Kidney Stones (Nephrolithiasis) Side Effect

Kidney stones (renal calculi) are polycrystalline aggregates composed of varying amounts of crystalloid and organic matrix.

Drug-induced kidney stones represent about 1-2% of all kidney stones.

About 70% of the drugs involved in crystalluria (the presence of crystals in the urine) can induce formation of kidney stones2.

Medications can interfere with calcium, oxalate and purine metabolism predisposing to the formation of kidney stones. Drug-induced urinary calculi may also result from the direct crystallization of a certain drug in the urine3 (drug-containing stones). In both situations a lithogenic substance may deposit on kidney stones already present. So, patients with existing renal calculi are at higher risk of drug-induced renal stones.

List of lithogenic drugs implicated in the development of kidney stones (nephrolithiasis):

Drug Incidence
Acetazolamide (Diamox®)16 Inhibits citrate excretion and increases urine pH leading to calcium phosphate stones.
Concomitant use of sodium bicarbonate, or underlying hypercalciuria potentiate the risk
Allopurinol oxypurinol metabolite can precipitate in the urinary tract leading to oxypurinol stones7, allopurinol produces severe xanthinuria leading to xanthine stones8
Amoxicillin drug-induced crystalluria, the risk is increased by low urinary pH, low urine output and high-dose4
Ampicillin drug-induced crystalluria
Antacids, containing aluminium, calcium and magnesium trisilicates and/or carbonates or bicarbonates
Caduet < 2%
Ceftriaxone (Rocephin®)22 7.8%, increases calcium urinary excretion
Celebrex 0.1% to 1.9%
Celexa Rare
Ciprofloxacin (Cipro®)12 high doses may cause crystalluria, crystallises as magnesium salts
Clinoril
Copaxone Infrequent
Crixivan 8.7% to 12.4%
Daranide
Dexamethasone (Decadron®, DexPak®)20 induces hypercalciuria
Dorzolamide (Trusopt®)18
Ephedrine14
Effexor Infrequent
Evoxac < 1%
Exelon Infrequent
Fortovase Rare
Furosemide (Lasix®)19 increases urinary calcium excretion
Guaifenesin (Mucinex®, Bidex 400®, Organidin NR®, Robitussin®)14 excessive amounts induce nephrolithiasis
HIVID < 1%
Humira < 5%
Imitrex Rare
Kaletra < 2%
Lexapro Infrequent
Lipitor < 2%
Methazolamide (Neptazane®)17
Miacalcin < 1%
Nipent < 3%
Nitrofurantoin (Macrobid®)13
Norfloxacin (Noroxin)
Norvir < 2%
Paxil Rare
Permax Infrequent
Phenazopyridine (Pyridium®)
Phenytoin(Dilantin®)21
Prevpac < 1%
Primidone (Mysoline®)15
Protonix < 1%
Relafen < 1%
Remicade > 0.2%
Reminyl Infrequent
Requip Infrequent
Rescriptor
Reyataz < 3%
Rilutek Infrequent
Rocephin
Sandostatin 1% to 15%
Sonata Infrequent
Sulfamethoxazole causes crystalluria in the form of N-acetyl-sulfamethoxazole hydrochloride losangic crystals
Sustiva < 1%
Symbyax Rare
Tasmar Infrequent
Teveten < 1%
Topiramate (Topamax®)5 1% to 20%, the underlying mechanism is carbonic anhydrase inhibition6
Triamterene (Dyrenium®, Maxzide®, Dyazide®)10 low urine volume is a key risk factor for the formation of triamterene-containing renal calculi
Tricor
Trileptal
Uniretic < 1%
Viracept < 2%
Zonisamide (Zonegran®)9 Rare

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Factors predisposing to specific stones:

  • Laxative abuse
  • Calcium or Vitamin D supplements consumption
  • Pre-existing renal calculi
  • Low fluid intake
  • Lack of physical activity
  • Family history
  • Renal anatomy
  • Hyperparathyroidism
  • Disorders predisposing to hyperuricemia
  • Urine pH - alkaline pH promotes formation of the calcium- and phosphate-containing stones, acidic pH promotes formation of the cystine and uric acid stones.
  • Metabolic abnormalities (e.g. hypercalciuria, hypocitraturia)

References

  • 1. Dorfman LE, Smith JP. Sulfonamide crystalluria: a forgotten disease. J Urol. 1970;104(3):482–3.
  • 2. Daudon M, Réveillaud RJ. Drug-induced crystalluria: myths and realities. Ann Biol Clin (Paris). 1986;44(1):25-34. PubMed
  • 3. Kohjimoto Y, Sasaki Y, Hara I. Clinical strategies for prevention of drug-induced urinary calculi. Clin Calcium. 2011 Oct;21(10):1457-63. PubMed
  • 4. Boffa JJ, De Preneuf H, Bouadma L, Daudon M, Pallot JL. Acute renal failure after amoxicillin crystallization. Presse Med. 2000 Apr 8;29(13):699-701. PubMed
  • 5. Maalouf NM, Langston JP, Van Ness PC, Moe OW, Sakhaee K. Nephrolithiasis in topiramate users. Urol Res. 2010
  • 6. Mirza N, Marson AG, Pirmohamed M. Effect of topiramate on acid-base balance: extent, mechanism and effects. Br J Clin Pharmacol. 2009 Nov;68(5):655-61 PubMed
  • 7. Stote RM, Smith LH, Dubb JW, Moyer TP, Alexander F, Roth JL. Oxypurinol nephrolithiasis in regional enteritis secondary to allopurinol therapy. Ann Intern Med. 1980 Mar;92(3):384-5. PubMed
  • 8. Sperling O, Brosh S, Boer P, Liberman UA, De Vries A. Urinary xanthine stones in an allopurinol-treated gouty patient with partial deficiency of hypoxanthine-guanine phosphoribosyltransferase Isr J Med Sci. 1978 Feb;14(2):288-92.
  • 9. Wroe S. Zonisamide and renal calculi in patients with epilepsy: how big an issue? Curr Med Res Opin. 2007 Aug;23(8):1765-73. PubMed
  • 10. Sörgel F, Ettinger B, Benet LZ. The true composition of kidney stones passed during triamterene therapy. J Urol. 1985 Nov;134(5):871-3. PubMed
  • 11. Verdesca S, Cucchiari D, Monari M, Podestà MA, Badalamenti S. Sulfamethoxazole crystalluria. G Ital Nefrol. 2015 May-Jun;32(3). PubMed
  • 12. Thorsteinsson SB, Bergan T, Oddsdottir S, Rohwedder R, Holm R. Crystalluria and ciprofloxacin, influence of urinary pH and hydration. Chemotherapy. 1986;32(5):408-17. PubMed
  • 13. Macdonald JB, Macdonald ET. Nitrofurantoin crystalluria. Br Med J. 1976 Oct 30;2(6043):1044-5. PubMed
  • 14. Assimos DG, Langenstroer P, Leinbach RF, Mandel NS, Stern JM, Holmes RP. Guaifenesin- and ephedrine-induced stones. J Endourol. 1999 Nov;13(9):665-7. PubMed
  • 15. Lehmann DF. Primidone crystalluria following overdose. Med Toxicol Adverse Drug Exp. 1987 Sep-Oct;2(5):383-7. PubMed
  • 16. Rubenstein MA, Bucy JG. Acetazolamide-induced renal calculi. J Urol. 1975 Oct;114(4):610-2. PubMed
  • 17. Shields MB, Simmons RJ. Urinary calculus during methazolamide therapy. Am J Ophthalmol. 1976 May;81(5):622-4. PubMed
  • 18. Carlsen J, Durcan J, Zabriskie N, Swartz M, Crandall A. Nephrolithiasis with dorzolamide. Arch Ophthalmol. 1999 Aug;117(8):1087-8.
  • 19. Ali SK. Renal calculi complicating short-term furosemide therapy after congenital heart surgery. Congenit Heart Dis. 2006 Sep;1(5):251-3. PubMed
  • 20. Kamitsuka MD, Peloquin D. Renal calcification after dexamethasone in infants with bronchopulmonary dysplasia. Lancet. 1991 Mar 9;337(8741):626. PubMed
  • 21. Kalorin CM, Bauer R, White MD. Phenytoin metabolite renal calculus: an index case.J Endourol. 2008 Aug;22(8):1665-8. PubMed
  • 22. Chutipongtanate S, Thongboonkerd V. Ceftriaxone crystallization and its potential role in kidney stone formation. Biochem Biophys Res Commun. 2011 Mar 18;406(3):396-402 PubMed

Published: August 22, 2016
Last updated: December 15, 2017

  • Sulfonamides were the first medications associated with renal stone formation 1.
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