What medications are associated with an increased risk of kidney stone formation in patients?

Medications Associated with Kidney Stone Formation

Clinicians must routinely query patients about stone-provoking medications during kidney stone evaluation, as certain drugs directly crystallize in urine or alter metabolic parameters that promote stone formation. 1, 2

Direct Stone-Forming Medications (Crystallize in Urine)

These medications have poor solubility and high urinary excretion, causing direct crystal precipitation:

Antiretroviral Agents

• Indinavir is the most notorious stone-forming drug, causing crystalluria in 20% of treated patients and symptomatic stones as a major side effect 2
• Risk increases with doses of 1000 mg twice daily, low lean-body mass, and concomitant trimethoprim-sulfamethoxazole use 2
• Ritonavir-boosted indinavir regimens further increase risk through higher peak drug concentrations 2
• Atazanavir and other protease inhibitors are among the most frequent causes of drug-induced calculi 3

Antimicrobial Agents

• Sulfonamides (particularly sulfadiazine used for cerebral toxoplasmosis) cause intratubular crystal precipitation leading to acute renal failure 2, 3
• Ciprofloxacin causes intratubular crystal precipitation; avoid rapid IV bolus and ensure adequate hydration 2
• Ceftriaxone may induce nephrolithiasis in patients receiving high doses or long-term treatment 3

Antiviral Agents

• Acyclovir causes intratubular crystal precipitation and acute renal failure when given as rapid IV bolus without adequate hydration 2
• Foscarnet similarly causes crystal-induced acute renal failure and requires hydration plus dose adjustment for renal dysfunction 2

Other Direct Stone Formers

• Ephedrine-containing preparations in subjects receiving high doses or long-term treatment 3

Metabolically-Induced Stone Formation

These medications alter urinary chemistry to promote stone formation:

Calcium and Vitamin D Supplements

• Calcium supplements (not dietary calcium) increase stone risk by 20% in observational studies of older women 1
• Uncontrolled calcium/vitamin D supplements provoke metabolically-induced calculi 3
• Dietary calcium (1,000-1,200 mg/day) is protective, while supplemental calcium increases risk 1

Carbonic Anhydrase Inhibitors

• Acetazolamide and topiramate cause metabolically-induced calculi through effects on urinary pH and calcium/phosphate excretion 3

Certain Diuretics

• Some diuretics (not thiazides, which are protective) can alter renal blood flow and intrarenal hemodynamics, increasing stone risk 2

Critical Prevention Strategies

All patients on stone-forming medications require specific preventive measures:

• Maintain daily water intake of at least 1.5-2.5 liters to achieve urine output of at least 2 liters daily, which lowers concentration of crystallizing substances 2, 4
• Avoid rapid IV bolus administration of acyclovir, ciprofloxacin, and foscarnet 2
• Adjust doses for renal dysfunction in patients receiving potentially nephrotoxic medications 2
• Monitor for crystalluria in high-risk patients, particularly those taking indinavir (urinalysis may show pyuria even without visible crystals) 2

Diagnostic Confirmation

Physical analysis methods are essential for drug-induced stones:

• Calculi analysis by infrared spectroscopy or X-ray diffraction is needed to demonstrate the presence of the drug or its metabolites within stones 3
• Identification of crystalluria or crystals within kidney tissue on renal biopsy has major diagnostic value for intratubular crystal precipitation 3
• Careful clinical inquiry differentiates between common calculi and metabolically-induced calculi, whose incidence is probably underestimated 3

Common Pitfall to Avoid

Do not confuse calcium supplements with dietary calcium—dietary calcium from foods (1,000-1,200 mg/day) reduces stone risk by 51% in randomized trials, while calcium supplements increase risk by 20% 1. Many patients obtain adequate calcium from traditional and calcium-fortified foods without requiring supplementation 1.