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Volume: 19 Issue: 9 September 2021

FULL TEXT

REVIEW
A Liver’s Iliad: Liver Graft Retransplant to a Second Recipient After Brain Death in a First Recipient

Abstract

With the current increased incidence of cirrhosis, the demand for liver transplant continues to grow. Here, we performed a systematic review to assess the feasibility, safety, and long-term outcomes of reused liver grafts for expansion of the donor pool. Our search identified 19 studies, including 36 patients plus 1 patient from our own institution. Ten studies were single case reports, 4 were case series, 4 were letters to the editor, and 1 was a literature review and also included a case report. Our patient presented with intentional acetaminophen overdose, received a transplant from a brain dead donor, and was confirmed brain dead 12 days posttransplant. The second recipient, who had alcohol-related liver disease cirrhosis, underwent orthotopic liver transplant with the reused liver and was discharged from the hospital after an uneventful postoperative course. Among the 19 studies, all donors had confirmed brain death and all transplants included the whole liver, except for 2 cases of auxiliary liver grafts (reduced liver transplant) and 1 case of extended right living-donor liver graft (donor and recipient being related sisters). Overall, among first recipients, the most frequent cause of liver disease was acetaminophen overdose followed by alcohol-related liver disease cirrhosis. There were 2 cases of retransplant. Among second recipients, hepatocellular carcinoma was the most frequent cause of liver disease followed by alcohol-related liver disease cirrhosis. We found that functional outcomes with these grafts were comparable to outcomes with grafts from conventional donors; in the absence of other contraindications, we suggest that, not only for liver transplant but for other organs, these reused grafts can be used for those awaiting transplantation. Because the ability to reuse grafts is an infrequent condition, it would be difficult to generally recommend this technique; however, on a case-by-case basis, this source could expand the donor pool.


Key words : Extended-criteria donor, Liver transplantation, Reuse

Introduction

Orthotopic liver transplant (OLT) is the only long-term effective treatment for end-stage liver disease1 and fulminant hepatic failure. With improvements in surgical techniques, anesthesiology, and intensive care management, morbidity and mortality have been reduced, thus making OLT an attractive benefit-to-risk option and with newer indications for OLT being accepted. The incidence of cirrhosis has increased as a result of different etiologies,2 both benign (hepatitis B and C virus [HBV and HCV], acute alcoholic hepatitis,3 chronic liver failure due to alcohol-related liver disease [ALD], and nonalcoholic steatohepatitis) and malignant (hepatocellular carcinoma [HCC],4 cholangiocarcinoma,5 or more recently colorectal liver metastasis6). This ever-increasing demand for liver transplant has resulted in a scarcity of grafts. Several strategies to increase the pool of donors7 have been attempted with the use of so-called marginal grafts,8 including split liver grafts, domino procedures,9 reduced-size OLT, and living related liver transplant. Despite the increased complications, applying extended donor criteria with appropriate donor-recipient selection has resulted in comparable outcomes, demonstrating a safe and feasible alternative, although not ending the problem of graft shortages. Here, we performed a systematic literature review of cases of reused liver grafts to assess their feasibility, safety, and long-term outcomes.

Materials and Methods

Search strategy
A systematic search of PubMed, Embase, and Scopus was conducted on March 31, 2020, by 2 independent investigators (MA, TS). Search terms were as follows: reuse, graft, and liver transplantation, either individually or in combination. We used the “related articles” function to broaden our search, and all citations were considered for relevance. The search was conducted using a combination of medical subject headings (MeSH) and free text words (tiab). The search strategy for Medline (via PubMed) was as follows: reuse*[tiab] OR “re use”[tiab] AND allograft*[tiab] OR graft*[tiab] AND “tissue and organ procurement”[MeSH] OR “organ transpla­ta­tion”[MeSH] OR “tissue transplantation”[MeSH] OR “trans­plan­tation”[tiab] OR “liver transplanta­tion”[tiab] OR “kidney transplantation”[tiab] OR “heart transplantation”[tiab] OR “lung transplan­tation”[tiab]. A manual search of reference lists in recent reviews and eligible studies was also conducted. Any disagreement regarding inclusion was resolved by discussion with a third member of the review team (DM). The included studies were saved in an EndNote database (version X9, Clarivate Analytics). This paper was reported in accordance with PRISMA guidelines, and detailed information on the screening process is illustrated in the PRISMA flow diagram presented in Figure 1.10 This study was prospectively registered with the PROSPERO database (CRD42020179554).

Inclusion and exclusion criteria
Inclusion criteria included any type of study reporting the use of reused liver grafts for OLT for any indication; there was no age or language restriction. Exclusion criteria included conference abstracts and articles reporting reuse of a graft other than liver or grafts procured from a donor who had previously undergone a transplant other than liver. After duplicates were excluded, 2 researchers (MA, TS) independently reviewed the titles and abstracts of studies identified by the literature search. When a study was considered to be potentially relevant to the research question, a full copy of the publication was obtained for further review. The reference lists of all included studies were hand-searched to identify other potentially relevant studies. Any areas of disagreement between the 2 primary researchers were resolved through discussion.

Study outcomes
The primary outcomes were complications and long-term survival post-OLT. Secondary outcomes were surgical features, such as technique, cold and warm ischaemia times, and time interval between transplants.

Definitions
Complications were defined as any deviation from an uneventful postoperative course. Surgical technique was any method of surgical removal and implantation of a liver graft.

Data extraction
The following data were extracted from the papers: name of first author, year of publication, study design, number of patients in each study, and patient characteristics (age, sex, liver disease, type of patient [donor, first recipient, second recipient], cause of death, specific type of graft, if biopsy was performed, serology, time interval between transplants, surgical technique, cold and warm ischemia times, whether both transplants were performed at the same center or not, major complications, follow-up duration, and status [dead or alive]).

Results

Our review identified 138 studies, which were title- and abstract-screened for inclusion. Of these, 118 were excluded due to ineligibility, as per the inclusion criteria mentioned above. Twenty studies were full text screened. Of these, 1 was excluded because the case report was included in a later case series published by the same authors.11

Study characteristics
The 19 studies included a total of 36 patients plus 1 patient from our own institution (unpublished and explained below). Ten studies were single case reports,12-21 4 studies were case series, which included 2 or 3 patients,22-25  4 studies were letters to the editor,26-29 and 1 was a literature review and also included a case report.30

Case reported by our institution
A 23-year-old female patient, with no prior medical history, presented with liver failure secondary to intentional acetaminophen overdose. The patient was initially admitted to a peripheral hospital and then transferred to our Liver Transplant Unit, being listed as super urgent. She received a liver transplant from a 20-year-old donor after brain death (DBD). Hepatectomy was uneventful, cold ischemia time was 4 hours and 14 minutes, and warm ischemia time was 43 minutes. Implantation required standard piggy-back venous anastomosis, end-to-end portal-portal anastomosis, gastroduodenal arterial patch to hepatic artery patch, and a standard choledochocholedochostomy. Total surgical time was 240 minutes. On day 1 post-OLT, the patient presented with unreactive and dilated pupils concerning for cerebral edema; a brain stem test confirmed brain death. Liver function tests remained normal, and Doppler ultrasonography showed normal postoperative findings. The possibility of reusing this liver graft was discussed and agreed. The new recipient was a 47-year-old male patient with ALD and a Model for End-Stage Liver Disease (MELD) score of 21. Cold ischemia time was 15 minutes, and warm ischemia time was 30 minutes. Total blood loss was 2 liters. The patient was discharged home on posttransplant day 14; at last follow-up at 18 months, findings were uneventful.

Selection bias
All studies were considered to have a high risk of bias due to their retrospective nature.

Patient characteristics and preoperative variables
In total, 37 patients were analyzed. Median ages of the donor, the first recipient, and the second recipient were 35 years (range, 8-69 y), 45 years (range, 4-65 y), and 52 years (range, 17-62 y), respectively. Causes of donor death involved severe head injury, stroke, brain hemorrhage, insulin intoxication, and valproic acid intoxication. All donors were DBDs, with grafts that included the whole liver except for 2 cases of auxiliary liver grafts (reduced liver consisting of segments 2 and 3 and part of 4 in both cases) and 1 case of extended right living-donor liver graft (donor and recipient being related sisters).

Among first recipients, the most frequent cause of liver disease was acute liver failure due to acetaminophen overdose (7 cases) followed by ALD cirrhosis in 5 cases. There were 2 cases of redo-OLT. Among first recipients, causes of death were mostly from neurological problems, as well as cerebral edema and herniation, stroke, cerebral hemorrhage, severe anoxic brain injury secondary to cardiac arrest, and gun shot in 1 recipient. Among second recipients, the most common cause of liver disease was HCC (9 patients); some of these patients also had underlying HCV (8 total patients) followed by ALD cirrhosis in 8 patients. Three cases were retransplant, with 1 being a second retransplant. Among first recipients, serology showed positive results in 4 patients (1 HCV, 1 HBV, 1 HCV and HBV, and 1 hepatitis A); the remaining patients had either negative results or results not reported (Table 1).

Postoperative complications and long-term survival
Postoperative complications were documented in 29 patients; 17 patients had an uneventful postoperative course, 6 patients had acute cellular rejection (the most frequent complication), 2 patients required endoscopic procedures (1 for donor common bile duct stricture and 1 for choledocholithiasis), 2 patients had hepatic artery thrombosis (1 required balloon dilatation), 2 patients presented with sepsis, 1 patient presented with severe renal impairment, 1 patient presented with bile leak, 1 patient had narrowing of the donor vena cava anastomosis that had been included and needed to undergo reoperation, and 1 patient died of recurrent cholangiocarcinoma. Median follow-up time was 14 months (range, 3 days to 125 months), with 30 patients alive at the time of publication of the study.

Surgical features
Regarding surgical techniques, a full description was not available for all reported cases. Different techniques were described with good outcomes, namely, piggyback end-to-side or side-to-side cava anastomosis (11 cases) and cava replacement (7 cases). Techniques used in the first recipient were also used in the second recipient, with 2 cases in which in both the first and second recipient underwent cava replacement. Inclusion or resection of prior anastomosis was reported in 4 and 7 cases, respectively, need for arterial conduits was reported in 1 case, and supra- and infra-hepatic vein donor vein interposition was reported in 1 case. Other techniques included extraction of portal vein thrombosis in 1 case. With regard to bile duct reconstruction, 11 patients underwent end-to-end choledochocholedochostomy, with 4 requiring a T tube and 1 requiring Roux-en-Y. Biopsies were reported for 13 patients. Eight patients had other organs retrieved (2 had lungs, 3 had hearts, and 4 had kidneys also retrieved). Median cold ischemia time was 195 minutes (range, 15-744 min). Median interval time between procedures was 5 days (range, 1 day to 13 years). “Early reuse” was considered when interval time was less than 7 days; 22 cases (59.4%) were considered early and 15 cases (40.6%) were considered delayed.

Limitations
The authors acknowledge some limitations, mainly the retrospective nature and the fact that most of the cases were single case reports. Follow-up was limited in most case reports, which could have missed long-term complications. Publication bias may have existed, with poor outcomes perhaps not reported and published.

Discussion

Reuse of a previously transplanted liver graft may be considered if the first recipient has neurological death at some time after liver transplant. Death from neurologic complications has been reported in up to 22% of overall deaths after OLT for fulminant hepatic failure31; this emphasizes the difficulty in predicting neurologic outcomes. Cerebrovascular disease is also a concern after OLT; intracranial hemorrhage has been found in 7% to 24% of autopsied liver transplant recipients.32,33 Those circumstances that lead to severe brain damage in liver transplant recipients should prompt evaluation for reuse of the liver grafts.

Reuse of a liver graft was initially described by Moreno and colleagues11 in 1991; since then, the indications have seemed to widen. Initially it was recommended that all reused grafts be obtained from young donors who have good hemodynamic and biochemical conditions, with short cold ischemia times, negative donor-recipient crossmatch, total ABO compatibility, negative HBV and HCV serology, and biopsies showing no or minimal preservation lesions. Later reports seemed less restrictive and included older patients23,29 and those with positive serology20 and longer cold ischemia times.13,26 Although biopsy seems to be recommended, it was not performed in all of these later cases. Clinical indications for reuse of liver grafts are varied, as shown in the current review, demonstrating that this procedure may be feasible regardless of etiology or recipient age. However, the incidence of HCC,15 patients with long wait times,18 recurrent disease,22 seriously impaired hepatic function, or older recipients suggests that candidates may have been offered this unconventional form of transplantation because access to conventional lists was limited. A recipient whose general condition is deteriorating or whose stage of malignancy is almost beyond the criteria for liver transplant, with suitable donor not available, could be a candidate for a reused liver graft. Interestingly, despite the recipients presenting with higher MELD or borderline indications, long-term survival of recipients of reused liver grafts seems comparable with survival of recipients of other primary liver transplants. Selection bias seems unlikely, despite the types of studies included, since patients with high numbers of risk factors have been reported.

Regarding the surgical technique, procurement is simplified for early reuse, which is more common (representing almost 60% of cases), involving only division of the vascular trunks and yielding a liver graft that has been previously prepared for implantation. Nevertheless, careful dissection of the anastomosis during the cold ischemia phase is needed, as this will allow precise length adaptation. Increased difficulty can be encountered during procurement of delayed reuse grafts, as adhesions will have developed. No limitation or preference has been described as to which cava anastomosis technique should be used regardless of previous reconstruction, and both end-to-side and side-to-side piggyback as well as cava replacement have been described. For example, in 1 case, portions of the 3 inferior vena cavas (IVC) were kept; the graft’s IVC was anastomosed to the first recipient’s IVC (ie, new donor) and then anastomosed to the second recipient’s IVC.15 In another case, where the first recipient had a side-to-side piggyback anastomosis, the IVC was oversewn at the site of lateral cavoplasty, and cava anastomosis was performed as standard cava replacement technique.28 If possible, intended resection of the primary arterial anastomosis is recommended to avoid segmental stenosis. An acceptable outcome has been reported when removal was not feasible.20 Although preservation of prior anastomoses would unavoidably lengthen the vessels, care should be taken to prevent redundancy and kinking. With regard to the bile duct, denuding the fibrous tissues around it might compromise its blood supply and increase the risk of biliary stricture. End-to-end choledochocholedochostomy seems to be safe, although no definitive recommendation can be given due to lack of information. Minimizing cold ischemia time, as in any setting, is of paramount importance but could be reduced to a minimum by performing both procedures in the same center and not removing the graft from the first recipient until the second patient is ready to undergo implantation; this is feasible during early reuse in centers like ours where all OLTs are centralized. Because increased difficulties may be encountered, mostly for delayed reuse, these procedures should only be performed in high-volume centers.

Along with aiding decision-making processes, our report offers a general view on the requirements and conditions for this particular type of graft and could help guide medical teams faced with unusual circumstances where a liver recipient unexpectedly dies after transplant in a manner that permits organ donation. Reuse of the liver graft should not be the only organ considered; other organs could also be procured if appropriate. The local ethical committee should be ideally called before accepting the reused liver, and this report may help those committees to understand the feasibility of this rare form of graft.

Conclusions

Our results show that there is adequate experience available demonstrating that the functional outcomes of reused grafts are similar to those with conventional donors; in the absence of other contraindications, reuse of not only a transplanted liver but also other organs should be considered for recipients waiting for transplant. Because this is an infrequent condition, it would be difficult to generally recommend this technique, although it should be considered on a case-by-case basis to expand the donor pool.


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Volume : 19
Issue : 9
Pages : 887 - 893
DOI : 10.6002/ect.2021.0079


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From St Vincent’s University Hospital, Dublin, Ireland
Acknowledgements: We acknowledge all members of the Liver Transplant Team, the Coordinating Teams, and the ICU Team and give a special thank you to the donors and their families for making liver transplantation possible at our center. The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest
Author contributions: MAB designed and performed the research and participated in the writing of the paper; LF and SN participated in the writing of the paper; AS performed research and participated in revising the paper critically as well as in final approval; DM contributed to final approval.
Corresponding author: Mar Achalandabaso Boira, St Vincent’s University Hospital, Dublin, Ireland
Phone: +34 689263375
E-mail: m.achalandabasoboira@gmail.com