The Role of Renal Denervation in the Management of Hypertension

Renal denervation is an emerging and promising new therapy for resistant hypertension. Although 54 percent of all hypertension is “uncontrolled” (1), not all uncontrolled hypertension is considered resistant. The American Heart Association (AHA) definition of resistant hypertension is BP above goal on at least three antihypertensive medications of different classes, one of which is a diuretic, or BP that requires four or more medications to get to goal. Prevalence in the general hypertensive population is relatively low, but resistant hypertension is commonly seen in nephrology offices.

In evaluating a patient with resistant hypertension, it’s important to consider reversible underlying causes, titrate current medications to maximum tolerated dose, and optimize adherence to both pharmacologic and lifestyle treatments. Thereafter, management involves the addition of one more medication after another. If each subsequent addition significantly lowers BP, even if it never gets to goal, then this treatment strategy is advantageous. However, taking four or more medications involves both financial and potential side effect burdens. A potential new treatment for resistant hypertension is on the horizon: renal denervation.

Renal denervation, achieved by radiofrequency ablation through an intra-arterial catheter, directly addresses the extent to which resistant hypertension is due to sympathetic overactivity. Denervation reduces efferent nerve activity (i.e., from the central nervous system [CNS] to the kidney) thus lowering renin secretion, stimulating natriuresis, and improving renal hemodynamics. It also reduces renal afferent nerve activity (i.e., from the kidney to the CNS) thus reducing outflow to the CNS and contralateral kidney, which further dampens sympathetic activity.

Human trials conducted outside the United States are very promising: in one randomized, controlled trial of 106 hypertensive patients, net reduction in BP 6 months after denervation was 33/11 mm Hg compared to control (2). Blood pressure reduction persisted for 12 months. There was no excess risk of renal damage or hypotension.

Larger trials in the United States, involving at least three different ablation devices, are either ongoing or planned for the near future. If these trials replicate the non–U.S. trials, it is reasonable to expect U.S. Food and Drug Administration (FDA) approval within the next year or two.

In considering implementation of this new treatment modality, there are several questions to consider:

Is renal denervation effective and safe in patients with chronic kidney disease (CKD)? The failing, ischemic kidney contributes to sympathetic hyperactivity, suggesting that patients with CKD may have greater BP lowering from denervation than those with normal kidney function. Pilot data in small numbers of patients with stage 3 to 4 CKD (3) and in ESRD (4,5) suggest favorable results, but in ESRD small renal arteries may limit feasibility. Results are promising in CKD, but clearly additional research is needed.

Is renal denervation a reasonable treatment option in patients with less severe hypertension? Most trials to date have enrolled patients with AHA-defined resistant hypertension and systolic BP greater than or equal to 160 mm Hg. Trials in resistant hypertension with systolic BP 140 mm Hg to 160 mm Hg are planned.

Are the benefits long lasting? Are there renal risks that become apparent several years after denervation? Patients in non–U.S. studies were followed for 3 years, with sustained BP response and kidney function. An ongoing U.S. trial will follow patients for 5 years, and a postmarketing registry will be an FDA requirement.

Can the results in relatively homogeneous non–U.S. populations be generalized to patients in the United States? Presumably, ongoing and planned studies in the United States will reflect our racial/ethnic and clinical diversity.

Will renal nerves regenerate after radioablation? From transplant experience we know that, to some extent, renal nerves grow back. Although 3-year follow-up after denervation in a limited number of patients suggests persistent BP effects, additional information will be available from ongoing and planned studies, which are longer and larger.

Will the cost of denervation be offset by savings in prescription drugs, outpatient visits, hypertension-related events, and quality of life? To date there is no formal cost-benefit analysis, but this analysis could potentially be estimated with mathematical modeling.

In summary, the preliminary data suggest that renal denervation in patients with resistant hypertension and relatively preserved renal function has a dramatic impact on BP and an acceptable safety profile. Additional data are accruing to substantiate (or not) these findings, determine long-term effects, and clarify the range of BP and level of kidney function that is appropriate for treatment of resistant hypertension with renal denervation.

References

1. 

Vital signs: Prevalence, treatment and control of hypertension – United States, 1999-2002 and 2005-2008. MMWR 2011; 60:103–108.

2. 

Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010; 376:1903–1909.

3. 

Hering D, et al. Renal denervation in moderate to severe CKD. J Am Soc Nephrol 2012; 23:1250–1257.

4. 

Di Danielle DN, et al. Renal sympathetic nerve ablation for the treatment of difficult-to-control or refractory hypertension in a haemodialysis patient. Nephrol Dial Transplant 2012; 27:1689–1690.

5. 

Ott C, et al. Renal denervation in a hypertensive patient with end-stage renal disease and small arteries: a direction for future research. J Clin Hypertens 2012; 14:799–801.