Normothermic liver machine perfusion as a dynamic platform for assessment and treatment of organs from septic donors

Abstract

Normothermic liver machine perfusion as a dynamic platform for regenerative purposes: What does the future have in store for us?Journal of HepatologyVol. 77Issue 3PreviewLiver transplantation has become an immense success; nevertheless, far more recipients are registered on waiting lists than there are available donor livers for transplantation. High-risk, extended criteria donor livers are increasingly used to reduce the discrepancy between organ demand and supply. Especially for high-risk livers, dynamic preservation using machine perfusion can decrease post-transplantation complications and may increase donor liver utilisation by improving graft quality and enabling viability testing before transplantation. Full-Text PDF Open Access It was with great interest that we read the review published by Lascaris et al.[1]Lascaris B. de Meijer V.E. Porte R.J. Normothermic liver machine perfusion as a dynamic platform for regenerative purposes. What does the future have in store for us?.J Hepatol. May 6 2022; https://doi.org/10.1016/j.jhep.2022.04.033Google Scholar in the Journal of Hepatology, which nicely summarizes the potential for normothermic liver machine perfusion (NLMP) as a dynamic platform for regenerative purposes. The authors rightly stress that NLMP promises to narrow the gap between organ supply and demand. NLMP permits longer preservation times and viability testing and thereby aids in the utilization and selection of liver grafts. This is ultimately expected to increase graft utilization.[2]Watson C.J.E. Kosmoliaptsis V. Pley C. Randle L. Fear C. Crick K. et al.Observations on the ex situ perfusion of livers for transplantation.Am J Transplant. Aug 2018; 18 (American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.): 2005-2020https://doi.org/10.1111/ajt.14687Google Scholar,[3]Mergental H. Laing R.W. Kirkham A.J. Perera M.T.P.R. Boteon Y.L. Attard J. et al.Transplantation of discarded livers following viability testing with normothermic machine perfusion.Nat Commun. Jun 16 2020; 11: 2939https://doi.org/10.1038/s41467-020-16251-3Google Scholar Many of the approaches cited in the article by Lascaris et al., including the possibility to treat donor livers for hepatitis C during NLMP, are still in an experimental phase and have yet to show clinical applicability. While the possibility to apply antiviral treatment to increase organ utilization is mentioned, the option to use antimicrobial therapy during NLMP was not addressed. Treating potentially contaminated organs from septic donors with the goal of preventing donor-derived infections could increase the safety profile of such transplantations and thus the number of potential donor organs available for transplantation.[4]Grossi P.A. Donor-derived infections, lessons learnt from the past, and what is the future going to bring us.Curr Opin Organ Transpl. Aug 2018; 23: 417-422https://doi.org/10.1097/mot.0000000000000551Google Scholar The Zurich group has recently published their experience of using NLMP as a platform for treating the liver ex situ with antimicrobial agents during an extended period of normothermic perfusion. This was done in an organ carrying a tumor of unclear nature retrieved from a donor with sepsis caused by multidrug-resistant micro-organisms.[5]Clavien P.A. Dutkowski P. Mueller M. Eshmuminov D. Bautista Borrego L. Weber A. et al.Transplantation of a human liver following 3 days of ex situ normothermic preservation.Nat Biotechnol. May 31 2022; https://doi.org/10.1038/s41587-022-01354-7Google Scholar In light of this observation, we would like to add our own experience, where we used NLMP as a platform to treat organs originating from septic donors.A liver from a standard criteria donor with pneumonia (positive bronchoalveolar lavage) and sepsis was offered to our center. The donor received antibiotic therapy with piperacillin/tazobactam before and during donor surgery. The liver was put on NLMP (OrganOx® metra®) and targeted antibiotic treatment was applied. Viability assessment and SeptiFast (SF) testing were done prior to the decision to go ahead with liver transplantation (LT). The SF test (Roche Diagnostics, Mannheim, Germany), a commercially available multiplex PCR assay, is designed to detect the DNA of 25 clinically important bacteria and fungi in the blood. SF test results are available within 6 hours.[6]Rath P.M. Saner F. Paul A. Lehmann N. Steinmann E. Buer J. et al.Multiplex PCR for rapid and improved diagnosis of bloodstream infections in liver transplant recipients.J Clin Microbiol. Jun 2012; 50: 2069-2071https://doi.org/10.1128/jcm.00745-12Google Scholar However, in contrast to blood cultures, no anti-microbial susceptibility testing is available. In response to donor blood culture findings the antimicrobial regimen was extended with ceftazidime/avibactam as well as fluconazole. Viability assessment performed during NLMP exhibited good graft performance (bile pH >7.4, bile glucose 2 mg/dl, perfusate pH ≥7.2 without the need for excessive HCO3− substitution, falling glucose levels beyond 2 hours, peak lactate fall >40 mg/dl, alanine aminotransferase <6,000 U/L at 2 hours).[2]Watson C.J.E. Kosmoliaptsis V. Pley C. Randle L. Fear C. Crick K. et al.Observations on the ex situ perfusion of livers for transplantation.Am J Transplant. Aug 2018; 18 (American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.): 2005-2020https://doi.org/10.1111/ajt.14687Google Scholar,[7]Weissenbacher A. Vrakas G. Nasralla D. Ceresa C.D.L. The future of organ perfusion and re-conditioning.Transpl Int. Jun 2019; 32: 586-597https://doi.org/10.1111/tri.13441Google Scholar After 12 hours of NMLP, perfusate samples were taken for SF testing. Following negative SF test results, we went ahead with LT. The patient did not experience reperfusion syndrome and no donor-derived infection was observed. Blood cultures from the perfusate during NLMP remained negative.We compared the clinical course with that of two other cases, in which the perfusate cultures taken at the end of NMLP were positive for Klebsiella pneumoniae and Staphylococcus aureus. Since no clinical information suggestive of bacteremia in the donors was available and perfusate analyses were completed only days after the LT, a standard antimicrobial regimen (cefuroxime) was administered during NLMP. After transplantation, both recipients experienced severe reperfusion syndrome, displayed exceptionally high peak IL-6 values and developed severe sepsis (Table 1). The possibility to apply antimicrobial therapy during NLMP and to monitor the treatment response via SF testing deserves recognition. Applying this concept in a liver from a septic donor resulted in successful transplantation of an organ, which otherwise would most likely have been discarded. Of note, both kidneys were retrieved but ultimately discarded in light of concerns about a donor-derived infection and the lack of a normothermic kidney machine perfusion platform.Table 1Antimicrobial and reperfusion characteristics.Case#1#2#3Perfusate culturesPositivePositiveNegativeRecipient blood cultures/IV catheter culturesPositivePositiveNegativeMicroorganisms culturedKlebsiella pneumoniaStaphylococcus aureusNoneReperfusion syndromeYesYesNoIL-6 peak in recipient330,717 ng/L169,433 ng/L651 ng/LCRP in recipient27 mg/dl12 mg/dl15 mg/dlPCT in recipient53 μg/L68 μg/L140 μg/LCRP, c-reactive protein; IL-6, interleukin-6; IV, intravenous; PCT, procalcitonin. Open table in a new tab In contrast to cold storage, normothermic machine perfusion creates an environment for microorganisms to grow. While this poses both a threat and an opportunity, the combination of SF testing and antimicrobial treatment during normothermic machine perfusion means that transplantation can be considered with organs that would otherwise be declined. This exemplifies the possibilities arising from the clinical introduction of NLMP as a platform for organ assessment, reconditioning and ultimately repair.Financial supportThe authors received no financial support to produce this manuscript.Conflict of interestThe authors declare no conflicts of interest that pertain to this work.Please refer to the accompanying ICMJE disclosure forms for further details.Authors’ contributionsThe authors declare that they have participated in the preparation of the manuscript and have seen and approved the final version. FJK was involved in acquisition of data, analysis and interpretation of data and drafting of the manuscript. RO was involved in study design, analysis and interpretation of data and drafting of the manuscript. RB was involved in study design and critical revision of the manuscript. GW was involved in interpretation of data and critical revision of the manuscript. SS was involved in study concept and design, analysis and interpretation of data, critical revision of manuscript and overall study supervision. It was with great interest that we read the review published by Lascaris et al.[1]Lascaris B. de Meijer V.E. Porte R.J. Normothermic liver machine perfusion as a dynamic platform for regenerative purposes. What does the future have in store for us?.J Hepatol. May 6 2022; https://doi.org/10.1016/j.jhep.2022.04.033Google Scholar in the Journal of Hepatology, which nicely summarizes the potential for normothermic liver machine perfusion (NLMP) as a dynamic platform for regenerative purposes. The authors rightly stress that NLMP promises to narrow the gap between organ supply and demand. NLMP permits longer preservation times and viability testing and thereby aids in the utilization and selection of liver grafts. This is ultimately expected to increase graft utilization.[2]Watson C.J.E. Kosmoliaptsis V. Pley C. Randle L. Fear C. Crick K. et al.Observations on the ex situ perfusion of livers for transplantation.Am J Transplant. Aug 2018; 18 (American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.): 2005-2020https://doi.org/10.1111/ajt.14687Google Scholar,[3]Mergental H. Laing R.W. Kirkham A.J. Perera M.T.P.R. Boteon Y.L. Attard J. et al.Transplantation of discarded livers following viability testing with normothermic machine perfusion.Nat Commun. Jun 16 2020; 11: 2939https://doi.org/10.1038/s41467-020-16251-3Google Scholar Many of the approaches cited in the article by Lascaris et al., including the possibility to treat donor livers for hepatitis C during NLMP, are still in an experimental phase and have yet to show clinical applicability. While the possibility to apply antiviral treatment to increase organ utilization is mentioned, the option to use antimicrobial therapy during NLMP was not addressed. Treating potentially contaminated organs from septic donors with the goal of preventing donor-derived infections could increase the safety profile of such transplantations and thus the number of potential donor organs available for transplantation.[4]Grossi P.A. Donor-derived infections, lessons learnt from the past, and what is the future going to bring us.Curr Opin Organ Transpl. Aug 2018; 23: 417-422https://doi.org/10.1097/mot.0000000000000551Google Scholar The Zurich group has recently published their experience of using NLMP as a platform for treating the liver ex situ with antimicrobial agents during an extended period of normothermic perfusion. This was done in an organ carrying a tumor of unclear nature retrieved from a donor with sepsis caused by multidrug-resistant micro-organisms.[5]Clavien P.A. Dutkowski P. Mueller M. Eshmuminov D. Bautista Borrego L. Weber A. et al.Transplantation of a human liver following 3 days of ex situ normothermic preservation.Nat Biotechnol. May 31 2022; https://doi.org/10.1038/s41587-022-01354-7Google Scholar In light of this observation, we would like to add our own experience, where we used NLMP as a platform to treat organs originating from septic donors. A liver from a standard criteria donor with pneumonia (positive bronchoalveolar lavage) and sepsis was offered to our center. The donor received antibiotic therapy with piperacillin/tazobactam before and during donor surgery. The liver was put on NLMP (OrganOx® metra®) and targeted antibiotic treatment was applied. Viability assessment and SeptiFast (SF) testing were done prior to the decision to go ahead with liver transplantation (LT). The SF test (Roche Diagnostics, Mannheim, Germany), a commercially available multiplex PCR assay, is designed to detect the DNA of 25 clinically important bacteria and fungi in the blood. SF test results are available within 6 hours.[6]Rath P.M. Saner F. Paul A. Lehmann N. Steinmann E. Buer J. et al.Multiplex PCR for rapid and improved diagnosis of bloodstream infections in liver transplant recipients.J Clin Microbiol. Jun 2012; 50: 2069-2071https://doi.org/10.1128/jcm.00745-12Google Scholar However, in contrast to blood cultures, no anti-microbial susceptibility testing is available. In response to donor blood culture findings the antimicrobial regimen was extended with ceftazidime/avibactam as well as fluconazole. Viability assessment performed during NLMP exhibited good graft performance (bile pH >7.4, bile glucose 2 mg/dl, perfusate pH ≥7.2 without the need for excessive HCO3− substitution, falling glucose levels beyond 2 hours, peak lactate fall >40 mg/dl, alanine aminotransferase <6,000 U/L at 2 hours).[2]Watson C.J.E. Kosmoliaptsis V. Pley C. Randle L. Fear C. Crick K. et al.Observations on the ex situ perfusion of livers for transplantation.Am J Transplant. Aug 2018; 18 (American journal of transplantation: official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.): 2005-2020https://doi.org/10.1111/ajt.14687Google Scholar,[7]Weissenbacher A. Vrakas G. Nasralla D. Ceresa C.D.L. The future of organ perfusion and re-conditioning.Transpl Int. Jun 2019; 32: 586-597https://doi.org/10.1111/tri.13441Google Scholar After 12 hours of NMLP, perfusate samples were taken for SF testing. Following negative SF test results, we went ahead with LT. The patient did not experience reperfusion syndrome and no donor-derived infection was observed. Blood cultures from the perfusate during NLMP remained negative. We compared the clinical course with that of two other cases, in which the perfusate cultures taken at the end of NMLP were positive for Klebsiella pneumoniae and Staphylococcus aureus. Since no clinical information suggestive of bacteremia in the donors was available and perfusate analyses were completed only days after the LT, a standard antimicrobial regimen (cefuroxime) was administered during NLMP. After transplantation, both recipients experienced severe reperfusion syndrome, displayed exceptionally high peak IL-6 values and developed severe sepsis (Table 1). The possibility to apply antimicrobial therapy during NLMP and to monitor the treatment response via SF testing deserves recognition. Applying this concept in a liver from a septic donor resulted in successful transplantation of an organ, which otherwise would most likely have been discarded. Of note, both kidneys were retrieved but ultimately discarded in light of concerns about a donor-derived infection and the lack of a normothermic kidney machine perfusion platform. CRP, c-reactive protein; IL-6, interleukin-6; IV, intravenous; PCT, procalcitonin. In contrast to cold storage, normothermic machine perfusion creates an environment for microorganisms to grow. While this poses both a threat and an opportunity, the combination of SF testing and antimicrobial treatment during normothermic machine perfusion means that transplantation can be considered with organs that would otherwise be declined. This exemplifies the possibilities arising from the clinical introduction of NLMP as a platform for organ assessment, reconditioning and ultimately repair. Financial supportThe authors received no financial support to produce this manuscript. The authors received no financial support to produce this manuscript. Conflict of interestThe authors declare no conflicts of interest that pertain to this work.Please refer to the accompanying ICMJE disclosure forms for further details. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Authors’ contributionsThe authors declare that they have participated in the preparation of the manuscript and have seen and approved the final version. FJK was involved in acquisition of data, analysis and interpretation of data and drafting of the manuscript. RO was involved in study design, analysis and interpretation of data and drafting of the manuscript. RB was involved in study design and critical revision of the manuscript. GW was involved in interpretation of data and critical revision of the manuscript. SS was involved in study concept and design, analysis and interpretation of data, critical revision of manuscript and overall study supervision. The authors declare that they have participated in the preparation of the manuscript and have seen and approved the final version. FJK was involved in acquisition of data, analysis and interpretation of data and drafting of the manuscript. RO was involved in study design, analysis and interpretation of data and drafting of the manuscript. RB was involved in study design and critical revision of the manuscript. GW was involved in interpretation of data and critical revision of the manuscript. SS was involved in study concept and design, analysis and interpretation of data, critical revision of manuscript and overall study supervision. 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