TY - JOUR
AU - Mann, Johannes F., E.
AB - Abstract Renal sympathetic denervation (RSD) has previously been discussed in this journal. Since then, it has become a common procedure in many countries to use RSD to treat patients with putatively resistant hypertension. In Germany alone, RSD is now routinely used to treat resistant hypertension at the expense of the health-care system [1]. The Germans have established a national registry to systematically and continuously follow up hypertensive patients who have undergone RSD. However, there are concerns because the registry is voluntary and physicians practicing the procedure may not have the accrual of new knowledge regarding the utility of RSD as their primary professional aim [2]. Since the previous editorial [3] on renal denervation, new results have been published. Therefore, it is appropriate to re-evaluate RSD. arterial hypertension, renal sympathetic denervation, antihypertensive therapy PRESENT RESULTS RSD has been known to lower blood pressure (BP) in humans for many years; however, previously a major operation was necessary [4, 5]. With the ingenious idea of a catheter-based percutaneous ablation of the renal nerves, Krum et al. demonstrated in the Simplicity HTN-1 pilot study that bilateral radiofrequency catheter-based RSD may substantially lower systolic BP by 20 to >30 mm Hg compared with baseline [6]. A following open-label, randomized controlled trial in 106 similar patients receiving stable antihypertensive therapy (Simplicity HTN-2) confirmed the results of the pilot study compared with a control group receiving no intervention [7]. The authors assessed the effectiveness of renal sympathetic denervation with renal norepinephrine spillover in a subgroup of patients and safety with systematic duplex-ultrasound studies in all Simplicity-HTN-2 patients and non-systematic follow-up renal angiography in few participants [6, 7]. The first trials were limited to a follow-up of about 6 months, while recent follow-up publications report sustained BP reduction after 2 years. Presentations at major meetings suggest that the above effects of RSD on BP last for at least 3 years (Esler, ACC, 2012). Intriguing studies of the allegedly pressure-independent effects of RSD have followed these encouraging results. Mahfoud et al. [8] randomly assigned 37 patients to RSD and 13 to a control group and observed a remarkable decrease in fasting blood glucose by 10 mg/dL which was accompanied by a fall in serum-insulin concentrations and C-peptide levels over 3 months. That substantial increase in insulin sensitivity after RSD was ascribed to reduced activation of the sympathetic nervous system, which is thought to contribute to insulin resistance, metabolic syndrome, obesity and risk of developing diabetes mellitus [8]. A further uncontrolled report on RSD in 10 patients with resistant hypertension and sleep-apnoea syndrome found that blood glucose after an oral glucose challenge was lower after RSD. Furthermore sleep-apnoea syndrome and several other illnesses were concomitantly improved [9]. The effect of RSD on sleep apnoea is supported by data on a pig model of sleep-apnoea syndrome [10]. Not surprisingly, but surprisingly quickly, RSD was shown to reduce left ventricular mass and improve cardiac diastolic function [11]. OPEN QUESTIONS AND CHALLENGES With all these impressive data, why should we not embrace RSD and treat as many hypertensive patients with this procedure as possible [12]? Indeed, with the commercialization of medicine in Germany and other countries, hospital administrators are enthralled with the prospects. First, our primary caveat is that none of us would administer antihypertensive drugs outside of controlled trials based on 6-month data in solely about 100 hypertensive patients. So why should we react to this treatment any differently? Second, we are concerned that the above trials could have been conducted more precisely. There was no blinded control group (catheter placement without ablation) and no assessment masking of outcomes in Simplicity-2 [7]. The latter state-of-affairs is particularly unfortunate because the change in BP is a surrogate result that must be blindly assessed. For an example, early studies of balloon angioplasty (PTA) of renal artery stenosis and open assessment of BP changes grossly overestimated the effectiveness of PTA and misdirected vast amounts of public health-care funds towards that treatment [13]. Third, the true effect size of RSD is highly uncertain. While office systolic BP was reduced in several trials by 20–30 mm Hg, ambulatory BP monitoring (ABPM) exhibited only 11 mm Hg systolic and 7 mm Hg diastolic reductions, respectively [7]. In accordance with these results, Hering et al. recently reported on patients with chronic renal disease in whom office BPs decreased to a much greater degree than observed with ABPM, 3 months after RSD in the same patients [14]. Cardiovascular (CV) outcomes, however, are driven far more by ABPM values and less so by clinic BP readings. Fourth, we are concerned that participants in the Simplicity trials rarely received aldosterone antagonists, let alone minoxidil. We also do not know whether the doses of all other drugs were appropriately administered. Fifth, we would expect some re-growth of renal nerves after RSD as occurs after renal transplantation [15]. Such re-growth may herald a reappearance of resistant hypertension years after the procedure. Sixth, how about side effects? On the short term, we know about risks of the intervention and the benefits for BP. In the patients' interest, we really need to gauge long-term benefits regarding CV events and mortality. The latter outcomes are much less common but are more important than a decrease in BP. Furthermore, we must consider the possibility of unusual complications and unwanted consequences. It is known that during transient haemorrhage, renal oxygen supply is better preserved in rats with intact innervation of the kidneys than after renal denervation [16]. This finding suggests a putative important role of renal innervation in protection from acute renal failure with reduced renal perfusion. Renal afferent denervation has been suggested as a mechanism to explain systemic decreases in sympathetic nerve activity after RSD [17]. This possibility is difficult to investigate experimentally as exemplified by two recent papers that examined peripheral sympathetic nerve activity sometime after RSD in hypertensive patients. While one study demonstrated absolutely no effect of RSD on peripheral sympathetic nerve activity [18], the other study reported a decrease in sympathetic nerve activity using single-fibre recordings [19]. We view the issue as not satisfactorily resolved. Experimental data suggest that renal afferent signalling results in a sympathoexcitatory effect only if the kidneys are diseased [20, 21]. In healthy kidneys, afferent renal innervation either suppressed sympathetic activity and prevented the development of hypertension [22] or the results suggested that the major transmitters of afferent renal nerves, calcitonin gene-related peptide and substance P, protected the experimental animal from salt sensitivity [23]. Such experimental aspects may influence decisions on RSD in hypertensive patients in further prospective studies. Eventually, the physiology and pathophysiology of afferent renal innervation could turn out to be quite complicated involving afferent nerve fibre activities and paracrine mechanisms linked to these very fibers [24]. In the end, it is biologically implausible that the renal nerves, either afferent sympathetic or afferent peptidergic, serve no useful physiological functions [25]. WHAT DATA DO WE NEED IN THE FUTURE? A controlled trial with sham-RSD treatment is currently underway in the USA with blinded assessment of BP as an outcome [26]. Thereafter, we definitely need a prospective trial with hard outcomes and prospective collection of adverse events. Consider a realistic scenario [27] with 10 000 patients, 5000 RSD and controls, each with 500 and 600 outcome deaths over 5 years, respectively. The absolute benefit of 100 deaths with RSD would shrink considerably if there were 25 additional cholesterol embolism-related deaths with RSD and another 20 or so casualties from sepsis and hypovolaemia-related AKI. After such pivotal trials, nephrologists will particularly be interested to learn about RSD-related effects in people with congestive heart failure, progressive CKD or specific renal diseases such as glomerulonephritis or polycystic kidney disease. Predicting the outcomes of such trials is not trivial or predictable since lowering BP is beneficial in kidney diseases; however, RSD caused glomerular hyperfiltration in some experimental reports [28]. At present, a registry, such as the one initiated in Germany [2], should be conduct in all countries offering RSD. Inclusion in the registry could be required for third-party remuneration. Demographic data, indications, short- and long-term complications, safety variables, efficacy and long-term outcomes could be the result of such a cohort. Furthermore, prediction models for those individuals most likely to benefit from intervention could be constructed. Since participation would of course require informed consent, the patients would be aware that they are taking part in prospective research. In parallel with a pivotal clinical trial, we also need data on large-animal models to demonstrate the extent of the nerve damage and get insights into the physiology of RSD [10]. RSD may conceivably be a potentially useful option for patients with comorbid refractory hypertension, glucose intolerance or sleep-apnoea syndrome, and may provide a unique insight into human physiology. In addition, our options for central blockade of the sympathetic nervous system medically have failed to pass muster. If devices can span that gap, the results would be welcomed. However, we should apply these new tools clinically in a responsible and evidence-driven fashion [2, 25]. If RSD is pursued without data from large randomized controlled outcome trials, the real benefit of this highly promising intervention may never be appreciated. That lack of such data may lead to underutilization of RSD in other areas like mild-to-moderate hypertension or congestive heart failure. Eventually, we will need joint efforts to give this fascinating but also very challenging procedure of RSD the place in hypertensive therapy that it deserves. CONFLICT OF INTEREST STATEMENT None declared. REFERENCES 1 Mann J , Hilgers K , Veelken R , et al. An experimental procedure paid for by the general public , Deutsches Arzteblatt Int , 2012 , vol. 109 (pg. 311 - 312 ) author reply 313–314. http://www.ncbi.nlm.nih.gov/pubmed/22611446 OpenURL Placeholder Text WorldCat 2 Mahfoud F , Vonend O , Bruck H , et al. 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TI - Renal sympathetic denervation as antihypertensive therapy—a reappraisal of first results
JF - Nephrology Dialysis Transplantation
DO - 10.1093/ndt/gft017
DA - 2013-11-01
UR - https://www.deepdyve.com/lp/oxford-university-press/renal-sympathetic-denervation-as-antihypertensive-therapy-a-M6PN0SlA0x
SP - 2698
EP - 2701
VL - 28
IS - 11
DP - DeepDyve
ER -