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# First and second author contributed equally to this work.
Mika S. Buijk
Footnotes
# First and second author contributed equally to this work.
Affiliations
Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, Netherlands
# First and second author contributed equally to this work.
Job B.L. van der Meer
Footnotes
# First and second author contributed equally to this work.
Affiliations
Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, Netherlands
Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, Netherlands
Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, Netherlands
Erasmus MC Transplant Institute, Department of Surgery, Division of HPB & Transplant Surgery, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, NetherlandsKing Faisal Specialist Hospital and Research Center, Organ Transplant Center of Excellence, Riyadh, 11211, Saudi Arabia
To this day, a discrepancy exists between donor liver demand and supply. Domino liver transplantation (DLT) can contribute to increasing the number of donor livers available for transplantation.
Methods
The design of this systematic review was based on the Preferred Reporting Items for Systematic Reviews (PRISMA). A qualitative analysis of included studies was performed. Primary outcomes were mortality and peri- and postoperative complications related to DLT.
Results
Twelve studies met the inclusion criteria. All included studies showed that DLT outcomes were comparable to outcomes of deceased donor liver transplantation (DDLT) in terms of mortality and complications. One-year patient survival rate ranged from 66.7% to 100%. Re-transplantation rate varied from 0 to 12.5%. Most frequent complications were related to biliary (3.7%–37.5%), hepatic artery (1.6%–9.1%), portal vein (12.5–33.3%) and hepatic vein events (1.6%), recurrence of domino donor disease (3.3%–17.4%) and graft rejection (16.7%–37.7%). The quality of the evidence was rated as moderate according to the Newcastle–Ottawa scale (NOS).
Conclusion
DLT outcomes were similar to DDLT in terms of mortality and complications. Even though DLT will not solve the entire problem of organ shortage, transplant programs should always consider using this tool to maximize the availability of liver grafts.
Abbreviations
Anti IL2RA
basiliximab
CIT
cold ischemia time
CNI
calcineurin inhibitor
CNS1
Crigler-Najjar syndrome
Cort
corticosteroids/steroids/glucocorticoid
CSA
cyclosporine A
DDLT
deceased donor liver transplantation
DLT
domino liver transplantation
ESLD
end stage liver disease
FAP
familial amyloid polyneuropathy
FK
Tacrolimus
GRWR
graft recipient weight ratio
HA
hepatic artery
HCC
hepatocellular carcinoma
ICU
intensive care unit
IQR
inter quartile range
LDLT
living donor liver transplantation
LT
liver transplantation
MMF
mycophenolate mofetil/purine inhibitor
MSUD
maple syrup urine disease
N/A
not available
OKT3
muromonab-CD3
OTCD
ornithine transcarbamylase deficiency
PV
Portal vein
SD
standard deviation
WIT
warm ischemia time
Introduction
Liver transplantation (LT) is the only cure for patients with End Stage Liver Disease (ESLD). The increasing number of indications for LT aggravates the common problem of organ shortage. Both the number of patients on the waiting list and the average waiting time have increased over the last years.
Eurotransplant reports a yearly wait list mortality of 19% with an average waiting time of 3 years. Moreover, 7% of these patients are delisted while waiting for a liver graft. The problem is that on one hand, patients have to reach higher MELD scores in order to get a liver allocated, while on the other hand, they pay for getting this chance with the closing window of being transplantable.
It might also lead to better outcomes as patients undergo surgery in better medical condition. Organ shortage is a contributing factor to a longer waiting time.
To diminish the discrepancy between organ demand and supply, more suitable liver grafts are needed. The latter is motivation to explore possibilities in increasing the donor pool. Established techniques are split liver transplantations and living donor liver transplantations (LDLT).
Domino liver transplantation (DLT) uses explanted livers from transplant recipients as graft for other patients. This re-use of explanted livers from transplant patients is possible in a limited number of diseases, which are an indication for LT. In these cases, development of the donor's disease in the domino recipient does not happen or takes longer than posttransplant life expectancy. Otherwise, the post LT graft function is normal. Typical examples are livers from metabolic disease patients re-used in elderly recipients with cancer as underlying indication for LT. Examples of the metabolic diseases forming an indication for domino liver transplantation are: Familial amyloid neuropathy, fibrinogen A2 chain amyloidosis, maple syrup urine disease, familial hypercholesterolemia, and neurogenic intestinal pseudo-obstruction. The domino donor can receive a liver from a deceased or a living donor.
For patients with a ESLD, who are mostly in a lower position on the waitlist, a domino liver transplantation can be considered.
Because of the lower chance of receiving a liver through the transplantation waitlist and the fact that these patients often have lower life expectancy, DLT can be a good option.
Safety is fundamental in order to re-use explanted livers of selected diseases. This systematic review assesses the peri- and postoperative outcomes of domino liver transplantation.
Methods
Search strategy
The criteria and guidelines as described in the Preferred Reporting Items for Systematic Reviews (PRISMA) were used for the design of this systematic review. Together with the help from a clinical librarian, we searched Embase, Medline, Web of Science, Cochrane and Google Scholar database. A search was conducted to identify studies on domino transplantation procedures. The search was performed on the on the 27th of October 2020. The exact search terms used are mentioned in the appendix.
Inclusion and exclusion criteria
All studies were firstly screened on title and abstract by two independent reviewers (MSB and JBLM). Studies describing cases of domino transplantation and patient characteristics (e.g., age, sex, comorbidities) and outcomes or complications (e.g., mortality, recurrence of disease) were included. Predefined exclusion criteria were non-English language and specific types of articles (e.g., editorials, letters to the editor, replies). Furthermore, studies not conducted in humans, reviews, and case reports were excluded. Regarding studies with overlapping patient populations, it was decided to include the study with the largest cohort. The reference lists of the included studies were examined to identify the studies that might have been missed during the search.
Disagreements or concerns regarding eligibility of different studies were resolved by consensus between both reviewers and, if necessary, consulted with a third party (RM and MUB).
Data extraction
The data extraction was performed independently by two reviewers. The extracted data from the included studies were patient characteristics: donor age, donor disease, recipient age, recipient sex and recipient disease. The extracted intraoperative characteristics were graft weight, graft-to-recipient weight ratio, second warm ischemia time, cold ischemia time, operative time, blood loss, blood transfusion and intraoperative complications. The second warm ischemia time was defined as the time between taking the liver out of the ice and reperfusion (anastomotic time). The extracted postoperative characteristics were postoperative complications, follow-up time, immunosuppressive regime, graft rejection, 1-year survival and 5-year survival.
Quality assessment
An adjusted version of the Newcastle–Ottawa Scale for observational studies (NOS)
was used to assess the quality of the included studies. The included articles were scored on seven different criteria, divided into three sections. Studies were graded based on selection of study groups, generalisability and ascertainment of exposure and outcomes. MSB and JBLM assessed the articles independently. A maximum of eight points could be obtained. Studies with more than seven points were considered of good quality. Studies with 4–6 points were considered as moderate quality and studies with less than 4 points were considered poor quality. MSB and JBLM assessed the studies independently.
Results
Study selection
A total number of 576 potentially relevant studies were identified. Fig. 1 presents the PRISMA flow diagram. Twelve studies met the inclusion criteria and were included in the eventual analysis. Of these, seven studies were retrospective cohort studies,
The baseline demographics of all included studies are given in Table 1. Table 2 shows the perioperative results of domino liver transplantation. Postoperative results are divided over two tables. Table 3 shows the survival rates and Table 4 shows the postoperative complications.
The studies included in this systematic review used living and deceased donor grafts for the transplantation of the domino donors (Table 1). Three studies included living donors (N = 147,
and reported the lowest mean and median CIT, these were 240 and 270 min respectively. One study reported a higher CIT range (481–764 min). This is likely due to the fact that the procedure of the domino graft recipient did not start until the domino liver graft was completely retrieved.
The follow-up time ranged from eight months to ten years. One-year patient survival rate ranged from 66.7% to 100%. Five studies reported a 5-year patient survival rate.
The survival rate and incidence of re-transplantation are shown in Table 3. Patients from cases in which the first donor was a living donor had 1-year patient survival rates between 77% and 100%.
Two studies reported complications with the hepatic artery. Both reported this in one patient, which lead to 1.6% and 9.1% hepatic artery complications.
Tincani et al. compared the survival of 61 FAP DLT's to 61 DDLT's as well. In this study, no difference in patient survival was found between the two groups (p = 1.0).
This systematic review shows that domino liver transplantation is a safe option for increasing the donor pool. Peri- and postoperative outcomes are comparable to DDLT. Domino liver transplantation is mainly an option for older patients with ESLD with anticipated long waiting time due to their lower MELD score.
Patients placed lower on the liver transplantation waiting list are often older patients and patients with extensive comorbidities. These patients can qualify for domino liver transplantation. Moreover, in older patients, it is highly unlikely for the recipient to develop the original domino donor's disease.
None of the DLT studies showed any disadvantage for the domino donor or domino recipient compared with conventional liver transplant procedures. Two studies compared the survival of DLT to DDLT and showed no statistical difference.
DLT, however rarely performed, is a valid method for increasing the donor pool and can consecutively help reduce the waitlist mortality. Grafts used for DLT come from donors with a metabolic disease originating in the liver. This implies that the liver is functionally good, except for one metabolic deficiency. When this liver is transplanted into a recipient who does not have this disease, the ‘healthy’ body will compensate for the disease and thus the patient will, in theory, not become ill.
In some cases, the recipient will develop the metabolic disease of the donor after a certain period of time. If this would be the case, it is important to take the life expectancy of the domino recipient into consideration. The life expectancy should not exceed the projected time for the recipient to develop the donors' disease. The authors are aware that previously published studies mention higher recurrence rates of the donors' disease in DLT recipients. However, these studies often have longer follow-up periods in which the disease recurrence occurs and identified. The included studies mentioning disease recurrence rates in this systematic review have follow-up times up to 46 months maximum, with the exception of Vollmar et al.
Domino liver transplantation has several advantages compared to DDLT. The domino liver is a living donor graft, consequently, the procedure has the advantages of living donation, which include a plannable procedure if possible, a shorter CIT and the possibility of transplanting patients before they become critically ill.
The latter is highly dependent on the number of grafts available for transplantation.
However, outcomes vary between different centers. Geyer et al. performed the most DLT's and was experienced in living donation. This study also had the lowest CIT and a one-year survival comparable to DDLT survival. They had a 5-year survival of 42.1%. However, these survival rates are based on patients still participating in the study. This would indicate that 42.1% of patients are still alive and taking part in the study, and the remaining 57.9% includes deceased patients as well as patients lost to follow up. Studies do indicate that the condition of the domino recipient before surgery should be taken into consideration when assessing outcomes, since many domino graft recipients have severe comorbidities such as HCC.
The study with the second most DLT's was relatively inexperienced with living donation (Marques et al.).
They had a long CIT and a lower patient survival than studies with experience in living donation. This systematic review showed slightly better survival in patients transplanted in transplantation centres where the first domino transplantation was with a living donor. These studies also had the lowest CIT. This is probably due to the fact that these centres have more experience in living liver donation and are familiar with working with multiple teams. These factors contribute to making CIT as short as possible. A prolonged CIT is correlated with biliary and hepatic artery complications, as well as with primary nonfunction of the liver and reduction of graft and patient survival.
reported that working with multiple teams would improve the outcomes because of logistical advantages. When multiple teams are working simultaneously, it reduces the CIT because the liver can be implanted almost directly, rather than having to wait for the first surgery to finish. However, Marques et al. reported that, for logistic reasons, the second LT was frequently performed immediately after the first LT.
While the overall impact of DLT on organ shortage will be limited, little is known on whether this resource is used sufficiently and efficiently. Further research is needed to assess whether the domino technique is being used to its full potential in patients needing a LT and what measures can be taken to optimize it.
Our study has several limitations. Only 11 studies, all observational, were included due to the highly specialized procedure that DLT is, which introduces a risk of bias for which it was not possible to correct. Furthermore, the included studies used both living and deceased donors as primary donor in the domino chain. In living donor liver transplantation, vascular complications occur more often because of the necessary reconstruction of the hepatic vein outflow. This makes the outcomes of living and deceased donor liver transplantation difficult to compare. Another risk of bias is that living donor liver transplant surgeons are more experienced surgeons, possibly performing better with lower complication rates. All studies included in this systematic review did not correct for case selection.
Conclusion
In conclusion, DLT is a safe procedure and provides similar outcomes compared with DDLT. The field of LT is significantly guided by the problem of organ shortage. The number of possible DLT procedures will remain a very low percentage of the overall LT numbers. Therefore, the usage of this option will not have a statistical effect on the waitlist mortality in a country or region. Nevertheless, every life which can be saved is worth saving; domino liver transplantation remains a beautiful option in the field of transplantation.
Funding sources
None.
Conflict of interest
None to declare.
Acknowledgements
The authors wish to thank Dr. W.M. Bramer from the Erasmus MC Medical Library for developing and updating the search strategies.
Appendix A. Supplementary data
The following are the Supplementary data to this article.
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