Resistant hypertension is defined as uncontrolled blood pressure despite the use of optimal doses of three antihypertensive agents, of which one is a diuretic. Using this definition prevalence of resistant hypertension can be as high as 30% in some recent studies [1,2]. The kidney is richly innervated with baroreceptors and chemoreceptors.

Renal denervation reduces whole-body noradrenaline spillover and reduces sympathetic nerve traffic to the skeletal muscle vasculature, as measured by muscle sympathetic nerve activity after renal sympathetic denervation. Catheter-based renal denervation selectively reduces renal sympathetic efferent activity and is accompanied by an increase in renal blood flow and reduction in plasma renin activity.

Thus, ablation of afferent and efferent renal nerves in patients with treatment-resistant hypertension probably leads to reductions in blood pressure [3]. Hence, the study was planned to assess the safety and effectiveness of renal denervation in patients with resistant hypertension.

Setting: The study was conducted in a tertiary care government general hospital (Osmania General Hospital, Hyderabad) after institutional ethics comittee approval.

Study duration: The study was conducted over a duration of 2 years. Patients were recruited from cardiology outpatient department and informed consent has been obtained from all the patients.

Study type: The study was a non randomized case control study where 15 patients were enrolled who underwent renal denervation therapy for resistant hypertension as cases and 16 patients who were on medical management for resistant hypertension served as controls.

Inclusion criteria- Patients aged 18–85 years with a systolic blood pressure of 160 mm Hg or more (≥150 mm Hg in patients with type 2 diabetes), despite compliance with three or more antihypertensive drugs were included.

Exclusion criteria- Patients with valvular heart disease, pregnancy or planned pregnancy during the study, a history of myocardial infarction, unstable angina, or cerebro-vascular accident in the previous

Discrete, radiofrequency ablations were applied lasting up to 2 min each and of 8 watts or less to obtain up to six ablations separated both longitudinally and rotationally within each renal artery. Simultaneous bilateral renal artery denervation was performed in all patients. Triplicate office blood pressures were measured with standard joint national committee VIII guidelines [4].

Averages of the triplicate measures was used. Patients were instructed to remain adherent to their prescribed anti hypertensive drugs. Information regarding medications and doses at all follow-up time points was collected. The enrollment criteria, evaluation of patients and study procedure were same in control group except for that the controls are continued on optimal medical therapy instead of denervation therapy. Patient’s blood pressures were recorded at every OPD visit and any change in medications (either decrease or increase in doses or drugs) noted. Strict compliance to medications was ensured with counseling and frequent phone calls if required.

Data analysis: Outcomes were assessed for safety, effectiveness of renal sympathetic nerve denervation, and change in office blood pressure in both cases and controls. Mean changes were calculated in the office blood pressures from baseline. Analysis was done with SPSS version 21.0.

The mean age of the renal denervation group and drug therapy group are 49.4±13.3 years and 55.6±7.7 years respectively. 66.7% (n=10) of the renal denervation group and 56.3%(n=9) of the drug therapy group are constituted by males. There is no statistically significant difference in age and sex distribution among both the groups (p = 0.552). Only one female patient in the RDN group and 2 patients in drug therapy group are known cases of hypothyroidism and on hormone supplementation. There is no statistically significant difference in the prevalence of smoking habit, diabetes, drug therapy, coronary artery disease, renal disease among the two groups (p = 0.433). The mean SBP, DBP and MBP at baseline in the renal denervation group are 190.7±25.8, 100.7±11.6 mm of Hg and 130.7±15.5 mm of Hg respectively. The mean SBP, DBP and MBP at baseline in the drug therapy group are 183.1±14.5 mm of Hg, 105.6±6.3 mm of Hg and 131.5±8.0 mm of Hg respectively. The differences at baseline are not statistically significant.

The mean SBP, DBP and MBP at 6 months after procedure in the renal denervation group are 135.3±16.9 mm of Hg, 83.3±8.2 mm of Hg and 100.7±10.8 mm of Hg respectively. The mean SBP, DBP and MBP at 6 months in the drug therapy group are 152.0±12.1 mm of Hg, 94.7±9.2 mm of Hg and 113.8±9.7 mm of Hg respectively.

All the values are lower in renal denervation group (Figure 1) and the mean differences of SBP, DBP and MBP at 6 months are -16.7±5.4 mm of Hg, -11.3±3.2 mm of Hg and -13.1±3.7 mm of Hg respectively. This difference is statistically significant (p= 0.002) (Figure 2). Table 1 shows the mean fall in absolute BP recordings in renal denervation group when compared to drug therapy group.

Table-1: Mean fall in absolute BP recordings.

The mean number of drugs at 6 months post procedure in the renal denervation group is 2.5 compared to 4.0 ± 0.5 in the drug therapy group (p = 0.001). There was no statistically significant change in eGFR pre and post intervention in both the groups.

There were two adverse effects reported in the study population, one patient required a transfusion for groin hematoma and another patient developed a femoral pseudo-aneurysm at the puncture site which was managed surgically. One patient died during the study period in the drug therapy group at 5 months and was excluded from analysis of six-month blood pressures. The cause of death is hemorrhagic CVA.

Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Identifiable causes of hypertension like chronic Kidney Disease, coarctation of aorta, cushings syndrome, drug induced causes, obstructive uropathy, pheochromocytoma, primary aldosteronism and other mineralocorticoid states, renovascular hypertension, sleep apnea, thyroid and parathyroid abnormalities should be screened and treated before labeling it as essential hypertension.

The signals are transmitted to the spinal cord and central nervous system via afferent fibers. Both efferent and afferent fibers enter and exit the kidneys within the adventitia of the renal arterial wall. Sympathetic nervous system regulates the renin secretion by two mechanisms. First by intrarenal baroreceptors of the afferent arterioles sen­sitive to changes in renal arterial perfusion(mechanoreceptors) and second by alterations in the delivery of sodium chloride to the macula densa cells of the distal tubule (chemoreceptors). The importance of the sym­pathetic nervous system has increasingly been reco­gnized in regulation of blood pressure.

Afferent sym­pathetic fibers from the kidney also directly influence the overall sympathetic tone [8]. Variety of cardiovascular diseases such as congestive heart failure, myocardial infarction and kidney dis­eases as well as in metabolic conditions including diabetes mellitus, obesity and the metabolic syn­drome are attributed to sympathetic overactivity [9]. Renal afferent nerve activity is increased in presence of ischemia or hypoxemia.

Renal afferent nerves further influences the overall sympathetic adrenergic activity by modulating posterior hypothalamic activity. Chronically elevated renal afferent activity seen in chronic renal failure is a major contributor to the initiation and maintenance of a high renal and overall sympathetic efferent activity. This may lead to adverse conse­quences including hypertension, vascular remodel­ing, left vermicular hypertrophy, ventricular arrhyth­mias and sudden cardiac death [10].

In summary, the kidney is a sensory organ richly innervated with baroreceptors and chemoreceptors. These receptors transmit information via afferent sym­pathetic fibers to the areas in the central nervous system that have a pivotal role in blood pressure con­trol. Stimulation of these renal receptors either by ischemic metabolites, or by uremic toxins, or by electrical impulses, evoke reflex increases in sympathetic nerve activity and blood pressure [11].

Based on the above described role of the sympathetic nervous system in the pathophysiology of hypertension, the proven results of surgical sympathectomy and nephrectomy in various previous animal models and humans, the high prevalence and our inability in the optimal treatment of resistant hypertension in routine clinical practice despite a wide array of

The primary efficacy end point was the change in office systolic blood pressure at 6 months; a secondary efficacy end point was the change in mean 24-hour ambulatory systolic blood pressure. The primary safety end point was a composite of death, end-stage renal disease, embolic events resulting in end-organ damage, renovascular complications, or hypertensive crisis at 1 month or new renal-artery stenosis of more than 70% at 6 months.

A total of 535 patients underwent randomization. The mean (±SD) change in systolic blood pressure at 6 months was -14.13±23.93 mm Hg in the denervation group as compared with -11.74±25.94 mm Hg in the sham-procedure group (P<0.001 for both comparisons of the change from baseline), for a difference of -2.39 mm Hg (95% confidence interval [CI], -6.89 to 2.12; P=0.26 for superiority with a margin of 5 mm Hg). This trial did not show a significant reduction of systolic blood pressure in patients with resistant hypertension 6 months after renal-artery denervation as compared with a sham control.

The present findings of renal denervation using a catheter-based approach for the treatment of 15 patients with resistant hypertension and follow up of 16 patients of resistant hypertension on optimal medical therapy showed that renal denervation led to a large and persistent decrease in blood pressure. This was achieved in patients resistant to multiple existing antihypertensive drug types and the fall in blood pressure at 1, 3 and 6 months were more significant in renal denervation group than drug therapy group.

However, the blood pressure response was also significant in drug therapy group at 1, 3 and 6 months when compared to baseline blood pressures. Moreover, reduction of blood pressure was evident as early as 1 month, was further reduced at 3 months, and persisted through subsequent assessment at 6 months. The present study design is similar to simplicity HTN 2 study except that current was a non-randomized study. In simplicity HTN 1 trial post procedure office BP recordings were reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months, respectively. In simplicity HTN 2 trial office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (p<0・0001), whereas they did not differ from baseline in the control group (p=0.77 systolic and p=0.83 diastolic).

There has been one other sham-controlled study, Simplicity Flex which failed to show benefit of RDN in BP lowering over doing a renal angiogram [19]. The results of other rigorously executed randomized controlled trials using the same or similar catheter systems like RAPID, Reduce-HTN, EnligHTN and DENERHTN [20] showed significant benefit of renal denervation in the treatment of resistant hypertension, whereas, the results of Oslo RDN [21] and Prague-15 [22] were not so favorable.

A recent meta-analysis of 15 RCTs by Agasthi P et al [23] showed no significant benefit of RDN on blood pressure control in patients with resistant hypertension. Subgroup analysis of sham control studies showed a modest benefit in 24 hr. systolic blood pressure at 6 months with RDN.

They concluded that, based on the current evidence, patients with resistant hypertension and no identifiable secondary cause, maximized on lifestyle interventions and medical therapy by a hypertension specialist may benefit from renal denervation with an experienced operator. When renal denervation efficacy was assessed, using measurements of the spillover of norepinephrine from the renal sympathetic nerves to plasma, the only test validated to this point, denervation in simplicity HTN 3 patients was found to be incomplete and nonuniform between patients [24].

A Post hoc analysis of simplicity HTN 3 study by Kandzari DE et al showed that several potential confounding factors may partially explain the unexpected blood pressure responses in both the sham control and RDN groups suggesting how important the design of subsequent research should be to evaluate the potential role of RDN in the treatment of resistant hypertension [25].

Even today the clinical dilemma is still continuing [26] and further evaluation in rigorously designed clinical trials are necessary to validate alternative methods of renal denervation or to confirm previously reported benefits of renal denervation.

Various Novel Renal Denervation Technologies are also emerging (Image 3) and are in the pipeline. As the technology advances more clinical benefit is anticipated with newer ablation systems. With better understanding of the renal neuroanatomy and neurophysiology, RDN may be more successful if attention is given to the more distal segments of the artery where it is easier to access the nerves [27].

This study shows that renal denervation is feasible, can be done at a low cost safely in patients with resistant hypertension and has a large bearing in low resource settings like India. However, it cannot be recommended yet, to all patients with resistant hypertension due to the lack of concrete evidence in the major trials.

Dr. Raghuram Palaparti: Concept, study design, manuscript preparation

Dr. Imamuddin Syed: Guidance, manuscript preparation

Authors are immensely grateful to Dr. C Narasimhan for guiding us and conducting renal denervation procedure free of cost to the patients at CARE Hospital, Hyderabad. Authors would also like to thank Dr. Palaparthi Sairam for his contribution in statistical analysis of findings.

Abbreviations: SBP - Systolic blood pressure, DBP - Diastolic blood pressure, MBP - Mean blood pressure, HTN - Hypertension, CKD - Chronic Kidney Disease, RDN - Renal Denervation, GFR - Glomerular Filtration Rate, MRI - Magnetic Resonance Imaging, MRA - Magnetic Resonance Angiography, CT - Computerized Tomography, OPD - Out Patient Department, CVA - Cerebrovascular Accident