Hydrochlorothiazide (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.

What 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

While 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

Complicating 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.

References:

1. Haas M.  The Na-K-Cl cotransporters.  Am J Physiol  1994;267:C869-C885.  
2. The 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. 
3. Rosendorff 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.  
4. Mount DB.  Molecular physiology and the four-component model of renal urate transport.  Curr Opin Nephrol Hypertens  2005;14:460-3.  
5. Rafey MA, Lipkowitz MS, Leal-Pinto E et al.  Uric acid transport.  Curr Opin Nephrol Hypertens  2003;12:511-6.  
6. Srimaroeng C, Perry JL, Pritchard JB.  Physiology, structure, and regulation of the cloned organic anion transporters.  Xenobiotica  2008;38:889-935. 
7. Hasannejad H, Takeda M, Taki K et al.  Interactions of human organic anion transporters with diuretics.  J Pharmacol Exp Ther  2004;308:1021-9.  
8. Gurwitz JH, Kalish SC, Bohn RL et al.  Thiazide diuretics and the initiation of anti-gout therapy.  J Clin Epidemiol 1997;50:953-9.  
9. Staessen 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.  
10. Reyes AJ.  Cardiovascular drugs and serum uric acid.  Cardiovasc Drugs Ther  2003;17:397-414.  
11. Savage 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.  
12. Carlsen JE, Kober L, Torp-Pedersen C.  Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects.  BMJ  1990;300:975-8.

Hydrochlorothiazide, HCTZ, Thiazide Diuretic, Uric Acid, Gout, Hyperuricemia, Thiazide Induced Gout