Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Nephrolithiasis in renal tubular acidosis

Gary C Curhan, MD, ScD
Section Editor
Richard H Sterns, MD
Deputy Editor
John P Forman, MD, MSc


Hypercalciuria, hypocitraturia, nephrolithiasis (often composed of calcium phosphate), nephrocalcinosis, and skeletal abnormalities are frequently associated with untreated distal (type 1) renal tubular acidosis (RTA) [1-4]. Stone disease is also seen with carbonic anhydrase inhibitors but typically not with proximal (type 2 RTA). Most of the studies on RTA and nephrolithiasis have been small, and there is variability in individual phenotype and the response to therapy. The following should be read with these cautions in mind.


Distal (type 1) RTA — Several factors can contribute to the relationship between distal renal tubular acidosis (RTA) and stone formation or nephrocalcinosis. In some families, for example, hypercalciuria appears to be the primary abnormality, with calcium-induced interstitial and tubular damage possibly responsible for the RTA [2].

In most cases, however, RTA is the initial condition with subsequent acidemia promoting stone formation both by increased calcium phosphate release from bone during bone buffering of retained acid and by direct reduction in the tubular reabsorption of these ions [1,5,6]. The degree of hypercalciuria is roughly proportional to the severity of the acidemia.

Two other factors also contribute importantly to stone formation in this disorder: the persistently high urine pH, which favors the precipitation of calcium phosphate (but not calcium oxalate, the solubility of which is relatively insensitive to pH); and reduced citrate excretion [7], since acidemia enhances proximal citrate reabsorption [8]. Urinary citrate is normally a potent inhibitor of calcium stone formation, both by forming a soluble complex with calcium and by inhibiting stone growth by agglomeration of calcium crystals. (See "Risk factors for calcium stones in adults".)

Kidney histopathology of stone formers with distal RTA reveals calcium phosphate deposits plugging inner medullary collecting and Bellini ducts [9]. Significant interstitial fibrosis is also observed, even in areas without plugging. Although further study is needed to verify these results, some of the radiographic calcifications in these patients may represent surgically approachable stones rather than nephrocalcinosis.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Sep 2016. | This topic last updated: Jan 13, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders, 5th ed, McGraw-Hill, New York 2001. p.616.
  2. Buckalew VM Jr. Nephrolithiasis in renal tubular acidosis. J Urol 1989; 141:731.
  3. Brenner RJ, Spring DB, Sebastian A, et al. Incidence of radiographically evident bone disease, nephrocalcinosis, and nephrolithiasis in various types of renal tubular acidosis. N Engl J Med 1982; 307:217.
  4. Gault MH, Chafe LL, Morgan JM, et al. Comparison of patients with idiopathic calcium phosphate and calcium oxalate stones. Medicine (Baltimore) 1991; 70:345.
  5. Bleich HL, Moore MJ, Lemann J Jr, et al. Urinary calcium excretion in human beings. N Engl J Med 1979; 301:535.
  6. Nijenhuis T, Renkema KY, Hoenderop JG, Bindels RJ. Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins. J Am Soc Nephrol 2006; 17:617.
  7. Norman ME, Feldman NI, Cohn RM, et al. Urinary citrate excretion in the diagnosis of distal renal tubular acidosis. J Pediatr 1978; 92:394.
  8. Hamm LL. Renal handling of citrate. Kidney Int 1990; 38:728.
  9. Evan AP, Lingeman J, Coe F, et al. Renal histopathology of stone-forming patients with distal renal tubular acidosis. Kidney Int 2007; 71:795.
  10. Tawil R, Moxley RT 3rd, Griggs RC. Acetazolamide-induced nephrolithiasis: implications for treatment of neuromuscular disorders. Neurology 1993; 43:1105.
  11. Ahlstrand C, Tiselius HG. Urine composition and stone formation during treatment with acetazolamide. Scand J Urol Nephrol 1987; 21:225.
  12. Kuo RL, Moran ME, Kim DH, et al. Topiramate-induced nephrolithiasis. J Endourol 2002; 16:229.
  13. Leppik IE, Willmore LJ, Homan RW, et al. Efficacy and safety of zonisamide: results of a multicenter study. Epilepsy Res 1993; 14:165.
  14. Kubota M, Nishi-Nagase M, Sakakihara Y, et al. Zonisamide - induced urinary lithiasis in patients with intractable epilepsy. Brain Dev 2000; 22:230.
  15. Sheth RD. Metabolic concerns associated with antiepileptic medications. Neurology 2004; 63:S24.
  16. Welch BJ, Graybeal D, Moe OW, et al. Biochemical and stone-risk profiles with topiramate treatment. Am J Kidney Dis 2006; 48:555.
  17. Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia 1996; 37 Suppl 2:S18.
  18. Dodgson SJ, Shank RP, Maryanoff BE. Topiramate as an inhibitor of carbonic anhydrase isoenzymes. Epilepsia 2000; 41 Suppl 1:S35.
  19. Preminger GM, Sakhaee K, Skurla C, Pak CY. Prevention of recurrent calcium stone formation with potassium citrate therapy in patients with distal renal tubular acidosis. J Urol 1985; 134:20.
  20. Fabris A, Lupo A, Bernich P, et al. Long-term treatment with potassium citrate and renal stones in medullary sponge kidney. Clin J Am Soc Nephrol 2010; 5:1663.
  21. 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.
  22. Lemann J Jr, Gray RW, Pleuss JA. Potassium bicarbonate, but not sodium bicarbonate, reduces urinary calcium excretion and improves calcium balance in healthy men. Kidney Int 1989; 35:688.
  23. Coe FL, Parks JH, Asplin JR. The pathogenesis and treatment of kidney stones. N Engl J Med 1992; 327:1141.
  24. Pongchaiyakul C, Domrongkitchaiporn S, Stitchantrakul W, et al. Incomplete renal tubular acidosis and bone mineral density: a population survey in an area of endemic renal tubular acidosis. Nephrol Dial Transplant 2004; 19:3029.
  25. Jhagroo RA, Wertheim ML, Penniston KL. Alkali replacement raises urinary citrate excretion in patients with topiramate-induced hypocitraturia. Br J Clin Pharmacol 2016; 81:131.