This was a prospective, nonrandomized, single center study that included 24 patients aged 38–77 years with resistant HTN, who were treated with RDN between May 2014 and October 2017.

A comprehensive medical history and a thorough revision of the medication was undertaken. The initial evaluation included 97 hypertensive patients; 73 were excluded from the study because they did not satisfy the inclusion criteria (Figure 1). The inclusion criteria were as follows: >18 years of age, presence of idiopathic resistant HTN confirmed by ambulatory blood pressure monitoring (ABPM) (mean BP >135/85 mm Hg in spite of a stable regimen of maximum tolerated doses of three or more anti-hypertensive drugs, including a diuretic), glomerular filtration rate >45 mL/min/1.73 m2 (modification of diet in renal disease formula), and compatible renal anatomy (atherosclerotic stenosis <50%, prior renal artery revascularization, fibromuscular dysplasia, or accessory renal arteries as assessed by either computed tomography angiography or duplex ultrasonographic scanning of renal arteries).

Figure 1.

Flowchart of study.

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The exclusion criteria were as follows: HTN due to secondary causes (screening by biochemical and imaging assessments and polysomnography), hemodynamically significant valvular disease, history of stroke or acute coronary syndrome over the past six months, refusal to sign informed consent, life expectancy <1 year, pregnancy, or presence of pseudo-resistant HTN.

All patients were admitted to the hospital two days prior to the procedure to confirm the presence of ‘true’ resistant HTN by assessing adherence to prescribed medications by witnessed intake of agents. Baseline evaluations included routine blood testing, including Vitamin D concentration, electrocardiography, transthoracic echocardiography, and 24 h Holter monitoring.

The study was approved by the Faculty of Medicine of the University of Coimbra and the Coimbra Hospital and University Center Ethics Committees (reference CE-031/2014. All study patients signed an informed consent.

All RDN procedures were performed by a cardiologist with expertise in endovascular procedures. The standard percutaneous technique used a 6/8 F introducer sheath to enter the femoral artery. A standard JR catheter was used for a selective bilateral renal angiogram performed before and after the procedure. The following three treatment catheters were used (ordered according to chronological use): Symplicity Flex™ catheter (Medtronic Inc, Santa Rosa, CA, USA: two patients), EnligHTN™ (St. Jude Medical, MN, USA: eight patients) and Symplicity Spyral™ (Medtronic Inc, Santa Rosa, CA, USA: 14 patients). A minimum of four and a maximum of 24 ablations that were separated both longitudinally and rotationally and performed in each renal artery. During ablation, the catheter system monitored the tip temperature and impedance and altered the radiofrequency energy in response to a predetermined algorithm. An anesthesiologist was present for all patients. Conscious sedation (via propofol, midazolam, and/or remifentanil) was commonly induced to prevent and manage visceral pain. Intra-arterial heparin and pre- and post-procedure nitrates were administered during the procedure. Hemostasis was achieved using a vascular closure device.

The patients were discharged from the hospital the day after the procedure unless there were immediate complications requiring medical attention. All patients underwent follow-up evaluations at one week, one month, and three, six, 12 months, followed by annual visits. The follow-up evaluations involved a clinical examination, BP measurements in both arms, and medication adjustment, if necessary. Information on adverse events and treatment compliance was recorded. Additionally, follow-up ABPM, electrocardiography, biochemical analysis, including Vitamin D levels, and transthoracic echocardiography were performed at six and 12 months. A renal angiogram was performed at six months in every patient to assess safety. The median duration of follow-up was 52 (range, 14-91) months. According to the response to RDN, the patients were classified as responders or non-responders. A responder to RDN was defined as a patient who obtained >5 mm Hg decrease in the mean systolic BP values determined by ABPM.

We planned a study of the continuous response variables, the systolic blood pressure (mm Hg) from matched pairs of study participants. Prior data indicated that the differences between the responses of matched pairs is normally distributed with standard deviation. If the true difference between the mean response of a matched pair is 13, we will need to study 22 pairs of study participants to be able to reject the null hypothesis that the difference is zero with a probability (power) of 0.8. The probability of type I error associated with the test of this null hypothesis is 0.05. Categorical variables were characterized by determining the absolute and relative frequencies, and the numerical variables were characterized by determining the means and standard deviation. The chi-squared test was used for between-group comparisons of the categorical variables. The Mann-Whitney U test was used to compare the continuous variables between two groups, and the Kruskal-Wallis test was used to compare the continuous variables between more than two groups. A general linear model for repeated measures was applied to analyze the variance of each laboratory parameter, which was measured several times in each participant from the responder and non-responder groups. SPSS 19.0 was used for statistical analysis, with a 5% significance level for hypothesis-testing.

A total of 24 patients underwent RDN in our department between May 2014 and October 2017. Based on BP values following the procedure, 20 patients (80.3%) were found to be responders to RDN, of whom 17 (70.8%) were responders at six months. Table 1 shows the baseline demographics and clinical characteristics of the responders and non-responders at six and 12 months.

Analysis of the catheter systems used for RDN show that differences between the systems were not significant. The mean number of ablations performed per each RDN was 25.3±9.10 ablations (a minimum of 10 ablations and a maximum of 41 ablations). Table 2 shows the procedure-related parameters. The differences between procedure-related parameters such as the diameters and lengths of renal arteries, number of renal artery branches, and number of ablations in the responders and non-responders at six and 12 months were not significant.

The patients who responded by six months after RDN had a significantly higher baseline vitamin D concentration than the baseline concentration of patients who were non-responders at six months after RDN (15.1±4.8 vs. 24.2±8.8 ng/mL, respectively), which was also observed at the six-month follow-up (16.6±7.2 vs. 25±9.2 ng/mL, respectively; p=0.008). The differences between the vitamin D concentrations of responders vs. non-responders at the 12-month follow-up were not significant. However, the responders at 12 months had higher mean vitamin D levels than those of the non-responders at 12 months both at baseline (15.6±5.1 vs. 23.0±9.0 ng/mL, respectively) and at six months after RDN (17.3±7.6 vs 23.8±9.5 mL, respectively). The receiver operating characteristic curve-derived optimal cut-off for determining response to RDN was ≥19.5 ng/mL (sensitivity 63.3%, specificity 81.8%; p=0.011) (Figure 2).

Figure 2.

Patients responding at 6 months to renal denervation have significantly higher levels of vitamin D than patients who do not respond at 6 months. Samples were obtained at twotwopoints (baseline and at six-month follow-up). (A) Estimated marginal mean levels of vitamin D in ‘responders’ at six months (early-responders, blue line) vs. ‘early non-responders’ (red line). (B) Curve of receiver operating characteristics: A vitamin D cut-off level of ≥19.5 ng/ml showed the best overall sensitivity and specificity for determining renal denervation response. (C) Estimated marginal mean levels of vitamin D in ‘responders’ at 1 year after renal denervation (blue line) vs. ‘non-responders’ (red line). Statistical analysis was performed using the Kruskal-Wallis test and a general linear model was applied to analyze the variance of each laboratory parameter. Data are presented as mean ± standard deviation.

FU: follow-up; RDN: renal denervation; AUC: area under the curve; ROC: receiver operating characteristics.

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We observed a significant decline in the mean 24 h-systolic BP (SBP) (+10.2 mmHg vs -22.3 mmHg; p=0.007) and 24 h-diastolic BP (DBP) (+5.7 mmHg vs. -13.0 mmHg; p=0.026) in the total responders group, with significantly lower values compared to the non-responders group (Figure 3 and Figure 4). The same findings were detected in both diurnal and nocturnal systolic blood pressure (SBP) and diastolic blood pressure (DBP) values. The differences between the number of antihypertensive agents used in each group at baseline and at six and 12 months of follow-up were not significant.

Figure 3.

Twenty four hour systolic blood pressure in six-month responders and non-responders at baseline, six months and 12 months after renal denervation.

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Figure 4.

Twenty-four hour systolic blood pressure in 12-month responders and non-responders at baseline, six months and 12 months after renal denervation.

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Regarding long-term follow-up, for a median period of 52 months, seventeen patients (70,8%) remained responders after RDN, one patient died (previous non-responder; cause of death unknown – 4.2%), two responders required new RDN, due to severe BP re-elevation after 18 months’ follow-up, with a positive BP response (8.3%) and four patients remained non-responders (16.7%).

In terms of safety, new renal artery stenosis was reported in one patient at six-month follow-up. He was a 46-year-old male patient, who had severe refractory hypertension with target-organ lesion (hypertensive nephropathy, stage three chronic kidney disease) and baseline atherosclerotic plaques were identified during baseline renal angiography. The Spyral system was used and a total of 30 ablations were applied (11 on the left renal artery and 19 on the right). No vasospasm was reported post-procedure. At six-month follow-up, the patient presented with flash pulmonary edema, which was treated with stent angioplasty following the identification of new renal artery stenosis (right renal artery, proximal portion, 75% stenosis). The patient had a significant BP reduction after treatment. No other complications were observed.

The differences between the variables of the non-responders at baseline and six months after RDN were significant: E/e’ septal (17.7±2.3 vs. 13.8±1.2, respectively; p=0.045), E/e’ lateral (13.3±2.4 vs 10.6±1.9, respectively; p=0.044), and E/e’ mean (14.6±2.6 vs. 11.8±1.8, respectively; p=0.033). No differences between variables were observed between the responders vs. the non-responders. Furthermore, a non-significant decline was detected in the non-responders at 12 months (Table 3).

Our study has several limitations. It was a single center prospective study with a small sample, there was no control group, and it was not blinded, for RDN (no control group) or for the physicians performing the follow-up echocardiograms. Additionally, different devices were used for RDN, and no specific techniques were used to control patient adherence to medication.