Advertisement

Drug Safety

, Volume 5, Issue 2, pp 94–108 | Cite as

Amphotericin B Nephrotoxicity

  • Ramzi Sabra
  • Robert A. Branch
Review Article Drug Experience

Summary

The frequency of fungal infections is increasing. Amphotericin B remains the antifungal drug of choice for most systemic infections, but a limiting factor for its use is the development of nephrotoxicity. Amphotericin B-induced nephrotoxicity is manifested as azotaemia, renal tubular acidosis, impaired renal concentrating ability and electrolyte abnormalities like hypokalaemia and sodium and magnesium wasting. All these abnormalities occur to varying degrees in almost all patients receiving the drug. Upon withdrawal of therapy renal function gradually returns to baseline, although in some instances permanent damage is sustained, especially when the cumulative dose exceeds 5g. Salt depletion enhances the development of nephrotoxicity. The mechanism of nephrotoxicity involves direct cell membrane actions to increase permeability, as well as indirect effects secondary to activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators (thromboxane A2). The latter effects are presumably responsible for the observed acute decreases in renal blood flow and filtration rate, responses that are inhibited by several physiological and pharmacological interventions. Changes in intracellular calcium levels may also contribute to the observed effects.

In the clinical situation, and in long term models of nephrotoxicity in the rat, salt loading protects against deterioration in renal function; recommendations are made for the optimisation of amphotericin B therapy by salt loading. New preparations of the drug, such as liposomal amphotericin B, may also prove useful in minimising nephrotoxicity while maintaining antifungal activity, but further research is needed with both salt loading and liposomal amphotericin B to confirm or deny their protective effect on kidney function.

Keywords

Amphotericin Renal Blood Flow Liposomal Amphotericin Renal Tubular Acidosis Ticarcillin 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Andriole VT. On the anatomy of amphotericin-B cholesterol pores in lipid bilayer membranes. Kidney International 4: 337–345, 1973CrossRefGoogle Scholar
  2. Atkinson AJ, Bennett JE. Amphotericin B pharmacokinetics in humans. Antimicrobial Agents and Chemotherapy 13: 271–276, 1978PubMedCrossRefGoogle Scholar
  3. Badr KF, DeBoer DK, Takahashi K, Harris RC, Fogo A, et al. Glomerular responses to platelet activating factor in the rat: role of thromboxane A2. American Journal of Physiology 256: F35–F43, 1989PubMedGoogle Scholar
  4. Barbour GL, Straub KD, O’Neal BL, Leatherman JW. Vasopressin-resistant diabetes insipidus, a result of amphotericin B therapy. Archives of Internal Medicine 139: 86–88, 1979PubMedCrossRefGoogle Scholar
  5. Barton CH, Pahl M, Vaziri ND, Cesario J. Renal magnesium wasting associated with amphotericin B therapy. American Journal of Medicine 77: 471–474, 1984PubMedCrossRefGoogle Scholar
  6. Beard HW, Richert JH, Taylor RR. The treatment of deep mycotic infections with amphotericin B, with particular emphasis on drug toxicity. American Review of Respiratory Diseases 81: 43–51, 1960Google Scholar
  7. Bell NH, Andriole VT, Sabesin SM, Utz JP. On the nephrotoxicity of amphotericin B in man. American Journal of Medicine 33: 64–69, 1962PubMedCrossRefGoogle Scholar
  8. Bode F, Baumann K, Kinne R. Analysis of the pinocytic process in rat kidney, II: biochemical composition of pinocytic vesicles compared to brush border microvilli, lysosomes and basolateral plasma membranes. Biochimica et Biophysica Acta 433: 294–310, 1976CrossRefGoogle Scholar
  9. Bolard J, Seignemet M, Boudet G. Interaction between phospholipid bilayer membranes and the polyene antibiotic amphotericin B. Biochimica et Biophysica Acta 599: 280–293, 1980PubMedCrossRefGoogle Scholar
  10. Branch RA. Prevention of amphotericin B-induced renal impairment, a review on the use of sodium supplementation. Archives of Internal Medicine 148: 2389–2394, 1988PubMedCrossRefGoogle Scholar
  11. Branch RA, Jackson EK, Jacqz E, Stein R, Ray WA, et al. Amphotericin B nephrotoxicity in humans decreased by sodium supplements with coadministration of ticarcillin or intravenous saline. Klinische Wochenschrift 65: 500–506, 1987PubMedCrossRefGoogle Scholar
  12. Brezis M, Rosen S, Silva P, Spokes K, Epstein F. Polyene toxicity in renal medulla: injury mediated by transport activity. Science 224: 66–68, 1984PubMedCrossRefGoogle Scholar
  13. Brune K-H, Branch RA, Heidemann HTh. The effect of flucytosine on acute amphotericin B nephrotoxicity in the rat. Renal Failure 11: 51, 1988Google Scholar
  14. Bullock WE, Luke RG, Nuttal CE, Bhathena D. Can mannitol reduce amphotericin B nephrotoxicity? Double blind study and description of a new vascular lesion in kidneys. Antimicrobial Agents and Chemotherapy 10: 555–563, 1976PubMedCrossRefGoogle Scholar
  15. Burgess JL, Birchall R. Nephrotoxicity of amphotericin B with emphasis on changes in tubular function. American Journal of Medicine 53: 77–84, 1972PubMedCrossRefGoogle Scholar
  16. Butler WT, Bennett JE, Alling DW, Wertlake PT, Utz JP, et al. Nephrotoxicity of amphotericin B, early and late events in 81 patients. Annals of Internal Medicine 61: 175–187, 1964aPubMedGoogle Scholar
  17. Butler WT, Hill GJ, Szwed CF, Knight V. Amphotericin B renal toxicity in the dog. Journal of Pharmacology and Experimental Therapeutics 143: 47–56, 1964bPubMedGoogle Scholar
  18. Butler WT, Alling DW, Cotlove E. Potassium loss from human erythrocytes exposed to amphotericin B. Proceedings of the Society for Experimental Biology and Medicine 118: 297–300, 1965PubMedGoogle Scholar
  19. Butler WT. Pharmacology, toxicology and therapeutic usefulness of amphotericin B. Journal of the American Medical Association 195: 127–131, 1966CrossRefGoogle Scholar
  20. Caltrider PG, Gottlieb D. Capacidin: a new member of the polyene antibiotic group. Antibiotics and Chemotherapy (Washington, DC) 10: 702–708, 1961Google Scholar
  21. Capasso G, Schuetz H, Vickerman B, Kinne R. Amphotericin B and amphotericin B methylester: effect on brush border membrane permeability. Kidney International 30: 311–317, 1986PubMedCrossRefGoogle Scholar
  22. Cheng JT, Witty RT, Robinson RR, Yarger WE. Amphotericin B nephrotoxicity: increased renal resistance and tubule permeability. Kidney International 22: 626–633, 1982PubMedCrossRefGoogle Scholar
  23. DeKruijiff B, Demel RA. Polyene antibiotic-sterol interactions in membranes of Acholeplesma laidlawii cells and lecithin liposomes, III: molecular structure of the polyene antibiotic-cholesterol complexes. Biochimica et Biophysica Acta 339: 57–70, 1974CrossRefGoogle Scholar
  24. Douglas JB, Healy JK. Nephrotoxic effects of amphotericin B, including renal tubular acidosis. American Journal of Medicine 46: 154–162, 1969PubMedCrossRefGoogle Scholar
  25. Finn JT, Cohen LH, Steinmetz PR. Acidifying defect induced by amphotericin B: comparison of bicarbonate and hydrogen ion permeabilities. Kidney International 11: 261–266, 1977PubMedCrossRefGoogle Scholar
  26. Gatzy JT, Reuss L, Finn AL. Amphotericin B and K+ transport across excised toad urinary bladder. American Journal of Physiology 237: F145–F156, 1979PubMedGoogle Scholar
  27. Gerkens JF, Branch RA. The influence of sodium status and furosemide on canine acute amphotericin B nephrotoxicity. Journal of Pharmacology and Experimental Therapeutics 214: 306–311, 1980PubMedGoogle Scholar
  28. Gerkens JF, Heidemann HTh, Jackson EK, Branch RA. Aminophylline inhibits renal vasoconstriction induced by intrarenal hypertonic saline. Journal of Pharmacology and Experimental Therapeutics 225: 609–615, 1983Google Scholar
  29. Gottlieb D, Carter HE, Sloneker JH, Amman A. Protection of fungi against polyene antibiotics by sterols. Science 128: 361, 1958PubMedCrossRefGoogle Scholar
  30. Gouge TH, Andriole VT. An experimental model of amphotericin B nephrotoxicity with renal tubular acidosis. Journal of Laboratory and Clinical Medicine 78: 713–724, 1971PubMedGoogle Scholar
  31. Hardie W, Ebert J, Takahashi K, Badr KF. Thromboxane A2 receptor antagonism reverses amphotericin B-induced renal vasoconstriction in the rat. American Society of Nephrology 22nd Annual Meeting, Program and Abstracts, 296A, 1989Google Scholar
  32. Harris RC, Hoover RL, Jacobson HR, Badr KF. Evidence for glomerular actions of epidermal growth factor in the rat. Journal of Clinical Investigation 82: 1028–1039, 1988PubMedCrossRefGoogle Scholar
  33. Heidemann HTh, Gerkens GF, Jackson EK, Branch RA. Effect of aminophylline on renal vasoconstriction produced by amphotericin B in the rat. Naunyn-Schmiedeberg’s Archives of Pharmacology 324: 148–152, 1983aPubMedCrossRefGoogle Scholar
  34. Heidemann HTh, Gerkens GF, Spickard WA, Jackson EK, Branch RA. Amphotericin B nephrotoxicity in humans decreased by salt repletion. American Journal of Medicine 75: 476–481, 1983bPubMedCrossRefGoogle Scholar
  35. Hellebusch AA, Salama F, Eadie E. The use of mannitol to reduce the toxicity of amphotericin B. Surgery, Gynecology and Obstetrics 134: 241–243, 1972PubMedGoogle Scholar
  36. Hoeprich PD. Chemotherapy of systemic fungal diseases. Annual Review of Pharmacology and Toxicology 18: 205–231, 1978PubMedCrossRefGoogle Scholar
  37. Holeman CW, Einstein H. The toxic effects of amphotericin B in man. California Medicine 99: 90–93, 1963PubMedGoogle Scholar
  38. Holz RW. The effects of the polyene antibiotics nystatin and amphotericin B on thin lipid membranes. Annals of the New York Academy of Sciences 235: 469–479, 1974PubMedCrossRefGoogle Scholar
  39. Ichikawa I. Direct analysis of the effector mechanism of the tubuloglomerular feedback system. American Journal of Physiology 243: F447–F455, 1982PubMedGoogle Scholar
  40. Kerridge D. The polyene antibiotics. Postgraduate Medical Journal 55: 653–656, 1979PubMedCrossRefGoogle Scholar
  41. Kinsky SC. The effect of polyene antibiotics on permeability in Neurospora crassa. Biochemical and Biophysical Research Communications 4: 353–357, 1961aPubMedCrossRefGoogle Scholar
  42. Kinsky SC. Alterations in the permeability of Neurospora crassa due to polyene antibiotics. Journal of Bacteriology 82: 889–897, 1961bPubMedGoogle Scholar
  43. Kinsky SC. Comparative responses of mammalian erythrocytes and microbial protoplast to polyene antibiotics and vitamin A. Archives of Biochemistry and Biophysics 102: 180–188, 1963PubMedCrossRefGoogle Scholar
  44. Kinsky SC, Avruch J, Permutt M, Rogers HB, Schonder AA. The lytic effects of polyene fungal antibiotics on mammalian erythrocytes. Biochemical and Biophysical Research Communications 9: 503–507, 1962PubMedCrossRefGoogle Scholar
  45. Kobayashi GS, Little JR, Medoff G:. In vitro and in vivo comparisons of amphotericin B and amphotericin B methyl ester. Antimicrobial Agents and Chemotherapy 27: 302–305, 1985PubMedCrossRefGoogle Scholar
  46. Koldin MH, Medoff G. Antifungal chemotherapy. Pediatric Clinics of North America 30: 49–61, 1983PubMedGoogle Scholar
  47. Kotler-Brajtburg J, Price HD, Medoff G, Schlessinger D, Kobayashi GS. Molecular basis for the selective toxicity of amphotericin B for yeast and filipin for animal cells. Antibiotic Agents and Chemotherapy 5: 377–382, 1974CrossRefGoogle Scholar
  48. Lawrence RM, Hoeprich PD. Comparison of amphotericin B and amphotericin B methyl ester: efficacy in murine coccidiomycosis and toxicity. Journal of Infectious Diseases 133: 168–174, 1976PubMedCrossRefGoogle Scholar
  49. Lichtenstein NS, Leaf A. Effect of amphotericin B on the permeability of the toad bladder. Journal of Clinical Investigation 44: 1328–1342, 1965PubMedCrossRefGoogle Scholar
  50. Lichtenstein NS, Leaf A. Evidence for a double series permeability barrier at the mucosal surface of the toad bladder. Annals of the New York Academy of Sciences 137: 556–565, 1966PubMedCrossRefGoogle Scholar
  51. Littman ML, Horowitz PL, Swadey JG. Coccidiomycosis and its treatment with amphotericin B. American Journal of Medicine 24: 568–592, 1958PubMedCrossRefGoogle Scholar
  52. Lopez-Berestein G. Liposomal amphotericin B in the treatment of fungal infections. Annals of Internal Medicine 105: 130–131, 1986PubMedGoogle Scholar
  53. Lopez-Berestein G, Fainstein V, Hopfer R, Mehta K, Sullivan MP, et al. Liposomal amphotericin B for the treatment of systemic fungal infections in patients with cancer: a preliminary study. Journal of Infectious Diseases 151: 704–710, 1985PubMedCrossRefGoogle Scholar
  54. Marini FP, Arnow P, Lampen JO. The effect of monovalent cations on the inhibition of yeast metabolism by nystatin. Journal of General Microbiology 24: 51–62, 1961PubMedCrossRefGoogle Scholar
  55. Massa T, Sinha DP, Frantz JD, Filipek ME, Weglei RC, et al. Subchronic toxicity studies of N-D-ornithyl amphotericin B methyl ester in dogs and rats. Fundamental and Applied Toxicology 5: 737–753, 1985PubMedCrossRefGoogle Scholar
  56. McCurdy DK, Frederic M, Elkinton JR. Renal tubular acidosis due to amphotericin B. Clinical Research 12: 471, 1964Google Scholar
  57. McCurdy DK, Frederic M, Elkinton JR. Renal tubular acidosis due to amphotericin B. New England Journal of Medicine 278: 124–131, 1968PubMedCrossRefGoogle Scholar
  58. McGowan JE. Changing etiology of nosocomial bacteremia and fungemia and other hospital acquired infections. Reviews of Infectious Diseases 7(Suppl. 2): S357–S370, 1985PubMedCrossRefGoogle Scholar
  59. Medoff G, Brajtburg J, Kobayashi GS. Antifungal agents useful in the therapy of systemic fungal infections. Annual Review of Pharmacology and Therapeutics 23: 303–330, 1983CrossRefGoogle Scholar
  60. Medoff G, Kobayashi GS. Strategies in the treatment of systemic fungal infections. New England Journal of Medicine 302: 145–155, 1980PubMedCrossRefGoogle Scholar
  61. Mehta R, Lopez-Berestein G, Hopfer R, Mills K, Juliano RL. Liposomal amphotericin B is toxic to fungal cells but not to mammalian cells. Biochimica et Biophysica Acta 770: 230–234, 1984PubMedCrossRefGoogle Scholar
  62. Miller RP, Bates JH. Amophericin B toxicity: a follow-up report of 53 patients. Annals of Internal Medicine 71: 1089–1095, 1969PubMedGoogle Scholar
  63. Morgan DJ, Ching MS, Raymond K, Buty R, Mashford L, et al. Elimination of amphotericin B in impaired renal function. Clinical Pharmacology and Therapeutics 34: 248–253, 1983PubMedCrossRefGoogle Scholar
  64. Norman AW, Spielvogel AM, Wong PG. Polyene antibiotic-sterol interaction. In Paoletti & Kritchevsky (Eds) Advances in lipid research, Vol. 14, pp. 127–170, Academic, New York, 1976Google Scholar
  65. Ohnishi A, Ohnishi T, Stevenhead W, Bobinson RD, Branch RA, et al. Sodium status influences chronic amphotericin B nephrotoxicity in the rat. Antimicrobial Agents and Chemotherapy 33: 1222–1227, 1989PubMedCrossRefGoogle Scholar
  66. Olivero TJ, Lozano-Mendez L, Ghafary EM, Eknoyan G, Suki WN. Mitigation of amphotericin B nephrotoxicity with mannitol. British Medical Journal 1: 550–551, 1975PubMedCrossRefGoogle Scholar
  67. Osswald H, Hermes HH, Nabakowski G. Role of adenosine in signal transmission of tubuloglomerular feedback. Kidney International 22: S136–S142, 1982CrossRefGoogle Scholar
  68. Osswald H, Nabakowski G, Hermes H. Adenosine as a possible mediator of metabolic control of glomerular filtration rate. International Journal of Biochemistry 12: 263–267, 1980PubMedCrossRefGoogle Scholar
  69. Powers Jr SR, Boba A, Hastirik W. Prevention of postoperative acute renal failure with mannitol in 100 cases. Surgery 55: 15–23, 1964PubMedGoogle Scholar
  70. Rosch JM, Pazin GJ, Fireman P. Reduction of amphotericin B nephrotoxicity with mannitol. Journal of the American Medical Association 235: 1995–1996, 1976PubMedCrossRefGoogle Scholar
  71. Rubin SI, Krawiec DR, Gilbers H, Shanks RD. Nephrotoxicity of amphotericin B in dogs: a comparison of two methods of administration. Canadian Journal of Veterinary Research 53: 23–28, 1989PubMedGoogle Scholar
  72. Sabra R, Takahashi K, Branch RA, Badr KF. Amphotericin B-induced reduction in the glomerular filtration rate: a micro-puncture study. Journal of Pharmacy and Experimental Therapeutics, in press, 1989Google Scholar
  73. Said R, Martin P, Anicama H, Quintanilla A, Levin ML. Effect of mannitol on acute amphotericin B nephrotoxicity. Research in Experimental Medicine 177: 85–90, 1980PubMedCrossRefGoogle Scholar
  74. Sanford WG, Rosch JR, Stonehill RB. A therapeutic dilemma, the treatment of disseminated coccidiomycosis. Annals of Internal Medicine 56: 553–563, 1962PubMedGoogle Scholar
  75. Schaffner CP, Mechlinski W. Polyene macrolide derivatives, II: Physical-chemical properties of polyene macrolide esters and their water soluble salts. Journal of Antibiotics (Tokyo) 25: 259–260, 1972CrossRefGoogle Scholar
  76. Schell RE, Tran NV, Bramhall JS. Amphotericin B-induced changes in membrane permeation: a model of nephrotoxicity. Biochemical and Biophysical Research Communications 59: 1165–1170, 1989CrossRefGoogle Scholar
  77. Schlondorff D. The glomerular mesangial cell: an expanding role for a specialized pericyte. FASEB Journal 1: 272–281, 1987PubMedGoogle Scholar
  78. Schnermann J. Regulation of single nephron filtration rate by feedback: facts and theories. Clinical Nephrology 3: 75–81, 1975PubMedGoogle Scholar
  79. Schnermann J, Osswald H, Hermle M. Inhibitory effect of methylxanthines on feedback control of glomerular filtration rate in the rat kidney. Pflügers Archiv 269: 39–48, 1977CrossRefGoogle Scholar
  80. Stein RS, Albridge K, Lenox RK, Ray W, Flexner JM. Nephrotoxicity in leukemic patients receiving empirical amphotericin B and aminoglycosides. Southern Medical Journal 81: 1095–1099, 1988PubMedCrossRefGoogle Scholar
  81. Steinmetz PR, Lawson LR. Defect in urinary acidification induced in vitro by amphotericin B. Journal of Clinical Investigation 49: 596–601, 1970PubMedCrossRefGoogle Scholar
  82. Sutton DD, Arnow PM, Lampen JO. Effect of high concentrations of nystatin upon glycolysis and cellular permeability in yeast. Proceedings of the Society for Experimental Biology and Medicine 108: 170–175, 1961PubMedGoogle Scholar
  83. Takacs FJ, Tomkiewicz ZM, Merrill JP. Amphotericin B nephrotoxicity with irreversible renal failure. Annals of Internal Medicine 59: 716–724, 1963PubMedGoogle Scholar
  84. Teerlink T, DeKruijiff B, Demel RA. The action of piramicin, etruscomycin, and amphotericin B on liposomes with varying sterol content. Biochimica et Biophysica Acta 599: 484–492, 1980PubMedCrossRefGoogle Scholar
  85. Thurau K. Modification of angiotensin-mediated tubuloglomerular feedback by extracellular volume. Kidney International 8: S202–S207, 1975Google Scholar
  86. Thurau K, Boylan JW. Acute renal success: the unexpected logic of oliguria in acute renal failure. American Journal of Medicine 61: 308–315, 1976PubMedCrossRefGoogle Scholar
  87. Tolins JP, Raij L. Chronic amphotericin B nephrotoxicity in the rat, protective effect of prophylactic salt loading. American Journal of Kidney Diseases 11: 313–317, 1988aPubMedGoogle Scholar
  88. Tolins JP, Raij L. Adverse effect of amphotericin B on renal hemodynamics in the rat: neurohumoral mechanisms and influence of calcium channel blockade. Journal of Pharmacology and Experimental Therapeutics 245: 594–599, 1988bPubMedGoogle Scholar
  89. Winn WA. Coccidiomycosis and amphotericin B. Medical Clinics of North America 47: 1131–1144, 1963PubMedGoogle Scholar
  90. Wright FS, Schnermann J. Interference with feedback control of glomerular filtration rate by furosemide, triflocin and cyanide. Journal of Clinical Investigation 53: 1695–1708, 1974PubMedCrossRefGoogle Scholar

Copyright information

© ADIS Press Limited 1990

Authors and Affiliations

  • Ramzi Sabra
    • 1
  • Robert A. Branch
    • 1
  1. 1.Division of Clinical Pharmacology, Departments of Pharmacology and MedicineVanderbilt University School of MedicineNashvilleUSA

Personalised recommendations