I. Drug-containing stones
1, protease inhibitors.
Protease inhibitors can be effective in treating HIV infection, and protease inhibitors known to cause urinary stones include indinavir, saquinavir, nelfinavir, amprenavir, ritonavir, and atazanavir. Indinavir stones are the most common type of drug-associated stones in recent years, with an incidence of 3-22% during drug administration. Indinavir is poorly soluble, easily crystallizes in the urine, and is associated with urine acidity. Clinical reports indicate that the detection rate of indinavir crystals is as high as 56% when the urine pH is >6,5, and 22% when the urine pH is <5,5. In addition to dose and urine pH, hepatitis C infection, coadministration of acyclovir or compound sulfamethoxazole, and abnormal urine metabolism are also risk factors for indinavir stone formation. The results of stone composition analysis show that indinavir urinary stones can be composed of either pure indinavir or mixed components. Pure indinavir stones are unremarkable on x-ray and CT, but can be suggested by ultrasound and IVU. Most indinavir stones can be expelled with conservative treatment.
2. Aminoglutethimide.
Aminopterin is a clinically used potassium-preserving diuretic. Prior to indinavir treatment of HIV infection, aminopterin stones were the most common drug-related stones, which were previously reported to account for 0.4% of urinary stones. It is now believed that the formation of aminopterin stones is mainly related to three factors: drug dose, urine pH, and previous history of stone disease Fairley et al. found that aminopterin crystals were mostly present at urinary pH <6,0. The incidence of these stones was 35% in patients with a history of stones and only 4% in patients without a history of stones. The results of stone composition analysis showed that only a few aminoglutethimide stones were composed entirely or mainly of aminoglutethimide, and the rest of the stones were mainly composed of calcium oxalate, uric acid and a small amount of aminoglutethimide.
3. Sulfonamides.
The sulfonamides sulfadiazine, compound sulfamethoxazole and salazosulfapyridine are capable of triggering urinary stones. Sulfasalazine is an antibiotic that has been used clinically for many years and is currently used mainly for the immunosuppressive treatment of toxoplasmosis encephalopathy in AIDS patients and transplant patients. The stone was previously reported to account for 0,1% of urinary stones. Sulfasalazine is acetylated by the liver to form N-acetyl sulfasalazine, which is the basic component of sulfasalazine stones because of its poor solubility. N-acetyl sulfasalazine solubility is urinary pH-dependent, tending to deposit at pH <5.5 and increasing 20-fold at pH >7.1.61 Alkalinizing the urine when using sulfasalazine and ensuring adequate Alkalinization of the urine while using sulfadiazine and ensuring adequate urine volume are necessary to prevent the formation of this stone. The stone components of compound sulfamethoxazole and salazosulfapyridine are N-acetyl sulfamethoxazole and acetyl sulfamethoxazole, respectively. 33 of the 40 cases of sulfonamide stone components reported by Albala et al,7 were N-acetyl sulfamethoxazole, 5 were N-acetyl sulfadiazine, and 2 were N-acetyl sulfamoisoxazole.
4. Ceftriaxone sodium.
Ceftriaxone sodium is a third generation cephalosporin, ceftriaxone sodium stones are easy to occur in children, two prospective investigations found that the incidence of this stone in children were 7, 8% and 1, 4%. chutipongtanate and Thongboonkerd. confirmed by in vitro experiments that ceftriaxone anion and cationic calcium can crystallize in artificial urine. In our previous study, we confirmed by infrared spectroscopy and energy spectroscopy that the stone was composed of ceftriaxone calcium, which is capable of causing renal failure. Because ceftriaxone is easy to form crystal precipitation with calcium, it is strictly forbidden to combine ceftriaxone sodium with calcium-containing preparations for infusion.
5. Silicates.
Animal silicate stones are relatively common, human silicate stones are very rare, and its main component to the antacid agent magnesium trisilicate is common. In recent years found that silicone-containing milk thickeners can lead to the formation of silicate stones in infants and children, the treatment of Lyme disease velvet crochet (cat’s claw) can also cause such stones. Silicate stones can be composed entirely of amorphous silica or can be a mixture of calcium oxalate or calcium phosphate. In addition, this type of stone has a high protein matrix content. In the identification of silicate stones, care should also be taken to distinguish artificially added glass or sand grains, whose composition is crystalline silica.
6. Ephedrine and guaiac glycerol ethers.
Ephedrine and guaiac glycerol ether is a plant component extracted drugs, ephedrine is often used as a stimulant, cold medicine and anesthetic boosters, guaiac glycerol ether is often used for expectorant, treatment of asthma. powell and other entanglement reported ephedrine stones containing ephedrine, norephedrine, pseudoephedrine components, the proportion of stones containing this component is 0, 06%. pickens et al. reported 30 cases of stones containing guaifenesin metabolite, B-(2, methoxyphenoxy)-lactic acid component, which accounted for 0, 05% of the stones analyzed in the same period. Patients with a history of renal colic attacks and ephedrine and guaiac glycerol ether administration should be suspected of urinary stones from this drug. Ephedrine and/or guaiac glycerol ether stones do not show up under X-ray and are better treated with ESWL, or by alkalinizing the urine lithotripsyu.
7. Ciprofloxacin.
Ciprofloxacin is a second-generation quinolone antibiotic, and clinically ciprofloxacin stones are very rare. chopra et al. reported a case of ciprofloxacin stones, in which the stone components were ciprofloxacin and uric acid. thorsteinsson et al. concluded that ciprofloxacin stones have urinary pH dependence, and can cause crystaluria at pH >7,3, especially at drug doses >1000 mg, while crystaluria is rare at pH <6,8. 8, crystaluria rarely occurs. Because ciprofloxacin crystals are related to urinary pH, patients with urease producing bacterial infections and renal tubular acidosis need to be cautious when using this drug.
8. Anti-epileptic drugs.
Phenytoin is an antiepileptic drug. kalorin et al. reported a case of phenytoin stone, which is composed of phenytoin metabolite 5-(p-phenylhydroxy)-5-phenylglycylamide and protein matrix. Firmanolide is also an antiepileptic drug that can trigger stones. Its stone component is felaminocardium.
9. Nefuramoxalate.
Nefuramoxalate is a drug for the treatment of ischemic cerebrovascular and peripheral vascular disease. 200 mg of this drug contains 38 mg of oxalic acid component. Retornaz et al. reported a case of stone caused by nefuramoxalate and the stone component was calcium oxalate monohydrate. A study found that the proportion of calcium oxalate monohydrate crystalluria was significantly higher in elderly people taking nefuramoxamate than in the control population (51% versus 31%). Since nefuramoxamate significantly increases urinary oxalate excretion, patients on long-term use of this drug should be encouraged to drink more water to prevent the formation of calcium oxalate stones.
II. Drug metabolic effect stones
1. Calcium supplements and vitamin D.
Since most urinary stones are calcium-containing, it used to be commonly believed that patients with stones needed to restrict their calcium intake. Current findings suggest that a calcium-restricted diet increases the risk of stones and that a higher level of calcium diet reduces the risk of stones. Several studies have concluded that calcium supplements neither increase nor decrease the risk of stones. One study found that postmenopausal women taking calcium supplements and vitamin D had a 17% higher risk of developing stones than the placebo group. The timing of calcium supplements is a key factor in their stone formation, and calcium supplements taken without food do not bind oxalic acid in the intestine, thereby reducing urinary excretion of oxalic acid B. Although the relationship between calcium supplements and vitamin D and stone development needs further study, it is not necessary to limit treatment for patients with stones who require calcium and vitamin D supplementation, and calcium and vitamin D supplements taken in moderation and taken at the same time as food appear to be safer.
2. Vitamin C.
Vitamin C is an essential micronutrient that cannot be synthesized by the body and requires in vitro intake; the dietary recommendation is 60 mg/d. Because vitamin C is metabolized to oxalic acid in the body, it was thought in the past that supplementation with vitamin C might increase the risk of calcium oxalate stone formation. The relationship between vitamin C supplementation and urinary oxalic acid excretion and pH is still controversial.Baxmann et al. found that urinary excretion of oxalic acid increased by 61% and 41% in patients with stones after supplementation with 1 g/d and 2 g/d of vitamin C, respectively, and urinary pH was not affected.Curhan et al. showed by a long-term questionnaire survey of female patients with no previous history of stones that vitamin C dose had no significant effect on stone incidence. Overall, the relationship between vitamin C and the risk of stone development needs further study.
3. Carbonic anhydrase inhibitors.
Acetazolamide, topiramate, and zonisamide are all carbonic anhydrase inhibitors and are used clinically for the treatment of glaucoma and intractable epilepsy. Carbonic anhydrase inhibitors inhibit renal tubular bicarbonate reabsorption and hydrogen ion secretion, thus secondary to increased reabsorption of constitutive citrate, so the urine pH of patients treated with this drug is usually high, while citrate is low, which is easy to induce calcium phosphate stones. The first clinical use of acetazolamide was found by Daudon and Jungers, who found that acetazolamide caused 0.08% of urinary stones in the same period, and that this type of stone was mainly composed of carbonate apatite. sterrett et al. found acetazolamide to be an effective supplement when citrate was not effective in dissolving cystine stones or uric acid stones, but attention should be paid to calcium phosphate stone formation. Mahmoud et al. found a 5,2% incidence of topiramate stones by following children treated with topiramate for ≥1 year. Kuo et al. reported two patients with topiramate stones, one with a stone composition of 100% calcium phosphate and the other with a stone composition of 92% calcium hydrogen phosphate, 5% calcium phosphate, and 1% calcium oxalate monohydrate. Wroe concluded that the risk of stone formation with zonisamide is low, and the results of clinical trials in the United States and Europe showed that stones occur in I,2% of patients after 8,7 years of zonisamide treatment.
4. Furosemide.
Furosemide is a powerful tab diuretic that can lead to elevated urinary calcium, and renal calcium deposits and kidney stones can occur in premature infants after long-term treatment with furosemide. Drug dose, urinary calcium concentration, oxalate concentration, uric acid concentration, and infant body mass are the major risk factors for renal calcium deposits. The component of furosemide that causes stones can be calcium oxalate, calcium phosphate, or a combination of both, and Saarela et al. found that long-term furosemide treatment also caused renal calcium deposits in term infants. There have been no reports of furosemide causing renal calcium deposits or kidney stones in adults.
5.Laxatives.
Laxatives are a class of drugs used in the clinical treatment of constipation. The results of clinical studies have shown that long-term use of laxatives can cause a kind of uric acid stones. Kuruma et al. analyzed the clinical data of 33 patients with ammonium urate stones in Japan. 7 cases of simple ammonium urate stones and 5 cases of mixed ammonium urate stones had a history of laxative abuse.
6. Bacillus oxalicus-sensitive antibiotics.
Bacillus oxalicus is a symbiotic bacterium parasitic in human colon and using oxalic acid as the only energy source, which can degrade oxalic acid in the intestine and reduce the absorption of oxalic acid. In recent years, there has been increasing interest in the role and potential application of B. oxalicum in the pathogenesis of stone disease. Findings suggest that B. oxalicus can significantly reduce oxalic acid levels in the urine and the risk of recurrence in patients with calcium oxalate stones. In both stone patients and control populations, the rate of detection of B. oxalate correlated with the use of antibiotics, and some antibiotics had specific sensitivity to B. oxalate. This suggests that antibiotic use, especially abuse, may increase the risk of calcium oxalate stone formation by affecting intestinal oxalobacteria and subsequently.
7. Allopurinol.
Allopurinol is a xanthine dehydrogenase inhibitor that limits the conversion of hypoxanthine to uric acid and reduces uric acid synthesis, but the concentration of hypoxanthine and the intermediate xanthine also increases during the process, leading to increased urinary concentrations of the latter two. Because xanthine is less soluble than hypoxanthine, stones may form when the urine is supersaturated with xanthine. Patients with myeloproliferative disorders and Lesch-Nyhan syndrome are clinically prone to xanthine stones after allopurinol therapy, which do not show up on x-ray and have similar attenuation values to uric acid stones on CT. The control measures for allopurinol stones are based on hydration, and alkalinization therapy is less likely to dissolve stones because xanthine solubility is less affected by acidity and alkalinity.
In summary, drug-related stones are mostly of medical origin, and patients have a history of related drug use. Clinicians should pay attention to patients’ drug use history during consultation. The risk factors for drug-related stone formation are related to both the characteristics of the drug itself, such as poor solubility of the drug or its metabolites, high drug dose, and long treatment time; and the physical condition of the patient, such as low urine volume, abnormal urine pH, abnormal urine metabolism into stone salts, and previous history of stone disease. Clinicians need to consider a combination of drug and patient-related lithogenic risk factors when treating patients with these drugs.
Stones containing drugs or their metabolites have a specific imaging presentation and are not usually visible on x-ray, but CT, ultrasound, IVU, etc. are needed to determine the diagnosis. Drug-related stones need to be prevented, and their treatment includes stopping or reducing the dosage of related drugs, conservative treatment such as hydration and urinary pH adjustment, and surgery, depending on the specific situation of drug-related stones.