title: Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury.
abstract: To explore why urine pH affects myoglobin (M)-induced renal injury, rats were infused with M under aciduric (NH4Cl) or alkalinuric (KHCO3) conditions with or without additional solute loading. Acute renal M retention (R) was highly pH dependent (pH 5.77, 68% R; pH 6.45, 49% R; pH 8.0, 28% R), the % R positively affecting the severity of renal injury (azotemia, proximal tubular necrosis, M casts, medullary vascular congestion, assessed 3 and/or 24 hours later). However, nonreabsorbable, nonalkalinizing salts (SO4) equiosmolar to KHCO3 decreased M retention to 21% and produced comparable functional/morphologic protection as HCO3. Equiosmolar reabsorbable salt (NaCl) did not decrease M retention (67%) or confer significant protection. M, when suspended in urine, but not in 0.45% NaCl, was highly acid precipitable (73% versus 10%). Electrophoretic/solubility studies indicated that M, not hematin, precipitated. M infusion did not decrease renal cortical soluble thiol groups (principally glutathione) or raise malondialdehyde concentrations at a time that tubular damage was apparent. Neither deferoxamine nor 2 hydroxyl radical scavengers (dimethylthiouria, Na benzoate) conferred significant functional/morphologic protection. These results indicate that aciduria promotes myoglobinuric-renal injury by acutely trapping M within the kidney, not by causing hematin formation. HCO3 protects by increasing urinary M solubility and by providing nonreabsorbed solute, both facilitating its excretion. Fe-stimulated hydroxyl radical formation does not appear to be necessary for M to cause renal damage.
authors.affiliation: Department of Medicine and Biostatistics, University of Washington, Seattle.
authors.forename: R A
authors.initials: RA
authors.lastname: Zager
mesh_terms: D058186:Acute Kidney Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006863:Hydrogen-Ion Concentration; D007668:Kidney / Q000473:pathology*; D009211:Myoglobin / Q000378:metabolism*; D009212:Myoglobinuria / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D051381:Rats; D011919:Rats, Inbred Strains; D012206:Rhabdomyolysis / Q000378:metabolism*; D012995:Solubility
chemical_list: D009211:Myoglobin