Nebivolol Versus Sustained Release Metoprolol Succinate in Patients With Chronic Kidney Disease
Condition: Chronic Kidney Disease
MeSH terms: Kidney Diseases; Renal Insufficiency, Chronic
Study type: Observational

Summary: 
      The investigators postulate that nebivolol will be more effective than an equivalent dose of
      a comparative BB, specifically sustained release metoprolol succinate, in improving the
      availability of NO, lowering blood pressure, and reducing albuminuria with implications for
      slowing progression of CKD and cardiovascular protection in this high risk population.

      The objective of this proposal is to conduct a randomized pilot clinical trial to determine
      the relative efficacy and tolerability of nebivolol versus sustained release metoprolol
      succinate in improving blood pressure in patients with CKD and albuminuria. The primary
      endpoint would be a decrease in asymmetric dimethyl arginine (ADMA). Secondary endpoints
      would include a reduction in blood pressure, urinary F2-isoprostanes and albuminuria.
    

Detailed description: 
      Patients with chronic kidney disease (CKD) are at an increased risk of mortality related to
      cardiovascular (CV) disease compared with the general population. Furthermore, a reduced
      glomerular filtration rate (GFR), defined as < 60 ml/min/1.73m², has been shown to be
      associated with increased risk of hospitalization, death and cardiovascular events
      independent of other known cardiovascular risk factors.

      Albuminuria, a marker of endothelial dysfunction or kidney damage, or both, frequently
      accompanies a reduction in GFR during the development of CKD, and is a well-recognized risk
      factor for kidney disease progression. Importantly, the presence of albuminuria has also been
      shown to be a powerful predictor of CV mortality independent of other risk factors.

      Endothelial dysfunction has been implicated in the pathophysiology of progressive renal
      disease and may be a link between CKD and CV mortality. Levels of asymmetric dimethyl
      arginine (ADMA), a competitive inhibitor of nitric oxide synthase, are elevated in patients
      with CKD. Elevated levels of ADMA have been shown to correlate with the presence of
      endothelial dysfunction and to predict mortality in patients with CKD. In addition, ADMA has
      been shown to be associated with progression of non-diabetic kidney disease and lowering ADMA
      levels could potentially prevent progressive renal impairment.

      Oxidative stress also plays a fundamental role in the development of endothelial function and
      cardiovascular disease. While markers of oxidative stress are notoriously difficult to
      measure, F2- isoprostanes are considered to be reliable biomarkers of in vivo lipid
      peroxidation. F2-isoprostanes are a family of prostaglandin F2 isomers produced by free
      radical peroxidation of arachidonic acid and have been used as end points in clinical studies
      of anti-oxidant therapies.

      Blood pressure control is an important factor in predicting CV mortality. However, in
      patients with CKD, blood pressure is frequently difficult to control. Angiotensin converting
      enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) with or without
      diuretics, are the antihypertensive agents of choice in patients with CKD. More recently, the
      combination of an ACEI and a dihydropyridine calcium channel blocker (CCB) have been shown to
      be more effective than an ACEI and a thiazide diuretic in controlling blood pressure in
      patients with essential hypertension including those with CKD or diabetes mellitus. However,
      even with this combination of medications, blood pressure control in patients with CKD is
      often difficult to achieve. The effect of beta adrenergic blocking agents (BB) on lowering
      blood pressure has not been extensively investigated in patients with CKD. A randomized
      control trial in hemodialysis patients from Italy showed that there was a higher two-year
      survival in those receiving carvedilol. Beta blockers are not routinely used to lower blood
      pressure in patients with CKD due to the possibility that these medications may have a
      deleterious effect on insulin resistance, although this theory has been disproved in a large
      clinical trial. A recent review points out that beta blockers are underused in patients with
      CKD although they offer many potential benefits in this patient population. This is not
      surprising, as sympathetic overactivity is an important contributor to cardiovascular disease
      and propensity to sudden death in patients with CKD. However, despite the potential benefits
      of BBs in patients with CKD their use remains limited because of the potential for inducing a
      relatively high rate of adverse effects and the lack of data in regard to their effectiveness
      in patients with CKD.

      The recent availability of the third generation beta blocker nebivolol, known to improve the
      availability of nitric oxide by reducing ADMA levels, thereby improving endothelial function,
      provides an opportunity to more effectively control blood pressure, prevent the progression
      of CKD, and also the occurrence of CV events. A reduction in the bioavailability of nitric
      oxide (NO) has been shown to play a significant role in both endothelial dysfunction and
      hypertension. Therefore, increasing the availability of nitric oxide can potentially be very
      beneficial. In a comparative study in patients with diabetes mellitus a trial of nebivolol
      versus metoprolol showed that metoprolol raised ADMA levels, suggesting a worsening of
      endothelial function, whereas nebivolol did not have this effect. Thus, nebivolol would
      appear to have a major advantage over other BBs in patients CKD due to diabetes mellitus or
      hypertension although this has not yet been systematically studied.
    

Observational model: Cohort
Time perspective: Prospective
Sampling method: Probability Sample
Study population: 
        A total of 50 patients with CKD meeting the inclusion and exclusion criteria listed below
        will after informed consent be randomized to either nebivolol or sustained release
        metoprolol succinate and followed for 3 months or early termination of the study.
      
Biospecimen description: 
      A total of 30 ml blood (CBC with differential and platelets-3ml, comprehensive panel-5-7ml,
      biomarkers-20ml) will be drawn by venipuncture typically from the antecubital vein at
      baseline visit (30ml), and week 6-study midpoint (30ml) and end of study (30ml). At the
      screening visit only 10ml blood will be required (CBC and Comprehensive Panel).