Synergistic renal protection by combining lipid peroxidation inhibitors with alkaline-diuresis in rhabdomyolysis-ARF: Possible interactions between oxidant and non-oxidant mechanisms

Both oxidant and non-oxidant mechanisms are considered to be important in the complex pathophysiology of myohemoglobin-mediated renal injury. Although recent studies suggest a therapeutic potential for the antioxidam 21-aminosteroid (AS), whether such a therapy is better than the existing fluid-alkali-mannitol diuresis (AD) or whether combining AS with AD provides additional renal protection has not been addressed. We examined in the glycerol-induced rhabdomyolysis model (G) the effect of 1) inhibiting renal lipid peroxidation by AS, 2) inhibiting the tubular cast formation by vigorous AD, or 3) inhibiting both lipid peroxidation and cast formation by combining these two therapies. AS group received AS, the AD group received NaHCO₃ and mannitol and combination group (C), both. At 24 hr (m±SE; * P<0.05 vs G; a vs AS,AD; b vs AD): Tubular cast score was G=AS>AD>C where as necrosis score was G>AD>AS>C. The novel G finding that combining AS AD with lipid AD peroxidation inhibitors C further lowers renal lipid peroxidation, tubular necrosis and cast formation and synergistically limits renal failure, 1) supports a role for lipid peroxidation in rhabdomyolysis ARF 2) underscores the role of intratubular heme retention, a cause for obstruction and excessive iron and 3) raises the possibility of interactions between nonoxidant and oxidant mechanisms. That combination therapy offers the best renal outcome may have clinical implications. n 6 S Cr mg/dl BUN mg/dl Renal C. Dienes nmol/mg prot Renal MDA nmol/mg prot G 2.5±02 118±10 0.09±0.01 0.74±0.04 AS 2.0±0.3* 84±13* 0.054±0.003* 0.41±0.02 AD 1.9±0.2* 73±10*a 0.059±0.004* 0.45±0.03* C 0.8±0.1*a 32±3.0*a 0.043±0.003*a 0.31±0.03*b.