Clinical trial NCT01427049: The Effect of Renal Denervation on Biological Variables
Official title: The Evaluation of Renal Denervation on Several Biological Variables in Patients With Uncontrolled Hypertension. An Observational Feasibility Study.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Hypertension
Keywords: renal denervation
renal sympathetic denervation
renal ablation
resistant hypertension
hypertension
renal oxygenation
renal perfusion
Lead sponsor: UMC Utrecht
Sponsor class: OTHER
First posted: 2011-09-01
Enrollment: 54
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Adults with a systolic BP ≥160 mmHg (≥150 mmHg for type 2 diabetics) with a stable drug regimen including 3 or more antihypertensive medications, including a diuretic, or inability to follow a stable drug regimen due to unacceptable side-effects of antihypertensive medication.

This current study is an observational exploratory-study.

Brief summary: Hypertension is a major and growing public health concern. Chronic elevation of sympathetic nervous system (SNS) activity has been identified as a major contributor to the complex pathophysiology of (essential) hypertension. The renal sympathetic nerves play a major role in the elevation of the SNS activity. Therapeutic renal denervation (RD), the deliberate disruption of the nerves connecting the kidneys with the central nervous system, has been shown to be an effective means of modulating elevated SNS activity - both by reducing the sympathetic modulation of renal function (renin release, sodium excretion and renal blood flow) and by removing the renal afferent sympathetic contribution to central blood pressure elevation.

This current study is an observational exploratory study. The main objective of this study is to learn more on the effects of RD. We wish to do that by quantifying the effects of RD on various biological variables. Those variables are studied in four sets of investigations: a radiological set, a laboratorial set, a set of blood pressure measurements and a set of investigations in the vascular laboratory. The radiological set consists of imaging of the heart and kidney function (renal perfusion) and structure (renal arteries), the laboratorial set of serum and urine tests, 24 h- home- and office- blood pressure measurements will be taken and finally the set of vascular tests contains investigations on pulse wave velocity(PWV) and heart rate variability(HRV). The data will most likely help us to define future studies, to describe the mode of action and the effects of RD on various organs and systems in more detail, and finally to define in more detail which type of hypertensive patients is especially likely to benefit of the procedure.

Hypothesis:

* We hypothesize that LV mass will decrease after RD. Because all patients have severe hypertension, it is likely that a substantial percentage will have increased LV mass.
* We hypothesize that renal perfusion and renal oxygenation increase after RD.
* We hypothesize that there will be no complications related to the device or procedure.
* We hypothesize that renal denervation has a beneficial effect on insulin resistance
* We hypothesize that renal denervation will decrease the blood pressure(office and 24-hour-measurements)
* We hypothesize that RD has a beneficial effect on PWV and HRV.

Detailed description: Objective: The objectives of this study are: the investigation of changes in left ventricular mass (LV mass) after RD using MRI, renal perfusion and renal oxygenation after RD using dynamic contrast enhanced MRI (DCE MRI)and blood oxygenation level dependent MRI (BOLD MRI), the evaluation of safety of RD, in terms of structural changes in the renal arteries and kidney using Magnetic resonance angiography (MRA). Secondly the evaluation of changes in various biological functions assessed by analysis of blood and/or urine samples. Thirdly the quantification of changes in blood pressure. Finally the changes in pulse wave velocity (PWV) and heart rate variability (HRV).

Study design: Observational exploratory-study.

Study population: Adults with a systolic BP ≥160 mmHg (≥150 mmHg for type 2 diabetics) with a stable drug regimen including 3 or more antihypertensive medications, including a diuretic, or inability to follow a stable drug regimen due to unacceptable side-effects of antihypertensive medication.

Main study parameters/endpoints: The effect of RD on: radiological variables: left ventricular wall mass, renal perfusion, renal oxygenation and the anatomy of the renal arteries. Secondly the effect of RD on biological variables assessed by analysis of blood and/or urine samples. Thirdly the changes in blood pressure. Finally the changes in PWV and HRV after RD.

Nature and extent of the burden and risks associated with participation, benefit and group relatedness: The risks associated with the tests and procedures performed for the clinical study are limited. There are no known risks associated with MRI when appropriate safety guidelines are followed. Based on the experience form our previous studies, we do not expect any potential risks regarding the cessation of anti-hypertensives.

Eligibility criteria: Inclusion Criteria:

* Individual has a systolic BP ≥160 mmHg (≥150 mmHg for type 2 diabetics) based on an average of 3 office BP readings measured according to the guidelines in appendix A.
* Individual is adhering to a stable drug regimen including 3 or more antihypertensive medications, including a diuretic (with no changes for a minimum of 2 weeks prior to enrolment) which is expected to be maintained for at least 6 months. Or:
* Has experienced side effects to several anti-hypertensive medications
* Individual is ≥18 years of age.
* Individual agrees to have all study procedures performed, and is competent and willing to provide written, informed consent to participate in this clinical study.

Exclusion Criteria:

* Individual has a treatable secondary cause of hypertension. (it is possible that during baseline procedures secondary causes of hypertension are discovered, those individuals will be excluded from participation of the study.)
* Individual has renal artery anatomy that is ineligible for treatment including:
* Main renal arteries \< 4 mm in diameter or \< 20 mm in length.
* Hemodynamically or anatomically significant renal artery abnormality or stenosis in either renal artery which, in the eyes of the operator, would interfere with safe cannulation of the renal artery or meets standards for surgical repair or interventional dilation.
* A history of prior renal artery stenting.
* Multiple main renal arteries in either kidney.
* Individual has an estimated glomerular filtration rate (eGFR) of \<30mL/min/1.73m2, using the MDRD calculation.
* Individual has type 1 diabetes mellitus.
* Individual has experienced a myocardial infarction, unstable angina pectoris, or a cerebrovascular accident within 6 months of the screening visit, or has widespread atherosclerosis, with documented intravascular thrombosis or unstable plaques.
* Individual has scheduled or planned surgery or cardiovascular intervention in the next 6 months.
* Individual has hemodynamically significant valvular heart disease for which reduction of BP would be considered hazardous.
* Individual has an implantable cardioverter defibrillator (ICD) or pacemaker whose settings cannot allow for RF energy delivery.
* Individual has any serious medical condition, which in the opinion of the investigator, may adversely affect the safety and/or effectiveness of the participant or the study (i.e., patients with clinically significant peripheral vascular disease, abdominal aortic aneurysm, bleeding disorders such as thrombocytopenia, haemophilia, or significant anaemia, or arrhythmias such as atrial fibrillation).
* Individual is pregnant, nursing or planning to be pregnant.
* Individual has a known, unresolved history of drug use or alcohol dependency, lacks the ability to comprehend or follow instructions, or would be unlikely or unable to comply with study follow-up requirements.
* Individual is currently enrolled in another investigational drug or device trial.
* Individual is currently being treated with any of the following medications:

  1. Drugs that cause salt retention (e.g., systemic corticosteroids and fludrocortisone)
  2. Warfarin or phenprocoumon that cannot be temporarily stopped for the procedure.
* Any contraindications for MRI:

  1. The presence of implanted cardiac pacemakers and/or auto-implanted cardioverter defibrillators.
  2. Mechanical cardiac valves.
  3. Implanted electronic devices like cochlear implants and nerve stimulators.
  4. Patients who are unable to fit into the bore of the magnet.
  5. Claustrophobia.
  6. Prosthesis of a joint.

Primary outcomes:
measure: Change in Blood pressure related endpoints:
timeFrame: t=0, t=6 and t=12 months
Secondary outcomes:
measure: Radiologic endpoint
timeFrame: t=0 and t=12 months
measure: radiologic endpoint
timeFrame: t=0 and t=12 months
measure: radiologic endpoint
timeFrame: t=0 and t=12 months
measure: radiologic endpoint
timeFrame: t=0 and t=12 months
measure: laboratorial endpoint
timeFrame: t=0 and t=12 months
measure: blood pressure related endpoint
timeFrame: t=0 t=6 and t=12 months
measure: blood pressure related endpoint
timeFrame: t=0 and t=12 months
measure: blood pressure related endpoint
timeFrame: measured every month after renal denervation
measure: endpoint derived from investigations at the vascular laboratory
timeFrame: t=0 and t=12 months
measure: endpoint derived from investigations at the vascular laboratory
timeFrame: t=0 and t=12 months
Other outcomes:
Locations:
city: Utrecht
country: Netherlands
facility: UMC Utrecht
Study officials:
affiliation: UMC Utrecht department of Nephrology and Hypertension
name: Peter Blankestijn, Dr.
role: PRINCIPAL_INVESTIGATOR
affiliation: UMC Utrecht Department of Nephrology and Hypertension
name: Eva Vink, PhD Student
role: PRINCIPAL_INVESTIGATOR
References:
citation: Blankestijn PJ, Ritz E. Renal denervation: potential impact on hypertension in kidney disease? Nephrol Dial Transplant. 2011 Sep;26(9):2732-4. doi: 10.1093/ndt/gfr190. Epub 2011 Apr 19. No abstract available.
citation: Symplicity HTN-2 Investigators; Esler MD, Krum H, Sobotka PA, Schlaich MP, Schmieder RE, Bohm M. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet. 2010 Dec 4;376(9756):1903-9. doi: 10.1016/S0140-6736(10)62039-9. Epub 2010 Nov 17.
citation: Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension. 2011 May;57(5):911-7. doi: 10.1161/HYPERTENSIONAHA.110.163014. Epub 2011 Mar 14.
citation: Siddiqi L, Joles JA, Grassi G, Blankestijn PJ. Is kidney ischemia the central mechanism in parallel activation of the renin and sympathetic system? J Hypertens. 2009 Jul;27(7):1341-9. doi: 10.1097/HJH.0b013e32832b521b.
citation: Krum H, Schlaich M, Whitbourn R, Sobotka PA, Sadowski J, Bartus K, Kapelak B, Walton A, Sievert H, Thambar S, Abraham WT, Esler M. Catheter-based renal sympathetic denervation for resistant hypertension: a multicentre safety and proof-of-principle cohort study. Lancet. 2009 Apr 11;373(9671):1275-81. doi: 10.1016/S0140-6736(09)60566-3. Epub 2009 Mar 28.
citation: Verloop WL, Vink EE, Spiering W, Blankestijn PJ, Doevendans PA, Bots ML, Vonken EJ, Voskuil M, Leiner T. Effects of renal denervation on end organ damage in hypertensive patients. Eur J Prev Cardiol. 2015 May;22(5):558-67. doi: 10.1177/2047487314556003. Epub 2014 Oct 17.