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Decoding Aminoglycoside Nephrotoxicity: From Molecular Insights to Practical Applications

This study delves into the molecular pharmacology and pathology of aminoglycoside-induced nephrotoxicity, exploring cytological and molecular mechanisms, apoptosis implications, and modulation strategies. Discover the latest research findings and their relevance in clinical settings.

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Decoding Aminoglycoside Nephrotoxicity: From Molecular Insights to Practical Applications

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  1. Aminoglycoside nephrotoxicity: from molecular pharmacology and pathology to some applications Paul M. Tulkens, MD, PhD Unité de Pharmacologie Cellulaire et Moléculaire Université Catholique de Louvain Brussels, Belgium

  2. Aminoglycosides... • highly bactericidal and wide spectrum • post-antibiotic effect • synergistic with beta-lactams • dose proportionate PKs • no metabolism and 95 % renal excretion • BUT… • neuro-muscular blockade (high doses) • nephrotoxicity • ototoxicity (irreversible)

  3. Aminoglycosides... • cytological and molecular mechanisms of nephrotoxicity • the “once-a-day” schedule • polyaspartic acid • recent data on apoptosis

  4. Evidence of apoptosis in proximal tubular cells Gentamicin 10 mg/kg 10 days; HE staining

  5. Evidence of apoptosis in proximal tubular cells: histology HE staining methyl green-pyronin gentamicin 10 mg/kg, 10 days

  6. Evidence of apoptosis in proximal tubular cells: TUNEL staining gentamicin 10 mg/kg, 10 days

  7. Apoptosis in proximal tubular cells:quantification and correlation between TUNEL and Brachet

  8. Apoptosis in proximal tubular cells:correlation with tubular/peritubular proliferation

  9. Apoptosis in cultured cells: EM chromatin condensation rat embryo fibroblats gentamicin 2 mM 4 days apoptotic body

  10. Apoptosis in cultured cells:DNA size analysis (agarose electrophoresis) control GM 2mM 4 days fibroboblats 1 2 MDCK cells 3 4 LLC-PK1 cells 5 6

  11. Gentamicin-induced apoptosis in cultured cells:Quantification by TUNEL

  12. Gentamicin-induced apoptosis in cultured cells:correlation with gentamicin accumulation

  13. Gentamicin-induced apoptosis in cultured cells:correlation with phospholipidosis

  14. Modulation of gentamicin-induced apoptosis in cultured cells • blocked by cycloheximide (fibroblasts and MDCK-cells) (LLC-PK1 cells show apoptosis with CH) • blocked by over-expression of BCl-2 protein in bcl-2 transfected cells (MDCK- and LLC-PK1 cells) • associated with increased caspase-3 activity (MDCK cells) • blocked by caspase-3 inhibitor ZVAD.fmk (MDCK-cells)

  15. Aminoglycosides... cytological and molecular mechanisms of nephrotoxicity G. Laurent B. Carlier R. Brasseur J.M. Ruysschaert Starting in the early 80’s ...

  16. Aminoglycosides... The once-a-day story... S. Ibrahim P. Maldague B. Carlier G. Laurent D. Beauchamp … and many others In the mid 80’s ...

  17. Aminoglycosides... The poly-aspartic acid saga... Z. Kallay B.K. Kishore J. Piret S. Ibrahim P. Maldague D. Beauchamp … and many others Early 90’s ...

  18. Aminoglycosides... The apoptosis finale ... P. Maldague (+ 1994) M. El Mouedden H. Taper M.P. Mingeot G. Laurent M. Dellale The 90’s ...

  19. Aminoglycosides... Where has that been published ? • So many papers, but start with two last reviews: • Mingeot-Leclercq, M.P. and Tulkens, P.M.: Aminoglycosides: nephrotoxicity. Antimicrob. Agents Chemother. 43: 1003-1012, 1999. • Mingeot-Leclercq, M.P., Glupczynski, Y. and Tulkens, P.M.: Aminoglycosides: activity and resistance. Antimicrob. Agents Chemother. 43: 727-737, 1999.

  20. Aminoglycosides... Where has that been published ? and then, make a Medline Search on the following names (a selection): • Laurent-G • Kishore-BK • Mingeot-Leclercq-MP • Carlier-MB • Beauchamp-D • Piret-J • Van-der-Auwera-P • …. • Lambricht-P • Wagner-R • Vanschepdael-A • Claes-JP • Vanderhaeghe-HJ • Langhendries-M • Porter-G • ...

  21. Aminoglycosides... Or, just come and visit us...

  22. Aminoglycosides... But, where is that ? Cellular and Molecular Pharmacology Unit Catholic University of Louvain, Belgium http://www.md.ucl.ac.be/facm

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