Renal Denervation for the Hypertension of Chronic Kidney Disease: A Special Case?

This month, Marcio Kiuchi and colleagues1 from Brazil publish a remarkable paper demonstrating catheter‐based renal denervation (RDN) to be outstandingly successful in the treatment of hypertension accompanying chronic kidney disease (CKD). This report comes at a time when enthusiasm for RDN as a therapy for drug‐resistant essential hypertension in some quarters is now muted, subsequent to the negative Symplicity HTN‐3 trial.2 There have been previous reports describing a good therapeutic response to RDN in hypertensive patients with kidney disease,3, 4 but not at this level. In the present unblinded, proof‐of‐principle trial, ambulatory blood pressure (BP) was very materially reduced out to 2 years of follow‐up, estimated glomerular filtration rate (GFR) rose substantially, and urinary microalbumin excretion fell, accompanied by a reduction in the number of antihypertensive drugs needed for BP control. What might have made the difference here, compared with other trials?

Most likely, perhaps, is the particular pathophysiology of the hypertension accompanying kidney disease. This form of hypertension appears to be ready‐made for RDN therapy. The pathophysiological features are: (1) high sympathetic nervous activation in patients with hypertension caused by CKD5, 6, 7; (2) stimulated renal afferent nerves that respond to renal injury, which contribute to this sympathetic activation and BP elevation8; (3) ablation of renal afferent nerves clinically,9 and disconnection of their central projections experimentally,8 which reduces central sympathetic outflow in CKD; and (4) improvement within the kidney following sympathetic activity reduction in hypertensive patients.10 Two landmark clinical studies of end‐stage CKD demonstrate the importance of the renal afferent nerves in generating sympathetic activation and elevating BP.7, 11 But why were the benefits of RDN greater here than in previous pilot studies of RDN in drug‐resistant renal hypertension?3, 4

Very unusual in the trial of Kiuchi and colleagues was the number of applications of radiofrequency (RF) energy within the renal arteries, with an average of nine in each artery, which is nearly unprecedented. Four or five applications is more common. There is not universal agreement on this, but a larger number of energy applications in recent trials has been reported to produce greater BP lowering,12, 13 an effect prominent in the otherwise negative findings from the Symplicity HTN‐3 trial.12 Why should this be so? In a study in pigs, Tzafriri and colleagues13 demonstrated that previously unexpected denervation technical failures can arise when administered intraluminal RF energy does not reach its target––the periarterial sympathetic nerves––owing to energy conductivity and temperature gradients being distorted by regional tissue microanatomical variations. Fibrous muscle sheaths and lymph nodes draw the electric field, increasing the lateral and circumferential extent of the ablation geometry, whereas veins act as an energy sink, limiting ablation depth.13 Nonhomogeneous local anatomy influences ablation zone orientation, shape, and dimensions so that the outflow of energy from the electrode toward the targeted nerves is not a predictable, symmetrical cone. Assessment of denervation efficacy with renal norepinephrine spillover measurements in clinical studies reflects this, where it has been documented that achieved denervation differs markedly between individual patients, sometimes up to <25%.14 Given this unpredictability concerning the number of RF energy applications, it appears that “the more the merrier.”15 The authors here also attribute particular benefit to the catheter used,1 specifically that it utilized irrigated cooling and had an electrode larger than usual, which could be additional pertinent factors.

Perhaps most surprising in the present trial was the extent of the beneficial effect of RDN on the kidney, the improvement in GFR and microalbuminuria being such that, in the words of the authors, “at the end of the 24‐month follow‐up period, 21 patients (70% of the sample) could no longer be classified as having CKD.”1 What does the observed improvement in CKD grade represent? Is this attributable to beneficial prerenal influences on GFR from the reduction in antihypertensive dosing? The reported reduction in the prescribing of diuretics, angiotensin receptor blockers, angiotensin‐converting enzyme inhibitors, and calcium channel blockers might have been the reason. Or perhaps the procedure of RDN changes vascular glomerular dynamics in such a way as to improve GFR and to lessen microalbuminuria? This is possible but has not been demonstrated. Could there really be improvement in renal parenchymal disease? The authors suggest so, which would certainly be a victory for the methodology, if this can be confirmed in a larger, blinded trial. Sympathetic activation in experimental renal hypertension has been demonstrated to contribute to progression of renal injury and its reversal is shown to minimize and reverse this damage.10, 16, 17

Application of RDN therapy in patients with CKD can present technical challenges. The first of these is to “do no harm” in performing the required renal angiography procedure. Minimizing administered radiocontrast volume and utilizing carbon dioxide angiography reduces the risk of renal damage.4 In patients with more severe grades of CKD (in end‐stage renal disease in particular), renal artery diameters are commonly small and overheating of tissues can occur with the low renal blood flow present4 so that the procedure may not be technically feasible in some patients. This said, in the study by Kiuchi and colleagues in patients with milder grades of CKD, the procedure was well tolerated, without adverse events.

RDN is at a watershed, with its future uncertain as a treatment for hypertension. It might possibly turn out that the procedure is better suited in treating renal hypertension than essential hypertension, although this is unknown. The broad body of published trials, however, indicate efficacy in essential hypertension, now that the Symplicity HTN‐3 trial was seen to be flawed.12, 14 In the words of its co‐chief investigator George Bakris: “it is highly likely that RDN as it was performed in the HTN‐3 was technically inconsistent at best, but technically inadequate at worst.”18 The current clinical and research practice of largely restricting RDN to the treatment of severe, drug‐resistant hypertension flowed from the first Symplicity trial,19 in which ethical considerations dictated restriction of the procedure to this patient group to optimize the benefit/risk balance. However, in the new round of trials, inclusion criteria are changing based more on notions of hypertension pathogenesis to include milder, untreated essential hypertension, where a neural pathophysiology is prominent,20 to exclude isolated systolic hypertension, where biophysical changes in the aorta are more important than sympathetic nervous system activation, and, in addition, to study renal hypertension in its differing severity grades.

Important in all future trials will be new knowledge on the anatomy of the renal nerves, generated from studies on pigs,21 dogs,22 and humans.23 The renal sympathetic nerves are more distant from the renal artery lumen proximally and converge on the distal renal artery and the renal artery divisions,21, 22, 23 where they are more accessible to RF energy. The essence of this anatomical knowledge has been known for more than 60 years24 but typically was not acted on in RDN trials, where RF energy was inexplicably preferentially directed into the proximal renal artery.12, 14 The evidence from experimental studies on this point is that delivery of RF energy into the proximal part of the renal arteries, near the ostia, produces suboptimal denervation, whereas energy delivered into the distal renal arteries and renal artery divisions produces near‐complete denervation, uniform between animals.21, 22 Perhaps there is a link with the multiplicity of RF applications in the study by Kiuchi and colleagues,1 with an average of nine applications in each renal artery, crowding the available space, and inevitably dosing the sympathetic nerves in close juxtaposition with the distal part of both arteries.

Some elements of the present study, including the stability of baseline for 3 months prior to the commencement of the trial and the frequent measurement of ambulatory BP throughout, were exemplary. What is required now is a larger, definitive trial of RDN in patients with drug‐resistant renal hypertension, building on the present study and incorporating blinding and a sham design.