In this study we found a methotrexate nephrotoxicity of 5.8%, which is
slightly higher than that reported by other authors (1.8–18%). One of the most important articles about it is that from Schmidt et al., who conducted a study with 218 ALL pediatric patients reporting a 3.2% of moderate to severe delayed elimination incidence when they were exposed to high-dose MTX with 5g/m2. This frequency was 4.2 times higher when 8g/m2 doses were used (4).
It is important to note that the relationship between nephrotoxicity and other side effects of MTX treatment was striking, showing that the damage caused by the drug provokes a retarded elimination leading to high concentrations of MTX itself. This occurs despite the rescue measures, such as an optimal hydration and folinic acid use. Thus, as a consequence of the high levels concentration of MTX, some other adverse effects like myelosuppression, mucositis, liver toxicity, and dermatitis increase (3, 18).
Even though few hospitals in Mexico have access to serum methotrexate determination levels, our hospital does not. Due to this, we use fixed doses of folinic acid as rescue based on the Total Therapy XV protocol, which are only modified when some clinical data suggest a drug elimination delay (mucositis, oliguria, rising creatinine, history of severe toxicity, etc.)
One of the most important findings of this study was to identify that the nephrotoxicity risk was higher in children older than 8 years of age. This is relevant because although several studies have shown that there is a greater number of nephrotoxicity cases at older ages in both children and adults, a cut-off point to determine the exact risk age has not been established. (4, 8, 19–21). Some researchers have suggested using the same cut-off age used in determining the relapse risk in ALL that is 10 years. Thommy Svahn et al. found that the MTX elimination time was shorter in those with a body surface area of less than 1 m2 (p < 0.004), and thus, a greater risk of retarded elimination and acute renal injury with inherent complications such as mucositis (18%) and dermatosis (6%) (18).
Close monitoring of kidney function and its correlation with MTX levels has been subject of research in several publications. Creatinine measurement has been described as a marker of acute kidney injury; however, the cut-off point for the absolute value and the time of measurement after the administration of the methotrexate infusion is still discussed. We found that the nephrotoxicity risk was higher from an absolute value of 0.44 mg/dl, which is similar to that reported by Schmidt et al. of 0.3 mg/dl or 1.5 times the baseline value (4). It is well known that young children have less muscle mass and thus less ability to raise creatinine. Thus, finding slightly elevated levels of creatinine in determinations is of great risk, as is finding a creatinine clearance less than 100 ml/min prior to methotrexate infusion; having lower creatinine clearance levels correlates with high risk of delayed elimination of the drug and with concomitant kidney injury. This was shown in this study as higher baseline creatinine levels were found in those with renal injury. It was proved that a fall in the glomerular filtration rate of 10–30 ml/min or a reduction to 50–60 ml/min was also sufficient to determine nephrotoxicity. (4, 5, 8, 20). The main weakness of this study is that it was retrospective and it was conducted in a single center. Nevertheless, it has the strength of having analyzed a considerable number of events with an adequate data record and a 100% patient follow-up.
This topic requires further prospective studies for monitoring the variation in nitrogen levels depending on the hours elapsed after methotrexate infusion to identify early data more accurately about nephrotoxicity.
Several efforts have been made to prevent the appearance of the nephrotoxic effects of MTX. Some of them focused on the acceleration of the renal excretion of the drug through modifications in the sodium concentration in hydration solutions and reducing dosing intervals in the administration of bicarbonate to favor the clearance and renal tubular excretion of MTX (15). Our results support that for centers in which the measurement of serum MTX levels is not possible, it is important to make a more frequent measurement of creatinine levels after the administration of MTX in order to identify kidney damage early and give longer schedules of hyperhydration to patients older than 8 years and / or baseline creatinine greater than 0.44 mg / dL.
Recent studies have discovered various mechanisms of renal protection in animal models. Through the administration of a compound that acts at the level of the cells of the renal tubular epithelium, it is possible to reduce the destruction of the organic anion transporters (OAT's) whose function is the elimination of MTX, in particular OAT3. This could guide future studies in the search for substances that promote the excretion of the drug without the risk of reducing the efficacy of the treatment (22).