BP and sympathetic nerve activity in patients with resistant hypertension [7–12]. The exact mechanisms by which RDN results in BP reduction are not yet fully understood, but are likely to include a progressive reduction in total peripheral resistance, reduced activity of the renin–angiotensin system and favorable alterations of water and salt handling. This prospective study aimed to investigate the effects of RDN on urinary sodium excretion and its relationship to the achieved BP reduction 6 months after RDN in 137 patients with resistant hypertension treated in three different specialized centers.
Methods
medically required. At the 6-month follow-up, patients were classified, based on their office BP, into a responder group (SBP reduction C10 mmHg) and a non-responder group (SBP reduction \10 mmHg). Renal sympathetic denervation procedure All patients underwent bilateral RDN. The RDN procedure was performed via femoral access with a special radiofrequency catheter (SymplicityTM Catheter System, Ardian/Medtronic Inc., California, USA) inserted percutaneously and advanced to the distal segment of the renal artery under fluoroscopy. A detailed description of the procedure has been published elsewhere [16]. All RDN procedures were performed by experienced interventionalists between February 2011 and October 2012 with subsequent follow-up of 6 months (FU). Based on their office SBP at 6-month FU, patients were classified into a responder group (SBP reduction C10 mmHg) and a nonresponder group (SBP reduction \10 mmHg). Office BP readings were taken in a seated position with an automatic oscillometric Omron HEM-705 monitor (Omron Healthcare, Vernon Hills, IL, USA) after 5 min of rest according to the Standard Joint National Committee VII Guidelines [17]. At baseline, BP was measured at each arm and the arm with the higher BP was used for all subsequent readings. Averages of the triplicate measures were calculated and used for analysis.
Studied patients Measurement of renin and aldosterone concentrations The study included 137 patients undergoing RDN in three different hypertension centers of excellence (Universita¨tsklinikum des Saarlandes, Homburg/Saar; Universita¨tsklinikum Erlangen; Universita¨tsklinikum Du¨sseldorf). Patients were aged C18 years with an office SBP above goal (C140 mmHg) despite the use of at least three antihypertensive agents of different classes, including a diuretic at the maximum or highest tolerated dose [13]. Patients with GFR \15 ml/min/1.73 m2 and patients on hemodialysis were excluded. The measurements were performed as an extension to the Symplicity protocols (NCT00664638, NCT00888433, and NCT01888315). The study was approved by the local ethic committees in accordance with the Declaration of Helsinki. Only patients with stable antihypertensive drug regimen were included and patients with known, treatable secondary causes of hypertension were excluded [14, 15]. All patients underwent a complete history and physical examination, assessment of vital signs, and review of medication. Patients were interviewed whether they had taken their complete medication at defined doses. Patients and physicians were instructed not to change antihypertensive medication during the study period except when
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Renin plasma concentrations were assessed by chemiluminescent immunoassay (Diasorin LIAISONÒ). Aldosterone concentrations were measured by ELISA (IBL). Estimation of 24-h sodium excretion 24-h urinary sodium excretion (UNa) was estimated at baseline and after 6 months from a fasting morning urine sample using the Kawasaki formula [18]. This equation is based on patient’s gender, age, body weight, height, as well as sodium and creatinine concentrations in the spot urine sample [19] and has been shown to provide a reliable estimation of 24-h sodium excretion in patients taking antihypertensive drugs [20]. The effect of RDN on kidney function was analyzed in all patients with impaired renal function either at baseline or after 6 months according to the KDOQI criteria (by cystatin C GFR \90 ml/min) [21]. To minimize interference induced by renal dysfunction, UNa was adjusted for cystatin C GFR. Furthermore, fractional sodium excretion (FENa), defined as the percentage of the sodium filtered by the kidney that is excreted in the urine, was assessed [22].
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Statistical analysis
Sodium excretion
Data are presented as mean ± standard error of the mean (SEM) unless otherwise specified. Statistical comparisons for continuous variables were made with paired student’s t test, ANOVA or Wilcoxon rank sum test, when appropriate. Categorical variables were compared by a Pearson Chi-square test or Wilcoxon rank sum test. Significance tests were two-tailed with p \ 0.05 considered significant. All statistical analyses were calculated using the SPSS statistical software (version 20.0, SPSS Inc., Chicago, Illinois).
Mean estimated urinary sodium excretion at baseline using the Kawasaki formula was 236 ± 9 mmol/day. After 6 months, urinary sodium excretion was increased by 13 % to 268 ± 9 (p = 0.003). This was paralleled by a significant increase in fractional sodium excretion (1.19 ± 0.11 at baseline vs. 1.64 ± 0.14 % after 6 months, p \ 0.001) (Fig. 1a–c).
Results A total of 137 patients with resistant hypertension (mean age of 63 ± 1 years) were included. The patients’ baseline characteristics are depicted in Table 1. Despite an average intake of 5.2 ± 0.1 antihypertensive drugs, average office SBP/DBP was 171 ± 2/93 ± 1 mmHg with a heart rate (HR) of 70 ± 1 bpm. RDN was performed in all patients without procedural complications. Six months after RDN, SBP was reduced by 18 ± 2 mmHg (p \ 0.001) and DBP by 10 ± 1 mmHg (p \ 0.001), respectively, and HR was reduced by 3 ± 1 bpm (p = 0.008). 90 patients (65.7 %) had SBP reductions C10 mmHg and, thus were classified as responders. We did not observe significant changes in kidney function measured by cystatin C GFR (Table 2).
Influence of antihypertensive medication Patients and physicians were instructed not to change antihypertensive medication during the study period. However, antihypertensive drug regimen was reduced in 11 patients (8 %) due to confirmed blood pressure levels below respective target BP or the development of symptomatic hypotension. Antihypertensive treatment was increased in 11 patients (8 %) who remained above target BP during FU. Censoring for these post-procedural medication changes did not affect the observed results regarding the increase in sodium excretion after RDN, making a relevant influence of treatment intensification unlikely. To further exclude a bias induced by antihypertensive medication, a sub-analysis was performed investigating sodium excretion in patients according to the intake of agents with relevant effects on urinary sodium excretion, namely diuretics and mineralocorticoid receptor antagonists (MRA). Herein, 115 patients (84 %) were treated with diuretics and 23 patients (17 %) with MRA, respectively. Notably, neither sodium excretion at baseline nor the observed increase after 6 months was different in patients taking MRA or diuretics (Fig. 2a, b).
Table 1 Baseline characteristics of all (n = 137) patients All patients n = 137
Renin and aldosterone
Age (years) Male
63 ± 1 86 (63 %)
BMI (kg/m2)
30.4 ± 0.4
In a subgroup of patients (n = 66), renin and aldosterone plasma concentrations were measured. RDN did not significantly change plasma renin (baseline: 95 ± 33 pg/ml, 6-month FU: 92 ± 32 pg/ml; p = 0.669) or aldosterone concentrations (baseline: 138 ± 8 pg/ml, 6-month FU: 150 ± 8 pg/ml; p = 0.06), although there was a trend towards an increase in aldosterone within 6 months after treatment. No differences in aldosterone concentrations were found after stratification of the patients in tertiles according to the extent of sodium excretion after RDN precluding a counter-regulatory effect of aldosterone.
Office SBP (mmHg)
171 ± 2
Office DBP (mmHg)
93 ± 1
Coronary artery disease
30 (22 %)
Hypercholesterolemia
60 (44 %)
Type 2 diabetes
53 (39 %)
Number of antihypertensive drugs
5.2 ± 0.1
ACE inhibitors/ARBs
125 (91 %)
Beta-blockers
109 (80 %)
Calcium-channel blockers
105 (77 %)
Diuretics
115 (84 %)
Aldosterone receptor antagonists
23 (17 %)
Sympatholytics
72 (53 %)
BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, ACE angiotensin-converting enzyme, ARB angiotensin receptor blocker
Sodium excretion and blood pressure reduction There was no correlation between sodium excretion and BP lowering after RDN (r = 0.101, p = 0.246). To further investigate the relationship between sodium excretion and BP reduction, patients were stratified in tertiles according
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Clin Res Cardiol Table 2 Changes of important parameters from baseline to 6-month follow-up
SBP systolic blood pressure, DBP diastolic blood pressure, GFR glomerular filtration rate, KDOQI kidney disease outcomes quality initiative
All patients Baseline
6-month FU
n
p values
Office SBP (mmHg)
171 ± 2
153 ± 2
137
\0.001
Office DBP (mmHg)
93 ± 1
83 ± 2
137
\0.001
Office heart rate (bpm)
70 ± 1
67 ± 1
137
0.008
Number of antihypertensive drugs
5.2 ± 0.1
5.2 ± 0.1
137
0.947
Decrease (number of patients)
11
137
Increase (number of patients)
11
137
Plasma aldosterone (pg/ml)
138 ± 8
150 ± 8
67
0.06
Plasma renin (pg/ml)
95 ± 33
92 ± 32
67
0.669
Cystatin C GFR (mL/min/1.73 m2)
72 ± 3
69 ± 3
78
0.062
KDOQI 1 (GFR C90 mL/min/1.73 m2)
21
20
27 97 ± 5
24 85 ± 5
2
KDOQI 4–5 (GFR \30 mL/min/1.73 m ) Urine creatinine (mg/dl)
0.567 137
0.567 0.037
Fig. 1 Urinary sodium excretion before and 6 months after RDN. a Estimated sodium excretion estimated by the Kawasaki formula. b Fractional sodium excretion. BL baseline, 6 months, FU 6-month follow-up
Fig. 2 Estimated sodium excretion by the Kawasaki formula stratified according to the intake of— a mineralocorticoid receptor antagonists (MRA) and b diuretics
to SBP reduction after 6 months. Interestingly, the most pronounced increase in sodium excretion was observed in patients within the lowest tertile of SBP reduction (\10 mmHg), (Fig. 3a). Non-responders (SBP reduction \10 mmHg) were characterized by a larger increase in sodium excretion compared to responders, Fig. 3b. Notably, this relationship was not found between HR and sodium excretion.
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Discussion Catheter-based RDN offers a novel approach to selectively interrupt renal sympathetic fibers and effectively reduce BP in certain patients with uncontrolled hypertension. However, the exact mechanisms by which RDN causes BP lowering are unknown. The results of the present study show an increased sodium excretion in patients with
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Fig. 3 Increase in sodium excretion according to SBP reduction stratified—a by tertiles and b by responder state
resistant hypertension after RDN, even after adjustment for kidney function and consideration of concomitant diuretic and antihypertensive therapy. Abundant evidence indicates the crucial role of sympathetic activation in the pathogenesis of hypertension [23]. Experimental studies showed that targeted stimulation of renal sympathetic nerves decreases sodium excretion and increases renal tubular sodium reabsorption [2]. However, these effects were noted acutely in experimental settings. The effect of sympathetic activation on renal sodium homeostasis is mainly mediated by two neuroeffectors in the kidney: (1) stimulation of a1B-adrenoceptors directly increases renal tubular sodium retention by renal tubular epithelial cells and (2) activation of juxtaglomerular cells induced by b1-adrenoceptors leading to an increased renin release with subsequent aldosterone synthesis and release which, in turn, increases sodium retention [2]. Numerous studies show an adverse effect of a surfeit of sodium on arterial pressure [24, 25]. Patients with resistant hypertension show increased salt sensitivity, exhibiting a considerably larger degree of BP reduction after dietary salt restriction than general hypertensive populations [26]. International guidelines recommend a salt restriction to 5–6 g per day (class IA recommendation) [13]. RDN can lower sympathetic nervous system activity and both office and 24-h BP in patients with resistant hypertension [10, 11, 14]. Experimentally, surgical and chemical RDN increased sodium excretion by decreasing tubular sodium reabsorption acutely [2]. Interestingly, the present study shows a significantly increased estimated sodium excretion after RDN. This finding needs interpretation in light of the fact that sodium excretion was estimated 6 months after RDN and not directly following the procedure. The magnitude of sodium excretion did not correlate with the BP lowering post RDN and non-responders were characterized by a larger increase in sodium excretion compared to responders. These results suggest that the increase in sodium excretion might at least partly reflect an
increased sodium intake after RDN. Furthermore, the findings raise the question whether dietary sodium restriction or intensified diuretic therapy might potentiate the BP-lowering effect of RDN, especially in non-responders. Interestingly, a subgroup analysis of the Symplicity HTN-3 trial showed a trend towards an increased blood pressurelowering effect of RDN in patients with aldosterone antagonist treatment at baseline. The underlying mechanism is unknown but besides others might include an increased sodium excretion induced by aldosterone blockers [27]. It has been suggested that RDN affects renin and aldosterone concentrations by reducing renal b1-adrenoceptor activation. However, in our study, no significant differences in renin or aldosterone levels after RDN were observed and consecutively, the aldosterone/renin ratio remained unchanged. Furthermore, no counter-regulatory increase in aldosterone was documented in patients with the highest compared to the lowest tertile of sodium excretion. These findings have to be interpreted with caution as the intake of antihypertensive drugs (especially MRA, ARB/ACE inhibitors, beta-blockers, renin inhibitors) might affect components of the RAS system. RDN did not significantly decrease kidney function measured by cystatin C GFR (Table 2) [28]. Herein, a slight, non-significant trend towards a reduction in cystatin C GFR by 3 ml/min (from 72 ± 3 ml/min at baseline to 69 ± 3 ml/min; p = 0.062) was observed. In addition, fractional sodium excretion (FeNa) was measured. FeNa was significantly increased by 72 % after RDN and remained in a physiologic range (according to the current definitions), making a relevant renal tubular damage at baseline or after RDN unlikely. Since the dose of diuretics was kept unchanged in all included patients throughout the study period, the observed increase in FeNa cannot be explained by a change of diuretic therapy. These findings indicate that the observed increase in urinary sodium excretion is unrelated to renal dysfunction. This is in line with the results of earlier experimental studies showing that modulation of
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renal sympathetic nerves influenced sodium excretion without affecting GFR [2]. Another relevant factor influencing sodium excretion is the intake of antihypertensive and diuretic drugs. The Kawasaki formula (used herein to estimate the 24-h urinary sodium excretion) has been validated in patients on antihypertensive therapy [20]. To further address this issue, we stratified the patients according to the intake of diuretics and MRA, known to impact natriuresis. Notably, there were no differences in baseline or 6-month sodium excretion in patients treated with diuretics or MRA compared to those not receiving these agents. Our study might have some limitations. Due to the lack of a control group and/or a sham procedure, a potential bias with regard to blood pressure and sodium excretion cannot be excluded. 24-h urine collection was not performed. However, the approximation of 24-h sodium excretion as done herein has been validated in patients with hypertension and represents a reliable method to estimate sodium excretion [20]. Importantly, daily sodium intake was not assessed, precluding further investigation of the sodium balance and the above-mentioned issue whether BP nonresponse to RDN is related to a compensatory increased sodium intake. This issue should be investigated in further studies. Furthermore, sodium excretion was assessed after 6 months and not directly after RDN or after a shorter period of time, which would also be interesting.
Conclusion In this study, a significant increase in urinary sodium excretion was observed 6 months after RDN in patients with resistant hypertension. This effect remained apparent after consideration of antihypertensive drug therapy. Further trials are needed to answer the questions to which extent this effect is attributable to a natriuretic effect of RDN or rather a compensatory increased sodium intake and, in the latter case, whether a dietary sodium restriction or an increased diuretic therapy might potentiate the blood pressure-lowering effect of RDN. Acknowledgments The institution (Universita¨tsklinikum des Saarlandes) has received scientific support from Medtronic/Ardian (Mountain View, California, US). MB is supported by Deutsche Forschungsgemeinschaft (Bonn, Germany; KFO 196). SE, OV and FM are supported by Deutsche Hochdruckliga (Heidelberg, Germany). FM and MB are supported by Deutsche Gesellschaft fu¨r Kardiologie (Du¨sseldorf, Germany). Conflict of interest RES, MB and FM were investigators of Symplicity HTN-1 and HTN-2 trial. OV, RES, MB and FM have received speaker honorarium and consultancy fees from Medtronic/Ardian (Mountain View, California, US), St. Jude Medical (Eschborn, Germany).
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