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Abstract

  1. Top of page
  2. Abstract
  3. REFERENCES

Key Points

1. Hypothermic machine perfusion (HMP) is in its infancy in clinical liver transplantation. Potential benefits include diminished preservation injury (PI) and improved graft function.

2. We have employed HMP in 21 extended criteria donor (ECD livers) at our center with excellent clinical outcomes.

3. Our experience with liver HMP is the only reported clinical experience worldwide representing a total of 41 successful liver transplant cases showing improved outcomes and diminished markers of ischemia/reperfusion injury.

4. Further multicenter and large scale trials are now warranted to further explore the benefits and applicability of liver HMP into the clinical mainstream. Liver Transpl, 2012. © 2012 AASLD.

Hypothermic machine preservation (HMP) is in its infancy in clinical liver transplantation. In renal transplantation, HMP has been correlated with improved graft and patient survival in a recent large, randomized trial, but clinical experience with liver transplantation has been reported only by our group. Because a discrepancy between the donor supply and the demand persists, extended criteria donors (ECDs) continue to be an important resource for closing this gap.

Unfortunately, cold storage liver preservation technology has seen no improvements in almost 25 years.1 The risk of severe preservation injury in ECD livers is high, and this puts the grafts and patients' lives at risk. Many ECD livers are turned down because of the inherent risk of preservation injury with existing preservation technologies. Within the kidney space, machine perfusion has increased the utilization of ECD kidneys directly because of the significantly lower likelihood of delayed graft function after transplantation.2-5

Preclinical work in various animal liver models has shown promising results for many years; however, the logistics and the more serious ramifications of delayed or poor liver graft function have hindered the extrapolation of HMP techniques from renal transplantation.

In 2009, we completed the first human trial using HMP to mediate preservation injury in low-risk donor grafts.6 In this study, we compared HMP to traditional cold storage liver transplantation to determine the safety and efficacy of this technique in a clinical setting. We used dual-inflow nonpulsatile perfusion via the portal vein and the hepatic artery. We used Vasosol solution, which is based biochemically on Belzer machine perfusion solution and University of Wisconsin solution but has added components that address multiple pathways in the ischemia/reperfusion injury cascade. A representative liver undergoing HMP is shown in Fig. 1. The results from this phase 1 study indicate that HMP is a safe and reliable method for preserving liver grafts. In addition, we found that HMP liver graft recipients had a shorter length of stay, fewer posttransplant complications (biliary and vascular), and a lower incidence of early allograft dysfunction. The HMP grafts showed improved graft function: transaminase and bilirubin levels were significantly lower in the HMP group, and all times to normalization were shorter.

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Figure 1. Representative liver undergoing HMP.

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HMP was also found to attenuate the classical ischemia/reperfusion markers of liver preservation injury and improve hepatic ultrastructural preservation in comparison with cold storage.7

We have now almost completed a US Health Resources and Services Administration–sponsored phase 2 trial using HMP to preserve 24 ECD livers (see Fig. 2). The study protocol was approved by the Columbia University Medical Center IRB. All patients gave prospective informed prior to the initiation of HMP. These cases will be compared to similarly matched cold-stored liver grafts. To date, we have pumped 21 ECD livers with excellent success and a very low incidence of early allograft dysfunction and biliary complications. Sixteen of the 21 grafts were imported from outside United Network for Organ Sharing (UNOS) region 9 (Fig. 3). The median recipient age was 56 years (range = 35-71 years). The peak aspartate aminotransferase (AST) and alanine aminotransferase levels on postoperative day 1 were 1583.19 ± 325.23 and 634.61 ± 113 IU/mL, respectively. The median international normalized ratio on postoperative day 3 was 1.32 (range = 1.08-2.14). Sixty-six percent of the patients had a length of stay less than 14 days, and 52% had a length of stay less than 10 days. One patient successfully underwent retransplantation for early hepatic artery thrombosis, which was deemed to be unrelated to the HMP procedure. One hypercoagulable patient required portal and inferior vena cava (IVC) thrombectomy. Three patients died because of infections [multidrug-resistant Klebsiella sepsis (2) or disseminated mucormycosis (1)]. Eighteen patients (86%) were alive and well at the time of this writing with a median follow-up of 17 months (range = 5-27 months).

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Figure 2. Liver HMP phase 2 trial.

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Figure 3. Origins of livers in the HMP phase 2 trial. The mean distance to the center was 686.45 ± 393.54 miles. The mean donor risk index was 2.33 ± 0.47, and the mean cold ischemia time was 9.55 ± 1.2 hours.

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These results suggest that machine perfusion facilitates the safe use and excellent outcomes of marginal livers deemed untransplantable by multiple centers. In collaboration with industry, we are now poised to begin a multicenter trial using a novel portable perfusion device that can be transported to the donor hospital. We anticipate that HMP will be an effective method for reducing the incidence of preservation injury within the most susceptible livers in the donor pool. The further development of this technique and new ergonomic perfusion equipment will facilitate the availability of liver HMP to other centers and patients. We hope that bringing this novel technique into clinical practice will assist in closing the gap between the organ supply and the demand.

REFERENCES

  1. Top of page
  2. Abstract
  3. REFERENCES
  • 1
    Guarrera JV, Karim NA. Liver preservation: is there anything new yet? Curr Opin Organ Transplant 2008; 13: 148-154.
  • 2
    Bae C, Henry SD, Guarrera JV. Is extracorporeal hypothermic machine perfusion of the liver better than the 'good old icebox'? Curr Opin Organ Transplant 2012; 17: 137-142.
  • 3
    Moers C, Smits JM, Maathuis MH, Treckmann J, van Gelder F, Napieralski BP, et al. Machine perfusion or cold storage in deceased-donor kidney transplantation. N Engl J Med 2009; 360: 7-19.
  • 4
    Matsuoka L, Shah T, Aswad S, Bunnapradist S, Cho Y, Mendez RG, et al. Pulsatile perfusion reduces the incidence of delayed graft function in expanded criteria donor kidney transplantation. Am J Transplant 2006; 6: 1473-1478.
  • 5
    Schold JD, Kaplan B, Howard RJ, Reed AI, Foley DP, Meier-Kriesche HU. Are we frozen in time? Analysis of the utilization and efficacy of pulsatile perfusion in renal transplantation. Am J Transplant 2005; 5: 1681-1688.
  • 6
    Guarrera JV, Henry SD, Samstein B, Odeh-Ramadan R, Kinkhabwala M, Goldstein MJ, et al. Hypothermic machine preservation in human liver transplantation: the first clinical series. Am J Transplant 2010; 10: 372-381.
  • 7
    Henry SD, Nachber E, Tulipan J, Stone J, Bae C, Reznik L, et al. Hypothermic machine preservation reduces molecular markers of ischemia/reperfusion injury in human liver transplantation. Am J Transplant 2012, doi:10.1111/j.1600-6143.2012.04086.x. [Epub ahead of print: May 17, 2012].