Perspectives
Renal sympathetic denervation for the treatment of resistant hypertension Long-term safety and durability data for this novel approach to treating resistant hypertension are eagerly awaited
H
ypertension is responsible for more deaths and disease than any other cardiovascular risk factor worldwide.1,2 For each 20 mmHg increment in systolic blood pressure (BP) or 10 mmHg increment in diastolic BP, the risk of cardiovascular disease doubles.2,3 Despite lifestyle modification and pharmacotherapy, achieving BP targets poses a significant challenge. Resistant hypertension is BP that remains above target levels in spite of adherence to three antihypertensive agents, one of which should ideally be a diuretic.1 The United States prevalence of resistant hypertension of 8.9%, reported in the National Health and Nutrition Examination Survey (2003–2008), is likely to be an underestimate.4,5 A promising alternative treatment modality for resistant hypertension — renal sympathetic denervation (renal denervation; RDN) — has recently been developed.
Sonny C Palmer MB BS, FRACP, Cardiology Research Fellow
Christopher Judkins MB BS, FRACP, Cardiology Research Fellow
Paul D Williams MA, BM BCh, Interventional Cardiology Fellow
Robert J Whitbourn MB BS, FRACP, Director of Coronary Care and Cardiac Catheterisation Laboratories Department of Cardiology, Cardiac Investigation Unit, St Vincent’s Hospital, Melbourne, VIC.
sonny.palmer@ svhm.org.au doi: 10.5694/mja12.11254
The procedure Numerous RDN devices are currently under development, and most use an endovascular catheterbased approach to ablate renal sympathetic nerves by delivering radiofrequency (RF) or ultrasound energy via an electrode catheter or balloon catheter. The only RDN device currently approved by the Therapeutic Goods Administration is the Symplicity Catheter (Medtronic). The renal artery is accessed via a femoral arterial approach, the denervation catheter is connected to an RF generator, and then the denervation catheter is advanced via a guide catheter into the main renal artery. Multiple RF treatments are applied (120 seconds in duration each) from distal to proximal in a circumferential pattern to maximise renal sympathetic nerve disruption in the artery. The individual treatments are separated from one another by about 5 mm and, depending on the length of the renal artery, four to eight RF treatments are delivered. During each RF treatment, the patient can experience transient visceral pain; adequate analgesia is of utmost importance.6
The proof of concept The clinical effect of RDN is presumed to result from its effect on sympathetic overactivity, which has been proven to have a role in the maintenance of high BP.3,6 Historically, the role of the sympathetic nervous system in BP control was demonstrated in patients who had surgical splanchnicectomy in the early 1900s.7 Profound 160
MJA 199 (3) · 5 August 2013
improvements in BP were achieved, but this was at the cost of significant morbidity, so the procedure was abandoned. Modern antihypertensive pharmacotherapy was introduced in the early 1970s. After promising data on RDN were obtained in swine models of hypertension, Symplicity HTN-1 was conducted as the proof-of-concept study for RDN.6 It was a multicentre feasibility, safety and efficacy trial of 45 patients with resistant hypertension. At baseline, the mean office BP was 177/101 mmHg. At 1 month, there was a significant 14/10 mmHg reduction in BP. The role of the sympathetic nervous system was supported in a subgroup of patients who underwent renal vein sampling for noradrenaline spillover, a marker of sympathetic activity; spillover was reduced by 47%.
Sustained reduction in blood pressure Longer-term durability and safety of RDN was demonstrated in a cohort study of 153 patients with resistant hypertension, which included Symplicity HTN-1 patients.8 When compared with baseline (mean office BP, 176/98 mmHg), BP was reduced by 32/14 mmHg at 24 months. Unpublished 36-month data showed an ongoing durable response (American College of Cardiology Annual Scientific Session, Chicago, 24–27 March 2012, personal communication). Ninetytwo per cent of patients had a greater than or equal to 10 mmHg reduction in systolic BP at 24 months.8 The average number of antihypertensive medications taken by patients did not change within 24 months. There were four procedural complications (three femoral pseudoaneurysms and one renal artery dissection caused by the guide catheter), which were managed without further sequelae. At 6 months, one patient had renal artery stenosis (not related to the site of RF ablation) and was treated with percutaneous intervention. During the fi rst year of follow-up, renal function (measured by estimated glomerular fi ltration rate [eGFR]) was stable for all 153 patients.
The randomised controlled trial Symplicity HTN-2 was a multicentre, randomised controlled trial of 106 patients who were assigned to RDN immediately (RDN group) or after a 6-month control period (control group).9 When compared with baseline (mean office BP, 178/96 mmHg), BP in the RDN group was reduced by 32/12 mmHg at 6 months (SD, 23/11 mmHg; P < 0.0001), and there was essentially no change (1/0 mmHg) in the control group. At 6 months, systolic BP was less than 140 mmHg in 39% of patients
Perspectives in the RDN group, compared with 6% of those in the control group. Twenty per cent of patients in the RDN group had their number of antihypertensive medications reduced during this follow-up period, compared with 6% of those in the control group (P = 0.04). There were no serious procedure-related complications. Renal artery imaging at 6 months did not show renal artery stenosis. Renal function was unchanged from baseline in both groups and was not adversely affected, even in patients with mild to moderate renal impairment.9
Limitations of current evidence There were two major criticisms of the fi rst two Symplicity trials that will be addressed in Symplicity HTN-3. First, potential bias will be reduced with the introduction of a sham procedure in the control group. Second, ambulatory BP monitoring, the gold standard for predicting cardiovascular morbidity and mortality,10 will be conducted for all patients. Only 42% of Symplicity HTN-2 patients underwent ambulatory BP monitoring, and they were not randomly assigned to this investigation. The mean reduction in ambulatory BP in these patients after 6 months was significant (11/7 mmHg; P = 0.006 for systolic BP change, P = 0.014 for diastolic BP change), but not as large as the reduction in office-based BP measurements. Although the numbers of antihypertensive medications taken by patients were recorded in the fi rst two Symplicity trials, observed benefits should be viewed with the knowledge that compliance was not strictly evaluated and changes to antihypertensive regimens were permitted during the trial. The long-term durability of RDN has been questioned based on the observation that sympathetic re-innervation has been described in cardiac transplantation. Although it is possible that re-innervation could similarly occur in the kidney, there is currently no evidence for this. Long-term safety data are currently lacking, but are eagerly anticipated given that medial and adventitial fibrosis in the renal artery has been demonstrated in a swine model11 and a human case report has described renal artery stenosis at the site of RF ablation.12 Whether the RDN procedure caused the stenosis is unknown, but vigilance should be encouraged. Cost-effectiveness studies will be required if renal denervation is to remain a viable intervention. Based on Symplicity HTN-2, a cost–benefit model suggested that RDN is a cost-effective strategy that may improve cardiovascular outcomes.13 Nevertheless, this was based on several assumptions that the Symplicity HTN-3 study should clarify. In Victoria, procedural and postoperative care costs are co-funded by the state government and public hospitals.
Indications and contraindications for RDN
Future challenges include developing biochemical and procedural markers of efficacy, assessing longterm health outcomes, and exploring novel applications of RDN
RDN is currently indicated in patients who have an office-based systolic BP greater than or equal to 160 mmHg and in patients with type 2 diabetes who have a systolic BP greater than or equal to 150 mmHg. All patients should be compliant with three or more antihypertensive agents (one of which should ideally be a diuretic).6,8,9 The current major contraindications are previous renal artery intervention (balloon angioplasty or stenting), renal artery stenosis greater than 50 per cent, presence of multiple main renal arteries or main renal arteries less than 4 mm in diameter or less than 20 mm in length, and/or eGFR less than or equal to 45 mL/min/1.73 m2.
Future developments and applications Further research is required to understand the variable effects of RDN. Responders are more likely to be those with excess renal sympathetic activity, which may explain why older patients are poorer responders (ie, because of a greater burden of arteriosclerosis relative to increased sympathetic drive). Future challenges include developing biochemical and procedural markers of efficacy, assessing long-term health outcomes, and exploring novel applications of RDN, such as atrial fibrillation,14 obstructive sleep apnoea,15 diabetes mellitus,16 chronic kidney disease,17 heart failure18 and polycystic ovary syndrome.3,19 Finally, more efficacious, safer, multi-electrode catheters and non-invasive ablation techniques are currently being tested in clinical trials;20 preliminary data on these were presented at international cardiology meetings held in 2012 (Transcatheter Cardiovascular Therapeutics, American College of Cardiology Annual Scientific Session, and EuroPCR).
Summary Improvements in BP control with pharmacotherapy undoubtedly translate into significant individual and population health benefits. RDN results in impressive reductions in BP, which are likely to be associated with further improvements in clinical outcomes. With more clinical trials and concurrent development of new devices, we hope that RDN holds up to its current accolades. Competing interests: Robert Whitbourn has received an honorarium and minor funding for research activities from Medtronic. Provenance: Not commissioned; externally peer reviewed. 1 Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis,
evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51: 1403-1419. 2 Lewington S, Clarke R, Qizilbash N, et al; Prospective Studies Collaboration.
Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903-1913.
MJA 199 (3) · 5 August 2013
161
Perspectives 3 Schlaich MP, Straznicky N, Grima M, et al. Renal denervation: a potential
new treatment modality for polycystic ovary syndrome? J Hypertens 2011; 29: 991-996. 4 Persell SD. Prevalence of resistant hypertension in the United States, 2003-
2008. Hypertension 2011; 57: 1076-1080. 5 Egan BM, Zhao Y, Axon RN, et al. Uncontrolled and apparent treatment
resistant hypertension in the United States, 1988 to 2008. Circulation 2011; 124: 1046-1058. 6 Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic
denervation for resistant hypertension: a multicentre safety and proof-ofprinciple cohort study. Lancet 2009; 373: 1275-1281. 7 Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension;
results in 1,266 cases. J Am Med Assoc 1953; 152: 1501-1504. 8 Symplicity HTN-1 Investigators. Catheter-based renal sympathetic
denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011; 57: 911-917. 9 Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al.
Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 trial): a randomised controlled trial. Lancet 2010; 376: 1903-1909. 10 Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N
Engl J Med 2006; 354: 2368-2374. 11 Rippy MK, Zarins D, Barman NC, et al. Catheter-based renal sympathetic
denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol 2011; 100: 1095-1101.
162
MJA 199 (3) · 5 August 2013
12 Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure
after renal denervation. Lancet 2012; 380: 778. 13 Geisler BP, Egan BM, Cohen JT, et al. Cost-effectiveness and clinical
effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol 2012; 60: 1271-1277. 14 Pokushalov E, Romanov A, Corbucci G, et al. A randomized comparison of
pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012; 60: 1163-1170. 15 Witkowski A, Prejbisz A, Florczak E, et al. Effects of renal sympathetic
denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011; 58: 559-565. 16 Mahfoud F, Schlaich M, Kindermann I, et al. Effect of renal sympathetic
denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 2011; 123: 1940-1946. 17 Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to
severe CKD. J Am Soc Nephrol 2012; 23: 1250-1257. 18 Davies JE, Manisty CH, Petraco R, et al. First-in-man safety evaluation of
renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol 2013; 162: 189-192. 19 Schlaich MP, Straznicky N, Grima M, et al. Renal denervation: a potential new treatment modality for polycystic ovary syndrome? J Hypertens 2011; 29: 991-996. 20 Mabin T, Sapoval M, Cabane V, et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012; 8: 57-61.
Renal sympathetic denervation for the treatment of resistant hypertension Long-term safety and durability data for this novel approach to treating resistant hypertension are eagerly awaited
H
ypertension is responsible for more deaths and disease than any other cardiovascular risk factor worldwide.1,2 For each 20 mmHg increment in systolic blood pressure (BP) or 10 mmHg increment in diastolic BP, the risk of cardiovascular disease doubles.2,3 Despite lifestyle modification and pharmacotherapy, achieving BP targets poses a significant challenge. Resistant hypertension is BP that remains above target levels in spite of adherence to three antihypertensive agents, one of which should ideally be a diuretic.1 The United States prevalence of resistant hypertension of 8.9%, reported in the National Health and Nutrition Examination Survey (2003–2008), is likely to be an underestimate.4,5 A promising alternative treatment modality for resistant hypertension — renal sympathetic denervation (renal denervation; RDN) — has recently been developed.
Sonny C Palmer MB BS, FRACP, Cardiology Research Fellow
Christopher Judkins MB BS, FRACP, Cardiology Research Fellow
Paul D Williams MA, BM BCh, Interventional Cardiology Fellow
Robert J Whitbourn MB BS, FRACP, Director of Coronary Care and Cardiac Catheterisation Laboratories Department of Cardiology, Cardiac Investigation Unit, St Vincent’s Hospital, Melbourne, VIC.
sonny.palmer@ svhm.org.au doi: 10.5694/mja12.11254
The procedure Numerous RDN devices are currently under development, and most use an endovascular catheterbased approach to ablate renal sympathetic nerves by delivering radiofrequency (RF) or ultrasound energy via an electrode catheter or balloon catheter. The only RDN device currently approved by the Therapeutic Goods Administration is the Symplicity Catheter (Medtronic). The renal artery is accessed via a femoral arterial approach, the denervation catheter is connected to an RF generator, and then the denervation catheter is advanced via a guide catheter into the main renal artery. Multiple RF treatments are applied (120 seconds in duration each) from distal to proximal in a circumferential pattern to maximise renal sympathetic nerve disruption in the artery. The individual treatments are separated from one another by about 5 mm and, depending on the length of the renal artery, four to eight RF treatments are delivered. During each RF treatment, the patient can experience transient visceral pain; adequate analgesia is of utmost importance.6
The proof of concept The clinical effect of RDN is presumed to result from its effect on sympathetic overactivity, which has been proven to have a role in the maintenance of high BP.3,6 Historically, the role of the sympathetic nervous system in BP control was demonstrated in patients who had surgical splanchnicectomy in the early 1900s.7 Profound 160
MJA 199 (3) · 5 August 2013
improvements in BP were achieved, but this was at the cost of significant morbidity, so the procedure was abandoned. Modern antihypertensive pharmacotherapy was introduced in the early 1970s. After promising data on RDN were obtained in swine models of hypertension, Symplicity HTN-1 was conducted as the proof-of-concept study for RDN.6 It was a multicentre feasibility, safety and efficacy trial of 45 patients with resistant hypertension. At baseline, the mean office BP was 177/101 mmHg. At 1 month, there was a significant 14/10 mmHg reduction in BP. The role of the sympathetic nervous system was supported in a subgroup of patients who underwent renal vein sampling for noradrenaline spillover, a marker of sympathetic activity; spillover was reduced by 47%.
Sustained reduction in blood pressure Longer-term durability and safety of RDN was demonstrated in a cohort study of 153 patients with resistant hypertension, which included Symplicity HTN-1 patients.8 When compared with baseline (mean office BP, 176/98 mmHg), BP was reduced by 32/14 mmHg at 24 months. Unpublished 36-month data showed an ongoing durable response (American College of Cardiology Annual Scientific Session, Chicago, 24–27 March 2012, personal communication). Ninetytwo per cent of patients had a greater than or equal to 10 mmHg reduction in systolic BP at 24 months.8 The average number of antihypertensive medications taken by patients did not change within 24 months. There were four procedural complications (three femoral pseudoaneurysms and one renal artery dissection caused by the guide catheter), which were managed without further sequelae. At 6 months, one patient had renal artery stenosis (not related to the site of RF ablation) and was treated with percutaneous intervention. During the fi rst year of follow-up, renal function (measured by estimated glomerular fi ltration rate [eGFR]) was stable for all 153 patients.
The randomised controlled trial Symplicity HTN-2 was a multicentre, randomised controlled trial of 106 patients who were assigned to RDN immediately (RDN group) or after a 6-month control period (control group).9 When compared with baseline (mean office BP, 178/96 mmHg), BP in the RDN group was reduced by 32/12 mmHg at 6 months (SD, 23/11 mmHg; P < 0.0001), and there was essentially no change (1/0 mmHg) in the control group. At 6 months, systolic BP was less than 140 mmHg in 39% of patients
Perspectives in the RDN group, compared with 6% of those in the control group. Twenty per cent of patients in the RDN group had their number of antihypertensive medications reduced during this follow-up period, compared with 6% of those in the control group (P = 0.04). There were no serious procedure-related complications. Renal artery imaging at 6 months did not show renal artery stenosis. Renal function was unchanged from baseline in both groups and was not adversely affected, even in patients with mild to moderate renal impairment.9
Limitations of current evidence There were two major criticisms of the fi rst two Symplicity trials that will be addressed in Symplicity HTN-3. First, potential bias will be reduced with the introduction of a sham procedure in the control group. Second, ambulatory BP monitoring, the gold standard for predicting cardiovascular morbidity and mortality,10 will be conducted for all patients. Only 42% of Symplicity HTN-2 patients underwent ambulatory BP monitoring, and they were not randomly assigned to this investigation. The mean reduction in ambulatory BP in these patients after 6 months was significant (11/7 mmHg; P = 0.006 for systolic BP change, P = 0.014 for diastolic BP change), but not as large as the reduction in office-based BP measurements. Although the numbers of antihypertensive medications taken by patients were recorded in the fi rst two Symplicity trials, observed benefits should be viewed with the knowledge that compliance was not strictly evaluated and changes to antihypertensive regimens were permitted during the trial. The long-term durability of RDN has been questioned based on the observation that sympathetic re-innervation has been described in cardiac transplantation. Although it is possible that re-innervation could similarly occur in the kidney, there is currently no evidence for this. Long-term safety data are currently lacking, but are eagerly anticipated given that medial and adventitial fibrosis in the renal artery has been demonstrated in a swine model11 and a human case report has described renal artery stenosis at the site of RF ablation.12 Whether the RDN procedure caused the stenosis is unknown, but vigilance should be encouraged. Cost-effectiveness studies will be required if renal denervation is to remain a viable intervention. Based on Symplicity HTN-2, a cost–benefit model suggested that RDN is a cost-effective strategy that may improve cardiovascular outcomes.13 Nevertheless, this was based on several assumptions that the Symplicity HTN-3 study should clarify. In Victoria, procedural and postoperative care costs are co-funded by the state government and public hospitals.
Indications and contraindications for RDN
Future challenges include developing biochemical and procedural markers of efficacy, assessing longterm health outcomes, and exploring novel applications of RDN
RDN is currently indicated in patients who have an office-based systolic BP greater than or equal to 160 mmHg and in patients with type 2 diabetes who have a systolic BP greater than or equal to 150 mmHg. All patients should be compliant with three or more antihypertensive agents (one of which should ideally be a diuretic).6,8,9 The current major contraindications are previous renal artery intervention (balloon angioplasty or stenting), renal artery stenosis greater than 50 per cent, presence of multiple main renal arteries or main renal arteries less than 4 mm in diameter or less than 20 mm in length, and/or eGFR less than or equal to 45 mL/min/1.73 m2.
Future developments and applications Further research is required to understand the variable effects of RDN. Responders are more likely to be those with excess renal sympathetic activity, which may explain why older patients are poorer responders (ie, because of a greater burden of arteriosclerosis relative to increased sympathetic drive). Future challenges include developing biochemical and procedural markers of efficacy, assessing long-term health outcomes, and exploring novel applications of RDN, such as atrial fibrillation,14 obstructive sleep apnoea,15 diabetes mellitus,16 chronic kidney disease,17 heart failure18 and polycystic ovary syndrome.3,19 Finally, more efficacious, safer, multi-electrode catheters and non-invasive ablation techniques are currently being tested in clinical trials;20 preliminary data on these were presented at international cardiology meetings held in 2012 (Transcatheter Cardiovascular Therapeutics, American College of Cardiology Annual Scientific Session, and EuroPCR).
Summary Improvements in BP control with pharmacotherapy undoubtedly translate into significant individual and population health benefits. RDN results in impressive reductions in BP, which are likely to be associated with further improvements in clinical outcomes. With more clinical trials and concurrent development of new devices, we hope that RDN holds up to its current accolades. Competing interests: Robert Whitbourn has received an honorarium and minor funding for research activities from Medtronic. Provenance: Not commissioned; externally peer reviewed. 1 Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis,
evaluation, and treatment. A scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Hypertension 2008; 51: 1403-1419. 2 Lewington S, Clarke R, Qizilbash N, et al; Prospective Studies Collaboration.
Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903-1913.
MJA 199 (3) · 5 August 2013
161
Perspectives 3 Schlaich MP, Straznicky N, Grima M, et al. Renal denervation: a potential
new treatment modality for polycystic ovary syndrome? J Hypertens 2011; 29: 991-996. 4 Persell SD. Prevalence of resistant hypertension in the United States, 2003-
2008. Hypertension 2011; 57: 1076-1080. 5 Egan BM, Zhao Y, Axon RN, et al. Uncontrolled and apparent treatment
resistant hypertension in the United States, 1988 to 2008. Circulation 2011; 124: 1046-1058. 6 Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic
denervation for resistant hypertension: a multicentre safety and proof-ofprinciple cohort study. Lancet 2009; 373: 1275-1281. 7 Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension;
results in 1,266 cases. J Am Med Assoc 1953; 152: 1501-1504. 8 Symplicity HTN-1 Investigators. Catheter-based renal sympathetic
denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011; 57: 911-917. 9 Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, et al.
Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 trial): a randomised controlled trial. Lancet 2010; 376: 1903-1909. 10 Pickering TG, Shimbo D, Haas D. Ambulatory blood-pressure monitoring. N
Engl J Med 2006; 354: 2368-2374. 11 Rippy MK, Zarins D, Barman NC, et al. Catheter-based renal sympathetic
denervation: chronic preclinical evidence for renal artery safety. Clin Res Cardiol 2011; 100: 1095-1101.
162
MJA 199 (3) · 5 August 2013
12 Vonend O, Antoch G, Rump LC, Blondin D. Secondary rise in blood pressure
after renal denervation. Lancet 2012; 380: 778. 13 Geisler BP, Egan BM, Cohen JT, et al. Cost-effectiveness and clinical
effectiveness of catheter-based renal denervation for resistant hypertension. J Am Coll Cardiol 2012; 60: 1271-1277. 14 Pokushalov E, Romanov A, Corbucci G, et al. A randomized comparison of
pulmonary vein isolation with versus without concomitant renal artery denervation in patients with refractory symptomatic atrial fibrillation and resistant hypertension. J Am Coll Cardiol 2012; 60: 1163-1170. 15 Witkowski A, Prejbisz A, Florczak E, et al. Effects of renal sympathetic
denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension 2011; 58: 559-565. 16 Mahfoud F, Schlaich M, Kindermann I, et al. Effect of renal sympathetic
denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation 2011; 123: 1940-1946. 17 Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to
severe CKD. J Am Soc Nephrol 2012; 23: 1250-1257. 18 Davies JE, Manisty CH, Petraco R, et al. First-in-man safety evaluation of
renal denervation for chronic systolic heart failure: primary outcome from REACH-Pilot study. Int J Cardiol 2013; 162: 189-192. 19 Schlaich MP, Straznicky N, Grima M, et al. Renal denervation: a potential new treatment modality for polycystic ovary syndrome? J Hypertens 2011; 29: 991-996. 20 Mabin T, Sapoval M, Cabane V, et al. First experience with endovascular ultrasound renal denervation for the treatment of resistant hypertension. EuroIntervention 2012; 8: 57-61.
