About Kidney Side Effects of Methotrexate

Methotrexate, sold under the trade names Rheumatrex and Trexall, is classified as an antimetabolite medication. This means that it effectively interferes with the normal metabolism of cells. Methotrexate is effective in treating Rheumatoid Arthritis, Psoriasis, cancers and ectopic pregnancies. Patients taking methotrexate should be monitored closely by their doctor as it can induce a variety of side effects including causing kidney damage.

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Methotrexate is used to treat rheumatoid arthritis, a chronic autoimmune inflammatory disease. The exact mode of action is not yet understood but methotrexate acts as an anti-inflammatory and may change the body's immune response, which contributes to causing the disease. Methotrexate is most known as a chemotherapy agent because it is effective at killing rapidly dividing cells. It does this by competing with folic acid (a B vitamin essential for cell growth and division) thereby causing a deficiency of folic acid within the cells. Without folic acid, the cells die. Methotrexate, however, also affects healthy cells within the body, such as in the kidney, thereby causing side effects.

Kidney Response

Methotrexate is excreted from the body through the kidneys. High doses of methotrexate, defined as more than 1 g m -2 body surface areas, can be toxic to the kidneys. As the methotrexate breaks down in the body, there are pieces that are not soluble in the acidic urine. These pieces can precipitate (meaning to fall out of solution) and accumulate, causing the toxicity to the kidney and also slowing down the excretion of the methotrexate from the body. If left untreated, this renal dysfunction can lead to kidney damage, renal failure and even death.


Leucovorin is a vitamin complex that is similar to folic acid. For patients receiving high doses of methotrexate to treat conditions such as leukemia, lymphoma or head and neck cancer, the addition of leucovorin to the treatment helps to decrease the incidence of kidney toxicity.

Carboxypeptidase G2

Carboxypeptidase G2 (CPDG2) is an enzyme that breaks down antifolates such as methotrexate. CPDG2 hyrolyzes (breaks down by means of water) methotrexate into an inactive molecule called DAMPA and glutamate. Therefore patients experiencing kidney toxicity due to methotrexate can be treated with CPDG2 to rapidly reduce the concentration of methotrexate in the blood before further damage and renal failure occur.


There are several steps that can be taken prior to treatment with methotrexate to decrease the incidence of kidney toxicity. Pretreatment hydration, making sure the patient's body is thoroughly hydrated by drinking plenty of fluids, helps to decrease the precipitation and accumulation of methotrexate debris. In addition, making the urine alkaline (more basic) helps as the methotrexate debris is more soluble in bases than acids. Most important is routine monitoring of the methotrexate levels in the blood to ensure doses are not high enough to induce kidney toxicity.

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