Protamine protects against vancomycin-induced kidney injury.

Area of Science:

• Nephrology
• Pharmacology
• Toxicology

Background:

• Vancomycin nephrotoxicity is a significant clinical concern, primarily linked to proximal tubule accumulation via megalin uptake.
• Protamine, an FDA-approved agent for heparin overdose, is a potential inhibitor of megalin due to shared binding sites.

Purpose of the Study:

• To evaluate the efficacy of protamine in mitigating vancomycin-induced kidney injury (VIKI) in a rat model.
• To investigate the mechanism of protamine's action, specifically its effect on megalin and renal transporters (OAT1, OAT3, OCT2).

Main Methods:

• A Sprague-Dawley rat model was used over 5 days, administering vancomycin, protamine alone, or vancomycin plus protamine.
• Kidney injury was assessed by urinary KIM-1 levels, and kidney function by plasma iohexol clearance.
• In vitro cellular inhibition studies examined protamine's effect on OAT1, OAT3, and OCT2 transporters.

Main Results:

• Vancomycin alone significantly increased urinary KIM-1. Co-administration with protamine delayed this increase by 1-3 days compared to vancomycin alone.
• No significant differences in iohexol clearance (a measure of kidney function) were observed between groups.
• Protamine showed minimal inhibition of OAT1, OAT3, and OCT2 in cellular studies (IC50 values: 0.1 mM for OAT1/OAT3, 0.043 mM for OCT2).

Conclusions:

• Protamine delays the onset of vancomycin-induced kidney injury in rats, likely through megalin blockade, without significantly impacting renal transporters OAT1, OAT3, or OCT2.
• As an approved medication, protamine holds potential for clinical use in reducing VIKI, although development of agents with improved safety profiles may offer greater benefit.