Renal mitochondria response to sepsis: a sequential biopsy evaluation of experimental porcine model.

Summary

In a randomized porcine fecal peritonitis model with sequential renal biopsies, high-severity sepsis caused an early decrease in oxidative phosphorylation and increased uncoupling that preceded macro-hemodynamic changes and coincided with rises in serum creatinine. Renal medulla exhibited lower mitochondrial capacity than cortex, and PGC-1α was reduced in high-severity animals. These data suggest severity-dependent mitochondrial endotypes in sepsis-induced AKI.

Key Findings

• High-severity sepsis caused decreased oxidative phosphorylation and increased uncoupling within 24 hours, preceding renal macro-hemodynamic changes.
• Serum creatinine rose early, indicating renal dysfunction not primarily driven by hemodynamics.
• Renal medulla had lower oxidative phosphorylation and ETS activity than cortex; PGC-1α decreased in high-severity animals.

Clinical Implications

Renal dysfunction in severe sepsis may be driven by early mitochondrial failure rather than macro-hemodynamics, supporting early mitochondrial-targeted diagnostics and therapies (e.g., biogenesis enhancers) and suggesting phenotype-specific trial designs for SA-AKI.

Limitations

• Small sample size (n=15) and open-label design in a single preclinical model
• Short observation window (~24 h) limits assessment of longer-term renal recovery or fibrosis

Future Directions

Define SA-AKI mitochondrial endotypes prospectively in humans, test mitochondrial biogenesis/uncoupling modulators, and integrate renal regional oxygenation imaging with bioenergetic biomarkers.