Febuxostat, Blood Pressure and the Intrarenal Renin-Angiotensin System (RAS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Paul N. Hopkins, University of Utah
ClinicalTrials.gov Identifier:
NCT01328769
First received: March 29, 2011
Last updated: April 10, 2014
Last verified: February 2014
  Purpose

In this study the investigators will recruit hypertensive subjects with higher than average uric acid levels to test the effect of lowering uric acid with febuxostat on several measures as listed below. This will be a randomized, double-blind, placebo-controlled, parallel group study.

Primary Aim

1. To examine the effects of febuxostat on the activity of the intrarenal renin-angiotensin system as measured indirectly by renal plasma flow response to infused Ang II.

Secondary Aims

  1. To examine the effects of febuxostat on proximal and distal tubular sodium excretion as estimated by uric acid clearance and sodium clearance.
  2. To determine effects of febuxostat on endothelial function in hypertensive subjects with higher than average uric acid.
  3. To determine effect of febuxostat on blood pressure (by 24-hour ambulatory monitoring).

3. To examine the correlation between change in uric acid and changes in inflammatory markers including hsCRP and (optionally) other markers of endothelial activation including soluble ICAM-1, VCAM-1, and MCP-1.


Condition Intervention Phase
Hypertension
Drug: Febuxostat
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Febuxostat, Blood Pressure and the Intrarenal Renin-Angiotensin System (RAS)

Resource links provided by NLM:


Further study details as provided by University of Utah:

Primary Outcome Measures:
  • Change in renal plasma flow in response to infused angiotensin II [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in endothelial function [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Enrollment: 70
Study Start Date: March 2011
Study Completion Date: January 2014
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: Febuxostat Drug: Febuxostat
This will be a randomized, double-blind, placebo-controlled, parallel group trial. Baseline measurements will be performed initially off all antihypertensive medication and without study medication. Subjects will then be randomized to febuxostat or placebo, treated for 6 weeks, and baseline measurements will then be repeated to assess change from baseline.

  Hide Detailed Description

Detailed Description:

Persons with hypertension (HTN) often have higher uric acid than normotensives, especially in hypertensives with metabolic syndrome.1-5 Recent prospective studies also suggest that persons with higher uric acid are at greater risk to develop hypertension.4-7 Uric acid in childhood appears to be particularly predictive of both early-onset hypertension and blood pressure later in life.4, 5, 8 While many had considered elevated uric acid as merely a marker for increased renal sodium reabsorption, recent data suggests a potentially causal role. Rats made mildly hyperuricemic by treatment with the uricase inhibitor oxonic acid become hypertensive. The increase in blood pressure in these rats was blocked by administration of renin-angiotensin system (RAS) blockers or by reduction of uric acid with allopurinol.9 More recently, febuxostat was also shown effective in this experimental model.10 Febuxostat was recently approved by the FDA as Uloric. Febuxostat is a xanthine oxidase (XO) inhibitor (like the older drug allopurinol), and is indicated for the chronic management of hyperuricemia in patients with gout.

The investigators have reported a clear relationship between higher serum uric acid and increased intrarenal angiotensin II as assessed by intravenous angiotensin II (Ang II) infusions in human subjects.11 In this model, the change in renal blood flow in response to infused Ang II serves as an indirect indicator of renal vascular exposure to endogenous Ang II. In the setting of high endogenous intrarenal Ang II, renovascular AT1 receptors are down-regulated and the normal reduction in renal blood flow in response to infused exogenous Ang II becomes blunted. The investigators found that increased serum uric acid is strongly correlated to blunting of the normal response to infused Ang II. Other studies by our colleagues in Boston have demonstrated that treatment with ACE inhibitors or angiotensin receptor blockers restores normal responsiveness to infused Ang II in hypertensives with this blunted response and that such patients may be particularly responsive to RAS blockade.12-14 The studies in rats and our results with the association of uric acid suggest that elevated uric acid may cause an increase in intrarenal Ang II or otherwise interact with Ang II and thereby promote hypertension. In this study, the investigators propose to explore the causality of uric acid in affecting blood pressure and, importantly, to begin to explore the underlying mechanism of such a response using our unique protocol in human subjects.

Recent results from a randomized cross-over study of 30 hyperuricemic, hypertensive adolescents showed that allopurinol (200 mg twice daily) resulted in a significant reduction in blood pressure as compared with placebo.4, 15, 16 However, similar studies in adults are lacking and no study has provided insights into mechanisms whereby uric acid might raise blood pressure in humans. Endothelial dysfunction was consistently improved by allopurinol treatment in patients with congestive heart failure17, 18 and several other conditions.19 It would be of great scientific and clinical interest if a mechanistic role for uric acid in adult hypertension could be demonstrated. The investigators have a unique opportunity to examine uric acid as a contributor to overactivity of the intrarenal RAS and impaired nitric oxide production. The investigators hypothesize that hypertensives with elevated uric acid will experience a significant fall in uric acid in response to administration of febuxostat which will correlate with an improvement in vascular responses to infused Ang II, and improved endothelial function.

As part of the same protocol the investigators will be able to assess the effect of febuxostat on proximal and distal sodium clearance by using uric acid clearance as a surrogate for proximal tubular sodium absorption. Uric acid reabsorption is indirectly coupled to sodium reabsorption: anions enter proximal tubular cells via a sodium-coupled electroneutral system and anions are then exchanged for urate.20 Renal uric acid clearance is directly and closely correlated with renal lithium clearance, a well-validated measure of proximal tubular sodium reabsorption, and both clearances have been used to estimate proximal tubular sodium handling in large, population-based studies,21, 22 as well as to measure acute responses to, for example, insulin infusion,23 beta-blocker treatment,24 and volume expansion.20, 25 Other studies have found decreased proximal tubular uric acid or lithium clearance associated with a positive family history of hypertension26 and with an adducin gene variant associated with hypertension.27 In summary, the investigators will examine the effects of lowering uric acid with febuxostat on both intrarenal RAS activity as measured by renovascular response to Ang II infusion, and on proximal tubular sodium absorption as measured by uric acid clearance. Potential effects on endothelial function, arterial stiffness, and blood pressure will also be tested.

  Eligibility

Ages Eligible for Study:   18 Years to 60 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Mild to moderate hypertension. For purposes of this study, the investigators define mild to moderate hypertension as being on no more than 1-2 antihypertensive medications and blood pressure <140 mm Hg systolic and <90 mm Hg diastolic based on mean seated blood pressure at the screening visit in our clinic. For these visits, the investigators measure blood pressure using a Dinamap automatic oscillometric cuff while subjects are seated quietly. The subjects are left in a quiet room without speaking for 5 minutes initially. The Dinamap is started and the technician leaves the room and 3 blood pressures are obtained at intervals of 2 minutes. The investigators use the mean of last 2 blood pressures for classification purposes. This is the approach the investigators have used in several multicenter studies including HyperGEN and the NHLBI Family Heart Study.
  • Age 18 to 60.
  • Uric acid =5.8 mg/dl. This was the mean uric acid among hypertensives in our prior study.11 As renal plasma flow response to Ang II infusion decreased linearly with higher uric acid, the investigators felt that using higher than average uric acid will provide greater power.

Exclusion Criteria:

  • Severe or poorly controlled hypertension (treated blood pressure >160 mm Hg systolic or >100 mm Hg diastolic).
  • Diabetes (type 1 or type 2).
  • Estimated GFR <60 ml/min.
  • Persons unable stop all medications (including antihypertensives) other than stable doses of thyroxine or estrogen for at least 2 weeks.
  • Secondary hypertension.
  • Prior history of clinically diagnosed coronary artery disease or congestive heart failure.
  • Taking uric acid lowering medication within 1 month of screening visit.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01328769

Locations
United States, Utah
Cardiovascular Genetics, University of Utah
Salt Lake City, Utah, United States, 84108
Sponsors and Collaborators
University of Utah
Investigators
Principal Investigator: Paul N Hopkins Cardiovascular Genetics
  More Information

No publications provided

Responsible Party: Paul N. Hopkins, Professor of Internal Medicine, University of Utah
ClinicalTrials.gov Identifier: NCT01328769     History of Changes
Other Study ID Numbers: 42916
Study First Received: March 29, 2011
Last Updated: April 10, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by University of Utah:
uric acid
febuxostat
hypertension
intra-renal renin-angiotensin system
renal plasma flow
angiotensin II

Additional relevant MeSH terms:
Hypertension
Vascular Diseases
Cardiovascular Diseases
Febuxostat
Gout Suppressants
Antirheumatic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on September 18, 2014