How is normothermic liver perfusion giving hope to patients needing liver transplantation?

At a Glance:

There are stories that you often hear about the extent of coordination that is required to ensure that a donor organ reaches the recipient for organ transplant on time. The harvested donor organs for transplants reach the destined hospital in time. However, it may not always be the case. Donor organs have a very short life and for a successful transplant, they should be retrieved, stored and transported within a few hours with least possible structural damage to the organ. Further, due to a shortage of advanced healthcare facilities to carry out a transplant in smaller cities, they are referred to dedicated centres, thus making transportation inevitable. Many organs are often lost due to shorter lifespan and logistical reasons.

What is Normothermic Liver Perfusion (NLP)?

NLP is an innovative technology of recent origin. The technology has a high potential for transforming the way liver preservation is done and the whole field of organ transplantation. The technique makes use of “extra‐corporeal membrane oxygenation” i.e oxygen enrichment carried out external to the body in order to recondition and repair the donor liver at near body temperature before the transplantation.

Organ preservation and repair using normothermic liver perfusion is required for many purposes that include: 

• To safely preserve organs from the time the organ is harvested from the donor until the transplantation is done.
• To minimize the damaging effects or injury on organs due to ischemia or reperfusion.
• To repair of the injuries sustained by the organ before or during the process of organ retrieval
• Viability assessment i.e. to identify those organs which are unlikely to function satisfactorily after transplantation.

What are marginal donated liver organs, why are they used?

There is an ever growing, unmet demand for donor livers for transplantation. The number of patients with liver disease requiring liver transplantation has increased not only in India, but in many parts of the world. In the wake of rising shortage of donor organs, it has been recognized that it is not always feasible to obtain organs that fulfil the ideal requirements. Hence over the last few years, the ideal criteria for selection of donor organs have been relaxed. As a result, the organs which were earlier considered unsuitable are now acceptable for transplantation. These are usually termed as “marginal” donor, or “expanded” donor and “extended criteria” donor organs. This category generally includes older donors or those with chronic diseases like diabetes mellitus, hypertension, renal insufficiency etc.

One of the greatest disadvantages of marginal organs is that these organs are very prone to injuries due to shortage of blood supply during cold storage i.e. ischemic injury. As a result, the risk of graft failure increases, and so does the chances of morbidity (complications) and mortality (deaths) in the recipient. Theoretically, damage to the organ can be prevented by reducing the time of cold storage, but it is practically and logistically not feasible. As a result, DCD (donated after circulatory death) donor organs and other high-risk donor organs when used for transplantation demonstrate poor outcomes in comparison to those from standard criteria donors. Successful outcomes and an increase in the utilization of these and other high-risk donor sources is dependent on better technology to improve the condition of these high‐risk organs before transplantation. An increasing trend in the use of liver donated after circulatory death (DCD) and their susceptibility to ischemic injury has led to the rapid evolution of the NLP technique.

What is the current state of liver transplantation?

Liver transplantation is the treatment of choice for patients with diseases like advanced cirrhosis of the liver, cancers of the liver (hepatocellular carcinoma) or severe metabolic or autoimmune hepatic disorders. In India, 20 liver patients in every 1 million population are in the need of liver transplantation and yearly demand for donor liver has touched 25,000. However, the number of transplants carried out is barely around 1.2/million population which is inadequate. Further, the rate of rejection of the donor liver is as high as 20-30 percent. Rejections happen due to poor quality of the donor organ or issues with the process of liver preservation, delay in access and logistics.

The advent of NLP technology has increased donor utilization rate by nearly 30%. In recent years, many commercially developed normothermic perfusion systems are undergoing various stages of clinical trials, which is indicative of the interest in the potential of this technology. There are many common design characteristics of these systems like the use of commercially available components in perfusion technology. However there may be some differences in features like automation & portability i.e the ability of the machine to be transported to the donor hospital that would help to minimize the duration of time for cold preservation.

What is organ preservation?

Organ preservation is an extremely crucial step in organ transplantation. The viability of a donated liver is around 12 hours and the quality and efficacy of donor organs determine the success of organ transplantation.

Preservation of the organ before the transplant procedure helps in buying ‘time’, for activities like organizing the staff and infrastructure, transporting the organs and carrying out the necessary laboratory tests. Organ transplantation is a very successful treatment option for a wide range of medical conditions leading to an irreversible damage and consequently the failure of an essential organ system.

What is static cold storage?

In one of the commonly used techniques, donor organ preservation is done by placing them in plastic bags in an ice box. The organs are first flushed with an organ preservation solution and then immersed in the solution in the first bag. This bag is then placed in another bag filled with saline which is then placed in a box containing ice, storing them at hypothermia. This technique is called static cold storage. One of the greatest disadvantages of this technique is that the organ usually becomes too cold. If the storage temperature remains more than ideal, it can lead to a “hypoxic injury” to the organ as there is a difficulty in efficiently decreasing the metabolism of the organ. On the other hand, lowering the temperature below 4°C during preservation can cause a cold injury to the organ with denaturation of proteins within the cells. The ideal temperature for organ preservation is 4°C – 8°C.

What is the role of normothermic liver perfusion in liver transplantation?

NLP plays an important role in improving the success of transplantation by:

• Preserving organs
• Reconditioning grafts
• Repairing injuries
• Using marginal organs

How is NLP better than cold storage?

The current organ preservation technique, i.e., static cold storage (SCS), is not suitable for marginal organs. Alternatively, normothermic liver perfusion (NLP) promises to recreate the physiological environment and hence holds promise for better preservation of organs.

Conventionally, static cold storage has been the technique used for liver preservation since many years. The reason for the popularity of this technique was the simplicity of the procedure and ease of use making transportation and portability convenient. However, the disadvantages are:

• Absence of oxygen delivery cause accumulation of harmful by-products of metabolism
• Lack of effective viability assessment
• Damage to the organ cells due to direct cooling.

Normothermic perfusion in contrast with the cold storage method is oriented towards recreation of the physiological or natural environment of the body by:

• Delivering oxygen continuously
• Maintaining a physiological (natural) temperature
• Supplying nutrition

As a result, the natural metabolism of the organ in presence of oxygen continues during the period of preservation. This helps to minimize the damaging effects of ischemia/reperfusion. Also, it becomes possible to assess the viability of the organ by measuring its function.

The potential benefits of normothermic donor organ preservation were demonstrated in early stages in experimental studies with large animals. Such studies gave evidence that

• Parameters like perfusion and biochemical values could be helpful in determining the viability.
• NLP has the potential to enable repair of the marginal organs before the transplantation.
• NLP can be used as a platform for delivery of therapeutics. In fact, many emerging therapies like delivery of therapeutic gases, nutrients, mesenchymal stromal cells, gene therapies, and nanoparticles have been delivered successfully during the technique of NLP.

Restoration of blood supply i.e. reperfusion to the donor organ after a period of ischemia i.e. lack of oxygen may lead to IRI. It is considered that NLP is effective in overcoming damage to the organ due to ischaemia reperfusion injury (IRI) and in the improvement of the outcomes of transplant.

As the number of transplants using marginal liver is growing, we need to overcome the problem of probability of ischemia- reperfusion injury (IRI) using Normothermic liver perfusion (NLP), an innovative technique for reconditioning and assessing the function in liver before transplantation.

How does organ repair happen with NLP?

Organs from marginal donors generally have a normal or near-normal function prior to death. However at the beginning of the process of organ recovery, preservation and transplantation, progressive injury starts taking place at every point of this process. The main reason for this injury is an inadequate amount or absence of the delivery of oxygen and nutrients. A deprivation of oxygen to the cells of the organs causes a rapid depletion of the stores of cellular energy. In the cold storage, depletion of energy takes place more slowly however the function of the cell membrane ie the covering structure of the cells begins to cease causing the cells to swell. In case of an ideal donor organ which is obtained from donors with brain dead standard criteria (SCD), this damage is physiologically acceptable as it recovers. However, in organs that are recovered or harvested from extended criteria donors (ECD) or donors after circulatory death (DCD), these sequential injuries have a permanently damaging effect, leading to an irreversible injury.

Contrary to other methods of perfusion at lower temperatures which require and necessitate the use of carriers of oxygen carriers i.e. mainly the red blood cells, NLP helps in maintaining the graft or the donor organ in a near-to-physiological state by use of “extra‐corporeal membrane oxygenation”. As a result, the depletion of cellular energy and accumulation of metabolic waste products is avoided which minimizes the preservation injury.

Conclusion:

With an increase in the number of donors in the past few years, there is an increase in the number of deaths due to liver diseases before a transplant and the waiting lists for a donor organ continue to grow. Cold preservation and ischemia-reperfusion injury (IRI) are important factors that define the suitability of donor organs suitable for liver transplantation. Transplantation done with marginal donor organs is creating a renewed interest in technology like NLP that can potentially improve the quality of preservation and its duration, help in viability assessment of the quality of the organ and also allow repair of the donor organ before the transplantation takes place.

Such techniques are capable of not only improving the outcome of currently transplanted marginal livers, but also help in addressing the shortage of donor organs by increase the donor pool. Evidence from early experiments is suggestive of the possibility of abrogation of IRI by preservation under near physiological conditions of temperature and oxygenation. Normothermic perfusion helps in maintaining the donor organ in a physiological state. This avoids the depletion of cellular energy and prevents the accumulation of metabolic waste products that takes place due to static cold storage. It enables viability assessment prior to transplantation thereby reducing the risk of transplanting inherently marginal organs.

Normothermic liver perfusion is thus ushering in a new era in the way organ preservation is done and transplant is carried out. There are hopes that with the help of this new technology, it may be possible to save more lives by transplanting more livers with improved outcomes.

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References:

• Mayo Clinic. Osteoporosis. Available at: https://www.mayoclinic.org/diseases-conditions/osteoporosis/symptoms-causes/syc-20351968. Accessed on September ’ 15, 2018.
• US National Library of Medicine. The case for normothermic liver perfusion in liver transplantation. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29272051. Accessed on September ’ 25, 2018
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• US National Library of Medicine. Preservation methods for kidney and liver. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2781089/. Accessed on September ’ 25, 2018
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