Summary
Ultrastructural alterations in the cortical, distal and collecting tubules have been examined in female Sprague-Dawley rats treated with various aminoglycosides in clinical use. Gentamicin, dibekacin (10 mg/ kg-day), netilmicin, tobramycin (4 or 10 mg/kg · day) or amikacin (37.5 mg/kg · day) were administered intraperitoneally twice a day over different periods of time, extending from 4 to 14 days. The kidney cortex was examined after 4, 7, 10 or 14 days of aminoglycoside administration by light (semithin sections) and electron microscopy. After 7 or more days of treatment, lysosomes in collecting tubular cells (and to a lesser extent in distal tubular cells) contained concentric lamellar material (myeloid bodies), an ultrastructural alteration typical of drug-induced lysosomal phospholipidosis. Although this alteration appeared qualitatively similar to that observed in proximal tubular cells, it was less conspicuous and occurred later during treatment. In addition, distal tubular cells occasionally showed marked vacuolization and disruption of the basal cell architecture. The possible relationship between these alterations and the urine hypo-osmolality characteristic of aminoglycoside-induced renal dysfunction is discussed.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Appel GB, Neu HC (1978) Gentamicin in 1978. Ann Int Med 89:528–538
Bennett WM, Luft F, Porter GA (1980) Pathogenesis of renal failure due to aminoglycosides and contrast media used in roentgenography. Am J Med 69:767–774
Brasseur R, Laurent G, Ruysschaert JM, Tulkens PM (1984) Interactions of aminoglycoside antibiotics with negatively charged lipid layers. Biochem Pharmacol 33:629–637
Cuppage FE, Setter K, Sullivan LP, Reitzes EJ, Melnykovych RO (1977) Gentamicin nephrotoxicity. II. Physiological, biochemical and morphological effects of prolonged administration to rats. Virchows Arch [Cell Pathol] 24:121–138
De Broe ME, Paulus GJ, Verpooten GA, Roels F, Buyssens N, Wedeen R, Van Hoof F, Tulkens PM (1984) Early effects of gentamicin, tobramycin and amikacin on the human kidney. Kidney Int 25:643–652
Fabre J, Rudhardt M, Blanchard P, Regamey C (1976) Persistence of sisomicin and gentamicin in renal cortex and medulla compared with other organs and serum of rats. Kidney Int 10:444–449
Gilbert DN, Plamp CE, Starr P, Bennett WM, Houghton DC, Porter GA (1978) Comparative nephrotoxicity of gentamicin and tobramycin in rats. Antimicrobiol Agents Chemother 13:34–40
Giurgea-Marion L, Toubeau G, Laurent G, Heuson-Stiennon JA, Tulkens PM (1986) Impairment of lysosome-pinocytic vesicle fusion in rat kidney proximal tubules after treatment with gentamicin at low dose. Toxicol Appl Pharmacol (in press)
Houghton DC, Hartnett MV, Campbell-Boswell MV, Porter GA, Bennett WM (1976) A light and electron microscopic analysis of gentamicin nephrotoxicity in rats. Am J Pathol 82:589–612
Houghton DC, Plamp CE, De Fehr JM, Bennett WM, Porter GA, Gilbert D (1978) Gentamicin and tobramycin nephrotoxicity. A morphologic and functional comparison in the rat. Am J Pathol 93:137–152
Josepovitz C, Levine R, Lane B, Kaloyanides GJ (1985) Contrasting effects of gentamicin and mercuric chloride on urinary excretion of enzymes and phospholipids in the rat. Lab Invest 52:375–386
Just M, Erdmann G, Habermann E (1977) The renal handling of polybasic drugs. I. Gentamicin and aprotinin in intact animals. Naunyn-Schmiedeberg’s Arch Pharmacol 300:57–66
Kosek JC, Mazze RI, Cousins MJ (1974) Nephrotoxicity of gentamicin. Lab Invest 30:48–57
Laurent G, Carlier MB, Rollmann B, Van Hoof F, Tulkens PM (1982) Mechanism of aminoglycoside-induced lysosomal phospholipidosis: in vitro and in vivo studies with Gentamicin and amikacin. Biochem Pharmacol 31:3861–3870
Lietman PS (1985) Aminoglycosides and spectinomycin: aminocyclitols. In: Mandell GL, Douglas RG, Bennett JE (eds) Principles and practice of infections diseases. John Wiley and Sons, New York, pp 192–206
Luft FC, Kleit SA (1974) Renal parenchymal accumulation of aminoglycoside antibiotics in rats. J Infect Dis 130:656–659
Luft FC, Patel V, Yum MN, Patel B, Kleit SA (1975) Experimental aminoglycoside nephrotoxicity. J Lab Clin Med 86:213–220
Maunsbach AB (1966a) The influence of different fixatives and fixation methods on the ultrastructure of rat kidney proximal tubule cells. I. Comparison of different perfusion fixation methods and of glutaraldehyde, formaldehyde and osmium tetroxide fixatives. J Ultrastruct Res 15:242–281
Maunsbach AB (1966b) The influence of different fixatives and fixation methods on the ultrastructure of rat kidney proximal tubule cells. II. Effects of varying osmolality, ionic strength, buffer system and fixative concentration of glutaraldehyde solutions. J Ultrastruct Res 15:282–309
Safirstein R, Miller P, Kahn G (1983) Cortical and papillary defects in gentamicin nephrotoxicity. Kidney Int 24:526–533
Sande ME, Mandell GL (1985) The aminoglycosides. In: Goodman, Gilman, Rall, Murad (eds) The pharmacological basis of therapeutics. Macmillan Publishing Company, New York, pp 1150–1169
Sastrasinh M, Knauss TC, Weinberg JM, Humes DH (1982) Identification of the aminoglycoside binding site in rat renal brush border membranes. J Pharmacol Exp Ther 222:350–358
Schentag JJ, Plaut ME, Cerra FB (1981) Comparative nephrotoxicity of gentamicin and tobramycin: pharmacokinetic and clinical studies in 201 patients. Antimicrobiol Agents Chemother 10:859–866
Silverblatt FJ, Kuehn C (1979) Autoradiography of gentamicin uptake by the rat proximal tubule cell. Kidney Int 15:335–345
Silverblatt FJ (1982) Autoradiographic studies of intracellular aminoglycoside disposition in the kidney. In: Whelton A, Neu HC (eds) The aminoglycosides: microbiology, clinical use, and toxicology. Marcel Dekker Inc., New York, pp 223–233
Soberon L, Bowman RL, Pastoriza-Munoz E, Kaloyanides GJ (1979) Comparative nephrotoxicities of gentamicin, netilmicin and tobramycin in the rat. J Pharmacol Exp Ther 210:334–343
Toubeau G, Laurent G, Heuson-Stiennon JA, Tulkens PM (1984) Aminoglycoside-induced alterations in distal and collecting tubules of rat kidney cortex [Abstr]. 2ème Colloque Annuel de la Société de Biologie Cellulaire de France, Paris
Tulkens P, Laurent G, Carlier MB, Toubeau G, Heuson-Stiennon JA, Maldague P (1983) Comparative study of the alterations induced in rat kidney by gentamicin, dibekacin, netilmicin, tobramycin and amikacin at low doses. Proceedings of the 13th International Congress of Chemotherapy, Vienna, August 28th–September 2nd 1983, Spitzy KH, Karrer K (eds) pp 86/30–86/35
Vaamonde CA (1984) Antibiotic-induced nephrotoxicity. In: Robinson RR (ed) Nephrology vol. 1. Proceedings of the IX International Congress of Nephrology, Los Angeles, Springer, New York, pp 844–868
Watanabe M (1978) Drug-induced lysosomal changes and nephrotoxicity in rats. Acta Pathol Jpn 28:867–889
Whelton A (1985) Therapeutic initiatives for the avoidance of aminoglycoside toxicity. J Clin Pharmacol 25:67–81
Williams PD, Trimble ME, Crespo L, Holohan PD, Freedman JC, Ross CR (1984) Inhibition of renal Na+, K+-adenosine triphosphatase by gentamicin. J Pharmacol Exp Ther 231:248–253
Wilmotte E, Maldague P, Tulkens PM, Baumgartner R, Schmook F, Walzl H, Obenaus H (1983) S 86451, a new derivative of gentamicin with reduced nephrotoxicity: biochemical, morphological and functional studies. Drugs Exptl Clin Res 9:467–477
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Toubeau, G., Maldague, P., Laurent, G. et al. Morphological alterations in distal and collecting tubules of the rat renal cortex after aminoglycoside administration at low doses. Virchows Archiv B Cell Pathol 51, 475–485 (1986). https://doi.org/10.1007/BF02899053
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF02899053