Renal Denervation in Patients With Chronic Kidney Disease
Renal Denervation in Patients With Chronic Kidney Disease
People with hypertension are at a higher risk for cardiovascular disease and death so it is
 important to lower blood pressure to normal levels as quickly as possible. Previous research
 has established that renal nerve denervation successfully lowers blood pressure measured in
 the arm in the physician's office. This study is being conducted so that the investigators
 can determine whether renal nerve denervation also helps to lower blood pressure over 24
 hours, as well as central aortic blood pressure, which is pressure exerted by the aorta
 closer to the heart and may be a better predictor of cardiovascular problems. The
 investigators also want to know whether these beneficial effects on blood pressure can last
 up to 2 years, whether renal denervation reduces the number of medications patients need to
 take, and whether it reduces glucose and insulin levels in the blood since hypertension is
 also related to obesity and diabetes.
Study design and patients:

 This study will be conducted using a prospective, single-arm pre-/post-intervention design
 over 2 years. Fifty consecutive stage 3 and 4 CKD patients with resistant hypertension from
 the Regina Qu'Appelle Health Region (RQHR) multidisciplinary CKD clinic who agree to undergo
 RDN will be included in the study. Patients will be considered eligible if they are >18 years
 of age, exhibit a systolic BP of greater than 140 mm Hg despite maximal doses of 3 agents (1
 of which is a diuretic) or are currently on 4 BP meds to control SBP to less than 140 mm Hg.
 Once identified as having resistant hypertension based on chart review, the patients will
 undergo the following assessments: 24-hour urine for catecholamines, sodium and cortisol; CT
 renal angiogram for the length and diameter of the renal arteries, to rule out
 stenosis/fibromuscular dysplasia, and assessment of the adrenal gland for nodules; and
 measurements of thyroid stimulating hormone (TSH) and serum cortisol to exclude secondary
 causes of hypertension. If no secondary causes of hypertension are identified, then the study
 coordinator will approach the patient at their next clinic appointment regarding
 participation in the trial

 Patients will be excluded if the evaluations identify functional adrenal adenoma; a CT scan
 reveals a renal artery length (on either side) of less than 20 mm or diameter of less than 4
 mm; they are pregnant or planning pregnancy within the study period; there is documented
 evidence of moderate-to-severe aortic stenosis; a cardiac event necessitating introduction of
 clopidogrel occurred during the prior 12 months; or they are currently using Warfarin or have
 a history of CVA within 6 months prior to the procedure. Patients on clonidine and other
 sympatholytic agents will not be excluded from the study. Our institutional review ethics
 board (REB-12-73) granted approval for the study. If a patient fit the criteria and agrees to
 undergo the procedure, the study coordinator will organize/perform the following assessments:

 Ambulatory blood pressures and office blood pressures: Patients will undergo 24-hour blood
 pressure monitoring (Welch Allyn, Skaneateles Falls, NY, USA), and the following information
 will be documented: 12-hour daytime systolic pressure (mm Hg), 12-hour daytime diastolic
 pressure (mm Hg), 12-hour night-time systolic pressure (mm Hg) and 12-hour night-time
 diastolic pressure (mm Hg). The following day, the patient will have the 24-hour arm cuff
 removed, and they will sit in a quiet room for 10 minutes before the study coordinator can
 take further peripheral blood pressure measurements using BP Tru (BPM 100, BP Tru medical
 devices, Coquitlam, BC, Canada) on the non-dominant arm, which measures 6 consecutive blood
 pressures (the first is excluded, and the average of the last 5 readings will be documented).

 Central blood pressure: After obtaining the mean of the 5 BP readings, radial artery
 waveforms will be recorded with a high-fidelity micromanometer from the wrist of the dominant
 arm and calibrated to the previously measured mean of 5 BP readings. Waveforms will be
 processed with dedicated software (Sphygmocor CPV (EM3) software version 9; AtCor Medical).
 The integral system software will be used to calculate an average radial artery waveform and
 to derive a corresponding central aortic pressure waveform using a previously validated
 generalized transfer function12,13. Aortic waveforms will be subject to further analysis
 using the SphygmoCor software to identify the time to the peak/shoulder of the first and
 second pressure wave components (T1, T2) during systole. The pressure at the peak/shoulder of
 the first component will be identified as the P1 height, and the pressure difference between
 this point and the maximal pressure during systole (Δ P, or augmentation) will be identified
 as the reflected wave during systole. The augmentation index (AIx), defined as the ratio of
 augmentation to the central pulse pressure, is expressed as a percentage: AIx: (Δ P/PP) X
 100, where P is pressure, and PP is pulse pressure. Pulse pressure amplification (PPA) is
 expressed as the ratio of central pulse pressure (CPP) to brachial pulse pressure (PPP):
 PPA=PPP/CPP. At least 2 consecutive radial pressure wave samplings will be recorded for each
 patient, and the mean will be used for analysis. The collected data will include the
 augmentation index (%), augmentation pressure (mm Hg), central pulse pressure (mm Hg),
 central systolic pressure (mm Hg), central diastolic pressure (mm Hg), pulse pressure
 amplification (mm Hg), time to reflection (Tr) in ms and pulse wave velocity.

 Pulse wave velocity: The carotid to femoral pulse wave velocity (PWV) will be measured in all
 patients during every clinic visit. PWV will be determined immediately after the central
 blood pressures. This parameter is determined by simultaneous measurement of arterial
 pressure waves at the carotid and femoral arteries with a pressure transducer. The surface
 distance from the suprasternal notch to the distal (femoral) recording site will be measured,
 and the pressure wave transit time will be calculated by dividing the distance to the distal
 site by the pressure wave transit time. The data will be collected by a single trained
 coordinator (RJ), and the mean of 2 PWV measurements will be taken for each patient.

 Echocardiogram:

 The following parameters will be documented: Left ventricle volume, left ventricle
 hypertrophy, left ventricle function, left atrial mass, E-wave velocity and E-prime velocity.

 Demographic information:

 During the same clinic visit, we will record the patient's age, height, weight, waist
 circumference, race, gender, current medications being taken and current medical conditions
 (peripheral artery disease, diabetes mellitus, coronary heart disease, cerebrovascular
 disease) and administer a quality-of-life questionnaire (EQ5D, a short standardized
 instrument to measure health-related quality of life), which is to be completed prior to the
 procedure.

 Laboratory measures: The patient will receive a requisition to have blood taken at a
 laboratory within 1 month prior to the renal denervation procedure to measure the following
 parameters: serum fasting glucose and insulin, a fasting lipid panel, a renal panel,
 electrolytes, osmolality, the complete blood count and 24-hour urine, for sodium, protein,
 creatinine clearance, potassium, osmolality and the albumin/creatinine ratio.

 Procedure:

 During renal nerve ablation, a catheter connected to a Medtronic radiofrequency generator
 will be inserted percutaneously through the groin via the femoral artery and advanced up the
 aorta to the renal arteries. Total of 4 to 6 discrete radiofrequency ablations lasting up to
 2 minutes, of 8 watts or less each, will be performed, separated both longitudinally and
 rotationally within each renal artery. The catheter system monitors tip temperature and
 impedance, altering radiofrequency energy delivery in response to a predetermined algorithm.
 The procedure will take approximately 40 minutes, to complete the ablations bilaterally. The
 patient will receive intravenous opiates and sublingual anxiolytics, as per the institutional
 protocol, to reduce visceral pain as well as 3000 IU of intra-arterial heparin in each renal
 artery prior to the ablations. Post-procedure, the patient will be monitored in the
 ambulatory care unit for 4 hours.

 The procedure time and contrast volume will be documented. The number of successful ablations
 in each renal artery will also be recorded. All adverse events and complications will be
 recorded during each study visit. Specific interventional-related safety data will include
 bleeding or a femoral pseudoaneurysm requiring intervention, renal artery dissection,
 myocardial infarction, stroke and death.

 Follow-up schedule:

 The patient will receive a phone call from the study coordinator after 7 days to check
 his/her clinical condition. He/she will be encouraged to continue to check his/her blood
 pressures routinely at home (2 times/week) and inform the attending physician if his/her
 blood pressures fall below 100 mm Hg systolic or remain higher than 180/90 mm Hg.3, 6, 12, 18
 and 24 month's post-procedure (within ±1 month), the study coordinators will perform/request
 the above-documented tests. The patient will also receive an echocardiogram to examine
 cardiac function at 12 and 24 months (±2 months). The insulin sensitivity index will be
 calculated from fasting glucose and insulin values as follows: homeostasis model
 assessment-insulin resistance (HOMA-IR) (FPG_FPI), where FPG and FPI are fasting plasma
 glucose and fasting plasma insulin, respectively.

 End points:

 The primary outcome of interest is the change in central blood pressure from baseline to 6
 months post-RDN. The secondary outcomes of interest include the change in central blood
 pressure from baseline to 3, 12, 18 and 24 months post-RDN as well as changes in 24-hour
 peripheral blood pressure, pulse wave velocity, cardiac parameters, renal biochemical
 parameters and fasting insulin and glucose levels and the change in the number of medications
 from baseline to 3, 6, 12, 18 and 24 months post-RDN.

 Sample size considerations With a one-sided type 1-error rate of 5%, a sample of 50 subjects
 would provide 90% power to detect a 10/5 mm Hg change in systolic/diastolic central pressures
 from baseline with a standard deviation of 23/12, which would be clinically significant.

 Statistical analyses Baseline data will be summarized descriptively. The primary outcome will
 be evaluated using a one-sided paired samples t-test for normally distributed data or
 Mann-Whitney U test for non-normally distributed data. Secondary outcomes will be examined
 using repeated measures or mixed model ANOVAs with correction for multiple comparisons
 (continuous outcomes) and Χ2 test(categorical outcomes) for normally distributed data and
 Friedman's test (continuous) or McNemar's test (categorical) for non-normally distributed
 data and two-sided alpha set to .05. Multiple linear regression may be used to account for
 potential covariates, such as age, BMI, gender, or comorbidities on changes in blood
 pressure, cardiac or renal parameters and insulin/glucose.
Inclusion Criteria:

 -  Glomerular filtration rate: 60-15 mls/min as per the modified diet in renal disease
 formula (Stage 3 and 4 Chronic Kidney Disease)

 -  Daytime systolic blood pressure on ambulatory monitor ≥ 135 mm Hg while taking 3 or
 more anti-hypertensives including a diuretic on maximal dose OR ambulatory monitor
 systolic blood pressure is <135 but taking 4 or more anti-hypertensives

 -  18 years and above

 -  A minimum of 20 mm of length and 4 mm of diameter for renal arteries on CT renal
 angiogram or formal renal angiogram

 Exclusion Criteria:

 -  not suitable for renal denervation based on the Indications for Use