Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
Information source: University of Florida
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Hypertension; Kidney Transplantation
Intervention: Nebivolol (Drug); Metoprolol (Drug)
Phase: Phase 1
Status: Completed
Sponsored by: University of Florida Official(s) and/or principal investigator(s): Alfonso Santos, MD, Principal Investigator, Affiliation: University of Florida
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 SNS activation and decreased prostaglandin and nitric oxide production.
Hypotheses:
1. Nebivolol is more beneficial than metoprolol in favorably affecting markers of
oxidative stress in hypertensive renal transplant patients.
2. Nebivolol has a better impact than metoprolol on kidney function among hypertensive
renal transplant patients
Clinical Details
Official title: Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: To determine the effect of nebivolol versus metoprolol on serum nitric oxide levels in hypertensive renal transplant patients
Secondary outcome: To determine the effect of nebivolol versus metoprolol on markers for oxidative stress.To determine the effect of nebivolol versus metoprolol on renal function in hypertensive renal transplant patients. To determine the effect of nebivolol versus metoprolol on blood pressure control in hypertensive renal transplant patients.
Detailed description:
Nitric Oxide (NO) otherwise called endothelial derived relaxing factor (EDRF), is a potent
vasodilator with myriad of protective effects in the endothelium. Deficiency of NO has been
associated with diseases of circulation and vasculature. It is deficient in states of
oxidative stress. It is a potent vasodilator with anti-thrombotic, anti-inflammatory,
anti-proliferative, and anti-oxidative properties. NO plays a plethora of functions in the
kidney including vascular and hemodynamic regulation, fluid and electrolyte transport, and
is believed to be 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 of renal
failure. NO has been shown to be deficient in ESRD patients on hemodialysis and peritoneal
dialysis together with its precursor substrate L-arginine, while ADMA which inhibits NOS, is
elevated.
It is hypothesized that deficient NO is a significant contributor to hypertension in ESRD
patients that is resistant to multiple antihypertensive agents and volume removal. Total NO
generation is less in hypertensive patients with ESRD undergoing hemodialysis versus
normotensive controls.
It has been shown that kidney transplantation improves endothelium-dependent vasodilation
in patients with ESRD and that the activities of nitric oxide and glutathione peroxidase
increased significantly after transplantation. However around 80%- 90% of kidney
transplant patients have hypertension.
In the collaborative transplant study, elevation in blood pressure was implicated in
increased renal allograft failure and mortality. Also the calcineurin inhibitors used as
maintenance immunosuppression are large contributors to post transplant BP elevation,
although studies have shown a lesser incidence of de novo or escalating hypertension in
tacrolimus against cyclosporine-treated patients. The mechanisms by which calcineurin
inhibitors cause hypertension include: SNS and RAAS activation causing intense afferent
arteriolar vasoconstriction , reduction in vasodilator prostaglandins and nitric oxide and
elaboration of vasoconstrictor cytokines. The sodium and water retaining effects of steroid
therapy aggravate post-transplant hypertension.
There are no randomized clinical trials of antihypertensive drugs and optimal blood pressure
goals in kidney transplant recipients. Extrapolating from large clinical trials in
non-transplant patients, the National Kidney Foundation guidelines recommend blood pressure
goals of 125/75 mm for renal transplant recipients with proteinuria and 130/85 mm in the
absence of proteinuria. There is no consensus on the specific drugs to use among transplant
patients. Considerations in choosing a BP regimen include potential drug interactions,
co-morbidities, renal function, and drug efficacy.
Nebivolol, is a third generation B1-selective B-blocker believed to have comparable
BP-lowering effect as other B-blockers, ACE-inhibitors, the ARB (telmisartan), and calcium
channel blockers. Nebivolol ameliorates hypertension by increasing NO release. Thus, it
has BP lowering mechanism other than its B1-blocking property i. e., it promotes arterial
and venous vasodilatation. As an antihypertensive, it has been shown to reduce peripheral
resistance and preserve cardiac output better than atenolol. In comparison to propranolol
and metoprolol, nebivolol inhibits cell proliferation of human coronary smooth muscle cells
and endothelial cells and moderated the apoptosis rate with concomitant increase in NO
formation and decrease endothelin secretion in human endothelial cells. Nebivolol may also
help in preventing vascular thrombosis by virtue of its inhibition of ADP and
collagen-induced aggregation of human platelets.
To date the only published study on nebivolol in renal transplant is on reduction of
experimentally induced warm ischemia reperfusion injury in rats. Animal studies had
elucidated the cellular mechanisms of the vasodilator effect of nebivolol on renal artery.
Another study in rat kidneys showed that infusion of vasodilatory B-adrenoreceptor
antagonists which included nebivolol caused a dose- dependent reduction in renal perfusion
pressure and increase in NO release with vasodilation of renal vasculature. These effects
were not seen in other B-blockers like propranolol or bisoprolol. Finally, studies in
animals with surgically reduced 5/6 renal mass showed that while nebivolol and atenolol
both reduced arterial pressures, those receiving nebivolol had lower levels of collagen
type 1 expression and less glomerular and interstitial fibrosis. The indicators of
oxidative stress were lower in animals that received nebivolol compared to those treated
with atenolol.
In this study the blood pressure effect of nebivolol will be compared to metoprolol. Both
drugs possess known SNS inhibitory effect but only nebivolol is known to have a significant
NO releasing effect. Likewise, the effects of the two drugs on measures of oxidative stress
and renal function will be compared. Specific measures will be: serum levels of NOx (the
stable oxidation products of NO), L-arginine (NO precursor), ADMA (NO inhibitor), and serum
creatinine (as measure of graft kidney function).
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
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 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 SBP > 210 or DBP > 120 mm Hg.
- Symptomatic hypotension
- Previous intolerance to beta blockers
- Cerebrovascular accident within 3 months of randomization
Locations and Contacts
University of Florida, Gainesville, Florida 32610, United States
Additional Information
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Starting date: July 2010
Last updated: February 3, 2015
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