Abstract
High-dose methotrexate (MTX) is widely used for the treatment of hematological malignancies. Despite the application of routine supportive care measures, such as intensive fluid hydration and urine alkalinization, nephrotoxicity is still a problem. The present study aimed to evaluate the risk factors for MTX-induced nephrotoxicity. We retrospectively reviewed 88 patients who received a regimen consisting of high-dose MTX (1000 mg/m2) and cytosine arabinoside between 2006 and 2018. Nephrotoxicity (≥ grade 2) was observed in 11 patients. Nephrotoxicity was observed only in patients with a high MTX concentration. Other than the MTX concentration, the serum uric acid level and urine pH at day 1 were associated with nephrotoxicity. A multivariate analysis revealed that urine pH was an independent risk factor for MTX-induced nephrotoxicity. Urine pH < 7.0 at day 1 was a significant risk factor for nephrotoxicity (odds ratio, 8.05; 95% confidence interval 1.95–33.3) and was also a predictor of delayed MTX elimination at 72 h after injection. Among pre-treatment factors, a low serum calcium level predicted urine pH < 7.0 at day 1. In conclusion, the present study suggests that low urine pH at day 1 is an independent risk factor for MTX-induced nephrotoxicity.
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References
Deborah AT, Stefan F, Susan O, Carlos BR, Jorge C, Guillermo GM, et al. Chemoimmunotherapy with hyper-CVAD plus rituximab for the treatment of adult Burkitt and Burkitt-type lymphoma or acute lymphoblastic leukemia. Cancer. 2006;106:1569–80.
Sand TE, Jacobsen S. Effect of urine pH and flow on renal clearance of methotrexate. Eur J Clin Pharmacol. 1981;19:453–6.
Skarby T, Jonsson P, Hjorth L, Behrentz M, Bjork O, Forestier E, et al. High-dose methotrexate: on the relationship of methotrexate elimination time vs renal function and serum methotrexate levels in 1164 courses in 264 Swedish children with acute lymphoblastic leukaemia (ALL). Cancer Chemother Pharmacol. 2003;51:311–20.
Jori M, Kenneth RC, Sara B, Weijian L, Nancy LB, Nina DWJ. High incidence of methotrexate associated renal toxicity in patients with lymphoma: a retrospective analysis. Leuk Lymphoma. 2014;55:1345–9.
Jacobs SA, Stoller RG, Chabner B, David GJ. 7- hydroxymethotrexate as a urinary metabolite in human subjects and rhesus monkeys receiving high dose methotrexate. J Clin Invest. 1976;57:534–8.
Mikkelsen TS, Mamoudou AD, Tuckuviene R, Wehner PS, Schroeder H. Extended duration of prehydration does not prevent nephrotoxicity or delayed drug elimination in high-dose methotrexate infusions: a prospectively randomized cross-over study. Pediatr Blood Cancer. 2014;61:297–301.
Jonathan S, Helena E, Robert S. Acetazolamide for alkalinisation of urine in patients receiving high-dose methotrexate. Cancer Chemother Pharmacol. 1991;28:150–1.
Yoshinobu K. Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant. 2013;48:452–8.
Relling MV, Fairclough D, Ayers D, Crom WR, Rodman JH, Pui CH, et al. Patient characteristics associated with high-risk methotrexate concentrations and toxicity. J Clin Oncol. 1994;12:1667–72.
Thode J, Fogh-Andersen N, Wimberley PD, Sorensen AM, Andersen OS. Relation between pH and ionized calcium in vitro and in vivo in man. Scand J Clin Lab Invest. 1983;165:79–82.
Pedersen KO. Binding of calcium to serum albumin, II: effect of pH via competitive hydrogen and calcium ion binding to the imidazole groups of albumin. Scand J Clin Lab Invest. 1972;29:75–83.
Craig BL, Jorge BC. Calcium in chronic kidney disease: myths and realities. Clin J Am Soc Nephrol. 2010;5:S1–2.
Remer T, Manz F. Potential renal acid load of foods and its influence on urine pH. J Am Diet Assoc. 1995;95:791–7.
Michaud DS, Troiano RP, Subar AF, Runswick S, Bingham S, Kipnis V, et al. Comparison of estimated renal net acid excretion from dietary intake and body size with urine pH. J Am Diet Assoc. 2003;103:1001–7.
Cameron JM, Elaine MW, Fredric LC, John A, Kristin JB, Benjamin K. Mechanisms for falling urine pH with age in stone formers. Am J Physiol Renal Physiol. 2019;317:F65–72.
Brandon JO, Shahab B, Jennifer K, Muna C, Vincent GB, Canales B. Age, body mass index, and gender predict 24-hour urine parameters in recurrent idiopathic calcium oxalate stone formers. J Endourol. 2017;31:1335–41.
Nicola A, Manisha C, Alberto VC Jr, Orson WM, Khashayar S. The metabolic syndrome and uric acid nephrolithiasis: novel features of renal manifestation of insulin resistance. Kidney Int. 2004;65:386–92.
Naoko N, Michiaki F, Muhei T, Hitoshi T, Saeko I, Masahiro Y, et al. Low urine pH is a predictor of chronic kidney disease. Kidney Blood Press Res. 2012;35:77–81.
Laura BR, John CP, Colton S, Wenjian Y, Yiping F, Naomi JW, et al. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood. 2013;121:898–904.
Evelien GEH, Marije JK, Sita HV, Melanie MH, Uta F, Bart HWS, et al. Analysis of drug metabolizing gene panel in osteosarcoma patients identifies association between variants in SULT1E1, CYP2B6 and CYP4F8 and methotrexate levels and toxicities. Front Pharmacol. 2020;11:1–9.
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SK designed the study and collected the data. SK, SI, and YK analyzed the data and wrote the manuscript. All authors read and approved the final manuscript.
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For this retrospective study, formal informed consents is not required. This retrospective study was approved by Jichi Medical University Clinical Research Ethics Committee.
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Kawaguchi, S., Fujiwara, Si., Murahashi, R. et al. Risk factors for high-dose methotrexate-induced nephrotoxicity. Int J Hematol 114, 79–84 (2021). https://doi.org/10.1007/s12185-021-03132-8
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DOI: https://doi.org/10.1007/s12185-021-03132-8