Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients

Hypertension Clinical Trial

Official title:

Nebivolol Effect on Nitric Oxide Levels, Blood Pressure, and Renal Function in Kidney Transplant Patients

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01157234
• Other study ID #: BYS-MD-42
• Status: Completed
• Phase: Phase 1
• First received: July 2, 2010
• Last updated: February 3, 2015
• Start date: July 2010
• Est. completion date: July 2014

Study information

• Verified date: February 2015
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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

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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2014
• Est. primary completion date: July 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hypertension
• Kidney Transplantation

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.
• Metoprolol
Metoprolol 25 mg twice daily, titrated to a maximum total daily dose of 400 mg to achieve a blood pressure < 140/90.

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Forest Laboratories

Country where clinical trial is conducted

United States, 

References & Publications (21)

Brehm BR, Wolf SC, Bertsch D, Klaussner M, Wesselborg S, Schüler S, Schulze-Osthoff K. Effects of nebivolol on proliferation and apoptosis of human coronary artery smooth muscle and endothelial cells. Cardiovasc Res. 2001 Feb 1;49(2):430-9. — View Citation

Cheng JW. Nebivolol: a third-generation beta-blocker for hypertension. Clin Ther. 2009 Mar;31(3):447-62. doi: 10.1016/j.clinthera.2009.03.007. Review. — View Citation

Curtis JJ, Luke RG, Jones P, Diethelm AG. Hypertension in cyclosporine-treated renal transplant recipients is sodium dependent. Am J Med. 1988 Aug;85(2):134-8. — View Citation

Gandhi C, Zalawadia R, Balaraman R. Nebivolol reduces experimentally induced warm renal ischemia reperfusion injury in rats. Ren Fail. 2008;30(9):921-30. doi: 10.1080/08860220802353900. — View Citation

Georgescu A, Pluteanu F, Flonta ML, Badila E, Dorobantu M, Popov D. The cellular mechanisms involved in the vasodilator effect of nebivolol on the renal artery. Eur J Pharmacol. 2005 Jan 31;508(1-3):159-66. Epub 2005 Jan 7. — View Citation

Ignarro LJ. Experimental evidences of nitric oxide-dependent vasodilatory activity of nebivolol, a third-generation beta-blocker. Blood Press Suppl. 2004 Oct;1:2-16. Review. — View Citation

Kakoki M, Hirata Y, Hayakawa H, Nishimatsu H, Suzuki Y, Nagata D, Suzuki E, Kikuchi K, Nagano T, Omata M. Effects of vasodilatory beta-adrenoceptor antagonists on endothelium-derived nitric oxide release in rat kidney. Hypertension. 1999 Jan;33(1 Pt 2):467-71. — View Citation

Kamp O, Sieswerda GT, Visser CA. Comparison of effects on systolic and diastolic left ventricular function of nebivolol versus atenolol in patients with uncomplicated essential hypertension. Am J Cardiol. 2003 Aug 1;92(3):344-8. — View Citation

Koomans HA, Ligtenberg G. Mechanisms and consequences of arterial hypertension after renal transplantation. Transplantation. 2001 Sep 27;72(6 Suppl):S9-12. Review. — View Citation

Mangrella M, Rossi F, Fici F, Rossi F. Pharmacology of nebivolol. Pharmacol Res. 1998 Dec;38(6):419-31. Review. — View Citation

Ojo AO. Cardiovascular complications after renal transplantation and their prevention. Transplantation. 2006 Sep 15;82(5):603-11. Review. — View Citation

Opelz G, Wujciak T, Ritz E. Association of chronic kidney graft failure with recipient blood pressure. Collaborative Transplant Study. Kidney Int. 1998 Jan;53(1):217-22. — View Citation

Passauer J, Büssemaker E, Lassig G, Gross P. Kidney transplantation improves endothelium-dependent vasodilation in patients with endstage renal disease. Transplantation. 2003 Jun 15;75(11):1907-10. — View Citation

Pires MJ, Rodríguez-Peña AB, Arévalo M, Cenador B, Evangelista S, Esteller A, Sánchez-Rodríguez A, Colaço A, López-Novoa JM. Long-term nebivolol administration reduces renal fibrosis and prevents endothelial dysfunction in rats with hypertension induced by renal mass reduction. J Hypertens. 2007 Dec;25(12):2486-96. — View Citation

Schmidt RJ, Domico J, Samsell LS, Yokota S, Tracy TS, Sorkin MI, Engels K, Baylis C. Indices of activity of the nitric oxide system in hemodialysis patients. Am J Kidney Dis. 1999 Aug;34(2):228-34. — View Citation

Schmidt RJ, Yokota S, Tracy TS, Sorkin MI, Baylis C. Nitric oxide production is low in end-stage renal disease patients on peritoneal dialysis. Am J Physiol. 1999 May;276(5 Pt 2):F794-7. — View Citation

Schwenger V, Zeier M, Ritz E. Hypertension after renal transplantation. Ann Transplant. 2001;6(4):25-30. Review. — View Citation

Sharma SP. Nitric oxide and the kidney: Review. Indian Journal of Nephrology 2004;14: 77-84.

Uzun H, Konukoglu D, Besler M, Erdenen F, Sezgin C, Muderrisoglu C. The effects of renal replacement therapy on plasma, asymmetric dimethylarginine, nitric oxide and C-reactive protein levels. Clin Invest Med. 2008;31(1):E1-7. — View Citation

Veenstra DL, Best JH, Hornberger J, Sullivan SD, Hricik DE. Incidence and long-term cost of steroid-related side effects after renal transplantation. Am J Kidney Dis. 1999 May;33(5):829-39. — View Citation

Zhang W, Zhou C, Xie J, Chen B, Chang L. Serum asymmetric dimethylarginine and endothelial function after renal transplantation. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2009 Apr;34(4):289-94. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	To determine the effect of nebivolol versus metoprolol on serum nitric oxide levels in hypertensive renal transplant patients		one year	No
Secondary	To determine the effect of nebivolol versus metoprolol on markers for oxidative stress.		One Year	No
Secondary	To determine the effect of nebivolol versus metoprolol on renal function in hypertensive renal transplant patients.		One Year	No
Secondary	To determine the effect of nebivolol versus metoprolol on blood pressure control in hypertensive renal transplant patients.		One Year	No