ACTIVITIES OF PROXIMAL TUBULE ENZYMES AND ALBUMIN CONCENTRATION IN URINE OF CHILDREN TREATED WITH METHOTREXATE

Authors

  • Tatjana Vujić Agency for Drugs and Medical Devices of Bosnia and Herzegovina, Veljka Mlađenovića bb, Banja Luka
  • Biljana Davidović Plavšić Banja Luka University, Faculty of Science, Mladena Stojanovića 2, 78000 Banja Luka, Republic of Srpska
  • Snežana Uletilović Banja Luka University, Faculty of Medicine, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska
  • Svjetlana Stoisavljević Šatara Banja Luka University, Faculty of Medicine, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska
  • Jelica Predojević Samardžić University-Clinical Center Banja Luka
  • Živko Saničanin Banja Luka University, Faculty of Medicine, Save Mrkalja 14, 78000 Banja Luka, Republic of Srpska

DOI:

https://doi.org/10.7251/cm.v1i6.1966

Abstract

In order to study methotrexate nephrotoxicity, the activities of proximal tubule epithelial cell membrane enzymes: alanine aminopeptidase (AAP) and gamma-glutamyltransferase (GGT), as well as of lysosomal N-acetyl-beta-D-glucosaminidase (NAG) and urinary albumin concentrations were determined in 12-h-urine samples of 30 patients with lymphoblastomous leukemia. The patients were i.v. receiving 4 individual methotrexate doses of 2000 mg/m2 every 15 days followed by leucovorin as a protector. Control and methotrexate-treated group, each consisting of 30 examinees, included 4–10 years old children of both sexes.

Statistically significant increase of AAP and GGT activities, expressed as U/mmol creatinine was observed after the first two (p < 0.05), as well as after the remaining two therapies (p < 0.01) in relation to the control. Enzymatic activities of these two enzymes decreased to control value before the second and the third methotrexate application, but they increased again after the third application and remained elevated up to the end of experiments. Significant increase of NAG activity expressed as U/mmol creatinine
(p < 0.01), as well as urinary albumin levels (mg/mmol creatinine; p < 0.01) were registered after the third methotrexate therapy and this elevation of the same statistical significance of the differences remained stable till the end of the therapy. Based on these results it can be concluded that during the time period of two first applications nephrotoxic methotrexate action is reversible and at the level of proximal tubule epithelial cell membranes. During the last two applications impairment is irreversible and at the level of cell organelles and glomerular filtration.

References

[1] J. Waling, From methotrexate to peme-trexed and beyond, A review of the pharmacody-namic and clinical properties of antifolates, Invest New Drugs, Vol. 2 (2006) 24−37.

[2] A. Comandone, R. Passera, A. Boglione, V. Tagini, S. Ferrari, R. Cattel, High-dose methotrexate in adult patients with osteosarcoma: clinical and pharmacokinetic results, Acta Oncol., Vol. 44 (2005) 406−409.

[3] H. Marika, M. D. Grönroos, Long-term follow-up of renal function after high-dose methotrexate treatment in children, Pediatric Blood Cancer, Vol. 51 (2008) 535−539.

[4] K. A. Janeway, H. E. Grier, Sequelae of osteosarcoma medical therapy: A review of rare acute toxicities and late effects, Lancet Oncol., Vol. 11 (2010) 670−678.

[5] U. Erdbrȕngger, K. de Groot, Is metho-trexate nephrotoxic? Dose-dependency, comorbidities and comedication, Z. Rheumatol., Vol. 70 (2011) 549−552.

[6] K. Suzuki, K. Doki, M. Homma, H. Ta-maki, S. Hori, H. Ohtani, et al., Co-administration of proton pump inhibitors delays elimination of plasma methotrexate in high-dose methotrexate therapy, Br Clin Pharmacol., Vol. 67 (2009) 44−49.

[7] R. Santucci, D. Leveque, A. Lascoute,
V. Kemmel, R. Herbrech, Delayed elimination of methotrexate associated with co-administration of proton pump inhibitors, Anticancer Res., Vol. 30 (2010) 3807−3812.

[8] B. C. Widemman, F. M. Balis, A. Kim,
M. Boron, N. Jayaprakash, A. Shalabi, et al., Glu-carpidase, leucovorin and thymidine for high-dose methotrexate-induced renal dysfunction: clinical and pharmacologic factors affecting outcome, J Clin Oncol., Vol. 28 (2010) 3979−3984.

[9] L. Hempel, J. Misselwitz, C. Fleck,
K. Kentouche, C. Leder, D. Appenroth, et al., Influence of high-dose methotrexate therapy (HD-MTX) on glomerular and tubular kidney function, Med Pediatr Oncol., Vol. 40 (2003) 348−354.

[10] H. Matsando, M. Fahim, D. S. Gill,
C. M. Hawley, D. W. Johnson, M. K. Gandhi, et al., High dose methotrexate and extended hours high-flux hemodialysis for the treatment of primary central nervous system lymphoma in a patient with end stage renal disease, Am J Blood Res., Vol. 2 (2012) 66−70.

[11] I. Badaganani, R. A. Castro, T. R. Taylor, C. M. Brett, C. C. Huang, D. Stryke, et al., Interaction of methotrexate with organic anion-transporting polypeptide 1A2 and genetic variants, J Pharmacol Exp Ther, Vol. 318 (2006) 521-529.

[12] E. Batlle-Gualda, A. C. Martinez,
A. Guerra, E. Pascual, Urinary albumin excretion in patients with systemic lupus erythematosus without renal disease, Ann Rheum Dis., Vol. 56 (1997) 386−389.

[13] W. S. Hsu, J. T. Kao, J. S. Chen, Clinical significance of urinary N-acetyl-beta-D-glucosaminidase and alanine aminopeptidase, Taiwan Yi Xue Hui Za Zhi, Vol. 88 (1989) 407−409.

[14] S. Skalova, The diagnostic role of uri-nary N-acetyl-beta-D-glucosaminidase (NAG) activity in the detection of renal tubular impairment, Acta Med., Vol. 48 (2005) 75−80.

[15] M. Werner, D. Muruhn, M. Atoba, Use of gel filtration in the assay of urinary enzymes, J Chromatog., Vol. 40 (1969) 254−263.

[16] K. Jung, D. Scholz, An optimized assay of alanine aminopeptidase activity in urine, Clin Chem, Vol. 26 (1980) 1251−1254.

[17] J. P. Persijn, W. van der Slik, A new method for the determination of gamma-glutamyl transferase in serum, J Clin Chem Clin Biochem., Vol. 14 (1976) 421−427.

[18] T. Yagi, R. Hisada, H. Shibata, 3,4-Dintrophenyl-N-acetyl-beta-D-glucosaminide a synthetic substrate for direct spectrophotometric assay of N-acetyl-beta-D-glucosaminidase or N-acetyl-beta-D-hexosaminidase, Anal Biochem, Vol. 183 (1989) 245−249.

[19] A. Hanbeyoglu, A. Kazez, B. Ustündag, N. Akpolat, Determination of urinary N-acetyl-beta-D-glucosaminidase (NAG) levels in experimental blunt renal trauma, Ulus Travma Acil Cerrahi Derg., Vol. 17 (2011) 475−481.

[20] H. Bartels, M. Böhmer, Microdetermination of creatinine, Clin Chim Acta, Vol. 32 (1971) 81−85.

[21] B. T. Doumas, W. A. Watson, H. G. Biggs, Albumin standards and the measurement of serum albumin with bromocresol green, Clin Chim Acta, Vol. 31 (1971) 87−96.

[22] B. T. Doumas, T. Peters, Serum and urine albumin: a progress report on their measurement and clinical significance, Clin Chim Acta, Vol. 258 (1997) 3−20.

[23] T. Vujić, S. Uletilović, J. Predojević Samardžić, B. Davidović-Plavšić, S. Stoisavljević Šatara, Ž. Saničanin, The activity of proximal tubule enzymes in the urine of cephalexin-treated patients, J. Med. Biochem., Vol. 30 (2011) 131−4.

[24] P. Wiland, J. Swierkot, J. Szechinski,
N-acetyl-beta-D-glucosaminidase urinary excretion as an early indicator of kidney dysfunction in rheumatoid arthritis patients on low-dose methotrexate treatment, Br J Rheumatol, Vol. 36 (1997) 59−63.

[25] T. Vujić, B. Davidović Plavšić,
S. Uletilović, S. Stoisavljević Šatara, J. Predojević Samardžić, Ž. Saničanuin, Alkaline phosphatase enzyme and lactate dehydrogenase activity in urine of patients treated with methotrexate, Con-temporary Materials, Vol. V−1 (2014)146−150.

[26] S. Ferrari, F. Piretti, E. Verri, L. Tolen-tins, M. Cesari, M. Versari, et al., Prospective evaluation of renal function in pediatric and adult patients treated with high-dose ifosfamide, cisplatin and high-dose methotrexate, Anticancer Drugs, Vol. 16 (2005) 733−7338.

[27] D. Spasovski, A. Latifi, N. Marina, J. Calovski, I. Kafedžiska, G. Božinovski, et al., Symmetric dimethyl arginine and N-acetyl-beta-D-glucosaminidase lysozymuria of proximal renal tubules as a target for nephrotoxicity in patients with rheumatoid arthritis treated with disease-modifying antirheumatic drugs, J Nephropathol., Vol. 2 (2013) 36−52.

Published

2015-11-11