Related Experiment Videos
Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury
1Department of Medicine and Biostatistics, University of Washington, Seattle.
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.
Insights
Urine acidity significantly increases myoglobin (M) retention in kidneys, worsening renal injury. Bicarbonate protects by enhancing M solubility and excretion, not by preventing hematin formation or free radical damage.
Area of Science:
- Nephrology
- Toxicology
- Biochemistry
Background:
- Myoglobin (M) infusion can cause acute kidney injury.
- The role of urine pH in myoglobinuric renal injury is not fully understood.
- Previous studies suggest oxidative stress may contribute to M-induced renal damage.
Purpose of the Study:
- To investigate the impact of urine pH on M retention and subsequent renal injury.
- To elucidate the protective mechanisms of bicarbonate (HCO3) in M-induced nephrotoxicity.
- To determine if hematin formation or hydroxyl radical generation mediates M nephrotoxicity.
Main Methods:
- Rats were infused with M under varying urine pH conditions (acidic, alkaline).
- Renal M retention, functional markers (azotemia), and morphological damage were assessed.
- Solubility studies and biochemical assays were performed to evaluate M precipitation and oxidative stress.
Main Results:
- Renal M retention was significantly higher in acidic urine (68% at pH 5.77) compared to alkaline urine (28% at pH 8.0).
- Increased M retention correlated positively with the severity of renal injury, including tubular necrosis and azotemia.
- Bicarbonate and nonreabsorbable salts reduced M retention and protected against injury, while reabsorbable salts did not.
- M precipitation was pH-dependent and occurred in urine, not saline.
- Oxidative stress markers and hydroxyl radical scavengers did not significantly affect M-induced renal injury.
Conclusions:
- Aciduria promotes myoglobinuric renal injury by increasing M retention within the kidney.
- Bicarbonate confers protection by increasing urinary M solubility and facilitating excretion via nonreabsorbed solute.
- Hematin formation and Fe-stimulated hydroxyl radical activity are not the primary mechanisms of M-induced renal damage.