Is methotrexate (MTX) nephrotoxic, especially in patients with impaired renal function?

Is Methotrexate Nephrotoxic?

Yes, methotrexate is nephrotoxic, particularly at high doses (≥500 mg/m²), where it causes acute kidney injury in 2-12% of patients through crystallization in renal tubules, but low-dose methotrexate used for rheumatic and dermatologic conditions has minimal direct nephrotoxic effects—the primary concern is that pre-existing renal impairment dramatically increases the risk of life-threatening myelosuppression rather than causing kidney damage itself. 1, 2

Dose-Dependent Nephrotoxicity Profile

High-Dose Methotrexate (≥500 mg/m²)

• Direct nephrotoxicity occurs through methotrexate crystallization in renal tubular lumen, leading to acute tubular toxicity and acute kidney injury. 2
• The FDA warns that methotrexate elimination is reduced in patients with impaired renal function, requiring especially careful monitoring for toxicity and dose reduction or discontinuation. 1
• Nephrotoxicity incidence ranges from 2-12% in patients receiving high-dose therapy despite appropriate hydration and urine alkalinization. 3, 2
• Risk factors for high-dose nephrotoxicity include: male gender (OR 2.3), low albumin <3 g/dL (OR 0.44), urine pH <7.0 at day 1 (OR 8.05), elevated serum uric acid, and concurrent use of interacting medications or furosemide (OR 2.56). 3, 4

Low-Dose Methotrexate (<30 mg weekly)

• Low-dose methotrexate used for psoriasis and rheumatoid arthritis has no clinically relevant direct nephrotoxic effects. 5
• The critical issue is not that low-dose methotrexate damages kidneys, but rather that renal impairment delays methotrexate clearance, leading to prolonged drug exposure and life-threatening myelosuppression—the most important cause of methotrexate-associated death. 6, 7
• Hematologic toxicity is significantly increased in patients with renal insufficiency, requiring dose adjustment rather than avoidance due to nephrotoxicity concerns. 8

Mechanism of Renal Involvement

• Renal excretion occurs by glomerular filtration and active tubular secretion, with 80-90% of administered dose excreted unchanged in urine within 24 hours. 1
• Nonlinear elimination due to saturation of renal tubular reabsorption occurs, making impaired renal function a major factor in delayed drug clearance and subsequent toxicity. 7, 1
• The aqueous solubility of the metabolite 7-hydroxymethotrexate is 3-5 fold lower than the parent compound, contributing to precipitation risk in renal tubules at high doses. 1

Dose Adjustment Requirements for Renal Impairment

Moderate Renal Impairment (CrCl 20-50 mL/min)

• Reduce methotrexate dose by 50% and consider a test dose at this reduced level to assess tolerability. 6, 7
• The British Association of Dermatologists specifically recommends halving the dose for patients with creatinine clearance 20-50 mL/min (CKD stage G3b). 6
• Enhanced monitoring with complete blood count, liver function tests, and renal function every 2-4 weeks initially after dose adjustment is essential. 6, 7

Severe Renal Impairment (CrCl <20 mL/min)

• Methotrexate should be avoided entirely in patients with creatinine clearance <20 mL/min. 7
• The American College of Rheumatology contraindicates methotrexate in rheumatoid arthritis patients with eGFR <30 mL/min. 9

Monitoring for Nephrotoxicity

• Urinalysis is recommended to detect early signs of kidney injury including hematuria, proteinuria, and crystalluria before serum creatinine rises, particularly for high-dose therapy. 6
• Baseline renal function assessment including serum creatinine, blood urea nitrogen, and calculated creatinine clearance using the Cockcroft-Gault equation (not estimated GFR alone) is essential before initiation. 6, 7
• For standard low-dose therapy, renal function monitoring should occur within 1-2 months of initiation and every 3-6 months thereafter, with more frequent monitoring (every 2-4 weeks) for patients with baseline renal impairment. 8, 6

Drug Interactions That Increase Nephrotoxicity Risk

• NSAIDs, penicillins, proton pump inhibitors, and trimethoprim-sulfamethoxazole compete for renal tubular secretion and significantly increase methotrexate toxicity risk. 8, 7
• The FDA specifically warns that unexpectedly severe (sometimes fatal) bone marrow suppression has been reported with concomitant NSAID administration, particularly in high-dose regimens. 1
• Number of drug interactions is an independent risk factor for nephrotoxicity development (OR 1.60). 3

Critical Pitfalls to Avoid

• Do not rely on estimated GFR alone—calculate actual creatinine clearance using the Cockcroft-Gault equation, as eGFR may overestimate renal function in patients requiring dose adjustment. 6, 7
• Monitor for downward trends in blood counts even if absolute values remain within normal range, as myelosuppression from delayed clearance can occur despite "normal" labs. 6
• Ensure folic acid supplementation at 1-5 mg daily (except on methotrexate day) to reduce hematologic toxicity without compromising efficacy. 6, 7
• Watch for mucositis, fever, diarrhea, and skin reactions as early signs of methotrexate toxicity requiring immediate intervention. 6