Cephaloridine nephrotoxicity: strain and sex differences in mice

Area of Science:

• Pharmacology
• Toxicology
• Nephrology
• Animal Models

Background:

• Cephaloridine (CPH) is a cephalosporin antibiotic with known nephrotoxicity.
• Previous studies indicated species and sex differences in CPH-induced kidney damage.
• Preliminary data suggested strain-specific variations in mouse susceptibility to CPH nephrotoxicity.

Purpose of the Study:

• To investigate strain and sex differences in cephaloridine (CPH) nephrotoxicity in mice.
• To assess the impact of CPH dosage on renal function across different mouse strains and sexes.
• To explore potential mechanisms underlying observed variations in CPH nephrotoxicity.

Main Methods:

• Male and female mice from six strains (C57BL, BALB/c, CD-1, CFW, CBA/J, DBA/2) were administered cephaloridine (CPH) subcutaneously at 4000 or 6000 mg/kg.
• Renal function was evaluated 48 hours post-administration.
• Assessments included renal cortical slice accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA), blood urea nitrogen (BUN) levels, and kidney-to-body weight ratios.

Main Results:

• CPH induced dose-dependent nephrotoxicity in C57BL female mice, with significant reductions in PAH and TEA uptake and a tenfold increase in BUN at 6000 mg/kg.
• CFW female mice showed no adverse effects from the same CPH dose, while other female strains exhibited intermediate toxicity.
• Male mice of all tested strains demonstrated no signs of CPH-induced nephrotoxicity.

Conclusions:

• Significant sex and strain differences exist in mouse susceptibility to cephaloridine (CPH) nephrotoxicity.
• Male mice are resistant to CPH nephrotoxicity, irrespective of strain.
• Differences in renal cortical accumulation of CPH, potentially due to variations in transport, binding, or metabolism, likely explain the observed toxicity disparities between sexes and strains.