Living related liver transplantation. Progress or regress?

The impetus for the devolopment of living related liver programmes lies with donor shortage, which relates inversely to the success of generating cadaveric donors. A shrinking or non-existent cadaveric donor pool leads to an increased death rate among potential recipients awaiting transplantation. The living related liver programmes have by and large been successful, though it is accepted that there is potentially a significant risk to the donors. The technique of live donor liver transplantation is clearly here to stay, but the selection of suitable donors is between the family and the unit. Consequently, because of the lack of international guidelines, the programmes are open to abuse. Steps should be taken to establish either mechanisms of control or a worldwide register to combat this potential.     

活体肝移植供者的死亡

为了探讨活体肝移植供者死亡的原因,我们通过网上外文期刊全文检索,收集到在2008年底以前在英文医学期刊上正式报道的活体肝移植供者死亡病例.结果 共检索到12例活体肝移植供者死亡病例.在有肝移植总数记载的文献中,供者死亡的发生率为0.2%.虽然活体肝移植供者死亡率不高,但任何供者的死亡对医疗机构和供者家庭都是灾难性的.不管受者情况如何,一旦发生供者死亡,则该手术都应该算是失败的.因此,如何能尽量避免供者死亡是活体肝移植的核心问题之一.     

Reduced size liver transplantation,split liver transplantation,and living related liver transplantation in relation to the donor organ shortage

Because of the shortage of cadaveric donors, three techniques of partial liver grarting have been developed. These techniques are placed in perspective in relation to the organ shortage. Reduced size liver transplantation (RSLTx) is widely used and has results comparable to those from whole liver grafting. However, this technique, while benefitting pediatric patients, reduces the adult donor liver pool. It also makes inefficient use of an available adult donor liver. In split liver transplantation (SPLTx), the whole liver is used after bipartition for two recipients. The results are comparable to those of RSLTx. The problem with SPLTx is that it is a very demanding technique applied only in centers with extensive experience with liver resection and reduction. Living related liver transplantation (LRLTx) yields excellent results; however, it places an otherwise healthy person at risk. It is argued that instead of performing risky operations on healthy persons, the health authorities should take specific measures to alleviate the organ shortage. In the meantime, SPLTx should be developed further because of its optimal use of donor tissue. As for LRLTx, its excellent results and the present shortage of size-matched pediatric liver donors justify its use, at least for now.     

The technical advance and impact of caudate lobe venous reconstruction in left liver: additional safety for living‐related donor liver transplantation

The key to obtaining good overall outcomes in small‐for‐size liver‐graft transplantation is ensuring sufficient blood flow to the graft during the initial period after surgery. In left lobe liver grafting, various reconstruction techniques have been devised to maximize the limited graft volume. The reconstructions of the caudate lobe (CL) vessels were one of the main streams. In this article, we focus on the clinical significance of CL vessel reconstructions after small‐for‐size liver‐graft transplantation and discuss the roles of various techniques. These techniques contribute to the enlargement of the margin of safety with respect to small‐for‐size liver‐graft transplantation.     

Living related liver transplantation in children with hypoxemia related to intrapulmonary shunting

Abstract  Living related liver transplantation (LRLT) was performed in seven children with hypoxemia related to intrapulmonary shunting. Based on the degree of the shunt ratio calculated by technetium ⁹⁹m macroaggregated albumin (MAA) scintigraphy, the seven patients were classified in the moderate (shunt ratio under 40 %, n = 4) or severe group (shunt ratio over 40 %, n = 3). While Pa was maintained over 60 mmHg in the moderate group, that in the severe group continued at a low level of under 40 mmHg in the early postoperative period. However, 48 h after surgery the arterial ketone body ratio recovered to a safe level of 1.0 in both groups. Values of aspartate aminotransferase and serum total bilirubin decreased at a constant rate in both groups. Six patients survived, but one died of portal vein thrombosis on the 53 rd postoperative day. Five of six surviving patients recovered from hypoxemia. We concluded that the transplanted liver can tolerate the stress of severe hypoxemia after LRLT.     

肝移植5年后生存影响因素分析

目的评估我院肝移植患者长期生存情况,分析肝移植5年后生存质量的影响因素。方法回顾性分析2000年3月至2007年8月完成46例生存超过5年的肝移植病例,分析死亡原因、各种并发症情况。结果生存超过5年的46例患者中,死亡4例,其中胆道并发症2例,重症乙型肝炎1例,心肌梗塞1例,各种并发症:高脂血症8例,高血压7例,糖尿病3例,胆道并发症6例,乙肝复发3例,肾功能损害2例,心肌梗塞1例。结论胆道并发症、乙肝复发及免疫抑制剂副作用是影响肝移植5年后生存质量的主要因素,加强多学科长期临床随访指导,低剂量免疫抑制剂联合应用是提高肝移植5年后生存质量的重要因素。     

Survival following right lobe split graft,living‐ and deceased‐donor liver transplantation in adult patients: a systematic review and network meta‐analysis

Graft and patient survival outcomes following split liver transplantation (SLT), living‐donor liver transplantation (LDLT) and deceased‐donor liver transplantation (DDLT) were estimated using Bayesian network meta‐analysis. Databases were searched for relevant articles over the previous 20 years (MEDLINE, Embase, Cochrane Library and Google Scholar). Systematic review, pairwise meta‐analysis and Bayesian network meta‐analysis were performed. Pairwise meta‐analysis demonstrated that there were no significant differences in graft and patient survival outcomes. Consequently, Bayesian network meta‐analysis demonstrated no significant differences in 1‐, 3‐ and 5‐year graft and patient survival between the three alternative liver transplantations. No discrepancies were demonstrated after comparisons of direct and indirect evidence of 1‐, 3‐ and 5‐year patient and graft survival of the three node‐split models namely SLT, LDLT and DDLT. The 1‐, 3‐ and 5‐year graft and patient survival of the SLT and LDLT cohorts compared to the DDLT cohort demonstrated no significant differences. The direct and indirect evidence of this study can serve as comparator for future studies.     

Graft size-matching in living related partial liver transplantation in relation to tissue oxygenation and metabolic capacity

The influence of graft size-matching on tissue oxygenation and metabolic capability was studied in living related partial liver transplantations for 47 pediatric patients. Their age ranged from 4 months to 17 years 3 months, their body weight from 4.0 to 58.0 kg, graft weight from 191 to 440 g, and graft weight/recipient body weight ratio from 0.61% to 6.0%. Tissue oxygenation and its heterogeneity were investigated by measuring oxygen saturation of hemoglobin in the liver sinusoid (SO₂), coefficient of variation of SO₂, and arterial ketone body ratio. The metabolic capacity of the graft was investigated by measuring bilirubin clearance, recovery of cholesterol esterification, and ketone body production. In infants with a relatively large liver graft, both intra- and extracellular oxygenation remained low soon after reperfusion but recovered to the control value by the end of the operation. In adolescent recipients of a relatively small graft, by contrast, synthetic and detoxification capacities were relatively deficient; however, these improved with time. These results indicate that sufficient tissue oxygenation and liver regeneration are essential for successful liver transplantation with relatively large and small grafts, respectively.     

Perioperative management of living‐donor liver transplantation for methylmalonic acidemia

Methymalonic acidemia (MMA) is a hereditary metabolic disorder characterized by a defect of the methylmalonyl‐CoA mutase that breaks down propionate. The efficacy of liver transplantation for MMA was recently reported. However, the anesthetic management of liver transplant for MMA is not clear. The aim of this article is to describe an anesthetic management algorithm of liver transplant for MMA by reviewing our cases of liver transplant for MMA. Fourteen patients received a liver transplant; three cases showed metabolic decompensation during the transplant and two of the patients died. In the two patients who expired, propofol was used for maintenance anesthesia and preoperative continuous hemodiafiltration was used to reduce plasma methylmalonic acid level in one case, and to control severe metabolic decompensation before transplant for the other case. Their renal function was also worse than others and they were already experiencing metabolic decompensation before induction of anesthesia. Based on our experience of these 14 cases, we have established an anesthetic algorithm for patients with MMA undergoing liver transplant or other procedures. There are three important points in our experience: propofol should be avoided, dextrose infusion therapy should be continued to prevent metabolic decompensation, and liver transplant or other procedures should be avoided during metabolic decompensation.     

Clinical application of arterialization of portal vein in living related donor partial liver transplantation

Arterialization of the portal vein was employed during hepatic arterial reconstruction in our first few clinical experiences of partial liver transplantation using liver grafts obtained from living related donors. This procedure reduced the time required for revascularization of the grafts to about 25 min, and could in fact reduce the ischemic phase of the grafts. Repeated practice of the clinical transplantation technique has shortened the time needed to complete vascular reconstruction, eliminating the need for this procedure in most of our subsequent cases. In many clinical cases, however, there may be emergency situations which require vascular reconstruction, resulting in a prolongation of ischemic phase and the deterioration of the cellular viability of the graft. In such situations, arterialization of the portal vein can be a useful way to prevent the prolongation of the ischemic phase and to rescue the graft.     

Guidelines for donor selection and an overview of the donor operation in living related liver transplantation

Guidelines for donor selection and an overview of the donor operation are reported on the basis of our experience with 120 cases of living related liver transplantation (LRLT) in pediatric patients. Once the parents had clearly expressed their desire to serve as donors, tests were performed to functionally and anatomically screen the donor livers to determine whether or not the parents' general physical condition allowed them to serve as donors. We then evaluated which of the two parental candidates was more suitable as a donor. The wishes of the family as to which parent should serve as donor was considered secondary and taken into account only in a few cases in which certain functional and/or anatomical abnormalities were uncovered that made the prime candidate less suitable. For the 120 LRLTs, 135 candidates were evaluated as potential donors, 15 (11.1%) of whom were rejected for various reasons. The mean volume of blood loss during the donor operation decreased significantly from 489 g in the first 60 LRLTs to 390 g in the latter 60 LRLTs; this was accompanied by a significant decrease in the mean volume of autologous blood transfused from 449 g to 390 g. Mean cold ischemia time of the graft increased significantly from 71.4 to 128.0 min, while mean operation time conversely decreased from 6.7 to 6.2 h. Bile leakage from the cut surface of the remnant lver, which was the only postoperative surgical complication encountered, was noted in five cases. We conclude that donor candidates should be strictly selected according to basic guidelines, taking into account both the results of preoperative screening and the wishes of the family. With this accumuled experience, we have been able to simplify our LRLT operative procedure, resulting in decreases in blood loss volume, blood transfused, and operation time.     

Living related liver transplantation across ABO blood groups with FK506 and OKT3

In living related liver transplantation (LRLT), the use of graft livers across ABO blood groups is unavoidable since the organ donor is usually one of the recipient's parents. This report presents our initial experiences with LRLT, focusing on ABO-incompatible cases. From June 1990 to May 1992, we successfully performed a series of 34 LRLT on children (15 males and 19 females) ranging in age from 7 months to 15 years. Overall recipient survival rates were 90% (25/28) in elective LRLT and 50% (3/6) in emergency LRLT. These cases were classified into three groups: ABO blood group-identical (n=21), compatible (n=10), and incompatible (n=3). The immunosuppressive regimen consisted of FK506 and low-dose steroids in the first two groups. In the incompatible cases, exchange transfusion was performed to decrease anti-A and/or-B antibody titers before LRLT, and prophylactic OKT3 was added to FK506 and steroids after LRLT. No significant difference in recipient and graft survifal was observed among the groups. In the identical group, no rejection episodes have been observed thus far. Rejection occurred in two out of the ten compatible cases. Among the incompatible cases, one recipient had mild rejection and was treated. The remaining two recipients have had no rejection episodes thus far. Although all three recipients had cytomegalovitus (CMV) infection, they were successfully treated with gancyclovir, and no lethal infection has developed in any of these cases. The present results suggest that graft livers from living related donors across ABO blood groups can function well with FK506, low-dose steroids, and prophylactic OKT3 without causing lethal complications.     

Impact of donor kidney function and donor age on poor outcome of living‐unrelated kidney transplantation (KT) in comparison with living‐related KT

Living‐unrelated donors (LURD) have been widely used for kidney transplantation (KT). We retrospectively reviewed 779 patients who underwent living‐donor KT from 2000 to 2012, to compare outcomes of 264 KT from LURD and 515 from living‐related donors (LRD), and to identify risk factors for living KT. Median follow‐up was 67 months. Mean donor age, total human leukocyte antigen (HLA) mismatches, and HLA–DR mismatches were higher, and mean estimated glomerular filtration rate (eGFR) was lower in LURD. Acute rejection (AR)‐free survival (p = 0.018) and graft survival (p = 0.025) were lower for LURD than LRD, whereas patient survival rate was comparable. Cox regression analysis showed HLA–DR mismatches (OR 1.75 for one mismatch; OR 2.19 for two mismatches), recipient age ≤ 42 yr, and donor age > 50 yr were significant risk factors for acute rejection. For graft survival, AR and donor eGFR (OR 1.90, p = 0.035) were significant. We also identified significant impact of recipient age > 50 yr and diabetes for patient survival. However, KT from LURD was not a significant risk factor for AR (p = 0.368), graft survival (p = 0.205), and patient survival (p = 0.836). Our data suggest that donor eGFR and donor age are independent risk factors for clinical outcomes of living KT, which can be related with poor outcome of KT from LURD.     

Small bowel transplantation using grafts from living‐related donors. Two case reports

Abstract A living‐related small bowel transplantation (SBT) was performed in two pediatric patients with short bowel syndrome. In both cases, the donor was the patient's mother. The distal ileum (100 cm, 120 cm) was harvested and the ileocolic vessels, ileocecal valve, and terminal ileum were left intact. The two donors were discharged from the hospital on postoperative days 15 and 6, respectively. Recipient 1 was a 2 year 6 month‐old boy with short bowel syndrome who underwent SBT due to loss of venous access. The graft vein was anastomosed to the recipient's infrarenal inferior vena cava. Despite triple immunosuppression (tacrolimus, steroid, and azathioprine), there were four episodes of rejection. The patient had been on total parenteral nutrition for almost his entire post‐transplant course. He died from Pneumocystis carinii pneumonia 16 months after the transplantation. Recipient 2 was a 4 year 5 month‐old girl with short bowel syndrome who underwent an isolated small bowel transplantation because of recurrent line sepsis. Her pretransplant bilirubin was 8.0 mg/dl and a biopsy showed severe fibrosis. The graft vein was anastomosed to the recipient's inferior mesenteric vein. After transplantation, her bilirubin level became normal within 10 days. Triple immunosuppression (tacrolimus, steroid, and cyclophosphamide) together with a 3‐day course of OKT‐3 made her post‐transplant course feasible. After overcoming a single episode of rejection she left the hospital 4 months after SBT. The patient is currently (10 months after transplantation) hospitalized due to rejection, which is being successfully controlled, and she is off total parenteral nutrition. From our experience, harvesting of the distal ileum for use as a bowel graft can be safely performed. The advantages of living‐related grafts, optimal graft length, and choice of vascular reconstruction in SBT are yet to be explored.     

Incidence and risk factors for new‐onset diabetes in living‐donor liver transplant recipients

With the increased number of long‐term survivors after liver transplantation, new‐onset diabetes after transplantation (NODAT) is becoming more significant in patient follow‐up. However, the incidence of new‐onset diabetes after living‐donor liver transplantation (LDLT) has not been well elucidated. The aim of this study was to evaluate the incidence and risk factors for NODAT in adult LDLT recipients at a single center in Japan. A retrospective study was performed on 161 adult patients without diabetes who had been followed up for ≥three months after LDLT. NODAT was defined according to the 2003 American Diabetes Association/World Health Organization guidelines. The recipient‐, donor‐, operation‐, and immunosuppression‐associated risk factors for NODAT were assessed. Overall, the incidence of NODAT was 13.7% (22/161) with a mean follow‐up of 49.8 months. In a multivariate analysis, the identified risk factors for NODAT were donor liver‐to‐spleen (L‐S) ratio (hazard ratio [HR] = 0.022, 95% confidence interval [CI] = 0.001–0.500, p = 0.017), and steroid pulse therapy for acute rejection (HR = 3.320, 95% CI = 1.365–8.075, p = 0.008). In conclusion, donor L‐S ratio and steroid pulse therapy for acute rejection were independent predictors for NODAT in LDLT recipients. These findings can help in screening for NODAT and applying early interventions.     

Intraoperative measurement of the graft oxygenation state in living related liver transplantation by near infrared spectroscopy

Graft oxygenation plays an important role in successful liver transplantation. Intraoperative changes in the oxygenation state of the liver graft were measured by near infrared spectroscopy in 28 cases of living related liver transplantation. Oxygen saturation of hemoglobin in the liver (hepatic SO₂) changed from 81.2%±1.5% (mean±SEM) before donation (in the donor) to 49.7%±4.2% after portal reflow, to 58.4%±5.0% after arterial reflow, and then to 71.4%±3.9% before closure. Mean hepatic SO₂ was positively correlated with portal flow rate as measured by duplex Doppler sonography. Cases with low portal flow rate showed a high coefficient of variation (SD/mean) of hepatic SO₂, indicating heterogeneous tissue oxygenation. Though graft size was expected to affect the graft oxygenation state, hepatic SO₂ was fairly independent of the graft-to-recipient weight ratio. In two cases with markedly low hepatic SO₂, postoperative graft dysfunction occurred. This study suggest that the method of near infrared spectroscopy is reliable and useful for assessing the graft oxygenation state in liver transplantation.     

Effect of graft size matching on pediatric living‐donor liver transplantation at a single center

We retrospectively analyzed 252 patients with end‐stage liver disease who had undergone LDLT from January 2009 to September 2015. Of these, 25 had a GRWR of <2.0% (Group A), 204 had a GRWR of ≥2.0% or <4.0% (Group B), and 23 had a GRWR ≥4.0% (Group C). The three GRWR groups demonstrated similar characteristics, except for recipient age and recipient BMI. The overall 1‐, 2‐, and 3‐year graft survival rates were 95.1%, 93.5%, and 93.5%, respectively. However, among the three groups, graft survival rates at 1 year, 2 years, and 3 years were significantly different (P = .0009). Hepatic artery stenosis/thrombosis was more frequently observed in Group C than in Groups A and B (P = .001). Wound infection was also more frequently observed in Group C than in Group A and B (P = .002). However, intestinal fistula/bile leakage/biliary‐enteric anastomotic fistula was more frequently observed in Group A than in Groups B and C (P = .001). In addition, reoperation more frequently occurred in Group A and C than in Group B (P = .001). Recipients with a GRWR between 2.0% and 4.0% had significantly better graft survival rates.     

Emergency living related liver transplantation for fulminant reactivation of hepatitis B virus after unrelated marrow transplantation

We report a unique case of emergency living related donor orthotopic liver transplantation (OLT) for late fulminant reactivation of hepatitis B virus (HBV) after matched unrelated bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Cessation of lamivudine after BMT for HBV positive patients may carry risks of late fatal HBV reactivation. Similar to fulminant HBV reactivation in the general population, OLT under resumption of lamivudine can be life saving. In our case, concomitantly molecular relapse of CML at the time of liver failure was also cleared by OLT, possibly via a 'liver-graft vs. leukemia' effect. Liver rejection (graft vs. graft disease) was mild due to inherent immunocompromise of the marrow graft. Hence BMT recipients in stable remission should not be denied the opportunity for life-saving solid organ transplantation. A choice of marrow and liver donors with innate HBV immunity may be needed to give the additional advantage of long-term HBV clearance.     

Living related liver transplantation for recurrent hepatocellular carcinoma in a normal liver

The role of liver transplantation for hepatocellular carcinoma (HCC) is evolving. In patients with advanced liver disease and early stage HCC, transplantation offers the best hope for cure. A living donor offers the optimal approach to a timely transplant, before disease progression obviates the potential benefit. But extending the indications beyond those designated by the United Network for Organ Sharing (UNOS) for liver transplantation for HCC is controversial [Hepatology 2001: 33: 1073; Liver Transplant 2000: 6: S1]. Cadaver split techniques and use of living donors are potentially compelling ways to test the limitations of liver transplantation for HCC, without notably reducing the cadaver organ pool. Herein, we report a rare case of a patient who developed a well-differentiated HCC in a normal liver. After resection of the index lesion and, later, of a remote recurrent lesion, a living donor liver transplant was offered. The natural history of this lesion and the management of transplantation in this setting are discussed.     

Incisional hernia after liver transplantation: risk factors and health‐related quality of life

The aim of this cross‐sectional study was to analyze the incidence of incisional hernia after liver transplantation (LT), to determine potential risk factors for their development, and to assess their impact on health‐related quality of life (HRQoL). Patients who underwent LT through a J‐shaped incision with a minimum follow‐up of three months were included. Follow‐up was conducted at the outpatient clinic. Short Form 36 (SF‐36) and body image questionnaire (BIQ) were used for the assessment of HRQoL. A total of 140 patients was evaluated. The mean follow‐up period was 33 (SD 20) months. Sixty patients (43%) were diagnosed with an incisional hernia. Multivariate analysis revealed surgical site infection (OR 5.27, p = 0.001), advanced age (OR 1.05, p = 0.003), and prolonged ICU stay (OR 1.54, p = 0.022) to be independent risk factors for development of incisional hernia after LT. Patients with an incisional hernia experienced significantly diminished HRQoL with respect to physical, social, and mental aspects. In conclusion, patients who undergo LT exhibit a high incidence of incisional hernia, which has a considerable impact on HRQoL. Development of incisional hernia was shown to be related to surgical site infection, advanced age, and prolonged ICU stay.