Author + information
- Received October 16, 2016
- Revision received December 6, 2016
- Accepted December 13, 2016
- Published online February 20, 2017.
- Reetu R. Singh, PhDa,∗ (, )
- Varsha Sajeesh, BScHonsa,
- Lindsea C. Booth, PhDb,
- Zoe McArdle, BScHonsa,
- Clive N. May, PhDb,
- Geoffrey A. Head, PhDc,
- Karen M. Moritz, PhDd,
- Markus P. Schlaich, MDc,e and
- Kate M. Denton, PhDa
- aCardiovascular Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Victoria, Australia
- bThe Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
- cBaker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
- dSchool of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia
- eSchool of Medicine and Pharmacology–Royal Perth Hospital Unit, University of Western Australia, Perth, Western Australia, Australia
- ↵∗Address for correspondence:
Dr. Reetu R. Singh, Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Wellington Road, Clayton VIC, 3800 Australia.
Background Clinical trials applying catheter-based radiofrequency renal denervation (RDN) demonstrated a favorable safety profile with minimal acute or procedural adverse events. Whether ablation of renal nerves adversely affects compensatory responses to hemodynamic challenge has not been extensively investigated.
Objectives The aim of this study was to examine the effect of RDN on mean arterial pressure, renal function, and the reflex response to hemorrhage in sheep with normotension (control) or with hypertensive chronic kidney disease (CKD).
Methods Sheep underwent RDN (control-RDN, n = 8; CKD-RDN, n = 7) or sham procedures (control-intact, n = 6; CKD-intact, n = 7). Response to hemorrhage (20% loss of blood volume), including plasma renin activity, was assessed at 2 and 5 months post-procedure.
Results RDN caused a complete reversal of hypertension and improved renal function in CKD-RDN sheep (p < 0.0001 for 2 and 5 months vs. pre-RDN). In response to hemorrhage, mean arterial pressure fell in all groups, with the fall being greater in the RDN than the intact group (2-month fall in mean arterial pressure: control-intact, −10 ± 1 mm Hg; control-RDN, −15 ± 1 mm Hg; p < 0.05; CKD-intact, −11 ± 3 mm Hg; CKD-RDN, −19 ± 9 mm Hg; p < 0.001). Hemorrhage increased heart rate and plasma renin activity in intact sheep, but these responses were significantly attenuated in control-RDN and CKD-RDN animals. Responses to hemorrhage were remarkably similar at 2 and 5 months post-RDN, which suggests that nerve function had not returned within this time frame.
Conclusions In hypertensive CKD sheep, RDN reduced blood pressure and improved basal renal function but markedly compromised compensatory hemodynamic responses to hemorrhage. Therefore, the capacity to respond to a physiological challenge to body fluid homeostasis may be compromised following RDN.
Treating human hypertension using radiofrequency catheter-based renal denervation (RDN) was met with great enthusiasm following the promising results of Symplicity HTN-1 (1) and HTN-2 (2) trials, but this was curtailed by HTN-3 (3), which failed to demonstrate a blood pressure (BP)–lowering effect beyond that of a sham control group. However, in the more recent DENERHTN (Renal Denervation for Hypertension) trial, though without sham control, RDN plus antihypertensive medication led to a greater decrease in BP compared with antihypertensive medication use alone (4). Sympathetic overactivity is implicated in the pathogenesis of hypertension and chronic kidney disease (CKD), and these conditions commonly coexist (5). Achieving BP control is the most important avenue for minimizing adverse renal outcomes in patients with CKD (6), providing a basis for RDN as an intervention for hypertensive CKD (5). In patients with concomitant resistant hypertension and moderate to severe CKD, RDN was demonstrated to be safe and associated with reduced BP (7,8) and improved renal function (8).
On the basis of sound underlying pathophysiology (5), and the acknowledged limitations of HTN-3 (9), RDN research continues to unequivocally determine whether it is an effective treatment for hypertension (10). Clinical studies are now outpacing experimental studies, which may be of concern because of the limited information available as to the functional impact of RDN for homeostasis. Although the procedure clearly causes incomplete RDN (11), it still may be associated with adverse consequences, specifically with regard to a limited ability to respond to physiological challenges. For example, hemorrhage causes reflex activation of the sympathetic nerves (12), and lack of renal sympathetic activation may affect restoration of BP in the short term following blood loss. This is not a hypothesis that can be systematically examined in humans.
In this study, we used our established model of hypertension and CKD in sheep (13) with demonstrated evidence of renal sympathetic overactivity and hypothesized that RDN would reduce resting BP in hypertensive CKD without major effects on renal function. Additionally, we hypothesized that cardiovascular and renal responses to hypotensive hemorrhage (20% loss of blood volume) would be impaired in animals subjected to RDN. Thus, we examined: 1) resting BP and renal function; and 2) cardiovascular and renal changes in response to hemorrhage at 2 and 5 months post-RDN in animals undergoing RDN or a sham procedure.
Experiments were approved by the animal ethics committee of Monash University and performed in accordance with the guidelines of the National Health and Medical Research Council of Australia. The Online Appendix contains additional procedural details. Hypertension with CKD was induced by performing unilateral nephrectomy in the sheep fetus (day 100 of 150-day gestation) in which the left renal artery, vein, and ureter were ligated and the left kidney excised (CKD group, n = 14). To generate a normotensive control group, a sham surgical procedure was performed (control, n = 14) as previously described (13). The full surgical procedure produces low-renin hypertension, with about a 25% reduction in glomerular filtration rate (GFR) at 6 months of age (14).
At 10 months of age, animals underwent either a denervation procedure (a total of 6 2-min radiofrequency ablations per artery) or the sham RDN procedure, as previously described (15), resulting in 4 groups: control-RDN (n = 8), CKD-RDN (n = 7), control-intact (n = 6), and CKD-intact (n = 7).
At 6 (pre-RDN), 12 (2 months post-RDN), and 15 (5 months post-RDN) months of age, BP (systolic blood pressure [SBP], diastolic blood pressure [DBP], and mean BP) and heart rate were measured via an indwelling carotid artery catheter (14). These measurements were acquired over a 72-h period and the average is reported as basal mean arterial pressure (MAP) and heart rate.
At these same ages, basal GFR and renal plasma flow were examined via clearance of chromium-51 ethylenediaminetetraacetic acid (dose: 15 μCi/h) and para-aminohippuric acid (dose: 750 mg/h), respectively, over a 4-h period. During this period, urine was collected at 20-min intervals, with an arterial blood sample (3 ml) taken at the midpoint. Additional 3-ml blood samples were collected at hourly intervals for analysis of plasma renin activity (PRA) via radioimmunoassay as described previously (14). Renal blood flow (RBF), renal vascular resistance (RVR), filtration fraction, and urinary sodium excretion (UNaV) were calculated as detailed previously (16). This basal experiment served as the time control for the hemorrhage experiment.
Response to hemorrhage was examined at 2 and 5 months post-RDN or sham procedure. Prior to hemorrhage experiments, blood volume was determined via the clearance of 250-kDa fluorescein isothiocyanate-dextran as previously described (14).
Following a 1-h baseline period, 20% blood volume was withdrawn over a 15-min period, with variables measured for a further 180 min to assess recovery. MAP, heart rate, urine flow rate (UFR), and UNaV were measured continuously. GFR and RBF were measured during the baseline period and between 40 and 180 min post-hemorrhage, once steady state of the clearance markers was reestablished. PRA was measured at baseline, at the end of the 15-min hemorrhage, and each hour thereafter.
Values are presented as mean ± SD. Statistical analysis was performed using Prism 6 for Windows (GraphPad Software, La Jolla, California), with the level of significance set at p ≤ 0.05. Baseline effects of RDN or the sham procedure were analyzed using an unpaired Student t test. In response to hemorrhage, renal and cardiovascular variables in the control or CKD groups were analyzed by repeated-measures analysis of variance with factors group (intact or RDN) and time and their interaction, with data analyzed separately at 2 and 5 months post-procedure, followed, where appropriate, by Sidak or Bonferroni post hoc analysis.
All lambs were born at 150 ± 1 day of gestation. Body weight was not different between the groups at any age of study (Online Appendix).
At baseline, MAP was significantly higher in CKD sheep compared with controls, but heart rate was similar between the groups (Table 1). CKD sheep had significantly lower GFR, RBF, filtration fraction, UNaV, and PRA but higher RVR compared with control counterparts (Table 1). UFR, plasma sodium, and hematocrit were not different between the groups (Table 1).
MAP increased with age in control-intact and CKD-intact sheep but not in control-RDN sheep (Figure 1A). In CKD sheep, when compared with pre-RDN, RDN caused a decrease in MAP at 2 months (ΔMAP −6.2 ± 0.6 mm Hg) and 5 months (ΔMAP −6.3 ± 0.6 mm Hg) post-RDN (p < 0.0001 for both) (Figure 1B). This was associated with a similar decrease in SBP and DBP (not shown). Following RDN, heart rate declined significantly in the control and CKD groups at 2 and 5 months, respectively (Figures 1C and 1D). RDN reduced basal PRA in the control and CKD groups (Figures 1E and 1F).
GFR and RBF were not affected by RDN in control sheep, but both increased in the CKD-RDN sheep (p < 0.001 for both) (Figures 2A to 2D) at 5 months post-RDN. RVR was unaffected in control sheep (Figure 2E) and significantly increased in the CKD-intact sheep with age (Figure 2F), but in the CKD-RDN sheep, significant decreases in RVR were observed at 2 and 5 months post-procedure (Figure 2F). Filtration fraction did not change with age or RDN in any group (Figures 2G and 2H). UFR and UNaV increased following RDN in both groups (Online Appendix).
There was no difference in blood volume or the percentage and rate of blood withdrawal between the groups at any age (Online Appendix). The response to hemorrhage was remarkably similar at 2 and 5 months post-procedure. Therefore, the following text does not differentiate between the 2 time points; the responses at both time points post-procedure are presented in Figures 3, 4, and 5. Data for plasma sodium and hematocrit are provided in the Online Appendix.
Changes in BP and heart rate during hemorrhage were not different between the intact-control and intact-CKD groups. During the blood-loss period, MAP fell in all groups, but the fall was greater in the RDN groups compared with their intact counterparts (Figures 3A and 3B). The fall in MAP was associated with decreases in both SBP and DBP. The fall in SBP was similar between RDN and intact groups (Figures 3C and 3D), whereas the DBP drop was greater in the RDN versus intact counterparts (Figures 3E and 3F). Heart rate increased in response to hemorrhage in the intact groups, but this response was significantly attenuated in the RDN groups (Figures 3G and 3H).
Following hemorrhage, the maximal decreases in MAP and DBP from baseline were greater in both RDN groups compared with intact counterparts, whereas the fall in SBP was similar in all groups (Table 2). In the control-intact sheep at both ages, MAP was restored to baseline levels during the recovery period after hemorrhage, but not in the control-RDN group (Figure 4A). In both CKD groups, MAP was not fully restored to baseline levels during the post-hemorrhage period, though the recovery was greater in the CKD-intact than CKD-RDN sheep (Figure 4B).
The maximal increase in heart rate in response to hemorrhage was significantly less in the RDN groups compared with the respective intact groups (Table 2, Figures 4C and 4D). Heart rate was not restored to baseline in any group during the post-hemorrhage period (Figures 4C and 4D).
At both 2 and 5 months, in response to hemorrhage, PRA increased significantly in both intact groups, but this response was significantly attenuated by RDN in both control and CKD groups (Table 2, Figures 4E and 4F). PRA did not return to baseline during the recovery period in any group.
In response to hemorrhage, there was a lesser fall in GFR in the RDN groups than in their respective intact group (Table 2, Figures 5A and 5B). GFR returned to baseline levels in the control-intact sheep, but not in the control-RDN sheep during the post-hemorrhage recovery period (Figure 5A). In the CKD-intact sheep, although recovery was observed, GFR was not fully restored to baseline levels and in the CKD-RDN group, no recovery of GFR was observed (Figure 5B).
RBF fell in response to hemorrhage in all groups (Figures 5C and 5D), but the response was attenuated in the RDN sheep (Figures 5C and 5D, Table 2). During the post-hemorrhage recovery period, RBF returned to baseline levels only in the control-intact group, not in the control-RDN (Figure 5C), CKD-intact, or CKD-RDN group (Figure 5D).
In response to hemorrhage, filtration fraction decreased significantly in the control-intact and CKD-intact groups by 60 min post-hemorrhage and then recovered to baseline levels thereafter (Figures 5E and 5F). This decrease in filtration fraction was absent in both the control-RDN and CKD-RDN groups compared with intact counterparts (Table 2, Figures 5E and 5F).
In the intact sheep, RVR increased significantly (Figures 5G and 5H) in response to hemorrhage. RVR returned to baseline levels by 120 min post-hemorrhage in the control-intact sheep (Figure 5G), whereas RVR remained elevated in the CKD-intact group throughout the recovery period (Figure 5H). In both RDN groups, the increase in RVR in response to hemorrhage was markedly attenuated (Table 2, Figures 5G and 5H).
UFR and UNaV fell in response to hemorrhage in all groups and did not recover to baseline levels in any group (Figure 3, Online Appendix). The maximal fall in UNaV was significantly attenuated in the RDN groups, but the fall in UFR was not different between the intact and RDN groups (Table 2).
At 2 and 5 months following RDN, BP was reduced to normotensive levels in sheep with hypertensive CKD, confirming RDN’s BP-lowering efficacy (1,2) (Central Illustration). These observations are clinically relevant given the similarity of approach and algorithm used for energy application in several clinical trials and this animal study. Additionally, this study showed that although GFR was not changed at 2 months post-procedure, increases in both GFR and RBF were observed at 5 months post-procedure in CKD-RDN sheep, demonstrating improved renal function. This was in line with available data from studies in humans indicative of the potential renoprotective effects of RDN irrespective of its BP-lowering efficacy (5).
Despite these benefits, in the present study compensatory cardiovascular and renal response to hypotensive hemorrhage (20% blood volume loss) was markedly impaired in sheep that underwent RDN. Responses to hemorrhage at 2 and 5 months following RDN were remarkably similar, suggesting that renal nerve function had not recovered within this time frame. Thus, our findings confirmed that RDN is effective in reducing BP in a hypertensive CKD model but also highlighted that compensatory responses to hemodynamic challenges, such as critical blood loss, might be impaired and, potentially, result in adverse consequences. Whether compensatory responses to more common and less severe forms of alterations in fluid homeostasis, such as dehydration or gastroenteritis, are affected by RDN should be addressed in future studies.
Basal cardiovascular and renal function following RDN
A major strength of our study, unlike some of the human (1,2) and experimental (17,18) studies, was that it included all important controls, including normotensive controls and a sham procedure. Furthermore, the ablation procedure followed the same protocol (6 circumferential ablations of the renal artery) using the same catheter system as used in the Symplicity HTN studies, and these criteria were met in all animals.
The sustained reduction in BP in the CKD-RDN sheep, although contrary to the reports of HTN-3 (3), corroborated those in animal models (17,18) and the majority of the clinical trials (Global Symplicity Registry, DENERHTN) involving the catheter evaluated in resistant hypertensive (1,2,4,19) and hypertensive CKD (7,8) populations. Consistent with previous observations (20), BP was not reduced in the control animals following RDN, but interestingly, the age-related increase in BP observed in the intact animals was not observed in the RDN sheep. Although speculative and not tested in humans, the notion of targeting renal sympathetic overactivity at earlier stages of hypertension or in younger patients to prevent onset of hypertension may have merit. Consistent with previous observations (21), reductions in PRA in response to RDN in both control and CKD groups were observed. However, this fall in PRA did not produce a marked fall in BP in the control-RDN group, and other compensatory mechanisms likely accounted for this.
Basal GFR and RBF were not affected by RDN in the control sheep, in contrast to observations in normotensive swine in which RDN increased RBF (22). However, in the swine, RBF was measured under anesthesia. In the CKD-RDN sheep, at 5 months post-procedure, significant increases in GFR and RBF of similar magnitude were observed; thus, filtration fraction was not affected. The elevation in GFR was consistent with a study in which RDN also led to increased GFR in patients with CKD (8). Importantly, in our study, RDN did not cause a decline in GFR, similar to findings in humans (7,8), supporting the concept that RDN may be a safe and effective treatment for hypertensive CKD in humans. However, future studies should continue to assess renal function over time.
The kidneys maintain extracellular fluid volume, and hence BP, by modulating sodium excretion, and the renal nerves contribute to this response (23). At 2 months post-procedure in CKD-RDN sheep, enhanced sodium excretion occurred without significant changes in GFR and RBF, consistent with observations in experimental hypertension models following surgical denervation (20) and in patients with resistant hypertension following RDN (24). However, sodium excretion in these studies might have reflected an increase in dietary intake, which was not assessed. Nevertheless, it is likely that a shift in pressure natriuresis/diuresis associated with removal of renal nerves contributed to the observed fall in BP following RDN.
Additionally, we observed decreases in heart rate in the control and CKD groups at both ages post-RDN. This decline might be independent of BP, because BP was decreased only in the CKD-RDN animals. Our findings were consistent with those in resistant hypertensive populations following RDN (25) in which heart rate was reduced following RDN and might be a consequence of the loss of renal afferent sympathoexcitatory input following RDN, leading to a global reduction in sympathetic outflow (26).
Effect of RDN on response to hemorrhage
The normal response to hemorrhage is a fall in BP, causing a reflex increase in sympathetic activity, which drives an increase in heart rate, total peripheral resistance (TPR; including RVR, leading to a reduction in GFR), renin release, and sodium excretion, which together promote BP maintenance (12,27). The relative importance of each mechanism depends on the species and vascular bed examined and the time course of the protocol used to induce hemorrhage (28). However, each mechanism (neural, humoral, and renal) contributes importantly to BP maintenance in response to blood loss. In control-intact animals, the fall in BP was restored to baseline levels within 60 min following blood loss, comparable with responses in humans (27) and sheep (29,30) to similar blood volume depletion. Similar changes in BP and renal function in response to hemorrhage were observed in the CKD-intact sheep, but recovery of these variables was slower than in control-intact animals. This suggested that the CKD-intact animals exhibited blunted compensatory responses to hemorrhage, potentially because of existing renal impairment in this low-renin disease model (16).
In contrast, during blood loss, the decreases in MAP were faster and greater in both RDN groups. The maximal decrease in MAP was about 15 to 48 mm Hg, reaching a trough of about 50 to 70 mm Hg in the RDN groups. From this low point in BP, there was little recovery during the ensuing 180 min in both control and CKD animals that underwent RDN. The exaggerated MAP response in RDN groups was due to a greater fall in DBP, because SBP was not different in the intact groups. TPR was not measured in our study. However, in conscious sheep, increases in heart rate and TPR both contribute to MAP maintenance during blood loss, and TPR remains significantly elevated in the recovery period post-hemorrhage (31,32). In the present study, the greater fall in DBP suggested that the increase in TPR was attenuated following RDN. Therefore, the greater fall in MAP following blood loss was likely due to both an attenuated TPR and heart rate response in the RDN groups, which may have resulted from the lack of efferent renal sympathetic nerves or an indirect effect of the loss of renal afferent nerves resulting in reduced cardiac sympathetic nerve activity (32,33).
Following RDN, the reduced increase in PRA and RVR will each have contributed to the greater fall, and lack of recovery, of BP in response to hemorrhage. The reduced increase in RVR will be due partly to the absence of the efferent renal sympathetic nerves, but this is likely insufficient on its own to account for the full effect on BP. It has been demonstrated previously that increased vasoconstriction occurs in most vascular beds, except cerebral and coronary, in response to hemorrhage (28). It is therefore possible that the greater fall in DBP is due to a global reduction in vasoconstriction, due to the reduced increase in PRA and global reduction in vasoconstriction caused by loss of renal afferent sympathoexcitation. These findings also demonstrated the relative importance of renal nerves in the physiological response to hemorrhage and suggested that decreased arterial pressure is not a major stimulus for renin release during hemorrhage. This aligns with evidence that points to sympathetic pathways predominating over moderate changes in arterial pressure in regulation of renin release (34). This suggests that in a situation of critical trauma, subjects who have undergone RDN have a greater risk for entering the decompensatory phase of hemorrhage more rapidly than nondenervated subjects.
This attenuated ability to maintain arterial pressure in response to blood loss may limit using RDN in clinical practice. However, to date, there have been no reports of adverse events related to blood loss from the Global Symplicity Registry of more than 2,500 patients (35,36). Our findings should be viewed in context of clinical findings in which RDN in patients with resistant hypertension has not been shown to affect chronotropic competence during exercise (37,38) or cause orthostatic dysfunction during tilting (39), though it should be noted that these constitute a more modest challenge than the hemorrhage we used. In support of our findings, the renal response to moderate lower body negative pressure in renal transplantation patients (thus denervated) has been shown to be impaired (40).
Strengths of our study were that we used the same radiofrequency catheter system and algorithm as in patients, and the studies were all in conscious animals, avoiding confounding influences of anesthesia. Also, in studies of RDN in hypertensive patients, these patients were treated with variable doses and combinations of antihypertensive drugs that likely mask RDN’s effects. In contrast, the sheep in this study were not treated with antihypertensive drugs.
A limitation of our study was that we have no direct evidence of the degree of renal nerve ablation achieved or whether regrowth occurred. However, using an identical RDN technique in sheep, we previously demonstrated complete denervation of the afferent and efferent renal nerves 2 weeks after RDN, using immunohistochemistry for tyrosine hydroxylase and calcitonin gene–related peptide and measurement of tissue norepinephrine levels (41), generating confidence that we achieved a significant degree of RDN here. Previously, we also reported evidence of functional reinnervation at 5.5 and 11 months post-RDN in normotensive sheep, as demonstrated by gradual return of renal responses to electric stimulation of the renal nerves with time (15). It is possible that coexistence of hypertension, which has been strongly associated with sympathetic overactivity and increased sympathetic innervation density (42), might alter subsequent nerve regrowth following RDN and account for the sustained reduction in BP observed in this study as well as in some human trials post-RDN (1,12,19). It could be argued that electric stimulation is not equivalent to reflex activation (43), and reinnervation may not always imply return of normal function (40). In the present study, by using hemorrhage to physiologically induce reflex activation of the renal sympathetic nerves, we observed virtually identical responses at 2 and 5 months post-RDN, suggesting little restoration of nerve function. Further studies are warranted to determine if renal nerve function returns over a longer time frame.
Radiofrequency catheter ablation of the renal arteries in a sheep model of hypertensive CKD reduced BP to normotensive levels and improved renal function out to 5 months post-procedure. Moreover, the reduction in resting BP and the similar responses to hemorrhage at 2 and 5 months post-RDN provided no evidence of renal nerve function recovery within this time frame. This suggests that the regrowth of renal nerves into the kidney, as previously demonstrated, does not imply return of normal function, which may explain the sustained and long-term effects of RDN. However, attenuated compensatory responses to hemorrhage present a potential caveat to widespread application of RDN. Although RDN in selected patient populations, such as those with CKD and hypertension, will likely yield beneficial BP reduction and potential renoprotection, it is possible such patients may have a reduced capacity to mount an adequate response to severe homeostatic challenges, such as hemorrhagic or septic shock.
COMPETENCY IN MEDICAL KNOWLEDGE: Radiofrequency catheter-based RDN is being trialed as an alternative approach for treatment of resistant hypertension. Initial reports (SYMPLICITY HTN-1 and HTN-2) demonstrated significant reductions in BP in patients with resistant hypertension, but the largest, sham control trial (HTN-3) did not support these findings. Limitations of HTN-3 have prompted further clinical trials examining the effectiveness of RDN in reducing BP. Given the contribution of renal sympathetic overactivity to CKD, RDN is also being trialed in patients with hypertensive CKD.
COMPETENCY IN PATIENT CARE & PROCEDURAL SKILLS: Catheter-based radiofrequency renal denervation in a sheep model of hypertensive chronic kidney disease compromised the compensatory hemodynamic response to hemorrhage.
TRANSLATIONAL OUTLOOK: Future studies of renal artery sympathetic denervation should consider impaired responsiveness to hemodynamic challenge in the estimation of net clinical benefit.
The authors thank Alan McDonald, Dr. Ross Young, and Lawrence Easton for providing assistance with surgical procedures. The authors thank Lawrence Easton for assistance with laboratory procedures.
For extended methods and materials, results, and discussion as well as supplementary figures, please see the online version of this article.
This research was supported by a project grant (#1046594) and fellowships to Prof. Denton (#1041844), Prof. Moritz (#1078164), Prof. Schlaich (#1080404), and Dr. Booth (#1054619) from the National Health Research Council of Australia. Prof. Schlaich is an investigator in studies sponsored by Medtronic, and his laboratories have received research funding from Medtronic. Prof. Schlaich serves on scientific advisory boards for Abbott (formerly Solvay) Pharmaceuticals, Boehringer Ingelheim, Novartis Pharmaceuticals, and Medtronic; and has received honoraria and travel support from Abbott, Boehringer Ingelheim, Servier, Novartis, and Medtronic. Prof. May has received honoraria and travel support for presentations from Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- blood pressure
- chronic kidney disease
- diastolic blood pressure
- glomerular filtration rate
- mean arterial pressure
- plasma renin activity
- renal blood flow
- renal denervation
- renal vascular resistance
- systolic blood pressure
- total peripheral resistance
- urine flow rate
- urinary sodium excretion
- Received October 16, 2016.
- Revision received December 6, 2016.
- Accepted December 13, 2016.
- American College of Cardiology Foundation
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