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Hypouricemia: Causes and clinical significance


Hypouricemia is arbitrarily defined as a serum urate concentration of less than 2 mg/dL (119 micromol/L). It occurs in about 2 percent of hospitalized patients and less than 0.5 percent of the normal population [1]. Hypouricemia may be caused by decreased uric acid production, uric acid oxidation due to treatment with uricase, or decreased renal tubular reabsorption due to inherited or acquired disorders [2]. There are no known abnormalities of intestinal uricolysis that produce hypouricemia. (See "Uric acid balance".)

Hypouricemia has been thought of as a biochemical disorder with no clinical significance other than as a marker of underlying disease [3]. However, individuals with renal tubular urate wasting may have an increased incidence of acute kidney injury (previously called acute renal failure). (See "Definition of acute kidney injury (acute renal failure)".)


Decreased uric acid production can be caused by several rare inherited disorders of purine synthesis and catabolism and, more commonly, by acquired deficiency of xanthine oxidase due to allopurinol therapy or liver disease.

Inherited disorders — Inherited disorders resulting in decreased uric acid production include hereditary xanthinuria and purine nucleosidase phosphorylase deficiency:

Hereditary xanthinuria − Xanthine oxidase catalyzes the conversion of hypoxanthine to xanthine and of xanthine to uric acid. Deficiency of xanthine oxidase, which is inherited as an autosomal recessive trait, results in hereditary xanthinuria [4,5]. Striking hypouricemia is seen with levels usually below 1 mg/dL (59.5 micromol/L). Increased urinary excretion of relatively insoluble xanthine leads to the development of xanthine stones in approximately one-third of patients. Xanthine stones are managed with fluids to increase the urine output (which reduces the urine xanthine concentration) and with alkali administration (which modestly increases xanthine solubility) [6]. In a smaller number of patients, deposition of xanthine crystals in skeletal muscle produces myopathic symptoms.

The diagnosis is suspected by the finding of hypouricemia, reduced urinary uric acid excretion, and increased xanthine excretion; it is confirmed by liver or intestinal biopsy with measurement of enzyme activity.


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Literature review current through: Mar 2014. | This topic last updated: Jan 16, 2014.
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  1. Ogino K, Hisatome I, Saitoh M, et al. Clinical significance of hypouricemia in hospitalized patients. J Med 1991; 22:76.
  2. Maesaka JK, Fishbane S. Regulation of renal urate excretion: a critical review. Am J Kidney Dis 1998; 32:917.
  3. Ramsdell CM, Kelley WN. The clinical significance of hypouricemia. Ann Intern Med 1973; 78:239.
  4. Holmes EW, Wyngaarden JB. Hereditary xanthinuria. In: The Metabolic Basis of Inherited Disease, 6th ed, Scriver C, Beaudet AL, Sly WS, et al (Eds), McGraw-Hill, New York 1989.
  5. Levartovsky D, Lagziel A, Sperling O, et al. XDH gene mutation is the underlying cause of classical xanthinuria: a second report. Kidney Int 2000; 57:2215.
  6. Seegmiller JE. Xanthine stone formation. Am J Med 1968; 45:780.
  7. Michelis MF, Warms PC, Fusco RD, Davis BB. Hypouricemia and hyperuricosuria in Laennec cirrhosis. Arch Intern Med 1974; 134:681.
  8. Sundy JS, Becker MA, Baraf HS, et al. Reduction of plasma urate levels following treatment with multiple doses of pegloticase (polyethylene glycol-conjugated uricase) in patients with treatment-failure gout: results of a phase II randomized study. Arthritis Rheum 2008; 58:2882.
  9. Greene ML, Marcus R, Aurbach GD, et al. Hypouricemia due to isolated renal tubular defect. Dalmatian dog mutation in man. Am J Med 1972; 53:361.
  10. Khachadurian AK, Arslanian MJ. Hypouricemia due to renal uricosuria. A case study. Ann Intern Med 1973; 78:547.
  11. Hisatome I, Ogino K, Kotake H, et al. Cause of persistent hypouricemia in outpatients. Nephron 1989; 51:13.
  12. Barajas de Frutos D, Bravo Mancheño B, Palomino Urda N, Pedrero Vera J. Familial hypouricaemia due to an isolated tubular defect of urate reabsorption. Pediatr Nephrol 1993; 7:83.
  13. Hisatome I, Kato T, Miyakoda H, et al. Renal hypouricemia with both drug-insensitive secretion and defective reabsorption of urate: a novel type of renal hypouricemia. Nephron 1993; 64:447.
  14. Shichiri M, Iwamoto H, Shiigai T. Hypouricemia due to increased tubular urate secretion. Nephron 1987; 45:31.
  15. Frank M, Many M, Sperling O. Familial renal hypouricaemia: two additional cases with uric acid lithiasis. Br J Urol 1979; 51:88.
  16. Hedley JM, Phillips PJ. Familial hypouricaemia associated with renal tubular uricosuria and uric acid calculi: case report. J Clin Pathol 1980; 33:971.
  17. Gofrit O, Verstandig AG, Pode D. Bilateral obstructing ureteral uric acid stones in an infant with hereditary renal hypouricemia. J Urol 1993; 149:1506.
  18. Hisatome I, Tanaka Y, Kotake H, et al. Renal hypouricemia due to enhanced tubular secretion of urate associated with urolithiasis: successful treatment of urolithiasis by alkalization of urine K+, Na(+)-citrate. Nephron 1993; 65:578.
  19. Iwai N, Mino Y, Hosoyamada M, et al. A high prevalence of renal hypouricemia caused by inactive SLC22A12 in Japanese. Kidney Int 2004; 66:935.
  20. Sperling O. Hereditary renal hypouricemia. Mol Genet Metab 2006; 89:14.
  21. 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.
  22. Ichida K, Hosoyamada M, Hisatome I, et al. Clinical and molecular analysis of patients with renal hypouricemia in Japan-influence of URAT1 gene on urinary urate excretion. J Am Soc Nephrol 2004; 15:164.
  23. 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.
  24. Bahn A, Hagos Y, Reuter S, et al. Identification of a new urate and high affinity nicotinate transporter, hOAT10 (SLC22A13). J Biol Chem 2008; 283:16332.
  25. Dinour D, Gray NK, Campbell S, et al. Homozygous SLC2A9 mutations cause severe renal hypouricemia. J Am Soc Nephrol 2010; 21:64.
  26. Matsuo H, Chiba T, Nagamori S, et al. Mutations in glucose transporter 9 gene SLC2A9 cause renal hypouricemia. Am J Hum Genet 2008; 83:744.
  27. Caulfield MJ, Munroe PB, O'Neill D, et al. SLC2A9 is a high-capacity urate transporter in humans. PLoS Med 2008; 5:e197.
  28. 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.
  29. Uribarri J, Oh MS. Renal hypouricemia and absorptive hypercalciuria: a real syndrome. Nephron 1993; 63:172.
  30. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Drug-induced Fanconi's syndrome. Am J Kidney Dis 2003; 41:292.
  31. 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.
  32. Peretz A, Decaux G, Famaey JP. Hypouricemia and intravenous infusions. J Rheumatol 1983; 10:66.
  33. Beck LH. Hypouricemia in the syndrome of inappropriate secretion of antidiuretic hormone. N Engl J Med 1979; 301:528.
  34. Decaux G, Schlesser M, Coffernils M, et al. Uric acid, anion gap and urea concentration in the diagnostic approach to hyponatremia. Clin Nephrol 1994; 42:102.
  35. Decaux G, Prospert F, Namias B, Soupart A. Utility of serum uric acid determination in the differential diagnosis between central diabetes insipidus and primary polydipsia (abstract). J Am Soc Nephrol 1996; 7:1348.
  36. Cappuccio FP, Strazzullo P, Farinaro E, Trevisan M. Uric acid metabolism and tubular sodium handling. Results from a population-based study. JAMA 1993; 270:354.
  37. Egan BM, Lackland DT. Biochemical and metabolic effects of very-low-salt diets. Am J Med Sci 2000; 320:233.
  38. 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.
  39. Del Río A, Rodríguez-Villamil JL. Metabolic effects of strict salt restriction in essential hypertensive patients. J Intern Med 1993; 233:409.
  40. 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.
  41. Ecelbarger CA, Kim GH, Terris J, et al. Vasopressin-mediated regulation of epithelial sodium channel abundance in rat kidney. Am J Physiol Renal Physiol 2000; 279:F46.
  42. Bugaj V, Pochynyuk O, Stockand JD. Activation of the epithelial Na+ channel in the collecting duct by vasopressin contributes to water reabsorption. Am J Physiol Renal Physiol 2009; 297:F1411.
  43. Bankir L, Fernandes S, Bardoux P, et al. Vasopressin-V2 receptor stimulation reduces sodium excretion in healthy humans. J Am Soc Nephrol 2005; 16:1920.
  44. Decaux G, Namias B, Gulbis B, Soupart A. Evidence in hyponatremia related to inappropriate secretion of ADH that V1 receptor stimulation contributes to the increase in renal uric acid clearance. J Am Soc Nephrol 1996; 7:805.
  45. Decaux G, Prospert F, Namias B, Soupart A. Hyperuricemia as a clue for central diabetes insipidus (lack of V1 effect) in the differential diagnosis of polydipsia. Am J Med 1997; 103:376.
  46. Sonnenblick M, Rosin AJ. Significance of the measurement of uric acid fractional clearance in diuretic induced hyponatraemia. Postgrad Med J 1986; 62:449.
  47. Maesaka JK, Venkatesan J, Piccione JM, et al. Abnormal urate transport in patients with intracranial disease. Am J Kidney Dis 1992; 19:10.
  48. Maesaka JK, Batuman V, Yudd M, et al. Hyponatremia and hypouricemia: differentiation from SIADH. Clin Nephrol 1990; 33:174.
  49. Sterns RH, Silver SM. Cerebral salt wasting versus SIADH: what difference? J Am Soc Nephrol 2008; 19:194.
  50. Maesaka JK, Cusano AJ, Thies HL, et al. Hypouricemia in acquired immunodeficiency syndrome. Am J Kidney Dis 1990; 15:252.
  51. Collazos J, Blanco MS, Guerra E, et al. Sequential evaluation of serum urate concentrations in AIDS patients with infections of the central nervous system. Clin Chem Lab Med 2000; 38:1293.
  52. Chertow GM, Seifter JL, Christiansen CL, O'Donnell WJ. Trimethoprim-sulfamethoxazole and hypouricemia. Clin Nephrol 1996; 46:193.
  53. YU TF, GUTMAN AB. Paradoxical retention of uric acid by uricosuric drugs in low dosage. Proc Soc Exp Biol Med 1955; 90:542.
  54. YU TF, GUTMAN AB. Study of the paradoxical effects of salicylate in low, intermediate and high dosage on the renal mechanisms for excretion of urate in man. J Clin Invest 1959; 38:1298.
  55. Uetake D, Ohno I, Ichida K, et al. Effect of fenofibrate on uric acid metabolism and urate transporter 1. Intern Med 2010; 49:89.
  56. Minghelli G, Seydoux C, Goy JJ, Burnier M. Uricosuric effect of the angiotensin II receptor antagonist losartan in heart transplant recipients. Transplantation 1998; 66:268.
  57. Hamada T, Ichida K, Hosoyamada M, et al. Uricosuric action of losartan via the inhibition of urate transporter 1 (URAT 1) in hypertensive patients. Am J Hypertens 2008; 21:1157.
  59. Urano W, Yamanaka H, Tsutani H, et al. The inflammatory process in the mechanism of decreased serum uric acid concentrations during acute gouty arthritis. J Rheumatol 2002; 29:1950.
  60. Wu VC, Huang JW, Hsueh PR, et al. Renal hypouricemia is an ominous sign in patients with severe acute respiratory syndrome. Am J Kidney Dis 2005; 45:88.
  61. Lind T, Godfrey KA, Otun H, Philips PR. Changes in serum uric acid concentrations during normal pregnancy. Br J Obstet Gynaecol 1984; 91:128.
  62. Derus CL, Levinson DJ, Bowman B, et al. Altered fractional excretion of uric acid during total parenteral nutrition. J Rheumatol 1987; 14:978.
  63. Cooper DS. Oat-cell carcinoma and severe hypouricemia. N Engl J Med 1973; 288:321.
  64. Magoula I, Tsapas G, Kountouras J, Paletas K. Cholangiocarcinoma and severe renal hypouricemia: a study of the renal mechanisms. Am J Kidney Dis 1991; 18:514.
  65. Bennett JS, Bond J, Singer I, Gottlieb AJ. Hypouricemia in Hodgkin's disease. Ann Intern Med 1972; 76:751.
  66. Shichiri M, Iwamoto H, Shiigai T. Diabetic renal hypouricemia. Arch Intern Med 1987; 147:225.
  67. Magoula I, Tsapas G, Paletas K, Mavromatidis K. Insulin-dependent diabetes and renal hypouricemia. Nephron 1991; 59:21.
  68. Zawadzki J, Jankowska I, Moszczyńska A, Januszewicz P. Hypouricemia due to increased tubular secretion of urate in children with Amanita phalloides poisoning. Nephron 1993; 65:375.
  69. Ohta T, Sakano T, Igarashi T, et al. Exercise-induced acute renal failure associated with renal hypouricaemia: results of a questionnaire-based survey in Japan. Nephrol Dial Transplant 2004; 19:1447.
  70. Ishikawa I, Sakurai Y, Masuzaki S, et al. Exercise-induced acute renal failure in 3 patients with renal hypouricemia. Nihon Jinzo Gakkai Shi 1990; 32:923.
  71. Murakami T, Kawakami H, Fukuda M, Furukawa S. Patients with renal hypouricemia are prone to develop acute renal failure--why? Clin Nephrol 1995; 43:207.
  72. Yeun JY, Hasbargen JA. Renal hypouricemia: prevention of exercise-induced acute renal failure and a review of the literature. Am J Kidney Dis 1995; 25:937.
  73. Mima A, Ichida K, Matsubara T, et al. Acute renal failure after exercise in a Japanese sumo wrestler with renal hypouricemia. Am J Med Sci 2008; 336:512.
  74. Paller MS, Hoidal JR, Ferris TF. Oxygen free radicals in ischemic acute renal failure in the rat. J Clin Invest 1984; 74:1156.
  75. Ohta T, Sakano T, Ogawa T, et al. Exercise-induced acute renal failure with renal hypouricemia: a case report and a review of the literature. Clin Nephrol 2002; 58:313.
  76. Peden DB, Hohman R, Brown ME, et al. Uric acid is a major antioxidant in human nasal airway secretions. Proc Natl Acad Sci U S A 1990; 87:7638.
  77. Vollaard NB, Shearman JP, Cooper CE. Exercise-induced oxidative stress:myths, realities and physiological relevance. Sports Med 2005; 35:1045.
  78. Kaneko K, Taniguchi N, Tanabe Y, et al. Oxidative imbalance in idiopathic renal hypouricemia. Pediatr Nephrol 2009; 24:869.
  79. Sahlin K, Ekberg K, Cizinsky S. Changes in plasma hypoxanthine and free radical markers during exercise in man. Acta Physiol Scand 1991; 142:275.
  80. Hellsten-Westing Y, Kaijser L, Ekblom B, Sjödin B. Exchange of purines in human liver and skeletal muscle with short-term exhaustive exercise. Am J Physiol 1994; 266:R81.
  81. Erley CM, Hirschberg RR, Hoefer W, Schaefer K. Acute renal failure due to uric acid nephropathy in a patient with renal hypouricemia. Klin Wochenschr 1989; 67:308.
  82. Bhasin B, Stiburkova B, De Castro-Pretelt M, et al. Hereditary renal hypouricemia: a new role for allopurinol? Am J Med 2014; 127:e3.
  83. Dinour D, Bahn A, Ganon L, et al. URAT1 mutations cause renal hypouricemia type 1 in Iraqi Jews. Nephrol Dial Transplant 2011; 26:2175.
  84. Sorensen CM, Chandhoke PS. Hyperuricosuric calcium nephrolithiasis. Endocrinol Metab Clin North Am 2002; 31:915.
  85. Kaneko K, Yamanobe T, Onoda M, et al. Analysis of urinary calculi obtained from a patient with idiopathic hypouricemia using micro area x-ray diffractometry and LC-MS. Urol Res 2005; 33:415.
  86. Nishizaki N, Fujinaga S, Hirano D, et al. Hereditary renal hypouricemia: a cause of calcium oxalate urolithiasis in a young female. Clin Nephrol 2012; 77:161.
  87. Fujinaga S, Ito A, Nakagawa M, et al. Posterior reversible encephalopathy syndrome with exercise-induced acute kidney injury in renal hypouricemia type 1. Eur J Pediatr 2013; 172:1557.
  88. Shima Y, Nozu K, Nozu Y, et al. Recurrent EIARF and PRES with severe renal hypouricemia by compound heterozygous SLC2A9 mutation. Pediatrics 2011; 127:e1621.