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Effects of diltiazem on netilmicin-induced nephrotoxicity in rabbits
O Lortholary1, F Blanchet, D Nochy
1Institut National de la Santé et de la Recherche Médicale U. 13, Paris, France.
Abstract:
Aminoglycoside nephrotoxicity remains a common clinical problem and is the major cause of acute toxic renal failure in hospitalized patients. In recent studies, calcium channel blockers gave controversial results in the prevention of acute ischemic or toxic renal failure. The aims of the study were (i) to describe a rabbit model of mild renal failure (50% reduction in glomerular filtration rate with a mean value of 1.78 +/- 0.46 ml/kg/min) induced by netilmicin given intramuscularly at 20 mg/kg of body weight every 8 h for 5 days, (ii) to investigate the protective effect of diltiazem given at a therapeutic dose (1 mg/kg given intramuscularly every 8 h for 5 days), and (iii) to investigate the mechanisms of this protection through evaluation of function tests, optic histology, and glomerular morphometry. Animals treated with netilmicin and diltiazem exhibited an unchanged glomerular filtration rate compared with controls (3.39 +/- 0.58 versus 3.68 +/- 0.78 ml/kg/min, respectively). This protective effect was not associated with any change in systemic or renal hemodynamics (i.e., no change in renal plasma flow) or changes in the pharmacokinetics of netilmicin, as assessed by fractional excretion and cortical uptake. Netilmicin-induced tubular toxicity was unchanged by diltiazem. Our results suggest that (i) netilmicin exhibits a toxic effect at both the glomerular and the tubular levels, (ii) diltiazem, a calcium channel blocker, when given at low therapeutic doses, is able to prevent the aminoglycoside-induced renal failure through a potential glomerular mechanism. The precise mechanisms of the protection remain to be elucidated. These results deserve clinical evaluation in high-risk patients.
Insights
Diltiazem, a calcium channel blocker, may prevent kidney damage from netilmicin, an antibiotic. This study explored its protective effects in a rabbit model, suggesting a potential glomerular mechanism for preventing aminoglycoside-induced renal failure.
Area of Science:
- Nephrology
- Pharmacology
- Toxicology
Background:
- Aminoglycoside antibiotics are a common cause of hospital-acquired acute kidney injury.
- Calcium channel blockers have shown controversial results in preventing acute kidney injury from toxins or ischemia.
Purpose of the Study:
- To establish a rabbit model of netilmicin-induced renal failure.
- To investigate the protective effect of diltiazem against netilmicin nephrotoxicity.
- To explore the mechanisms underlying diltiazem's potential protective action.
Main Methods:
- Induction of mild renal failure in rabbits using netilmicin (20 mg/kg IM every 8h for 5 days).
- Administration of diltiazem (1 mg/kg IM every 8h for 5 days) to assess its protective effect.
- Evaluation of renal function, histology, and glomerular morphometry to elucidate protective mechanisms.
Main Results:
- Diltiazem treatment maintained glomerular filtration rate in netilmicin-exposed rabbits.
- No significant changes in renal hemodynamics or netilmicin pharmacokinetics were observed.
- Diltiazem did not alter netilmicin-induced tubular toxicity, indicating a potential glomerular protective effect.
Conclusions:
- Netilmicin induces toxicity at both glomerular and tubular levels.
- Low-dose diltiazem may prevent aminoglycoside-induced renal failure via a glomerular mechanism.
- Further clinical evaluation is warranted for high-risk patients.