What Does Methotrexate Do to Urine? A Pharmacological Guide

October 12, 2025 •

4 min read

Approximately 90% of a methotrexate dose is cleared by the kidneys. This process can significantly alter the properties of urine, most notably its pH level, potentially leading to complications like kidney damage if not properly managed, which directly addresses what does methotrexate do to urine.

Quick Summary

Methotrexate primarily affects urine pH, causing it to become more acidic, which can lead to the precipitation of drug crystals and potential acute kidney injury, particularly with high-dose therapy. Management includes aggressive hydration and urinary alkalinization.

Key Points

Acidic Urine: Methotrexate can lower the urine's pH, making it more acidic.
Crystal Formation Risk: In acidic urine, especially at high doses, methotrexate can precipitate and form crystals in the kidneys, leading to potential acute kidney injury.
Urinary Alkalinization: For high-dose therapy, keeping the urine pH alkaline (above 7) with IV fluids containing sodium bicarbonate is crucial to increase methotrexate solubility and prevent crystal formation.
Role of Hydration: Aggressive hydration is a key preventative measure, as it helps flush the kidneys and maintain adequate urine flow.
Low-Dose Considerations: While less prone to crystal nephropathy, low-dose methotrexate users have an increased risk of urinary tract infections due to the drug's immunosuppressive effects.
Signs of Trouble: Decreased urination, pain, dark urine, or blood in the urine are important urinary side effects that should be reported to a doctor immediately.
Medical Intervention: Severe toxicity resulting from delayed clearance may require specialized treatments like glucarpidase to rapidly lower methotrexate levels.

The Primary Effect: Urinary Acidification

Methotrexate (MTX) is a weak acid, and its elimination from the body primarily occurs through the kidneys. The natural process of renal excretion means that the drug itself, and its metabolic byproducts, pass through the urinary system. When MTX is cleared, it tends to lower the urine's pH, making it more acidic. This change in pH is the root cause of many of the urinary complications associated with the drug.

At a low urine pH (below 7), the solubility of methotrexate is significantly reduced. The acidic environment causes the drug to precipitate and form crystals. These needle-shaped crystals can accumulate within the renal tubules, leading to potentially severe kidney issues, especially with high-dose therapy.

Risk of High-Dose Methotrexate (HD-MTX) and Crystalline Nephropathy

The most significant urinary risks are associated with high-dose methotrexate (HD-MTX), which is used in the treatment of various cancers. In this setting, the large quantity of the drug being eliminated poses a substantial risk for crystalline nephropathy.

Crystalline Nephropathy and Acute Kidney Injury (AKI)

Crystal Precipitation: When urine is too acidic, MTX crystals can form and obstruct the renal tubules.
Acute Kidney Injury: This tubular obstruction can lead to acute kidney injury (AKI), characterized by a rapid decline in kidney function.
Delayed Clearance: AKI impairs the kidneys' ability to excrete MTX, causing drug levels in the blood to remain dangerously high for an extended period, which can cause severe, life-threatening systemic toxicity.

For this reason, patients receiving HD-MTX in a hospital setting are meticulously monitored. This includes checking urine pH and output, as well as serum creatinine and plasma methotrexate levels, to ensure the drug is clearing safely.

Management Strategies for Preventing Renal Toxicity

To prevent the formation of crystals and ensure safe methotrexate clearance, clinicians implement proactive strategies that focus on aggressive hydration and urinary alkalinization.

Aggressive Hydration

High fluid intake is critical. In HD-MTX protocols, intravenous (IV) fluids are administered to promote a brisk diuresis, meaning a high urinary flow rate. This increased flow helps to flush the kidneys and prevent the drug from concentrating enough to form crystals. Protocols specify precise hydration rates, often starting before the MTX infusion begins and continuing for several days afterward.

Urinary Alkalinization

Urinary alkalinization is the process of raising the urine's pH to make it more alkaline (usually 7 or higher). This is typically achieved by adding sodium bicarbonate to the IV fluids. Making the urine more alkaline dramatically increases the solubility of methotrexate, preventing crystal formation. The urine pH is monitored throughout the treatment and adjusted as needed to maintain the target level.

Treatment for Delayed Clearance

If, despite preventative measures, a patient experiences delayed MTX clearance due to renal toxicity, additional interventions may be necessary:

Increased Hydration and Leucovorin Rescue: The rate of hydration may be increased, and high-dose leucovorin is administered to rescue healthy cells from the toxic effects of MTX.
Glucarpidase: For severe cases, glucarpidase, a rescue medication that rapidly breaks down methotrexate in the bloodstream, may be used.

Urinary Side Effects with Low-Dose Methotrexate

Patients on low-dose methotrexate for autoimmune conditions like rheumatoid arthritis or psoriasis also need to be aware of potential urinary effects, although the risk of severe kidney damage is much lower.

Increased Risk of Urinary Tract Infections (UTIs)

Methotrexate is an immunosuppressant, meaning it reduces the activity of the immune system. This can increase susceptibility to infections, including UTIs. Symptoms of a UTI can include frequent or painful urination, cloudy or dark urine, and pelvic pain.

Other Reported Urinary Symptoms

Some patients may experience less common urinary side effects, which should be reported to a healthcare provider:

Burning or painful urination
Blood in the urine (hematuria)
Dark urine
Changes in urination frequency or volume

Comparison of Methotrexate Effects on Urine by Dosage


Feature	Low-Dose Methotrexate (e.g., Rheumatoid Arthritis)	High-Dose Methotrexate (e.g., Cancer)
Primary Effect	Minimal direct impact on urine pH, but can lead to increased risk of UTIs due to immunosuppression.	Significant urinary acidification, leading to low urine pH.
Renal Toxicity Risk	Low, but monitoring is still important, especially in patients with pre-existing kidney issues.	High risk of crystalline nephropathy and acute kidney injury if not proactively managed.
Management	Requires standard hydration to maintain overall kidney health. Management focuses on preventing and treating infections.	Requires aggressive, monitored hydration and urinary alkalinization. Leucovorin and glucarpidase may be used in rescue situations.
Urinary Symptoms	Can include symptoms of UTIs (painful urination, dark or cloudy urine), although these may be related to underlying conditions.	Symptoms of AKI may include decreased or absent urine output, swelling, and back pain. Microscopic examination of urine can show MTX crystals.

Conclusion

Methotrexate has a significant and dose-dependent impact on urine. While low-dose therapy poses a lower risk, primarily associated with immune system suppression, high-dose administration presents a serious risk of renal toxicity due to the drug's acidic nature. The formation of methotrexate crystals in the renal tubules can cause blockages and lead to acute kidney injury if the urine remains acidic. The cornerstone of prevention for high-dose treatment is aggressive hydration and urinary alkalinization to maintain an alkaline urine pH, ensuring the drug remains soluble and is safely excreted. Patients receiving methotrexate, regardless of dose, should be aware of potential urinary side effects and report any concerning symptoms, such as changes in urination or blood in the urine, to their healthcare team promptly. Vigilant monitoring and management are key to mitigating these risks and ensuring patient safety.

NIH Study on High-Dose Methotrexate Toxicity

Frequently Asked Questions

Maintaining an alkaline urine pH (7 or higher) is crucial because methotrexate is a weak acid that becomes less soluble in acidic environments. Alkalinization increases the drug's solubility, preventing it from precipitating as crystals in the kidneys and causing damage.

Yes, methotrexate is an immunosuppressant and can increase a person's risk of developing urinary tract infections (UTIs). Symptoms like frequent urination, burning, or cloudy urine should be reported to a healthcare provider.

Crystalline nephropathy is a type of acute kidney injury caused by the formation and precipitation of methotrexate crystals within the kidney tubules. This can block the tubules and impair kidney function, particularly with high-dose methotrexate therapy.

During high-dose methotrexate therapy, a patient's urine pH is checked frequently, sometimes with every void, using a urine dipstick or other lab tests. This ensures the pH stays at the target level, typically 7 or higher, to prevent crystal formation.

Delayed clearance of methotrexate, often due to kidney injury, can lead to prolonged exposure to toxic drug levels in the body. This can result in serious, life-threatening side effects affecting the bone marrow, liver, and other organ systems.

If you notice blood in your urine, dark urine, or any other significant changes, you should contact your healthcare provider immediately. These can be signs of kidney problems or other serious side effects that require prompt medical evaluation.

For low-dose methotrexate, no special precautions are generally necessary. For high-dose therapy, hospital protocols may advise flushing the toilet twice for the first 48 hours to ensure complete disposal of waste containing the hazardous drug.