Verve Medical’s Non-Vascular Treatment for Hypertension: A New Target for Renal Denervation

A billion individuals suffer from hypertension worldwide. It is the number-one risk factor for death and is directly responsible for 9.4 million annual deaths.¹ Recent studies suggest that achieving a systolic BP goal of 120 mmHg as compared to 140 mmHg can reduce the rate of cardiovascular (CV) events by one-third and death by almost one-quarter.² A meta-analysis of 61 perspective observational studies of a million adults with 12.7 million person years, suggests even a simple 2 mm decrease in mean systolic blood pressure results in a 7% reduction in risk of ischemic heart disease mortality and 10% in stroke mortality.³

Grimson described a treatment for hypertension with surgical sympathectomy with good success, but there was significant morbidity associated with this operation.⁴ It did result in immediate blood pressure drop with the destruction of these nerves. Levin and Gelfand described the concept of delivering energy via the renal arteries to potentially denervate the kidneys less invasively.⁵ Ardian was the first medical device company that utilized the renal artery approach to access the renal nerves for radiofrequency (RF) application.⁶ We recently published a book on the treatment of hypertension with renal denervation, providing a description of 14 diverse medical devices for renal denervation.⁷ One consistency across all of these innovative devices is that all but one approach the peri-arterial nerves paralleling the renal arteries to perform renal denervation. Renal denervation via the renal arteries results in a response rate ranging from 50-85% and the response is not immediate.^6,8 In some patients, there are multiple renal arteries that arise. Sometimes the size of the arteries makes this approach to renal denervation impossible. Disease, fibrosis, aneurysm, or ectopic takeoff can make renal denervation via the renal artery route difficult. A study by Rimoldi et al described a retrospective angiographic study of nearly 1,000 consecutive hypertensive patients undergoing selective renal angiography.⁹ They note that currently recommended anatomic vascular eligibility would allow cardiologists to select only about 50% of hypertensive patients for this novel therapy, a major limiting factor. 

Renal artery stenosis has also been described after this procedure, which can occur with any renal artery intervention.^10,11 A recent study with optical computed tomography (OCT) analysis after renal denervation with 5 balloon- and non-balloon-based systems concluded 32.6% of cases demonstrated OCT evidence of renal artery dissections.¹² Overall, it is estimated that less than 5% of patients will have some significant complication with the peri-arterial approach to renal denervation.12 In 2014, Vink et al detailed what occurs pathophysiologically in a human after treatment, describing a patient that had been treated with renal denervation for resistant hypertension.¹³ Her blood pressure did not drop, and in fact, she died several weeks after the procedure from an aortic dissection (not related to the renal denervation procedure). Post mortem exam revealed that the treatment catheter that showed an ablation depth of 2 mm did not, in fact, reach the site of the major renal nerve bundles. It was speculated that this may have been the reason the patient did not have a reduction in her blood pressure. It was also speculated that there was no interruption of the nerve bundles, and the authors note that if this is a pattern that occurs in other cases, it might explain, at least in part, the great variability in blood pressure lowering effect.¹³ Either way, it may be one explanation of why SYMPLICITY HTN-3 failed (additional explanations for the failure of this seminal study have been described elsewhere). The case described by Vink et al leads to the question of whether the peri-arterial renal denervation (RDN) approach is fraught with problems because only partial denervation occurs in some patients. After the disappointing results of SYMPLICITY HTN-3, Mahfoud et al stressed that we need to learn from the human anatomy.¹⁴ 

The preclinical studies influenced all the peri-arterial approaches, and the animals treated did not have underlying arteriosclerosis. It may be that these devices are not sufficiently affecting the afferent nerves. In human anatomy, the depth of nerve distribution around the arteries also appears to be different. There appears to be a paucity of afferent nerves paralleling the renal arteries in humans and the afferent nerves become less abundant as you move distally in the renal artery.¹⁵ Overall, the nerves become more superficial to the arterial lumen as the renal hilum is approached. As energy is delivered toward the hilum, the dilemma is that the device is not going to ablate enough afferent nerves and treating proximally means not as many nerves will be ablated because of their depth. In order to fully ablate the peri-arterial nerves, energy needs to be delivered up to 10 mm.15,16 In some cases, no treatment, whether with heat, ultrasound, or injected toxic compounds, will deliver therapy that deep without causing collateral damage. 

If the treatment affected the afferent nerves, an immediate blood pressure drop in these patients should occur, potentially obtaining a higher response rate. In 2011, Kopp stated that in contrast to the widespread distribution of efferent sympathetic nerve fibers in the kidney, the majority of the afferent renal sensory nerves are located in the renal pelvic area (Figures 1-3).^17,18 

We began the Verve Medical non-vascular approach after many of the peri-arterial approaches had began in humans.¹⁹ We felt that we needed to show biological proof of effect of peri-pelvic renal denervation in a human model. After the failure of SYMPLICITY HTN-3, some investigators felt that the human neuro-anatomy had not been fully studied. Our work was primarily done with urologists and nephrologists. The urologists proposed that patients who were planned to undergo nephrectomy for severe renal disease would be an excellent human model to confirm the location of the nerves and degree of nerve ablation. Our philosophy was to go to the source of the nerves, in the renal pelvic system. Our first subjects were treated at Muljibhai Patel Urological Hospital in Nadiad, India, concentrating on patients already planned for a nephrectomy a week later. Under general anesthesia with cystoscopy, we treated 3 non-hypertensive patients (we were able to analyze 4 kidneys: 1 patient was to undergo bilateral kidney removal, the other 3 patients were planned for single kidney removal). A week later, the harvested kidneys were sent for evaluation. Figure 4 shows the NephroBlate catheter (Verve Medical) in a patient in the operating room. The pelvic wall area distal to the ablation zone shows the plexus of nerves that are extremely superficial, with the majority of the nerves less than 1 mm from the renal pelvic space (Figure 4). The area of treatment shows that the nerves have been completely damaged with very few present after ablation. 

Following this proof of concept study, 4 resistant hypertensive patients were treated. Immediate and 1-month results revealed a 44 mm systolic drop and 13 mm diastolic drop (Figure 5) in blood pressure. Although a significant drop in norepinephrine and renal denervation on a tissue level in the swine model were both observed, it was felt we were getting too much focal heat and too much damage, with some of the animals sustaining calyceal stenosis in follow-up. We redesigned a new helical probe to eliminate circumferential ablation. We treated 24 swine and followed them for up to 3 months with no calyceal damage after use of the modified prototype (Figure 6). In the initial hypertensive study, we were treating at a 60-degree Celsius tissue temperature for a duration of 6 minutes in each kidney. In the swine studies, we switched to 2 minutes at 60 degrees centigrade with the new spiral or helical design. It was thought that a helical design would not apply as much circumferential heat and would reduce the chance of structuring in the renal pelvis. In a swine model, we confirmed that the nerves are extremely superficial to the pelvic lumen and are damaged after RF treatment. We then again went into the human nephrectomy model, treating 6 patients with no urologic complications or dissections (Figure 7). In the single patient with hypertension, an immediate 22 mmHg drop in systolic blood pressure was achieved, even though only one kidney was treated (Figures 8-12). Based on this work, we believe that the Verve Medical device more easily approaches the nerves in the collecting system because of their proximity as well as the fact that there is no arteriosclerosis or fibrosis at this site. As has been described, the renal pelvis is where the majority of the afferent nerves are located, which appear to affect sympathetic tone. 

Nephrologists in the United States manage up to 75% of patients with resistant hypertension, the first group that the renal denervation devices targeted. Only 12% of resistant patients are managed by cardiologists.^20,21 As we continue with early studies in hypertensive patients, our joint urologic-nephrology procedure has the urologists treating the patient at first in the operating room and eventually in an outpatient facility. Since hypertension is an equal opportunity killer, it is important to develop a cost-effective therapy. This may be more cost effective in the third world, since cystoscopy is a standard urologic procedure that potentially could be performed in a urologist’s office. 

There are 26 million patients in the United States with chronic kidney disease. Sympathetic tone is increased as the renal function is diminished.²¹ Importantly, the renal patient is not exposed to iodinated contrast with the Verve Medical device. The peri-pelvic approach, unlike the peri-arterial approaches, does not expose the patient to the possibility of arterial restenosis nor does it require anticoagulation or antiplatelet agents. Although the number of patients treated with hypertension with our device is small, it appears to be an approach that can result in an immediate blood pressure drop, similar to open sympathectomy.

Conclusion

Renal denervation may still be the most innovative therapy for hypertension over the last 70 years. There are many patients with hypertension who remain inadequately identified or treated. Their medications have side effects and can be expensive. Most people do not like to take medications and would instead prefer a procedure. Over 50% of hypertension patients do not take their medications or cannot adequately control their blood pressure. With the Verve Medical device, virtually all patients with hypertension can be treated with an immediate blood pressure drop. We believe we are the only group to describe the pathophysiology of treatment in a human clinical nephrectomy model. We also believe we are the only renal denervation device that heats a sufficient number of afferent nerves. 

Previous studies in end-stage renal disease (ESRD) patients showed that a significant percentage had renal artery damage precluding the peri-arterial approach.²² We are continuing our studies in treatement-resistant hypertensive patients, and patients with severe hypertension and renal disease, including patients post-renal transplant. The Verve Medical device could one day be used in a doctor’s office. In patients with hypertension and kidney disease, this device may offer a reliable and safe treatment.

References

1. Poulter N, Prabhakaran D, Caulfield M. Hypertension. Lancet. 2015; 386: 801-812.
2. O’Riordan M. BP targets far below guidelines cut mortality, CV events: SPRINT Trial. Medscape. September 11, 2015.
3. Lewington S, Clarke R, Quizilbash N, Peto R, Collins R. 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(9349): 1903-1913. 
4. Grimson KS. Total thoracic and partial to total lumbar sympathectomy and celiac ganglionectomy in treatment of hypertension. Ann Surg 1941; 114: 753-775.
5. Levin and Gelfand patent No. US PTO 7,162,303. 
6. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009; 373: 1275-1281.
7. Heuser RR, Schlaich M, Sievert H, eds. Renal denervation: a new approach to treatment of resistant hypertension. Springer-Verlag: London; 2015.
8. Esler MD, Krum H, Sobotka PA, Schlaich MP, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomized controlled trial. Lancet. 2010; 376: 1903-1909.
9. Rimoldi SF, Scheidegger N, Scherrer U, et al. Anatomical Eligibility of the renal vasculature for catheter-based renal denervation in hypertensive patients. J Am Coll Cardiol. 2014; 7(2): 187-192.
10. Bhamra-Ariza OP, Rao S, Muller DW. Renal artery stenosis following renal percutaneous denervation. Catheter Cardiovasc Interv. 2014; 84: 1180-1183.
11. Kaltenbach B, Id D, Franke JC, Sievert H, et al. Renal artery stenosis after renal sympathetic denervation. J Am Coll Cardiol. 2012; 60: 2694-2695.
12. Karanasos A, Van Mieghem N, Bergmann MV, et al. Multimodality intra-arterial imaging assessment of the vascular trauma induced by balloon-based and nonballoon-based renal denervation systems. Circ Cardiovasc Interv. 2015 Jul;8(7):e002474.
13. Vink EE, Goldschmeding R, Vink A, Weggemans C, Bleijs R, Blankestijn PJ. Limited destruction of renal nerves after catheter-based renal denervation: results of a human case study. Nephrol Dial Transplant. 2014 Aug;29(8):1608-10. doi: 10.1093/ndt/gfu192. 
14. Mahfoud F, Edelman ER, Bohn M. Catheter-based renal denervation is no simple matter: lessons to be learned from our anatomy? J Am Coll Cardiol. 2014; 64(7): 644-646.
15. Sakakura K, Virmani R, Joner M, et al. Anatomic assessment of sympathetic peri-arterial renal nerves in man. J Am Coll Cardiol. 2014; 64: 635-643.
16. Pathak A, Coleman L, Roth A, Stanley J, et al. Renal sympathetic nerve denervation using intraluminal ultrasound within a cooling balloon preserves the arterial wall and reduced sympathetic nerve activity. EuroIntervention. 2015; 11: 477-484.
17. Kopp UC. Neural Control of Renal Function. In: Granger DN, Granger JP, editors. Colloquium Series on Integrated Systems Physiology: From Molecule to Function to Disease. San Rafael (CA): Morgan & Claypool Life Sciences; 2009-2011.
18. Kopp UC. Role Role of renal sensory nerves in physiological and pathophysiological conditions. Am J Physiol Regul Integr Comp Physiol. 2015 Jan 15; 308(2): R79-R95. doi: 10.1152/ajpregu.00351.2014.
19. Heuser RR, Buelna TJ, Gold A, et al. NephroBlate™ renal denervation system: urologic-nephrologic based approach to resistant hypertension. In: Heuser RR, Schlaich M, Sievert, Eds. The New Approach to Treatment of Resistant Hypertension. Philadelphia, PA: Springer; 2015.
20. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD, 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 Jun; 51(6): 1403-1419. doi: 10.1161/HYPERTENSIONAHA.108.189141.
21. DeNicola L, Gabbai FB, Agarwal R, et al. Prevalence and prognostic role of resistant hypertension in chronic kidney disease patients. J Am Coll Cardiol. 2013 Jun 18; 61(24): 2461-2467. doi: 10.1016/j.jacc.2012.12.061.
22. Schlaich MP, Bart B, Hering D, Walton A, et al. Feasibility of catheter-based renal nerve ablation and effects on sympathetic nerve activity and blood pressure in patients with end-stage renal disease. J Int J Cardiol 2013; 168(3): 2214-2220.