Renal denervation therapy for hypertension: all that glitters is not gold

Systemic hypertension is a common condition that substantially increases the risk of cardiovascular events. Despite this, blood pressure (BP) control with pharmacological antihypertensive therapy remains challenging and control rates are well below the optimal level. This common unmet need meant that mechanical approaches to treat hypertension were enthusiastically received. As a result, the development and potential utility of renal denervation (RDN) to treat hypertension, especially resistant hypertension, was welcomed as a ‘spectacular’ breakthrough in modern therapeutics. It seemed that the unmet need in hypertension might finally be fulfilled. Clinical research in RDN advanced at a ‘hasty’ speed, perhaps now recently matched by the rapid development of a vaccine against the SARS-CoV-2 virus. However, the enthusiasm for this mechanical marvel subsided as quickly as it developed. The target of RDN is the sympathetic nervous system, which does play a role in the elevation of BP. Therefore, RDN selectively reverses one mechanism of hypertension. But hypertension is a multifactorial disease. Therefore, will targeting a single pathogenetic mechanism really be enough to produce effective and sustained reductions in BP in a large number of patients with hypertension? The clinical evaluation of RDN has played out in the medical literature, from promising early uncontrolled trials to negative sham-controlled studies, and demonstration of clinical efficacy. When data from sham-controlled trials of catheter-based RDN are aggregated in meta-analyses, there does appear to be some benefit overall, although absolute reductions in BP are modest.1–3 In fact, the BP-lowering effects of RDN may only be equivalent to taking ‘one’ antihypertensive drug.4 How well does this fit with guideline recommendations to start with dual antihypertensive therapy to achieve rapid and effective BP control?5,6 As noted above, the fact that hypertension is a multifactorial disorder means that the response to any monotherapy (be it mechanical or pharmacological) is highly variable and, often, suboptimal. Clearly, RDN therapy is no exception. The initial enthusiasm for RDN after the publication of the first uncontrolled trials waned when sham-controlled studies failed to replicate these findings. Subsequent trials have resurrected the RDN field to some extent, but the BP reduction in these studies was modest at best. Even in the best operational hands, the BP reduction associated with RDN appears to be marginal (a decrease of 3–6 mmHg in systolic BP). Even the early enthusiasts for RDN therapy have ACCEPTED these modest changes in BP. At an individual level, some patients experience a substantial decrease in BP after RDN while others show no change or even an increase in some. But how can those patients who will respond to RDN be identified? Since a correlation between RDN and BP fall has been hard to prove, it has been proposed that complex markers such as norepinephrine turnover, heart rate variability, baroreflex sensitivity, serum levels of soluble fms-like tyrosine kinase 1 (sFLT-1), intercellular adhesion molecule 1 (ICAM-1), plasma renin activity, and vascular cell adhesion molecule 1 (VCAM-1) can be used as predictors of response.7 Are these approaches really feasible in clinical practice? Studying peripheral sympathetic nerve impulses before and after RDN has also been proposed to evaluate the efficacy of RDN. This too is an impractical tool in clinical practice. For a condition as common as hypertension, it is absurd to recommend highly complex research markers as parameters to evaluate the response to RDN therapy. Not exactly comparable to checking body temperature in response to aspirin in a febrile patient! Modifications and improvements to devices and techniques have occurred over time, and options for RDN include radiofrequency, ultrasound-guided, chemical, etc. Nevertheless, procedural success has not translated consistently or predictably to BP reduction in most studies. Failure of RDN therapy should not be a call to abandon the procedure but instead to reconsider indices that might reliably predict meaningful BP responses in the real world, not just in specialised research facilities. In addition, perhaps we should be lowering our expectations of the BP reduction that can be achieved with a monotherapy approach, such as regional RDN. Overall, RDN has not turned out to be a magic bullet that provides freedom from antihypertensive drug therapy.8 Therefore, should use of RDN be more judicious rather than widespread? Yes, according to the Joint UK Societies statement that ‘RDN should not be offered to patients outside the context of clinical trials’,9 and advice from expert centres that ‘RDN should remain the last resort in patients in whom all other means to control BP failed’.10 Perhaps RDN may serve as a temporary reprieve for patients who voluntarily opt for the procedure instead of taking yet another pill. After years of dedicated exciting research, RDN has come of age; it has gone through ups and downs evolving through a rapid rise, steep fall, and hopeful resurrection. Despite the lessons learnt from various trials, improvements in device and trial design, technique, and much hard work, RDN therapy remains adrift. The RDN ship is sailing on bewildering and ambiguous waters searching for a safe harbor. For now, the RDN experience affirms the aphorism ‘All that glitters is not gold’. The author thanks Ms N. Madhavi Latha for editorial assistance and manuscript transcription. Help from Ms Nicola Ryan in the final proofreading and reference verification is appreciated. none declared.