Domino liver transplantation: risks and benefits

Domino liver transplantation, wherein a patient who himself undergoes liver transplantation in turn donates his liver to another recipient, has been performed since the mid-1990 s. Although livers from a handful of metabolic disorders cured by liver transplantation have been used for domino transplantation, familial amyloidotic polyneuropathy (FAP) livers are by far the most common source. FAP is an inherited disorder never presenting its clinical manifestation before the age of 15. In many carriers, the genetic disorder never manifests during lifetime. Thus, only a proportion of patients with FAP develop disease symptoms, which has been the rationale for using such livers for other patients on the waiting list for liver transplantation. According to the Familial Amyloidotic Polyneuropathy World Transplant Registry (FAPWTR), only 2 out of more than 500 patients so far have developed symptoms after domino liver transplantation using an FAP liver. Domino recipients with nonmalignant indications for liver transplantation show excellent long-term survivals. With careful selection of recipients, the procedure helps to reduce the organ shortage and the time on the waiting list for patients with malignant disorders.     

Whole-Liver Graft Without the Retrohepatic Inferior Vena Cava for Sequential (Domino) Living Donor Liver Transplantation

Grafts used in Domino liver transplantation (LT) obtained from living donor liver transplantation (LDLT) for familial amyloid polyneuropathy (FAP) patients have been mainly used as reduced grafts. Because of small-for-size problems seen in LDLT, using whole liver grafts could improve post-LT outcome. Eight consecutive Domino LDLT using whole livers without retrohepatic inferior vena cava (IVC) from FAP patients were retrospectively analyzed. The graft weight/recipient's body weight ratio (GWRW) in the domino recipients ranged from 1.28% to 2.4% (mean: 1.52). Multiple vascular reconstructions in the whole-liver domino LT resulted in longer than usual warm ischemia time (mean: 64 min); however immediate post-operative recovery of hepatic function was uneventful. At 8-40 months after the transplant, all the FAP patients are well and all of the domino recipients are alive. Domino LT using a whole FAP liver from a LDLT for a FAP patient presents satisfactory results, even though the transplant procedure is technically complicated.     

Domino liver transplantation

Orthotopic liver transplantation is today an established treatment for end stage liver diseases. However, the ongoing shortage of suitable livers together with progressively longer waiting lists prevents many patients from being transplanted, and many patients die while being on the waiting list. Using livers from living donors is one way to increase the supply of liver grafts. Another group of potential living liver donors are some selected liver recipients, whose native explanted liver in turn can be considered for transplantation into another patient. This unorthodox procedure have been named domino liver transplantation (DLT). The domino approach can be considered in patients with some genetic or biochemical disorders that today are treated by liver transplantation. The underlying rationale is that such livers ultimately cause severe systemic disease but are otherwise normal. In this review we present the current world status of DLT as well as updated results from the Domino Liver World Transplant Register (DLTR) and our own experience at the Karolinska University Hospital Huddinge with the DLT procedure.     

Domino liver transplantation: how far can we push the paradigm?

Domino liver transplantation (DLT) has emerged as a strategy for increasing the number of liver grafts available: morphologically normal livers from donors with metabolic diseases can be used for select recipients with hepatocellular carcinoma (usually outside the Milan criteria). Familial amyloidotic polyneuropathy (FAP) is the most common indication for DLT. When FAP patients are involved in DLT, the indications and outcomes are clear and good, although de novo FAP development within various periods of time has been described in DLT recipients of FAP livers. With the increasing need for organs, livers explanted from patients with rare metabolic diseases, such as primary hyperoxaluria (PH), acute intermittent porphyria (AIP), maple syrup urine disease (MSUD), and homozygous familial hypercholesterolemia (HFHC), are being used for DLT. However, insufficient data about the use of livers from patients with these rare metabolic diseases are available. In this review, we focus on the latter disorders. PH is not a good indication for DLT because recipients of PH livers develop hyperoxaluria and early acute renal failure. AIP also seems to be a debatable indication for DLT because of the rapid development of neurotoxicity in AIP liver recipients. However, the outcomes of DLT with HFHC and MSUD liver grafts (which include the risk of the de novo development of these genetic diseases) are promising. For rare metabolic liver diseases to be established as indications for DLT, more reports and studies are needed.     

Domino liver transplantation in living donors

Domino liver transplantation (DLT) has been developed as a method to expand the donor pool. In living donors DLT, the prime concern is to avoid any disadvantage to the donor and the first recipient. Seven DLTs were performed among 211 patients who underwent living donor liver transplantation. The domino recipients included six with hepatocellular carcinoma and one with citrullinemia. The domino grafts were obtained from patients with familial amyloid polyneuropathy (FAP) including the left liver in three cases and the right liver in four. Among the seven domino recipients, a 64-year-old woman with advanced hepatocellular carcinoma died of lung metastasis. The other six domino recipients are alive without FAP symptoms. In living donor liver transplantation, because the vessels of the graft from the first donor are not long enough for anastomosis, the hepatic vessels must be left as long as possible when removing the liver from the FAP patients in order to ensure sufficient safety for vascular reconstruction. With careful decision making during the procedure, such as where to divide the vessels in the FAP patients, DLT may help address the shortage of liver grafts.     

Transthyretin-derived amyloid deposition on the gastric mucosa in domino recipients of familial amyloid polyneuropathy liver.

Familial amyloid polyneuropathy (FAP) is a form of hereditary generalized amyloidosis. Liver tissue explanted from FAP patients has normal structure and function, except for the production of amyloidogenic variant transthyretin (TTR), and domino liver transplantation (DLT) using grafts from FAP patients was first performed in 1995. FAP symptoms usually develop in genetically determined individuals after the age of 20, but it is difficult to estimate when FAP symptoms will appear in domino recipients. Concerning this problem, histological findings showing amyloid deposition have recently been obtained in a few domino recipients of FAP livers. This study investigated the presence of de novo amyloid deposition in the gastroduodenal mucosa of domino recipients transplanted at our institution. Biopsy of gastroduodenal mucosa was carried out in 5 recipients of FAP livers and TTR-derived amyloid deposits were detected in 2 patients, both of whom had undergone DLT 47 months previously. In FAP liver recipients, de novo systemic amyloid deposition may begin much sooner than previously supposed. Therefore, careful follow-up of domino recipients of FAP livers is required.     

Domino liver transplantation: indications, techniques, and outcomes

The long-term shortage of livers available for transplantation has spurred the development of many strategies to bolster the donor organ supply. One particularly innovative strategy is domino liver transplantation in which a select group of liver transplant recipients can donate their explanted native livers for use as liver grafts in other patients. Several hereditary metabolic diseases (such as familial amyloid polyneuropathy, maple syrup urine disease, and familial hypercholesterolemia) are caused by aberrant or deficient protein production in the liver, and these conditions can be cured with an orthotopic liver transplant. Although their native livers eventually caused severe systemic disease in these patients, these livers are otherwise structurally and functionally normal, and they have been used successfully in domino liver transplants for the past 15 years. This article will review the indications for donating or receiving a domino liver transplant, the surgical techniques necessary to perform these transplants, as well as the recently revealed long-term outcomes and risks of domino transplantation.     

Operative Risks of Domino Liver Transplantation for the Familial Amyloid Polyneuropathy Liver Donor and Recipient: A Double Analysis

Although domino liver transplantation (LT) is an established procedure, data about the operative risks are limited. This study aimed at evaluating the operative risks of domino LT. Two retrospective analyses were conducted (comparison of familial amyloid polyneuropathy [FAP] liver donors [61 patients] vs. FAP nondonors [39 patients] and FAP liver recipients [61 patients] vs. deceased donor liver recipients [61 patients]). First analysis showed a 60‐day mortality of 6.6% for FAP donors and 7.7% for FAP nondonors (p = 1.0). No patient developed primary graft nonfunction. Acute rejection was higher in FAP nondonors compared to FAP donors (38.5% vs. 13.1%). Both groups had similar vascular and biliary complication rates. ICU stay was similar, whereas total hospitalization was longer for FAP nondonors. Both groups had similar 1‐ and 5‐year patient and graft survival rates (83.4% vs. 87.2%, and 79.8% vs. 71.8%, p = 0.7) and (83.3% vs. 87.2%, and 79.1% vs.71.8%, p = 0.7). The second analysis showed a 1.6% mortality for FAP liver recipients vs. 3.2% of the control group (p = 1). Both groups had similar morbidity and technical complication rates (18.0% vs. 13.1%, p = 0.45) and (0.18 vs. 0.15, p = 0.65). The domino procedure does not add any risk to FAP donor or recipient. It increases the organ pool allowing transplantation of marginal recipients who otherwise are denied deceased donor liver transplantation.     

Sequential (domino) transplantation of the liver in a transthyretin-50 familial amyloid polyneuropathy

Background: General shortage of cadaveric organs has led to a search for alternative methods to expand the donor pool. Sequential (domino) transplantation is yet another attempt to compensate for the declining consent to organ donation. Patients and methods: To qualify for a domino liver transplantation, the following preconditions must be fulfilled: (1) extrahepatic disease must exist, (2) liver must be fully functional, and (3) the genetic defect in the host should recur within a sufficient latency period. Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease which involves a genetic defect for transthyretin (TTR), which is predominantly produced in the liver. Results: In this report, we describe a rare case of a FAP TTR-50 variant undergoing domino liver transplantation. Since myocardial symptoms precede peripheral polyneuropathy, special emphasis should be placed on arrhythmias and the restrictive cardiomyopathy necessitating a veno-venous bypass or a cardiac pacemaker in order to improve cardiac contractility. The type of anastomosis of the suprahepatic inferior vena cava and possible alternatives are discussed. Conclusion: Despite ethical problems, the advantages of the domino procedure are obvious: (1) expansion of the donor pool, (2) ability to use living donors, and (3) presence of very short ischemic time and thus excellent liver function. Due to the kinetics of TTR production and deposition, donors and recipients of FAP livers should be followed up using an extensive neurological and cardiological protocol. Received: 15 June 1999 Accepted: 12 November 1999     

Domino and split liver transplantation: technical problems

Because the shortage of donor livers has been the rate-limiting factor in the expansion of liver transplantation, several innovative techniques including reduced, split, and living donor liver transplantation have been developed to expand the relatively constant pool of organs. Domino liver transplantation, which was first reported from Portugal in 1995, has been performed worldwide and allows a donor organ to be used for a subsequent graft in a second liver recipient. Domino liver transplantation involves specific ethical and technical problems. The most important ethical problem in the procedure is the use of a diseased liver (e.g., familial amyloid polyneuropathy [FAP]) for a second recipient. Furthermore, the safety of the first recipient (FAP patient) should be the primary consideration. From the technical point of view, the management of short vascular cuffs is important, especially in domino liver transplantation from a living donor. The results of split liver transplantation have significantly improved and it is now recognized as an ideal method to expand the donor pool, especially for small children. Either the ex vivo or in vivo technique can be used with comparable results.     

Domino hepatic transplantation using the liver from a patient with primary hyperoxaluria

BACKGROUND: We report a case of domino liver transplantation using the liver harvested from a patient who underwent a combined liver and kidney transplantation for primary hyperoxaluria (PH). METHOD: A cadaveric liver transplantation was performed in a 19-year-old man with PH. In a second step, the PH liver harvested from the first patient was transplanted in a 69-year-old man with hepatitis C-related cirrhosis, not a candidate for a classic liver graft owing to multifocal hepatocellular carcinoma. RESULTS: At 8 months after transplantation, the domino recipient has normal hepatic function and no signs of tumoral recurrence, but he progressively developed hyperoxalemia, hyperoxaluria, and renal insufficiency. CONCLUSION: Regarding the favorable postoperative clinical evolution, domino liver transplantations using livers from PH patients may represent a new opportunity for marginal candidates for liver transplantation. However, the progressive renal insufficiency expected in such domino recipients should limit this procedure to selected cases.     

Low incidence and severity of transplant-associated coronary artery disease in heart transplants from live donors.

BACKGROUND: Hearts transplanted from patients undergoing heart-lung transplantation (domino hearts) are unique because they have not been subjected to the deleterious effects of brain-stem death. This study examines the incidence and severity of transplant-associated coronary artery disease in recipients of domino hearts. METHODS: We retrospectively reviewed angiographic and clinical data from 97 patients who survived more than 1 year after domino heart transplantation at our hospital. Duration of follow-up ranged from 1 to 11 years after transplantation. The diagnosis of coronary artery disease was based on angiographic criteria. RESULTS: At 1 year, freedom from angiographic coronary artery disease was 99% (70% confidence interval [CI], 97-100), at 5 years it was 83% (70% CI, 78-89), and at 10 years it was 77% (70% CI, 70-84). Donor age, cystic fibrosis in the donor, organ ischemia time during transplantation, and acute rejection after transplantation did not influence risk for the disease. We found an increased incidence of coronary disease in hearts from male donors compared with those from female donors: freedom from disease at 5 years was 72% (70% CI, 63-81) in men vs 93% (87-99) in women. Thirteen patients experienced coronary artery disease at a median of 3 years after transplantation; 4 patients died but most patients remained asymptomatic with angiographically mild disease at their last follow-up examination. CONCLUSIONS: We found decreased incidence and severity of transplant-associated coronary artery disease in recipients of domino hearts compared with that reported in recipients of cadaveric hearts. This data supports the continued practice of domino heart transplantation and also supports the hypothesis that brain death may contribute to the development of transplant coronary artery disease in recipients of hearts transplanted from cadaveric organ donors.     

Extended criteria for organ acceptance. Strategies for achieving organ safety and for increasing organ pool

The terms extended donor or expanded donor mean changes in donor acceptability criteria. In almost all cases, the negative connotations of these terms cannot be justified. Factors considered to affect donor or organ acceptability have changed with time, after showing that they did not negatively affect graft or patient survival per se or when the adequate measures had been adopted. There is no age limit to be an organ donor. Kidney and liver transplantation from donors older than 65 years can have excellent graft and patient actuarial survival and graft function. Using these donors can be from an epidemiological point of view the most important factor to esablish the final number of cadaveric liver and kidney transplantations. Organs with broad structural parenchyma lesion with preserved functional reserve and organs with reversible functional impairment can be safely transplanted. Bacterial and fungal donor infection with the adequate antibiotic treatment of donor and/or recipient prevents infection in the latter. The organs, including the liver, from donors with infection by the hepatitis B and C viruses can be safely transplanted to recipients with infection by the same viruses, respectively. Poisoned donors and non-heart-beating donors, grafts from transplant recipients, reuse of grafts, domino transplant and splitting of one liver for two recipients can be an important and safe source of organs for transplantation.     

Outcomes of Domino Liver Transplantation: A Single Institution's Experience

Aims

Domino liver transplantation (DLT) is a strategy to increase the donor pool. Explanted liver from patients with familial amyloidotic polyneuropathy (FAP) are often used as domino grafts, because the liver is normal apart from the production of the mutated transthyretin variant. We present the outcomes for both donors and recipients of DLT.

Materials and Methods

Retrospective analysis of initial DLT for 16 consecutive adult patients performed between July 2004 and July 2009. All cases of FAP donor to grafts were removed preserving the cava vein with reconstruction of the hepatic veins, except the first and seventh cases, where in we removed the retrohepatic vena cava with the liver without venovenous bypass. The postoperative follow-up period for surviving DLT recipients at the end of September 2009 was 2-62 months (mean, 26).

Results

Two patients out of 8 FAP donors died due to pulmonary thromboembolism on the 31st postransplant day, or sepsis at 35 days namely, an overall survival of 75%. One patient out of 8 recipients died namely, an early portal thrombosis on the 22nd postransplant day) with a crude survival of 87.5% in the recipient group (P = no significant [NS]). Four grafts from 8 FAP donors were lost—2 deaths and 2 retransplants due to thrombotic events on the first and second postransplant day—with a crude survival of 50%. Two of 8 recipients lost their grafts: 1 death and 1 retransplantation for an acute Budd-Chiari syndrome on the first postransplant day with a crude survival of 75% in the recipient group (P = not significant [NS]).

Conclusion

We believe that the FAP liver graft is an excellent option for selected patients. Special care must be taken with thrombotic events.     

Use of "O" blood group liver donors for nonidentical recipients: does this represent a double penalty for "O" blood group candidates?

Candidates for liver transplantation with AB blood group remain on the waiting list for shorter times than candidates with O blood group. To investigate the reasons of this phenomenon, we analyzed data concerning deceased donors, liver transplant candidates, and liver first transplants performed in the United States during the period 2003 to 2004. The percentage of deceased donors with blood group O was higher than that of candidates on the waiting list with the identical blood group (P < .05). On the other hand, for blood groups A, B, and AB an opposite situation was observed: the percentages of deceased donors were significantly lower compared to those candidates with the identical blood group (A blood group, P < .05; B and AB blood groups, P < .001). When the number of grafts from deceased donors was compared with the number of those effectively transplanted, a negative difference for O blood group recipients was found (ie, transplanted livers < harvested livers) and a positive one for AB blood group (transplanted livers > harvested livers) were found. Since disease progression and causes of acute liver failure, including primary nonfunction and hepatic artery thrombosis leading to retransplantation were similar among the various blood groups, we concluded that the shorter waiting time for AB patients in the pre-MELD era was due to the use of compatible livers to the detriment of group O recipients.     

Liver transplantation with monosegments.

BACKGROUND: Shortage of size-matched pediatric donors led to the development of surgical techniques to reduce or split livers and thus increase the potential pool of donors. Despite this, neonatal transplantation remains a problem because of the small size of the recipients. Further reduction of the left lateral segment is possible to provide a single segment graft (segment III). We report our experience of transplanting 6 babies using this technique. METHODS: Of 310 children transplanted in our center between October 1989 and March 1998, 6 patients, 2 male and 4 female, median age 37.5 days (range 5 to 92 days), median weight 3.45 kg (range 2.45 to 5.46 kg) were transplanted with a monosegment. The cause of liver failure was neonatal hemochromatosis in 4, retransplantation for hepatic artery thrombosis in 1, and hepatitis B in one. The donor liver was reduced or split to a left lateral segment. Segment II was then resected and discarded before transplantation. RESULTS: Overall, graft and patient survival is 83.3%. Five patients are alive with good graft function at a mean follow-up of 30.4 months (range 8 to 82 months). One child who was transplanted for hepatic artery thrombosis died from sepsis and multiorgan failure 48 hrs after transplant. None of the survivors had vascular or biliary complications. CONCLUSIONS: Monosegment liver transplantation with segment III appears to be a satisfactory option for treating small babies with liver failure.     

Present status and prospects of living-related liver transplantation

Living-related liver transplantation (LRLT) is a relatively new surgical modality that has developed, in part, to overcome the shortage of available cadaveric livers for transplantation and as a method to provide liver graft implants from living donors for patients end-stage with liver disease in areas where the use of cadaveric livers is not yet practiced or permitted. Since 1988 almost 500 LRLTs have been performed globally. The safety of donors who provide a portion of their liver for grafting is of utmost concern, and only one donor death from this procedure has been reported in the literature. Postoperative survival in recipients depends on their pretransplant physical status, but emergency patients in rapid need of a liver have a poorer survival than elective LRLT patients for whom survival is about 80%. Children and infants are the main recipients of LRLTs, but adult patients particularly in Japan, are increasing in number, and present indications for LRLT surgery include not only cholestatic end-stage liver diseases but also metabolic disorders affecting the liver and emergency LRLTs for fulminant hepatic failure. Many ethical problems relating to the concept of liver transplantation, donor liver source, recipient selection, and reimplantation have yet to be resolved. But we believe that LRLTs and cadaveric liver transplantations are saving lives and that the practice should be continued.     

Logistics and technique for procurement of intestinal, pancreatic, and hepatic grafts from the same donor

OBJECTIVE: To assess a technique for simultaneous recovery of the intestine, pancreas, and liver from the same donor. SUMMARY BACKGROUND DATA: With the more frequent use of pancreatic and intestinal transplantation, a procurement procedure is needed that permits retrieval of both organs as well as the liver from the same cadaveric donor for transplantation to different recipients. It is believed by many procurement officers and surgeons, however, that this objective is not technically feasible. METHODS: A technique for simultaneous recovery of the intestine, pancreas, and liver was used in 13 multiorgan cadaver donors during a 26-month period, with transplantation of the organs to 33 recipients. The intestine was removed from 11 donors separately and in continuity with the pancreas in the other 2. Six additional pancreases were excised and transplanted separately. Thirteen livers were retrieved, one of which was discarded because of steatorrhea. Ten of the remaining 12 livers were transplanted intact; the other 2 were split in situ and used as reduced-size hepatic allografts in four recipients. RESULTS: None of the 11 intestinal, 6 pancreatic, 2 intestinal-pancreatic, or 14 whole or partial liver allografts sustained serious ischemic injury or were lost as a result of technical complications. One liver recipient died 25 months after surgery of recurrent C virus hepatitis. The other 32 recipients had adequate allograft function with a mean follow-up of 8 months. CONCLUSION: It was possible using the described technique to retrieve intestine, pancreas, and liver allografts safely from the same donor and to transplant these organs to different recipients.     

Liver transplantation from old donors into HCV and non-HCV recipients

BACKGROUND: Chronic liver failure due to HCV-related cirrhosis is the leading indication for liver transplantation in Western countries. Inferior long-term results have been reported for liver transplantation in HCV patients, especially when marginal donor livers are utilized. The aim of this study was to retrospectively analyze the outcome of liver transplantation from elderly donors in HCV versus non-HCV recipients. METHODS: One hundred seventy-nine patients receiving 204 liver transplantations were divided into four groups according to HCV positivity and donor age (> or <65 years). Long-term survivals were calculated by the Kaplan-Meier method. RESULTS: Grafts from donors of >65 years into HCV-positive patients displayed lower patient and graft survival rates than HCV-negative cases, although macrosteatosis was more frequent (55% vs 9%, P =.02) among organs used for non-HCV cases. Moreover, HCV-positive recipients transplanted with a donor aged >65 years had significantly lower patient and graft survival (40% vs 78% [P =.01] and 40% vs 68% [P =.06], respectively) than patients receiving a liver from a younger donor. CONCLUSIONS: Our retrospective analysis, although hampered by a small number of patients transplanted with an old liver, suggest that the results of liver transplantation with a donor graft >65 years of age into an HCV-positive recipient shows a worse outcome than those from younger donors. Older livers should be reserved for non-HCV cases.     

Amplification of engrafted hepatocytes by preparative manipulation of the host liver

Scarcity of donor livers is a major obstacle to the general application of hepatocytes for the development of bioartificial liver assist devices as well as intracorporeal engraftment of hepatocytes for the treatment of inherited metabolic diseases. The number of hepatocytes that can be transplanted into the liver safely in a single sitting also limits the utility of this procedure. These limitations could be addressed by providing preferential proliferative advantage to the transplanted cells. Studies using transgenic mouse recipients or donors have indicated that massive repopulation of the host liver by engrafted hepatocytes requires that the transplanted cells are subjected to a proliferative stimulus to which the host hepatocytes cannot respond. Prevention of host hepatocyte proliferation has been achieved by treatment with a plant alkaloid, retrorsine. Because retrorsine is carcinogenic, we have evaluated preparative irradiation for this purpose. The proliferative stimulus may consist of the loss of hepatic mass (e.g., partial hepatectomy, reperfusion injury or induction of Fas-mediated apoptosis by gene transfer) or administration of stimulants of hepatocellular mitosis (e.g., growth factors or thyroid hormone). Potential applications of these preparative manipulations of the host liver include the treatment of inherited metabolic disorders by transplantation of allogeneic hepatocytes, hepatocyte-mediated ex vivo gene therapy, rescuing liver cancer patients from radiation-induced liver damage, and expansion of human hepatocytes in animal livers.