Safety and Efficacy of Ultrasound Renal Denervation in Kidney Transplantation Patients With Uncontrolled Hypertension

Study Overview
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Brief Summary
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This prospective, single-arm, interventional study is designed to assess the short-term and long-term safety and efficacy of bilateral ultrasound renal sympathetic denervation (RDN) of the native kidneys in renal transplant patients with uncontrolled hypertension. Objectives: To assess the short-term and long-term changes in ambulatory and office blood pressure (BP) following native kidney RDN in renal transplant patients To assess the long-term safety of native kidney RDN in renal transplant patients To assess the short-term and long-term change in antihypertensive drug prescriptions following native kidney RDN in renal transplant patients To assess the short-term and long-term change in adherence to antihypertensive drugs following native kidney RDN in renal transplant patients

Detailed Description
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The RESTART study is an investigator-initiated, prospective, single-center, single-arm interventional study investigating the safety and efficacy of bilateral native kidney RDN in 40 renal transplant patients with uncontrolled hypertension despite antihypertensive medication (or with a documented intolerance to antihypertensive drugs). Previously, RDN demonstrated to safely reduce BP as compared to sham-control in multiple randomized clinical trials, both in patients with and without concomitant antihypertensive medication. Up until now, patients with a history of renal failure or kidney transplantation have been excluded from these studies. As the pathophysiology of hypertension is considered different in hypertensive renal transplant patients as compared to the previously studied populations (without kidney transplantation), the effect of native kidney RDN in hypertensive patients with a history of kidney transplantation remains unknown. The current study aims to provide novel insights on the safety and efficacy of RDN in this particular population. Adjustment for routine therapy adherence will also be performed as this proved to be an important confounding factor in previous research.

Official Title
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Safety and Efficacy of Ultrasound Renal Denervation in Kidney Transplantation Patients With Uncontrolled Hypertension: the RESTART Study

Conditions
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Hypertension, Kidney Transplantation

Intervention / Treatment
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* Device: Paradise® ultrasound renal denervation system.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years Kidney transplantation ≥ 12 months ago with stable immunosuppressive drug treatment Estimated Glomerular Filtration Rate (eGFR) ≥ 40 ml/min/1.73m2 Office systolic BP ≥ 140 mmHg and a mean 24-hour ambulatory systolic BP ≥ 130 mmHg at screening Antihypertensive medication regimen: Stable regimen of at least two antihypertensive drugs of different classes, including a diuretic (defined a thiazide diuretic, loop diuretic or mineralocorticoid receptor antagonist), for at least three months, or Documented intolerance to three classes of antihypertensive drugs, and A change in antihypertensive drug regimen is not anticipated within the oncoming three months. Patient is willing and able to provide written informed consent Exclusion Criteria: Native renal artery anatomy not eligible for RDN, defined as at least one of the following conditions: History of renal artery stenting or angioplasty History of renal denervation History of kidney tumors Renal artery diameter < 3 mm or > 8 mm Renal artery length < 20 mm Fibromuscular disease (FMD) of the native renal arteries Renal artery aneurysm Renal artery stenosis > 30% Presence of a remnant transplant kidney after re-transplantation or absence of native kidneys Solitary native kidney History of intravenous contrast dye allergy or nephropathy Iliac/femoral artery stenosis precluding insertion of the Paradise catheter Uncorrected, treatable secondary cause of hypertension Pregnancy Life expectancy < one year at the discretion of the investigator

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Renal sympathetic denervation<br> | Device: Paradise® ultrasound renal denervation system.<br>* Bilateral renal sympathetic denervation of the native kidneys using the Paradise® ultrasound renal denervation system.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: change in mean 24-hour ambulatory systolic blood pressure |  | Baseline vs. 3-month follow-up | 
| Safety: occurrence of the composite endpoint | Consisting of (whichever occurs first): All-cause mortality New onset (acute) end-stage renal disease (eGFR< 15 mL/min/m2 or need for renal replacement therapy) Significant embolic event resulting in end-organ damage Renal artery perforation requiring an invasive intervention Renal artery dissection requiring an invasive intervention Major vascular complications Hospitalization for hypertensive or hypotensive crisis | Baseline vs. 3-month follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy: change in mean 24-hour ambulatory diastolic blood pressure |  | Baseline vs. 3-month follow-up | 
| Efficacy: change in daytime ambulatory systolic and diastolic blood pressure |  | Baseline vs. 3-month follow-up | 
| Efficacy: change in nighttime ambulatory systolic and diastolic blood pressure |  | Baseline vs. 3-month follow-up | 
| Efficacy: change in office systolic and diastolic blood pressure |  | Baseline vs. 3-month follow-up | 
| Efficacy: changes in ambulatory (mean 24-hour, daytime, nighttime) systolic and diastolic blood pressure | In a subpopulation of patients with an equal level of therapy adherence at both timepoints | Baseline vs. 3-month follow-up | 
| Efficacy: changes in office systolic and diastolic blood pressure | In a subpopulation of patients with an equal level of therapy adherence at both timepoints | Baseline vs. 3-month follow-up | 
| Efficacy: changes in the number of prescribed defined daily dosages and number of classes of antihypertensive drugs |  | Baseline vs. 3-month follow-up | 
| Efficacy: change in the percentage therapy adherence | The percentage adherence will be calculated as the proportion of drugs that could be detected using dried blood spot testing out of all drugs prescribed to the patient at the time of the testing. | Baseline vs. 3-month follow-up | 
| Efficacy: annual changes in ambulatory (mean 24-hour, daytime, nighttime) systolic and diastolic blood pressure |  | Baseline up until and including 5-year follow-up | 
| Efficacy: annual changes in office systolic and diastolic blood pressure |  | Baseline up until and including 5-year follow-up | 
| Efficacy: annual changes in in the number of prescribed defined daily dosages and number of classes of antihypertensive drugs |  | Baseline up until and including 5-year follow-up | 
| Efficacy: annual change in the percentage therapy adherence | The percentage adherence will be calculated as the proportion of drugs that could be detected using dried blood spot testing out of all drugs prescribed to the patient at the time of the testing. | Baseline up until and including 5-year follow-up | 
| Safety: the number of patients in whom no successful bilateral renal denervation procedure can be performed | E.g. due to anatomical difficulties | Periprocedural | 
| Safety: change in renal function (estimated Glomerular Filtration Rate) |  | Baseline vs. 3-month follow-up | 
| Safety: change in renal function (urine protein/creatinine ratio) |  | Baseline vs. 3-month follow-up | 
| Safety: occurrence of the individual components of the primary safety outcome | All-cause mortality New onset (acute) end-stage renal disease (eGFR< 15 mL/min/m2 or need for renal replacement therapy) Significant embolic event resulting in end-organ damage Renal artery perforation requiring an invasive intervention Renal artery dissection requiring an invasive intervention Major vascular complications Hospitalization for hypertensive or hypotensive crisis | Baseline up until and including 5-year follow-up | 
| Safety: occurrence of any major adverse cardiovascular and cerebrovascular event (MACCE) | Including myocardial infarction, coronary revascularization, stroke and cardiovascular mortality | Baseline up until and including 5-year follow-up | 
| Safety: occurrence of the individual components of major adverse cardiovascular and cerebrovascular event (MACCE) | Including myocardial infarction, coronary revascularization, stroke and cardiovascular mortality | Baseline up until and including 5-year follow-up | 
| Safety: annual change in renal function (estimated Glomerular Filtration Rate) |  | Baseline up until and including 5-year follow-up | 
| Safety: annual change in renal function (urine protein/creatinine ratio) |  | Baseline up until and including 5-year follow-up |