Abstract
The prevalence of uric acid nephrolithiasis in the general US population is approximately 8 %. However, the prevalence of uric acid stones among diabetic and obese populations has been reported to be significantly high, approaching 3.5-fold greater than the general population. Although three main etiologic factors, including low urine volume, hyperuricosuria, and unduly urine acidity, have been implicated in the pathogenesis of uric acid nephrolithiasis, abnormal urine pH has been shown to play a key pathogenic role in uric acid precipitation and uric acid stone formation. Uric acid is a weak organic acid with an ionization constant (pKa = 5.5); hence, at a urinary pH ≤ 5.5 the urinary environment becomes supersaturated with highly insoluble undissociated uric acid, which greatly imposes the risk of uric acid development and precipitation. Under normal circumstances, uric acid solubility is limited to 96 mg/L; thus, humans with urinary uric acid excretion of approximately 600–800 mg/day must be at risk for uric acid precipitation. However, urinary pH plays a dominate role in keeping uric acid in the solution. Careful studies have demonstrated that at urinary pH between 6.2 and 6.4, the urinary environment becomes undersaturated with respect to undissociated uric acid content. Such an environment has been shown to be associated with a significantly reduced risk of uric acid stone formation. Given this predominate role of urinary pH, urinary uric acid must exceed 1,100 mg/day in order to promote uric acid precipitation. This condition rarely occurs in the majority of patients with idiopathic nephrolithiasis in whom urinary acid excretion was reported to be normal. Uric acid-lowering drugs must only be tried in some patients with primary gout, with genetic abnormalities in uric acid pathways including inborn errors in metabolism, uric acid metabolism, and those with accelerated tissue turnover.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Mandel NS, Mandel GS. Urinary tract stone disease in the United States veteran population. 2. Geographical analysis of variations in composition. J Urol. 1989;142:1516–21.
Pak CY, Sakhaee K, Moe O, Preminger GM, Poindexter JR, Peterson RD, et al. Biochemical profile of stone-forming patients with diabetes mellitus. Urology. 2003;61:523–7.
Lieske JC, de la Vega LS, Gettman MT, Slezak JM, Bergstralh EJ, Melton LJ 3rd, et al. Diabetes mellitus and the risk of urinary tract stones: a population-based case-control study. AM J Kidney Dis. 2006;48:897–904.
Ekeruo WO, Tan YH, Young MD, Dahm P, Maloney ME, Mathias BJ, et al. Metabolic risk factors and the impact of medical therapy on the management of nephrolithiasis in obese patients. J Urol. 2004;172:159–63.
Daudon M, Lacour B, Jungers P. Influence of body size on urinary stone composition in men and women. Urol Res. 2006;34:193–9.
Daudon M, Traxer O, Conort P, Lacour B, Jungers P. Type 2 diabetes increases the risk for uric acid stones. J Am Soc Nephrol. 2006;17:2026–33.
Portis AJ, Hermans K, Culhane-Pera KA, Curhan GC. Stone disease in the Hmong of Minnesota: initial description of a high-risk population. J Endourol. 2004;18:853–7.
Portis AJ, Laliberte M, Tatman P, Moua M, Culhane-Pera K, Maalouf NM, et al. High prevalence of gouty arthritis among the Hmong population in Minnesota. Arthritis Care Res (Hoboken). 2010;62:1386–91.
Cameron MA, Maalouf NM, Adams-Huet B, Moe OW, Sakhaee K. Urine composition in type 2 diabetes: predisposition to uric acid nephrolithiasis. J Am Soc Nephrol. 2006;17:1422–8.
Prasongwatana V, Sriboonlue P, Suntarapa S. Urinary stone composition in North-East Thailand. Br J Urol. 1983;55:353–5.
Herbstein FH, Kleeberg J, Shalitin Y, Wartski E, Wielinski S. Chemical and x-ray diffraction analysis of urinary stones in Israel. Isr J Med Sci. 1974;10:1493–9.
Sakhaee K. Uric acid metabolism and uric acid stones. In: Rao NP, Preminger GM, Kavanagh JP, editors. Urinary tract stone disease. Manchester: Springer; 2011.p. 185–93.
Sakhaee K. Recent advances in the pathophysiology of nephrolithiasis. Kidney Int. 2009;75:585–95.
Rafey MA, Lipkowitz MS, Leal-Pinto E, Abramson RG. Uric acid transport. Curr Opin Nephrol Hypertens. 2003;12:511–6.
Sakhaee K, Adams-Huet B, Moe OW, Pak CY. Pathophysiologic basis for normouricosuric uric acid nephrolithiasis. Kidney Int. 2002;62:971–9.
Asplin JR. Uric acid stones. Sem Nep. 1996;16:412–24.
Coe FL, Strauss AL, Tembe V, Le Dun S. Uric acid saturation in calcium nephrolithiasis. Kidney Int. 1980;17:662–8.
Finlayson B, Smith A. Stability of first dissociable proton of uric acid. J Chem Eng Data. 1974;19:94–7.
Sakhaee K, Nicar M, Hill K, Pak CY. Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts. Kidney Int. 1983;24:348–52.
Gutman AB, Yu TF. Uric acid nephrolithiasis. Am J Med. 1968;45:756–79.
Pak CY, Moe OW, Sakhaee K, Peterson RD, Poindexter JR. Physicochemical metabolic characteristics for calcium oxalate stone formation in patients with gouty diathesis. J Urol. 2005;173:1606–9.
Kok DJ, Papapoulos SE, Bijvoet OL. Excessive crystal agglomeration with low citrate excretion in recurrent stone-formers. Lancet. 1986;1:1056–8.
Sakhaee K, Nigam S, Snell P, Hsu MC, Pak CY. Assessment of the pathogenetic role of physical exercise in renal stone formation. J Clin Endocrinol Metab. 1987;65:974–79.
Deren JJ, Porush JG, Levitt MF, Khilnani MT. Nephrolithiasis as a complication of ulcerative colitis and regional enteritis. Ann Intern Med. 1962;56:843–53.
Moe OW, Abate N, Sakhaee K. Pathophysiology of uric acid nephrolithiasis. Endocrinol Metab Clin North Am. 2002;31:895–914.
Tanaka M, Itoh K, Matsushita K, Matsushita K, Wakita N, Adachi M, et al. Two male siblings with hereditary renal hypouricemia and exercise-induced ARF. Am J Kidney Dis. 2003;42:1287–92.
Ichida K, Hosoyamada M, Hisatome I, Enomoto A, Hikita M, Endou H, 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;15:164–73.
Maalouf NM, Sakhaee K, Parks JH, Coe FL, Adams-Huet B, Pak CY. Association of urinary pH with body weight in nephrolithiasis. Kidney Int. 2004;65:1422–5.
Maalouf NM, Cameron MA, Moe OW, Sakhaee K. Metabolic basis for low urine pH in type 2 diabetes. Clin J Am Soc Nephrol. 2010;5:1277–81.
Cameron M, Maalouf NM, Poindexter J, Adams-Huet B, Sakhaee K, Moe OW. The diurnal variation in urine acidification differs between normal individuals and uric acid stone formers. Kidney Int. 2012;81:1123–30.
Pak CY, Sakhaee K, Peterson RD, Poindexter JR, Frawley WH. Biochemical profile of idiopathic uric acid nephrolithiasis. Kidney Int. 2001;60:757–61.
Pak CY, Waters O, Arnold L, Holt K, Cox C, Barilla D. Mechanism for calcium urolithiasis among patients with hyperuricosuria: supersaturation of urine with respect to monosodium urate. J Clin Invest. 1977;59:426–31.
Pak C, Holt K, Britton F, Peterson R, Crother C, Ward D. Assesment of pathogenetic role of uric acid, monpotassium urate, monoammonium urate, monosodium urate in hyperuricosuric calcium oxalate nephrolithiasis Miner Electrolyte Metab. 1980;4:130–6.
Pak CY, Arnold LH. Heterogeneous nucleation of calcium oxalate by seeds of monosodium urate. Proc Soc Exp Biol Med. 1975;149:930–2.
Lonsdale K. Epitaxy as a growth factor in urinary calculi and gallstones. Nature. 1968;217:56–8.
Zerwekh JE, Holt K, Pak CY. Natural urinary macromolecular inhibitors: attenuation of inhibitory activity by urate salts. Kidney Int. 1983;23:838–41.
Grover PK, Ryall RL. Urate and calcium oxalate stones: from repute to rhetoric to reality. Miner Electrolyte Metab. 1994;20:361–70.
Pak CY, Sakhaee K, Fuller C. Successful management of uric acid nephrolithiasis with potassium citrate. Kidney Int. 1986;30:422–8.
Maalouf NM, Cameron MA, Moe OW, Sakhaee K. Novel insights into the pathogenesis of uric acid nephrolithiasis. Curr Opin Nephrol Hypertens. 2004;13:181–9.
Cameron MA, Baker LA, Maalouf NM, Moe OW, Sakhaee K. Circadian variation in urine pH and uric acid nephrolithiasis risk. Nephrol Dial Transplant. 2007;22:2375–8.
Freed SZ. The alternating use of an alkalizing salt and acetazolamide in the management of cystine and uric acid stones. J Urol. 1975;113:96–9.
Gordon EE, Sheps SG. Effect of acetazolamide on citrate excretion and formation of renal calculi. N Engl J Med. 1957;256:1215–9.
Kuo RL, Moran ME, Kim DH, Abrahams HM, White MD, Lingeman JE. Topiramate-induced nephrolithiasis. J Endourol. 2002;16:229–31.
Gelzayd EA, Breuer RI, Kirsner JB. Nephrolithiasis in inflammatory bowel disease. Am J Dig Dis. 1968;13:1027–34.
Knudsen L, Marcussen H, Fleckenstein P, Pedersen EB, Jarnum S. Urolithiasis in chronic inflammatory bowel disease. Scand J Gastroenterol. 1978;13:433–6.
Bambach CP, Robertson WG, Peacock M, Hill GL. Effect of intestinal surgery on the risk of urinary stone formation. Gut. 1981;22:257–63.
Fukushima T, Yamazaki Y, Sugita A, Tsuchiya S. Prophylaxis of uric acid stone in patients with inflammatory bowel disease following extensive colonic resection. Gastroenterol Jpn. 1991;26:430–4.
Clarke AM, McKenzie RG. Ileostomy and the risk of urinary uric acid stones. Lancet. 1969;2:395–7.
Obialo CI, Clayman RV, Matts JP, Fitch LL, Buchwald H, Gillis M, et al. Pathogenesis of nephrolithiasis post-partial ileal bypass surgery: case-control study. The POSCH Group. Kidney Int. 1991;39:1249–54.
Yu T, Gutman AB. Uric acid nephrolithiasis in gout. Predisposing factors. Ann Intern Med. 1967;67:1133–48.
Wyngaarden JB, Kelley WN. Gout. In: Stanbury JB, Wyngaarden JB, Frederickson DS, editors. The metabolic basis of inherited disease. 3rd ed. New York: McGraw-Hill; 1972.p. 889–968.
Roche A, Perez-Duenas B, Camacho JA, Torres RJ, Puig JG, García-Cazorla A, et al. Efficacy of rasburicase in hyperuricemia secondary to Lesch-Nyhan syndrome. Am J Kidney Dis. 2009;53:677–80.
Bollee G, Harambat J, Bensman A, Knebelmann B, Daudon M, Ceballos-Picot I. Adenine phosphoribosyltransferase deficiency. Clin J Am Soc Nephrol. 2012;7:1521–7.
Yu T, Weinreb N, Wittman R, Wasserman LR. Secondary gout associated with chronic myeloproliferative disorders. Semin Arthritis Rheum. 1976;5:247–56.
Acknowledgments
The author would like to acknowledge Ashlei L. Johnson for her primary role in the preparation and editorial review of this manuscript.
The author was supported by the National Institutes of Health Grant R01-DK81423.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2014 Springer Science+Business Media New York
About this chapter
Cite this chapter
Sakhaee, K. (2014). Uric Acid Nephrolithiasis: Uric Acid or Urine pH?. In: Pearle, M., Nakada, S. (eds) Practical Controversies in Medical Management of Stone Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-9575-8_7
Download citation
DOI: https://doi.org/10.1007/978-1-4614-9575-8_7
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-9574-1
Online ISBN: 978-1-4614-9575-8
eBook Packages: MedicineMedicine (R0)