Caspofungin is less nephrotoxic than amphotericin B in vitro and predominantly damages distal renal tubular cells.
BACKGROUND
Caspofungin (CAS) has recently been approved for treatment of invasive aspergillosis. In clinical trials, CAS-induced nephrotoxicity was markedly less pronounced compared to amphotericin B (AmB). Nevertheless, in a recent trial, nephrotoxicity in CAS-treated patients was considerably more pronounced than in preceding studies. Therefore, the aim of this study was to assess toxic effects of CAS on human renal proximal and distal tubular epithelial cells (PTC and DTC) in vitro, and to compare them to those of AmB.


METHODS
Cells were isolated from human kidney tissue, and exposed to clinically relevant concentrations of CAS and AmB for 24 h. Total DNA content and cell viability were determined by DAPI staining and a modified MTT assay. For testing of cytotoxicity, LDH activity was measured in cell culture supernatants. To assess apoptotic effects, AnnexinV-binding assay and DAPI staining for detection of fragmented DNA were performed.


RESULTS
DTC were more vulnerable towards the antifungal agents than PTC. In contrast to AmB, cell-damaging effects of CAS were less severe. DAPI staining revealed slight and dose-dependent antiproliferative effects of CAS at concentrations reflecting relevant plasma levels. At these concentrations, cell viability, determined by MTT assay, was not decreased in PTC and DTC. LDH release was marginally increased in a dose-dependent manner; apoptosis was not detected. Nevertheless, at CAS concentrations reflecting potential tissue concentrations, cell damaging effects were considerably more pronounced.


CONCLUSIONS
Our results suggest that CAS is less nephrotoxic than AmB in vitro. The antiproliferative and cytotoxic effects of CAS predominantly affect DTC, which seem to be more susceptible to CAS-induced damage.
Department of Nephrology, J.W. Goethe-University, Theodor-Stern-Kai 7, 60590 Frankfurt, Germany. b.wegner@em.uni-frankfurt.de
Binytha
B
Wegner
Patrick
P
Baer
Stefan
S
Gauer
Gerhard
G
Oremek
Ingeborg A
IA
Hauser
Helmut
H
Geiger
D000666:Amphotericin B / Q000633:toxicity*; D017304:Annexin A5 / Q000378:metabolism; D000935:Antifungal Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D000077336:Caspofungin; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D053938:DNA Fragmentation / Q000187:drug effects; D054714:Echinocandins; D005456:Fluorescent Dyes; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007686:Kidney Tubules, Distal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D055666:Lipopeptides; D009336:Necrosis; D010456:Peptides, Cyclic / Q000633:toxicity*
D017304:Annexin A5; D000935:Antifungal Agents; D054714:Echinocandins; D005456:Fluorescent Dyes; D007211:Indoles; D055666:Lipopeptides; D010456:Peptides, Cyclic; C007293:DAPI; D000666:Amphotericin B; D007770:L-Lactate Dehydrogenase; D000077336:Caspofungin