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Hypothermic Oxygenated Machine Perfusion of the Human Pancreas University of Groningen Hypothermic oxygenated machine perfusion of the human pancreas for clinical islet isolation Doppenberg, Jason B.; Leemkuil, Marjolein; Engelse, Marten A.; Krikke, Christina; de Koning, Eelco J. P.; Leuvenink, Henri G. D. Published in: Transplant International DOI: 10.1111/tri.13927 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: 2021 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Doppenberg, J. B., Leemkuil, M., Engelse, M. A., Krikke, C., de Koning, E. J. P., & Leuvenink, H. G. D. (2021). Hypothermic oxygenated machine perfusion of the human pancreas for clinical islet isolation: a prospective feasibility study. Transplant International, 1-12. https://doi.org/10.1111/tri.13927 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: 24-09-2021 Transplant International ORIGINAL ARTICLE Hypothermic oxygenated machine perfusion of the human pancreas for clinical islet isolation: a prospective feasibility study Jason B. Doppenberg1,* , Marjolein Leemkuil2,* , Marten A. Engelse1 , Christina Krikke2, Eelco J. P. de Koning1 & Henri G. D. Leuvenink2 1 Transplantation Center, Leiden SUMMARY University Medical Center, Leiden, the Due to an increasing scarcity of pancreases with optimal donor characteris- Netherlands tics, islet isolation centers utilize pancreases from extended criteria donors, 2 Department of Surgery, University Medical Center Groningen, such as from donation after circulatory death (DCD) donors, which are Groningen, the Netherlands particularly susceptible to prolonged cold ischemia time (CIT). We hypothesized that hypothermic machine perfusion (HMP) can safely Correspondence increase CIT. Five human DCD pancreases were subjected to 6 h of oxy- Marjolein Leemkuil, University genated HMP. Perfusion parameters, apoptosis, and edema were measured Medical Center Groningen, P.O. prior to islet isolation. Five human DBD pancreases were evaluated after Box 30.001, 9700 RB Groningen, the static cold storage (SCS). Islet viability, and in vitro and in vivo functional- Netherlands. ity in diabetic mice were analyzed. Islets were isolated from HMP pan- Tel.: +31 50 361 9801; creases after 13.4 h [12.9–14.5] CIT and after 9.2 h [6.5–12.5] CIT from e-mail: [email protected] SCS pancreases. Histological analysis of the pancreatic tissue showed that HMP did not induce edema nor apoptosis. Islets maintained >90% viable *Both authors contributed equally to during culture, and an appropriate in vitro and in vivo function in mice this work. was demonstrated after HMP. The current study design does not permit to demonstrate that oxygenated HMP allows for cold ischemia extension; however, the successful isolation of functional islets from discarded human DCD pancreases after performing 6 h of oxygenated HMP indicates that oxygenated HMP may be a useful technology for better preservation of pancreases. Transplant International 2021; Key words donation after circulatory death, hypothermic machine perfusion, islet isolation Received: 11 March 2021; Revision requested: 14 May 2021; Accepted: 16 May 2021 characteristics for islet isolation [3]. This has led to Introduction greater numbers of pancreases accepted for isolation Allogeneic transplantation of pancreatic islets is an from extended criteria donors (ECDs) such as donation effective treatment for a selected group of patients with after circulatory death donors (DCDs) [4]. In fact, in long-standing type 1 diabetes mellitus. Using modern the Netherlands DCD procedures accounted for 34% of immunosuppression regimes, improved glycemic con- all multi-organ donation procedures in 2010, which trol can be achieved in most transplanted patients [1,2]. increased to 59% in 2019 [5]. There are perceived In the Eurotransplant region, pancreases are preferen- added risks for the utilization of DCD organs as DCD tially offered for vascularized pancreas transplantation, kidneys and livers have been shown to be more suscep- leaving pancreases with less favorable donor tible to the harmful effects of warm and cold ischemia ª 2021 The Authors. Transplant International published by John Wiley & Sons Ltd on behalf of Steunstichting ESOT 1 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. doi:10.1111/tri.13927 Doppenberg et al. [6–9]. Islet isolation from DCD donors has shown to Table 1. Donor characteristics of pancreases from the result in lower yields compared with DBD pancreases SCS and HMP groups (87 000–100 000 IEQ less) [10,11]. Therefore, donor characteristics are often more favorable for DCD pan- Donor variable HMP SCS creases: younger age, more often male donors, without DCD/DBD 5/0 0/5 a recent history of cardiac arrest, leading to comparable Cause of death Postanoxia 3/5 SAB 4/5 viability, and function after islet isolation [10]. Pro- iCVA 1/5 Trauma capitis 1/5 Euthanasia 1/5 longed cold ischemia time (CIT) has been demonstrated Cardiac arrest 4/5 1/5 to be an independent risk factor for technical failure Duration cardiac arrest 18 min [14–30] 20 min after pancreas transplantation [12–14]. It is hypothe- Age (years) 50 [33.5–54.5] 64 [47–68] sized that these harmful effects are even more pro- Sex (M/F) 4/1 2/3 nounced in DCD pancreases [14,15]. Coupled with cold Weight (kg) 83 [67–95] 82 [57.5–89.5] – – ischemia, during islet isolation from a donor pancreas, Height (cm) 185 [180 187.5] 169 [162.5 176] BMI (kg/m2) 23 [19.5–29] 28 [20.5–30.5] islets are lost because of exposure to multiple physio- Donor amylase (U/l) 46.5[27.3–89] 77 [44.8–128] chemical stress factors [16,17]. One possibility to extend fWIT (min) 26 [24.5–30.5] - the CIT without sacrificing quality is to decrease injury CIT (hours) 13.4 [12.9–14.5] 9.2 [6.5–12.5] during preservation [18]. Hypothermic machine perfu- Pancreas mass (grams) 96 [76–121.5] 103 [81.5–127] sion (HMP) has been proposed as an alternative strat- Donor demographics for islet isolations after HMP group egy to fulfill this role. HMP is shown to decrease (n = 5) and after SCS group (n = 5). Variables are described delayed graft function (DGF) after kidney transplanta- as median and interquartile range. tion and to improve the quality of higher risk livers BMI, body mass index; CIT, cold ischemia time (start of aortic prior to transplantation [19–23]. Recently, it was preservation solution flush until start enzymatic perfusion); reported that adequate preservation of pancreatic tissue DBD, donation after brain death; DCD, donation after circu- could be achieved by oxygenated HMP [24,25], but an latory death; fWIT, functional warm ischemia time (O2 satu- ration <80% or MAP <50 mmHg until cardiac arrest, extensive examination of the effects of oxygenated HMP minutes); HMP, hypothermic machine perfusion; iCVA, in human islet isolation and during the subsequent days ischemic cerebrovascular accident; SAB, subarachnoid bleed- in culture is still lacking. We hypothesized that we can ing; SCS, static cold storage. safely extend CIT of human DCD pancreases by per- forming 6 h of oxygenated HMP. Organ procurement and transport The pancreases were procured by the regional multi- Methods organ recovery teams according to the no-touch tech- nique as described earlier [26]. Initially, all pancreases Donor selection were flushed and stored by SCS in the University of Wis- Ten human donor pancreases procured from multi- consin Cold Storage Solution (UWS; Bridge to Life, Lon- organ donors in the Netherlands were included in this don, UK). The DCD pancreases were transported under study. For this study, a statement of no objection was hypothermic conditions in UWS to the machine perfu- given by the Medical Ethical Committee of the Univer- sion facility at the University Medical Center Groningen sity Medical Center Groningen (METc2012-438). The (UMCG) to prepare for perfusion. Oxygenated HMP was clinical and research activities were in line with the performed during transport to the islet isolation facility principles of the Declaration of Istanbul as outlined in at the Leiden University Medical Center (LUMC). DBD the “Declaration of Istanbul on Organ Trafficking and pancreases were directly transported (SCS) to the islet Transplant Tourism.” To study the effect of oxy- isolation facility at the LUMC. CIT was calculated as time genated HMP on the islets of marginal donor pan- from the start of aortic cold flush in the donor to the ini- creases, five discarded DCD organs were included. tiation of ductal enzymatic perfusion in the pancreas, After 6 h of oxygenated HMP, islets were isolated, and therefore including oxygenated HMP. after 3–4 days of culture, islets were tested for viability and functionality, both in vitro and in vivo. Also, five Oxygenated hypothermic machine perfusion discarded DBD pancreases preserved by static cold storage (SCS) were studied. Table 1 summarizes donor Upon arrival at the UMCG, the pancreases were pre- demographics. pared to be connected to the transportable pressure- 2 Transplant International 2021; ª 2021 The Authors.
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