Advertisement

Cancer Chemotherapy and Pharmacology

, Volume 56, Issue 5, pp 535–542 | Cite as

Magnesium depletion enhances cisplatin-induced nephrotoxicity.

  • H. Lajer
  • M. Kristensen
  • H. H. Hansen
  • S. Nielsen
  • J. Frøkiær
  • L. F. Østergaard
  • S. Christensen
  • G. Daugaard
  • T. E. N. Jonassen
Original Article

Abstract

Purpose: Nephrotoxicity and magnesium (Mg)-depletion are well-known side effects to cisplatin (CP) treatment. The purpose of this present study was to investigate the role of Mg on CP induced changes in renal function. CP induced renal dysfunction was achieved by treatment with CP or vehicle (2.5 mg/kg) once weekly for 3 weeks. Since the CP-induced renal damage, including tubular reabsorption defects, is most prominent within the outer medulla (OM), changes in the expression pattern of OM aquaporins and sodium transporters including the Na,K-ATPase (α-subunit), type III Na,H-exchanger (NHE3), aquaporin 1 (AQP1) and 2 (AQP2) and the Na,K,2Cl-cotransporter (NKCC2) were investigated by semi-quantitative Western blotting. Experimental design: Rats had access to either a diet with standard Mg or to a Mg-depleted diet. Cisplatin was administered to female Wistar rats once a week for 3 weeks according to four regimens: (1) Cisplatin 2.5 mg/kg body weight i.p., to rats on a diet with standard Mg, (2) Cisplatin 2.5 mg/kg body weight i.p., to rats on a diet with low Mg, (3) Isotonic NaCl 2.5 ml/kg body weight i.p., to rats on a diet with standard Mg, (4) Isotonic NaCl 2.5 ml/kg body weight i.p., to rats on a diet with low Mg. Results: CP had no effect on plasma creatinine or urea in rats with standard Mg intake, but the expression of all five transporters was significantly reduced when compared to vehicle treated rats on standard Mg-intake. Vehicle treated rats on low Mg-intake had a significant reduction in the expression of Na,K-ATPase, NHE3 and NKCC2, but unchanged expression levels of AQP1 or AQP2 when compared to standard treated controls. Forty percent of the CP-treated rats on low Mg-intake died during the experiment and the remaining animals had marked increased plasma creatinine and urea. Furthermore, the Western blot analysis revealed an almost complete disappearance of all four transporters, suggesting a dramatic synergistic effect of CP and Mg-depletion on renal function including the expression pattern of outer medullary sodium transporters and aquaporins. Conclusions: This study indicates a substantial additive effect of Mg-depletion on cisplatin induced renal toxicity as evidenced by significant changes in plasma creatinine and urea, renal failure induced mortality and loss of renal transporters. This should give cause for concern since the nephrotoxicity observed during cisplatin treatment might be substantiated by the known Mg-loss associated with cisplatin treatment especially in patients suffering from intense gastro-intestinal side effects.

Keywords

Hypomagnesemia Cisplatin Renal transporters Renal function Side effect 

Notes

Acknowledgements

The authors are grateful to Bioanalysts Babara Seider and Anette Sørensen for skilled technical assistance.

References

  1. 1.
    Daugaard G, Abildgaard U, Holstein-Rathlou NH, Bruunshuus I, Bucher D, Leyssac PP (1988) Renal tubular function in patients treated with high-dose cisplatin. Clin Pharmacol Ther 44(2):164–172PubMedGoogle Scholar
  2. 2.
    Dobyan DC, Levi J, Jacobs C, Kosek J, Weiner MW (1980) Mechanism of cis-platinum nephrotoxicity: II. Morphologic observations. J Pharmacol Exp Ther 213(3):551–556PubMedGoogle Scholar
  3. 3.
    Willox JC, McAllister EJ, Sangster G, Kaye SB (1986) Effects of magnesium supplementation in testicular cancer patients receiving cis-platin: a randomised trial. Br J Cancer 54(1):19–23PubMedGoogle Scholar
  4. 4.
    Mavichak V, Wong NL, Quamme GA, Magil AB, Sutton RA, Dirks JH (1985) Studies on the pathogenesis of cisplatin-induced hypomagnesemia in rats. Kidney Int 28(6):914–921PubMedGoogle Scholar
  5. 5.
    Lajer H, Daugaard G (1999) Cisplatin and hypomagnesemia. Cancer Treat Rev 25(1):47–58PubMedGoogle Scholar
  6. 6.
    Evans TR, Harper CL, Beveridge IG, Wastnage R, Mansi JL (1995) A randomised study to determine whether routine intravenous magnesium supplements are necessary in patients receiving cisplatin chemotherapy with continuous infusion 5-fluorouracil. Eur J Cancer 31A(2):174–178PubMedGoogle Scholar
  7. 7.
    Lofts FJ, Evans TR, Wastnage R, Mansi JL (1996) Magnesium supplements with cisplatin chemotherapy. Eur J Cancer 32A(3):556–557PubMedGoogle Scholar
  8. 8.
    Macaulay VM, Begent RH, Phillips ME, Newlands ES (1982) Prophylaxis against hypomagnesaemia induced by cis-platinum combination chemotherapy. Cancer Chemother Pharmacol 9(3):179–181PubMedGoogle Scholar
  9. 9.
    Asai T, Nakatani T, Yamanaka S, Tamada S, Kishimoto T, Tashiro K et al (2002) Magnesium supplementation prevents experimental chronic cyclosporine a nephrotoxicity via renin-angiotensin system independent mechanism. Transplantation 74(6):784–791PubMedGoogle Scholar
  10. 10.
    Magil AB, Mavichak V, Wong NL, Quamme GA, Dirks JH, Sutton RA (1986) Long-term morphological and biochemical observations in cisplatin-induced hypomagnesemia in rats. Nephron 43(3):223–230PubMedGoogle Scholar
  11. 11.
    Orlowski J, Kandasamy RA (1996) Delineation of transmembrane domains of the Na+/H+ exchanger that confer sensitivity to pharmacological antagonists. J Biol Chem 271(33):19922–19927PubMedGoogle Scholar
  12. 12.
    Ecelbarger CA, Terris J, Hoyer JR, Nielsen S, Wade JB, Knepper MA (1996) Localization and regulation of the rat renal Na(+)-K(+)-2Cl- cotransporter, BSC-1. Am J Physiol 271(3 Pt 2):F619–F628PubMedGoogle Scholar
  13. 13.
    Nielsen S, Smith BL, Christensen EI, Knepper MA, Agre P (1993) CHIP28 water channels are localized in constitutively water-permeable segments of the nephron. J Cell Biol 120(2):371–383PubMedGoogle Scholar
  14. 14.
    Christensen S, Ottosen PD (1983) Lithium-induced uremia in rats—a new model of chronic renal failure. Pflugers Arch 399(3):208–212PubMedGoogle Scholar
  15. 15.
    Regan RF, Guo Y (2001) Magnesium deprivation decreases cellular reduced glutathione and causes oxidative neuronal death in murine cortical cultures. Brain Res 890(1):177–183PubMedGoogle Scholar
  16. 16.
    Bussiere FI, Gueux E, Rock E, Mazur A, Rayssiguier Y (2002) Protective effect of calcium deficiency on the inflammatory response in magnesium-deficient rats. Eur J Nutr 41(5):197–202PubMedGoogle Scholar
  17. 17.
    Bussiere FI, Gueux E, Rock E, Girardeau JP, Tridon A, Mazur A et al (2002) Increased phagocytosis and production of reactive oxygen species by neutrophils during magnesium deficiency in rats and inhibition by high magnesium concentration. Br J Nutr 87(2):107–113PubMedGoogle Scholar
  18. 18.
    Sato S, Yamate J, Saito T, Hosokawa T, Saito S, Kurasaki M (2002) Protective effect of taurine against renal interstitial fibrosis of rats induced by cisplatin. Naunyn Schmiedebergs Arch Pharmacol 365(4):277–283PubMedGoogle Scholar
  19. 19.
    Ecelbarger CA, Sands JM, Doran JJ, Cacini W, Kishore BK (2001) Expression of salt and urea transporters in rat kidney during cisplatin-induced polyuria. Kidney Int 60(6):2274–2282PubMedGoogle Scholar
  20. 20.
    Kjeldsen K, Norgaard A (1987) Effect of magnesium depletion on 3H-ouabain binding site concentration in rat skeletal muscle. Magnesium 6(1):55–60PubMedGoogle Scholar
  21. 21.
    Daugaard G, Rossing N, Rorth M (1988) Effects of cisplatin on different measures of glomerular function in the human kidney with special emphasis on high-dose. Cancer Chemother Pharmacol 21(2):163–167PubMedGoogle Scholar
  22. 22.
    Lajer H, Bundgaard H, Secher NH, Hansen HH, Kjeldsen K, Daugaard G (2003) Severe intracellular magnesium and potassium depletion in patients after treatment with cisplatin. Br J Cancer 89(9):1633–1637PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2005

Authors and Affiliations

  • H. Lajer
    • 1
    • 5
  • M. Kristensen
    • 4
  • H. H. Hansen
    • 1
  • S. Nielsen
    • 2
  • J. Frøkiær
    • 2
  • L. F. Østergaard
    • 3
  • S. Christensen
    • 4
  • G. Daugaard
    • 1
  • T. E. N. Jonassen
    • 4
  1. 1.Department of Oncology, RigshospitaletCopenhagen University HospitalCopenhagen ØDenmark
  2. 2.The Water and Salt Research Center University of AarhusAarhus CDenmark
  3. 3.Risø National LaboratoryRoskildeDenmark
  4. 4.The Panum InstituteUniversity of CopenhagenCopenhagen NDenmark
  5. 5.Department of OncologyThe Finsen Center, RigshospitaletCopenhagenDenmark

Personalised recommendations