Diuretic-induced hyperuricemia and gout
- Michael A Becker, MD
Michael A Becker, MD
- Section Editor — Crystal Diseases
- Professor of Medicine
- Pritzker School of Medicine of the University of Chicago
Hyperuricemia is a relatively common finding in patients treated with a loop or thiazide diuretic and may, over a period of time, lead to gouty arthritis [1-4]. Diuretics reduce urate excretion by both directly and indirectly increasing urate reabsorption and decreasing urate secretion [2,5-7]; the effect is dose dependent (figure 1). Treatment of asymptomatic hyperuricemia is not necessary. If diuretic-induced gout occurs, it is usually treated with a urate-lowering drug such as allopurinol.
The pathogenesis, epidemiology, and an overview of treatment of diuretic-induced hyperuricemia and gout are presented in this topic. The pathophysiology, clinical manifestations, diagnosis, and treatment of acute gouty arthritis as well as the prevention of recurrent gout are discussed separately. (See "Pathophysiology of gouty arthritis" and "Clinical manifestations and diagnosis of gout" and "Treatment of acute gout" and "Prevention of recurrent gout".)
The proximal tubule is the major site of urate handling; both secretion and reabsorption occur in this segment, with the net effect being reabsorption of most of the filtered urate (figure 2 and figure 3) [2,8-15]. Urate enters the proximal tubular cell from peritubular capillary blood through organic anion transporters 1 and 3 (OAT1 and OAT3) located on the basolateral membrane, and is secreted from the cell into the tubular fluid through solute carrier (SLC) family members SLC17A1 and SLC17A3, multidrug resistance protein 4 (MRP4), and ATP-binding cassette G2 (ABCG2) located on the luminal membrane. Urate reabsorption from the tubular fluid into the cell is mediated by urate transporter 1 (URAT1), OAT4, and OAT10, located on the luminal membrane, and from the cell back to the peritubular capillary blood through glucose transporter 9 (GLUT9) located on the basolateral membrane.
Loop and thiazide diuretics decrease urate excretion by increasing net urate reabsorption; this can occur either by enhanced reabsorption or by reduced secretion [2,5]. Two mechanisms have been proposed as contributing to diuretic-induced hyperuricemia [2,5-7]:
●A direct effect of diuretics on promoting urate reabsorption by the proximal tubule
- Langford HG, Blaufox MD, Borhani NO, et al. Is thiazide-produced uric acid elevation harmful? Analysis of data from the Hypertension Detection and Follow-up Program. Arch Intern Med 1987; 147:645.
- Kahn AM. Effect of diuretics on the renal handling of urate. Semin Nephrol 1988; 8:305.
- Choi HK, Atkinson K, Karlson EW, Curhan G. Obesity, weight change, hypertension, diuretic use, and risk of gout in men: the health professionals follow-up study. Arch Intern Med 2005; 165:742.
- Choi HK, Soriano LC, Zhang Y, Rodríguez LA. Antihypertensive drugs and risk of incident gout among patients with hypertension: population based case-control study. BMJ 2012; 344:d8190.
- Weinman EJ, Eknoyan G, Suki WN. The influence of the extracellular fluid volume on the tubular reabsorption of uric acid. J Clin Invest 1975; 55:283.
- Hagos Y, Stein D, Ugele B, et al. Human renal organic anion transporter 4 operates as an asymmetric urate transporter. J Am Soc Nephrol 2007; 18:430.
- El-Sheikh AA, van den Heuvel JJ, Koenderink JB, Russel FG. Effect of hypouricaemic and hyperuricaemic drugs on the renal urate efflux transporter, multidrug resistance protein 4. Br J Pharmacol 2008; 155:1066.
- Enomoto A, Kimura H, Chairoungdua A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature 2002; 417:447.
- Dalbeth N, Merriman T. Crystal ball gazing: new therapeutic targets for hyperuricaemia and gout. Rheumatology (Oxford) 2009; 48:222.
- Hosomi A, Nakanishi T, Fujita T, Tamai I. Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2. PLoS One 2012; 7:e30456.
- Iharada M, Miyaji T, Fujimoto T, et al. Type 1 sodium-dependent phosphate transporter (SLC17A1 Protein) is a Cl(-)-dependent urate exporter. J Biol Chem 2010; 285:26107.
- Jutabha P, Anzai N, Kitamura K, et al. Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate. J Biol Chem 2010; 285:35123.
- Russel FG, Koenderink JB, Masereeuw R. Multidrug resistance protein 4 (MRP4/ABCC4): a versatile efflux transporter for drugs and signalling molecules. Trends Pharmacol Sci 2008; 29:200.
- Eraly SA, Vallon V, Rieg T, et al. Multiple organic anion transporters contribute to net renal excretion of uric acid. Physiol Genomics 2008; 33:180.
- Caulfield MJ, Munroe PB, O'Neill D, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 2008; 5:e197.
- Carlsen JE, Køber L, Torp-Pedersen C, Johansen P. Relation between dose of bendrofluazide, antihypertensive effect, and adverse biochemical effects. BMJ 1990; 300:975.
- Nijenhuis T, Vallon V, van der Kemp AW, et al. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115:1651.
- Steele TH, Oppenheimer S. Factors affecting urate excretion following diuretic administration in man. Am J Med 1969; 47:564.
- Page LB, Damon A, Moellering RC Jr. Antecedents of cardiovascular disease in six Solomon Islands societies. Circulation 1974; 49:1132.
- Egan BM, Lackland DT. Biochemical and metabolic effects of very-low-salt diets. Am J Med Sci 2000; 320:233.
- Masugi F, Ogihara T, Hashizume K, et al. Changes in plasma lipids and uric acid with sodium loading and sodium depletion in patients with essential hypertension. J Hum Hypertens 1988; 1:293.
- Del Río A, Rodríguez-Villamil JL. Metabolic effects of strict salt restriction in essential hypertensive patients. J Intern Med 1993; 233:409.
- Skrabal F, Auböck J, Hörtnagl H. Low sodium/high potassium diet for prevention of hypertension: probable mechanisms of action. Lancet 1981; 2:895.
- Ruppert M, Diehl J, Kolloch R, et al. Short-term dietary sodium restriction increases serum lipids and insulin in salt-sensitive and salt-resistant normotensive adults. Klin Wochenschr 1991; 69 Suppl 25:51.
- Kahn AM. Indirect coupling between sodium and urate transport in the proximal tubule. Kidney Int 1989; 36:378.
- Cogan MG. Angiotensin II: a powerful controller of sodium transport in the early proximal tubule. Hypertension 1990; 15:451.
- Bruderer S, Bodmer M, Jick SS, Meier CR. Use of diuretics and risk of incident gout: a population-based case-control study. Arthritis Rheumatol 2014; 66:185.
- Hunter DJ, York M, Chaisson CE, et al. Recent diuretic use and the risk of recurrent gout attacks: the online case-crossover gout study. J Rheumatol 2006; 33:1341.
- Janssens HJ, van de Lisdonk EH, Janssen M, et al. Gout, not induced by diuretics? A case-control study from primary care. Ann Rheum Dis 2006; 65:1080.
- Liang MH, Fries JF. Asymptomatic hyperuricemia: the case for conservative management. Ann Intern Med 1978; 88:666.
- Hande KR, Noone RM, Stone WJ. Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 1984; 76:47.
- Stamp LK, O'Donnell JL, Zhang M, et al. Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum 2011; 63:412.
- Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res (Hoboken) 2012; 64:1431.
- Weinberger MH. Influence of an angiotensin converting-enzyme inhibitor on diuretic-induced metabolic effects in hypertension. Hypertension 1983; 5:III132.
- Shahinfar S, Simpson RL, Carides AD, et al. Safety of losartan in hypertensive patients with thiazide-induced hyperuricemia. Kidney Int 1999; 56:1879.
- Soffer BA, Wright JT Jr, Pratt JH, et al. Effects of losartan on a background of hydrochlorothiazide in patients with hypertension. Hypertension 1995; 26:112.
- Manolis AJ, Grossman E, Jelakovic B, et al. Effects of losartan and candesartan monotherapy and losartan/hydrochlorothiazide combination therapy in patients with mild to moderate hypertension. Losartan Trial Investigators. Clin Ther 2000; 22:1186.
- Tikkanen I, Omvik P, Jensen HA. Comparison of the angiotensin II antagonist losartan with the angiotensin converting enzyme inhibitor enalapril in patients with essential hypertension. J Hypertens 1995; 13:1343.
- Würzner G, Gerster JC, Chiolero A, et al. Comparative effects of losartan and irbesartan on serum uric acid in hypertensive patients with hyperuricaemia and gout. J Hypertens 2001; 19:1855.