Full-size Liver Transplantation Research Articles

Outcome of Extended Right Lobe Liver Transplantations.

Split-liver transplantation offers a solution to the organ shortage problem. However, the outcomes of extended right lobe liver transplantation (ERLT) and whether it is a suitable alternative to full-size liver transplantation (FSLT) remain controversial. We compared the outcomes of ERLT and FSLT in adult recipients of 43,409 first deceased donor liver transplantations using Cox regression. We also analyzed 612 ERLT and 1224 FSLT 1:2 matched cases to identify factors that affect ERLT outcome. The risk of graft loss was significantly higher following ERLT than following FSLT during the first posttransplantation year in the matched and unmatched collective (hazard ratio [HR], 1.39 and 1.27 and P=0.01 and 0.006, respectively). Every additional hour of cold ischemia time (CIT) increased the risk of 1-year graft loss by 10% in the ERLT group compared with only 3% in the FSLT group (P=0.003 and <0.001, respectively). Importantly, the outcome of ERLT and FSLT did not differ significantly if the CIT was below 10hours (HR, 0.71; P=0.22). One-year graft and patient survival were lower in high-risk ERLT recipients with a Model for End-Stage Liver Disease (MELD) score of ≥20 (HR, 1.88; P=0.03 and HR, 2.03; P=0.02). In the male recipient-male donor combination, ERLT recipients had a higher risk of 1-year graft loss than FSLT recipients (HR, 2.44; P=0.006). This was probably because of the significantly higher MELD score in ERLT recipients (P=0.004). ERLT in adults is an adequate alternative to FSLT and offers an elegant solution to the problem of organ shortage as long as the cold storage is less than 10hours and the recipient's MELD score is <20.

Long-term follow-up after endovascular treatment of hepatic venous outflow obstruction following liver transplantation.

Hepatic venous outflow obstruction (HVOO) is a rare complication after liver transplantation (LT) associated with significant morbidity and reduced graft survival. Endovascular intervention has become the first-line treatment for HVOO, but data on long-term outcomes are lacking. We have analysed outcomes after endovascular intervention for HVOO in 905 consecutive patients who received 965 full-size LT at our unit from January 2007 to June 2014. There were 27 (3%) patients who underwent hepatic venogram for suspected HVOO, with persistent ascites being the most common symptom triggering the investigation (n = 19, 70%). Of those, only 10 patients demonstrated either stricture or pressure gradient over 10 mmHg on venogram, which represents a 1% incidence of HVOO. The endovascular interventions were balloon dilatation (n = 3), hepatic vein stenting (n = 4) and stenting with dilatation (n = 3). Two patients required restenting due to stent migration. The symptoms of HVOO completely resolved in all but one patient, with a median follow-up period of 74 (interquartile range 39-89) months. There were no procedure-related complications or mortality. In conclusion, the incidence of HVOO in patients receiving full-size LT is currently very low. Endovascular intervention is an effective and safe procedure providing symptom relief with long-lasting primary patency.

Incidence of heparin-induced thrombocytopenia type II and postoperative recovery of platelet count in liver graft recipients: a retrospective cohort analysis

BackgroundThrombocytopenia in patients with end-stage liver disease is a common disorder caused mainly by portal hypertension, low levels of thrombopoetin, and endotoxemia. The impact of immune-mediated heparin-induced thrombocytopenia type II (HIT type II) as a cause of thrombocytopenia after liver transplantation is not yet understood, with few literature citations reporting contradictory results. The aim of our study was to demonstrate the perioperative course of thrombocytopenia after liver transplantation and determine the occurrence of clinical HIT type II. MethodWe retrospectively evaluated the medical records of 205 consecutive adult patients who underwent full-size liver transplantation between January 2006 and December 2010 due to end-stage or malignant liver disease. Preoperative platelet count, postoperative course of platelets, and clinical signs of HIT type II were analyzed. ResultsA total of 155 (75.6%) of 205 patients had thrombocytopenia before transplantation, significantly influenced by Model of End-Stage Liver Disease score and liver cirrhosis. The platelet count exceeded 100,000/μL in most of the patients (n = 193) at a medium of 7 d. Regarding HIT II, there were four (1.95%) patients with a background of HIT type II. ConclusionsThe incidence of HIT in patients with end-stage hepatic failure is, with about 1.95%, rare. For further reduction of HIT type II, the use of intravenous heparin should be avoided and the prophylactic anticoagulation should be performed with low-molecular-weight heparin after normalization of platelet count.

Post liver transplantation acute kidney injury in a rat model of syngeneic orthotopic liver transplantation

Acute kidney injury (AKI) is a frequent complication after liver transplantation (LT). The mechanism of post-LT AKI remains unclear. We used the rat model of syngeneic orthotopic LT (SOLT) to investigate the mechanism of post-LT AKI. We hypothesized that the condition of the graft, rather than intraoperative hemodynamic instability, has an important role in post-LT AKI in the SOLT model. Rats were randomly assigned into four groups: sham-operated group; vessel-clamped group; full-size LT group; and reduced-size LT group. We identified AKI in both full-size and reduced-size LT groups. In addition to renal tubular necrosis and apoptosis, renal peritubular capillary injury was also present. Pathological changes were more severe in the reduced-size than in the full-size LT group. We found that the systemic inflammatory response induced by LT was the initiating factor in post-LT AKI. This is the first study to investigate the pathological mechanism of AKI in an animal model of SOLT. Our results demonstrate that protection of the liver graft and inhibition of the systemic inflammatory response are vital in reducing the risk of post-LT AKI.

Prolonged Cold Ischemia Does Not Trigger Lethal Rejection or Accelerate the Acute Rejection in Two Allogeneic Rat Liver Transplantation Models

Prolonged cold ischemia (CI) might induce lethal liver graft rejection and/or accelerate the course of lethal rejection in BN-Lew and ACI-Lew liver transplantation (LT) models, which have been successfully challenged by liver-size reduction. Survival rate of recipients and body weight development after subjecting the grafts to prolonged CI in saline were assessed. Severity of rejection was assessed based on histology and the size of portal infiltration. Hepatic expression of CD25, CD28, CD38, granzyme B, and perforin were assessed to further judge the severity of allogeneic immune response. An enhancement of allogeneic immune response after prolonged CI was observed, indicated by up-regulated mRNA expression of CD25, CD28, CD38, granzyme B, and perforin. However, the enhancement of allogeneic immune response did not reverse the BN-Lew spontaneous liver graft acceptance to lethal rejection. Eight-hour CI led to 100% 4 wk survival rate and graft acceptance and did not impair postoperative body weight recovery. Nine-hour CI caused the death of 2/6 rats due to primary non-function (PNF) of the graft within 48 h. Ten-hour CI caused lethal PNF in all rats within 96 h. Histology of surviving recipients revealed an expansion of the portal tract due to an inflammatory infiltrate. In rats dying from PNF, extended centrilobular necrosis was observed, but no sign of rejection. In the ACI-Lew full-size LT model, 8 h CI did not accelerate the course of lethal rejection. Prolonged CI was associated with an discrete enhancement of allogeneic immune response, but did not trigger lethal rejection in BN-LEW spontaneousliver graft acceptance model and did not accelerate acute rejection in ACI-Lew rejection model.

Oral Tacrolimus Bioavailability Is Increased After Right Split Liver Transplantation

Objective Tacrolimus (Tac) is mainly metabolized in the liver. The aim of this trial was to analyze Tac bioavailability after partial liver transplantation. Patients and Methods A total of 33 patients after right split liver grafting (n = 8 living related, LRLT; n = 8 cadaver split, CS) or full-size liver transplantation (n = 17, FS) were included in this trial. All of them received Tac perorally with an initial dose of 2 × 5 mg/d. Dose adjustment was performed according to the Tac trough level (T0) with an initial target T0 levels of 12 to 15 ng/mL. Results The time to reach target T0 levels tended to be lower ( P = .05) in the split liver groups (LRLT: 2.8 ± 1.6 days; CS: 2.1 ± 0.9 days; FS: 4.5 ± 3.2 days). In addition, mean Tac dose to maintain the target T0 level was significantly decreased ( P = .01) in the split liver cohorts (LRLT: 5.8 ± 1.1 mg/d; CS: 5.5 ± 2.5 mg/d; FS: 9.8 ± 3.9 mg/d). Only graft weight/standard liver volume ratio ( r = .566, P = .02) and graft weight/body weight ratio ( r = .709, P = .002) showed significant correlations with Tac maintenance doses in the split liver group. Conclusions Peroral Tac bioavailability was significantly higher after partial liver transplantation using the right hepatic lobe compared with full-size transplants. The volume of the split liver graft highly correlated with Tac maintenance therapy and should be used to calculate the most appropriate initial posttransplantation Tac dose.

Partial liver transplantation-living donor liver transplantation and split liver transplantation

In the last two decades, liver transplantation (LTx) has become the treatment of choice for several liver diseases including hepatocellular carcinoma in selected cases. Improvements in surgical and anesthesiological procedures have increased patient survival after LTx, resulting in excellent 1-year survival rates. The rate-limiting factor to further increase the number of LTx is the extreme shortage of suitable organs with the consequence that pediatric and adult patients are dying on the waiting list. At present, mortality reported for pediatric and adult patients on the waiting list is 10 to 20%. Living-donor liver transplantation and split liver transplantation are measurements to reduce the severe lack of cadaveric grafts by expanding the donor pool. Major centers around the world now routinely perform partial LTx in infants and adults with survival success equivalent to that after full-size liver transplantation.

Cadaveric full-size liver transplantation and the graft alternatives in adults: A comparative study from a single centre

This study aims to compare the results of living donor (LDLT), cadaveric split (SLT) and domino (DO) liver transplantation which are currently available alternatives to the conventional cadaveric full-size liver transplantation (CAD). Immunologic, vascular and biliary complications (BC) were evaluated in 38 LDLT, 20 SLT, 17 DO and 38 CAD recipients. The incidence of acute rejection (AR) was similar between groups, and between blood-related and blood-unrelated patients. AR was more severe in the SLT group according to the Banff scores (P=0.03, P<0.001, P<0.001). The evolution of AR was similar between the groups, in terms of development of chronic rejection. No venous complications occurred in the overall population. The rate of arterial thrombosis (10.5, 10, 0 and 3%, respectively) was statistically similar between groups. The rate of BC (26, 40, 12, and 8%, respectively) was higher in the partial grafts than in the whole grafts (P=0.006), but was not significantly different within each group. There was an association between the severity of preservation injury and occurrence of AR (P=0.01) and arterial thrombosis (P=0.016), but not BC. One- and 2-year graft and patient survival rates were similar between groups. None of the graft types seemed to confer immunological advantage. BC remained problematic in the partial grafts, independently from ischemia time.

Initial hepatic microcirculation correlates with early graft function in human orthotopic liver transplantation

Microcirculatory disturbances are an initial causative determinant in hepatic ischemia/reperfusion injury. The aim of this study was to assess sinusoidal perfusion during human liver transplantation using orthogonal polarization spectral imaging and to evaluate the significance of intraoperative microcirculation for early postoperative graft function. Hepatic microcirculation was measured in 27 recipients undergoing full-size liver transplantation and compared to a group of 32 healthy living-related liver donors. The microvascular parameters were correlated with postoperative aspartate aminotransferase and bilirubin levels. Hepatic perfusion following liver transplantation was found to be significantly decreased when compared with the control group. Volumetric blood flow within the individual sinusoids increased due to sinusoidal dilatation and enhanced flow velocity. Regression analysis of postoperative aspartate aminotransferase and bilirubin with microvascular parameters revealed significant correlations. The extent of volumetric blood flow increased within the first 30 minutes after reperfusion and showed a significant correlation with postoperative aspartate aminotransferase release and bilirubin elimination. In conclusion, postischemic hepatic microvascular perfusion was analyzed in vivo, demonstrating significant microvascular impairment during liver transplantation. Sinusoidal hyperperfusion appears to confer protection against postischemic liver injury, as given by the correlation with aspartate aminotransferase and bilirubin levels. Thus, these findings may have therapeutic importance with respect to mechanisms mediating postischemic reactive hyperemia.

Endothelin-A receptor antagonist reduces microcirculatory disturbances and transplant dysfunction after partial liver transplantation

Endothelin-1 can induce microcirculatory disorders by mediating sinusoidal vasoconstriction, lowering the perfusion rate and promoting leukocyte adhesion, all of which may play a role in the pathogenesis of the damage sustained by partial liver transplants. In this pilot study, we investigated a selective endothelin-A receptor antagonist (Darusentan; Knoll GmbH, Ludwigshafen, Germany) for its potential influence on the microcirculation in the setting of partial liver transplantation. One hundred and forty isogeneic Lewis rats were divided into four groups: 1. partial liver transplantation (30% of the initial liver volume); 2. partial liver transplantation treated with Darusentan (1 mg/kg bodyweight intravenously) immediately before reperfusion; 3. full-size liver transplantation; and 4. sham operation. Subsequently, the liver microcirculation was evaluated by intravital microscopy, and survival, liver function, and morphology were followed up to the fourteenth day. Compared with full-size transplanted animals, rats subjected to partial liver transplantation without Darusentan (group I) displayed severe microcirculatory lesions characterized by a significantly decreased perfusion rate, increased leukocyte velocity, and increased leukocyte adhesion. Disintegration of endothelium and increased recruitment of Kupffer cells were frequent morphologic findings. The Darusentan-treated group II showed improved parameters of microcirculatory function and morphology as well as improved liver function. Microcirculatory disturbances play a key role in the pathogenesis of partial liver transplant dysfunction. Treatment with selective endothelin-A receptor antagonists represent a new therapeutic approach to improve the function of partial liver transplants by reducing microcirculatory lesions and their sequelae affecting sinusoidal endothelium and hepatocytes. (Liver Transpl 2003;9:929-939.)

Analysis of survival and morbidity after pediatric liver transplantation with full-size and technical-variant grafts.

To alleviate the shortage of size-matched whole-donor organs, too-large-for-size cadaveric donor grafts are modified by liver resection techniques. These modifications result in technical-variant liver transplantation (TVLTx). Patient and graft survival rates after TVLTx are considered comparable to those after full-size liver transplantation (FSLTx). However, morbidity after TVLTx is often underexposed. The aim of this study was to analyze the results of FSLTx and TVLTx in terms of patient and graft survival rates and morbidity. A consecutive series of 97 primary and elective pediatric liver transplantations performed in a single center was retrospectively analyzed. Forty-seven children had a FSLTx and 50 a TVLTx (38 reduced-size liver grafts and 12 split-liver grafts). The overall median follow-up period was 3.5 years. There were no differences in patient and graft survival rates between FSLTx and TVLTx. However, after TVLTx there was a significantly higher complication rate (1.42 vs. 0.81 after FSLTx). TVLTx is more hampered by biliary complications (30% vs. 17%), expressed by a higher incidence of cholangitis and leakage of bile. These complications led to a significantly higher incidence of sepsis (44% vs. 19%) and a significantly higher intervention rate (0.40 vs. 1.28) after TVLTx. There was no difference in the incidence of retransplantations between FSLTx and TVLTx. Both FSLTx and TVLTx offer the same prognosis in terms of patient and graft survival rates for children after a primary and elective liver transplantation. However, TVLTx has a higher morbidity.

In vivo immune response to allogeneic (ALLO) hepatocytes (HC)

Endothelin-1 can induce microcirculatory disorders by mediating sinusoidal vasoconstriction, lowering the perfusion rate and promoting leukocyte adhesion, all of which may play a role in the pathogenesis of the damage sustained by partial liver transplants. In this pilot study, we investigated a selective endothelin-A receptor antagonist (Darusentan; Knoll GmbH, Ludwigshafen, Germany) for its potential influence on the microcirculation in the setting of partial liver transplantation. One hundred and forty isogeneic Lewis rats were divided into four groups: 1. partial liver transplantation (30% of the initial liver volume); 2. partial liver transplantation treated with Darusentan (1 mg/kg bodyweight intravenously) immediately before reperfusion; 3. full-size liver transplantation; and 4. sham operation. Subsequently, the liver microcirculation was evaluated by intravital microscopy, and survival, liver function, and morphology were followed up to the fourteenth day. Compared with full-size transplanted animals, rats subjected to partial liver transplantation without Darusentan (group I) displayed severe microcirculatory lesions characterized by a significantly decreased perfusion rate, increased leukocyte velocity, and increased leukocyte adhesion. Disintegration of endothelium and increased recruitment of Kupffer cells were frequent morphologic findings. The Darusentan-treated group II showed improved parameters of microcirculatory function and morphology as well as improved liver function. Microcirculatory disturbances play a key role in the pathogenesis of partial liver transplant dysfunction. Treatment with selective endothelin-A receptor antagonists represent a new therapeutic approach to improve the function of partial liver transplants by reducing microcirculatory lesions and their sequelae affecting sinusoidal endothelium and hepatocytes. (Liver Transpl 2003;9:929-939.)

The Impact of Liver Reductions in Pediatric Liver Transplantation

Reduced-size liver transplantation (RSLT) in children was introduced to alleviate a shortage of small-organ donors. The impact of RSLT on the waiting time for an organ and on morbidity and mortality was investigated. Between March 25, 1988, and August 11, 1990, 61 hepatic transplantations were performed in 55 children at the Pacific Transplant Institute in San Francisco, Calif. Full-size liver transplantation was performed in 41 cases and RSLT in 20 cases. The overall 30-month actuarial patient and graft survival rates were 89% and 73%, respectively. A comparison between full-size liver transplantation and RSLT showed no difference in patient and graft survival, reoperations, infections, or rejection. Benefits of RSLT were an increase in the donor pool size, a decrease in waiting time for a suitable donor, and a decrease in the rate of arterial thrombosis. The main morbidity of RSLT was an increase in perioperative blood requirement. We conclude that RSLT offers small children with end-stage liver disease a chance for long-term survival.