Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients
Overview[ - collapse ][ - ]
| Purpose | 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 |
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| Condition | Hypertension Kidney Transplantation |
| Intervention | Drug: Nebivolol Drug: Metoprolol |
| Phase | Phase 1 |
| Sponsor | University of Florida |
| Responsible Party | University of Florida |
| ClinicalTrials.gov Identifier | NCT01157234 |
| First Received | July 2, 2010 |
| Last Updated | November 19, 2013 |
| Last verified | November 2013 |
Tracking Information[ + expand ][ + ]
| First Received Date | July 2, 2010 |
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| Last Updated Date | November 19, 2013 |
| Start Date | July 2010 |
| Estimated Primary Completion Date | July 2015 |
| Current Primary Outcome Measures | To determine the effect of nebivolol versus metoprolol on serum nitric oxide levels in hypertensive renal transplant patients [Time Frame: one year] [Designated as safety issue: No] |
| Current Secondary Outcome Measures |
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Descriptive Information[ + expand ][ + ]
| Brief Title | Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients |
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| Official Title | Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients |
| 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 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 |
| 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). |
| Study Type | Interventional |
| Study Phase | Phase 1 |
| Study Design | Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment |
| Condition |
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| Intervention | Drug: Nebivolol Nebivolol 5 mg once daily, titrated to a maximum total daily dose of 40 mg to achieve a blood pressure of < 140/ 90. Other Names: BystolicDrug: Metoprolol Metoprolol 25 mg twice daily, titrated to a maximum total daily dose of 400 mg to achieve a blood pressure < 140/90. Other Names: Lopressor |
| Study Arm (s) |
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Recruitment Information[ + expand ][ + ]
| Recruitment Status | Enrolling by invitation |
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| Estimated Enrollment | 50 |
| Estimated Completion Date | July 2015 |
| Estimated Primary Completion Date | July 2015 |
| 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 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 |
| Gender | Both |
| Ages | 18 Years |
| Accepts Healthy Volunteers | No |
| Contacts | Not Provided |
| Location Countries | United States |
Administrative Information[ + expand ][ + ]
| NCT Number | NCT01157234 |
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| Other Study ID Numbers | BYS-MD-42 |
| Has Data Monitoring Committee | No |
| Information Provided By | University of Florida |
| Study Sponsor | University of Florida |
| Collaborators | Forest Laboratories |
| Investigators | Principal Investigator: Alfonso Santos, MD University of Florida |
| Verification Date | November 2013 |
Locations[ + expand ][ + ]
| University of Florida | Gainesville, Florida, United States, 32610 |
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