Febuxostat, Blood Pressure and the Intrarenal Renin-Angiotensin System (RAS)
Condition: Hypertension
MeSH terms: Hypertension
Study type: Interventional
Phase: Phase 4

Summary: 
      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.
    

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.
    

Intervention name(s): Febuxostat; Placebo
Intervention type(s): Drug; Drug
Intervention MeSH terms: Febuxostat
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: uric acid; febuxostat; hypertension; intra-renal renin-angiotensin system; renal plasma flow; angiotensin II