(HCTZ) is a thiazide diuretic that, at least initially, exerts its
antihypertensive effect by inhibiting the Na+-Cl- cotransporter on the
luminal (apical) side of the distal tubule in the kidney.1 Numerous
clinical trials and practice guidelines support the use of thiazide diuretics
as first line or add-on therapy for hypertension in a broad range of patients.2,3
In addition to its demonstrated benefit, HCTZ is well tolerated and
contraindications or warnings against its use are few. As such, HCTZ
remains one of the most widely prescribed antihypertensives available in the
United States. One clinical scenario in which the use of HCTZ must
be carefully considered is the patient with hyperuricemia or gout.
is the mechanism by which HCTZ impairs uric acid excretion?
Serum uric acid concentration is largely controlled by multiple transporters in
the proximal tubule in the kidney.4
These include organic anion transporter 1 (OAT1) and urate/anion exchanger 1
(URAT1).4,5 Organic anion transporter 1 is responsible for the movement
of organic acid compounds into the renal proximal tubule cells from the
peritubular space (blood).6 Uric acid, as well as a number of other
naturally occurring organic acids, also utilize this transporter. In
addition, OAT1 appears to be particularly active in the transport of
medications that are recognized as organic acids, including HCTZ.7
there are multiple mechanisms for uric acid entry into proximal tubule cells,
competition between HCTZ and uric acid for transport via OAT1 at least
partially explains an increase in uric acid concentration when HCTZ is
initiated and again when the dose is increased.7 Another plausible contribution to increased
serum uric acid concentration involves URAT1 on the luminal side of the renal
proximal tubule cell.4,5 As suggested by its name, URAT1 is
responsible for moving uric acid intracellularly from the renal filtrate in
exchange for organic acid.4,5 As mentioned previously, HCTZ is recognized
as an organic acid and thus serves as a substrate for this exchange.
Greater availability of organic acid (HCTZ in this case) results in more uric
acid being transported back into the cell from the renal filtrate and
potentially reabsorbed into the blood. Again, this scenario is most
likely to present itself shortly after HCTZ initiation or an increase in the
dose. Any one or combination of the above mechanisms can put certain
patients at increased risk for hyperuricemia and/or acute gout exacerbation.8,9
these explanations are a number of inter-patient variabilities. Diet is
often a key factor in patients with hyperuricemia and/or gout. Patients
are often counseled to reduce purine intake from meats, vegetables and
alcohol. In addition, a number of polymorphisms exist in the transporters
involved in uric acid and HCTZ movement into and out of the renal proximal
tubule cells.6 It has also been hypothesized that additional transporters
or channels and polymorphisms likely exist and may have an effect on the
mechanisms described above. As previously described, the dose of thiazide
used and concomitant medications may impact the development of hyperuricemia or
an acute gout exacerbation.10-12 Thus, there are a number of reasons why
some patients experience the hyperuricemic effects of HCTZ while others do not.
- Haas M. The Na-K-Cl cotransporters. Am J Physiol 1994;267:C869-C885.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research
Group. Major Outcomes in High-Risk Hypertensive Patients Randomized to
Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs
Diuretic The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:2981-2997.
C, Black HR, Cannon CP, et. al. Treatment of Hypertension in the
Prevention and Management of Ischemic Heart Disease: A Scientific
Statement from the American Heart Association Council for High Blood
Pressure Research and the Councils on Clinical Cardiology and
Epidemiology and Prevention. Circulation. 2007;115:2761-2788.
DB. Molecular physiology and the four-component model of renal urate
transport. Curr Opin Nephrol Hypertens 2005;14:460-3.
- Rafey MA, Lipkowitz MS, Leal-Pinto E et al. Uric acid transport. Curr Opin Nephrol Hypertens 2003;12:511-6.
C, Perry JL, Pritchard JB. Physiology, structure, and regulation of
the cloned organic anion transporters. Xenobiotica 2008;38:889-935.
H, Takeda M, Taki K et al. Interactions of human organic anion
transporters with diuretics. J Pharmacol Exp Ther 2004;308:1021-9.
JH, Kalish SC, Bohn RL et al. Thiazide diuretics and the initiation of
anti-gout therapy. J Clin Epidemiol 1997;50:953-9.
J. The determinants and prognostic significance of serum uric acid in
elderly patients of the European Working Party on High Blood Pressure in
the Elderly trial. Am J Med 1991;90:50S-54S.
- Reyes AJ. Cardiovascular drugs and serum uric acid. Cardiovasc Drugs Ther 2003;17:397-414.
PJ, Pressel SL, Curb JD et al. Influence of long-term, low-dose,
diuretic-based, antihypertensive therapy on glucose, lipid, uric acid,
and potassium levels in older men and women with isolated systolic
hypertension: The Systolic Hypertension in the Elderly Program. SHEP
Cooperative Research Group. Arch Intern Med 1998;158:741-51.
JE, Kober L, Torp-Pedersen C. Relation between dose of bendrofluazide,
antihypertensive effect, and adverse biochemical effects. BMJ