University of Groningen Brain death and organ donation Hoeksma, Dane IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2017 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Hoeksma, D. (2017). Brain death and organ donation: Observations and interventions. Rijksuniversiteit Groningen. Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 28-09-2021 Brain Death and Organ Donation Observations and Interventions Dane Hoeksma Brain Death and Organ Donation Observations and Interventions Proefschrift ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen Dane Hoeksma op gezag van de PhD-thesis rector magnifcus prof. dr. E. Sterken en volgens besluit van het College voor Promoties. This PhD-project was fnancially supported by De openbare verdediging zal plaatsvinden op University Medical Center Groningen woensdag 6 september 2017 om 12.45 uur Junior Scientifc Masterclass, Faculty of medicine University Of Groningen Research Institute GUIDE door The printing of this thesis was kindly supported by: University Medical Center Groningen Research Institute GUIDE Noord-Negentig B.V. Chipsoft B.V. Dane Hoeksma geboren op 14 februari 1988 Cover and invitation: Anne van Erp and Dane Hoeksma te Ispingo, Zuid-Afrika Layout: Rens Dommerholt, Persoonlijk Proefschrift, www.persoonlijkproefschrift.nl Printing: Ipskamp printing, www.ipskampprinting.nl Copyright: Dane Hoeksma, 2017-06-11 ISBN number: 978-94-028-0690-8 All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form without explicit prior permission of the author. Promotores Paranimfen Prof. dr. H.G.D. Leuvenink M. Kirschbaum Prof. dr. H. van Goor R. Mencke Beoordelingscommissie Prof. dr. J.L. Hillebrands Prof. dr. D.J. Reijngoud Prof. dr. B. Yard CONTENTS Chapter 1 Introduction 9 Chapter 2 Slow induction of brain death leads to decreased renal function and increased hepatic apoptosis in brain-dead rats 21 Chapter 3 Quality of donor lung grafts: A comparative study between explosive and gradual brain death induction models in rats 41 Chapter 4 Inadequate anti-oxidative responses in kidneys of brain-dead rats 55 Chapter 5 Differences between kidney and liver perfusion, oxygen consumption, and metabolism during brain death 73 Chapter 6 MnTMPyP, a selective superoxide dismutase mimetic, reduces oxidative stress in kidneys of brain-dead rats 95 Chapter 7 MnTMPyP treatment of brain-dead rats leads to improved renal function during ex vivo reperfusion 115 Chapter 8 Discussion and future perspectives 129 Chapter 9 English and Dutch summary 137 List of abbreviations 146 Author affliations 151 Acknowledgments 152 Biography 157 CHAPTER Introduction 1 CHAPTER 1 INTRODUCTION Renal transplantation is the most effective therapy for end-stage renal disease. In 2015, 442 kidneys from deceased donors, the largest donor pool, were transplanted in the Graft survival 1 1 Netherlands . At the end of this year, 554 patients were still awaiting a kidney transplant. 100 1 The total amount of kidneys transplanted in the Eurotransplant region was 3206 in the year LD kidney 2015 while 10400 patients were waiting for a kidney transplant. In the United states, 17.107 80 DBD kidney kidney transplants were performed while 100.791 patients were still on the waiting list2,3. DCD kidney These data indicate that the demand of donor organs outweighs the supply. Therefore, an 60 increase in donor organs is necessary to meet the pressing demand. 40 Kidneys can be retrieved from living donors (LD) and deceased donors. Between the two, deceased donors form the majority since living donors are scarce4. Deceased donors can Percent survival 20 be classifed into deceased brain-dead (DBD) and deceased circulatory death donors 0 5 (DCD) . Of the kidneys transplanted from deceased donors, most are retrieved from 0 5 10 15 20 25 brain-dead donors. However, in many countries, the number of kidneys obtained from Years DCD donors are increasing and in some countries, like the Netherlands, these kidneys Figure 1. Renal graft survival in transplant recipients transplanted between 1993 and 2015 in the University are already transplanted as frequently as DBD kidneys. This is because increased amounts Medical Center Groningen. Graft survival is superior when organs are retrieved from living donors (LD) compared of kidneys from DCD donors who die unexpectedly are being more frequently used for to deceased donors. Within the deceased donor group, organs retrieved from brain-dead donors (DBD) show transplantation. Most DCD donor kidneys used for transplantation are from donors who superior graft survival compared to cardiac-death donors (DCD). die expectedly in the sense that cardiac arrest is anticipated. In the future, an increased amount of DCD donors could be realized as some countries are starting to use organs from unexpected DCD donors. There are different options to meet the increasing demand for donor organs. Many countries have resorted to the use of expanded criteria donors (ECD) to meet the increased 6 The outcome of kidneys retrieved from different donor types varies. The graft survival rates demand of donor organs . ECD donors are older donors (>60 years) or donors aged 50 of kidneys from different donor types from the University Medical Center Groningen are to 59 years with two of the following: cerebrovascular accident as the cause of death, pre- depicted in Figure 1. Kidneys from living donors are superior to deceased donor kidneys existing hypertension, or terminal serum creatinine greater than 1.5 mg/dl. In the future, which can be explained by shorter warm- and cold ischemia times. DBD kidneys do not more ECD donors will be evident due to the aging population. Regarding DCD donors, suffer warm ischemia but are usually subjected to long periods of cold ischemia during an increased amount of DCD donors could be realized by increased use of organs from transport. In addition to cold ischemia, DCD kidneys usually suffer prolonged periods of unexpected DCD. In Spain and Russia, kidneys from unexpected DCD donors are being 7-9 warm ischemia which results in the worst outcomes amongst the three donor types. This increasingly used . Unexpected DCD donors form a large group and may represent a effect is typically observed soon after transplantation as the incidence of primary non- potential option to decrease the demand for donor kidneys. function (PNF) of DCD grafts is 9%, while DBD and LD grafts show PNF rates of 5 and 1%, respectively. However, overall graft survival of DCD-, DBD- and LD transplantation Transplanting kidneys from more marginal donors like ECD and DCD donors is likely to is 86%, 86% and 93%, respectively. Therefore, outcomes from LD kidneys is superior to be associated with decreased rates of graft survival. Therefore, developing strategies to deceased donors but overall outcome is not compromised between either two deceased improve graft survival rates of transplanted kidneys could be advantageous. By doing donor types. However, short term outcome of DCD kidneys is inferior compared to DBD so, these strategies could result in increased graft survival and thereby prevent patients kidneys with regard to, like mentioned above, PNF, but also delayed graft function (DGF; from being relisted on the kidney waiting list. These strategies could also beneft more 82% and 30%, respectively). Yet, despite that deceased donation infuences graft survival conventional donor types such as DBD donors as these kidneys suffer numerous insults in negatively, transplanting deceased donor kidneys represent a good solution for patients the donor. Furthermore, all transplants are subjected to ischemia-reperfusion (I-R) injury with end stage renal disease as the ten-year graft survival rate exceeds 85%. during the transplantation process and therefore even LD donor kidneys could beneft from such strategies. A major break-through was evident with the benefcial effect of machine perfusion on graft survival of deceased donor kidney transplants compared to cold storage10. As mentioned above, kidneys from brain-dead donors lead to inferior outcomes compared to kidneys from living donation4. This phenomenon is related to pathophysiological changes that take place in the brain-dead donor. Brain death (BD) leads to major hemodynamic derailments, systemic infammation, and altered metabolism which potentially affects future donor organs11-13. Furthermore, brain dead donor organs suffer increased I-R injury 14. Major hemodynamic derailments are due to the catecholamine storm which is characteristic for the onset of BD13. The catecholamine storm is believed to be the bodies fnal attempt to maintain cerebral perfusion against increasing intracranial pressure. The 10 11 CHAPTER 1 INTRODUCTION large amounts of secreted catecholamines lead to severe vasoconstriction and possible mitochondrial electron transport chain (ETC), by xanthine and NADPH oxidase, the ischemic damage to organs15. Furthermore, spinal cord ischemia will result in vascular tricarboxylic acid (TCA) cycle enzymes aconitase and α-ketoglutarate dehydrogenase, 1 collapse and consequently decreased blood fow and increased ischemia. Circulating by non-TCA cycle enzymes and by monoamine oxidases and cytochrome b5 reductase, 1 cytokines are evident soon after the onset of BD with IL-6 being the most implicated located in the outer mitochondrial membrane39.