195: Protamine Protects Against Vancomycin Induced Kidney Injury in a Translational Rat Model

Statement of Purpose: Vancomycin (VAN) is the most frequently administered antibiotic in the hospital setting and is known to cause attributable kidney injury in over 10% of patients; however, few clinical options exist to prevent this toxicity. Vancomycin uptake into the proximal tubule kidney cell ultimately leads to cell mediated injury. Protamine is an EMEA and FDA approved polycationic low-molecular-weight protein used to reverse excessive anticoagulation from heparin. Additionally protamine has shown off-target action that can reduce gentamicin accumulation in kidney cells [1]. We employed our translational rat kidney injury model [2] to see if protamine could reduce VAN kidney injury.

Description of Methods & Materials: Six male Sprague Dawley rats weighing approximately 300g were studied for each treatment (n=12 total). Rats received VAN 150 mg/kg/day intravenously (n=6) or VAN+Protamine (n=6) starting on Day 1; baseline measurements were obtained pre-treatment (Day 0). All rats received iohexol 51.8 mg/0.22mL intravenously daily to later calculate glomerular filtration rate. Urine was collected continuously with volumes measured every 24 hours for biomarker standardization. The urinary injury biomarker kidney injury molecule-1 [KIM-1] was used to define kidney injury as it best defines vancomycin induced kidney injury in rats. A repeated measures mixed model was used to compare KIM-1 between the treatment groups, and by day of dosing controlling for baseline values.

Data & Results: Both VAN and VAN+Protamine resulted in rises of KIM-1 from baseline day 0. VAN only treated rats had elevated KIM-1 amounts per 24-hour urinary collection on Day 1 and over the first 3 days of study compared to baseline (P < 0.05) whereas rats treated with VAN+Protamine increased later on Day 3 (Figure 1). Rats treated VAN+protamine had lower KIM-1 than rats receiving VAN only on Days 1 and 2 post-dosing (P < 0.05).

Interpretation, Conclusion or Significance: In our translational rat model assessing kidney function, rats that received protamine in addition to vancomycin had lower KIM-1 on Days 1 and 2 after dosing, demonstrating a protective effect of 2 days. These data are supportive of progressing protamine as a combination therapy with vancomycin to prevent kidney injury.

Disclosures: M. H. S. has ongoing research contracts with Nevakar and SuperTrans Medical as well as having filed patent US10688195B2.