Getting the best out DCD livers for transplantation: Will machine perfusion (MP) be the answer?

Foreward by Professor D M Manas (pictured) BSc, MBBCh, MMed, FCS(SA), FRCS(Edin).  The burden of chronic liver disease (CLD) continues to grow worldwide and the UK is no exception. Liver transplantation is now part of routine practice and is accepted as treatment for end stage liver failure.

As a result of the excellent graft and patient survival (91% – 97% at 1 year), the indications have evolved to include conditions previously not considered transplantable even 10 years ago. As an example, most centers would have no problem listing a patient with HIV and CLD provided there are low or undetectable levels of HIV RNA, a CD4 count > 200/ml and no AIDS defining conditions. This, coupled with a dwindling list of contraindications, has resulted in a widening gap between supply and demand.  In an attempt to bridge this gap, a concerted effort has been made to increase the number of deceased donor livers available in the UK. In 2008, the organ donor taskforce (ODT) report produced 14 recommendations, the most important of which was to increase deceased organ donation in the UK by 50% in 5 years. Those who attended the British Transplant Society meeting in Bournemouth last month would have heard from Sally Johnson, the chief executive of ODT, report that this target has almost been reached (48% – March 2013). Having said that, the increase has been almost exclusively due to an unexpected increase in organs recovered from donors after cardiac (circulatory) death (DCD), with the UK now toping the list of European countries – at 6 DCD donors per million population.  In 2012, of the 1088 deceased donors in the UK, 436 were DCD donors. While donation after cardiac death is a welcome and valuable source of organ donors for the growing national requirements, for recipients waiting for liver transplantation it has significant implications.  So what are the implications?

• Firstly, only 30% of the DCD donors proceeding will eventually donate transplantable livers as opposed to brain dead donors (80%).
• Secondly, most DCD donors are older (mean age 52 years) and heavier (30% have a BMI > 30) increasing the risk for the potential recipients.
• In addition the unavoidable added warm ischaemia inherent in the DCD recovery increases the risk of primary non-function, initial poor function and long-term intrahepatic biliary strictures.

As a consequence, clinicians involved in liver transplantation have had to adapt their practice. This has included modifying recipient selection, developing new surgical techniques and changing post-operative management including medical management and immunosuppression.

 

In an endevour to increase the supply of transplantable livers, reduce the risk of poor function, and ameliorate the effects of warm ischaemia a number of groups around the world have been developing experimental techniques to prevent further injury. The focus of these innovations have been largely on preventing depletion of ATP stores and cell death by using some form of liver perfusion as opposed to cold storage. The ideal method of preservation of these DCD liver grafts is now the focus of new exciting research. Prolonging preservation time, reducing the rate of primary graft non-function after transplantation, developing methods of assessing the viability of the liver before transplantation, preventing late intrahepatic biliary strictures and facilitating the use of more extended criteria livers is the order of the day. Considering these characteristics, simple cold storage (SCS) – where the liver is flushed with a cold (4°C) preservation solution and then immersed and stored in this solution until transplanted, is probably not the ideal preservation method for a DCD/marginal organ. In contrast to SCS, machine perfusion (MP) preserves the organ by a constant perfusion through its blood vessels with either a sanguineous or non-sanguineous machine perfusion solution (MPS), with the hope that MP will have more potential benefits compared with SCS. For example, allowing for a better preserved microcirculation and penetration of the preservation solution during MP will prevent the sinusoids becoming constricted, often seen in SCS, preventing impaired microcirculation at reperfusion. In contrast, with MP, nutrients and oxygen are continuously supplied. It may then be possible to reduce waste products by dialysis in the circuit or by changing the type of perfusion fluid. In addition, the whole organ is accessible for different types of pharmacological intervention over the entire period of MP.

 

To date two different types of liver machine perfusion have been developed in experimental settings: Hypothermic (HMP) at 4–10°C and Normothermic (NMP) at normal body temperature. As yet, no clear evidence has emerged as to which of these MP methods is best. For example, HMP increases energy stores compared to SCS with beneficial effects as shown by both Dutkowski et al [1], in a series of ischaemically damaged pig livers transplanted after HMP following a period SCS avoiding the graft failure observed after SCS alone, and Guarrera et al [2],  who performed 20 clinical transplants after 4-7 hours of HMP with equally positive  results. HMP is less complex, may have less risk of bacterial contamination when compared to NMP and requires less essential nutrients and oxygen demand but may increase the production of reactive oxygen species (ROS) inducing an inflammatory cascade within the sinusoids with subsequent deleterious effects.  NMP shows additional resuscitative potential and Friend and colleagues [3],  have performed porcine transplantations after NMP of 4-20 h and univocally demonstrated the significant resuscitative effects on ischaemically damaged grafts otherwise destined to fail. Whereas NMP promises resuscitative effects, it demands challenging, near-physiologic conditions. Sub-normothermic perfusion is also being tested as a promising medium in between.

 

Despite recent exciting developments with NMP in kidney transplantation – as shown by Nicholson et al and the Leicester group and the global revival of kidney HMP (LifePort ®), the transfer of liver preservation by machine perfusion into clinical practice remains limited. However, NMP of recovered livers for clinical transplantation may be closer than we think. In the UK, centers have put their efforts into two techniques both involving Normothermic Perfusion, either as an in-situ technique using NECMO (Cambridge) or an ex-situ bespoke system developed in Oxford (OrganOx®). At the time of writing there have been three successful liver transplants performed following ex-situ NMP using OrganOx® and one following NECMO.History shows that ‘proof of principle’ alone does not guarantee immediate clinical use. To reach acceptance by the liver transplant community, machine perfusion will need to improve outcomes compared with SCS, provide objective measures of graft viability, and resuscitate less-than-ideal grafts before transplantation. This will be our challenge for future national trials.

 

1. Dutkowski P, Furrer K, Tian Y, Graf R, Clavien PA. Novel short-term hypothermic oxygenated perfusion (HOPE) system prevents injury in rat liver graft from non-heart beating donor. Ann Surg.2006;244:968–76; discussion 976-7.
2. Guarrera JV,Estevez J,Boykin J,Boyce R,Rashid J,Sun S,Arrington B. 2005. Hypothermic machine perfusion of liver grafts for transplantation: technical development in human discard and miniature swine models. Transplant Proc 37: 323–325
3. Friend PJ,Imber C,St Peter S,Lopez I,Butler AJ,Rees MA. 2001. Normothermic perfusion of the isolated liver. Transplant Proc 33:3436–3438.

 

Further Reading

 

1. NHS Blood and Transplant. Transplant Activity in the UK, Activity Report. https://www.organdonation.nhs.uk/ukt/…/ transplant_activity_report/
2. M Thamara PR Perera, Simon R Bramhall. Current status and recent advances of liver transplantation from donation after cardiac death World J Gastrointest Surg 2011 November 27; 3(11): 167-176
3. Katrien Vekemans, Qiang Liu, Jacques Pirenne, Diethard Monbaliu.  Artificial Circulation of the Liver: Machine Perfusion as a Preservation Method in Liver Transplantation The anatomical record 291:735–740 (2008)
4. Monbaliu D, Brassil J Machine perfusion of the liver: past, present and future Curr Opin Organ Transplant. 2010 Apr;15(2)
5. Brockmann J, Reddy S, Coussios C, Pigott D, Guirriero D, Hughes D, Morovat A, Roy D, Winter L, Friend PJ. Normothermic perfusion: a new paradigm for organ preservation Ann Surg. 2009 Jul;250(1):1-6.