Clinical trial NCT01157234: Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
Official title: Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypertension
Keywords: Hypertension
Kidney transplantation
Renal function
Nitric Oxide
Nebivolol
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: Forest Laboratories
First posted: 2010-07-05
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will investigate the blood pressure lowering efficacy of nebivolol among renal transplant recipients who are on calcineurin inhibitors which are believed to contribute to hypertension by sympathetic nervous system (SNS) activation and decreased prostaglandin and nitric oxide production. Hypotheses:

1. There is a significant difference in the effect of 12 months of Nebivolol versus Metoprolol treatment on the plasma nitric oxide level of hypertensive renal transplant patients.
2. There is a significant difference in the effect of 12 months of Nebivolol versus Metoprolol treatment on the estimated glomerular filtration rate of hypertensive renal transplant patients.
3. There is a significant difference in the effect of 12 months of Nebivolol versus Metoprolol treatment on the systolic, diastolic and mean arterial blood pressures of hypertensive renal transplant patients.

Detailed description: Nitric Oxide (NO) plays a plethora of functions in the kidney including vascular and hemodynamic regulation, fluid and electrolyte transport, and is an important component of pressure natriuresis and tubule-glomerular feedback.

Deficient NO levels have been associated with oxidative stress in conditions like hypertension, diabetes mellitus, and cardiovascular disease. NO deficiency has been identified in states of chronic progressive renal disease and altered NO production and/or decreased bioavailability is believed to characterize the endothelial dysfunction and resistant hypertension of renal failure.

It has been shown that kidney transplantation improves endothelium-dependent vasodilation in patients with end-stage renal disease (ESRD) and the NO activity significantly increases after transplantation. However, calcineurin inhibitor drugs used in the anti-rejection regimen can reduce endothelial NO production and aggravate hypertension through vascular and renal mechanisms. In turn, uncontrolled elevation in blood pressure has been associated with increased renal allograft failure and post-transplant mortality.

In the absence of randomized clinical trials of antihypertensive drugs and optimal blood pressure goals in kidney transplant recipients. There is no scientifically-robust consensus on the specific drugs to use among transplant patients. Nebivolol, is a third generation B1-selective B-blocker shown to have similar BP-lowering effect as other B-blockers, angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor blocker (ARB) drugs, and calcium channel blockers. Nebivolol ameliorates hypertension by increasing NO release, promoting arterial and venous vasodilatation and beta-blockade. Nebivolol has beneficial effect on the kidney allograft. Studies in animal transplants have shown that nebivolol could reduce ischemia-induced reperfusion injury, alleviate renal perfusion pressure and increase NO release with associated vasodilation of the renal vasculature. These effects have not been seen with older generation B-blockers like propranolol or bisoprolol. Finally, in surgically reduced renal mass, nebivolol has been demonstrated to attenuate collagen type 1 expression with lessening of glomerular and interstitial fibrosis.

In this study, the effect of nebivolol and metoprolol on the change in NO level at baseline and at the 12th month of treatment will be compared. Similarly,the effects of the two drugs on the change in renal function, blood pressure, and blood pressure regimen from baseline to month-12 of treatment will also be compared.

Eligibility criteria: Inclusion Criteria:

* Men or women at least 18 years of age who are recipients of - a solitary kidney or combined kidney-pancreas transplant within the last twenty four months
* Current diagnosis of hypertension
* Normal hepatic enzymes
* Estimated creatinine clearance (by cockcroft-gault formula) \>or= 30 ml/min

Exclusion Criteria:

* Any contraindication to taking beta-blockers, specifically Nebivolol or Metoprolol. Conditions such as : (bradycardia heart rate (HR) \<60 beats per minute , heart block \> 1st degree, decompensated cardiac failure, sick sinus syndrome (unless permanent pacemaker in place), severe hepatic impairment( defined as elevation of aspartamine aminotransferase , alanine aminotransferase, or bilirubin levels to three times upper limit of normal reference range), severe peripheral arterial circulatory disorder, history of bronchospasm and /or asthma and /or regular medication with inhaled bronchodilators. or , or any medical condition that in the opinion of the investigator may interfere with the subject's ability to successfully complete the protocol.
* Any medical condition which, in the opinion of the Principal Investigator, might compromise the safety of the subject in participating in the protocol such as hypotension or not requiring antihypertensive medications.
* Any serious systemic disease that might complicate management and reduce life expectancy.
* Uncontrolled hypertension defined as systolic blood pressure (SBP) \> 210 or diastolic blood pressure (DBP) \> 120 mm Hg.
* Symptomatic hypotension
* Previous intolerance to beta blockers
* Cerebrovascular accident within 3 months of randomization

Primary outcomes:
measure: Plasma Nitric Oxide Level Change From Baseline to Month 12 Between the Groups.
timeFrame: Change in Baseline, Month-12
Secondary outcomes:
measure: Estimated Glomerular Filtration Rate (ml/Minute) Change From Baseline to Month-12 Between the Groups
timeFrame: Change in Baseline, Month-12
measure: Systolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 of Treatment Between the Groups
timeFrame: Change in Baseline, Month-12
measure: Diastolic Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups
timeFrame: Change in Baseline, Month-12
measure: Mean Arterial Blood Pressure (Millimeter, Mercury) Change From Baseline to Month-12 Between the Groups
timeFrame: Change in Baseline, Month-12
measure: Number of Antihypertensive Drug Classes Change From Baseline to Month-12 Between the Groups.
timeFrame: Change in Baseline, Month-12
measure: Plasma Asymmetric Dimethylarginine (ADMA) Change From Baseline to Month 12 Between the Groups
timeFrame: Baseline, Month-12
measure: Plasma Arginine (ARG) Level Change From Baseline to Month-12 Between Groups
timeFrame: Baseline, Month-12
Other outcomes:
measure: Plasma Nitric Oxide Level (Nmol/L) at Month-12 Between the Groups.
timeFrame: 12 Months
Locations:
city: Gainesville
country: United States
facility: University of Florida
state: Florida
Study officials:
affiliation: University of Florida
name: Alfonso Santos, MD
role: PRINCIPAL_INVESTIGATOR
References:
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