Arlabán Carpintero, Maite

Ballesteros Sanz, María Ángeles

Barreda, Paloma

Miñambres García, Eduardo

Rodrigo Calabia, Emilio

Ruiz San Millán, Juan Carlos

Suberviola, Borja

Valero, Rosalia

Transplantation Proceedings

English

UCrea

Accepted ManuscriptStatic cold storage vs. ex vivo machine perfusion: results from a comparative study onrenal transplant outcome in a controlled donation after circulatory death programMaite Arlaban Carpintero, Paloma Barreda, Maria Angeles Ballesteros, EmilioRodrigo, Borja Suberviola, Rosalia Valero, Eduardo Miñambres, Juan Carlos Ruiz-San MillánPII: S0041-1345(18)31211-9DOI: https://doi.org/10.1016/j.transproceed.2018.12.010Reference: TPS 28835To appear in: Transplantation ProceedingsReceived Date: 7 September 2018Revised Date: 29 November 2018Accepted Date: 9 December 2018Please cite this article as: Carpintero MA, Barreda P, Ballesteros MA, Rodrigo E, Suberviola B, ValeroR, Miñambres E, Ruiz-San Millán JC, Static cold storage vs. ex vivo machine perfusion: results from acomparative study on renal transplant outcome in a controlled donation after circulatory death program,Transplantation Proceedings (2019), doi: https://doi.org/10.1016/j.transproceed.2018.12.010.This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain. © 2019. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/by-nc-nd/4.0/MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPTStatic cold storage vs. ex vivo machine perfusion: results from a comparative stud y on renal transplant outcome in a controlled donation a fter circulatory death program.   The 5th Congress of the Spanish Transplantation Society (SET ) (oral presentation)    Authors:    Maite Arlaban Carpintero 1, Paloma Barreda 2, Maria Angeles Ballesteros 1,3, Emilio Rodrigo 2, Borja Suberviola 1,3, Rosalia Valero 2, Eduardo Miñambres 3,4, Juan Carlos Ruiz-San Millán 2.  1. Service of Intensive Care. University Hospital Marqués de Valdecilla-IDIVAL. Santander. SPAIN. 2. Service of Nephrology. University Hospital Marqués de Valdecilla-IDIVAL. Santander. SPAIN. 3. Transplant Coordination Unit. University Hospital Marqués de Valdecilla-IDIVAL. Santander. SPAIN. 4. School of Medicine, University of Cantabria, Santander. SPAIN   Email addresses of authors:   Arlabán Carpintero: maitearlaban@gmail.com, Barreda:  paloma.barreda@gmail.com, Ballesteros:  gelesballesteros@yahoo.com, Rodrigo:  emilio.rodrigo@scsalud.es, Borja Suberviola: borja.suberviola@scsalud.es, Valero : rosalia.valero@scsalud.es, Miñambres:  eminambres@yahoo.es, Ruiz-San Millán:  juancarlos.ruiz@scsalud.es  Corresponding author: Paloma Barreda.  Service of Nephrology. University Hospital Marqués de Valdecilla-IDIVAL, REDINREN (RD/0009/0027). Avda.  Marqués de Valdecilla s/n, E-39008 Santander, Spain. E-mail: paloma.barreda@gmail.com  Grant information: None Key words:  ex vivo machine perfusion, static cold storage, renal transplant, controlled donation after circulatory death  Abbreviations:   (in alphabetical order) brain death donors (DBD) donation after circulatory death (cDCD). delayed graft function (DGF) primary non-function (PNF) withdrawal of life sustaining therapy (WLST)  Tables:   2 Figures:0  (color – NO)  MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPTStatic cold storage vs. ex vivo machine perfusion: results from a comparative study on renal transplant outcome in a controlled donation after circulatory death program.   Abstract Introduction: We aimed to evaluate if ex vivo machine perfusion could minimize the negative impact of cold ischemia on those renal grafts obtained from controlled donation after circulatory death (cDCD). Material and methods: Prospective observational paired study of kidney transplants from cDCD performed in our center. The kidney from each pair which preserved on ice was transplanted first within the next few hours following procurement while the contralateral kidney being machine perfused (LifePort®; Organ Recovery System, Brussels, Belgium) got transplanted during the next day. Results: A total of 12 cDCD’s were included. No differences were observed in delayed graft dysfunction or graft survival between both groups. Conclusion: The use of these ex vivo perfusion devices is simple and do not require any large infrastructural or high economic investments, considering the facts that it allows a better selection of recipients and no longer discard viable organs for prolonged warm ischemia times. Key words: ex vivo machine perfusion, static cold storage, renal transplant, controlled donation after circulatory death  MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  1 Static cold storage vs. ex vivo machine perfusion: results from a comparative study on renal transplant outcome in a controlled donation after circulatory death program.   Introduction:  Further widespread expansion of all type of organ transplants has been limited by the persistent mismatch between supply and demand of organs for transplantation. In an attempt to expand the donor pool and to make more grafts eligible for transplantation; several strategies have been proposed like further improving donor management of brain death donors (1) as well as the introduction of a donation after circulatory death program (2;3). However, the unpredictable consequences of warm ischemia which characterizes controlled donation after circulatory death (cDCD); together with impaired organ perfusion during the agonal phase, result in reluctance for accepting grafts from these donors, leading to fewer eligible donors being converted to actual donors as seen in brain death donors (DBD) (4,5). In cDCD, the effects of warm ischemia, resulting from the hypotensive phase after withdrawal of life sustaining therapy (WLST) as well as following circulatory arrest are further exacerbated during the later period of cold ischemia. In kidney transplantation these phenomena have been identified as major risk factors for a higher incidence of primary non-function (PNF) and delayed graft function (DGF) (6).  Despite these problems, several studies in kidney transplantation have shown that the long-term results in terms of survival and functionality are comparable to those seen in kidneys from brain death donors (7,8). Despite these higher risks at short-term, nowadays it seems evident that the survival benefit from receiving a DCD renal graft outweighs the risks from remaining on dialysis while waiting for a DBD graft (9). Several groups have studied the impact of ex vivo renal perfusion devices as an alternative method for the preservation of kidneys compared to the traditional method of static conservation MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  2 on ice with encouraging results in favor of perfusion for reducing rates of delayed graft dysfunction in children and cDCD’s. (10,11). Since the results were not yet fully conclusive; we designed a paired study for kidneys obtained from cDCD’s in order to evaluate whether or not ex vivo machine perfusion could minimize the negative impact of cold ischemia on those renal grafts.  Material and methods:  Prospective observational paired study of kidney transplants from donors after controlled cardiac arrest performed at the University Hospital “Marqués de Valdecilla” in the period from September 2014 to December 2017. One kidney from each pair was preserved on ice and transplanted first within the next few hours following procurement (Group A) while the contralateral kidney of the same pair was machine perfused (LifePort®; Organ Recovery System, Brussels, Belgium) and transplanted in the next day after retrieval (Group B). All kidneys were removed from cDCD donors after a period of regional normothermic abdominal perfusion and after controlled cardiac arrest occurred. Recipient characteristic such as mean age, gender distribution, number of retransplants and number of HLA incompatibilities were compared between groups. The primary endpoints for the analysis of our study were incidence of delayed graft function (defined as the need for dialysis during the first week after transplantation) and overall graft survival. The secondary endpoints were renal function (creatinine at 1, 3, 6 and 12 months) and in case DGF occurred, the number of dialysis sessions required. Data were analyzed using the T-student test for quantitative variables and the Mc Nemar test for categorical variables. Kidneys from donors with prolonged functional warm ischemia time (greater than 1 hour) were excluded from the study.  MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  3  Results: During the study period, a total of 12 cDCD’s were identified and resulted in 24 renal grafts procured from those donors and transplanted at our center. Cold ischemia time was 6h on average in Group A and 19,9h on average in Group B. Main characteristics of donors are detailed in Table 1. Twenty five percent of donors fulfilled the criteria for expanded criteria donors.  Both groups were comparable with respect to recipients’ characteristics. Cold ischemia time was significantly longer in Group B. No significant differences were observed between groups with respect to incidence of DGF, number of dialysis sessions and renal function during the first postransplant year. Table 2. In terms of graft survival, one kidney in the machine group presented an early vascular thrombosis at 72 hours.   Discussion: Every year the proportion of cDCD’s gains more weight, which contributes to increasing the number of organs eligible for transplantation. Several series have shown that the main disadvantage for using renal graft from such cDCD donors as compared to DBD donors is the higher rate of delayed graft function, with advanced donor age and prolonged cold ischemia time being identified as extra major risk factors (12). Ex vivo perfusion machine might offer a solution to this problem since it might allow safe prolongation of the time window between procurement and transplantation. Although our series of cases is small, the fact that we have used a pair design for our study implies that both kidneys received identical pre-extraction care; in combination with the observation that recipients in both arms had similar characteristics in terms of age and comorbidities, allowed us to demonstrate that by using these perfusion devices we could safely increase cold ischemia MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  4 time without jeopardizing renal outcome in terms of survival and functionality. Other studies carried out in the United Kingdom in recent years (13, 14) have demonstrated similar results in terms of safe mild prolongation of cold ischemic time. In contrast to the UK studies in which most of the kidneys were first cold stored prior to being machine perfused upon arrival at the transplant hospital, the kidneys in our study were machine perfused as from procurement until transplant. Palayo et al have shown that in DCD kidneys, prolonged use of cold storage preceding machine perfusion was associated with worse results (15). In clinical practice, the use of ex vivo perfusion devices might enable longer transportation time between centers which could facilitate organ exchange between centers located remotely from each other. This somewhat wider time window could allow more optimal selection of recipients; hereby increasing the possibility for getting a transplant for hyperimmunized patients.  Using these perfusion devices for donors with prolonged warm ischemia times also generates additional viability assessment information: Poor machine perfusion parameters like renal resistance and flow have been associated with higher incidence of DGF and graft loss. This additional viability information might prevent us from discarding perfectly viable organs on the one hand while on the other hand, it might avoid transplanting kidneys with poor function post-operatively.  So, in conclusion, the use of ex vivo perfusion devices might allow to significantly prolong the cold ischemia time compared to cold storage maintaining similar results with respect to DGF and mid-term graft function. This longer period might allow a more accurate selection of recipients.  BIBLIOGRAPHY 1) Miñambres E, Pérez-Villares JM, Chico M,et al. Lung donor treatment protocol in brain dead-donors: a multicenter study J Heart Lung Transplant  2015;34:773-80 MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  5 2) Organ procurement and Transpantation Network. Available at: https://optn.transplant.hrsa.gov/data/view-data-reports. Accessed July 19, 2016. 3) Miñambres E, Rubio JJ, Coll E, Domínguez-Gil B. Donation after circulatory death and its expansion in Spain. Curr Opin Organ Transplant 2018;23:120-129 4) 3NHS Blood and Transplant. Organ donation and transplantation activity report 2015/16.  Available at: http://www.odt.nhs.uk/pdf/activity-report/activity_report_2015_16.pdf. Accessed August 10, 2016. 5) Goldberg DS, Abt PL. Improving outcomes in DCDD liver transplantation: there can only be strength in numbers. Am J Transplant 2014;14:1016-20 6) Wadei HM, Heckman MG, Rawal B, et al. Comparison of kidney function between donation after cardiac death and donation after brain death kidney transplantation. Transplantation 2013; 96:274-281. 7) Summers DM, Watson CJ, Pettigrew GJ, et al. Kidney donation after circulatory death (DCD): state of the art. Kidney Int 2015;88:241-9. 8) Miñambres E, Suberviola B, Dominguez-Gil B, et al. Improving the Outcomes of Organs Obtained  From Controlled Donation After Circulatory Death Donors Using Abdominal Normothermic Regional Perfusion. Am J Transplant. 2017 Aug;17(8):2165-2172 9) Snoeijs MG, Schaubel DE, Hené R, et al.  Kidneys from donors after cardiac death provide survival benefit. J Am Soc Nephrol. 2010 Jun;21(6):1015-21 10) Gill J, Dong J, Eng M, Landsberg D, et al. Pulsatile perfusion reduces the risk of delayed graft function in deceased donor kidney transplants, irrespective of donor type and cold ischemic time. Transplantation. 2014 Mar 27;97(6):668-74. 11) Guy A, McGrogan D, Inston N, et a.  Hypothermic machine perfusion permits extended cold ischemia times with improved early graft function. Exp Clin Transplant. 2015;13:130-137. MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  6 12) Lim WH, McDonald SP, Russ GR, et al. Association Between Delayed Graft Function and Graft Loss in Donation After Cardiac Death Kidney Transplants-A Paired Kidney Registry Analysis. Transplantation. 2017 Jun;101(6):1139-1143. 13) Patel K, Nath J, Hodson J, et al.  Outcomes of donation after circulatory death  Kidneys undergoing hypothermic machine perfusion following static cold storage: A UK population-based cohort study. Am J Transplant. 2017, 1-7. 14) Jochmans I, Moers C, Smits JM, et al.Machine perfusion versus cold storage for the preservation of kidneys donated after cardiac death: a multicenter, randomized, controlled trial. Ann Surg. 2010 Nov;252(5):756-64. 15) Paloyo S, Sageshima J, Gaynor JJ, et al. Negative impact of prolonged cold storage time before machine perfusion preservation in donation after circulatory death kidney transplantation. Transpl Int. 2016 Oct;29(10):1117-25.   TABLES. Table 1. Donor characteristics Donor Characteristics  N: 12 Age (years) 51.4 (SD 11.9) Sex (male) 10 (83.3%) Cause of death:  CVA 1 (8.3%) Anoxia 6 (50%) TBI    1 (8.3%) Other 4 (33.3%) Diabetes mellitus 2 (16.7%) Hypertension 2 (16.7%) MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  7 Expanded-criteria donor. 3 (25%) TBI: traumatic brain injury. CVA: cerebrovascular accident;  Table 2. Kidney transplants and recipients’ characteristics Recipients Cold stored kidney   (n: 12) Machine perfused kidney (n: 12) p Gender (male) 10 (83.3%) 7 (58.3%) 0.375 Age (years) 52.6 (SD 14.8) 51 (SD 10,1) 0.983 Retranplanted 0 3 (25%) --- HLA Incompatibility > 3 9 (75%) 9 (75%) 1.000 HLA A Incompatibility 0 1 2  1 (8.3%) 6 (50%) 5 (41.7%)  2 (16.7%) 7 (58.3%) 3 (25%)  0.549 HLA B Incompatibility 1 2  6 (50%) 6 (50%)  5 (41.7%) 7 (58.3%)  1,000 HLA DR Incompatibility 0 1 2  1 (8.3%) 4 (33.3%) 7 (58.3%)  1 (8,3%) 7 (58.3%) 4 (33.3%)  0.392 Cold Ischemia (min) 365.3 (SD 81.3) 1203.7 (SD 371) 0.0001 Creat 10 days (mg/dl) 3.2 (SD 2) 2.9 (SD 2.2) 0.367 Creat 1 month (mg/dl) 1.3 (SD 0.5) 1.5 (SD 0,7) 0.190 Creat 90 days (mg/dl) 1.3  (SD 0.4) 1.4 (SD 0.6) 0.09 MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT  8 Creat 180 days (mg/dl) 1.3 (SD 0.4) 1.5 (SD 0.7) 0.121 Creat 1 year (mg/dl) 1.3 (SD 0.4) 1.5 (SD 0.7) 0.521 DGF 3 (25%) 4 (33.3%) 1.000 Dialysis sessions 1 or 2 2 (16.7%) 2 (16.7%) 1.000 Dialysis sessions > 3 1 (8.3%) 2 (16.7%) 1.000 Creat.,serum creatinine. DGF, delayed graft function.  MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPTStatic cold storage vs. ex vivo machine perfusion: results from a comparative study on renal transplant outcome in a controlled donation after circulatory death program.    Highlights  • ex vivo machine perfusion could attenuate the negative impact of cold ischemia. • mimimizing the efect of cold ischemia.  • outcomes of kidney obtained from controlled donation after circulatory death donors. MANUSCRIPT ACCEPTEDACCEPTED MANUSCRIPT TRANSPLANTATION   PROCEEDINGS BARRY D. KAHAN, PhD, MD, Editor-in-Chief   Editorial Office: 11707 Trudeau Drive Houston, TX   77065 Email:  bkahan@transplantation-proceedings.org  MANUSCRIPT RECEIPT  -  FINANCIAL AGREEMENT   Title Page With ALL Author Email Addresses: yes Submitted Text Pages: 7 Submitted Tables:   2       Abstract Included yes Submitted Figures 1 Total Pages Submitted (excluding Title Page and Abstract): 5    Manuscript Title:   Static cold storage vs. ex vivo machine perfusion: results from a comparative study on renal transplant outcome in a controlled donation after circulatory death program.  By submission of this manuscript to Transplantation Proceedings, I acknowledge I have read the Guidelines to Authors of Manuscripts Submitted in Conjunction with Meetings and agree with the contents, and that I have attached a completed and signed Conflict of Interest form on behalf of each author listed on this manuscript.  I also acknowledge that if accepted, I am responsible for all manuscript page charges, which will be billed to me by Elsevier, the publisher of Transplantation Proceedings, at the rate of US$99.95 per submitted manuscript page, understanding that each Table and Figure will count as one manuscript page each along with the text.  I understand that page charges are based on the typed, submitted page, not on the printed page, and no complimentary pages are automatically provided by Transplantation Proceedings. Authors will be contacted by the Editorial Office with a tracking number and will be informed of the final number of pages for which they are responsible.  Further, I understand that use of color reproduction of graphics will result in an additional charge.  The Abstract and Title page are complimentary by Transplantation Proceedings.  Additionally, I agree that this manuscript has not been submitted or published in any other journal, including Transplantation Proceedings, and no parts of the manuscript are duplicated.  I understand that if the manuscript is accepted for publication, copyright of the manuscript is transferred to Elsevier.           Paloma BARREDA      Eduardo MIÑAMBRES  _____________________________            _________________________________ Corresponding Author                                         Person to be invoiced  

Static Cold Storage vs Ex Vivo Machine Perfusion: Results From a Comparative Study on Renal Transplant Outcome in a Controlled Donation After Circulatory Death Program

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Static Cold Storage vs Ex Vivo Machine Perfusion: Results From a Comparative Study on Renal Transplant Outcome in a Controlled Donation After Circulatory Death Program

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