Pathophysiology and strategy for small-for-size graft syndrome after living-donor liver transplantation

Small-for-size (SFS) graft syndrome is an important problem after living-donor liver transplantation in adults. Hemodynamic change is thought to be the main cause of graft injury. Excessive portal flow is associated with hepatic sinusoidal injury, and reduction of portal flow improves postoperative liver function. Increased venous outflow due to hepatic venoplasty or reconstruction of the middle hepatic vein decrease the risk of graft congestion. However, the intragraft acute-phase response remains unclear. Recent studies have revealed that downregulation of heat shock protein (HSP) may account for SFS graft injury, and induction of HSP may prevent SFS syndrome. On the other hand, derangement in the regulation of liver regeneration is recognized as another important factor. Further investigation of the regulatory mechanisms of liver regeneration in SFS grafts may suggest a strategy for the prevention and treatment of SFS syndrome. Successful transplantation of marginal-size liver grafts would improve outcome for recipients and increase the margin of safety for living donors.     

Attenuation of acute phase shear stress by somatostatin improves small-for-size liver graft survival.

The major concern of living donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be developed. To investigate the protective effect of somatostatin related to hemodynamic stress on small-for-size liver graft injury, we applied a treatment regimen of low-dose somatostatin in a rat orthotopic liver transplantation model using small-for-size grafts (median, 38.7%; range, 35-42%). Somatostatin was given at 5 minutes before total hepatectomy and immediately after reperfusion in the recipient (20 microg/kg). Graft survival, portal hemodynamics, intragraft gene expression and hepatic ultrastructural changes were compared between the rats with or without somatostatin treatment. Seven-day graft survival rates in the somatostatin treatment group were significantly improved compared to the control group (66.7% vs. 16.7%, P = 0.036). In the treatment group, portal pressure and hepatic surface blood flow were significantly decreased within the first 30 minutes after reperfusion, whereas in the control group, transient portal hypertension and excessive hepatic blood flow were observed. Intragraft expression (both messenger RNA and protein) of endothelin-1 was significantly downregulated accompanied with upregulation of heme oxygenase-1 and A20. Better preservation of liver function was found in the treatment group. Hepatic ultrastructure, especially the integrity of sinusoids, was well protected in the treatment group. In conclusion, low-dose somatostatin rescues small-for-size grafts from acute phase injury in liver transplantation by attenuation of acute-phase shear stress that resulted from transient portal hypertension.     

Sinusoidal microcirculatory changes after small‐for‐size liver transplantation in rats

Small‐for‐size graft injury is characterized by portal venous hypertension and loss of intracellular homeostasis early after transplant. The long‐term alteration of sinusoidal microcirculatory hemodynamic state remains unknown. A syngeneic rat orthotopic liver transplantation model was developed using small‐for‐size grafts (35% of recipient liver weight) or whole grafts (100% of recipient liver weight). Graft survival, portal pressure, liver function, hepatocellular apoptosis as well as morphological changes (by light microscopy and electron microscopy) were assessed. Sinusoidal microcirculatory hemodynamics was examined by intravital fluorescence microscopy. Although portal hypertension lasted only for 1 h after performance of small‐for‐size liver transplantation, a sustained microcirculatory disturbance was accompanied by dramatic reduction of sinusoidal perfusion rate, elevation of sinusoidal diameter as well as increase in the number of apoptotic hepatocytes during the first 7 days. These resulted in lower survival rate (50% vs. 100%, P = 0.012), higher level of liver function, and more severe morphological changes, which could induce small‐for‐size syndrome. In conclusion, persistent microcirculatory hemodynamic derangement during the first 7 days after reperfusion as well as transient portal hypertension is significant manifestation after small‐for‐size liver transplantation. Long‐term microcirculation disturbance displayed as decrease of sinusoidal reperfusion area and increase of spread in functional liver mass seems to be the key factor for graft injuries.     

FK 409 ameliorates small-for-size liver graft injury by attenuation of portal hypertension and down-regulation of Egr-1 pathway

OBJECTIVE: To investigate whether low-dose nitric oxide donor FK 409 could attenuate small-for-size graft injury in liver transplantation using small-for-size grafts. SUMMARY BACKGROUND DATA: The major concern of live donor liver transplantation is small-for-size graft injury at the early phase after transplantation. Novel therapeutic strategies should be investigated. METHODS: We employed a rat orthotopic liver transplantation model using small-for-size (40%) graft. FK 409 was given at 30 minutes before graft harvesting (2 mg/kg) to the donor and immediately after reperfusion (1 mg/kg) to the recipient (FK group). Graft survival, intragraft genes expression, portal hemodynamics, and hepatic ultrastructural changes were compared between the 2 groups. RESULTS: Seven-day graft survival rates in the FK group were significantly improved compared with those of rats not receiving FK 409 (control group; 80% versus 28.6%, P = 0.018). In the FK group, portal pressure was significantly decreased within the first 60 minutes after reperfusion whereas in the control group, transient portal hypertension was observed. Intragraft expression (both mRNA and protein) of early growth response-1, endothelin-1, endothelin-1 receptor A, tumor necrosis factor-alpha, macrophage-inflammatory protein-2, and inducible nitric oxide synthase was significantly down-regulated accompanied with up-regulation of heme oxygenase-1, A20, interferon-gamma-inducible protein-10, and interleukin-10 during the first 24 hours after reperfusion. Hepatic ultrastructure, especially the integrity of sinusoids was well protected in the FK group. CONCLUSIONS: Low-dose FK 409 rescues small-for-size grafts in liver transplantation by attenuation of portal hypertension and amelioration of acute phase inflammatory response by down-regulation of Egr-1, together with prior induction of heat shock proteins.     

Current concept of small-for-size grafts in living donor liver transplantation

The extended application of living donor liver transplantation (LDLT) has revealed the problem of graft size mismatching called “small-for-size (SFS) graft syndrome.” The initial trials to resolve this problem involved increasing the procured graft size, from left to right, and even extension to include a right lobe graft. Clinical cases of living right lobe donations have been reported since then, drawing attention to the risks of increasing the liver volume procured from a living donor. However, not only other modes of increasing graft volume such as auxiliary or dual liver transplantation, but also control of the increased portal pressure caused by an SFS graft, such as a portosystemic shunt or splenectomy, have been trialed with some positive results. To establish an effective strategy for transplanting SFS grafts and preventing SFS graft syndrome, it is essential to have precise knowledge and tactics to evaluate graft quality and graft volume, when performing these LDLTs with portal pressure control. We reviewed the updated literature on the pathogenesis of and strategies for using SFS grafts.     

Distinct Mechanism of Small‐for‐Size Fatty Liver Graft Injury—Wnt4 Signaling Activates Hepatic Stellate Cells

In this study, we aimed to investigate the significance of hepatic stellate cells (HSCs) activation in small‐for‐size fatty liver graft injury and to explore the underlying molecular mechanism in a rat liver transplantation model. A rat orthotopic liver transplantation model using fatty grafts (40% of fatty changes) and cirrhotic recipients was applied. Intragraft gene expression profiles, ultrastructure features and HSCs activation were compared among the rats received different types of grafts (whole vs. small‐for‐size, normal vs. fatty). The distinct molecular signature of small‐for‐size fatty graft injury was identified by cDNA microarray screening and confirmed by RT‐PCR detection. In vitro functional studies were further conducted to investigate the direct effect of specific molecular signature on HSCs activation. HSCs activation was predominantly present in small‐for‐size fatty grafts during the first 2 weeks after transplantation, and was strongly correlated with progressive hepatic sinusoidal damage and significant upregulation of intragraft Wnt4 signaling pathway. In vitro suppression of Wnt4 expression could inhibit HSC activation directly. In conclusion, upregulation of Wnt4 signaling led to direct HSC activation and subsequently induced small‐for‐size fatty liver grafts injury. Discovery of this distinct mechanism may lay the foundation for prophylactic treatment for marginal graft injury in living donor liver transplantation.     

Graft injury in relation to graft size in right lobe live donor liver transplantation: a study of hepatic sinusoidal injury in correlation with portal hemodynamics and intragraft gene expression

OBJECTIVE: To investigate the degree and mechanism of hepatic sinusoidal injury in different graft sizes in right lobe live donor liver transplantation (LDLT). SUMMARY BACKGROUND DATA: Liver grafts from living donors are likely to be small-for-size for adult recipients. Graft injury after reperfusion is common, but the mechanism and degree of injury remain unclear. The hepatic sinusoidal injury in different graft sizes and its relationship with portal hemodynamics and intragraft gene response at the early phase after reperfusion have not been studied in right lobe LDLT. METHODS: From May 2000 to November 2001, 40 adults receiving right lobe LDLT had portal pressure measured continuously before and after reperfusion. Liver biopsies were taken before and after reperfusion for detection of vasoregulatory genes (endothelin-1 and endothelial nitric oxide synthase) and heat shock genes (heat shock protein 70 and heme oxygenase-1), and electron microscope examination. Blood samples from the portal vein and suprahepatic inferior vena cava were taken for the measurement of plasma nitric oxide level. RESULTS: The recipients were grouped according to the ratio of graft weight to estimated standard liver weight: group 1 (n = 10), less than 40%; group 2 (n = 21), 40% to 60%; and group 3 (n = 9), more than 60%. The portal pressures recorded after reperfusion in group 1 were significantly higher within 30 minutes of reperfusion than those in groups 2 and 3. After reperfusion, the intragraft endothelin-1 mRNA level in group 1 increased by 161% of the basal level but decreased by 31.5% and 62% of the basal level in groups 2 and 3, respectively. The intragraft mRNA level of heme oxygenase-1 in groups 1 and 2 decreased by 75.5% and 25.3% of the basal level respectively but increased by 41% of basal level in group 3. The intragraft protein level of heat shock protein 70 decreased by 50 ng/mL after reperfusion in group 1 but increased by 12.4 ng/mL and 0.6 ng/mL in groups 2 and 3, respectively. The portal vein plasma nitric oxide level decreased more significantly after reperfusion in group 1 than in group 2. Electron microscope examination of liver biopsies in group 1 showed tremendous mitochondrial swelling as well as irregular large gaps between the sinusoidal lining cells. There were two hospital deaths in group 1 and none in the other two groups. CONCLUSIONS: Patients implanted with grafts less than 40% of standard liver weight suffered from transient portal hypertension early after reperfusion. The phenomenon was accompanied by intragraft upregulation of endothelin-1 and ultrastructural evidence of sinusoidal damage. The transient portal hypertension after reperfusion, subsequent endothelin-1 overexpression, and plasma nitric oxide level reduction, together with downregulation of heme oxygenase-1 and heat shock protein 70, may account for the small-for-size graft injury.     

Successful super-small-for-size graft liver transplantation by decompression of portal hypertension via splenectomy and construction of a mesocaval shunt: a case report

We performed a successful super-small-for-size graft liver transplantation by decompressing portal hypertension via splenectomy and a mesocaval shunt. A 46-year-old woman with Child-Pugh class C liver cirrhosis associated with Wilson's disease underwent a living donor liver transplantation (LDLT). The donor had an anomalous portal vein, hepatic vein, and bile duct, so we had to use the right lateral segment for the graft. Preoperative computed tomographic (CT) volumetry showed the volume of this area to be 433 mL; graft-to-recipient weight ratio (GRWR) was 0.72; and graft-to-standard liver volume (GV/SLV) was 39.0%. However, the real volume of the resected right lateral segment was 281 g; GRWR was 0.47; and GV/SLV was 25.3%--a super-small-for-size graft. After implantation, congestion of the small graft was severe due to excessive portal hypertension. Therefore, we tried decompressing the portal vein. First, we performed splenectomy which reduced the portal pressure which remained excessive. Second, a mesocaval shunt was constructed decreasing the portal pressure from 38 to 30 cm H2O. Additionally, we initiated continuous portal injection of prostaglandin E1. The postoperative course was not smooth, but the general status slowly recovered. Over 25 cm H2O of portal hypertension was observed until postoperative day 21 when it improved. At last, the recipient was discharged on postoperative day 156. Accurate preoperative CT volumetry is important to obtain sufficient graft volume. Our case may be one of the smallest-for-size grafts that was successfully transplanted. Management of excessive portal hypertension is important for LDLT, especially using a small-for-size graft. Splenectomy and construction of a mesocaval shunt may be useful strategies to decompress the portal vein.     

Splenectomy improves survival by increasing arterial blood supply in a rat model of reduced‐size liver

Prevention of acute portal hyperperfusion in small‐for‐size livers by inflow modulation results in beneficial postoperative outcome. The objective of this study was to unravel the underlying mechanism, emphasizing the intimate relationship between portal venous (PV) and hepatic arterial (HA) blood flow (BF). Rats underwent partial hepatectomy (pHx), splenectomy before pHx or splenectomy and ligation of the A. hepatica before pHx. Portal venous blood flow (PVBF), hepatic arterial blood flow (HABF), and tissue pO₂ were assessed during stepwise resection from 30% to 90%. Hepatic regeneration and hypoxia‐responsive gene expression were analyzed in each group after nonlethal 85% pHx. 90% pHx caused a fourfold rise in PVBF, a slight decrease in HABF with a 50% reduction in pO₂, and high mortality. Splenectomy before pHx reduced the PVBF and caused a rise in HABF with doubling in tissue pO₂. An attenuation of hypoxia‐responsive gene expression turned into enhanced hepatocellular regeneration and improved survival. A. hepatica ligation abolished the beneficial effect of splenectomy on tissue oxygenation, proliferation, and outcome. In conclusion, the beneficial effect of splenectomy in small‐for‐size livers can be attributed to a rise in HABF with sufficient oxygen supply rather than to a reduced portal venous hyperperfusion to the remnant liver.     

Hemodynamic interaction between portal vein and hepatic artery flow in small-for-size split liver transplantation

In split-liver transplantation, the entire portal flow is redirected through relatively small-for-size grafts. It has been postulated that excessive portal blood flow leads to graft injury. In order to elucidate the mechanisms of this injury, we studied the hemodynamic interactions between portal vein- and hepatic artery flow in an experimental model in pigs. Six whole pig liver grafts were implanted in Group 1 ( n=6) and six whole liver grafts were split into right and left grafts and transplanted to Groups 2 ( n=6) and 3 ( n=6), respectively. The graft-to-recipient liver volume ratio was 1:1, 2:3 and 1:3 in Groups 1, 2 and 3, respectively. Portal vein- and hepatic artery flows were measured with an ultrasonic flow meter at 60,120 and 180 min after graft reperfusion. Portal vein pressure was also recorded at the same time intervals. Graft function was assessed at 3,6h and 12h, and morphological changes at 12h after reperfusion. Following reperfusion, portal vein flow showed an inverse relationship to graft size, while hepatic artery flow was reduced proportionately to graft size. The difference was significant among the three groups ( P<0.05). Portal vein pressure was significantly higher in group 3, compared to groups 1 and 2 ( P<0.05). Hepatic artery buffer response was significantly higher in Group 3, compared to Groups 1 and 2 in relation to pre-occlusion values ( P<0.05). Split-liver transplantation, when resulting in small-for-size grafts, is associated with portal hypertension, diminished arterial flow, and graft dysfunction. Arterial flow impairment appears to be related to increased portal vein flow.     

Rapamycin Attenuates Liver Graft Injury in Cirrhotic Recipient—The Significance of Down-Regulation of Rho-ROCK-VEGF Pathway

To investigate whether rapamycin could attenuate hepatic I/R injury in a cirrhotic rat liver transplantation model, we applied a rat orthotopic liver transplantation model using 100% or 50% of liver grafts and cirrhotic recipients. Rapamycin was given (0.2 mg/kg, i.v.) at 30 min before graft harvesting in the donor and 24 h before operation, 30 min before total hepatectomy and immediately after reperfusion in the recipient. Rapamycin significantly improved small-for-size graft survival from 8.3% (1/12) to 66.7% (8/12) (p = 0.027). It also increased 7-day survival rates of whole grafts (58.3%[7/12] vs. 83.3%[10/12], p = 0.371). Activation of hepatic stellate cells was mainly found in small-for-size grafts during the first 7 days after liver transplantation. Rapamycin suppressed expression of smooth muscle actin, which is a marker of hepatic stellate cell activation, especially in small-for-size grafts. Intragraft protein expression and mRNA levels of vascular endothelial growth factor (VEGF) were down-regulated by rapamycin at 48 h both in whole and small-for-size grafts. Consistently, mRNA levels and protein expression of Rho and ROCK I were decreased by rapamycin during the 48 h after liver transplantation. In conclusion, rapamycin attenuated graft injury in a cirrhotic rat liver transplantation model by suppression of hepatic stellate cell activation, related to down-regulation of Rho-ROCK-VEGF pathway.     

Impact of donor gender on male rat recipients of small-for-size liver grafts.

The aim of this study was to assess the impact of donor gender on small-for-size (SFS) liver transplantation in male recipients using a rat model. Adult female or male Lewis rats were used as donors and male Lewis rats as recipients. Size-matched (SM) and SFS liver grafts from either male or female donors were transplanted into male recipients. Animals receiving SFS grafts were sacrificed at postoperative week 1, week 4, and week 12, respectively (n = 6-8 per group), those receiving SM grafts after 3 months. The cumulative survival rate (SVR) in the female-to-male (F-M) SFS group was significantly lower (62%; 13 of 21) compared with the male-to-male (M-M) group (90%; 18 of 20) (P < 0.05). Spontaneous death occurred in the F-M SFS combination either in the early postoperative period (<3 weeks) in animals with confluent hepatic necrosis or in the late postoperative period (>8 weeks) in animals with biliary obstruction. In contrast, no death was observed in the early posttransplantation period after M-M liver transplantation. The relative graft size in the SM F-M group was significantly higher (graft-to-recipient weight ratio [GRWR] 2.40% +/- 0.8%) than in the SFS M-M group (GRWR 1.35% +/- 0.2%; P < 0.001). Regardless of graft size, the outcome was worse in terms of SVR as well as regarding the incidence and severity of biliary complications in F-M compared with M-M liver transplantation. In conclusion, male recipients of female livers had a less favorable outcome irrespective of graft size. Confluent hepatic necrosis as well as biliary obstruction were perceived as consequence of a severe perfusion problem in F-M liver transplantation, which was possibly related to an enhancement of ischemia-reperfusion (I/R) injury by the lack of estrogen in male recipients of female grafts.     

Small-for-size syndrome in living-donor liver transplantation using a left lobe graft

In living-donor liver transplantation with a left lobe graft, which can reduce the burden on the donor compared to right lobe graft, the main problem is small-for-size (SFS) syndrome. SFS syndrome is a multifactorial disease that includes aspects related to the graft size, graft quality, recipient factors and even technical issues. The main pathophysiology of SFS syndrome is the sinusoidal microcirculatory disturbance induced by shear stress, which is caused by excessive portal inflow into the smaller graft. The donor age, the presence of steatosis of the graft and a poor recipient status are all risk factors for SFS syndrome. To resolve SFS syndrome, portal inflow modulation, splenectomy, splenic artery modulation and outflow modulation have been developed. It is important to establish strict criteria for managing SFS syndrome. Using pharmacological interventions and/or therapeutic approaches that promote liver regeneration could increase the adequate outcomes in SFS liver transplantation. Left lobe liver transplantation could be adopted in Western countries to help resolve the organ shortage.     

Strategies for improving the outcomes of small-for-size grafts in adult-to-adult living-donor liver transplantation

Living-donor liver transplantation (LDLT) has been refined and accepted as a valuable treatment for patients with end-stage liver disease in order to overcome the shortage of organs and mortality on the waiting list. However, graft size problems, especially small-for-size (SFS) grafts, remain the greatest limiting factor for the expansion of LDLT, especially in adult-to-adult transplantation. Various attempts have been made to overcome the problems regarding SFS grafts, such as increasing the graft liver volume and/or controlling excessive portal inflow to a small graft, with considerable positive outcomes. Recent innovations in basic studies have also contributed to the treatment of SFS syndrome. Herein, we review the literature and assess our current knowledge of the pathogenesis and treatment strategies for the use of SFS grafts in adult-to-adult LDLT.     

Short‐term effects of extracorporeal graft rinse versus circulatory graft rinse in living donor liver transplantation. A prospective randomized controlled trial

Living donor liver transplantation has shorter cold ischemia time, less preservative volume, and lower metabolic load compared to transplantation from deceased donors. We investigated the impact of rinsing the graft contents into the systemic circulation on operative course and postoperative outcomes. Donors had right hepatectomy, and grafts were preserved with cold histidine‐tryptophan‐ketoglutarate solution. On ending portal vein anastomosis, grafts were flushed by patient's portal blood either through incompletely anastomosed hepatic vein (extracorporeal rinse group, EcRg, n = 40) or into systemic circulation (circulatory rinse group, CRg, n = 40). The primary outcome objective was the lowest mean arterial blood pressure within 5 min after portal unclamping as a marker for postreperfusion syndrome (PRS). Secondary objectives included hemodynamics and early graft's and patient's outcomes. Within 5 min postreperfusion, mean arterial blood pressure was significantly lower in the CRg compared to the EcRg, yet this was clinically insignificant. Postoperative graft functions, early biliary and vascular complications, and three‐month survival were comparable in both groups. Rinsing the graft into the circulation increased the incidence of PRS without significant impact on early graft or patient outcome in relatively healthy recipients.     

Endothelin antagonist treatment for successful liver transplantation from non-heart-beating donors

BACKGROUND: With the shortage of cadaveric donors, non-heart-beating donors (NHBDs) are a potential source of liver allografts. However, warm ischemic injury in NHBDs seriously affects the viability of graft liver. Endothelin (ET)-1 has been reported to be involved in the hepatic microcirculatory disturbances after ischemia-reperfusion. METHODS: In a porcine orthotopic liver transplantation model, changes in the serum and liver tissue ET-1 concentration were measured and the effects of an ET receptor antagonist, TAK-044, were evaluated. After cardiac arrest of the donors, liver allografts were subjected to 90 min of warm ischemia, flushed, and preserved for 4 hr at 4 degrees C. The pigs were divided into two groups: a control group (no drug treatment) and a drug-treated group, in which donors and recipients were treated with TAK-044 (10 mg/kg body, drip intravenous injection). Both groups had six donor/recipient pairs. RESULTS: -The ET-1 concentration in the hepatic venous blood increased after reperfusion of the graft in the control group recipients. ET-1 in the graft liver significantly increased during the cold preservation period. TAK-044 treatment significantly increased recipient 7-day survival rate. After reperfusion of the graft, the concentrations of serum liver enzymes and arterial lactate in the drug-treated group were significantly lower than in the control group. The postoperative increase in portal venous pressure was significantly reduced in the drug-treated group. Measurements of liver enzymes in the washed-out preservation fluid at the time of graft rinsing indicated that TAK-044 treatment of the donors significantly suppressed liver enzyme release during ischemia. CONCLUSIONS: These findings indicate TAK-044 treatment has protective effects on postoperative function of hepatic allografts procured from NHBDs.     

Inhibition of Matrix Metalloproteinase‐9 Attenuates Acute Small‐for‐Size Liver Graft Injury in Rats

Ischemia/reperfusion (I/R) and portal hypertension have been implicated in small‐for‐size liver graft dysfunction. Matrix metalloproteinases‐2 and ‐9 (MMP‐2/9) are critically proposed to involve in hepatic I/R injury and activated by hemodynamic force. We hypothesized that MMP‐2/9 overexpression played a crucial role in acute graft injury following small‐for‐size liver transplantation (LT). Rats were randomly assigned into four groups: 75% partial hepatectomy (PH); 100% LT; 25% LT and 25% LT treated with CTT peptide (MMP‐2/9 inhibitor). ELISA, real‐time PCR, gelatin zymography and immunohistochemistry were used to determine the expression pattern of MMP‐2/9 in liver tissue. MMP‐9 expression was significantly increased 6 h after reperfusion and reached a peak 12 h in the 25% LT group, whereas MMP‐2 was expressed in all groups invariably. Compared with the 25% LT group, rats from CTT‐treated group exhibited markedly decreased alanine aminotransferase and total bilirubin values, downregulated proinflammatory cytokines, attenuated malondialdehyde (MDA) and myeloperoxidase (MPO) activities, and improved liver histology. Likewise, MMP‐9 inhibition significantly reduced number of TUNEL‐positive cells and caspase‐3 activity, along with decreased protein levels of Fas and Fas‐L. Specifically, rat survival was also improved in the CTT‐treated group. These results support critical function of MMP‐9 involved in acute small‐for‐size livergraft injury.     

The quality of a liver graft

Abstract Because transplantation success is influenced by the quality of the graft, the objective of this study was to find parameters to evaluate transplant livers in the recipient centre. In 64 liver grafts, the venous effluates of a portal back‐table flush were investigated for various parameters. Amongst them, glutathione S‐transferase (GST), glutamate dehydrogenase (GLDH) and the leucocyte count were found superior in predicting graft survival. Using the combination of these parameters, 100‐day graft survival of between 95% (all parameters positive) and 0% (all parameters negative) was predicted. We concluded that good liver grafts are characterized by a low width of injury (cytosolic component: GST), a low depth of injury (mitochondrial component: GLDH), as well as by a potential to induce tolerance (passenger leucocytes). Perfusate analysis seems to be a valuable tool to recognize problematic grafts in advance and to quantify the “graft factor” in considerations concerning quality control.     

Concomitant Endothelin‐1 Overexpression in Lung Transplant Donors and Recipients Predicts Primary Graft Dysfunction

Primary graft dysfunction (PGD) causes significant morbidity following lung transplantation (LTX). Mortality is high in PGD and therapeutic strategies are limited. To investigate whether endothelin‐1 (ET‐1) that mediates increased vascular permeability and edema formation in lung grafts can predict PGD, ET‐1 mRNA expression was examined in lung tissue biopsies of 105 donors and recipients obtained shortly before LTX. Serum ET‐1 concentration was assessed by ELISA. PGD grade was diagnosed and scored by oxygenation and radiological characteristics according to ISHLT guidelines. PGD grade 3 developed in 11% of patients. ET‐1 mRNA expression was significantly increased in both donor (p < 0.0001) and recipient (p = 0.01) developing PGD as compared to no PGD group. Pretransplant ET‐1 serum concentrations were elevated in recipients with PGD as compared to no PGD group (p < 0.0001), although serum ET‐1 was not different between donors whose grafts developed PGD grades 0–3. In regression analysis, concomitant elevated donor tissue ET‐1 and recipient serum ET‐1 predicted PGD grade 3. This study indicates that pretransplant ET‐1 mRNA overexpression in donors associated with elevated pretransplant serum ET‐1 in recipients contribute to PGD development and that their assessment might be beneficial to predict PGD and to identify recipients who could benefit from a targeted ET‐1 blockade.     

ABO‐incompatible liver transplantation for severe hepatitis B patients

Effect of ABO‐incompatible liver transplantation on patients with severe hepatitis B (SHB) remains unclear. Herein, we summarized 22 cases with SHB in whom were performed emergency liver transplantation from ABO‐incompatible donors. The immunosuppressive protocol consisted basiliximab, tacrolimus, steroids and mycophenolate mofetil. The mean MELD score was 35.2 ± 7.1. Major complications included rejection, infections, biliary complications, hepatic artery thrombosis or stenosis and portal vein thrombosis. Patient survival rates were 40.9%, 78.9% and 82.3% in 1 year, 29.2%, 66.8% and 72.9% in 3 years, and 21.9%, 60.1% and 62.5% in 5 years for ABO‐incompatible, ABO‐compatible and ABO‐identical groups. Graft survival rates were 39%, 78.9% and 82.3% in 1 year, 27.8%, 66.4% and 71.1% in 3 years, and 20.9%, 57.9% and 61.0% in 5 years for incompatible, compatible and identical ABO graft‐recipient match. The 1‐, 3‐, 5‐year graft and patient survival rates of ABO‐incompatible were distinctly lower than that of ABO‐compatible group (P < 0.05). Our results suggested that ABO‐incompatible liver transplantation might be a life‐saving procedure for patients with SHB as a promising alternative operation when ABO‐compatible donors are not available and at least bridges the second opportunity for liver retransplantation.