Renal nerve denervation unraveled. Is the dream over?

Background

Resistant hypertension has been the focus of interest in the last few years due to renal nerve denervation (RND) that set forth as a miracle solution to correct it. 
Resistant Hypertension is most often defined as blood pressure remaining above 140/90 mm Hg even after treatment with three antihypertensive drugs including a diuretic has been administered. The term “resistant” indicates that the clinician does not find any way to control such blood pressure; however, is it really resistant? Have all possible means to decrease blood pressure adequately been used? 

I - Management of resistant hypertension

Several steps need to be checked before deciding that blood pressure is indeed resistant. First and foremost, all regular examinations are to be done as you would with every hypertensive patient obviously. Once that is done, compliance to drug treatment should be verified by all means (plasma or urine levels of drug; use of pill box; active control by family members or nurses…). In cases where compliance is good, a test treatment with spironolactone should be run as many of these patient react quite well on this old therapy (1). Home or ambulatory blood pressure should also be performed because a number of these patients have some type of white coat hypertension - showing much lower blood pressure values in regular life conditions. It is only after all of these steps have been taken, that one can conclude to a case “resistant hypertension”. 

II - The reality of resistance and Renal Nerve Denervation 

In fact, once all steps are taken, many of those “resistant” hypertensives, turn out to actually much be less resistant than anticipated: many patients do not take their drugs as they are prescribed, some clearly have lower ambulatory pressures and quite a large number of them react well to treatment with spironolactone. No doubt, however: a minority's hypertnesion remains truly too high and one does not need to be a high-level expert to realise that these patients are at risk.
 
For those patients, Renal Nerve Denervation has been offered as a solution. The brilliant idea originated from the group headed up by Professor Esler in Australia (2) - it was immediately viewed as extremely appealing. The technique consists in interrupting the nerves around the renal arteries on both sides delivering Laser through a specially devised catheter introduced in the renal artery much in the same way as what is done in renal artery angiography.
That it does interrupt all sympathetic nerve traffic through these nerves is proven from catecholamine output checks on the renal veins; that it works is illustrated by manifest blood pressure decreases in this type of patient who failed to respond to all measures described above, largely resistant to all other type of treatment.  

The first Studies (Simplicity 1 and 2)

In Simplicity 1 (3), positive results were given already. A decrease of around 15 mm Hg systolic and 10 mm Hg diastolic was obtained quite soon after the procedure. Remarkably, such decreases were maintained and even amplified after 6 or 9 months. Still, the numbers were too small to consider the results conclusive; therefore, Simplicity 2 (2) was put together and yielded quite similar positive results on many more patients followed over a longer time. Meanwhile, many hypertension centres all over the world published their own first results which in general were quite positive in the majority of patients. These studies were assembled into a large Simplicity Registry (4). 
 
While these clinical studies were running, very interesting research was carried out to unravel the mechanisms of the blood pressure decrease. It was found that blood pressure decrease not only was due to interruption of efferent sympathetic nerve activity to the kidney but also owed to the interruption of afferent nerve activity; such afferent nerve traffic travels through the same route in opposite direction to the sympathetic nervous centres in the brain and exerts a continuous stimulation of these centres. Renal nerve denervation interrupts this stimulation leading to blood pressure decrease. This system is very similar to the afferent nerve stimuli produced by muscle afferents during static muscle exercise (5). 
 
These two initial studies (Simplicity 1 and 2) sent an extremely promising signal to clinicians eager to find a solution for their resistant hypertensive patients. However, clinical thinking lead to the realisation of the necessity of including higher numbers of patients, longer follow up and essentially, strict comparison to controls. This was examined in a third study (Simplicity 3). 

Simplicity 3

Simplicity 3 (6) was set up to answer the most strict scientific questions regarding the results of the procedure compared to best medical antihypertensive treatment alone; patients were divided in a “control” group where a sham procedure was performed (renal arteriography), compared to the “active” group in whom RDN was performed; in both groups, best medical treatment was carefully followed up. Also, ambulatory blood pressure was recorded on a routine basis. 
 
Results were surprising. The blood pressure decrease obtained in these strict conditions by RND was not significantly different from blood pressure decrease obtained from best medical treatment.
 
How to explain these disappointing results after the many positive studies published in highly ranked journals?  A series of possible explanations has been proposed. First, due to necessity of enrolling many centres, physicians performing RND were still in their teaching phase; as a consequence, denervation may have been incomplete compared to what had been realised previously in centres with high expertise. The fact that blood pressure decrease in the RDN group from Simplicity 3 was smaller than in previous studies might be explained by this “incomplete” denervation. Still, it should be said that all participating centres had gone through a training period and thus, were supposedly keen enough to perform the procedure carefully. Moreover, the technique is not very complex. 
 
Another explanation might be the definition of patients included in the study. Were they really resistant? As said above, a number of patients are claimed to be resistant while they in fact are not so. A quite plausible point also is that compliance to medical therapy was far better in this study compared to all previous studies; that could lead to the surprisingly large response in the control group in the present study receiving “best medical treatment” alone. Such experience is quite common: the better a study is controlled and followed up, the better attention is given to all practical aspects such as compliance to drug intake. No doubt, further studies are absolutely needed. 

III - Should we forget about renal denervation?

Certainly not. One can hardly ignore the many studies performed in centres with high expertise showing, maybe in another type of patients or other conditions, that RND indeed seems capable of decreasing blood pressure. Results of Simplicity 3 hav come over as “negative” but we should be careful to conclude that RND is not active; the data could be due to the balance between a relatively smaller blood response to nerve denervation in the “active” group and a surprisingly large response in the control group. As said above, we should look for further studies before throwing away a completely new tool to control blood pressure which is, by definition, most welcome.
 
This is particular important in light of the results on blood pressure control in treated hypertensive patients worldwide. There is good evidence that goal pressure in patients treated with antihypertensive drugs is not reached in at least 50 % of patients; further studies have to be organised to see whether renal nerve denervation can be of help to improve such a figure. If so, it would be a major step forward. 
 
Also from scientific point of view, the technique has given us new insights in blood pressure regulation, the function of the sympathetic system and the role of afferent and efferent renal nerves. 
 
Simplicity also has taught us once again how critical one needs to remain toward the results of clinical studies. In drug studies, we all have experienced several times that a drug seeming to have an excellent effect, loses that effect as soon as properly compared to a control. 

Conclusion

Hopefully, investigators will not be discouraged by the results of Simplicity 3 and will continue furthering their research by defining for what patients RND would help to control blood pressure and how to define completeness of the denervation. However, the study has again reminded us the problem of the issue of compliance to antihypertensive therapy which, together with physicians’ inertia, is one of the major reasons why we do not get better figures on blood pressure control in the population.