Drug Safety

, Volume 31, Issue 10, pp 877–884 | Cite as

Drug-Related Nephrotoxic and Ototoxic Reactions

A Link through a Predictive Mechanistic Commonality
  • Bertha Maria Verdel
  • Eugène P. van Puijenbroek
  • Patrick C. Souverein
  • Hubert G. M. Leufkens
  • Antoine C. G. Egberts
Orginal Research Article

Abstract

Background: Drug-induced ototoxicity is a subject of interest because many diseases are treated with drugs that have potential toxic effects on the ear. There is evidence that both inner ear and kidney tissue are immunologically, biochemically and functionally related. It has been suggested that drugs that influence the transport of sodium and/or potassium change ionic homeostasis in the inner ear and, hence, induce functional disturbances such as hearing loss, tinnitus and vertigo.

Objectives: To assess whether renal suspected adverse drug reactions (sADRs) have predictive value for ear and labyrinth adverse drug reactions (ADRs) and whether drug classes involved have influence ion transport systems.

Study design: Data were obtained from the Netherlands Pharmacovigilance Centre Lareb. The study base comprised all reports of sADRs up until 1 January 2007. Cases were all sADRs for relevant renal disorders and all sADRs for relevant ear disorders. All other reported sADRs were selected as ’non-cases’. The relationship between drug classes and renal, ear and labyrinth sADRs was evaluated by calculating reporting odds ratios (RORs). An ROR >1.50 was regarded as a cut-off value for an association. Drug classes were classified into four groups: (A) ROR kidney <1.50 and ROR ear <1.50 or no reports on ear sADRs (reference group); (B) ROR kidney <1.50 and ROR ear >1.50; (C) ROR kidney >1.50 and ROR ear <1.50 or no reports on ear sADRs; and (D) ROR kidney >1.50 and ROR ear >1.50. For each group, we calculated odds ratios (ORs) for the association between the group classification and the effect on ion channels/ ion transport systems in kidney and ear tissues.

Results: Of 193 drug classes with relevant ADRs for renal disorders, 120 drug classes also had reports on ototoxic reactions. Fourteen out of 120 drug classes had an ROR >1.50 for the association between the drug class and both renal and ear sADRs. Among these drug classes were several with a well known ability to induce renal (adverse) effects and ear and labyrinth disorders, such as loop diuretics, aminoglycosides and quinine. We found that one mechanistic commonality of the drug classes mentioned in the reports was the ability to affect ion transport systems. The percentage of drugs having this property differed between the four groups. The ORs for groups D and B were significantly higher compared with the reference group (OR 12.2, 95% CI 3.0, 30.5 and OR 8.7, 95% CI 2.4, 18.7, respectively), whereas there was no association for group C.

Conclusion: Our data suggest that renal sADRs as such are not a marker for druginduced ear and labyrinth disorders. However, the ability of drugs to act on ion channels or ion transport systems and, therefore, have an influence on ionic homeostasis in the kidney and ear might be a predictor for the possible occurrence of drug-related ototoxicity.

Keywords

Drug Class Loop Diuretic Alport Syndrome Endocochlear Potential Reporting Odds Ratio 

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References

  1. 1.
    Seligmann H, Podoshin L, Ben-David J, et al. Drug-induced tinnitus and other hearing disorders. Drug Saf 1996; 14: 198–212PubMedCrossRefGoogle Scholar
  2. 2.
    Palomar Garcia V, Abdulghani Martinez F, Bodet Agusti FE, et al. Drug-induced otoxicity: current status. Acta Otolaryngol 2001; 121: 569–72PubMedGoogle Scholar
  3. 3.
    Lee CA, Mistry D, Uppal S, et al. Otologic side effects of drugs. J Laryngol Otol 2005; 119: 267–71PubMedGoogle Scholar
  4. 4.
    Committee for Proprietary Medicinal Products (CPMP). Note for guidance on repeated dose toxicity [report no. CPMP/SWP/ 1042/99 corr.]. London: European Agency for the Evaluation of Medical Products, 2000Google Scholar
  5. 5.
    Committee for Proprietary Medicinal Products (CPMP). Note for guidance on safety pharmacology studies for human pharmaceuticals [report no. CPMP/ICH/539/00]. London: European Agency for the Evaluation of Medical Products, 2000Google Scholar
  6. 6.
    Center for Drug Evaluation and Research (CDER). Guidance for industry: S7A safety pharmacology studies for human pharmaceuticals. Rockville (MD): Food and Drug Administration, 2001Google Scholar
  7. 7.
    Arslan E, Orzan E, Santarelli R. Global problem of druginduced hearing loss. Ann N Y Acad Sci 1999; 884: 1–14PubMedGoogle Scholar
  8. 8.
    Vasquez R, Mattucci KF. A proposed protocol for monitoring ototoxicity in patients who take cochleoor vestibulotoxic drugs. Ear Nose Throat J 2003; 82: 181–4PubMedGoogle Scholar
  9. 9.
    Walker Jr EM, Fazekas-May MA, Bowen WR. Nephrotoxic and ototoxic agents. Clin Lab Med 1990; 10: 323–54PubMedGoogle Scholar
  10. 10.
    Black FO, Pesznecker SC. Vestibular ototoxicity: clinical considerations. Otolaryngol Clin North Am 1993; 26: 713–36PubMedGoogle Scholar
  11. 11.
    Izzedine H, Tankere F, Launay-Vacher V, et al. Ear and kidney syndromes: molecular versus clinical approach. Kidney Int 2004; 65: 369–85PubMedCrossRefGoogle Scholar
  12. 12.
    Thodi C, Thodis E, Danielides V, et al. Hearing in renal failure. Nephrol Dial Transplant 2006; 21: 3023–30PubMedCrossRefGoogle Scholar
  13. 13.
    Arnold W. Inner ear and renal diseases. Ann Otol Laryngol 1984; 112: S119–24Google Scholar
  14. 14.
    Lang F, Vallon V, Knipper M, et al. Functional significance of channels and transporters expressed in the inner ear and kidney. Am J Physiol Cell Physiol 2007; 293: C1187–208PubMedCrossRefGoogle Scholar
  15. 15.
    Hunter M. Accessory to kidney disease. Nature 2001; 414: 502–3PubMedCrossRefGoogle Scholar
  16. 16.
    Peters TA, Monnens LA, Cremers CW, et al. Genetic disorders of transporters/channels in the inner ear and their relation to the kidney. Pediatr Nephrol 2004; 19: 1194–201PubMedCrossRefGoogle Scholar
  17. 17.
    World Health Organization. Anatomical Therapeutic Chemical (ATC) classification index. Oslo: WHO Collaborating Centre for Drug Statistics Methodology, 1994Google Scholar
  18. 18.
    van Puijenbroek EP, Bate A, Leufkens HG, et al. A comparison of measures of disproportionality for signal detection in spontaneous reporting systems for adverse drug reactions. Pharmacoepidemiol Drug Saf 2002; 11: 3–10PubMedCrossRefGoogle Scholar
  19. 19.
    Lee JH, Marcus DC. Estrogen acutely inhibits ion transport by isolated stria vascularis. Hear Res 2001; 158: 123–30PubMedCrossRefGoogle Scholar
  20. 20.
    Liu J, Marcus DC, Kobayashi T. Inhibitory effect of erythromycin on ion transport by stria vascularis and vestibular dark cells. Acta Otolaryngol 1996; 116: 572–5PubMedCrossRefGoogle Scholar
  21. 21.
    Lumley CE, Walker SR, Hall GC, et al. The under-reporting of adverse drug reactions seen in general practice. Pharmaceut Med 1986; 1: 205–12Google Scholar
  22. 22.
    Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf 2006; 29: 385–96PubMedCrossRefGoogle Scholar
  23. 23.
    Milstien JB, Faich GA, Hsu JP, et al. Factors affecting physician reporting of adverse drug reactions. Drug Inf J 1986; 20: 157–64Google Scholar
  24. 24.
    Martin RM, Kapoor KV, Wilton LV, et al. Underreporting of suspected adverse drug reactions to newly marketed (“black triangle”) drugs in general practice: observational study. BMJ 1998; 317: 119–20PubMedCrossRefGoogle Scholar
  25. 25.
    De Bruin ML, Pettersson M, Meyboom RH, et al. Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death. Eur Heart J 2005; 26: 590–7PubMedCrossRefGoogle Scholar
  26. 26.
    Humes HD. Insights into ototoxicity: analogies to nephrotoxicity. Ann N Y Acad Sci 1999; 884: 15–8PubMedGoogle Scholar
  27. 27.
    Tran BH. Endolymphatic deafness: a particular variety of cochlear disorder. ORL J Otorhinolaryngol Relat Spec 2002; 64: 120–4PubMedCrossRefGoogle Scholar
  28. 28.
    Ikeda K, Oshima T, Hidaka H, et al. Molecular and clinical implications of loop diuretic ototoxicity. Hear Res 1997; 107: 1–8PubMedCrossRefGoogle Scholar
  29. 29.
    Stypulkowski PH. Mechanisms of salicylate ototoxicity. Hear Res 1990; 46: 113–45PubMedCrossRefGoogle Scholar
  30. 30.
    Prepageran N, Rutka JA. Salicylates, nonsteroidal anti-inflammatory drugs, quinine, and heavy metals. In: Roland PS, Rutka JA, editors. Ototoxicity. Hamilton (ON): BC Decker Inc., 2004: 29–41Google Scholar
  31. 31.
    Takeuchi S, Ando M. Inwardly rectifying K+ currents in intermediate cells in the cochlea of gerbils: a possible contribution to the endocochlear potential. Neurosci Lett 1998; 247: 175–8PubMedCrossRefGoogle Scholar
  32. 32.
    Martini M, Rispoli G, Farinelli F, et al. Intracellular Ca2+ buffers can dramatically affect Ca2+ conductances in hair cells. Hear Res 2004; 195: 67–74PubMedCrossRefGoogle Scholar
  33. 33.
    Curtis LM, ten Cate WJ, Rarey KE. Dynamics of Na,K-ATPase sites in lateral cochlear wall tissues of the rat. Eur Arch Otorhinolaryngol 1993; 250: 265–70PubMedCrossRefGoogle Scholar
  34. 34.
    Pondugula SR, Sanneman JD, Wangemann P, et al. Glucocorticoids stimulate cation absorption by semicircular canal duct epithelium via epithelial sodium channel. Am J Physiol Renal Physiol 2004; 286: F1127–35PubMedCrossRefGoogle Scholar
  35. 35.
    Herman P, Tan CT, van den Abbeele T, et al. Glucocorticosteroids increase sodium transport in middle ear epithelium. Am J Physiol 1997; 272: C184–90PubMedGoogle Scholar
  36. 36.
    Marcotti W, van Netten SM, Kros CJ. The aminoglycoside antibiotic dihydrostreptomycin rapidly enters mouse outer hair cells through the mechano-electrical transducer channels. J Physiol 2005; 567: 505–21PubMedCrossRefGoogle Scholar
  37. 37.
    Juhn SK, Hunter BA, Odland RM. Blood-labyrinth barrier and fluid dynamics of the inner ear. Int Tinnitus J 2001; 7: 72–83PubMedGoogle Scholar
  38. 38.
    Wangemann P. Supporting sensory transduction: cochlear fluid homeostasis and the endocochlear potential. J Physiol 2006; 576: 11–21PubMedCrossRefGoogle Scholar
  39. 39.
    Marcus DC, Chiba T. K+ and Na+ absorption by outer sulcus epithelial cells. Hear Res 1999; 134: 48–56PubMedCrossRefGoogle Scholar
  40. 40.
    Wangemann P. K(+) cycling and its regulation in the cochlea and the vestibular labyrinth. Audiol Neurootol 2002; 7: 199–205PubMedCrossRefGoogle Scholar

Copyright information

© Adis Data Information BV 2008

Authors and Affiliations

  • Bertha Maria Verdel
    • 1
  • Eugène P. van Puijenbroek
    • 2
  • Patrick C. Souverein
    • 1
  • Hubert G. M. Leufkens
    • 1
  • Antoine C. G. Egberts
    • 1
    • 3
  1. 1.Pharmacoepidemiology and Pharmacotherapy, Faculty of ScienceUtrecht Institute for Pharmaceutical SciencesUtrechtthe Netherlands
  2. 2.Netherlands Pharmacovigilance Centre Lareb’s-Hertogenboschthe Netherlands
  3. 3.Department of Clinical PharmacyUniversity Medical Centre UtrechtUtrechtthe Netherlands

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