Succinate Accumulation and Ischemia-Reperfusion Injury: Of Mice but Not Men, a Study in Renal Ischemia-Reperfusion

Area of Science:

• Biomedical Science
• Organ Transplantation
• Ischemia-Reperfusion Injury

Background:

• A seminal paper suggested ischemia-related succinate accumulation drives organ injury.
• This mechanism was proposed as universal across organs (kidney, liver, heart, brain) in mice.

Purpose of the Study:

• To investigate the translation of mouse findings on succinate and ischemia-reperfusion injury to human kidney transplantation.
• To determine if succinate accumulation occurs during human renal graft procurement and reperfusion.

Main Methods:

• Analysis of succinate content in human renal grafts during procurement.
• Assessment of mitochondrial susceptibility to warm ischemia in rodent, pig, and human mitochondria.
• Monitoring of allantoin release as an indicator of oxidative stress during reperfusion.

Main Results:

• Succinate levels progressively decreased with increasing ischemia time in human renal grafts.
• Human and pig mitochondria were highly susceptible to warm ischemia, unlike rodent mitochondria.
• Minimal allantoin release was observed, indicating low oxidative stress during clinical reperfusion.

Conclusions:

• Succinate accumulation is not a universal event in ischemia and does not occur during human renal graft procurement.
• Succinate-driven reactive oxygen species formation is unlikely to be a major mechanism of injury in human kidney transplantation.
• Human kidney transplantation involves different injury mechanisms compared to rodent models, with minimal oxidative stress during reperfusion.