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Life of a liver awaiting transplantation

People waiting for a liver transplant can die before an organ is found, or, if one is available but of poor quality, there is a risk of transplant failure. A machine that preserves livers might offer a way forward.
Stefan Schneeberger is in the Department of Visceral, Transplant and Thoracic Surgery, Innsbruck Medical University, 6020 Innsbruck, Austria.
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The standard approach for handling donated livers before transplantation is storing them on ice. In a paper published in Nature, Nasralla et al.1 report the results of a clinical trial that compared two organ storage methods. More than 200 people who received a liver transplant were randomly allocated either a donor liver that had been stored on ice or one preserved with the aid of a machine that perfuses the organ at body temperature (37 °C) with oxygenated blood containing nutrients (Fig. 1). The latter method is called normothermic machine perfusion (NMP), and this technique enables organ function to be monitored outside the body before transplantation.

Figure 1 | Supporting the human liver outside the body. Nasralla et al.1 report a clinical trial that compared methods of liver storage before transplantation. a, In the current standard approach, livers are stored on ice in preservation fluid. However, this can lead to a decrease in levels of the energy-storage molecule ATP, an increase in harmful reactive oxygen species (ROS) and damage to mitochondrial cellular organelles when blood flow returns after transplantation3. b, In an approach termed normothermic machine perfusion (NMP), donated livers are maintained at body temperature (37 °C) by a machine. This device pumps the liver’s deoxygenated blood (dark red) through the machine, and then returns oxygenated blood (light red) containing nutrients and essential factors such as bile salts, heparin and insulin to the liver. On the basis of analyses of enzyme levels (not shown), the authors found that NMP results in less liver damage than that incurred when livers are stored on ice. This might be because perfusion results in higher ATP levels and fewer ROS compared with ice storage. c, Machine-based organ perfusion could perhaps be adapted to repair liver damage before transplantation. Such an approach might require the addition of biological agents such as growth factors, or the introduction of stem cells.

The concept of machine perfusion of an organ awaiting transplantation is not new. Indeed, machine-assisted perfusion was in use before cold storage became the method of choice owing to its simplicity and reproducibility2. However, interest in revisiting perfusion as a transplant approach has been gaining momentum.

The main outcome monitored in the latest trial was the post-transplantation level of the enzyme aspartate transaminase in patients’ blood. This measurement is commonly used to assess liver damage and to estimate the risk of transplant failure. The authors found that the use of NMP was associated with less liver damage than that found in livers preserved on ice. Moreover, preservation by NMP reduced the number of organs that were discarded as unsuitable for transplantation compared with livers preserved on ice, and was associated with a better blood-flow profile in the recipient.

The liver’s bile ducts can be a point of vulnerability for transplant success, and whether NMP has a positive effect on the viability of these ducts might only be revealed after long-term monitoring. It could therefore be premature to assert that NMP technology has been shown to be a more effective and suitable method for organ storage until additional studies can fully determine the long-term effect of the NMP approach. But it is also fair to say that Nasralla and colleagues’ work makes a convincing case for NMP’s superiority. Moreover, mimicking the normal conditions for an organ outside the body is a persuasive idea. This clinical trial represents a milestone by directly comparing ice and NMP storage approaches. It could pave the way for the clinical application of NMP and drive a research push in this area.

Organ storage on ice slows the liver’s metabolism, and can result in tissue damage by decreasing levels of the energy-storage molecule ATP. The alterations result in accumulation of harmful reactive oxygen species, damage to mitochondrial organelles, and trigger an inflammatory response when blood flow is restored to the transplanted organ3. NMP probably boosts transplant success through mimicking the normal conditions for the organ and enabling ATP replenishment. Such effects would eventually limit the generation of reactive oxygen species and cell damage.

Although Nasralla and colleagues’ study is convincing regarding the clinical impact of NMP, it does not clarify the underlying molecular events. Factors including organ architecture and cellular composition will need to be explored in detail to determine the length of preservation times that can be safely used. Other clinical trials of machine-assisted organ perfusion are under way, testing a range of temperatures and conditions4. NMP has been performed successfully for 48 hours before transplantation in porcine livers5. The median duration of NMP in Nasralla and colleagues’ study was around 9 hours.

Pioneering advances in surgical techniques, immunosuppressive drug treatment and patient care have made organ transplantation the standard treatment for chronic organ failure. Yet three fundamental limitations remain: organ shortages; a decline in the quality of donor organs6; and restrictions on the time permitted for handling and transporting organs. The use of NMP has the potential to increase the number of organs available for transplantation, and could lessen the need to rapidly transplant an organ after its removal from the donor’s body, enabling more time for assessing the liver.

Nevertheless, NMP poses certain challenges. It might be straightforward to set up the machine, prepare the organ for perfusion and do basic technical problem-solving, but substantial training and experience in using this method will be required before it can be routinely used in the clinic. Furthermore, the travel and care plan for an NMP organ is more complex than that for shipment on ice because extra steps are needed in the clinical routine. Standardized protocols and reporting methods need to be established to enable this procedure to advance in a controlled fashion. The sharing of information by medical professionals using NMP could help clinicians gain the collective experience necessary to minimize procedural risks.

Perhaps the greatest advance from this technology is that it might provide proof of principle that organs can survive when a machine helps to mimic the conditions organs encounter in the human body. The human liver itself then becomes like a patient. It is perfused, monitored and fed by a machine. If it performs well, it is transplanted immediately; if not, it might undergo treatment, modification or repair before transplantation.

The routine clinical use of NMP might boost interest and investment in finding new ways to treat, regenerate and recreate organs that are supported outside the body. The ability to preserve an organ under close-to-normal conditions could be instrumental in advancing not only liver transplantation, but also liver surgery and organ care. Tissue engineering, like transplantation, works towards the goal of providing human organs suitable for transplantation. As NMP offers the potential to modify and monitor an organ, the methods used in both fields might start to merge. This idea is fascinating, because not only would this change many aspects of transplantation, but it might also eventually close the gap between the two technologies.

Nature 557, 40-41 (2018)

doi: 10.1038/d41586-018-04458-w

References

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    Nasralla, D. et al. Nature 557, 50–56 (2018).

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    Clark, E. A., Terasaki, P. I., Opelz, G. & Mickey, M. R. N. Engl. J. Med. 291, 1099–1102 (1974)

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    Eltzschig, H. K. & Eckle, T. Nature Med. 17, 1391–1401 (2011).

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    Verhoeven, C. J. et al. J. Hepatol. 61, 672–684 (2014).

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    Vogel, T. et al. PLoS ONE 12, e0188494 (2017).

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    Orman, E. S. et al. Liver Transplant. 19, 59–68 (2013).

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