Current Controversies and Future Opportunities
Technical Failure versus Non-responder
One of the main problems with current application of all RSD technologies is the inability to separate technical failure of the procedure from lack of response of patients to effective RSD. This latter problem could arise because either that renal SNS signalling is not paramount to RHTN in that patient (i.e. other mechanisms are driving the RHTN phenotype) or that the patient's anatomy/ physiology is unable to respond to the reduction in SNS signalling (i.e. large vessel stiffening). Furthermore, a purported cumulative effect to RF RSD in terms of BP lowering over 3 years30 may mean that early lack of BP lowering does not reflect lack of either procedural success or response to RSD. This would seriously complicate decision-making regarding re-do procedures (clinicaltrials.gov: NCT01834118) or proceeding to other interventional technologies, such as baroreflex activation therapy (BAT)65,66 or arterio-venous coupling,67 in early non-responders to RSD.68 Furthermore, the recent announcement of the failure of Symplicity HTN-3 to meet its primary efficacy end-point at 6 months with a first-generation sequential ablation catheter system may reflect difficulties in demonstrating effective neural destruction, a primary end-point that was too early in the natural history of the response to RSD, effective guidelinedriven treatment of RHTN in the placebo-sham arm or that RF RSD was truly ineffective in BP lowering in a cohort of patients that had true RHTN in and out of office.
Further research to determine which patients are suitable/likely to respond to RSD is essential. To date, only baseline BP correlates to the magnitude of BP response to RF RSD across multiple cohorts.10,30,31,69,70 Single-unit muscle sympathetic nerve activity is reduced within 3 months of RF RSD and may predict future BP response but this is not established yet.71 Impaired cardiac baroreflex sensitivity predicts BP response to,72 and improves after,73 RF RSD.
More recently, intra-arterial BP response to high-frequency stimulation ([HFS] 20 Hz for 10 seconds) at the renal artery ostium immediately post procedure suggests a potential test of procedural efficacy.74 In this study, HFS pre-procedure caused an immediate >15 mmHg increase in BP in all patients that was almost entirely blunted (<6 mmHg) post RF RSD.74 Other investigations that have been utilised in subsets of patients include renal NE spillover10 and single-unit muscle sympathetic nerve activity.71 However, both techniques are time consuming, require invasive testing preand post-procedure and are currently only available in specialist centres with expertise of autonomic function assessment. These concerns highlight the growing importance of collaboration with autonomic neurophysiologists and cardiovascular physiologists to develop the means to accurately phenotype individual patients with respect to the role of the SNS and its many subdivisions in their hypertension. In a similar fashion, the clinician already subjects patients to detailed biochemical and imaging characterisation as a pre-requisite to adrenalectomy for patients with adrenal nodules. Why then should (expensive and invasive) RSD be offered to all patients with RHTN without first determining the involvement of their renal SNS?
Clinical Trials Inadequacies
Criticisms of published RSD clinical trials have been widely propagated75-78 and include lack of sham control; non-blinded design; no per protocol exclusion of both secondary causes of hypertension and non-adherence to therapy; intermediate soft end-points (often 6 month office BP); and lack of ambulatory BP use as standard for both inclusion to exclude white coat effect, and also as a BP outcome and lack of durability and safety beyond 3 years. Ambulatory BP has been included in more recent small studies in moderate RHTN,79,80 and both sham control (clinicaltrials.gov: NCT01418261) and major adverse cardiovascular events as primary end-points (clinicaltrials.gov: NCT01903187) are included in current large international studies but the results from these studies will not be known for many years, so the current use of RSD technologies is based on low numbers of non-high-quality studies. Durability of BP lowering has recently been demonstrated for at least 3 years,30 but concerns about renal nerve regrowth remain81 although the potential impact of any re-innervation on BP is unclear.30 Reassuringly, denervated renal transplants have preserved functions of solute clearance, electrolyte transport and hormonal function82 and RF RSD in moderate to severe CKD is both effective and safe up to 1 year post procedure.39
What is the Best Renal Sympathetic Denervation System?
Currently it is difficult to recommend one RSD technology above and beyond any other, as there are no head-to-head comparisons of intra- or inter-class RSD technologies. The majority of clinical trial experience is with the first-generation RF Symplicity catheter, though as outlined previously methodological and technological advances in second-generation RF and other non-RF systems give theoretical preference to more recent iterations. A clinical study of four RSD technologies, including one single electrode RF system, two multi-electrode systems and one non-RF system, may help answer this question with respect to BP lowering and procedural and renal artery safety (clinicaltrials.gov: NCT01888315). Notably, it remains unproven whether any technological form of RSD is equivalent (or superior) to guideline-driven pharmacological management of RHTN5 and specific trials of this type are not currently under way. Until this is the case, RSD should remain a treatment of last resort for RHTN.