The garden of renal denervation and its tree of knowledge

Dr Melissa Walton-Shirley

Disclosures

September 03, 2013

I am Eve and I am naked and ashamed. I have eaten the fruit of the tree of renal denervation and I now forage fig leaves to hide my embarrassment.

How long I've managed hypertension while underestimating the importance of the sympathetic nervous system on glucose resistance, sleep apnea, and heart failure. It's wasn't so much the Symplicity presentation regarding its mechanical success and complications that helped clarify things; it was the entire slate of the morning's basic physiology discussion that did it. Thanks to rats and mice and polycystic female humans, my eyes are forever opened, and I do not see the world of hypertension as the same.

A special thanks goes out to the morning's investigators like JFR Paton from Bristol, UK, F Mahoud from Homburg, Germany,A Wiotkowski from Poland, H Krum from Melbourne, A Konradi of St Petersburg,M Schlaich from Melbourne, M Bohm from Homburg, G Mancia of Milan, and thoughtful commentary by TF Luscher of Zurich, combined with a very brief but thoughtful discussion with John Floras from Canada. I transcribed a total of 19 pages of notes on their teachings as a testimony to the vast amount of information delivered.

I have lived for 25 years in the concrete universe of angiography but very much enjoyed working in the abstractness of hypertension. My lust for improving numbers, however, was for two decades mostly detached from causality. I have been known to brag "I can take amlodipine and a beta-blocker in a coronary disease patient and make their BP nearly any number I want." I was "puffed up" early in my career; like an alchemist I discovered just the right mix of stacking and combining medications that found patients smiling a visit or two later. Their beautiful, mercurial 120s/70s gleamed back at me all shiny and perfect. I discovered lots of renal artery stenosis, a few pheos and hyperfunctioning adenomas, but how much did I actually help the patient? Or have I been as guilty as niacin of making everything lovely on paper, yet helping not one whit?

The byproducts of denervating the nephron and therefore partially castrating the carotid body are multiple. This small organ nestled between the internal and external great vessels, only 2.5 to 7 mm long, is one of the most highly perfused organs per unit weight in the entire body. It is essential for controlling and maintaining perfusion to the brain. In the rat, inflammation causes a huge increase in the size of the carotid body, a likely hint why diabetics and dyslipidemics writhe with hypertension resistance. Interestingly, rats subjected to hyperoxygenation demonstrate a significant fall in blood pressure. Pigs modeled for sleep apnea who undergo renal denervation cease to exhibit sharp increases in blood pressure following tracheal obstruction. The negative effects on sleep apnea and vice versa are well borne out in human trials as well. Since there is such tight coupling of respiratory patterns and hypoxia to sympathetic discharge, no patient should exit any office visit without a screening history for sleep apnea. Its incidence is estimated at 80% in resistant hypertensives.

Other byproducts of a sympathetic nervous system "gone wild" include gluconeogenesis, insulin resistance, LVH, ischemia, heart failure, renin secretion, sodium retention, proteinuria, oxidative stress, endothelial dysfunction, vasoconstriction, myocardial fibrosis, and putrefaction of skeletal muscle, which along with redistribution of pulmonary fluid can also explain poor exercise tolerance. Consequently, improvements in BP control, insulin resistance, and six-minute walks have been documented to improve in renal-denervation procedures in both animals and humans. A fascinating case report was shown in which a patient with poor EF had multiple ICD shocks from ventricular tachycardia storm. He was resistant to antiarrhythmics and literally begged his team to let him die. Renal denervation came riding in on its white horse and two years later, the patient is alive and ICD-shock free.

Based on today's presentations, renal denervation is thus far a safe procedure with an occasional case report of renal-artery stenosis, most of which is not clinically significant "yet." There are occasional access-site issues as with any arteriotomy based procedure. At three years, according to reporting on Symplicity 1, we have a sustained 38-mm-Hg reduction in systolic blood pressure and a 19-mm-Hg diastolic-blood-pressure reduction. Other denervation trials have demonstrated decreases in fasting blood glucose, a halting of progression from glucose intolerance to diabetes, reductions in hemoglobin A1c, and reductions in LV mass and septal thickness, as well as a reduction in the severity of obstructive sleep apnea. More astoundingly, even in patients whose blood pressures were not controlled, there was a noted reduction in LV mass; a testimony that like a battered spouse, once the myocardium can get relief from the daily pounding of the sympathetic nervous system it can become healthy and happy again. Formerly, I was tempted to say that fluid restriction, weight reduction, treatment of sleep apnea, and insuring compliance are the first lines of therapy (not wrong thinking), but then the rest of concept could be relegated to nothing more than academic exercise. To cling only to that notion is to ignore both the consequences and etiology of the disease process, leaving many patients to languish on a long list of medications, many of which are only partially effective and some of whom suffer significant intolerances.

This is, however, a cautionary tale. Running beside the beautiful garden of renal denervation flows the river Styx. It is there that Thetis dangles our patient with multiple vulnerabilities as likely candidates for the Achilles heel of the renal-denervation concept. 50% of patients are nonresponders. Our ablators are blinded with regard to the completeness of their procedure. The sample sizes of our current trial are too small and underpowered for hard end points like heart attack, death, stroke, and renal failure. Ambulatory blood pressures are far less affected than office blood pressures at follow-up. Does the decline in GFR continue or flatten? Will the nephron reinnervate over time? Will it work for normal-EF or even reduced-EF heart failure as a separate therapy aside from hypertension control? Could it have an impact on flash pulmonary edema even more than theoretically estimated? Is the entire procedure a sham owed to improvements in blood pressure from newly proselytized patients who finally recognize the importance of medicating consistently and regularly? With regard to this last question, I think not.

The big story here isn't just whether or not renal denervation works. The big story is that the entire process entices us to acknowledge the complex mechanisms that bring the hypertensive patient to our door for help.

Today, the fruit of the tree of knowledge that stands in the garden of renal denervation "was both good for food and pleasing to the eye and also desirable for gaining wisdom." Today, "the woman took some of the fruit and ate it." I have also given some to you.

Take and eat.

See also:

Renal Denervation Debate Tackles Efficacy, Patient Selection

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