NephroBlate™ Renal Denervation System: Urologic-Nephrologic Based Approach to Resistant Hypertension

Fig. 15.1

Illustration of renal enervation. The netter collection of medical illustrations, volume 6, kidneys, ureters, and urinary bladder, page 27 (With permission from Elsevier, Health Sciences Division)

Verve Medical has developed NephroBlate™, a proprietary RF catheter system which can be introduced trans-urethrally to the renal pelvis, exploiting the proximity of the renal nerves to the renal pelvis with standard urologic techniques [15] (Figs. 15.2 and 15.3). It has been shown in the pelvic location, both efferent and afferent nerves are located and intertwined within the multiple layers of the renal pelvic wall [16]. This procedure is not restricted by anatomic variances of the artery and does not necessitate utilization of intra-arterial contrast. If contrast is administered, it will be delivered in a retrograde manner and not systemically (Fig. 15.4). The procedure can be performed in patients with bleeding diathesis without treatment with antiplatelets agents or heparin.

Fig. 15.2

The radiofrequency generator used for the Verve Medical device (Reprinted from Heuser et al. [17] with permission from Europa Digital and Publishing)

Fig. 15.3

The monopolar radiofrequency electrode catheter for delivery to the renal pelvis (Reprinted from Heuser et al. [17] with permission from Europa Digital and Publishing)

Fig. 15.4

Fluoroscopic image of the device in a swine’s renal pelvis (Reprinted from Heuser et al. [17] with permission from Europa Digital and Publishing)

The Verve Medical system consists of a monopolar radiofrequency electrode catheter and a low power 50 W custom radiofrequency generator which monitors and regulates power, temperature, time and impedance. A standard 0.035 guidewire is delivered into the renal pelvis under direct vision through the working channel of a cystoscope. The 9f catheter is then threaded over a standard 0.035 guidwire into the renal pelvis, distal to the UPJ and proximal to the calyces. The electrode array is located at the distal end of the catheter and radially expands to contact and dilate the renal pelvis. Low power, <10 W, monopolar energy is delivered from the generator through the electrodes into the renal pelvic wall for 4–6 min ablating the residing afferent and efferent nerves (Figs. 15.2, 15.3 and 15.4).

Methods and Results

Sixteen female domestic swine weighing 60–65 kg underwent bilateral renal denervation via ureteral access. Sixteen other similar animals were used for control. In each of the groups, three animals were euthanized immediately after delivery of RF energy; five animals at 7 days, six animals at 14 days and two animals at 30 days. Renal cortical tissue was harvested and Norepinephrine (NE) levels were measured using HPLC in all groups of animals. Histopathology of the treated zone was performed to confirm nerve damage.

Animals were fasted overnight then sedated with Ketamine, intubated, and maintained on Isoflurane anesthesia throughout the procedure. No anticoagulant was administered. A ventral midline laparotomy was performed to expose the urinary bladder. A 5 cm incision was made in the ventral aspect of the bladder to access the ureteral orifice. The Verve Medical device was passed retrograde over a 0.035″ guidewire from the bladder to the renal pelvis and RF ablation was performed. Treatment time/temperature algorithms were established with a range from 1 to 12 min and temperatures from 55 to 90 °C. The procedure was repeated in the contralateral kidney. In two animals, RF energy was not applied to the contralateral kidney (sham procedure). The device was not passed into the contralateral kidney. The urinary bladder and laparotomy were closed and the animals were allowed to recover from anesthesia. Bilateral pyelogram, ureterogram, and renal angiography were performed to insure no procedural related injury to the renal pelvis, ureters or the renal arteries. Immediately following euthanasia renal cortical tissue was harvested for determination of tissue norepinephrine concentration by High Performance Liquid Chromatography (HPLC) (Fig. 15.5). The kidneys were then perfusion fixed for histopathologic analysis (Fig. 15.6). In all animals there was a reduction of NE levels compared to control samples. Mean reduction of norepinephrine levels was 57 %, compared to control (Fig. 15.5). Histopathology confirmed nerve ablation in the treated zone with no parenchymal or vascular thermal injury.

Fig. 15.5

Reduction from baseline of norepinephrine in the swine model post-intrapelvic RF ablation. Note that the data are per kidney (Reprinted from Heuser et al. [17] with permission from Europa Digital and Publishing)

Fig. 15.6

(a) Image shows the relation to the surrounding renal pelvis tissue. Not all nuclei are damaged. (b) High power showing severe nerve injury with necrosis of endoneural cells and perineural thermal injury. Not all nuclei are damaged (From Heuser et al. [17] with permission from Europa Digital and Publishing)

With these results, we developed a protocol to treat a small number of patients (n = 3, four kidneys) undergoing elective nephrectomy at Muljibhai Patel Urological Hospital in Nadiad, India. After submission to the hospital institutional review board and after patient informed consent we treated three patients with chronic kidney disease (two with nephrolithasis, one with end stage kidney disease from poly-cystic kidney disease (PKD)). The patients were treated on the side which was planned for elective nephrectomy. One patient (PKD) was pre-renal transplant and had both kidneys were treated. The RDN treatment was done under general anesthesia. One week after transurethral RDN treatment (Fig. 15.7a, b), the previously planned nephrectomy was performed. The procedure time was between 9 and 15 min. The procedures were well tolerated and no adverse effects were recorded. The histopathological results on the treated kidney in all cases showed a significant destruction of the peri-pelvic nerves from the renal pelvic space to the serosa (1.75 mm) (Figs. 15.8, 15.9, 15.10, 15.11, 15.12, 15.13, 15.14 and 15.15). With a virtual elimination of the afferent and efferent nerves in the treated area and no change to the nerves in the control (untreated) segments in the histopathologic specimens, we proceeded with our clinical studies on resistant hypertensive patients.

Fig. 15.7

(a) Verve’s NephroBlate™ (From Verve Medical with their permission) (b) NephroBlate™ Catheter – Fluoroscopic View – with wings extended

Fig. 15.8

Explanted human kidney 7 days post treatment (From Verve Medical with their permission)

Fig. 15.9

Tissue sectioning for pathology (From Verve Medical with their permission)

Fig. 15.10

Histopathology sampling zones (From Verve Medical with their permission)

Fig. 15.11

Pelvis wall – distal to ablation zone (Control) (From Verve Medical with their permission)

Fig. 15.12

Pelvis wall – distal to ablation zone (Landscape) (From Verve Medical with their permission)

Fig. 15.13

Treatment depth (From Verve Medical with their permission)

Fig. 15.14

Pelvis wall – ablation zone (From Verve Medical with their permission)

Fig. 15.15

Pelvis wall – ablation zone (From Verve Medical with their permission)

With the above data, we proceeded with our clinical trial after Ethics Committee approval. Four patients were treated via trans-urethral approach under general anesthesia. The catheter was introduced via 9FR sheath. The RF energy was applied for 6 min, 70° Centigrade, 5 W. The operating room (OR) time ranged from 16 to 25 min. All patients had Double-J Stent placed post procedure as a precaution, and were removed 2 weeks later. The patients characteristics pre-procedure:

Systolic BP Ave 172 mmHg
eGFR Ave 82.4* ml/min/1.7
Creatinine Ave 1.03* ml/dL

(*Average not including the end-stage renal disease ESRD patient). If the ESRD patient data is included, the average systolic BP is the same (172 mmHg, GFR 65.02 ml/min/1.73 m², and Serum Creatinine is 1.80 mg/dL).

The inclusion criteria included: Office systolic blood pressure (SBP) ≥160 mmHg (SBP ≥ 150 mmHg with Type II diabetes mellitus), on >2 antihypertensive agents, with at least one agent being a diuretic. The procedures were performed in India. Practically speaking, few patients in our demographic territory could afford any more than two antihypertensive agents. As in the diseased kidney study, the procedure was done under general anesthesia. In either study, no patients received aspirin, heparin or any antiplatelet agents. Within minutes of treatment of the first kidney, a blood pressure response was noted and following the procedure, none of the patients had significant pain post procedure, bleeding, or urologic complications such as perforation or stricture formation or obstruction. There was a mean drop in systolic blood pressure of 44 mmHg (Systole: 20.55; Diastole: 13.58), with no significant change in renal function (Fig. 15.16 and Table 15.1)

Table 15.1

Kidney function: 1 month follow up. Consistent results; minimal change (From Verve Medical with their permission)