HYDROCORTISONE, ASCORBIC ACID, AND THIAMINE THERAPY DECREASE RENAL OXIDATIVE STRESS AND ACUTE KIDNEY INJURY IN MURINE...

Area of Science:

• Critical care medicine
• Sepsis pathophysiology
• Renal injury mechanisms

Background:

• Acute kidney injury (AKI) is common in sepsis and linked to higher mortality.
• Previous clinical trials on hydrocortisone, ascorbic acid, and thiamine (HAT) therapy for sepsis have yielded mixed results.
• Stratification of septic patients based on predicted mortality may help identify candidates for therapy and elucidate organ injury mechanisms.

Purpose of the Study:

• To test if predicted non-survivors (P-Die) in a sepsis model exhibit greater kidney injury than predicted survivors (P-Live).
• To determine if HAT therapy can correct physiological deterioration and organ injury in P-Die septic mice.
• To investigate the mechanisms of kidney injury, including inflammation, oxidative stress, and endothelial cell damage in sepsis.

Main Methods:

• Sepsis was induced via cecal ligation and puncture (CLP) in mice.
• Mice were stratified into P-Live and P-Die groups based on heart rate 6 hours post-CLP.
• Stratified mice received either HAT or vehicle treatment 7 hours post-CLP, with physiological and biochemical assessments at 24 hours.

Main Results:

• P-Die mice showed significant declines in heart rate, cardiac output, breath rate, and temperature, which were reversed by HAT therapy.
• Ascorbic acid levels were depleted in P-Die mice and restored by HAT.
• HAT therapy reduced elevated inflammatory markers (IL-6, KC, MIP-2, IL-1RA), endothelial injury markers (glypican 1 & 4), and renal oxidative stress in P-Die mice.
• Kidney injury markers (BUN, cystatin C) were elevated in P-Die mice and reduced by HAT, while hepatic parameters remained normal.

Conclusions:

• Septic mice predicted to die (P-Die) exhibit increased inflammation, oxidative stress, and kidney injury.
• HAT therapy administered after the onset of sepsis-induced physiological changes effectively decreased renal oxidative stress and injury in P-Die mice.
• Mortality stratification can identify septic patients who may benefit from specific therapies like HAT, targeting key injury pathways.