Year: 2014
Type: article
Abstract: The increasing discrepancy between organ supply and demand resulting from the successful application of liver transplantation (LT) has motivated select centers in areas of particular scarcity to adopt strategies for the utilization of these organs, with overall satisfactory results. As organ scarcity intensifies, there will be further emphasis on expanding donor criteria. Guidelines defining this category of donor, level of acceptable risk, principles of consent, and posttransplantation surveillance have not been well defined. Incumbent upon expansion of the donor pool is the establishment of well-defined guidelines that distinguish standard-criteria from extended-criteria donors (ECD). To date, this has not been achieved. Although predictors of early graft dysfunction from deceased donors have been identified, there has been no uniform acceptance and agreement on these criteria. Current practice defines ECD on the basis of assessment of the risk incurred by the recipient. In such an approach, increased risk incurred by a recipient includes a recognized higher risk of early graft failure or early allograft dysfunction; alternatively, the recipient may be assuming an added risk of known or potential donor-transmitted disease. Although all deceased donor organ recipients assume a theoretical risk associated with the process of organ transplantation, the transplantation of an allograft with positive serologic analysis or donor history of neoplasm significantly elevates the risk profile. Accepting increased risk must be accompanied by a process of informed consent that specifically addresses the concerns of the patient with respect to the particular donor's "issues" as well as the transplant procedure. Long-term surveillance of outcomes of such cases in which disease transmission may occur is critical to accurate risk assessment and informed consent. Most organs derive from deceased donors, whose organs sustain a varying degree of ischemia/reperfusion injury (IRI) contributing to graft injury, which may manifest as early allograft dysfunction or even primary nonfunction.1, 2 Donation from cardiac death (DCD) donors remains a great potential source of viable livers, but the morbidity associated with ischemic cholangiopathy has limited this potential. Utilization of DCD livers has been stagnant at most centers as a result of disappointing outcomes. However, there are some champion centers worldwide that are leading the charge to discover novel protocols to bring the risks of ischemic choloangiopathy to an acceptable level. There is consensus that minimizing cold and warm ischemic injury is imperative. Arterial prior to portal reperfusion has also gained favor among several centers. In addition, instituting a national policy of granting United Network for Organ Sharing (UNOS) exception points for patients with ischemic cholangiopathy requiring retransplant would likely reduce the perceived risk at transplant centers in geographically underserved donor catchment areas. The recent disappointment with DCD highlights the largely unmet challenge of finding novel techniques to attenuate IRI. Mitigating and reversing IRI is the key to reclaiming organs from marginal donors and consequently expanding the donor pool. Many investigators are actively working on innovative strategies that address IRI in clinical LT. The successful use of extracorporeal membrane oxygenation (ECMO) in uncontrolled DCD has been championed by Fondevilla et al.3 in Spain, where there is presumed donor consent and significant infrastructure resulting in the highest donation rate worldwide. There has also been interest and some experience in the United States in controlled DCD. Further exploration of the use of ECMO is ongoing. There has also been significant interest in finding novel therapeutic agents to reduce IRI. Recent findings from experimental and clinical studies demonstrated the potential of therapeutic conditioning of the liver, using recombinant P-selectin glycoprotein ligand IgG (rPSGL-Ig).4, 5 rPSGL-Ig blocks P-selectin glycoprotein ligand, which mediates leukocyte adhesion, rolling, and eventual recruitment to the site of inflammation. The randomized, phase 2, single-center clinical trial treated livers from deceased donor livers ex vivo with rPSGL-Ig via portal vein and intravenous administration at a systemic concentration of 1 mg/kg prior to reperfusion.3 In this prospective study, the treatment arm illustrated decreased peak transaminases and bilirubin levels, faster normalization of transaminases, and faster recovery after transplantation. Similarly, allografts treated with a pancaspase inhibitor, IDN-6556, via cold storage solution and flush solution were correlated with a significant reduction of transaminases and serum markers of apoptosis in a multicenter clinical trial.6 Other methods of pharmacological conditioning of the liver using methylprednisolone,7 nitric oxide,8 and sevoflurane9 have all demonstrated efficacy over placebo in clinical trials. Ex vivo techniques have been a hot topic over the last several years. The novel strategy with the most clinical traction is hypothermic machine preservation (HMP) of the liver, which has regained clinical interest. The advantages of HMP over standard cold storage include continuous supply of metabolic substrates for adenosine triphosphate production, washout/dilution of waste products such as lactic acid and reactive oxygen species, assessment of organ viability and functionality prior to transplant, and intraoperative therapeutic interventions. HMP of the liver has reached clinical feasibility, with safety illustrated by a clinical trial.10 HMP resulted in significantly decreased serum markers of hepatic injury, shorter recovery time, and diminished biliary complications compared with preservation by static cold storage. In addition, proinflammatory cytokines, including interleukin-8, tumor necrosis factor-α, and intercellular adhesion molecule-1, were reduced by HMP as seen in posttransplant reperfusion biopsies, showing mechanisms by which HMP mitigates IRI.11-13 Other groups have shown similar experimental benefits in animal DCD models. HMP has been shown to ameliorate lipid peroxidation while amplifying adenosine triphosphate production during preservation.14 Likewise, HMP has been shown to reduce IRI damage in steatotic rat livers.15 From the most recent experience at our institution, we report outcomes of 31 ECD "orphan livers" that were turned down by all centers from their originating UNOS regions, underwent HMP, and were subsequently transplanted at our center.16 These HMP cases showed less early allograft dysfunction, fewer biliary complications, less acute kidney injury, and shorter length of stay in patients compared with static cold storage controls. The Zurich group and the Groningen group (Robert Porte, personal communication) have also recently both begun clinical trials with HMP for both DCD17 and donation after brain death (DBD) livers. These reports have relatively small numbers, but results have been encouraging in the short follow-up period. Two recent comprehensive reviews of the current status of liver HMP have been published by Graham and Guarrera18 and Schlegel and Dutkowski19 and are good additional references for the interested reader. In addition, a proof-of-concept study with normothermic machine perfusion (NMP) is currently underway in the United Kingdom under the direction of Professor Peter Friend. This study has enrolled 20 patients to date, with up to 18 hours of NMP, with outcome results similar to those of cold-storage controls (presented at World Transplant Congress, San Francisco, 2014). There is more concern for potential equipment failure with NMP, because there is not the intrinsic cold-storage backup of the insulated perfusion chamber of the HMP devices. If the NMP device fails while in transit, this would essentially turn the allograft into an "ex vivo DCD" until another method of preservation could be initiated. This is obviously at least a logistical concern if not a limitation. The development of a reliable and sustainable normothermic perfusion system and protocol in the future might offer a sustainable platform for more sophisticated graft resuscitation and ex vivo conditioning by allowing gene or stem cell therapy for repair mechanisms or blockade of IRI gene expression. There is a pressing need for multicenter clinical trials to verify the early clinical experience with these new ex vivo liver machine perfusion techniques. The advent of a portable perfusion machine will further expedite the application of machine perfusion in clinical LT. Ex vivo techniques hold great promise for reducing IRI in LT from marginal ECD donors. Safer utilization of more ECD and DCD donors will facilitate improved outcomes and reduction of wait-list mortality, which would benefit the practice of transplantation and especially the lives of the patients we serve.
Source: Liver Transplantation
DOI: 10.1002/lt.24001
Author: James V. Guarrera
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1965128358