Digestive Diseases and Sciences

, Volume 51, Issue 2, pp 406–415 | Cite as

Renal Effects of Gentamicin in Chronic Bile Duct Ligated Rats

  • Zvi Ackerman
  • Fanny Karmeli
  • Galina Pizov
  • Iddo Ben-Dov
  • Orit Pappo
Pancreatic and Biliary Disorders


Patients with advanced cirrhosis and rats with short-term bile duct ligation (BDL) are prone to develop nephrotoxicity from aminoglycosides. In this study, we characterized the renal response to gentamicin in rats with chronic BDL. BDL and sham-operated (SO) rats were given gentamicin (20 and 40 mg/kg/d) for 7 consecutive days, starting on the 18th postoperative day. Administration of gentamicin to SO group caused a decrease in cortical and medullary prostaglandin E2(PGE2) generation. However, mild reduction in creatinine clearance and an increase in fractional excretion of sodium occurred only in the BDL rats given the high gentamicin dose. This was accompanied by a reduction in cortical and medullary PGE2 generation and a reduction in plasma nitric oxide production. In conclusion, gentamicin administration to rats with chronic BDL causes impairment of renal function. This happens only after the occurrence of simultaneous multiple insults to the renal protective mechanisms.

Key Words

bile duct ligation cirrhosis prostaglandin E2 plasma nitrites nephrotoxicity gentamicin 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Caly WR, Strauss E: A prospective study on bacterial infections in patients with cirrhosis. J Hepatol 18:353–358, 1993CrossRefPubMedGoogle Scholar
  2. 2.
    Schentag JJ, Plaut ME, Cerra FB, Wels PB, Walczak P, Buckley RJ: Aminoglycoside nephrotoxicity in critically ill surgical patients. J Surg Res 26:270–279, 1979CrossRefGoogle Scholar
  3. 3.
    Smith CR, Lipsky JJ, Laskin OL, et al..: Double blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med 302:1106–1109, 1980PubMedGoogle Scholar
  4. 4.
    Moore RD, Smith CR. Lipsky JJ, Mellits ED, Lietman PS: Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 100:352–357, 1984PubMedGoogle Scholar
  5. 5.
    Moore RD, Smith CR, Lietman PS: Increased risk of renal dysfunction due to interaction of liver disease and aminoglycosides. Am J Med 80:1093–1097, 1986PubMedGoogle Scholar
  6. 6.
    Cabrera J, Arroyo V, Ballesta AM, et al..: Aminoglycoside nephrotoxicity in cirrhosis. Gastroenterology 82:97–105, 1982PubMedGoogle Scholar
  7. 7.
    Felisart J, Rimola A, Arroyo V, et al..: Cefotaxime is more effective than is ampicillin-tobramycin in cirrhotics with severe infections. Hepatology 5:457–462, 1985PubMedGoogle Scholar
  8. 8.
    Desai TK, Tsang TK: Aminoglycoside nephrotoxicity in obstructive jaundice. Am J Med 85:47–50, 1988CrossRefPubMedGoogle Scholar
  9. 9.
    Lucena MI, Andrade RJ, Cabella MR, Hidalgo R, Gonzalez-Correa JA, Sanchez de la Cuesta F: Aminoglycoside associated nephrotoxicity in extrahepatic obstructive jaundice. J Hepatol 22:189–196, 1995Google Scholar
  10. 10.
    McCormick PA, Greenslade L, Kibbler CC, Chin JKT, Burroughs AK, McIntyre N: A prospective randomized trial of ceftazidime versus netilmicin plus mezlocillin in the empirical therapy of presumed sepsis in cirrhotic patients. Hepatology 25:833–836, 1997CrossRefPubMedGoogle Scholar
  11. 11.
    Camps J, Sola X, Rimola A, et al..: Comparative study of aminoglycoside nephrotoxicity in normal rats and rats with experimental cirrhosis. Hepatology 8:837–844, 1988PubMedGoogle Scholar
  12. 12.
    Zager RA: A focus of tissue necrosis increases renal susceptibility to gentamicin administration. Kidney Int 33:84–90, 1988PubMedGoogle Scholar
  13. 13.
    Vakil N, Abu-Alfa A, Mujais SK: Gentamicin nephrotoxicity in extrahepatic cholestasis. Modulation by dietary calcium. Hepatology 9:519–524, 1989Google Scholar
  14. 14.
    Lucena MI, Gonzalez-Correa JA, Andrade RJ, Ibanez J, Torres D, Sanchez de la Cuesta F: Enhanced gentamicin nephrotoxicity after experimental biliary obstruction in rats. Pharmacol Toxicol 65:352–356, 1989Google Scholar
  15. 15.
    Vakil NB, Gutkowska J, Abu-Alfa A, Mujais S: Effects of acute and chronic bile duct ligation on plasma atrial natriuretic factor in the rat (abstract). Am J Hypertens 1:135A, 1988Google Scholar
  16. 16.
    Koepke JP, Jones S, DiBona GF: Renal nerves mediate blunted natriuresis to atrial natriuretic peptide in cirrhotic rats. Am J Physiol 252:R1019–R1023, 1987PubMedGoogle Scholar
  17. 17.
    Ackerman Z, Karmeli F, Amir G, Rachmilewitz D: Renal vasoactive mediator generation in portal hypertensive and bile duct ligated rats. J Hepatol 24:478–486, 1996CrossRefPubMedGoogle Scholar
  18. 18.
    Quarum ML, Houghton DC, Gilbert DN, McCarron DA, Bennett WM: Increasing dietary calcium moderates experimental gentamicin nephrotoxicity. J Lab Clin Med 103:104–114, 1984PubMedGoogle Scholar
  19. 19.
    Stuehr DJ, Marletta MA: Mammalian nitrite biosynthesis: Mouse macrophages produce nitrite and nitrate in response to Escherichia coli lipopolysaccharide. Proc Natl Acad Sci USA 82:7738–7742, 1985PubMedGoogle Scholar
  20. 20.
    Bennett WM: Aminoglycoside nephrotoxicity. Nephron 35:73–77, 1983PubMedGoogle Scholar
  21. 21.
    Glyselynck AM, Forrey A, Cutler R: Pharmacokinetics of gentamicin: Distribution and plasma and renal clearance. J Infect D 124:S70–S76, 1971Google Scholar
  22. 22.
    Sundin DP, Sandoval R, Molitoris BA: Gentamicin inhibits renal protein and phospholipid metabolism in rats: Implications involving intracellular trafficking. J Am Soc Nephrol 12:114–123, 2001PubMedGoogle Scholar
  23. 23.
    Laurent G, Kishore BK, Tulkens PM: Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem Pharmacol 40:2383–2392, 1990CrossRefPubMedGoogle Scholar
  24. 24.
    Lipsky JJ, Lietman PS: Aminoglycoside inhibition of renal phosphatidylinosotol phospholipase C. J Pharmacol Exp Ther 220:287–292, 1982PubMedGoogle Scholar
  25. 25.
    Assael BM, Chiabrando C, Gagliardi L, Noseda A, Bamonte F, Salmona ML: Prostaglandins and aminoglycoside nephrotoxicity. Toxicol Appl Pharmacol 78:386–394, 1985CrossRefPubMedGoogle Scholar
  26. 26.
    Vesce F, Pavan B, Buzzi M, et al..: Effect of different classes of antibiotics on amniotic prostaglandin E release. Prostaglandins Other Lipid Mediat 57:207–218, 1999PubMedGoogle Scholar
  27. 27.
    Piret J, Kishore BK, Tulkens PM: Effect of substrate organization on the activity and on the mechanisms of gentamicin-induced inhibition of rat liver lysosomal phospholipase A-1. Biochem Pharmacol 43:895–898, 1992CrossRefPubMedGoogle Scholar
  28. 28.
    Zager RA, Sharma HM, Johannes GA: Gentamicin increases renal susceptibility to an acute ischemic insult. J Lab Clin Med 101:670–678, 1983PubMedGoogle Scholar
  29. 29.
    Wiest R, Shah V, Sessa WC, Groszmann RJ: NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats. Am J Physiol 276:G1043–G1051, 1999PubMedGoogle Scholar
  30. 30.
    Niederberger M, Gines P, Martin PY, et al..: Comparison of vascular nitric oxide production and systemic hemodynamics in cirrhosis versus prehepatic portal hypertension in rats. Hepatology 24:947–951, 1996PubMedGoogle Scholar
  31. 31.
    Cahill PA, Redmond EM, Hodges R, Zhang S, Sitzmann J: Increased endothelial nitric oxide synthase activity in hyperemic vessels of portal hypertensive rats. J Hepatol 25:370–378, 1996CrossRefPubMedGoogle Scholar
  32. 32.
    Morales-Ruiz M, Jimenez W, Perez-Sala D, et al..: Increased nitric oxide synthase expression in arterial vessels of cirrhotic rats with ascites. Hepatology 24:1481–1486, 1996PubMedGoogle Scholar
  33. 33.
    Gadano AC, Songi P, Heller J, Moreau R, Bories PN, Lebrec D: Vascular nitric oxide production during the development of two experimental models of portal hypertension. J Hepatol 30:896–903, 1999CrossRefPubMedGoogle Scholar
  34. 34.
    Bech JN, Nielsen CB, Pedersen EB: Effects of systemic nitric oxide synthesis inhibition on renal plasma flow, glomerular filtration rate, urinary sodium excretion and vasoactive hormones in healthy humans. Am J Physiol 270:F845–F851, 1996PubMedGoogle Scholar
  35. 35.
    Lumsden AB, Henderson MJ, Kutner MH: Endotoxin levels measured by chromogenic assay in portal hepatic and peripheral venous blood in patients with cirrhosis. Hepatology 8:232–236, 1988PubMedGoogle Scholar
  36. 36.
    Tilz H, Wilmer A, Vogel W, et al..: Serum levels of cytokines in chronic liver diseases. Gastroenterology 103:264–274, 1992Google Scholar
  37. 37.
    Wilkinson SP, Moodie H, Stamatakis JD, Kakkar VV, Williams R: Endotoxemia and renal failure in cirrhosis and obstructive jaundice. Br Med J 2:1415–1418, 1976PubMedGoogle Scholar
  38. 38.
    Kocsar LT, Bertok L, Vartereresz V: Effect of bile acids on the intestinal absorption of endotoxin in rats. J Bacteriol 100:220–223, 1969PubMedGoogle Scholar
  39. 39.
    Stark ME, Szurszewski JH: Role of nitric oxide in gastrointestinal and hepatic function and disease. Gastroenterology 103:1928–1949, 1992PubMedGoogle Scholar
  40. 40.
    Navasa M, Follo A, Fillella X, et al..: Tumor necrosis factor and interleukin-6 in spontaneous bacterial peritonitis in cirrhosis: Relationship with the development of renal impairment and mortality. Hepatology 27:1227–1232, 1998CrossRefPubMedGoogle Scholar
  41. 41.
    Zager RA, Prior RB: Gentamicin and gram negative bacteremia. A synergism for the development of experimental nephrotoxic acute renal failure. J Clin Invest 78:196–204, 1986Google Scholar
  42. 42.
    Coopersmith CM, Amiot DM 2nd, Stomberg PE, et al..: Antibiotics improve survival and alter the inflammatory profile in murine model of sepsis from Pseudomonas aeruginosa. pneumonia. Shock 19:408–411, 2003PubMedGoogle Scholar
  43. 43.
    Tsumura H, Hiyama E, Kodama T, Sueda T, Yokoyama T: Relevance of antimicrobial agent-induced endotoxin release from in vitro cultured Escherichia coli.and in vivo experimental infection with Gram-negative bacilli. Int J Antimicrob Agents 21:463–470, 2003PubMedGoogle Scholar
  44. 44.
    Rivas-Cabanero L, Rodriguez-Barbero A, Arevalo M, Lopez-Novoa JM: Effect of NG-nitro-arginine methyl ester on nephrotoxicity induced by gentamicin in rats. Nephron 71:203–207, 1995PubMedGoogle Scholar
  45. 45.
    Zetterstrom R, Ernster L: Bilirubin, an uncoupler of oxidative phosphorylation in isolated mitochondria. Nature 178:1335–1337, 1956PubMedGoogle Scholar
  46. 46.
    Parkinson TM, Olson JA: Inhibitory effects of bile acids on adenosine triphosphate, oxygen consumption and the transport and diffusion of water soluble substances in the small intestine of the rat. Life Sci 3:107–112, 1964CrossRefPubMedGoogle Scholar
  47. 47.
    Weissman G: Studies of lysosomes. VI. The effects of natural steroids and bile acids on lysosomes in vitro. Biochem Pharmacol 14:525–535, 1965Google Scholar
  48. 48.
    Humes HD: Aminoglycoside nephrotoxicity. Kidney Int 33:900–911, 1988PubMedGoogle Scholar
  49. 49.
    Leung N, Croatt AJ, Haggard JJ, Grande JP, Nath KA: Acute cholestatic liver disease protects against glycerol-induced acute renal failure in the rat. Kidney Int 60:1047–1057, 2001CrossRefPubMedGoogle Scholar
  50. 50.
    Agarwal A, Balla J, Alam J, Croatt AJ, Nath KA: Induction of heme oxygenase in toxic renal injury: A protective role in cisplatin nephrotoxicity in the rat. Kidney Int 48:1298–1307, 1995PubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Zvi Ackerman
    • 1
    • 3
  • Fanny Karmeli
    • 1
  • Galina Pizov
    • 2
  • Iddo Ben-Dov
    • 1
  • Orit Pappo
    • 2
  1. 1.Departments of Medicine, Departments of Mount ScopusHadassah Hebrew University Medical CenterJerusalemIsrael
  2. 2.Departments of Medicine, Departments of PathologyHadassah Hebrew University Medical CenterJerusalemIsrael
  3. 3.Department of Medicine, Mount ScopusHadassah University HospitalJerusalemIsrael

Personalised recommendations