Apheresis Therapy for Living‐Donor Liver Transplantation

Abstract: Liver transplantation is a fundamental treatment for patients with end‐stage hepatic failure. In order to perform living‐donor liver transplantations under safer conditions, apheresis plays a major role in Japan due to the prevalence of living‐donor liver transplantation wherein later retransplantation is difficult. In our department, the roles of apheresis in liver transplantation are as follows: as bridge therapy to liver transplantation (n = 45); as a supplement to the graft liver until the recovery of hepatic function (n = 77); as treatment for multiple organ failure including posttransplantation renal failure (n = 15); and as a means with which to reduce antibody titers for antibodies such as anti‐A or anti‐B in persons with ABO blood type = incompatible liver transplantation (n = 23). In our department, we have performed 822 liver transplantations at present. Of those cases, 183 were selected wherein apheresis was performed around the time of the operation. In all cases, transplantation with sufficient apheresis was performed before the surgical operation, however, 22 patients (48.9%) died after undergoing surgery. Among the patients who underwent the postoperative apheresis, those in the nonsurvivor group had lower grafted liver weights compared to those of the survivor group. The kidney was the organ that most frequently failed due to postoperative complications. In cases of ABO blood type‐incompatible liver transplantations, patients with high preoperative anti‐A/B IgM antibody titers sustained bile duct complications, patients with high preoperative anti‐IgG antibody titers sustained hepatic necrosis, and patients with high postoperative anti‐A/B IgM and anti‐IgG antibody titers sustained hepatic necrosis most frequently.     

Antibody Elimination by Apheresis in Living Donor Liver Transplant Recipients

Abstract: In the present study, we investigated retrospectively the indications and the efficacy of the elimination of preexisting antiallogeneic antibodies in liver transplant recipients. Three patients who were ABO blood type incompatible were subjected to plasmapheresis and double filtration plasmapheresis before the living donor liver transplantation (LDLTx), and the titers decreased to less than 8. After transplantation, plasmapheresis was also performed in 3 cases, and continuous hemodiafiltration in 1 case, and in 2 out of these 3 patients acute rejection was recognized. Two patients who were crossmatch positive were subjected to plasmapheresis before transplantation, and the T warm titers were reduced to less than Score 2. These 2 patients had no acute rejections after transplantation. We conclude that in liver transplant patients apheresis is effective to prevent acute rejection induced by preexisting anti‐A and/or anti‐B antibodies and anti‐donor specific antibodies before transplantation, but it is not effective in a patient with accelerated humoral rejection occurring after transplantation.     

Risk Factors for Recurrence of Primary Sclerosing Cholangitis After Living Donor Liver Transplantation: A Single Center Experience

We retrospectively reviewed our 10-year experience with living donor liver transplantation (LDLT) in 30 consecutive patients with end-stage primary sclerosing cholangitis (PSC) to determine long-term patient and graft survival and risk factors for recurrence of PSC. For strict diagnosis of recurrence, patients with hepatic artery thrombosis (n = 2), ABO blood type incompatible transplantation (n = 3), and postoperative survival shorter than 1 year (n = 5) were excluded from the study, leaving 20 patients for analysis. Recurrence was diagnosed in 11 patients 26–71 months after transplantation. Multivariate analysis showed that cytomegalovirus diseases within 3 months after transplantation and related donors were independent risk factors for recurrence. When the effects on recurrence were compared among donor-recipient relationships, there were significant differences, especially between nonrelated donors and parents. Multivariate analysis showed that age was an independent risk factor for time to graft loss. Cytomegalovirus prophylaxis and avoidance of related donors are important in reducing PSC recurrence, although this is a preliminary report with limitations due to the small number of patients. LDLT for young patients with PSC using grafts from their parents might have to be avoided where deceased donor liver transplantation is available.     

Therapeutic strategy and the role of apheresis therapy for ABO incompatible living donor liver transplantation

Although in Japan, transplant organs obtained from brain-dead donors (BDD) has been allowed since October 1997, to date only 27 liver grafts from BDD have been obtained. The severe shortage of transplantable organs is a big problem, not only in liver transplantation but also other organ transplants. Liver transplantation is a fundamental treatment for end-stage liver disease. In order to perform living-donor liver transplantation (LDLT) in a safer manner, apheresis (plasmapheresis) plays a major role in Japan because of the prevalence of LDLT wherein later re-transplantation is difficult. Therefore, because of a limited donor supply and because the need of patients with end-stage liver disease is critical, use of grafts from ABO-incompatible donors may be the only available option. From June 1990 to November 2004, 1010 patients underwent 1060 LDLT cases at Kyoto University Hospital. Of these, 139 LDLT cases (13.1%) received ABO-incompatible living-donor liver grafts. The role of apheresis in ABO-incompatible LDLT is the reduction of antibody titers such as anti-A or anti-B antibody. We perform preoperative apheresis as a general rule for incompatible cases, and the recipient's antibody level against the donor's blood type is decreased to one eighth of the baseline value before LDLT. Up to the present, baseline antirejection regimens included steroids, tacrolimus and cyclophosphamide. At first, splenectomy was performed during operation to suppress antibody production, and intraportal infusion therapy was performed to control local disseminated intravascular coagulation (DIC) occurring in ABO-incompatible grafts. At that time, three agents--methylprednisolone, prostaglandin E1, and gabexate mesilate--were infused continuously for 3 weeks after LDLT. At present, instead of intraportal infusion therapy, hepatic artery infusion therapy without splenectomy is adopted because of portal thrombosis, and two agents--methylprednisolone and prostaglandin E1--are infused continuously for 3 weeks after LDLT. Recently, we introduced an anti-CD20 monoclonal antibody (Rituximab) instead of splenectomy for B cell deletion before ABO-incompatible LDLT. In this article, we describe our therapeutic strategy and the role of apheresis around ABO-incompatible LDLT.     

Liver Regeneration in Donors Evaluated by Tc-99m-GSA Scintigraphy after Living Donor Liver Transplantation

The impact of hepatic steatosis on regeneration of the remnant liver after living donor liver transplantation is unclear. We evaluated the impact of steatosis on regeneration and function of the remnant liver by using technetium-99m-diethylenetriaminepentaacetic acid-galactosyl human serum albumin scintigraphy. Twelve living donors were classified into groups with or without mild hepatic steatosis according to the liver-to-spleen attenuation ratio on computed tomography: 6 donors had a ratio ≥ 1.20 (control group) and 6 donors had a ratio < 1.20 (fatty liver group). Scintigraphy was performed to determine the hepatic uptake ratio of the tracer (corrected for disappearance from the blood) and the maximum removal rate of the tracer by hepatocytes as parameters of the hepatic functional reserve. The fatty liver group had a significantly lower corrected hepatic uptake ratio and removal rate compared with the control group at 6 and 12 months after partial hepatectomy. These parameters were decreased at 1 month after surgery in both groups. However, both parameters returned more rapidly to prehepatectomy levels in the control group. The regenerated liver volume estimated by scintigraphy did not differ significantly between the two groups at any time. Liver scintigraphy may be useful for evaluating the regeneration of functioning hepatocytes. Because donors with mild hepatic steatosis showed impaired liver regeneration at 1 year after partial hepatectomy, management of these donors requires more care.     

Pharmacokinetics of Cyclosporine A After Massive Hepatectomy: A Hint for Small-for-Size Graft in Living Donor Liver Transplantation

In living donor liver transplantation, graft size is very important, and various studies have been conducted regarding these problems in small-for-size (SFS) grafts. The administration of immunosuppressants for SFS graft, in which the functional liver mass is small and necessary for excessive liver regeneration, has not been reported so far. The aims of this study were to investigate the optimal administration of cyclosporine (CyA) and characteristics of metabolism of CyA, according to liver volume. Seven-week-old male Wister rats were randomly divided into four groups: two CyA-administered groups (CyA groups), 70% and 90% hepatectomy (Hx); and two control groups, 70% and 90% Hx. The 70% Hx and 90% Hx were used as the surrogate model of SFS for 30% and 10% graft models. In CyA groups, CyA (5 mg/kg/day) was given for 3 days before Hx and after surgery until sacrifice. Animals were sacrificed at 0, 12, 24, 48, and 72 hr after Hx. The blood concentration of CyA and the expression of the CYP3A2 gene were measured at each point in CyA groups, and liver regeneration was evaluated by measuring the ratio of remnant liver weight to body weight in each group. Regarding the blood concentration of CyA, no difference was recognized between 30% and 10% graft models except for 72 hr after Hx. As for liver regeneration, no significant difference was recognized. Regarding the expression of CYP3A2, no change was noted in the 30% graft model; on the other hand, CYP3A2 expression was reduced. Significant differences between the 30% and the 10% graft model were observed 48 and 72 hr after Hx. The blood concentration of CyA was not dependent on the volume of the liver graft.     

The role of apheresis therapy for ABO incompatible living donor liver transplantation: the Kyoto University experience

Liver transplantation is a radical surgical therapy for end-stage liver disease. Although in Japan organ transplantation from brain-dead donors (BDD) has been allowed since October 1997, to date, only 29 liver grafts from BDD have been obtained. Thus, most of the liver transplantations carried out use living-donor liver transplantation (LDLT), and BDD liver transplantation is only used in rare cases. In order to carry out LDLT more safely, apheresis (plasmapheresis: PE) plays a major role in our country because of the prevalence of LDLT wherein later re-transplantation is difficult. Thus, because of a limited donor supply and because the needs of patients with end-stage liver disease is critical, use of grafts from ABO-incompatible (ABO-I) donors might be the only available option. From June 1990 to November 2005, 1100 patients underwent 1151 LDLT cases at Kyoto University Hospital. Additionally, 159 LDLT cases (13.8%) received ABO-I living-donor liver grafts. The role of apheresis in ABO-I LDLT is the reduction of antibody titers such as anti-A or anti-B antibody. We carry out preoperative PE as a general rule for ABO-I cases, and the recipient's antibody level against the donor's blood type is decreased to one eighth of the baseline value before LDLT. Until now, baseline immunosuppressive agents included steroids, tacrolimus and cyclophosphamide. At first, splenectomy was carried out during surgery to suppress antibody production, and intraportal (PV) infusion therapy was carried out to control local disseminated intravascular coagulation (DIC) occurring in ABO-I grafts. At that time, three drugs-methylprednisolone, prostaglandin E1 (PGE1), and gabexate mesylate (FOY) were infused continuously for 3 weeks after LDLT. At present, instead of PV infusion therapy, hepatic artery infusion therapy without splenectomy is adopted because of portal thrombosis, and two drugs- methylprednisolone and PGE1- are infused continuously for 3 weeks following LDLT. Recently, we introduced anti-CD20 monoclonal antibody (Rituximab) instead of splenectomy for B cell deletion before ABO-I LDLT. In the present article, we describe the role of apheresis around ABO-I LDLT based on our recent experiences.     

Management of anti-allogeneic antibody elimination by apheresis in living donor liver transplantation

In this study, we report on the indications and efficacy of the elimination of antiallogeneic antibodies in living donor liver transplant recipients. Seven patients incompatible with the ABO-blood type were subjected to apheresis before transplantation. The procedure resulted in titers being decreased to less than a score of 8. After transplantation, apheresis was also performed in 6 cases and continuous hemodiafiltration in 1 case. In addition, three out of 11 ABO-blood type incompatible recipients were administered anti-CD20 antibody (rituximab). Two crossmatch positive patients were subjected to apheresis before transplantation, and in these cases the titers were reduced to less than a score of 2. Moreover, these two patients had no acute rejections after transplantation. We concluded that apheresis is effective for preventing acute rejection induced by pre-existing anti-A and/or anti-B antibodies, as well as antidonor specific antibodies, but is not effective in some patients who had accelerated humoral rejection.     

Acute Deterioration of Idiopathic Portal Hypertension Requiring Living Donor Liver Transplantation: A Case Report

Case reports of severe idiopathic portal hypertension (IPH) requiring liver transplantation are very rare. We report the case of a 65-year-old woman who was diagnosed as having IPH. At the age of 60 years, her initial symptom was hematemesis, due to ruptured esophageal varices. Computed tomography of the abdomen showed splenomegaly and a small amount of ascites, without liver cirrhosis. She was diagnosed as having IPH and followed-up as an outpatient. Five years later, she developed symptoms of a common cold and rapidly progressive abdominal distension. She was found to have severe liver atrophy, liver dysfunction, and massive ascites. Living donor liver transplantation was then performed, and her postoperative course was uneventful. Histopathological findings of the explanted liver showed collapse and stenosis of the peripheral portal vein. The areas of liver parenchyma were narrow, while the portal tracts and central veins were approximate one another, leading to a diagnosis of IPH. There was no liver cirrhosis. The natural history of refractory IPH could be observed in this case. Patients with end-stage liver failure due to severe IPH can be treated by liver transplantation.     

Successful resolution of very severe hepatopulmonary syndrome following adult‐to‐adult living donor liver transplantation: Report of two cases

Hepatopulmonary syndrome (HPS) is a severe complication in patients with chronic liver disease with poor prognosis. Liver transplantation (LT) is a promising treatment for HPS; however, very severe HPS, which is defined by an arterial oxygen pressure (PaO₂) of less than 50 mmHg and a right–left intrapulmonary shunt rate of more than 20%, may be a contraindication to LT, including living donor LT (LDLT). Here, we report two cases of decompensated liver cirrhosis with very severe HPS which were resolved after adult‐to‐adult LDLT including ABO‐incompatible LDLT. Both patients required oxygen supportive therapy in combination with specialized respiratory care postoperatively, followed by improvement of oxygenation and substantial decreases of intrapulmonary shunt rate. These findings suggest very severe HPS can be resolved by LDLT, including ABO‐incompatible LDLT, and reduced graft volume did not impede the reversal of intrapulmonary shunting. Our current report may indicate that adult‐to‐adult LDLT, including ABO‐incompatible LDLT, is becoming an effective therapeutic method and prompt a review of previous reports as well as our own files with particular regard to the indication of LDLT for decompensated liver cirrhosis with very severe HPS.     

Removal of Anti‐A/B Antibodies with Plasmapheresis in ABO‐Incompatible Kidney Transplantation

Abstract: Because of a shortage of cadaver donors in Japan, ABO‐incompatible living kidney transplantation has been carried out. Sixty‐seven ABO‐incompatible living kidney transplantations (LKT) were performed between January 1989 and December 1995 at our institution. In our previous report on the long‐term results of ABO‐incompatible LKT, graft survival of ABO‐incompatible LKT up to 3 years was significantly lower than that of ABO‐compatible LKT, but no significant difference was seen from 4 to 8 years. We removed anti‐A/B antibodies by immunoadsorption and/or double filtration plasmapheresis before kidney transplantation. There was a significant difference between the anti‐A/B antibody titers before and after plasmapheresis. The anti‐A/B antibody titers also were well suppressed over the long term after transplantation.     

Neuropsychiatric Complications After Liver Transplantation: Role of Immunosuppression and Hepatitis C

Neuropsychiatric complications are an important source of morbidity following orthotopic liver transplantation. Etiology of liver disease and type of immunosuppression are possible related factors. The aim of this study was to describe the prevalence of neuropsychiatric complications after liver transplantation, the role of immunosuppression, and the association between these and specific liver diseases such as hepatitis C. One hundred twenty-eight patients with liver transplants were studied. Tacrolimus was the primary immunosuppressant in 101 patients and cyclosporine in 27 patients. Seventy-five complications in 49 patients (38.2%) were reported. In 43 patients, the etiology was associated with immunosuppression: 36 on tacrolimus and 7 on cyclosporine (P = 0.34). Seventeen and four-tenths percent of patients with hepatitis C and 4.6% of patients without hepatitis C developed depression (P = 0.02). There is no difference between types of primary immunosuppression and neuropsychiatric complications. There is a significantly greater incidence of depression in patients transplanted for hepatitis C.     

Liver transplantation in Japan: Registry by the Japanese Liver Transplantation Society

As of 31 December 2017, a total of 9242 liver transplants have been carried out in 67 institutions in Japan. There were 447 deceased donor transplants (444 from heart‐beating donors and 3 from non‐heart‐beating donors) and 8795 living‐donor transplants. The annual total of liver transplants in 2017 was 416 (69 deceased donor transplants and 347 living‐donor transplants). The most frequent indication was cholestatic disease, followed by neoplastic disease and hepatocellular disease. In terms of hepatocellular disease in 2017, cirrhosis due to hepatitis C and B decreased (13 and 8, respectively), whereas alcoholic cirrhosis markedly increased (32). Patient survival following transplantation from heart‐beating donor (444 transplants: 1 year, 89.1%; 3 years, 85.2%; 5 years, 82.9%; 10 years, 75.4%; 15 years, 70.7%) was similar to that from living‐donor (8794 transplants: 1 year, 85.0%; 3 years, 80.9%; 5 years, 78.5%; 10 years, 73.2%; 15 years, 68.5%; 20 years, 65.7%; 25 years, 64.6%). Graft survival was very much the same as patient survival (heart‐beating donor: 1 year, 88.4%; 3 years, 84.5%; 5 years, 82.2%; 10 years, 74.7%; 15 years, 70.1%; living donor: 1 year, 84.3%; 3 years, 79.9%; 5 years, 77.3%; 10 years, 71.4%; 15 years, 66.3%; 20 years, 63.3%; 25 years, 61.9%). Survival data are reported according to age and sex of recipient, indication, age and sex of donor, ABO compatibility, and other factors.     

Impact of Living Donor Liver Transplantation on COVID-19 Clinical Outcomes from a Quaternary Care Centre in Delhi

Background and AimsThe anticipated fear of serious outcomes in coronavirus infected liver transplant recipients led to disruption of transplant services globally. The aim of our study was to analyze COVID-19 severity in transplant recipients and to compare the difference of COVID-19 clinical outcomes in early (<1 year) vs. late (>1 year) post-transplant period.Methods41 post-living donor liver transplant recipients with COVID-19 infection were studied retrospectively from 1st April 2020 to 28th February 2021.ResultsThe median age was 49.00 years with a male preponderance (80.49%). Fifteen patients had infection within 1 year of transplant and 26 were infected after 1 year of transplant. The overall median interval between transplantation and COVID-19 diagnosis was 816.00 days. Fever and malaise were the common presenting symptoms. The most common associated comorbidities were diabetes mellitus (65.85%) and hypertension (46.34%). The severity of illness was mild in 28 (68.29%), moderate in 4 (9.76%), severe in 6 (14.63%) and critical in 3 (7.32%). To identify associated risk factors, we divided our patients into less severe and more severe groups. Except for lymphopenia, there was no worsening of total bilirubin, transaminases, alkaline phosphatase, and gamma-glutamyl transferase in the more severe group. Eight (19.51%) patients required intensive care unit admission and three (7.32%) died, while none suffered graft rejection. In recipients with early vs. late post-transplant COVID-19 infection, there were similar outcomes in terms of severity of COVID-19 illness, intensive care unit care need, requirement of respiratory support, and death.ConclusionLiving donor liver transplantation can be performed during the COVID-19 pandemic without the fear of poor recipient outcome in cases of unfortunate contraction of severe acute respiratory syndrome coronavirus-2.     

Donor Rejection Before Living Donor Liver Transplantation: Causes and Cost Effective Analysis in an Egyptian Transplant Center.

Background:

In the living donor liver transplant setting, the preoperative assessment of potential donors is important to ensure the donor safety.

Objectives:

The aim of this study was to identify causes and costs of living liver-donors rejection in the donation process.

Materials and Methods:

From June 2010 to June 2012, all potential living liver donors for 66 liver transplant candidates were screened at the Ain Shams Center for Organ Transplantation. Potential donors were evaluated in 3 phases, and their data were reviewed to determine the causes and at which phase the donors were rejected.

Results:

One hundred and ninety two potential living liver donors, including 157 (81.7%) males, were screened for 66 potential recipients. Of these, 126 (65.6%) were disqualified for the donation. The causes of rejection were classified as surgical (9.5 %) or medical (90.5 %). Five donors (3.9 %) were rejected due to multiple causes. Factor V Leiden mutation was detected in 29 (23 %) rejected donors (P = 0.001), 25 (19.8 %) donors had positive results for hepatitis serology (P = 0.005), and 16 (12.7 %) tested positive for drug abuse. Portal vein trifurcation (n = 9, 7.1%) and small size liver graft estimated by CT volumetric analysis (n = 6, 4.8 %) were the main surgical causes which precluded the donation.

Conclusions:

Among potential Egyptian living liver donors, Factor V Leiden mutation was a significant cause for live donor rejection. A stepwise approach to donor assessment was found to be cost-effective.