Skip to main content
SpringerLink
Log in

Ifosfamide toxicity in cultured proximal renal tubule cells

  • Original Aricle
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Renal injury is a common side effect of the chemotherapeutic agent ifosfamide. Current evidence suggests that ifosfamide metabolites, particularly chloroacetaldehyde, produced within the kidney contribute to nephrotoxicity. The present study examined the effects of ifosfamide and its metabolites, chloroacetaldehyde and acrolein, on rabbit proximal renal tubule cells in primary culture, using a transwell culture system that allows separate access to apical and basolateral cell surfaces. The ability of the uroprotectant medications sodium 2-mercaptoethanesulfonate (mesna) and amifostine to prevent chloroacetaldehyde-and acrolein-induced renal cell injury was also assessed. Ifosfamide (2,000–4,000 μM) did not affect transcellular inulin diffusion but caused a modest but significant impairment in organic ion transport; this impairment was greater when ifosfamide was added to the basolateral compartment of the transwell. Chloroacetaldehyde and acrolein (6.25–100 μM) produced dose-dependent impairments in transcellular inulin diffusion and organic ion transport. Chloroacetaldehyde was a more potent toxin than acrolein. Co-administration of mesna or amifostine prevented metabolite toxicity. Amifostine was only protective when added to the apical compartment of transwells. These results show that ifosfamide is taken up by renal tubule cells preferentially through their basolateral surfaces, and supports the hypothesis that chloroacetaldehyde is primarily responsible for ifosfamide-induced nephrotoxicity. The protective effect of mesna and amifostine in vitro contrasts with clinical experience showing that these medications do not eliminate ifosfamide nephrotoxicity in vivo.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Skinner R, Sharkey IM, Pearson AD, Craft AW (1993) Ifosfamide, mesna and nephrotoxicity in children. J Clin Oncol 11:173–190

    Article  CAS  Google Scholar 

  2. Ho PT, Zimmerman K, Wexler LH, Blaney S, Jarosinski P, Izraeli S, Balis FM (1995) A prospective evaluation of ifosfamide related nephrotoxicity in children and young adults. Cancer 76:2557–2564

    Article  CAS  Google Scholar 

  3. Skinner R, Cotterill SJ, Stevens MC (2000) Risk factors for nephrotoxicity after ifosfamide treatment in children. Br J Cancer 82:1636–1645

    Article  CAS  Google Scholar 

  4. Furlanut M, Franceschi L (2003) Pharmacology of ifosfamide. Oncology 65 (Suppl 2):2–6

    Article  CAS  Google Scholar 

  5. Springate JE, Zamlauski-Tucker M, Lu H, Chan K (1997) Renal clearance of ifosfamide. Drug Metab Dispos 29:1081–1082

    Google Scholar 

  6. Springate JE, Chan K, Lu H, Davies S, Taub M (1999) Toxicity of ifosfamide and its metabolite chloroacetaldehyde in cultured renal tubule cells. In Vitro Cell Dev Biol Anim 35:314–317

    Article  CAS  Google Scholar 

  7. Zamlauski-Tucker M, Morris M, Springate JE (1994) Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney. Toxicol Appl Pharmacol 129:170–175

    Article  CAS  Google Scholar 

  8. Springate JE (1997) Ifosfamide metabolite chloroacetaldehyde causes renal dysfunction in vivo. J Appl Toxicol 17:75–79

    Article  CAS  Google Scholar 

  9. Zaki EL, Springate JE, Taub M (2003) Comparative toxicity of ifosfamide metabolites and protective effect of mesna and amifostine in cultured renal tubule cells. Toxicol In Vitro 17:397–402

    Article  CAS  Google Scholar 

  10. Brodehl J (1992) The Fanconi syndrome. In: Edelmann CM (ed), Pediatric Kidney Disease. Little Brown, Boston, p 1849

    Google Scholar 

  11. Taub M (1990) Primary kidney cells. In: Pollard J, Walker J (eds) Methods in molecular biology, Vol. 5, Animal Cell Culture. Humana Press, Clifton NJ, pp 189–196

    Google Scholar 

  12. Kurowski V, Cerny T, Kupfer A, Wagner T (1991) Metabolism and pharmacokinetics of oral and intravenous ifosfamide. J Cancer Res Clin Oncol 117:S148–S153

    Article  Google Scholar 

  13. Takamoto S, Sakura N, Namera A, Yashiki M (2004) Monitoring of urinary acrolein concentration in patients receiving cyclophosphamide and ifosphamide. J Chromat B 806:59–63

    Article  CAS  Google Scholar 

  14. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  CAS  Google Scholar 

  15. Genestie I, Morin J, Vannier B, Lorenzon G (1995) Polarity and transport properties of rabbit kidney proximal tubule cells on collagen IV-coated porous membranes. Am J Physiol 269:F22–F30

    Article  CAS  Google Scholar 

  16. Woodland C, Ito S, Granvil CP, Wainer IW, Klein J, Koren G (2000) Evidence of renal metabolism of ifosfamide to nephrotoxic metabolites. Life Sci 68:109–117

    Article  CAS  Google Scholar 

  17. Aleska K, Ito S, Koren G (2004) Renal tubule metabolism of ifosfamide to the nephrotoxic chloroacetaldehyde-pharmacokinetic modeling for estimation of intracellular levels. J Lab Clin Med 143:156–162

    Google Scholar 

  18. Jones DP, Jiang B, Chesney R, Goren M (1994) Relative toxicity of ifosfamide and metabolites in cultured renal tubular cells. Pediatr Res 41:809A

    Google Scholar 

  19. Broadhead CL, Walker D, Skinner R, Simmons NL (1998) Differential cytotoxicity of ifosfamide and its metabolites in renal epithelial cell cultures. Toxicol In Vitro 12:209–217

    Article  CAS  Google Scholar 

  20. Mohrmann M, Pauli A, Ritzer M, Schonfeld B, Seifert B, Brandis M (1992) Inhibition of sodium-dependent transport systems in LLC-PK1 cells by metabolites of ifosfamide. Renal Physiol Biochem 15:289–301

    CAS  PubMed  Google Scholar 

  21. Mohrmann M, Kupper N, Schonfeld B, Brandis M (1995) Ifosfamide and mesna: effects on the Na/H exchanger in renal epithelial cells in culture. Renal Physiol Biochem 18:118–127

    CAS  PubMed  Google Scholar 

  22. Benesic A, Schwerdt G, Mildenberger S, Freudinger R, Gordjani N, Gekle M (2005) Disturbed Ca2+-signaling by chloroacetaldehyde: a possible mechanism for chronic ifosfamide nephrotoxicity. Kidney Int 68:2029–2041

    Article  CAS  Google Scholar 

  23. Ormstad K, Orrenius S, Lastbom T (1983) Pharmacokinetics and metabolism of sodium 2-mercaptoethanesulfonate in the rat. Cancer Res 43:333–338

    CAS  PubMed  Google Scholar 

  24. Goren MP, Hsu LC, Li JT (1998) Reduction of dimesna to mesna by the isolated perfused rat liver. Cancer Res 58:4358–4362

    CAS  PubMed  Google Scholar 

  25. Schwerdt G, Gordjani N, Benesic A, Freudinger R, Wollny B, Kirchhof A, Gekle M (2006) Chloroacetaldehyde- and acrolein-induced death of human proximal tubule cells. Pediatr Nephrol 21:60–67

    Article  Google Scholar 

  26. Capizzi RL (1996) Amifostine: preclinical basis for broad-spectrum selective cytoprotection of normal tissues from cytotoxic therapies. Semin Oncol 23:2–17

    CAS  PubMed  Google Scholar 

  27. Dubourg L, Michoudet C, Cochat P, Baverel G (2001) Human kidney tubules detoxify chloroacetaldehyde, a presumed nephrotoxic metabolite of ifosfamide. J Am Soc Nephrol 12:1615–1623

    CAS  PubMed  Google Scholar 

  28. Chung SD, Alavi N, Livingston D, Hiller S, Taub M (1982) Characterization of primary rabbit kidney cultures that express proximal tubule functions in a hormonally defined medium. J Cell Biol 95:118–126

    Article  CAS  Google Scholar 

  29. Hartmann JT, Knop S, Fels LM, Van Vangerow A, Stolte H, Kanz L, Bokemeyer C (2000) The use of reduced doses of amifostine to ameliorate nephrotoxicity of cisplatin/ifosfamide-based chemotherapy in patients with solid tumors. Anticancer Drugs 11:1–6

    Article  CAS  Google Scholar 

  30. Rick O, Beyer J, Schwella N, Schubart H, Schleicher J, Siegert W (2001) Assessment of amifostine as protection from chemotherapy-induced toxicities after conventional and high-dose chemotherapy in patients with germ cell tumor. Ann Oncol 12:1151–1155

    Article  CAS  Google Scholar 

  31. Petrilli AS, Oliveira DT, Ginani VC, Kechichian R, Tanaka C, Dias CG, Brunetto AL, Cardoso-Almeida MT, de Camargo B (2002) Use of amifostine in the therapy of osteosarcoma in children and adolescents. J Pediatr Hematol Oncol 24:188–191

    Article  Google Scholar 

  32. de Kraker J, Bierins M, Offringa M (2000) Lack of protection of proximal tubular cells by amifostine in ifosfamide-containing regimens. Med Pediatr Oncol 34:78–79

    Article  Google Scholar 

Download references

Acknowledgements

This work was supported by a grant from The National Kidney Foundation of Western New York and The James H. Cummings Foundation.

Author information

Authors and Affiliations

  1. Department of Pediatrics, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    James Springate

  2. Department of Biochemistry, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, 14214, USA

    Mary Taub

  3. Division of Nephrology, Women & Children’s Hospital, 219 Bryant Street, Buffalo, NY, 14222, USA

    James Springate

Authors
  1. James Springate
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mary Taub
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James Springate.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Springate, J., Taub, M. Ifosfamide toxicity in cultured proximal renal tubule cells. Pediatr Nephrol 22, 358–365 (2007). https://doi.org/10.1007/s00467-006-0328-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-006-0328-7

Keywords

Search

Navigation