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

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.

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.