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Antimicrobial Agents and Chemotherapy, March 2001, p. 679-685, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.679-685.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Apoptosis Contributes to Amphotericin B- Induced Nephrotoxicity

Despina E. Varlam,1,dagger Mustafa M. Siddiq,1 Lance A. Parton,1,Dagger and Holger Rüssmann2,*

Department of Pediatrics, SUNY at Stony Brook, Stony Brook, New York 11794-8111,1 and Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig Maximilians University, 80336 Munich, Germany2

Received 8 September 2000/Returned for modification 17 October 2000/Accepted 5 December 2000

The aim of this study was to investigate whether apoptosis contributes to nephrotoxicity caused by amphotericin B (AmB). By detecting apoptosis-specific DNA fragmentation, it is demonstrated that proximal tubular cells (LLC-PK1) and medullary interstitial cells (RMIC) respond with programmed cell death when treated with therapeutic doses of AmB. Concomitant application of AmB and recombinant human insulin-like growth factor-1 (rhIGF-1), a known antiapoptotic agent, abrogated apoptosis in vitro. To validate that the observed apoptotic effects on renal tissue culture cells are applicable to an in vivo setting, an animal model was used for verification. Therefore, Sprague-Dawley rats were treated with AmB. The drug caused hypokalemia, decreased weight gain, loss of renal concentrating ability, and dehydration in a dose-dependent fashion. Microscopic examination of renal tissue sections revealed apoptotic alterations predominantly in proximal and distal tubular epithelial cells. To verify that the observed clinical side effects were linked to apoptosis, rhIGF-1 was applied concomitantly with AmB. In all animals, rhIGF-1 prevented the above-mentioned clinical side effects. Moreover, significantly reduced apoptosis was observed in renal tissue sections of these animals, indicating the relevance of apoptosis in nephrotoxicity. This is the first report to demonstrate that AmB induces apoptosis in the rat kidney in a dose-dependent fashion. The incidence of apoptosis correlates with renal toxicity and can be abrogated by concomitant treatment with rhIGF-1.

* Corresponding author. Mailing address: Max von Pettenkofer-Institute for Hygiene and Medical Microbiology, Ludwig Maximilians University, Pettenkoferstr. 9a, 80336 Munich, Germany. Phone: 0049-89-51605261. Fax: 0049-89-51605223. E-mail: ruessmann{at}m3401.mpk.med.uni-muenchen.de.

dagger Present address: Children's Hospital, Technical University, 80804 Munich, Germany.

Dagger Present address: New York Medical College, Valhalla, NY 10595.

Antimicrobial Agents and Chemotherapy, March 2001, p. 679-685, Vol. 45, No. 3
0066-4804/01/$04.00+0   DOI: 10.1128/AAC.45.3.679-685.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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