Methotrexate Should Not Be Used for Patients With End-Stage Kidney Disease

Abstract

Methotrexate is a widely used disease-modifying anti-rheumatic drug. Its effectiveness has been proven in placebo-controlled trials and in comparison with other disease-modifying anti-rheumatic drugs. The pharmacokinetics of methotrexate are highly variable and unpredictable. In patients with normal renal function, the recommended dose in rheumatoid arthritis ranges between 7.5 and 15 mg/week, but in recent years, even dosages up to 25 mg weekly are used. Toxicity includes myelosuppression, gastrointestinal adverse effects, hepatotoxicity and pneumonitis. Renal impairment and age are considered major risk factors for developing methotrexate toxicity, but studies show conflicting results. Whether methotrexate can be administered to patients with end-stage kidney disease has not been formally tested. The present case illustrates the severe side effects of low-dose methotrexate treatment in a patient with end-stage kidney disease. Seven other cases have reported similar and even more severe and irreversible consequences after low-dose regimen. In view of these side effects we strongly recommend to monitor toxicity rigorously in patients with stage 3 or stage 4 kidney disease and not to use methotrexate in patients with stage 5 kidney disease.

Slow release properties and liver‐targeting characteristics of methotrexate erythrocyte carriers

“…Indeed, for MTX‐RBCs, the elevation of liver distributions was 94%, much higher than the 24% value observed for the kidney. This not only shows the high selectivity of MTX‐RBCs for the liver tissues, but also suggests a helpful role in minimizing renal impairment, which (together with age) is considered a major risk factor in developing MTX toxicity [23,24], because of its narrow therapeutic index [2]. Furthermore, the lowered peak concentration but longer exposure time for MTX‐RBCs compared with free MTX injection, may also contribute to avoiding cytotoxicity generally caused by long duration exposure to high threshold concentrations of MTX [1].…”

How Does a Patient's Primary Renal Disease Impact Chronic Dialysis Management?

“…Methotrexate is renally excreted and while it is dialyzed, removal is limited because of its large volume of distribution; it is contraindicated in ESRD (8).…”

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also more susceptible to arrhythmias, and the rapid fluxes in potassium, calcium, and bicarbonate during conventional dialysis may exacerbate this predisposition (7,8). While there are no prospective randomized studies comparing HD and PD in patients with severe cardiorenal syndrome, it is intuitive that the slow continuous UF and the stable potassium, calcium, and bicarbonate levels achievable with PD should attenuate the predisposition to develop hypotension and arrhythmias.

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Elevated level of serum cystatin-C concentration is a useful predictor for myelosuppression induced by methotrexate for treatment of rheumatoid arthritis

“…MTX-induced myelosuppression has certain risk factors, including renal insufficiency, advanced age, and hypoalbuminemia [6,7]. These risk factors are mutually dependent: elderly patients often have insufficient renal function and hypoalbuminemia, resulting in a decreased rate of renal clearance.…”