Species specific differences in the sensitivity of the *-ketoglutarate dehydrogenase to ischemia/reperfusion injury.

Ischemia-reperfusion injury (I/R injury) is the paradoxical development of
tissue damage after reperfusion of previously ischemic tissue and can cause
organ dysfunction. I/R injury occurs in numerous settings such as
transplantation, myocardial infarction and ischemic stroke. The pathophysiology
of I/R injury is complex and not well understood. This is partly due to the
fundamental differences between animals and humans, interfering with
translation of preclinical findings to the human context.

Our group has been studying the mechanisms of clinical I/R injury in the
context of renal transplantation. The data of these studies show that clinical
I/R injury relates to critical metabolic deficiencies due to mitochondrial
failure. 1-3 Post-reperfusion release of *-ketoglutarate in kidneys with I/R
injury implies that impaired oxidative phosphorylation involves an almost
instantaneous and persistent post-reperfusion defect at the level of the *-
ketoglutarate dehydrogenase complex (*-KGDH). This observation is contrast to
the observations in rodents4, and points to clear species specific differences
in the susceptibility of the *-KGDH complex, with an almost instantaneous
inactivation of the *-KGDH complex in humans. As such, the question arises
whether there are species specific differences in the sensitivity of the *-KGDH
complex, and to identify the sensitive positions in the enzyme complex on basis
of species differences in protein structure.
Recently we performed a pilot study with porcine kidney tissues and data showed
that the *-KGDH complex is very sensitive to warm ischemia. Therefore,
non-ischemic human kidney tissue is desired to study the dynamics of the *-KGDH
complex and to identify the sensitive positions in the enzyme complex.

The aim of this study is to evaluate whether there are species specific
differences in the sensitivity of the *-KGDH complex and to identify the
sensitive positions in the enzyme complex.

Exploratory patient study.

The study has no personal benefit for the patients themselves, but the risks
associated with participation and the burden can be considered minimal.
Follow-up is according to standard medical care.