Nephrotoxicity methotrexate

The pathogenesis of methotrexate-induced nephrotoxicity is not understood, but it is thought to result from crystallization of methotrexate in the renal tubules. Adequate hydration and urinary alkalinization are necessary to minimize this effect (61). Urinary beta2 microglobulin may be a useful marker of methotrexate nephrotoxicity (62). 

Co-administration of methotrexate and procarbazine in the treatment of medulloblastomas increases the risk of methotrexate nephrotoxicity. Delayed administration of methotrexate until 72 hours after procarbazine therapy has been given may reduce this risk (65). 

Methotrexate has been used successfully with cyclosporine, either concurrently34 or in rotation. Rotational therapy is particularly effective since it minimizes the serious adverse effects of both agents hepatotoxidty from methotrexate and hypertension and nephrotoxicity from cyclosporine. Having an overlapping treatment period may not be necessary and patients have been successfully switched after a 1-week washout period.21,35 This is a very useful combination of systemic agents in the longterm management of this chronic disease. 

Methotrexate -antifolate antimetabolite cell cycle dependent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hepatotoxicity—more common in high-dose therapy -CNS toxicity—dizziness, malaise, blurred vision, encephalopathy -nephrotoxicity—including acute renal failure, particularly at high doses... 

Concomitant administration of methotrexate and Voltarol, a proprietary preparation of diclofenac, a non-steroidal anti-inflammatory drug, may result in accumulation of methotrexate as its excretion is reduced. The use of diclofenac and diuretics such as bendroflumethiazide may increase the risk of nephrotoxicity. Concomitant use of alcohol and an angiotensin-converting enzyme inhibitor such as lisinopril (Zestril) may result in an enhanced hypotensive effect. Alcohol and the benzodiazepine diazepam (Valium) may result in enhanced sedation. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Q66 Methotrexate should be avoided in a patient v/ith a creatinine clearance of 12 mL/minute. Methotrexate is an antimetabolite drug that is nephrotoxic. 

Methotrexate is an antimetabolite drug that is excreted primarily by the kidney. It is contraindicated in significant renal impairment and in hepatic impairment. It is nephrotoxic and accumulation may occur in renal impairment. Dose should be reduced in renal impairment that is not severe and drug should be avoided if creatinine clearance is less than 20 mL/minute. 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

The principal advantage of MMF over alternative systemic immunosuppressive agents (e.g., methotrexate, cyclosporine) is its relative lack of hepatotoxicity and nephrotoxicity. Adverse effects produced by MMF most commonly include nausea, abdominal cramps, diarrhea, and possibly an increased incidence of viral and bacterial infections. Whether MMF may be associated with an increased long-term risk of lymphoma or other malignancies is controversial however, any such risk is likely to be lower in patients treated for skin disease with MMF monotherapy than in transplant patients treated with combination immunosuppressive therapy. 

Trimethoprim has been reported to decrease the therapeutic effect of cyclosporine with a concomitant increased risk of nephrotoxicity. Increased levels of dapsone, warfarin, methotrexate, zidovudine, and sul-fonylureas may occur when given together with trimethoprim dosages of these drugs should be modified and the patient monitored accordingly. 

Methotrexate acts by inhibition of dihydrofolate reductase, the enzyme requisite for the reduction of dihydrofolic acid (3) to 5,6,7,8-tetrahydrofolic acid (4). In turn, (4) is a precursor to a series of enzyme cofactors (5-7) essential for the transfer of one carbon unit necessary for the biosynthesis of purines and pyrimidines and hence, ultimately, DNA. As an inhibitor of dihydrofolate reductase, methotrexate kills cells during the S phase of the cell cycle, when the cells are in the log phase of growth. Unfortunately, this cytotoxicity is non-selective, and rapidly proliferating normal cells, e.g., gastrointestinal epithelium cells and bone marrow, are dramatically affected as well. In addition, recent use of high dose methotrexate therapy with leucovorin rescue has led to additional clinical problems arising from a dose-related nephrotoxic metabolite, 7-hydroxy methotrexate (8). Finally, the very polar nature of methotrexate renders it virtually impenetrable to the blood-brain barrier, which can necessitate direct intrathecal injection in order to achieve therapeutic doses for the treatment of CNS tumours. 

Tetracycline Tetracycline injections have an acid pH. Incompatibility may reasonably be expected with alkaline preparations or with drugs unstable at low pH. Care should be taken when administering tetracyclines, since chelation takes place with metal ions. Tetracyclines interact with inorganic metal ions. They should not be used with drugs that cause hepatotoxicity and nephrotoxicity (e.g., digoxin, theophylline, ergot alkaloids, methotrexate, oral contraceptives, and penicillins). 

Etodolac This drug has effects similar to those of the other NSAIDs. Gastrointestinal problems may be less common. However, other adverse effects such as fluid retention and abnormal kidney and liver function have been reported. Etodolac may increase the serum levels and thus raise the risk of adverse reactions caused by digoxin, lithium, methotrexate, and enhance the nephrotoxicity of cyclosporine. 

Low-dose methotrexate is usually not regarded as nephrotoxic, and one report of nephrotic syndrome with minimal change disease on renal biopsy should be regarded with caution, since there was recovery after glucocorticoid treatment and withdrawal of concomitant NSAIDs (SEDA-22, 416). 

However, renal toxicity occurs with high-dose methotrexate and more likely to occur with concomitant administration of other nephrotoxic agents, such as aminoglycosides, cephalosporins, NSAIDs, and diuretics (60). 

A patient with no other risk factors developed irreversible nephrotoxicity after four cycles of carboplatin 300 mg/m and methotrexate 50 mg/m (278). This appears to have been an additive effect of drugs that are not individually nephrotoxic until much higher doses. 

Pittman SW, and Frei E. 1977. Weekly methotrexate-calcium leucovorin rescue effect ofalkalinization on nephrotoxicity pharmacokinetics in the CNS, and use in CNS non Elodgkin s lymphoma. CancerTreat Rep. 61 695-701. 

Antimetabolites Nephrotoxicity is generally not a major toxicity of antimetabolite therapy, except when these drugs are administered in high doses or in susceptible patients. Acute renal failure is the most common type of nephropathy induced by the antimetabolites with methotrexate treatment possessing the greatest risk. Acute renal failure has also been reported as a potential toxicity for 5-fluorouracil, 6-thioguanine, cytosine arabinoside, and 5-azacytidine. 

OAT Penicillin Methotrexate Cidofovir Furosemide Various Probenecid NSAIDS Probenecid Probenecid Uremic Toxins f duration of action of penicillin f plasma exposure of methotrexate leading to toxicity J, kidney accumulation and lower incidence of cidofovir nephrotoxicity J, diuretic activity of furosemide J, excretion of OAT substrates... 

Severe somnolence and lethargy may occur with combinations of zidovudine and acyclovir. Concomitant cyclosporine enhances nephrotoxicity. Probenecid decreases acyclovir renal clearance and prolongs the plasma t of elimination. Acyclovir may decrease the rerml clearance of other drugs eliminated by active renal secretion (e.g., methotrexate. ... 

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