Renal Denervation: Paradise Lost? Paradise Regained?

Endovascular techniques for renal denervation (RDN) as a treatmentfor hypertension were initially highly encouraging with reductions inblood pressure (BP) in the range of 30 mmHg. 1 However, these highexpectations received a major setback following the unexpectedresults of the sham-controlled Renal Denervation in Patients WithUncontrolled Hypertension (SYMPLICITY HTN-3) trial. This promisingprocedure was faced with a major roadblock and, in general, theexpectations that this would stand the test of time were markedlytempered. 2 Like all good trials, SYMPLICITY HTN-3 provided answers,but also generated new questions, particularly in regard to proceduraland technical issues. This, in turn, has led to a series of new andongoing trials, which hopefully will resolve the issue of whether thisprocedure will become a routine aspect of hypertension management.In the present article, we review the literature in support of the RDNconcept as well as emphasize the potential pitfalls and possible futuredirection of RDN.

Proof of Concept: A Historical Perspective The renal system, through the maintenance of fluid–electrolyte balanceand its interplay with the autonomic nervous system, plays an essentialrole in the pathophysiology of hypertension. Increased sympatheticnervous system activity as a cause and result of hypertension has beenproven in various human experiments. 3 The activation of the efferentsympathetic system via the postganglionic sympathetic neuronal chainrelayed to the kidneys over the renal vasculature results in one or allof three effects; increased renin secretion from the juxtaglomerularapparatus; renal vasoconstriction decreasing renal blood flow; andenhanced sodium and water absorption. This contributes to anincreased intravascular volume and arteriolar vasoconstriction addingto hypertension. 4,5

Renal structures are also richly innervated with baroreceptors and chemoreceptors. Stimulation of these nerves by metabolites like adenosine, which form under conditions of ischemia and oxidative stress, result in increased input into the hypothalamus augmenting the sympathetic outflow, not only to the kidneys, but also to other structures like the heart and peripheral arteries, resulting in neurogenic hypertension. 5–7 Interruption of this neural traffic underlies the concept of RDN for the treatment of hypertension. Esler et al. demonstrated increased renal sympathetic nervous activity in adults with essential hypertension. His assessment of renal norepinephrine spillover using isotope dilution measurements showed elevated levels in comparison to normal individuals. 8 Also, this increase was higher in young adults (<40 years) with essential hypertension compared to older individuals. On comparison of 34 patients with essential hypertension and 23 normal patients, Esler et al. demonstrated than in those with hypertension, plasma concentration of noradrenaline and rate of release of noradrenaline into plasma was 32 % and 38 % higher, respectively, than in normal individuals. 9 Schlaich further demonstrated a sustained decrease in BP from 161/107 to 127/81 mmHg at 12 months following bilateral renal artery ablation (Figure 1). 10

One of the earliest treatment modalities for hypertension preceding the use of medications was surgical RDN. Smithwick and Thompson followed up 1,266 cases of thoracolumbar sympathetic splanchnicectomy over a minimum of 5 years. They compared the management of hypertension in these patients with that of in 467 medically treated controls to assess the mortality and efficacy of surgery as treatment for hypertension. 11 Sympathetic splanchnicectomy decreased all-cause mortality in contrast to medically treated controls. However, this nonselective sympathectomy technique resulted in very severe debilitating

side-effects, including orthostatic hypotension, palpitations, peripheralvasoconstriction, gastrointestinal dysfunction and sexual dysfunctionas varying accompaniments. The introduction of the newer potentantihypertensive drugs soon drove surgical denervation into nearextinction given the risk of potential complications as well as the efficacyof the newer medications. 12,13

Catheter-based Renal Denervation Ablation using radiofrequency (RF) has been the subject of multipletrials (Figure 2) using different catheter-based systems among whichthe majority used the SYMPLICITY RDN catheter (Medtronic Inc). Thishad unipolar platinum-iridium electrodes at the tip and the catheter wasintroduced percutaneously into the renal artery. 14 Multiple (four to six) RFablations of 8 W for up to 2 minutes applied in a helical manner to thearterial endothelium were used to ablate the sympathetic nerves; thiswas then replicated in the other renal artery to achieve RDN. Measures toconfirm the completeness of this procedure were variably used.

SYMPLICITY HTN-1, published in 2009, was the first trial to establishthat catheter-based RDN reduced BP (−27/−17 mmHg at 12 months) inpatients with rHTN with a reduction of sympathetic activity measured byrenal noradrenaline spillover. 1