Ischemia/reperfusion injury : a metabolic meltdown

Wijermars, L.G.M. (2018)

Doctoral Thesis

This thesis provides insights into the mechanisms of renal I/R injury based on human kidney transplantation (i.e. the status of delayed graft function: DGF). A severe energetic crisis differentiates DGF kidneys from adequately functioning controls. Although intact beta-oxidation, aerobic glycolysis and glutaminolysis provide Krebs Cycle intermediates, these intermediates are not able to enter the mitochondrial Krebs cycle. Hence, dysfunctional mitochondria disable efficient ATP production leading to the metabolic incompetence that causes DGF and underlies renal I/R injury. This finding sheds a whole new light on I/R injury and explains why ATP-dependent therapeutics are ineffective as treatment for I/R injury.
A major difference in the vulnerability of mitochondria to ischemia and reperfusion between rodents and humans was found. This could explain the current differences in effectiveness of therapies in the experimental versus the clinical setting.
Big cohort studies give insights in donor, recipient and transplant-procedure variables and challenge the reluctance towards the use of DCD donor kidneys.
New preventive strategies could limit I/R injury by preserving mitochondria (hypothetically with peptide SS-31 or activation of mitochondrial aldehyde dehydrogenase). This will overcome the detrimental effects of I/R injury on graft function and survival - thereby increasing the success rate of kidney transplantation.

• Ischemia reperfusion injury
• Kidney transplantation
• Delayed graft function
• Metabolomics
• Mitochondria
• Transcriptomics

• All authors: Wijermars, L.G.M.
• Supervisor: Hamming, J.F.
• Co-supervisor: Lindeman, J.H.N.; Schaapherder, A.F.M.
• Committee: Rabelink, A.J.; Reinders, M.E.J.; Alwayn, I.P.W.; Hankemeier, T.; Goldschmeding, R.; Ploeg, R.J.
• Qualification: Doctor (dr.)
• Awarding Institution: Medicine, Leiden University Medical Center (LUMC), Leiden University
• Date: 2018-03-21
• Sponsorship: Nierstichting, Nederlandse transplantatie stichting, Pfizer, Sanofi, Astellas, Chipsoft