American Journal of Kidney Diseases
Volume 54, Issue 5 , Pages 795-797, November 2009

Renal Denervation for Resistant Hypertension

  • Emmanuel L. Bravo, MD
    • ,
  • Mohammed A. Rafey, MD
    • ,
  • Joseph V. Nally Jr, MD

      Affiliations

    • Corresponding Author InformationAddress correspondence to Joseph V. Nally Jr, MD, Department of Nephrology and Hypertension, Glickman Urological and Kidney Institute, Cleveland Clinic, 9500 Euclid Ave-Q7, Cleveland, OH 44195

Cleveland Clinic, Cleveland, Ohio

published online 07 September 2009.

Article Outline

 

Commentary on Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275-1281.

Despite an armamentarium of safe and effective antihypertensive medications, rates of control for hypertension in the United States and worldwide are suboptimal.1 Much of the failure to obtain adequate blood pressure control in patients treated pharmacologically has been ascribed to ineffective physician prescribing strategies and/or patient nonadherence to lifelong medications for an asymptomatic disease.2 However, for the subset of patients with hypertension that is resistant to an appropriate multidrug regimen, the recent report of a novel catheter-based technique for renal sympathetic denervation by Krum et al3 in the Lancet may represent an intriguing new therapeutic avenue for resistant hypertension.

The renal sympathetic efferent nerves have a role in volume and blood pressure homeostasis because they innervate the renal tubules, vasculature, and juxtaglomerular apparatus. Historically, surgical lumbar sympathectomy was used for reduction of “malignant hypertension” in an era before effective antihypertensive medications. However, this life-saving approach was complicated by debilitating side effects, such as postural hypotension, syncope, and impotence.4 The new minimally invasive technique of selective renal denervation may offer promise for patients with resistant hypertension. In addition, this catheter-based technique raises some interesting questions regarding its use in patients with chronic kidney disease (CKD), a disease state increasingly recognized for its increased sympathetic activity.5, 6, 7

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What Does this Important Study Show? 

Krum et al3 performed in Australia and Europe a proof-of-principle study showing that a novel catheter-based device produced renal denervation and a substantial decrease in blood pressure in a select group of 45 patients with resistant hypertension. Mean baseline office systolic and diastolic blood pressures were 177 ± 20 and 101 ± 15 mm Hg, respectively, in patients with an estimated glomerular filtration rate (eGFR) of 81 ± 23 mL/min/1.73 m2 administered an average of 4.7 antihypertensive medications. The catheter-based radiofrequency energy delivery resulted in renal denervation with a 47% reduction in renal noradrenaline spillover (a marker of sympathetic efferent activity) without serious adverse events. Office systolic and diastolic blood pressures after the procedure (while maintaining patients on their usual antihypertensive medication therapy) were decreased by 14/10, 21/10, 22/11, 24/11, and 27/17 mm Hg at 1, 3, 6, 9, and 12 months, respectively. The authors present evidence suggesting that catheter-induced renal denervation decreased systemic blood pressure for up to 12 months, and the decrease in sympathetic efferent activity may have mediated these effects. Of note, eGFR was reported to be stable from baseline (79 ± 21 mL/min/1.73 m2) to 6 months' follow-up (83 ± 25 mL/min/1.73 m2), with 6 of 25 patients having an increase > 20% in eGFR and only 1 patient with a decrease in eGFR. Data related to the mechanism of the hypotensive response, such as natriuresis or suppression of renin, angiotensin II, and plasma catecholamines, are not reported.

The authors deserve recognition for their ground-breaking study. However, limitations of their observations must be recognized. As a proof-of-principle study, a control group understandably was lacking. Data to exclude secondary forms of hypertension, such as primary aldosteronism and strict medication adjustment protocols, are not available. Six of 45 patients (13%) were deemed to be blood pressure “nonresponders,” and 13 of 41 patients had medications changed during follow-up (9 of 13 with increased medications). In sum, the limitations of this important study point to the need for a randomized controlled trial (RCT) of catheter-induced renal sympathetic denervation versus rigorous medical antihypertensive therapy.

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How Does the Study Compare With Prior Studies? 

Sympathetic activation has an important role in the initiation, development, and maintenance of hypertension.8 Increased efferent renal sympathetic nerve activity (EFRSNA) has been shown in various experimental models of hypertension and in patients with essential hypertension. Increased EFRSNA leads to volume expansion through renal sodium reabsorption mediated selectively through renal α1-adrenoreceptors located on the basolateral membrane of the renal tubular epithelial cells throughout the nephron.8 Increased EFRSNA also activates the renin-angiotensin-aldosterone system by stimulation of renin release from the juxtaglomerular apparatus, leading to generation of angiotensin II and increased aldosterone biosynthesis.8 Conversely, angiotensin II can stimulate sympathetic nerve activity though central mechanisms and by facilitation of adrenergic neurotransmission at the sympathetic nerve terminal.

Renal denervation results in increased sodium excretion at all levels of renal perfusion pressure.8 It delays the development of hypertension in several experimental models when performed before, but not after, hypertension has been established.9 The eventual development of hypertension is paralleled by evidence of renal efferent reinnervation and renal sodium retention. These findings provide evidence for an important role of the renal nerves in the development of hypertension. As noted, surgical lumbar sympathectomy performed 6 decades ago in 1,266 patients with “malignant hypertension” resulted in a significant decrease in systemic blood pressure.4

Sympathetic activation also has an important role in the hypertension and target-organ damage associated with CKD. Available data suggest that afferent signals from diseased kidneys of patients with end-stage renal disease are centrally integrated and cause an increase in sympathetic nerve discharge.5 In rats, renal mass reduction led to decreases in renal and systemic nitric oxide synthesis, resulting in sympathetic activation and further deterioration in renal function.6 Experimentally, renal denervation in the five-sixth nephrectomy remnant kidney model results in a decrease in systemic blood pressure and preservation of GFR.10 This remnant kidney model also is notable for a severe deficiency of renalase, a novel monoamine oxidase that metabolizes catecholamines, such as dopamine and norepinephrine, which may prove to be a key factor in the enhanced sympathetic tone in patients with CKD.11 In addition, renal denervation performed before ischemia attenuated the ischemic-reperfusion–induced renal dysfunction of ischemic acute renal failure.12

It is postulated that the enhanced sympathetic activity in patients with significant hypertension (with or without kidney disease) may have a vital role in subsequent target-organ damage, such as left ventricular hypertrophy, congestive heart failure, and/or progressive renal damage.7 The combined effects of stimulated sympathetic activity on blood pressure and renal sodium avidity make selective denervation an attractive therapeutic intervention for hypertensive patients with CKD or congestive heart failure.

Consequently, selective inhibition of the renal sympathetic nervous systems is an appealing therapeutic option. A potentially beneficial therapeutic approach for patients with resistant hypertension with CKD or congestive heart failure would be the ability to antagonize α1-adenoreceptors selectively within the kidney. This would avoid the offsetting antinatriuretic influence of the decrease in arterial pressure (caused by increased EFRSNA) with blockade of systemic α1-adenoreceptors. However, to date, there is no drug that can be given systemically that can exert its effects preferentially within the kidney. Selective renal denervation using this catheter-based technology provides a new tool to probe this hypothesis.

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What Should Clinicians and Researchers Do? 

The development of this novel catheter-based technology offers an opportunity for clinical investigators to examine the impact of selective renal denervation on resistant hypertension. An RCT is required to examine the safety and effectiveness of invasive/costly renal sympathetic denervation versus rigorous medical antihypertensive therapy. The primary end point of the RCT should be sustained blood pressure decrease with secondary end points examining cardiovascular events and renal function. A substudy should probe potential mechanisms of action of the intervention, such as renal function, naturiesis, cardiovascular hemodynamics, and the neurohumoral axes. Detailed information regarding renal noradrenaline spillover (a marker of sympathetic efferent activity) would be appropriate to determine whether denervation is sustained. One wonders whether blood pressure “responders” might be sequentially tapered off their antihypertensive medicines after successful renal denervation. In addition to this required RCT, a pilot study of renal denervation in patients with resistant hypertension and CKD would be intriguing. Given the animal data cited, end points should include a decrease in blood pressure and measurement of GFR over time.

For clinicians learning of this new technology, data are too preliminary to rush to judgment. The analogy that readily comes to mind is the initial wave of enthusiasm for renal angioplasty/stenting of atherosclerotic renal artery stenosis for resistant hypertension. Subsequent RCTs showed that the procedure is controversial at best, with little improvement in blood pressure control and lack of benefit on renal and/or cardiovascular end points.13, 14 Hence, further rigorous investigation is required to identify hypertensive patients who might benefit from catheter-induced renal sympathetic denervation. Krum et al3 have presented us with stimulating information about this new catheter-based technology of selective renal denervation to embark on future studies for the management of resistant hypertension. Additional inquiries using this novel technology in hypertensive patients with CKD or congestive heart failure also may be illuminating.

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Acknowledgements 

Financial Disclosure: None.

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References 

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  3. Krum H, Schlaich M, Whitbourn R, et al. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009;373(9671):1275–1281
  4. Smithwick RH, Thompson JE. Splanchnicectomy for essential hypertension: results in 1,266 cases. JAMA. 1953;1:403–408
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  12. Fujii T, Kurata H, Takaoka M, et al. The role of renal sympathetic nervous system in the pathogenesis of ischemic acute renal failure. Eur J Pharmacol. Nov 28 2003;481(2-3):241–248
  13. van Jaarsveld BC, Krijnen P, Pieterman H, et al. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis (Dutch Renal Artery Stenosis Intervention Cooperative Study Group). N Engl J Med. 2000;342(14):1007–1014
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 Originally published online as doi: 10.1053/j.ajkd.2009.07.005 on September 9, 2009.

PII: S0272-6386(09)00977-9

doi:10.1053/j.ajkd.2009.07.005

American Journal of Kidney Diseases
Volume 54, Issue 5 , Pages 795-797, November 2009

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