This thesis demonstrates that kidneys from DCD donors can be fully embraced, and that the perception of DCD kidney transplantation being inferior to DBD kidney transplantation – mainly motivated by... Show moreThis thesis demonstrates that kidneys from DCD donors can be fully embraced, and that the perception of DCD kidney transplantation being inferior to DBD kidney transplantation – mainly motivated by concerns regarding high incidences of DGF and EGL – is no longer justified. One explanation for this phenomenon is that outcomes of transplanted DCD kidneys have improved over time, with a similar incidence of EGL following DBD and DCD kidney transplantation in the current era. Another explanation is that both donor types have different biological responses to DGF: whilst DGF severely impacts on DBD graft survival, DGF has no impact on DCD graft survival. This difference relates to donor type-specific regulation of resilience and pro-inflammatory pathways benefitting the DCD graft and its outcomes. As such, the persistent high incidence of DGF in DCD grafts should not be regarded an impediment toward the use of these donor kidneys.This thesis additionally explores a series of physiological and methodological contrasts between preclinical and clinical I/R injury, that all may contribute to the impaired translatability of preclinical studies in clinical practice. Awareness of these pitfalls may help to improve study designs in future research, bringing us one step closer towards bridging the translational gap. Show less
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... Show moreThis 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. Show less
Endothelial injury and repair are most important concepts for our understanding of renal disease and allograft injury. The concept that injury to the endothelium may precede renal fibrosis strongly... Show moreEndothelial injury and repair are most important concepts for our understanding of renal disease and allograft injury. The concept that injury to the endothelium may precede renal fibrosis strongly suggests that interventions to maintain vascular integrity are of major importance for renal function. This thesis focuses on the mechanisms involved in the process of endothelial damage and repair in renal disease, (early) diabetes mellitus (DM) and renal ischemia-reperfusion (I/R) injury. Furthermore, microvascular alterations were assessed, using sidestream darkfield (SDF) imaging and measurement of endothelial dysfunction markers (including angiopoietins), in chronic kidney disease (CKD) and DM patients before and after (pancreas) kidney transplantation. The results of this thesis demonstrate an important role for endothelial damage and repair in renal disease and after transplantation. Both renal I/R and DM induced systemic capillary damage reflected by increased capillary tortuosity by SDF imaging and a dysbalance in angiopoietins. In addition, patients with CKD and allograft rejection after renal transplantation also had systemic microvascular derangements. Transplantation was effective in reversing the systemic microvascular alterations. Complementary use of SDF imaging to measure microvascular tortuosity and the assessment of endothelial dysfunction markers may be useful diagnostic tool for monitoring the microvasculature before and after transplantation. Show less
