TY - JOUR
T1 - Synergistic renal protection by combining alkaline-diuresis with lipid peroxidation inhibitors in rhabdomyolysis
T2 - Possible interaction between oxidant and non-oxidant mechanisms
AU - Salahudeen, Abdulla K.
AU - Wang, Chunyou
AU - Bigler, Steven A.
AU - Dai, Zhongyi
AU - Tachikawa, Hiroyasu
N1 - Funding Information:
Acknowledgements. This study was supported by funding from the American Heart (MS affiliate) grant-in-aid program and the Baxter extramural grant program to AKS. The continued support of Dr John O'Connell and Dr John Bower of University of Mississippi Medical Center is appreciated, so is the gift of 21-aminosteroid (Lazaroid) compounds by Dr John McCall of Upjohn Company. C. Wang was a post-doctoral fellow from the Department of Surgery, Union Hospital, Tongji Medical University, Wuham, People's Republic of China.
PY - 1996/4
Y1 - 1996/4
N2 - Background and purpose. 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. Methods and 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 intratubular heme retention, a cause for tubular obstruction as well 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.
AB - Background and purpose. 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. Methods and 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 intratubular heme retention, a cause for tubular obstruction as well 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.
KW - 21-aminosteroid
KW - Acute renal failure
KW - Hemeproteins
KW - Lipid peroxidation
KW - Raman spectroscopy
KW - Rhabdomyolysis
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U2 - 10.1093/oxfordjournals.ndt.a027352
DO - 10.1093/oxfordjournals.ndt.a027352
M3 - Article
C2 - 8671851
AN - SCOPUS:0029915595
SN - 0931-0509
VL - 11
SP - 635
EP - 642
JO - Nephrology Dialysis Transplantation
JF - Nephrology Dialysis Transplantation
IS - 4
ER -