Clinical Trial of New Hypothermic Oxygenated Perfusion System Versus Static Cold Storage

Liver Diseases Clinical Trial

Official title:

Expanded Criteria Donors in Liver and Kidney Transplantation: Protocol of a Randomised Single Center Clinical Trial of Hypothermic Oxygenated Perfusion Versus Static Cold Storage

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03837197
• Other study ID #: RF-2016-02364732
• Status: Recruiting
• Phase: N/A
• Start date: December 21, 2018
• Est. completion date: December 2021

Study information

• Verified date: September 2019
• Source: University of Bologna
• Contact: Matteo Ravaioli, PhD
• Phone: 0512144810
• Email: mrava1[@]hotmail.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

With the present study the investigators will evaluate the benefit of end-ischemic HOPE on ECD grafts (livers and kidneys) as compared to SCS. Organs will be perfused through a recently developed machine perfusion (MP) device, from the beginning of back-table procedures till implantation, without increasing CIT. The aim of the study will be demonstrating the ability of HOPE to improve graft function and post-operative outcomes of ECD kidney and liver recipients.

Description:

Extended criteria donors (ECD) are widely utilized due to organ shortage, but this may increase the risk of graft dysfunction and of poorer outcomes.

Hypothermic oxygenated perfusion (HOPE) is a recent organ preservation strategy for marginal kidney and liver grafts, which allows to redirect anaerobic metabolism to aerobic metabolism under hypothermic conditions and to protect grafts from oxidative species-related damage; these mechanisms may potentially improve graft function and survival.

Methods This is an open-label, randomized multicenter clinical trial with the aim of comparing HOPE vs. static cold storage (SCS) in ECD kidney and liver transplantation.

In the study protocol - approved by ethics committee - 220 patients (110 liver recipients and 110 kidney recipients) will be enrolled. Livers and kidneys assigned to HOPE will be perfused by machine perfusion with cold Belzer solution (4°-10°C) and with continuous oxygenation (partial pressure of oxygen = 500-600 mmHg). In the control group, livers and kidneys undergoing SCS will be steeped in Celsior or University of Wisconsin Belzer solutions and stored in ice. Using the same perfusion machine for both liver and kidney grafts, organs will be perfused from the start of the back-table procedure until implantation, without increasing cold ischemia time (CIT). For each group the investigators will evaluate clinical outcomes, graft function tests and histologic findings, as well as perfusate and the number of allocated organs.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: December 2021
• Est. primary completion date: December 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 100 Years

Eligibility

Inclusion Criteria:

• For kidneys: donor age = 60 years or 50-59 years with two or more of the sequent risk factors: death due to cerebrovascular accident, history of hypertension, donor serum creatinine > 1.5 mg/dL, cold ischemia time (CIT) > 20 h;

• For livers: donors with hemodynamic deterioration, donor age > 65 years, donor body mass index > 30 kg/m2, serum bilirubin > 3 mg/dl, AST or ALT above three times the upper reference threshold, sodium > 165 mmol/l, intensive care unit (ICU) stay > 7 days, steatosis > 40%, CIT > 12 h.

Exclusion Criteria:

• Donor age =18 years;

• Donors after circulatory death (DCD) will be excluded, because Italian law requires 20 minutes of "no touch period" before death declaration, causing prolonged warm ischemia and subsequent mandatory perfusion of the organ.

• Split-liver recipients, liver transplantation (LT) for acute liver failure, pre-emptive renal transplant, dual kidney transplantation, and patients with intra-operative surgical complications before the organ implantation.

Related Conditions & MeSH terms

• Kidney Diseases
• Liver Diseases

Intervention

Device:
• Kidney-Hypothermic oxygenated
Kidney perfusion will be performed through the renal artery at 25-30 mmHg pressure. Flow, pressure and temperature will be monitored and registered on a Universal Serial Bus (USB) memory system during organ perfusion. Gas analysis of the effluent perfusate will be accomplished at the start of perfusion (T0) then every 30 minutes. Two perfusate samples will be collected at the beginning and at the end of perfusion to rule out bacterial or fungal contamination. HOPE will start by flushing the organ at low flow values (20 ml/min) with new oxygenated perfusion fluid during back-table preparation. Organ will be treated with continuous HOPE until transplant. Organ perfusion will be continuously monitored. Minimal perfusion time will be 2 hours for kidneys.
• Liver-Hypothermic oxygenated
Liver perfusion will be performed through the portal vein at a 5 mmHg pressure. Flow, pressure and temperature will be monitored and registered on a Universal Serial Bus (USB) memory system during organ perfusion. Gas analysis of the effluent perfusate will be accomplished at the start of perfusion (T0) then every 30 minutes. Two perfusate samples will be collected at the beginning and at the end of perfusion to rule out bacterial or fungal contamination. HOPE will start by flushing the organ at low flow values (30 ml/min) with new oxygenated perfusion fluid during back-table preparation. Organ will be treated with continuous HOPE until transplant. Organ perfusion will be continuously monitored. Minimal perfusion time will be 1 hour for livers.

Locations

Country	Name	City	State
Italy	Azienda Ospedaliera di Bologna - Policlinico S. Orsola Malpighi	Bologna

Sponsors (1)

Lead Sponsor	Collaborator
University of Bologna

Country where clinical trial is conducted

Italy, 

References & Publications (17)

Agopian VG, Harlander-Locke MP, Markovic D, Dumronggittigule W, Xia V, Kaldas FM, Zarrinpar A, Yersiz H, Farmer DG, Hiatt JR, Busuttil RW. Evaluation of Early Allograft Function Using the Liver Graft Assessment Following Transplantation Risk Score Model. JAMA Surg. 2018 May 1;153(5):436-444. doi: 10.1001/jamasurg.2017.5040. Erratum in: JAMA Surg. 2018 May 1;153(5):498. — View Citation

Attia M, Silva MA, Mirza DF. The marginal liver donor--an update. Transpl Int. 2008 Aug;21(8):713-24. doi: 10.1111/j.1432-2277.2008.00696.x. Epub 2008 May 19. Review. — View Citation

Belzer FO, Southard JH. Principles of solid-organ preservation by cold storage. Transplantation. 1988 Apr;45(4):673-6. Review. — View Citation

Dutkowski P, Polak WG, Muiesan P, Schlegel A, Verhoeven CJ, Scalera I, DeOliveira ML, Kron P, Clavien PA. First Comparison of Hypothermic Oxygenated PErfusion Versus Static Cold Storage of Human Donation After Cardiac Death Liver Transplants: An International-matched Case Analysis. Ann Surg. 2015 Nov;262(5):764-70; discussion 770-1. doi: 10.1097/SLA.0000000000001473. — View Citation

Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA, Greenstein SM, Merion RM. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant. 2006 Apr;6(4):783-90. Erratum in: Am J Transplant. 2018 Dec;18(12):3085. — View Citation

Humar A, Ramcharan T, Kandaswamy R, Gillingham K, Payne WD, Matas AJ. Risk factors for slow graft function after kidney transplants: a multivariate analysis. Clin Transplant. 2002 Dec;16(6):425-9. — View Citation

Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009 Nov;9 Suppl 3:S1-155. doi: 10.1111/j.1600-6143.2009.02834.x. — View Citation

Kron P, Schlegel A, de Rougemont O, Oberkofler CE, Clavien PA, Dutkowski P. Short, Cool, and Well Oxygenated - HOPE for Kidney Transplantation in a Rodent Model. Ann Surg. 2016 Nov;264(5):815-822. — View Citation

Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, Shaked A, Christie JD. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010 Aug;16(8):943-9. doi: 10.1002/lt.22091. — View Citation

Port FK, Bragg-Gresham JL, Metzger RA, Dykstra DM, Gillespie BW, Young EW, Delmonico FL, Wynn JJ, Merion RM, Wolfe RA, Held PJ. Donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors. Transplantation. 2002 Nov 15;74(9):1281-6. — View Citation

Ravaioli M, Baldassare M, Vasuri F, Pasquinelli G, Laggetta M, Valente S, De Pace V, Neri F, Siniscalchi A, Zanfi C, Bertuzzo VR, Caraceni P, Trerè D, Longobardi P, Pinna AD. Strategies to Restore Adenosine Triphosphate (ATP) Level After More than 20 Hours of Cold Ischemia Time in Human Marginal Kidney Grafts. Ann Transplant. 2018 Jan 12;23:34-44. — View Citation

Ravaioli M, De Pace V, Comai G, Busutti M, Del Gaudio M, Amaduzzi A, Cucchetti A, Siniscalchi A, La Manna G, D'Errico AAD, Pinna AD. Successful Dual Kidney Transplantation After Hypothermic Oxygenated Perfusion of Discarded Human Kidneys. Am J Case Rep. 2017 Sep 20;18:1009-1013. — View Citation

Ravaioli M, De Pace V, Comai G, Capelli I, Baraldi O, D'Errico A, Bertuzzo VR, Del Gaudio M, Zanfi C, D'Arcangelo GL, Cuna V, Siniscalchi A, Sangiorgi G, La Manna G. Preliminary experience of sequential use of normothermic and hypothermic oxygenated perfusion for donation after circulatory death kidney with warm ischemia time over the conventional criteria - a retrospective and observational study. Transpl Int. 2018 Nov;31(11):1233-1244. doi: 10.1111/tri.13311. Epub 2018 Jul 20. — View Citation

Schlegel A, de Rougemont O, Graf R, Clavien PA, Dutkowski P. Protective mechanisms of end-ischemic cold machine perfusion in DCD liver grafts. J Hepatol. 2013 Feb;58(2):278-86. doi: 10.1016/j.jhep.2012.10.004. Epub 2012 Oct 11. — View Citation

Schlegel A, Muller X, Dutkowski P. Hypothermic Machine Preservation of the Liver: State of the Art. Curr Transplant Rep. 2018;5(1):93-102. doi: 10.1007/s40472-018-0183-z. Epub 2018 Jan 22. Review. Erratum in: Curr Transplant Rep. 2018;5(1):103. — View Citation

Tanrisev M, Hoscoskun C, Asçi G, Sözbilen M, Firat Ö, Ertilav M, Özkahya M, Töz H. Long-term outcome of kidney transplantation from elderly living and expanded criteria deceased donors. Ren Fail. 2015 Mar;37(2):249-53. doi: 10.3109/0886022X.2014.982488. Epub 2014 Dec 3. — View Citation

Versteilen AM, Di Maggio F, Leemreis JR, Groeneveld AB, Musters RJ, Sipkema P. Molecular mechanisms of acute renal failure following ischemia/reperfusion. Int J Artif Organs. 2004 Dec;27(12):1019-29. Review. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Liver Transplant - Early allograft dysfunction (EAD)	Present/Non present	0-30 days after procedure
Primary	Kidney Transplant- Delayed graft function (DGF)	Present/Non present	0-30 days after procedure
Secondary	Liver and Kidney surgical complications	Present/Non present	0-6 months after procedure
Secondary	Liver and Kidney graft function at 6 and 12 months	Functioning/non functioning	0-12 months after procedure
Secondary	Patient survival at 6 and 12 months	Alive/Death	0-12 months after procedure

External Links

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