Auxiliary Partial Liver Transplantation Research Articles

Successful combined auxiliary partial liver and intestinal transplantation in two highly sensitized, cross-match positive patients.

Sensitization to human leukocyte antigen (HLA) creates an immunological barrier to intestinal transplantation (ITx). Current desensitization therapies are limited and ineffective in the most highly sensitized patients. A co-transplanted whole liver transplant can protect a kidney, heart, or intestinal allograft from antibody-mediated injury. Whether an auxiliary partial liver allograft provides effective protection for highly sensitized intestinal transplant recipients is unknown. Two patients with strong HLA donor-specific antibody at high titer against their deceased donors underwent combined auxiliary partial liver and ITx across a positive cross-match. The left lateral lobes from the combined-graft recipients and the right liver lobes from the deceased donors were transplanted as a domino procedure to other four patients. Two combined-graft recipients have had an uneventful postoperative course without major complications at a 12- and 24-month follow-up, respectively. Intestinal graft function has been excellent with no evidence of humoral or cellular rejection. While a positive cross-match turned negative, titers of donor-specific HLA antibodies gradually declined over time after transplant. The left liver lobes procured from the combined-graft recipients were successfully transplanted into two pediatric patients (age 1.9, 2.4years) and the right lobes from two deceased donors were successfully transplanted into two adult patients. All transplant procedures went well, without post-operative complications related to the splitting technique. Our results indicate that an auxiliary liver transplant can effectively protect a co-transplanted intestinal allograft against rejection and suggest that this combined procedure may serve as a useful therapeutic adjunct for a highly sensitized intestinal transplant candidate.

Auxiliary liver transplantation for acute liver failure

Contents 1. What is auxiliary LT (ALT)? 2. When does ALT need? 3. What are issues of ALT for acute liver failure (ALF)? 4. Who can be a good candidate for ALT? 5. How to carve out a niche of technical challenges 6. How to manage Post-ALT patients 7. A SNUH case: A video clip 8. Reappraisal of ALT for ALF for Expanding Organ Utility. An APOLT (auxiliary partial orthtopic liver transplantation) for ALF has a benefit of immunosuppressant discontinuation in 60%-100% without compromising patients' survival outcome. This can also provide to expand the donor pool in some aspect. However, it's technically challenging as well as graft function and native liver regeneration is usually unpredictable. Thus, selection of good candidates (young, biopsy guided, hemodyenamically stable) and delicate surgical modification are important to lead a successful APOLT for ALF. In addition, this should be supported by careful postoperative monitoring and slow/steady immunosuppressant withdrawal after confirmation of native liver function restoration.

Regeneration and Cell Recruitment in an Improved Heterotopic Auxiliary Partial Liver Transplantation Model in the Rat

Auxiliary partial liver transplantation (APLT) in humans is a therapeutic modality used especially to treat liver failure in children or congenital metabolic disease. Animal models of APLT have helped to explore therapeutic options. Though many groups have suggested improvements, standardizing the surgical procedure has been challenging. Additionally, the question of whether graft livers are reconstituted by recipient-derived cells after transplantation has been controversial. The aim of this study was to improve experimental APLT in rats and to assess cell recruitment in the liver grafts. To inhibit recipient liver regeneration and to promote graft regeneration, we treated recipients with retrorsine and added arterial anastomosis. Using green fluorescence protein transgenic rats as recipients, we examined liver resident cell recruitment within graft livers by immunofluorescence costaining. In the improved APLT model, we achieved well-regenerated grafts that could maintain regeneration for at least 4 weeks. Regarding the cell recruitment, there was no evidence of recipient-derived hepatocyte, cholangiocyte, or hepatic stellate cell recruitment into the graft. Macrophages/monocytes, however, were consistently recruited into the graft and increased over time, which might be related to inflammatory responses. Very few endothelial cells showed colocalization of markers. We have successfully established an improved rat APLT model with arterial anastomosis as a standard technique. Using this model, we have characterized cell recruitment into the regenerating grafts.

Surgical Model of Auxiliary Partial Liver Transplantation in the Rat

Surgical Model of Auxiliary Partial Liver Transplantation in the Rat

A new rat model of auxiliary partial heterotopic liver transplantation with liver dual arterial blood supply.

Auxiliary partial heterotopic liver transplantation (APHLT) with portal vein arterialization is a valuable procedure to be considered in the treatment of patients with acute liver failure and metabolic liver diseases. The aim of this study was to develop a new rat model of APHLT with liver dual arterial blood supply (LDABS). A total of 20 rats were used. The donor liver was resected, and the celiac trunk was reserved. Left and medial hepatic lobes accounting for 70% of the liver mass were removed en bloc and the suprahepatic caval vein was ligated simultaneously. Thus, 30% of the donor liver was obtained as the graft. Sleeve anastomosis of the graft portal vein and splenic artery were performed after narrowing the portal vein lumen through suturing. The right kidney of the recipient was removed, and sleeve anastomosis was performed between the celiac trunk of the graft and the right renal artery of the recipient. In addition, end-to-end anastomosis was performed between the infrahepatic caval vein of the graft and the right renal vein of the recipient. Following the reperfusion of the graft, the blood flow of the arterialized portal vein was controlled within the physiological range through suturing and narrowing under monitoring with an ultrasonic flowmeter. The bile duct of the graft was implanted into the duodenum of the recipient through an internal stent catheter. A 70% section of the native liver (left and medial hepatic lobes) was resected using bloodless hepatectomy. The mean operative duration was 154.5±16.4 min, and the warm and cold ischemia times of the graft were 8.1±1.1 min and 64.5±6.6 min, respectively. The blood flow of the arterialized portal vein to the graft was 1.8±0.3 ml/min/g liver weight. The success rate of model establishment (waking with post-surgical survival of >24 h) was 70% (7/10). Following successful model establishment, all rats survived 7 days post-surgery (100%; 7/7). The graft was found to be soft in texture and bright red in color following exploratory laparotomy. In conclusion, a new rat model of APHLT with LDABS without stent for vascular reconstruction was developed. This is a feasible and reliable rat model for liver transplantation study.

Native Portal Vein Embolization for Persistent Hyperoxaluria Following Kidney and Auxiliary Partial Liver Transplantation

Type 1 primary hyperoxaluria (PH1) causes renal failure, for which isolated kidney transplantation (KT) is usually unsuccessful treatment due to early oxalate stone recurrence. Although hepatectomy and liver transplantation (LT) corrects PH1 enzymatic defect, simultaneous auxiliary partial liver transplantation (APLT) and KT have been suggested as an alternative approach. APLT advantages include preservation of the donor pool and retention of native liver function in the event of liver graft loss. However, APLT relative mass may be inadequate to correct the defect. We here report the first case of native portal vein embolization (PVE) to increase APLT to native liver mass ratio (APLT/NLM-R). Following initial combined APLT-KT, both allografts functioned well, but oxalate plasma levels did not normalize. We postulated the inadequate APLT/NLM-R could be corrected by trans-hepatic native PVE. The resulting increased APLT/NLM-R decreased serum oxalate to normal levels within 1 month following PVE. We conclude that persistently elevated oxalate levels after combined APLT-KT for PH1 treatment, results from inadequate relative functional capacity. This can be reversed by partial native PVE to decrease portal flow to the native liver. This approach might be applicable to other scenarios where partial grafts have been transplanted to replace native liver function.

A New Pig Model of Auxiliary Partial Liver Transplantation Based on Anastomosis with Intrahepatic Inferior Vena Cava of Recipient

A New Pig Model of Auxiliary Partial Liver Transplantation Based on Anastomosis with Intrahepatic Inferior Vena Cava of Recipient Auxiliary partial orthotopic liver transplantation (APOLT) is a feasible approach to treat patients with fulminant hepatic failure and metabolic liver diseases. It is still necessary to establish a simple and reliable APOLT model using large animals for deep research.Ten healthy male or female domestic pigs, weighing 20- 35 kg, were randomly selected to be either donor group (n=8) or recipient group (n=8). The right liver of donor was used as a graft. After the left lobe of recipient was resected, the anterior wall of the distal intrahepatic inferior vena cava was properly dissected. Endto- side anastomosis was performed between graft suprahepatic inferior vena cava and host distal intrahepatic inferior vena cava. End-to-side anastomosis was performed between the donor and recipient portal veins. After the spleen of recipient was resected, end-to-end anastomosis was made between graft hepatic artery and host splenic artery, and a cannula was inserted into host splenicvein for postoperative portal phlebography. The common bile duct of donor was intubated for external drainage.

A New procedure for temporary auxiliary partial liver transplantation using living donor graft for patients with familial amyloid polyneuropathy

To introduce duct-to-duct biliary anastomosis to conventional temporary auxiliary partial orthotopic liver transplantation (APOLT) using living donor graft for patients with familial amyloid polyneuropathy, we modified the conventional APOLT procedure in a manner characterized by the use of the recipient's common hepatic duct for biliary reconstruction and the preservation of the right posterior section alone for the certain placement of a tube into the corresponding biliary tree for external biliary drainage (modified APOLT). This procedure was performed in 3 patients without biliary complications. No complications associated with the external drainage tube occurred. Here we report the techniques and results for this new procedure.

Cryopreserved iliac artery allograft for primary arterial revascularization in adult liver transplantation

Arterial allograft represents a material of choice for primary arterial revascularization in liver transplantation (LT) when interposition of a vascular conduit is required. In case of non-availability of such graft, the use of cryopreserved vessels should be an interesting option. Three patients were grafted using a cryopreserved iliac artery allograft (CIAA) previously harvested and stored at -140°C in a tissue bank. An auxiliary partial LT was performed in one patient for acute liver failure. During follow-up, an efficient regeneration of the native hemi-liver was observed while atrophy of the auxiliary graft occurred, leading to functional portal vein and hepatic artery thrombosis at six and nine months, respectively. Two other patients presented with celiac trunk compression because of arcuate ligament without available arterial allograft in the donor. Late arterial thrombosis occurred at six months in one patient without impairment of graft function. The last patient was alive and symptom free 29 months after LT with a patent cryopreserved arterial conduit. Our preliminary results suggest that CIAA might represent an efficient solution as vessel interposition for primary arterial hepatic revascularization in LT setting when no other suitable graft is available. However, long-term patency of CIAA remains questionable.

Barriers to the successful treatment of liver disease by hepatocyte transplantation

Management of patients with hepatic failure and liver-based metabolic disorders is complex and expensive. Hepatic failure results in impaired coagulation, altered consciousness and cerebral function, a heightened risk of multiple organ system failure, and sepsis [1]. Such manifold problems are only treatable today and for the foreseeable future by transplantation. In fact, whole or auxiliary partial liver transplantation is often the only available treatment option for severe, even if transient, hepatic failure.

Feasibility of Auxiliary Partial Living Donor Liver Transplantation for Fulminant Hepatic Failure as an Aid for Small-for-Size Graft: Single Center Experience

Auxiliary partial orthotopic liver transplantation (APOLT) or heterotopic auxiliary partial liver transplantation (HAPLT) was initially indicated for potentially reversible fulminant hepatic failure (FHF). We started auxiliary partial living donor liver transplantation (LDLT) for FHF in February 2002. Since then, 5 FHF patients (3 females and 2 males) underwent auxiliary partial LDLT: 3 cases of APOLT and 2 cases of HAPLT. All of them received a small-for-size graft: graft-to-recipient weight ratio (GRWR) ≤ 1.0%. The etiologies of FHF were hepatitis B virus (HBV) in 1, Wilson's disease in 1, and unknown origin in 3 cases. Three were the acute type and 2 the subacute type of FHF. Median age was 45 years (range, 14–54 years). Blood type was identical in all cases. A left lobe graft was used in 4 instances and a right lobe graft in 1 case. Median GRWR was 0.74 (range, 0.42–0.85). Median follow-up was 42 months (range, 3 days to 70 months). Three of 5 patients (60%) were alive (at 42, 67, and 70 months) and 1 was free of immunosuppression after sufficient recovery of the native liver. Two cases succumbed: 1 at postoperative day 3 because of cytomegalovirus pneumonia and 1 at 10 months after APOLT because of sepsis. Complications were seen in all 5 patients: Relaparotomy for hemostasis in 3, decompression surgery of the abdominal cavity in 1, rehepaticojejunostomy in 1, and biliary strictures in 2 cases. Auxiliary partial LDLT may be a choice as an aid for a small-for-size graft in FHF.

Liver as an ideal target for gene therapy: expression of CTLA4Ig by retroviral gene transfer.

Liver has been a target organ for gene therapy as it plays a central role in metabolism and production of serum proteins. Many metabolic disorders result from a deficiency of liver-derived protein products. In transplantation settings, modulation of the immune responses caused by CTLA4Ig protein has been shown to be an attractive direction. In this study, we investigated the efficacy of hepatocyte transduction via introduction of the exogenous CTLA4Ig gene to the rat liver graft by retrovirus vector, and examined the presence of target serum protein after gene transfers. We constructed a replication defective retroviral vector that contained the CTLA4Ig gene. The liver graft regeneration index was first examined by 5-bromo-2-deoxyuridine, Ki-67 and proliferating cell nuclear antigen antibodies to determine the optimal time of gene transduction. The liver graft was then perfused with the retroviral vector, and animals were killed at constant time points to examine for the presence of CTLA4 protein in the graft and peripheral blood. CTLA4 protein was detected on postoperative days 5, 9 and 14, with liver graft tissue transduction indexes of 7.2, 10.9 and 1.8, respectively. Blood protein levels were at 151.6, 26.5 and 21.4 rhog/mL, respectively. A transduction index reaching 22.1 was observed in the graft with the most rapid liver regeneration. We had established the gene delivery model in rat with auxiliary partial liver transplantation. Expression of the exogenous gene delivered by retrovirus was demonstrated in the liver with secretion of diffusible protein in the bloodstream. The present study provides important information for gene transfer using the liver to produce the target protein in situ and as serum protein. This will also be applicable to the treatment of other metabolic diseases.

Auxiliary partial liver grafting in rats: effect of host hepatectomy on graft regeneration, and review of literature on surgical technique.

Auxiliary partial liver transplantation (APLT) is beneficial for fulminant liver failure when there is potential for recovery of the diseased liver. However, the impact of host hepatectomy on regeneration of the grafted liver is unclear. In this study, we modified a previous rat model of auxiliary whole liver transplantation without portal vein reconstruction, and studied the effect of host hepatectomy on regeneration of the cut liver graft. Thirty percent of the liver was heterotopically transplanted, to connect the recipient's left renal artery and vein with the graft's aortic cuff of the hepatic artery and inferior vena cava, respectively, using a cuff technique; 30% of the recipient liver then was cut. The control group was left intact. The liver grafts were weighed preoperatively and 2 weeks postoperatively. This procedure prevented congestion of the graft liver and achieved a high success rate, even when performed by a surgeon who was relatively inexperienced with the technique. The weight of the grafted liver in the host hepatectomized group significantly increased (P < 0.05) compared with that of the control group. We developed an experimental model of APLT and reviewed the literature on rat heterotopic liver transplantation, and compared the surgical techniques.

Current Status of Liver Transplantation

Liver transplantation is widely accepted as an effective therapeutic modality for a variety of irreversible acute and chronic liver diseases for which no satisfactory therapy is available. Following the first unsuccessful efforts at human liver transplantation in 1963, development of the procedure evolved at first slowly and steadily for 20 years and then rapidly over the past two decades. The growth of liver transplantation was facilitated by the conclusion of the national institutes of health consensus development conference in 1983 that liver transplantation is not an experimental procedure but an effective therapy that deserves broader application. The number of liver transplantations increased 2.4-fold(from 1.713 to 4.058) from 1988 to 1996. but the number of patients on the UNOS(united network of organ sharing) liver list increased 12.1-fold(from 616 to 7,467); as would be expected, the number of deaths of listed patients increased 4.9-fold(from 195 to 954), The current supply of donor livers is insufficient to meet this need, and organ donation has been stagnant or increased by only a few percent in recent years. These facts underscore the importance of the appropriate selection of candidates for liver transplantation and the development of operative procedures, such as living donor liver transplant, split liver transplant and auxiliary partial liver transplant.

Comparison of the intraoperative transfusion requirements and arterial blood gases in hetero-versus orthotopic liver transplantation

SINCE its introduction in 1963, orthotopic liver transplantation (OLT) has become the ultimate therapy for all patients with end-stage or intractable liver disease. Although OLT is well established, the operative trauma is prohibitive in many patients with end-stage liver cirrhosis because of the severe changes in intraoperative homodynamics, especially during the anhepatic phase. In heterotopic liver transplantation (HLT), or auxiliary partial liver transplantation, the diseased native liver is left in situ, and the graft is transplanted to a position that differs from the normal anatomic position. This technique has several theoretical advantages over OLT; total hepatectomy is avoided and the recipient has the chance to benefit from the residual functional capacity of the diseased native liver. Because total hepatectomy is not carried out in HLT, it is conceivable that intraoperative transfusion requirements may be less. Also, due to the above mentioned reasons, acid-base disturbances may be less frequent and less severe. We carried out this retrospective study to investigate these possibilities.

Directing portal flow is essential for graft survival in auxiliary partial heterotopic liver transplantation in the dog

Background/Purpose: Auxiliary liver transplantation is an attractive alternative for orthotopic liver transplantation in patients with certain inborn errors of metabolism of the liver in which complete resection of the liver is unnecessary or even contraindicated. Because in these diseases portal hypertension is mostly absent, finding a balance in portal blood distribution between native liver and graft is complicated. The objective of this study was to investigate requirements for long-term (180 days) graft survival in auxiliary partial heterotopic liver transplantation (APHLT) in a dog model. Methods: A metabolic defect was corrected in 26 dalmation dogs with a 60% beagle heterotopic auxiliary liver graft. Four groups of different portal inflow were studied. In the ligation group the portal vein to the host liver was ligated. In the split-flow group graft and host liver received separate portal inflow. In the banding group the distribution of the portal flow was regulated with an adjustable strapband and in the free-flow group the portal blood was allowed to flow randomly to host or graft liver. Results: Metabolic correction increased in all groups after transplantation from 0.19 ± 0.02 to 0.70 ± 0.05 ( P < .0001) but remained significantly better in the ligation and split-flow groups (graft survival, 135 ± 27 and 144 ± 31 days). In the banding group metabolic correction decreased significantly after 70 days, and although the grafts kept some function for 155 ± 14 days, in 4 of 6 dogs portal thrombosis was found. In the free-flow group, competition for the portal blood led to reduced correction within 12 days and total loss of function in 96 ± 14 days. Graft function also was assessed with technetium (Tc) 99m dimethyl-iminodiacetic acid uptake. A good linear association between HIDA uptake and metabolic correction was observed (r = 0.74; P < .0005). Grafts that contributed more than 15% to the total uptake of HIDA showed biochemical correction. This indicates a critical graft mass of about 15% to 20% of the hepatocyte volume to correct this metabolic defect. Conclusion: Auxiliary partial heterotopic liver transplantation can be a valuable alternative treatment for inborn errors of hepatic metabolism if the native liver and the graft receive separate portal blood inflow.

Immunosuppression in auxiliary partial liver transplantation with FK506 in rats

Immunosuppression in auxiliary partial liver transplantation with FK506 in rats

In situ gene transfer into rat auxiliary liver transplant.

A replication-defective retrovirus BAG vector was tested for in situ delivery of the beta-galactosidase gene to auxiliary liver transplant in a rat model. The BAG vector, which was shown to be effective in genetic transduction of cultured NIH/3T3 cells, was produced in a psi2 packaging cell and later amplified in a selected PA317 clone. Hepatocyte replication was induced by one-third hepatectomy of the donor liver, and the procedure was followed by auxiliary partial liver transplantation. Twenty-four hours after hepatic induction or transplantation, viral supernatant at 37 degrees C was perfused into the liver graft via the portal vein during a temporary occlusion of the graft portal vein. All animals survived the transplantation procedures and were killed at specified time intervals. Histochemical staining of the liver graft specimens indicated the expression of beta-galactosidase in the gene transferred group but not in the control animals. As demonstrated by polymerase chain reaction assay, the proviral beta-galactosidase sequence was present in the graft specimens, but absent from all other tissues tested. In short, the retrovirus BAG vector can be useful for in situ delivery of foreign genes to liver graft in transplantation and other clinical settings, providing a simple, consistent, and reliable alternative in hepatic gene therapy experiments.

Auxiliary liver transplantation: A negative viewpoint

Auxiliary heterotopic liver transplantation is theoretically attractive because it leaves the recipient's liver in place. The surgical trauma of hepatectomy is avoided, and failure of the graft does not necessarily lead to the death of the patient or a second, emergency transplantation. Another advantage is that matching the body sizes of the donor and the recipient is not mandatory, which increases the number of possible donors. However, previous clinical results of auxiliary liver transplantation have been poor. We performed auxiliary partial liver transplantation in six consecutive patients with end-stage chronic liver disease who were not accepted for orthotopic liver transplantation because they had massive ascites, deficient clotting function, cachexia, or poor pulmonary reserve. The donor liver was transplanted to the right subhepatic region after removal of segments II and III, and it was provided with portal and arterial blood. There were no major changes in hemodynamic measurements during surgery. The mean hospital stay after transplantation was 22.7 days (range, 14 to 29). After a mean follow-up period of 14 months (range, 5 to 23), all patients were alive, with good graft function as demonstrated by scintigraphy, Doppler ultrasonography, and synthesis of clotting factors. From these observations we conclude that auxiliary partial liver transplantation is an attractive alternative to orthotopic liver transplantation in high-risk patients. Its role in other patients who need liver transplants remains to be defined.

Infections after auxiliary partial liver transplantation. Experiences in the first ten patients

In ten auxiliary partial liver transplant recipients selective bowel decontamination (SBD) was used to reduce infections due to gram-negative microorganisms and fungi. During SBD no gram-negative infections occurred. Candida peritonitis was observed in one patient. After discontinuation of SBD serious infections of gram-negative origin did occur and three fungal infections were seen. SBD seems to have a favourable effect in reducing infections by gram-negative microorganisms and fungi. Most striking was the number of enterococcal infections that occurred. Five out of ten patients developed enterococcal infections which in two cases contributed to a fatal outcome. These infections occurred after increase of the number of enterococci in faeces and concomitant positive cultures of bile, ascites or wound drains. This increase could be due to the use of SBD. Also, the kind of biliary anastomosis may play an important role in the relatively high incidence of enterococcal infections. In the postoperative period, recurrence of hepatitis B infection in the liver graft was observed in all patients with cirrhosis due to this virus. Problems caused by other viral infections or protozoal infections remained limited in these ten patients.