Renal Sympathetic Denervation: is it Effective in the Management of Resistant Hypertension?

Abstract

Prevalence of Resistant Hypertension (RHTN) is increasing. Uncontrolled Hypertension (HTN) increases risk for stroke, and ischemic heart disease. Renal Denervation (RDN) was developed as a treatment procedure for RHTN. Currently there are no markers to determine the technical success of the procedure. There is evidence both in favor and against the procedure and it is based on performing the procedure with a catheter from a single manufacture.

Keywords: Percutaneous renal denervation; Renal denervation; Resistant hypertension

Introduction

Hypertension (HTN) has significant impact both at the patient level and also on health care. Nearly 25% of the world population suffers from HTN accounting for nearly 13% of the deaths worldwide [1]. Maintaining Blood Pressure (BP) levels at recommended targets is crucial. Between the ages 40-69 a sustained decrease in the Systolic Blood Pressure (SBP) by 20 mmHg or the Diastolic Blood Pressure (DBP) by 10 mmHg, reduces the incidence of stroke, ischemic heart disease, and other vascular diseases by approximately half [2]. Above the age of 69, the average annual absolute risk reduction in the incidence of complications is much higher. Lowering the BP target ranges to a SBP <115 mmHg and/or DBP to < 75 mmHg has also demonstrated increasing benefits [2].

RHTN is defined as a SBP > 140 or DBP > 90 mmHg despite optimal dosing of at least three different classes of antihypertensive agents or the near maximal dosing of four or more agents including one diuretic [3,4]. The prevalence of RHTN has gradually increased to its current level of almost 21% of all HTN patients [3,4]. This high prevalence is partially explained by an increase in risk factors for RHTN which include old age, obesity, DM, CKD, high salt consumption and female gender [1,3]. It is crucial to differentiate between resistant HTN, secondary HTN and pseudo-resistant HTN. The latter involves improper technique, inappropriate cuff size and timing of BP check during the office visit, patient non-adherence to medications and inadequate treatment by the provider [3]. Patients with RHTN are at higher risk for cardiovascular events than patient with non-resistant HTN [5].

The sympathetic nervous system has a significant role in both initiating and sustaining HTN [1,6,7]. Historically, surgical sympathectomy was used as a treatment for HTN but fell out of favor due to its significant morbidity and mortality as well as the development of multiple safe and effective pharmacological agents. However, sympathectomy helped establish the role of the sympathetic nervous system in the pathophysiology of HTN as well as generated a large volume of literature demonstrating its effects on Blood Pressure (BP), cardiac chamber size, cerebrovascular events and renal function [1,7]. The kidneys play a critical role in overall sympathetic nervous system activity with the presence of both afferent and efferent nerve endings. Changes in the renal pelvis hydrostatic pressure and renal interstitial chemical milieu transmit impulses through the afferent nerve endings via the sympathetic dorsal root neurons to the central sympathetic nervous system. Sympathetic nervous system activation increases sodium and water retention (alpha 1B Receptor), reduces renal blood flow by vasoconstriction (alpha 1A receptors), and increases renin release from juxtaglomerular apparatus (B1 receptors) thus activating the renin angiotensin system. These responses are driven by the amount of sympathetic tone and not by an all or none phenomenon. Moreover, sympathetic nervous system activation can be organ specific with local regulation at specific organ sites [1,7].

Percutaneous Renal Sympathetic Denervation (PRDN)

Multiple companies have developed percutaneous radiofrequency catheters for performing PRDN. However, the Medtronic SYMPLICITY catheter is used most frequently. Prior to the procedure, patients will be heparinized and a renal angiogram is usually done to identify anatomical details about renal artery size, and the presence or absence of accessory renal arteries. PRDN is performed percutaneously, accessing the renal vasculature via the femoral artery. The SN neurons in the tunica adventitia are then ablated from distal to proximal segments. Currently, there are no reliable markers for establishing success of the procedure. Some studies have used norepinephrine spill over as a marker of the success [8,9], while others have measured sympathetic nervous system activity in skeletal muscles as a surrogate success marker [6]. Currently, there are no reliable markers for technical success of the procedure.

The overall complication rate is very low with femoral artery pseudo aneurysm and renal artery stenosis occurring occasionally [9,10].

The Hawthorne effect is a common bias seen in many clinical trials that test a procedure. It occurs when some or all of the outcome effects of a study occur secondary to changes in the behavior of the patients or researches and not because of the intervention being studied.

Evidence in favor of the PRDN

Catheter-based renal sympathetic denervation for resistant hypertension: A multicenter safety and proof-of-principle cohort study: It was a sponsored study with the sponsor actively involved in the study design, data analysis and manuscript preparation. It was designed for evaluating the safety and efficacy of the procedure. It was conducted at five Australian and European centers. Only 4% of patients who underwent the procedure were non-white and 44% of patients were female. Baseline office BP was 177/101 mm of hg. Fifty (50) patients were enrolled in the study and five patients were excluded because of a dual renal arterial system. The remaining 45 patients had the procedure. The first 10 patients had bilateral PRDN done in two stages with a follow-up angiogram one month after second PRDN. The next eight patients had simultaneous bilateral RDN with a one month follow up angiogram. The remaining 38 patients had simultaneous RDN without angiographic follow up. Some patients had a renal MRI six months post-procedure. Investigators showed a drop of office systolic blood pressures by –14/–10, –21/–10, –22/– 11, –24/–11, and –27/–17 mm Hg at 1, 3, 6, 9, and 12 months. One patient developed a femoral artery pseudoaneurysm, and other had a renal artery dissection requiring stent placement. Limitations of the study included active sponsor involvement, white coat HTN, placebo effect, and a relatively short duration of follow-up (12 months). Most of the patients who had the procedure were male [8].

Catheter-Based Renal Sympathetic Denervation for Resistant Hypertension Durability of Blood Pressure Reduction Out to 24 Months: A multicenter, open label proof of principal study that was designed to evaluate the safety of PRND with a longer period of follow up of 24 months. Patients were excluded if they had renal vascular abnormalities, CKD, type 1diabetes, or secondary HTN. The study was done at 19 centers in Australia, Europe and US and was also a proof of concept study with a drop in office SBP as the primary end point. One hundred and fifty three (153) patients underwent the procedure with follow-up BP measurements at 1,3,6,12,18, and 24 months and corresponding SBP/DBP drops of 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg respectively. Mean baseline office BP was 176/98 mmHg ± 17/14. At the end of 24 months, 27 patients had a drop in the number of anti-hypertensive agents while 18 patients had an increase in the number of anti HTN agents (10 of who had increases in antihypertensive despite adequate drops in BP). Limitations of the study included the lack of a control arm, potential placebo and Hawthorne effects and failure to exclude white coat HTN. Another limitation of the study is only 5% of patients who underwent the procedure were non-white, while 39% of patients were female. As far as complications, one patient had renal artery dissection and three patients had pseudo aneurysm or hematoma but none had worsening renal function or symptomatic orthostatic hypotension [10].

  

    
Studies In favor of RDN 
    
Study population
    
Results
    
Limitation
  
  

    
Catheter-based renal    sympathetic denervation for resistant hypertension: A multicenter safety and proof-of-principle cohort study
    
Five Australian and European centers.
      
 
    
A drop  of office systolic blood    pressures by –14/–10, –21/–10, –22/–11, –24/–11, and –27/––17 mm Hg at 1, 3,    6, 9, and 12 months
    
Most of the patients are white.     Short term follow-up
  
  

    
Catheter-Based Renal Sympathetic Denervation for Resistant    Hypertension Durability of Blood Pressure Reduction Out to 24 Months 
    
Nineteen  centers in Australia,    Europe and US
      
 
    
Follow-up BP measurements at 1,3,6,12,18, and 24 months  showed a corresponding SBP/DBP drops of    20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg respectively
    
Most of the patients are white.     Hawthorne effect
  
  

    
 
    
 
    
 
    
 
  
  

    
Symplicity HTN-2 Trial
    
Twenty six centers in Australia and Europe
      
98% who had the
    
Eighty-four percent of the treatment group had a drop in BP by at    least 10 mmHg
    
Most of the patients are white. Hawthorne effect
  
  

    
Global SYMPLICITY registry
    
World wide
    
A drop in ambulatory systolic BP of 7.9 mm hg in patients with SBP    greater than 140 and 9.2 mm hg is SBP greater than 160.
    
Real time data
  
  

    
Studies Against RDN 
    
 
    
 
    
 
  
  

    
SYMPLICITY HTN-3
    
Australia, Europe and US
    
RDN failed to show superiority to sham procedure
    
Hawthorne effect
  
  

    
Renal Sympathetic denervation in patients with treatment resistant    hypertension after witnessed intake of medication before qualifying    ambulatory blood pressure
    
Oslo University Hospital
      
Norway
    
Out of six patients only two patients had drop in BP.
    
Very small sample size
  
  

    
Adjusted Drug Treatment Is Superior to Renal Sympathetic Denervation    in Patients with True Treatment-Resistant Hypertension
    
Oslo University Hospital
      
Norway
    
Drug adjustment is superior to RDN
    
Single center study
      
Small sample size
  

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