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Uric Acid Nephrolithiasis: A Systemic Metabolic Disorder

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Abstract

Uric acid nephrolithiasis is characteristically a manifestation of a systemic metabolic disorder. It has a prevalence of about 10% among all stone formers, the third most common type of kidney stone in the industrialized world. Uric acid stones form primarily due to an unduly acid urine; less deciding factors are hyperuricosuria and a low urine volume. The vast majority of uric acid stone formers have the metabolic syndrome, and not infrequently, clinical gout is present as well. A universal finding is a low baseline urine pH plus insufficient production of urinary ammonium buffer. Persons with gastrointestinal disorders, in particular chronic diarrhea or ostomies, and patients with malignancies with a large tumor mass and high cell turnover comprise a less common but nevertheless important subset. Pure uric acid stones are radiolucent but well visualized on renal ultrasound or computer tomography. A 24 h urine collection for stone risk analysis provides essential insight into the pathophysiology of stone formation and may guide therapy. Management includes a liberal fluid intake and dietary modification. Potassium citrate to alkalinize the urine to a goal pH between 6 and 6.5 is essential, as undissociated uric acid deprotonates into its much more soluble urate form.

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References

  1. Balinsky JB. Phylogenetic aspects of purine metabolism. S Afr Med J. 1972;46(29):993–7.

    PubMed  CAS  Google Scholar 

  2. Campbell JW, Comparative biochemistry of nitrogen metabolism. In: Campbell JW, editor. The vertebrates, Vol. 2. New York: Academic Press; 1970.

  3. Moe OW. Uric acid nephrolithiasis: proton titration of an essential molecule? Curr Opin Nephrol Hypertens. 2006;15(4):366–73.

    Article  PubMed  CAS  Google Scholar 

  4. Shoemaker VH, et al. Uricotelism and low evaporative water loss in a South American frog. Science. 1972;175(25):1018–20.

    Article  PubMed  CAS  Google Scholar 

  5. Christen P, et al. Urate oxidase in primates. Folia Primatol (Basel). 1970;13(1):35–9.

    Article  CAS  Google Scholar 

  6. Varela-Echavarria A, Montes de Oca-Luna R, Barrera-Saldana HA. Uricase protein sequences: conserved during vertebrate evolution but absent in humans. FASEB J. 1988;2(15):3092–6.

    PubMed  CAS  Google Scholar 

  7. Shattock SG. Prehistoric or predynastic Egyptian calculus. Trans Path Sci Lond. 1905;56–62.

  8. Moran ME. Uric acid stone disease. Front Biosci. 2003;8:s1339–55.

    Article  PubMed  CAS  Google Scholar 

  9. Sydenham T. Tractatus de podagra et hydrope. London: Walter Kettibly; 1683.

  10. Scheele C. Examen Chemicum Calculi Urinari. Opuscula. 1776;2:73.

    Google Scholar 

  11. Coley NG. Medical chemists and the origins of clinical chemistry in Britain (circa 1750–1850). Clin Chem. 2004;50(5):961–72.

    Article  PubMed  CAS  Google Scholar 

  12. Wollaston WH. On gouty and urinary concretions. Philos Trans R Soc Lond. 1797;87:386–400.

    Article  Google Scholar 

  13. Wollaston WH. On cystic oxide, a new species of urinary calculus. Philos Trans R Soc Lond. 1810;100:223–30.

    Article  Google Scholar 

  14. Pearson G. Experiments and observations, tending to show the composition and properties of urinary concretions. Philos Trans R Soc Lond. 1798;88:15–46.

    Article  Google Scholar 

  15. Smeaton WA (1963) Fourcroy, chemist and revolutionary (1755–1809). 7(3):287.

  16. Ellis H. A history of bladder stone. J Royal Soc Med. 1979;72(4):248–51.

    CAS  Google Scholar 

  17. Osler W. The principles and practice of medicine: designed for the use of practitioners and students of medicine. Young J Pentland: Edinburgh & London; 1892. pp. 765–770.

  18. Gutman AB, Yu TF. Uric acid nephrolithiasis. Am J Med. 1968;45(5):756–79.

    Article  PubMed  CAS  Google Scholar 

  19. Mandel NS, Mandel GS. Urinary tract stone disease in the United States veteran population. II. Geographical analysis of variations in composition. J Urol. 1989; 142(6):1516–21.

    Google Scholar 

  20. Gault MH, Chafe L. Relationship of frequency, age, sex, stone weight, composition in 15, 624 stones: comparison of resutls for 1980 to 1983, 1995 to 1998. J Urol. 2000;164(2):302–7.

    Article  PubMed  CAS  Google Scholar 

  21. Knoll T, et al. Urolithiasis through the ages: data on more than 200, 000 urinary stone analyses. J Urol. 2011;185(4):1304–11.

    Article  PubMed  Google Scholar 

  22. Gentle DL, et al. Geriatric urolithiasis. J Urol. 1997;158(6):2221–4.

    Article  PubMed  CAS  Google Scholar 

  23. Henneman PH, Wallach S, Dempsey EF. The metabolism defect responsible for uric acid stone formation. J Clin Invest. 1962;41:537–42.

    Article  PubMed  CAS  Google Scholar 

  24. Zaidman JL, Pinto N. Studies on urolithiasis in Israel. J Urol. 1976;115(6):626–7.

    PubMed  CAS  Google Scholar 

  25. Portis AJ, et al. Stone disease in the Hmong of Minnesota: initial description of a high-risk population. J Endourol. 2004;18(9):853–7.

    Article  PubMed  Google Scholar 

  26. Ansari MS, et al. Spectrum of stone composition: structural analysis of 1050 upper urinary tract calculi from northern India. Int J Urol. 2005;12(1):12–6.

    Article  PubMed  Google Scholar 

  27. Hossain RZ, et al. Urolithiasis in Okinawa, Japan: a relatively high prevalence of uric acid stones. Int J Urol. 2003;10(8):411–5.

    Article  PubMed  Google Scholar 

  28. Pak CY, et al. Biochemical profile of stone-forming patients with diabetes mellitus. Urology. 2003;61(3):523–7.

    Article  PubMed  Google Scholar 

  29. Daudon M, Lacour B, Jungers P. High prevalence of uric acid calculi in diabetic stone formers. Nephrol Dial Transplant. 2005;20(2):468–9.

    Article  PubMed  Google Scholar 

  30. Hershfield MS, et al. Treating gout with pegloticase, a PEGylated urate oxidase, provides insight into the importance of uric acid as an antioxidant in vivo. Proc Natl Acad Sci USA. 2010;107(32):14351–6.

    Article  PubMed  CAS  Google Scholar 

  31. Pession A, Melchionda F, Castellini C. Pitfalls, prevention, and treatment of hyperuricemia during tumor lysis syndrome in the era of rasburicase (recombinant urate oxidase). Biologics. 2008;2(1):129–41.

    PubMed  CAS  Google Scholar 

  32. LaRosa C, et al. Acute renal failure from xanthine nephropathy during management of acute leukemia. Pediatr Nephrol. 2007;22(1):132–5.

    Article  PubMed  Google Scholar 

  33. Fellstrom B, et al. The influence of a high dietary intake of purine-rich animal protein on urinary urate excretion and supersaturation in renal stone disease. Clin Sci (Lond). 1983;64(4):399–405.

    CAS  Google Scholar 

  34. Kamel KS, et al. Recurrent uric acid stones. QJM. 2005;98(1):57–68.

    Article  PubMed  CAS  Google Scholar 

  35. Steele TH, Boner G. Origins of the uricosuric response. J Clin Invest. 1973;52(6):1368–75.

    Article  PubMed  CAS  Google Scholar 

  36. Enomoto A, et al. Molecular identification of a renal urate anion exchanger that regulates blood urate levels. Nature. 2002;417(6887):447–52.

    PubMed  CAS  Google Scholar 

  37. Lipkowitz MS, et al. Functional reconstitution, membrane targeting, genomic structure, and chromosomal localization of a human urate transporter. J Clin Invest. 2001;107(9):1103–15.

    Article  PubMed  CAS  Google Scholar 

  38. Leal-Pinto E, et al. Functional analysis and molecular model of the human urate transporter/channel, hUAT. Am J Physiol Renal Physiol. 2002;283(1):F150–63.

    PubMed  CAS  Google Scholar 

  39. Sorensen CM, Chandhoke PS. Hyperuricosuric calcium nephrolithiasis. Endocrinol Metab Clin North Am. 2002;31(4):915–25.

    Article  PubMed  CAS  Google Scholar 

  40. Robertson WG. Renal stones in the tropics. Semin Nephrol. 2003;23(1):77–87.

    Article  PubMed  Google Scholar 

  41. Pak CY, et al. Physicochemical metabolic characteristics for calcium oxalate stone formation in patients with gouty diathesis. J Urol. 2005;173(5):1606–9.

    Article  PubMed  CAS  Google Scholar 

  42. Pak CY, et al. Biochemical distinction between hyperuricosuric calcium urolithiasis and gouty diathesis. Urology. 2002;60(5):789–94.

    Article  PubMed  Google Scholar 

  43. Pak CY, et al. Biochemical profile of idiopathic uric acid nephrolithiasis. Kidney Int. 2001;60(2):757–61.

    Article  PubMed  CAS  Google Scholar 

  44. Sakhaee K, et al. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int. 2002;62(3):971–9.

    Article  PubMed  CAS  Google Scholar 

  45. Sakhaee K, et al. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int. 1983;24(3):348–52.

    Article  PubMed  CAS  Google Scholar 

  46. Jones HB. On the variations of the acidity of the urine in the state of health. Philos Trans R Soc. 1845;135–8.

  47. Mills JN, Stanbury SW. Intrinsic diurnal rhythm in urinary electrolyte output. J Physiol. 1951;115(1):18p–9p.

    PubMed  CAS  Google Scholar 

  48. Moore-Ede MC, Herd JA. Renal electrolyte circadian rhythms: independence from feeding and activity patterns. Am J Physiol. 1977;232(2):F128–35.

    PubMed  CAS  Google Scholar 

  49. Stanbury SW, Thomson AE. Diurnal variation in electrolyte excretion. Clin Sci (Lond). 1951;10(3):267–93.

    CAS  Google Scholar 

  50. Murayama T, et al. Role of the diurnal variation of urinary pH and urinary calcium in urolithiasis: a study in outpatients. Int J Urol. 2001;8(10):525–31. (discussion 532).

    PubMed  CAS  Google Scholar 

  51. Cameron MA et al. Diurnal variation in urinary acidification parameters in normal subjects and uric acid stone formers. 2011: Manuscript in preparation.

  52. Cameron MA, et al. Circadian variation in urine pH and uric acid nephrolithiasis risk. Nephrol Dial Transplant. 2007;22(8):2375–8.

    Article  PubMed  Google Scholar 

  53. Hamm LL, Simon EE. Roles and mechanisms of urinary buffer excretion. Am J Physiol. 1987; 253(4 Pt 2):F595–605.

    Google Scholar 

  54. Kamel KS, Cheema-Dhadli S, Halperin ML. Studies on the pathophysiology of the low urine pH in patients with uric acid stones. Kidney Int. 2002;61(3):988–94.

    Article  PubMed  CAS  Google Scholar 

  55. Cameron MA, et al. Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis. J Am Soc Nephrol. 2006;17(5):1422–8.

    Article  PubMed  CAS  Google Scholar 

  56. Maalouf NM, et al. Metabolic basis for low urine pH in type 2 diabetes. Clin J Am Soc Nephrol. 2010;5(7):1277–81.

    Article  PubMed  CAS  Google Scholar 

  57. Ekaratanawong S, et al. Human organic anion transporter 4 is a renal apical organic anion/dicarboxylate exchanger in the proximal tubules. J Pharmacol Sci. 2004;94(3):297–304.

    Article  PubMed  CAS  Google Scholar 

  58. Lieske JC, et al. Diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. Am J Kidney Dis. 2006;48(6):897–904.

    Article  PubMed  Google Scholar 

  59. Abate N, et al. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int. 2004;65(2):386–92.

    Article  PubMed  CAS  Google Scholar 

  60. Bobulescu IA, et al. Effect of renal lipid accumulation on proximal tubule Na +/H + exchange and ammonium secretion. Am J Physiol Renal Physiol. 2008;294(6):F1315–22.

    Article  PubMed  CAS  Google Scholar 

  61. Bobulescu IA, et al. Reduction of renal triglyceride accumulation: effects on proximal tubule Na+/H+ exchange and urinary acidification. Am J Physiol Renal Physiol. 2009;297(5):F1419–26.

    Article  PubMed  CAS  Google Scholar 

  62. Curhan GC, Taylor EN. 24-h uric acid excretion and the risk of kidney stones. Kidney Int. 2008;73(4):489–96.

    Article  PubMed  CAS  Google Scholar 

  63. Calado J, et al. A novel heterozygous missense mutation in the UMOD gene responsible for Familial Juvenile Hyperuricemic Nephropathy. BMC Med Genet. 2005;6:5.

    Article  PubMed  Google Scholar 

  64. Bleyer AJ, et al. Renal manifestations of a mutation in the uromodulin (Tamm Horsfall protein) gene. Am J Kidney Dis. 2003;42(2):E20–6.

    Article  PubMed  Google Scholar 

  65. Pak CY, et al. Predictive value of kidney stone composition in the detection of metabolic abnormalities. Am J Med. 2003;115(1):26–32.

    Article  PubMed  CAS  Google Scholar 

  66. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844–54.

    Article  PubMed  CAS  Google Scholar 

  67. Diamond HS, et al. Hyperuricosuria and increased tubular secretion of urate in sickle cell anemia. Am J Med. 1975;59(6):796–802.

    Article  PubMed  CAS  Google Scholar 

  68. Reddy ST, et al. Effect of low-carbohydrate high-protein diets on acid-base balance, stone-forming propensity, and calcium metabolism. Am J Kidney Dis. 2002;40(2):265–74.

    Article  PubMed  CAS  Google Scholar 

  69. Pak CY, et al. Mechanism for calcium urolithiasis among patients with hyperuricosuria: supersaturation of urine with respect to monosodium urate. J Clin Invest. 1977;59(3):426–31.

    Article  PubMed  CAS  Google Scholar 

  70. Graff L. A handbook of routine urinalysis. Philadelphia: J.B.Lippincott Company; 1982.

    Google Scholar 

  71. Pais VM Jr, et al. Xanthine urolithiasis. Urology 2006; 67(5):1084 e9–11.

  72. Coe FL. Treated and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria, or no metabolic disorder. Ann Intern Med. 1977;87(4):404–10.

    PubMed  CAS  Google Scholar 

  73. Ettinger B, et al. Randomized trial of allopurinol in the prevention of calcium oxalate calculi. N Engl J Med. 1986;315(22):1386–9.

    Article  PubMed  CAS  Google Scholar 

  74. Becker MA, et al. Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med. 2005;353(23):2450–61.

    Article  PubMed  CAS  Google Scholar 

  75. Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int. 1986;30(3):422–8.

    Article  PubMed  CAS  Google Scholar 

  76. Moran ME, et al. Utility of oral dissolution therapy in the management of referred patients with secondarily treated uric acid stones. Urology. 2002;59(2):206–10.

    Article  PubMed  Google Scholar 

  77. Rodman JS. Prophylaxis of uric acid stones with alternate day doses of alkaline potassium salts. J Urol. 1991;145(1):97–9.

    PubMed  CAS  Google Scholar 

  78. Preminger GM, Sakhaee K, Pak CY. Alkali action on the urinary crystallization of calcium salts: contrasting responses to sodium citrate and potassium citrate. J Urol. 1988;139(2):240–2.

    PubMed  CAS  Google Scholar 

  79. Odvina CV. Comparative value of orange juice versus lemonade in reducing stone-forming risk. Clin J Am Soc Nephrol. 2006;1(6):1269–74.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Nephrology, Baylor University Medical Center, 3500 Gaston Avenue, Dallas, TX, 75246, USA

    Michael R. Wiederkehr

  2. Department of Internal Medicine, Division of Nephrology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390-8885, USA

    Orson W. Moe

  3. Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Orson W. Moe

  4. Charles and Jane Pak Center of Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, USA

    Orson W. Moe

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Correspondence to Michael R. Wiederkehr.

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Wiederkehr, M.R., Moe, O.W. Uric Acid Nephrolithiasis: A Systemic Metabolic Disorder. Clinic Rev Bone Miner Metab 9, 207–217 (2011). https://doi.org/10.1007/s12018-011-9106-6

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