Renal denervation – a different tool for hypertension care – Organised by MEDTRONIC

Symposium Summary

Written by Jasna Trbojevic-Stankovic
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Endovascular renal sympathetic denervation (RDN) was first proposed as a treatment method for resistant hypertension a decade ago. The treatment methodology and clinical evidence have advanced significantly since that time. Several renowned experts in the field of RDN presented the latest evidence on the procedure, its applicability in practice, and possibilities that this method is offering to chronic kidney disease (CKD) patients at a symposium held during the 58th ERA-EDTA Congress (only virtual).

Latest Evidence on Renal Denervation

Konstantinos Tsioufis, Greece

RDN appears to be a promising alternative for blood pressure (BP) control, and the procedure has demonstrated safety in multiple clinical trials. RDN requires a complete treatment of the distal main renal artery, branches, and accessory arteries. Renal nerves generally originate from proximal ganglia and converge on the renal artery, but accessory arteries are also common and always innervated and can contribute to the development of hypertension.

The application of radiofrequency (RF) RDN relies on extensive clinical experience with RF ablation on more than 6,700 patients and 12,000 patient years of follow-up. The multi-electrode RDN Symplicity Spyral catheter is able to position electrodes to generate 360 degrees of ablation and also treat the renal branches and accessory arteries to maximize the probability of complete denervation. The efficacy of this technique in the absence of antihypertensive medications was evaluated in the SPYRAL HTN-OFF MED Pivotal trial, a prospective, randomised, sham-controlled trial. The investigation randomly assigned 331 patients with office systolic blood pressure between 150 and 180mmHg, and diastolic BP≥90mmHg to either RDN (166 patients) or sham procedure (165 patients). Recently published results revealed that RDN showed superiority in achieving the baseline-adjusted change in 24-h systolic BP and baseline-adjusted change in office systolic BP from baseline to 3 months after the procedure with a favorable safety profile. The BP-lowering effect was consistent regardless of the time of the day, thus precluding the traditionally increased early morning risks for stroke and cardiovascular events. Similar results were obtained in the SPYRAL HTN-ON MED trial in which RDN in the main renal arteries and branches combined with medications significantly reduced BP compared to antihypertensive therapy alone. Also, evaluation of hourly changes in 24-h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24-h period for the renal denervation group.

The largest and longest investigation of long-term safety and efficacy of RDN in real-world patients was undertaken based on the data from the Global SYMPLICITY Registry. This prospective, open-label registry conducted worldwide followed office and 24-h ambulatory systolic BP three years after RDN with Symplicity Flex or Spyral in 2,590 patients demonstrating significant and sustained office and ambulatory BP reductions with no long-term safety concerns. These results were corroborated in a recently published meta-analysis by Ahmad et al. suggesting that should the observed effect of RDN on BP continue long term, this procedure might provide a life-long 10% relative risk reduction in major cardiac events and 7.5% relative risk reduction in all-cause mortality.

Renal Denervation in Practice

Roland E. Schmieder, Germany

The initial promising results of RDN prompted the introduction of this method into practice providing an insight into specific situations where the procedure could be of particular value. Some of these cases are presented in this symposium.

Case 1 underlines the importance of recognizing apparent resistant hypertension which is, in fact, a result of poor adherence to drug treatment. It presents a 50-year-old hypertensive female with a positive history of CV disease and variable adherence to the prescribed medication therapy which included an angiotensin II antagonist and a calcium channel blocker. She is overweight, with office BP 159/93mmHg and 24-h ambulatory BP 149/82mmHg. The serum creatinine level, eGFR, and HbA1c are within a normal range, but LDL is borderline high. This is a typical case identifying nonadherence to antihypertensive treatment as a critical contributor to suboptimal BP control. Studies have identified that each increase in the number of antihypertensive medications led to a substantial increase in nonadherence, especially when converting from two to three medication classes. Poor adherence is associated with increased all-cause and cerebrovascular mortality risk. The major barriers to medication adherence include economic, physiological, and social issues, such as side effects, perceived lack of efficacy, lack of visible symptoms, poor understanding of the illness and its risks, cost concerns, and cultural beliefs. Therefore, RDN might be a convenient option for nonadherent patients to decrease mortality and improve quality of life.

Case 2 presents a 70-year-old male with a 10-year history of hypertension, type 2 diabetes, left ventricular hypertrophy, and CKD. Despite good adherence to a four antihypertensive medication treatment protocol, office BP is 176/95mmHg, and 24-h ambulatory BP is 154/91mmHg. Large-scale studies have found RDN to be effective and durable in high-risk populations with various comorbidities including diabetes, CKD, resistant hypertension, and atrial fibrillation. The procedure reduced Office systolic BP at three years by -16.4 mmHg in patients with diabetes, -11.6 mmHg in CKD, -23.5 mmHg for resistant hypertension, and -17.6 mmHg in atrial fibrillation. In patients aged ≥65 years, the observed reduction was -18.4 mmHg. These results were associated with a 26% relative risk reduction in major cardiovascular events over three years.

Case 3 represents a typical example of the onset of a hypertensive disease continuum. It presents a 40-year-old male with a sedentary profession, sleep apnea, obesity, dyslipidemia, well-controlled type 2 diabetes, smoking habit, and a newly diagnosed hypertension with an office BP of 160/110mmHg and 24-h ambulatory BP of 150/103mmHg. Being young, the patient is concerned about the lifelong medication treatment and is exploring other options to effectively and persistently control hypertension. While in current practice referring physicians and proceduralists are more likely to recommend RDN procedure to patients with higher BP and a greater number of antihypertensive medications, patient preference for renal denervation is unrelated to their baseline blood pressure or medication status. The rationale for this premise is substantiated by the fact that hypertensive patients often regard the choice of RDN to lower BP differently from physicians and a considerable proportion of them, especially those not taking medications, might prefer a device-based approach to reduce their BP.

Should Renal Denervation be an Option for CKD Patients?

José Antonio García Donaire, Spain

It is a well-known fact that CKD is associated with an increased sympathetic activity which contributes to the progression of the disease and is associated with adverse cardiovascular outcomes. End-stage renal disease (ESRD) is associated with an even higher increase in plasma norepinephrine than hypertension alone. The RDN procedure was first introduced as an option to reduce sympathetic nerve activity and BP in patients with resistant hypertension and preserved renal function rendering promising results.

Later on, concerns arose whether the technique would be safe and effective in hypertensive patients with CKD. Initial studies performed nearly a decade ago suggested a favorable short-term safety profile and beneficial BP effects of renal nerve ablation in patients with CKD stages 3-4 and resistant hypertension. Later research even underlined the role of RDN in further mitigation or even cessation of renal function decline, irrespective of BP-lowering effects in CKD patients, an effect that lasted well over 6 months after the procedure. The most recent recognition of these results originates from the Global SYMPLICITY Registry which supported previous findings.

Even with these promising results, ESRD patients on hemodialysis (HD) still represent a challenge, even though this population often suffers from resistant hypertension despite the administration of many antihypertensive drugs. Ott et al. were the first to report performing the procedure in HD patients corroborating the data on renal safety of RDN even in small arteries. More recently, Scalise et al. supported these findings concluding that the BP reduction in HD patients persisted over a one-year follow-up.

Kidney transplant patients represent yet another population in which sympathetic activity is frequently observed and post-transplant hypertension is a major contributing factor to graft failure and cardiovascular morbidity. This process is maintained by the preservation of sympathetic afferent activity from the native non-functional kidneys, in the absence of efferent feedback to the renal transplant, which would otherwise modulate neurohumoral activity. A small study by Schneider et al. found that RDN is feasible and safe in this population as well, with a significant reduction in office BP persisting 6 months after the procedure.

Upcoming larger prospective trials should focus on the identification of patients with uncontrolled hypertension with all levels of CKD who may derive a substantial benefit from RDN.

Further reading

Persu A, Maes F, Renkin J, Pathak A. Renal Denervation in Hypertensive Patients: Back to Anatomy? Hypertension. 2020;76(4):1084-1086. doi: 10.1161/HYPERTENSIONAHA.120.15834.

Sato Y, Kawakami R, Jinnouchi H, et al. Comprehensive Assessment of Human Accessory Renal Artery Periarterial Renal Sympathetic Nerve Distribution. JACC Cardiovasc Interv. 2021;14(3):304-315. doi: 10.1016/j.jcin.2020.09.043.

Böhm M, Kario K, Kandzari DE; SPYRAL HTN-OFF MED Pivotal Investigators. Efficacy of catheter-based renal denervation in the absence of antihypertensive medications (SPYRAL HTN-OFF MED Pivotal): a multicentre, randomised, sham-controlled trial. Lancet. 2020;395(10234):1444-1451. doi: 10.1016/S0140-6736(20)30554-7.

Kandzari DE, Böhm M, Mahfoud F; SPYRAL HTN-ON MED Trial Investigators. Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial. Lancet. 2018;391(10137):2346-2355. doi: 10.1016/S0140-6736(18)30951-6.

Mahfoud F, Böhm M, Schmieder R, et al. Effects of renal denervation on kidney function and long-term outcomes: 3-year follow-up from the Global SYMPLICITY Registry. Eur Heart J. 2019;40(42):3474-3482. doi: 10.1093/eurheartj/ehz118.

Ahmad Y, Kane C, Arnold AD, et al. Randomized blinded placebo-controlled trials of renal sympathetic denervation for hypertension: A meta-analysis. Cardiovasc Revasc Med. 2021:S1553-8389(21)00082-8. doi: 10.1016/j.carrev.2021.01.031.

Gupta P, Patel P, Štrauch B, et al. Risk Factors for Nonadherence to Antihypertensive Treatment. Hypertension. 2017;69(6):1113-1120. doi: 10.1161/HYPERTENSIONAHA.116.08729.

Mahfoud F, Mancia G, Schmieder R, et al. Renal Denervation in High-Risk Patients With Hypertension. J Am Coll Cardiol. 2020;75(23):2879-2888. doi: 10.1016/j.jacc.2020.04.036.

Schmieder RE, Kandzari DE, Wang TD, Lee YH, Lazarus G, Pathak A. Differences in patient and physician perspectives on pharmaceutical therapy and renal denervation for the management of hypertension. J Hypertens. 2021;39(1):162-168. doi: 10.1097/HJH.0000000000002592.

Hering D, Mahfoud F, Walton AS, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol. 2012;23(7):1250-7. doi: 10.1681/ASN.2011111062.

Hering D, Marusic P, Duval J, et al. Effect of renal denervation on kidney function in patients with chronic kidney disease. Int J Cardiol. 2017;232:93-97. doi: 10.1016/j.ijcard.2017.01.047.

Ott C, Schmid A, Ditting T, Veelken R, Uder M, Schmieder RE. Effects of renal denervation on blood pressure in hypertensive patients with end-stage renal disease: a single centre experience. Clin Exp Nephrol. 2019;23(6):749-755. doi: 10.1007/s10157-019-01697-7.

Scalise F, Sole A, Singh G, et al. Renal denervation in patients with end-stage renal disease and resistant hypertension on long-term haemodialysis. J Hypertens. 2020;38(5):936-942. doi: 10.1097/HJH.0000000000002358.

Schneider S, Promny D, Sinnecker D, et al. Impact of sympathetic renal denervation: a randomized study in patients after renal transplantation (ISAR-denerve). Nephrol Dial Transplant. 2015;30(11):1928-36. doi: 10.1093/ndt/gfv311.