Renal denervation beyond the bifurcation: The effect of distal ablation placement on safety and blood pressure

Abstract

Renal denervation may be more effective if performed distal in the renal artery because of smaller distances between the lumen and perivascular nerves. The authors reviewed the angiographic results of 97 patients and compared blood pressure reduction in relation to the location of the denervation. No significant differences in blood pressure reduction or complications were found between patient groups divided according to their spatial distribution of the ablations (proximal to the bifurcation in both arteries, distal to the bifurcation in one artery and distal in the other artery, or distal to the bifurcation in both arteries), but systolic ambulatory blood pressure reduction was significantly related to the number of distal ablations. No differences in adverse events were observed. In conclusion, we found no reason to believe that renal denervation distal to the bifurcation poses additional risks over the currently advised approach of proximal denervation, but improved efficacy remains to be conclusively established.

1. Introduction

Renal denervation (RDN) was developed as a nonpharmacologic treatment option for hypertension, particularly for patients who fail to reach target blood pressure (BP) despite adequate antihypertensive medication.1 RDN is performed by delivering radiofrequency (RF) energy to the renal artery lumen to damage the adjacent sympathetic nerves, thus reducing the efferent and afferent sympathetic signaling to and from the kidney. However, the effectiveness of RDN for lowering BP varies greatly among studies and patients.2, 3, 4, 5, 6, 7

This variability in treatment effect has been partly attributed to incomplete interruption of the renal sympathetic nerves due to insufficient penetration of the RF energy. We previously published a case report that demonstrated histological damage restricted to maximum 2 mm from the luminal surface, leaving a large part of the nerves unaffected.8 Recently, this observation was confirmed in a porcine model, with only 14% of nerves located within the lesion areas.9 Thus, optimization of the RDN procedure is needed to ensure successful disruption of the sympathetic signaling. Several anatomical studies have investigated the anatomical distribution of the renal nerves and consistently demonstrated that the distance between the renal artery lumen and the renal sympathetic nerves decreases in the distal segments of the artery.10, 11, 12, 13 Therefore, it is to be expected that more successful disruption of the sympathetic nerves and subsequently more consistent treatment effects can be achieved through distal delivery of RF applications. However, in fear of excess complications due to smaller vessel diameters, RDN has been most commonly performed in the main renal artery only, where the distance between renal artery lumen and the sympathetic nerves is at its greatest.

Therefore, we studied a cohort of patients treated with RDN in two expert hospitals in the Netherlands to assess whether RDN beyond the bifurcation may be safe and whether differences could be observed in BP effects compared with proximal denervation.

2. Methods

This study is part of the Dutch National Renal Denervation Registry (NCT02482103) that was approved by the medical ethics committee of the University Medical Center Utrecht. The study was conducted in accordance with the Declaration of Helsinki14 and the Dutch Medical Research Involving Human Subjects Act. The registry holds clinical and procedural data of patients who are treated with RDN in the Netherlands.

2.1. Study population

Patients were screened and treated according to the Dutch consensus on RDN for the treatment of hypertension.15 Patients were eligible for RDN if they had resistant hypertension, defined as an office systolic BP ≥160 mm Hg and/or a 24‐hour systolic BP ≥135 mm Hg, despite the use of three or more antihypertensive drugs from different classes at optimal doses, preferably including a diuretic.16 Patients were also eligible if BP remained above the same thresholds but intolerance to antihypertensive drugs prevented adequate pharmacological treatment. The presence of pseudoresistant hypertension and significant white‐coat effect was excluded by ambulatory BP monitoring (ABPM; ie, mean 24‐hour systolic BP ≥135 mm Hg). Secondary causes of hypertension and pseudoresistance were excluded by a hypertension specialist according to international guidelines.17 Exclusion of other contraindications and the final decision for eligibility was made by a multidisciplinary team according to the consensus documents. Presence of obstructive sleep apnea syndrome was not considered a contraindication if patients were treated appropriately. In contrast to the consensus document, presence of multiple renal arteries was not considered a contraindication for RDN based on advancing insights.

2.2. Location of RDN

For the current analysis, we reviewed cineangiographic images of all RDN procedures performed at the Departments of Cardiology of the University Medical Center Utrecht, Utrecht, and the Isala Hospital, Zwolle, between July 2010 and December 2014. Both centers recorded angiographic images of the renal arteries at the start and the end of the procedure, as well as images of all individual ablations. To avoid interobserver variability, all cineangiographic images were evaluated by a single researcher who was blinded for clinical outcome. The location of each individual RF application in relation to the renal artery bifurcation was determined. Subsequently, patients were categorized into one of three groups: (1) bilateral proximal, if all ablations in both arteries were performed proximal to the bifurcation; (2) unilateral distal, if only one artery was ablated proximal to the bifurcation and the contralateral artery was treated distally; and (3) bilateral distal, if in both arteries one or more ablations were performed beyond the bifurcation (Figure 1). The total number of ablations beyond the bifurcation for each artery and for each patient was determined, as well as the overall number of ablations per patient.

Figure 1.

Change in 24‐hour ambulatory blood pressure (BP) monitoring (ABPM) for different renal denervation (RDN) locations. This figure shows the change in 24‐hour systolic (light blue) and diastolic (dark blue) ABPM for the different categories of RDN location. Error bars represent the standard error of the mean. The P value represents the probability value for between‐groups differences obtained by the Jonckheere‐Terpstra test.

2.3. Renal denervation

All RDN procedures were performed via transfemoral approach according to the respective instructions for use of the device. The choice for the type of RDN catheter, the total number of RF applications, the location of the ablations, and whether to ablate beyond the bifurcation were at the discretion of the interventionalist. In practice, ablations were placed as distally as possible regardless of the presence of any branching, as long as the diameter of the vessel or branch was sufficient (ie, ≥4 mm). The procedures were performed by three experienced interventionalists (two electrophysiologists and an interventional cardiologist) with extensive experience with the procedure.

2.4. Measurements

Medical history, prescribed antihypertensive medication, lifestyle factors, physical examination, and basic laboratory and BP measurements were recorded at baseline and at 12‐month follow‐up. Measurements of 24‐hour ABPM and office BP were performed in accordance with the international guidelines using validated BP monitors.18

Prescribed dosages of antihypertensive drugs for each time point were converted into defined daily doses (DDDs) using conversion factors provided by the World Health Organization19 The cumulative daily intake of antihypertensive drugs was calculated for each patient using the sum of all DDDs.

Creatinine levels were recorded at baseline, preprocedure, postprocedure, and at 12‐month follow‐up. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration method.20

2.5. Statistical analysis

The difference between mean values of baseline and 12‐month follow‐up measurements (eg, office BP, ABPM, body mass index, eGFR) were calculated. Thus, a negative value represents a decrease at 12 months after RDN. Results are presented as mean±standard deviation (SD), mean (minimum–maximum), or as an absolute number with percentages, unless otherwise specified.

For paired samples analysis, the paired Student t test or Wilcoxon signed‐rank test was used when appropriate. Differences in BP reduction between the three categories of RDN ablation patterns (ie, bilateral proximal, unilateral distal, and bilateral distal) were assessed using the independent samples Jonckheere‐Terpstra test for ordered alternatives. The Jonckheere‐Terpstra test is a nonparametric method for testing differences between treatments. The advantage of the Jonckheere‐Terpstra test over the Kruskal‐Wallis test is that it is more powerful when a particular direction in group medians is expected (ie, bilateral proximal<unilateral distal<bilateral distal).21

Differences in BP reduction between patients with proximal ablations only (group 1) and patients with distal ablation (groups 2 and 3 combined) were assessed using the independent samples Mann‐Whitney U test.

The relationship between BP changes and the categories of RDN ablation placement were further assessed using multivariable linear regression models to correct for possible confounding factors by entering preselected variables (age, sex, eGFR, body mass index, prescribed dosages of antihypertensive drugs, and RDN device) into the model. The rule of thumb of 10 cases per variable in multivariable analysis was applied to avoid overfitted models.22 Age and sex were entered into the crude model (model I) to create model II, and model III was composed of all above‐mentioned variables. The B coefficient for each model represents the change in BP for each additional artery that is treated distal to the bifurcation.

Linear regression was also performed to assess the relationship between the change in BP and the total number of ablations, and the number of distal ablations.

Results were considered statistically significant if the 95% confidence interval (CI) did not include 0 or if the two‐tailed P value did not exceed 0.05. All analyses were performed with SPSS statistical software version 22 (IBM Corp, Armonk, NY, USA).

3. Results

Between July 2010 and December 2014, 123 patients were treated with RDN for hypertension at the University Medical Center Utrecht and the Isala Hospital Zwolle in the Netherlands. Ten patients were excluded from analysis because of unavailable or incomplete angiography data, and 16 patients had no clinical follow‐up available. The baseline characteristics of the remaining 97 patients are provided in Table 1. During 12 months of follow‐up, no significant changes occurred in body mass index (Δ −0.1±1.7 kg/m², P=.97), eGFR (Δ 1.5±10 mL/min per 1.73 m², P=.50), or the amount of prescribed antihypertensive drugs (Δ −0.3±2.7 DDD, P=.18).

Table 1.

Baseline Characteristics

Baseline Characteristics	All (N=97)
Male sex	62 (64%)
Age, y	62±10
BMI, kg/m²	29±5
eGFR, mL/min per 1.73 m²	76±16
Cerebrovascular history	14 (14%)
Cardiovascular history	19 (20%)
Peripheral arterial disease	12 (12%)
Diabetes mellitus	20 (21%)
Dyslipidemia	39 (40%)
OSAS	5 (5%)
Office BP, mm Hg	175/97±26/15
24‐h BP, mm Hg	156/91±19/14
No. of AHDs and DDDs	4.9±2.8
No. of AHD pills	4 (0–6)

Abbreviations: AHD, antihypertensive drug; BMI, body mass index; BP, blood pressure; DDDs, daily defined doses of antihypertensive medication; eGFR, estimated glomerular filtration rate; OSAS, obstructive sleep apnea syndrome.

Table 2 shows the procedure‐related characteristics. Thirty‐nine patients were ablated only proximal to the renal artery bifurcation (group 1), 34 patients were treated distal to the bifurcation in one of the renal arteries (group 2), and 24 patients were treated distally in both renal arteries (group 3). An average of 13±4 (bilateral proximal), 13±3 (unilateral distal), and 14±3 (bilateral distal) RF applications were delivered in each patient (P=.2). Previous vascular disease (defined as coronary artery disease, cerebrovascular disease, and/or peripheral coronary artery disease), as an approximation for more advanced arterial disease, were not statistically different among the three treatment groups (P=.52).

Table 2.

Procedural Aspects

Procedure	All (N=97)
Device
Medtronic Symplicity flex	79 (81%)
Medtronic Spyral	10 (10%)
St Jude EnligHTN	8 (8%)
Total ablations	13 (3–24)
Location of renal denervation
Bilateral proximal	39 (40%)
Unilateral distal	34 (35%)
Bilateral distal	24 (25%)
Contrast administered, mL	174±66

3.1. Effects on BP

Overall, office BP decreased from 175/97 mm Hg (SD 26/15) at baseline to 161/89 mm Hg (SD 25/15) at 12 months after RDN (P<.001 for both systolic and diastolic BP). An absolute reduction of 14/8 mm Hg (standard error 3/2) was achieved for office BP. The changes in office and 24‐hour mean BP in the different treatment groups are depicted in Table 3.

Table 3.

Absolute Reductions in Office and Ambulatory BP at 12 Months After Renal Denervation in Each Treatment Group

	Bilateral Proximal	Unilateral Distal	Bilateral Distal	P Value for Between‐Group Differences
Office BP
SBP	−16.0±4.8	−13.0±3.5	−10.7±6.2	.15
DBP	−5.4±2.5	−10.6±2.3	−6.0±3.2	.72
24‐h ambulatory BP
SBP	−3.0±2.5	−8.4±3.0	−9.7±4.0	.17
DBP	−3.0±1.5	−5.3±2.1	−5.7±2.1	.26

The change in office and 24‐hour mean blood pressure (BP) from baseline to 12‐month follow‐up for each of the three treatment groups. Values are expressed as absolute changes±standard error of the mean. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure.

ABPM measurements both before and 12 months after RDN were available for 70 patients. Unavailability of ABPM was mostly due to patient refusal. In the total patient group, mean 24‐hour BP decreased from 156/91 mm Hg (SD 19/14) at baseline to 146/84 mm Hg (SD 19/13) after RDN (absolute reduction 7/4 mm Hg, SE 2/1; P=.002/<.001 [Figure 2]). The changes in office and 24‐hour BP between baseline and 12‐month follow‐up for the three groups were not significantly different.

Figure 2.

Angiography examples of different renal denervation (RDN) locations. Angiographic images of the right (A1, B1, C1) and left (A2, B2, C2) renal artery of three patients demonstrating the different locations of the renal denervation procedures. The white dots represent the location of the ablation points. Patient A was treated proximal to the renal artery bifurcation only (group 1), patient B was treated distal to the bifurcation in one renal artery (group 2), and patient C was treated distal to the bifurcation in both arteries (group 3).

In multivariable linear regression, the relationship between BP effect and location of the ablations remained nonsignificant after correction for prespecified variables (Table 4). When comparing patients with proximal ablations only (group 1) with patients with distal ablations (groups 2 and 3 combined), no significant differences in systolic office and ambulatory BP reduction was observed (P=.25 for office BP, P=.15 for ambulatory BP). There was no relationship between the change in systolic ambulatory BP and the total number of ablations (−0.3 mm Hg for each ablation; 95% CI, −1.3 to 0.7), the amount of prescribed antihypertensive medication (−0.5 mm Hg for each DDD; 95% CI, −2.1 to 1.1), or the use of an aldosterone antagonist (−2.5 mm Hg for patients using an aldosterone antagonist compared with patients who did not; 95% CI, −11.8 to 6.9). However, the change in systolic ambulatory BP was significantly related to the number of distal ablations (−1.7 mm Hg for each distal ablation; 95% CI, −3.1 to 0.4).

Table 4.

Univariable and Multivariable Regression Analysis of Denervation Location and Change in BP

	Systolic BP			Diastolic BP
	No.	B	95% CI	No.	B	95% CI
Office BP
Model I (univariate)	93	2.7	(−4.2 to 9.6)	93	−0.7	(−4.4 to 3.1)
Model II (corrected for age and sex)	93	1.2	(−5.8 to 8.3)	93	−0.9	(−4.8 to 3.0)
Model III (corrected for age, sex, eGFR, BMI, DDD, and device)	93	2.5	(−5.3 to 10.3)	93	−0.3	(−4.7 to 4.1)
24‐h ambulatory BP
Model I (univariate)	71	−3.5	(−7.9 to 0.9)	71	−1.4	(−4.2 to 1.3)
Model II (corrected for age and sex)	71	−3.1	(−7.8 to 1.6)	71	−1.2	(−4.1 to 1.7)
Model III (corrected for age, sex, eGFR, BMI, DDD, and device)	71	−3.4	(−8.6 to 1.9)	71	−1.8	(−5.0 to 1.3)

Univariable and multivariable analysis of the relationship between location of denervation and the change in blood pressure (BP). The B coefficient represents the additional change in BP for each artery that is ablated beyond the bifurcation. Abbreviations: BMI, body mass index; CI, confidence interval; DDD, daily defined dose of antihypertensive medication; eGFR, estimated glomerular filtration rate.

3.2. Procedure‐related complications

Ablation notches or spasm occurred in 19 patients and required treatment with intra‐arterial nitroglycerin in 13 cases. In all patients, the spasm resolved without any clinically relevant sequelae (in three patients, a nonsignificant stenosis remained without consequences for renal function). The occurrence of spasm was not related to the location of the ablations (P=.58). No other periprocedural complications occurred. Four postprocedural complications were recorded: three groin hematomas and one femoral pseudoaneurysm, all of which resolved without sequelae. Periprocedural renal function remained stable (73±17 mL/min per 1.73 m² before the procedure, 72±15 mL/min per 1.73 m² directly after the procedure [P=.87], and 71±18 mL/min per 1.73 m² at 4 weeks after RDN [P=.98]).

4. Discussion

In the current analysis, we demonstrated that RDN distal to the renal artery bifurcation may be feasible and safe. Despite the smaller diameter of renal artery branches, the occurrence of vascular spasm was similarly low in patients with distal ablations compared with proximal ablations, nor did we find an adverse effect on renal function. Yet, we did not demonstrate that denervation beyond the bifurcation is more potent, ie, results in greater BP reductions.

Recently, the focus of RDN research has shifted towards identification of predictors of success and optimization of the procedural approach in an attempt to explain and counteract the variation in BP reductions among clinical trials and between patients within trials.23 After the neutral results of the sham‐controlled Renal Denervation in Patients With Uncontrolled Hypertension (SYMPLICITY HTN‐3) trial4 experts from the United States and Europe published important considerations for future studies, including procedural aspects, trial design, patient selection, outcome measurements, and preclinical studies.24, 25 The possible improvement of the procedural aspects relies for a large part on a better understanding of the depth, location, and distribution of the renal sympathetic nerves, as well as the type and extent of tissue damage that is induced by RDN. In the past 2 years, several histological studies have been performed to fill these gaps in our knowledge.10, 12, 13, 26, 27 These studies have uniformly demonstrated that the nerves surrounding the distal segments of the renal artery (containing the renal artery bifurcation) are smaller in number and located in closer proximity to the arterial lumen. This provides a foundation for the hypothesis that distal ablations are more effective. The RF energy could more easily reach the renal artery nerves in the perivascular tissue and fewer nerves need to be adequately targeted to disrupt the sympathetic pathway to and from the kidney. This hypothesis has been supported by preclinical research in canine and porcine models that have demonstrated greater reductions in renal norepinephrine (NE) levels when RDN was performed distal to the renal artery bifurcation.11, 28 Our results could not demonstrate solid data substantiating a clinical benefit from distal denervation. In linear regression, there was a relationship between change in ambulatory BP and the absolute number of distal ablations, but we were unable to demonstrated significant differences in both office and ambulatory BP between patients treated bilateral proximal, unilateral distal, or bilateral distal to the bifurcation. There are several possible explanations for our findings. First, it is possible that, although the nerves are located closer to the renal artery lumen in the distal segments, they were still located out of reach for the RF energy, preventing successful disruption of the sympathetic signaling to and from the kidney. The extent of nerve damage caused by RDN is poorly studied, partly because a functional test to assess the successful destruction of the renal sympathetic nerves in vivo is lacking. Electrical stimulation as used by Gal and associates29 is a promising technique to verify nerve destruction intraoperatively, but has not yet been validated. The currently available histological evidence indicates that the current catheters may have insufficient tissue penetration to adequately target the perivascular nerves in all patients. Vink and colleagues8 reported on the limited destruction of renal nerves after RDN in a case study of a human subject. Subsequent animal studies have confirmed that the average depth of RDN lesions are confined to a maximum of 2.2 mm for the currently available catheters.9, 28 Given the fact that the average distance to the renal nerves ranges from 3.4 to 4.3 mm proximally to 2.0 to 2.6 mm in the distal segment, a large proportion of nerves is located out of reach, even if RDN is performed distal to the bifurcation.10, 12 Henegar and colleagues11 demonstrated that in the distal segment of the renal artery, 96% of the nerves are located within 3.0 mm from the lumen‐intimal transition, but RDN resulted in damage of only 50% of the nerves in that segment. Moreover, deeper penetration does not necessarily lead to increased nerve damage. A study involving a prototype catheter achieved lesions up to 3.8 mm, but affected ≤20% of the nerves.27

This observation raises another critical issue. Thus far, instructions on the location, duration, intensity, and circumference of the ablations have been based on expert knowledge aiming to achieve sufficient damage to the renal sympathetic nerves. However, compelling scientific evidence to support these recommendations is lacking. More importantly, it is unknown what percentage of damaged nerves is necessary to interrupt the sympathetic signaling to and from the kidneys. Several preclinical animal studies have demonstrated that the mean percentage of injured nerves does not exceed 50%, with percentages as low as 14%.9, 11, 27, 30, 31 Whether these percentages are sufficient to achieve BP reduction in humans is unknown, but the results of Tzafriri and coworkers27 suggest that higher percentages are needed: renal NE levels remained stable in 7 of 8 treated renal arteries and were only significantly reduced in an artery with more than 60% nerve damage.

Last, the translation from preclinical research to clinical practice may be too difficult. The majority of animal studies utilize a measurement of sympathetic nervous activity, such as renal tissue NE levels. However, direct measurement of sympathetic nervous activity in human subjects is not available and indirect measurements, such as muscle sympathetic nerve activity, are cumbersome. Although it is known that renal NE levels correspond to sympathetic nerve activity, the relationship between renal NE levels and BP has not yet been quantified. Henegar and colleagues32 previously demonstrated a correlation between BP change and renal tissue NE levels in a hypertensive canine model, but these correlations were not statistically significant. This may explain why we were unable to reproduce the results in the studies by Mahfoud28 and Henegar11 and colleagues.

4.1. Strengths and limitations

There are some limitations to our study. When interpreting the results of our study, it is important to realize that our study was a retrospective analysis and did not have the appropriate design to test for superiority. It was mainly meant as a hypothesis‐generating analysis. Further research, preferably using a randomized design, is needed to determine whether RDN distal to the bifurcation is an improvement of the current procedural technique. Furthermore, the lack of randomization may have introduced other potentially confounding factors to our study. The location of the denervation as well as the choice for RDN device was unprotocolized and left at the discretion of the interventionalist. This may have introduced bias, because the reasons to choose a certain device or the location of the ablations are unknown. Systematic differences in patient sickness and arterial disease, among others, could have biased our results. Also, the difference in ablation location between study groups 1, 2, and 3 is less pronounced than it would have been in a randomized setting.28 Further research in which the location of the ablations is predetermined should address these issues.

Since the current research question was derived from advancing insights and was not a premeditated analysis of the Dutch National Renal Denervation Registry, we were unable to perform a power analysis. Our sample size is relatively small and may suffer from limited power after further separation into three groups. The sample size also prohibited proper subgroup analysis of a potential bias caused by the use of three different RDN catheters in our cohort. We did perform a sensitivity analysis including only the patients with the most used device (81%), which yielded similar results to the complete cohort.

Last, we did not perform toxicological analysis to confirm adherence to medication.

Despite these limitations, this study adds to the current knowledge on RDN. We were among the first to analyze the effects of RDN beyond the bifurcation in human subjects. To this day, many clinical trials have restricted RDN to the renal artery segments proximal to the renal artery bifurcation out of safety concerns. However, we found no reason to believe that distal denervation poses an impermissible additional risk over the currently advised approach of proximal denervation that may obstruct prospective studies.

4.2. Conclusions and future perspectives

RDN is still a relatively new field of research, with many gaps in our knowledge to be filled. The current study aimed to provide some insight into the effects and side effects of ablations in the distal segments in humans. Low incidence of vascular spasm and other adverse events in both proximal and distal denervation strategies were noted. This finding may facilitate the design and planning of future studies aimed to identify a superior treatment strategy for this procedure. Although we found a trend towards a dose‐response relationship between distal ablation placement and ABPM, we were unable to provide solid evidence. Further research, preferably in a randomized design, is needed to determine whether RDN distal to the renal artery bifurcation will improve the BP‐lowering effect of the RDN procedure. Yet, many other gaps in our knowledge remain, including the achieved lesion depth, the achieved nerve damage, and the threshold nerve damage that is needed for effective BP reduction. A technique that could be used as readout of the procedure may further increase the success rate of RDN. In addition, a better understanding of the relationship between outcomes in preclinical research (eg, renal NE levels) and clinical outcomes used in human research (eg, BP reduction) will contribute to a better translation from bench to bedside. The field of RDN is likely to benefit greatly from (pre)clinical studies aimed to elucidate these issues.

Beeftink MMA, Spiering W, De Jong MR, et al. Renal denervation beyond the bifurcation: The effect of distal ablation placement on safety and blood pressure. J Clin Hypertens. 2017;00:1–8. 10.1111/jch.12989