title: Synergistic renal protection by combining alkaline-diuresis with lipid peroxidation inhibitors in rhabdomyolysis: possible interaction between oxidant and non-oxidant mechanisms.
abstract: OBJECTIVE
  Heme-proteins, besides causing renal tubular obstruction, may contribute to rhabdomyolysis-induced renal injury through a heme-iron-mediated lipid peroxidation process. In the present study, we compared the combined therapy of a lipid peroxidation inhibitor, 21-aminosteroid (21-AS) and fluid-alkaline-mannitol (FAM) diuresis with either of them alone to determine the efficacy of the combination therapy and to delineate the roles of lipid peroxidation and cast formation.
  
  
  RESULTS
  Employing Raman spectroscopy, we confirmed in vitro the ability of 21-AS to inhibit iron-induced fatty acid peroxidation. 21-AS was then administered to rats developing renal failure from glycerol-induced rhabdomyolysis. Although 21-AS inhibited rhabdomyolysis-induced plasma and renal lipid peroxidation, renal protection was incomplete. Administration of FAM to inhibit cast formation afforded a better renal protection. However, when these therapies were combined to inhibit both lipid peroxidation and cast formation, there was a synergistic renal functional protection. This was accompanied by a maximum inhibition of renal and plasma lipid peroxidation, as well as, renal tubular necrosis and cast formation. Compared to combination therapy, FAM therapy alone, despite identical volume, was accompanied by a higher tubular necrosis and cast formation.
  
  
  CONCLUSIONS
  That combining a lipid peroxidation inhibitor with fluid-alkaline diuresis in rhabdomyolysis further lowers renal lipid peroxidation, tubular necrosis and cast formation and synergistically limits renal dysfunction (i) supports a role for lipid peroxidation in the pathophysiology of rhabdomyolysis ARF, (ii) underscores the role of the intratubular heme retention, a cause for tubular obstruction as well as a source for prodigious amount of iron, likely involved in the lipid peroxidation, and (iii) raises the possibility of interactions between non-oxidant and oxidant mechanisms.
authors.affiliation: Department of Medicine, University of Mississippi Medical Center, Jackson, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Salahudeen
authors.forename: C
authors.initials: C
authors.lastname: Wang
authors.forename: S A
authors.initials: SA
authors.lastname: Bigler
authors.forename: Z
authors.initials: Z
authors.lastname: Dai
authors.forename: H
authors.initials: H
authors.lastname: Tachikawa
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood; D004231:Diuresis / Q000187:drug effects; D004234:Diuretics, Osmotic / Q000494:pharmacology*; D004338:Drug Combinations; D004357:Drug Synergism; D005227:Fatty Acids / Q000378:metabolism; D005990:Glycerol / Q000633:toxicity; D007668:Kidney / Q000187:drug effects*; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D008353:Mannitol / Q000494:pharmacology*; D009211:Myoglobin / Q000378:metabolism; D011281:Pregnatrienes / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012206:Rhabdomyolysis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D013059:Spectrum Analysis, Raman
chemical_list: D000975:Antioxidants; D004234:Diuretics, Osmotic; D004338:Drug Combinations; D005227:Fatty Acids; D009211:Myoglobin; D011281:Pregnatrienes; D008353:Mannitol; D003404:Creatinine; D005990:Glycerol; C053355:tirilazad