By Juan Parodi
Hypertension is one of the most prevalent diseases in the world and represents a major cardiovascular risk factor. Sympathetic nerves of the renal arteries play an important role in the development of hypertension, and both afferent and efferent nerves are responsible for stimuli that through different mechanisms result in an increase of sympathetic tone.
A hyperactive sympathetic nervous system is the driver of hypertension. Electrical signals travel from the brain down the spinal cord, and then to and from the kidney in the renal sympathetic nerves, returning up the spinal cord to the brain. This circuit increases sympathetic outflow to the entire cardiovascular system. Stimulation of the kidney via the efferent renal nerves produces vasoconstriction of the renal vasculature, increased release of renin, and tubular reabsorption of sodium. Signals from the kidney via afferent renal nerves increase total peripheral vascular resistance. The net effect of these events is a rise in blood pressure. Furthermore, the sympathetic nervous system has effects on glucose metabolism, renal function, left ventricular hypertrophy, and vascular function.
Resistant hypertension has been defined as a failure to reach blood pressure targets despite a combination of three to four antihypertensive drugs from different drug classes (including a diuretic) at optimal dosages. The goal blood pressure is defined as <140/90mmHg for the general population and <130/80mmHg for those with diabetes mellitus or chronic kidney disease.
The publication of the SYMPLICITY HTN-1 trial in 2009 was a landmark in the field. The trial reported on the first experience using the Symplicity renal denervation system (Medtronic).
A variety of renal denervation systems have been developed using either energy (radiofrequency or ultrasound) or chemical methods to interrupt the renal sympathetic nervous system. The SYMPLICITY trials and others that followed proved the efficacy of renal denervation in decreasing the blood pressure in patients with resistant hypertension. The three-year results from the SYMPLICITY HTN-1 clinical trial were presented at the European Society of Cardiology Congress 2013. The study demonstrated that the significant decrease in systolic and diastolic pressures after renal denervation with the device lasts for at least three years and there are no signs of re-inervation. Complications are minimal.
After learning the technique, our group started to use the device in our own practice, with good initial results (Figure 1).
In spite of the extensive use of endovascular techniques for aneurysms and occlusive diseases of the aorta in our practice, occasionally we perform open procedures to treat aneurysms and occlusion of the aorto-iliac system. Many of our patients are hypertensive and/or diabetic.
In view of the excellent results, lack of side-effects and very low incidence of complications in the SYMPLICITY trial, we decided to design a prospective, randomised, multicentre study using surgical denervation of the renal arteries taking advantage of the vicinity of the renal arteries to the surgical field. The procedure was limited to denudate the initial 3 to 4cm of the renal arteries to prevent side-effects and complications of the extensive operation performed in the past to treat hypertension.
Removal of tissue and adventitia of the coeliac trunk during the treatment of median arquate ligament syndrome proved that the denuded artery does not dilate over time.
The renal sympathetic nervous system was a therapeutic target for antihypertensive treatment decades ago, when surgical sympathectomy was the only option for patients with blood pressure that was difficult to control.
Although effective, surgical targeting of renal sympathetic nerves lacked precision and resulted in collateral nerve damage, which led to orthostasis, bowel and bladder incontinence, and sexual dysfunction. This technique was abandoned with the advent of effective pharmacologic antihypertensive therapy.
The procedure we propose is performed once the main operation—either abdominal aortic aneurysm replacement or aorto-bifemoral bypass for occlusive disease— is finished. Circulation to the feet is checked; if it is appropriate, heparin is reversed and open renal denervation initiated. Both renal arteries are exposed and tissue around the initial 3cm of the arteries is resected using a Strully or Potts scissors. The adventitia is carefully removed (Figure 2). The procedure takes approximately 20 minutes. Surgical methods of sympathectomy were associated with high perioperative morbidity and mortality, as well as long-term complications, including bowel, bladder, and erectile dysfunction, in addition to profound postural hypotension.
It has been well known for many years that extensive denervation of the renal arteries using resection of sympathetic ganglia and splanchnic nerves caused many undesirable effects. We limited our denervation to the initial 3 to 4cm of the renal arteries. Sympathetic renal nerves are found around the arteries and in the adventitia.
The number of nerves increased along the length of the artery, with a total of 216 in the proximal section, 323 in the middle section, and 417 in the distal section. The increasing nerve counts along the length of the artery likely reflect an arborisation pattern of the nerves according to one anatomic study (Atherton DS, Deep NL, Mendelsohn FO. Microanatomy of the renal sympathetic nervous system: a human postmortem histologic study. Clin Anat. 2012;25:628–633).
We decided to perform the procedure only in non-obese, low risk patients suffering from hypertension and/or diabetes in whom the procedure could not prolong significantly the operation. We included patients with blood pressure above 130/90mmHg and resistant to three drugs including a diuretic. The Ethical Board of the hospital approved the trial and an informed consent was presented to the patient.
Before proceeding with the operation ambulatory blood pressure monitoring and measurements of sodium excretion in the urine for 24 hours are performed, as well as fasting glucose in blood and after two hours of the ingestion of 50g of glucose (glucose tolerance test).
Surgical technique
The first part of the operation consisted of the procedure to treat the aneurysm or occlusive disease. After finishing the initial part of the operation both renal arteries were exposed and using a Strully scissors removal of the periadventitial and adventitial tissue was performed on the initial 3 to 4cm of the artery. Specimens of tissue were sent to the pathology department to study the presence of nerves. The retro peritoneum was closed in the usual way.
Type and dose of medications were carefully recorded and both tests (glucose tolerance test and ambulatory blood pressure monitoring) were repeated at three months after the procedure. In addition, sodium in urine (24h) was measured before and after the procedure as well as the 24h urinary output.
Initial recruitment started in July 2013. An independent statistician performed randomisation. In order to control that the denervated segment does not dilate, we performed colour duplex studies or MRI of the renal arteries after three months and one year thereafter.
Due to the small number of open cases we perform in the aorta we expect to complete the required number of patients in one year.
As an example I will describe the initial case we performed: a 58-year-old male with resistant hypertension harbouring a 6cm infra-renal aneurysm requested to have an open surgical correction of his aneurysm. We discussed our protocol of surgical renal denervation and he agreed to be included and signed and informed consent.
Through a midline abdominal incision the aneurysm was replaced using a bifurcated aorto-bi-iliac Dacron graft. After checking the distal perfusion, heparin was reversed and both initial 3cm of the renal arteries were denervated using Strully scissors. The patient had an uneventful recovery and was sent home after four days.
We compared preoperative findings with those after three months. Ambulatory blood pressure monitoring during 24 hours: under treatment with three drugs, the preoperative blood pressure was 152/95mmHg; after three months under treatment with one drug, the blood pressure average was 134/83mmHg. Sodium excretion in urine for 24h was 164meq in the pre-operative measurement and 251.1meq after three months.
Preoperative glucose tolerance test showed the following results: 233mg% at 60 minutes of the ingestion of 50g of glucose and 147 mg% at 120 minutes. After three months at 60 minutes blood glucose was 1.98 mg/dl and 125 mg/dl at 120 minutes.
Conclusions
Renal denervation has shown promising results in several trials to treat resistant hypertension. When the renal arteries are close to the surgical field during open procedures to treat aneurysms or occlusive disease of the aorta and iliac arteries, the simple procedure of surgical denervation could help the patient to control hypertension and glucose tolerance without adding significant morbidity and time in the operating room. Potential use of the procedure in diabetics without resistant hypertension is under consideration. We still have a small number of patients in the trial to raise conclusions regarding the utility of the proposal but initial results are promising.
Juan Parodi, S Fernandez and A Alarcon are with the Trinidad Hospital, Buenos Aires, Argentina
