The promise of chemical renal denervation

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By Tim A Fischell

The sobering results from Symplicity-HTN 3 trial,1 which found that Medtronic’s Symplicity system was not associated with significant reductions in blood pressure compared with a sham procedure, have left some casual observers sceptical about the promise of renal denervation as a means to manage resistant hypertension.


H
owever, more sophisticated experts in the field have begun to shed light on the root cause of the trial’s failure. It has become increasingly clear that the major problem with radiofrequency-mediated renal denervation is poor efficacy caused by incomplete and inconsistent sympathetic nerve injury and, consequently, “inadequate denervation”. “Non-responders” are not necessarily unresponsive to renal sympathetic denervation—they are just not adequately denervated.


Radiofrequency-based burning from the intima, in a point by point, or even multipoint array suffers from the two main limitations. Firstly, it provides inadequate depth of nerve kill, with porcine studies and a recent human autopsy report2 showing that the maximum depth of nerve injury is as little as 2mm from the intimal surface (even less in diseased arteries); therefore, a radiofrequency-based system may potentially miss more than half of the sympathetic nerves. Secondly, with radiofrequency-based burning, there is a lack of circumferential nerve kill as each point burn creates only an about 25–30 degrees arc of damage. Thus, with only 4–5 burns (as was typically done in the US trial), one can only attain—at best—a 100-150 degree arc. With both a lack of depth and a lack of circumferential effects, it is likely that 4–6 “burns” would only achieve 15–30% denervation in many cases.


The anatomical challenges related to renal denevation with the radiofrequency-based approach are have also been suggested in a recent analysis of the Symplicity-HTN 3 data by David Kandzari.3 This analysis showed a dose-response to radiofrequency, such that patients receiving 4–6 burns have essentially no blood pressure lowering effect vs. the sham group. Blood pressure lowering was not observed until one performed ≥8–9 burns per artery. That a certain number of burns has to be achieved if radiofrequency renal denervation is to be effective may pose a major challenge to the radiofrequency “spiral” burning concept; there are very few patients (<15%) who have the 4–5cm long renal arteries needed to safely achieve this threshold number of burns.


Chemical renal denervation using micro-doses of dehydrated alcohol (ethanol) is a potential alternative to radiofrequency-based renal denervation. It has been evaluated in preclinical and early clinical studies, and has the potential to overcome many of the serious limitations of radiofrequency-based denervation.
For example, the Peregrine infusion catheter (Ablative Solutions) has been extensively tested in a porcine model to deliver micro-doses of ethanol to the adventitia.4 The device’s three 0.008” needles are deployed simultaneously at 120 degrees one to another at a depth of about 3.5mm measured from the intima. At this depth, the needle tips are located in the adventitia and thus in very close proximity to the sympathetic nerve fibres. Ethanol doses of 0.3ml and 0.6ml consistently achieve about 85–92% nerve inactivation, as evidenced by drops in renal parenchymal norepinephrine measurements, and by histopathological evaluation.4 Histopathology demonstrates 360 degrees of nerve kill at depths of 8-12mm from the intimal surface.


In the early human experience (18 patients treated in a first human use study), there were consistent and significant blood pressure reductions in all patients in the face of a significant reduction of antihypertensive medications. The delivery of 0.3ml of ethanol to the adventitia in these patients was also essentially painless, which offers a major advantage over treatment with radiofrequency catheters. There have been no adverse events at six months of follow-up. Complete analysis of these data will be presented in a peer-reviewed publication.


Conclusion


Chemical renal denervation using ethanol may have numerous advantages over energy-based “burning” technologies, including:

  • Its ability to achieve 360 degrees of nerve kill at substantial depth to achieve rapid, complete and predictable denervation even in short (<1cm long) renal arteries

  • Its ability to target the nerves where they are located (in the adventitia), sparing injury to the media
  • That it provides essentially painless denervation
  • It does not require expensive capital equipment.

Additional clinical evaluations are underway to better define the safety and efficacy of this promising next generation technology for renal sympathetic denervation.

 


References

 

1. Bhatt et al. N Engl J Med 2014. Epub

 

2. Vink, et al. Nephrol Dial Transplant 2014; 0: 1–3

 

3. Zoller. Cardiology news 2014 (report on Kandzari data presented)

 

4. Fischell et al. EuroIntervention 2013; 9: 140–47

 


Tim A Fischell is professor of Medicine, Michigan State University, East Lansing, USA. 
 
He is also CEO and chief medical
officer of Ablative Solutions