FIGURE 2 - uploaded by John Julian Fung
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(Top) Explanted liver with features of acute rejection, chronic rejection, and hepatitis. (a) Portal tract with a mixed inflammatory infiltrate and a damaged bile duct with intraepithelial lymphocytes (arrow) (hematoxylin-eosin, 100). (b) Inflamed portal tract with artery (arrow) without accompanying bile duct (hematoxylin-eosin, 200). (c) Large perihilar hepatic artery with subintimal foam cell accumulation (periodic acid Schiff stain, 200). (d) Hepatic lobule with sinusoidal lymphocytes and hepatocellular cholestasis (hematoxylin-eosin, 200). (Bottom) Patients (n3) with a drastic reduction or discontinuation of immunosuppression, showing evidence of chronic rejection. Liver function has recovered after optimization of immunosuppression. (a) Case 1. There is fibrosis of the central vein and obliteration of its lumen (trichrome stain, 100). (b) Case 2. Loss of bile ducts. There is an artery (arrow) without a corresponding bile duct. The portal infiltrate is minimal. (hematoxylin-eosin, 100). (c) Case 3. Some portal areas show preserved bile ducts (arrows) (cytokeratin AE1/AE3; 100). (d) Case 3. Other portal areas show lack of bile ducts (cytokeratin AE1/AE3, 100).
Source publication
Although the outcome of liver transplantation has improved significantly during the past two decades, graft loss caused by chronic rejection after liver transplantation still occurs in 2% to 20% of recipients. The overall incidence of chronic rejection is also reported to be low in adult recipients, and risk factors have been identified. Chronic re...
Similar publications
Hepatitis C is the most common indication for liver transplantation (LT) in the United States. Recurrence of hepatitis C virus (HCV) infection post-LT remains a problem for which there is no completely satisfactory treatment. The aim of the present study is to evaluate mycophenolate mofetil (MMF), which has both immunosuppressive and antiviral prop...
Citations
... Tacrolimus, a calcineurin inhibitor, is recognized for its potent ability to suppress T cell activity, thereby suppressing immunoreactions. Due to its effective inhibition of transplant rejection events, and its capacity to reduce chronic rejection episodes in liver transplantation patients [1][2][3], it has become a foundational medication in the treatment of liver transplantation patients, post-operation. Tacrolimus is highly bound to red blood cells with a whole blood/plasma concentration distribution ratio of about 20:1, and also highly bound to plasma proteins (> 98.8%) [4]. ...
Objective
We aim to describe the population pharmacokinetics (PPK) of tacrolimus in Chinese pediatric patients under 4 years old after liver transplantation and to develop individualized tacrolimus dosing software.
Methods
A total of 663 blood concentrations from 85 patients aged 4.57 months to 3.97 years were collected in this study. PPK analysis was performed using a nonlinear mixed effects modeling approach with the software, Phoenix. Using C#, an individualized tacrolimus dosing software was created. The software was then used to predict the concentrations of another ten pediatric liver transplantation patients to verify the accuracy of said software. The predictive error (PE) and the absolute predictive error (APE) for each predicted time point were computed.
Results
A one-compartment model with first-order elimination best fitted the data. The apparent volume of distribution (V/F) and apparent clearance (CL/F) were 198.65 L and 2.41 L/h. Postoperative days (POD), total bilirubin (TBIL), and the use of voriconazole significantly influenced tacrolimus apparent clearance. The incorporation of an increasing number of actual blood drug concentrations into the prediction resulted in a decrease in both PE (72%, 17%, 7%) and APE (87%, 53%, 26%).
Conclusions
A qualified PPK model of tacrolimus was developed in Chinese pediatric patients. The individualized tacrolimus dosing software could be used as a suitable tool for the personalization of tacrolimus dosing for pediatric patients after liver transplantation.
... Accordingly, CR is the most debating and concerning survival-limiting complication in liver transplanted patients and is encountered in 2-20% of the patients [1,2]. CR is generally defined by foamy changes in sinusoidal and vascular beds as well as the loss of >50% of portal bile ducts [3,4]. The most identifiable feature in biopsy specimens, however, is the loss of bile ducts as foamy changes which are usually restricted to large arteries. ...
... In another study, however, none of 36 patients who received long-term low dose immunosuppressive therapy developed CR [26]. In fact, tacrolimus based immunosuppressive treatment has been reported as an effective factor for preventing CR [4,27], however, other studies suggested that immunosuppression regimes could not be definitive determinants in prevention of CR [6,26]. DSAs which have been mainly against HLA II and C3d component of complement system are seen in increasing frequencies with the time after transplantation (8% within 5 years while 50% in >15 years of LT) [23]. ...
Background. Chronic graft rejection (CR) represents an increasing concern in pediatric liver transplantation (LT). Risk factors of CR in this population are uncertain. In present study, we aimed to ascertain if clinical parameters could predict the occurrence of CR in LT children.
Methods. We retrospectively analyzed the results from 47 children who had experienced acute hepatic rejection in Namazee hospital, Shiraz, Iran during 2007–2017.
Results. Out of 47 children, 22 (46.8%) and 25 (53.2%) were boys and girls respectively. Ascites, gastrointestinal bleeding, and spontaneous bacterial peritonitis were observed in 20 (44.4%), 14 (31.1%), and 4 (9.1%) respectively. Posttransplant vascular and biliary complications were observed in 3 (7%) and 4 (9.3%) cases respectively. The mean time from LT to normalization of liver enzymes was 14.2 ± 7.5 days. The mean of acute rejection episodes was 1.4 ± 0.6 (median = 1 (22, 46.8%), range of 1–3). Six (12.7%) patients experienced CR. The mean time from LT to CR was 75 ± 28.4 days. A significant association was found between CR and patients’ condition (being inpatient or outpatient) before surgery (P = 0.03). No significant relationship was found between CR and post-transplant parameters except for biliary complications (P = 0.01). Both biliary complication (RR = 33.7, 95% CI: 2.2–511, P = 0.01) and inpatient status (RR = 10.9, 95% CI: 1.1–102.5, P = 0.03) significantly increased the risk of CR.
Conclusion. Being hospitalized at the time of LT, and development of biliary complications might predict risk factors for development of CR in LT children.
... Prospective clinical trial of weaning of immunosuppression in liver transplant recipients was described a cohort of 23 patients free from immunosuppressive drugs among 104 liver transplantations, however it requires a permanent management and follow-up of rejections events (13)(14). Accordingly to a publication their findings suggest that chronic rejection does not occur in pediatric liver transplant recipients receiving tacrolimusbased immunosuppression, provided baseline immunosuppression is maintained (15,16). Protocols inducing mixed chimerism are described with infusion of donor bone marrow into recipients, however these protocols have revealed to have toxic side effects. ...
Amaç Karaciğer transplantasyonu sonrası tolerans kavramı son yıllarda giderek popülarite kazanmaktadır. Bu çalışmada amacımız çok özenli parametrelerle seçilmiş yaklaşık on yıllık bir seride düşük doz immünosupressif kullanan bir grupta toleransın varlığını CD3+ hücrelerde mikrokimerizmin yokluğu ile kanıtlamaya çalışmaktır. Gereç ve Yöntem Mikrokimerizm yokluğunu araştırma yöntemi; retrospektif olarak donör kanlarından cross match yapılarak DNA izolasyonunun ardından, mikrosatellit markerlarının PCR ile amplifikasyonu ve dönör ve alıcı allellerinin karşılaştırılması ilkesine dayanıyordu. Bulgular Postoperatif takiplerinde organ reddi ya da buna bağlı komplikasyonları olmayan alkole bağlı sirozu olan 12 hastadan bir izogrup oluşturuldu. Bu hastalar immunsüpresif olarak takrolimus ve mikofenolat mofetil kullanıyordu ve ilaç kan düzeyleri 5 ng/l yani kabul edilebilir sınırın altında idi. Çalışmamızda hiçbir hastamızda kimerizm gözlemlemedik. Sonuç Biyokimyasal stabiliteyi koruyan mikrokimerizmin yokluğu yani transplantasyona tolerans olması durumunda immunsupressif tedavilerin kesilebilir olmasının düşünülebilirliği gündeme gelmektedir.Böylelikle immünsüpressif tedavilerin yan etkileri azalacak ve hastalar böbrek yetmezliği, metabolik bozukluklar, diyabet ve kanserlerin artmış riskinden korunacak, dolayısı ile yaşam kalitesi artmış ve transplantasyon sonrası kullanılan ilaçların ülke ekonomisine yükü azalmış olacaktır.
... Moreover, chronic rejection is characterized by the loss of small bile ducts [69][70][71]. Although the incidence of chronic rejection has decreased from 15-20% to 2-3% due to effective immunosuppression and early assessment of liver biopsies [69][70][72][73][74], it is still an important cause of liver allograft failure. Our previous study showed that accelerated telomere intensity decline occurred in hepatocytes in chronic rejection within a year of transplantation. ...
... Our aim was to identify factors related to the progression or reversibility of CR. Although several authors have reported an absence of CR under tacrolimus-based immunosuppression (21,22), the incidence of CR in our population was 5.4%, and most of these CR cases were observed in children already on a tacrolimus regimen. Interestingly, the median tacrolimus levels at the time of CR diagnosis were deemed adequate (9). ...
Objective:
Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation.
Methods:
Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups.
Results:
Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01).
Conclusion:
The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.
... Graft disease, and particularly CR, constituted the main indication for late reLT in 59% (Table 3). It was previously published that CR can be prevented in pediatric recipients of a primary liver transplant who are maintained on tacrolimus-based immunosuppression [15,16]. Such immunosuppressive protocol, by reducing CR incidence, could also contribute in the prevention of late reLT. ...
In this study, the epidemiology and outcome of graft loss following primary pediatric liver transplantation (LT) were analysed, with the hypothesis that early retransplantation (reLT) might be associated with lower immunologic risks when compared with late reLT. Between March 1984 and December 2005, 745 liver grafts were transplanted to 638 children at Saint-Luc University Hospital, Brussels. Among them, a total of 90 children (14%) underwent 107 reLT, and were categorized into two groups (early reLT, n = 58; late reLT, n = 32), according to the interval between either transplant procedures (< or >30 days). Ten-year patient survival rate was 85% in recipients with a single LT, vs. 61% in recipients requiring reLT (P < 0.001). Ten-year patient survival rates were 59% and 66% for early and late reLT, respectively (P = 0.423), the corresponding graft survival rates being 51% and 63% (P = 0.231). Along the successive eras, the rate of reLT decreased from 17% to 10%, whereas progressive improvement of outcome post-reLT was observed. No recurrence of chronic rejection (CR) was observed after reLT for CR (0 of 19). Two children developed a positive cross-match at reLT (two of 10, 20%), both retransplanted lately for CR secondary to immunosuppression withdrawal following a post-transplant lymphoproliferative disease. In summary, the results presented could not evidence better results for late reLT when compared with early reLT. The former did not seem to be associated with higher immunologic risk, except for children having withdrawal of immunosuppression following the first graft.
... Additionally, no specific association between the number of episodes of late acute rejection and the appearance of autoantibodies could be seen according to other groups. 23,34 A comparison of the patients of the 2 study groups justifies the following questions: (1) is there a relationship between close controls with readily strengthened immunosuppression and the lack of fully developed de novo AIH and (2) are features of de novo AIH and unreliable compliance related as in our group of transplanted NAIC patients. Furthermore, the similarity of outcome in terms of late fibrotic transformation of the graft with or without follow-up protocol biopsies calls for a critical review of the indication for protocol biopsies during late follow-up. ...
Chronic graft dysfunction, manifesting with elevated liver enzymes and histological features of interface hepatitis (IH), is being increasingly recognized as a long-term problem after liver transplantation. The aim of this study was to characterize our group of post-orthotopic liver transplantation (OLT) patients with respect to clinical, laboratory, and histological signs of IH. A retrospective study of charts and liver biopsy specimens from patients transplanted between 1986 and 1999 was used. Histological features of IH were found in 29/119 patients at a median interval of 23.9 months (95% confidence interval -28.2 to 52.6) after OLT. All patients with IH had risk factors for chronic rejection, such as steroid-resistant rejection, acute rejection later than 3 months post-OLT, female receiver of male graft, or pretransplant cytomegalovirus (CMV)-positive serology with a CMV-negative donor liver. None of the 29 had features favoring a diagnosis of de novo autoimmune hepatitis, but 4 had isolated hypergammaglobulinemia, and 4 had non-organ-specific autoantibodies without hyperimmunoglobulin G. Sixteen of 29 patients also had features of chronic rejection, such as foam cell arteriopathy, loss of bile ducts, or pericentral fibrosis. After abnormal biopsy, all but 1 patient were switched to tacrolimus. During a median follow-up of 12 years, death occurred in 5, retransplantation occurred in 7, and definite cirrhosis occurred in 4. In conclusion, IH was detected in 24.4% of our patients and was associated with a high degree of fibrosis development. Most likely, IH represents a form of chronic rejection directed against periportal hepatocytes.
... per patient year (0.20 in infants and 0.44 in adolescents), and only 1.5% of patients developed graft failure, with few patients dying directly or indirectly due to rejection. The era effect does indicate that rejection rates are now acceptably low and chronic rejection is almost absent in the tacrolimus era, confirming recent large single center analyses (21). Moreover, recent evidence suggests that the immune response toward a liver allograft is not necessarily always harmful. ...
Rejection and infection are important adverse events after pediatric liver transplantation, not previously subject to concurrent risk analysis. Of 2291 children (<18 years), rejection occurred at least once in 46%, serious bacterial/fungal or viral infections in 52%. Infection caused more deaths than rejection (5.5% vs. 0.6% of patients, p < 0.001). Early rejection (<6 month) did not contribute to mortality or graft failure. Recurrent/chronic rejection was a risk in graft failure, but led to retransplant in only 1.6% of first grafts. Multivariate predictors of bacterial/fungal infection included recipient age (highest in infants), race, donor organ variants, bilirubin, anhepatic time, cyclosporin (vs. tacrolimus) and era of transplant (before 2002 vs. after 2002); serious viral infection predictors included donor organ variants, rejection, Epstein-Barr Virus (EBV) naivety and era; for rejection, predictors included age (lowest in infants), primary diagnosis, donor-recipient blood type mismatch, the use of cyclosporin (vs. tacrolimus), no induction and era. In pediatric liver transplantation, infection risk far exceeds that of rejection, which causes limited harm to the patient or graft, particularly in infants. Aggressive infection control, attention to modifiable factors such as pretransplant nutrition and donor organ options and rigorous age-specific review of the risk/benefit of choice and intensity of immunosuppressive regimes is warranted.
... The concerning impact of chronic rejection on LGL seen in this study is confirmed by our findings. Although small in absolute numbers, there is clearly a subset of patients who suffer LGL due to chronic rejection, contrasting published accounts of an almost insignificant incidence of this complication (9,10). ...
... Similar to other studies, steroid-resistant rejection was also found to be associated with LGL (8). Although tacrolimus has been shown to dramatically decrease the rate of chronic rejection in pediatric liver-transplant recipients (9)(10)(11)(12), analysis of the SPLIT data did not show any difference in LGL in those children receiving cyclosporine versus tacrolimus (data not shown). Our data also demonstrated that the incidence of LGL was similar in patients transplanted before 2002 when compared to those receiving LT after 2002. ...
Late graft loss (LGL) and late mortality (LM) following liver transplantation (LT) in children were analyzed from the studies of pediatric liver transplantation (SPLIT) database. Univariate and multivariate associations between pre- and postoperative factors and LGL and LM in 872 patients alive with their primary allografts 1 year after LT were reviewed. Thirty-four patients subsequently died (LM) and 35 patients underwent re-LT (LGL). Patients who survive the first posttransplant year had 5-year patient and graft survival rates of 94.2% and 89.2%, respectively. Graft loss after the first year was caused by rejection in 49% of the cases with sequelae of technical complications accounting for an additional 20% of LGL. LT for tumor, steroid resistant rejection, reoperation in the first 30 days and >5 admissions during the first posttransplant year were independently associated with LGL in multivariate analysis. Malignancy, infection, multiple system organ failure and posttransplant lymphoproliferative disease accounted for 61.8% of all late deaths after LT. LT performed for FHF and tumor were associated with LM. Patients who are at or below the mean for weight at the time of transplant were also at an increased risk of dying. Frequent readmission was also found to be associated with LM.
... Results of liver transplantation (LTx) have improved significantly in the last three decades [1]. Graft loss from acute or chronic rejection is rare [2][3][4] with currently available modern immunosuppressive agents. One of the commonest reasons of early graft loss is hepatic artery thrombosis (HAT). ...
Arterial complications have a major impact on survival after liver transplantation (LTx). The aim of this study was to examine arterial complications in adults and children after LTx. A total of 1000 consecutive primary LTx patients [mean age 40.5 years: 600 males, 400 females, 834 adults; 166 children (age <18 years)] were studied. Forty-two patients (4.2%; 31 adults, 11 children) developed hepatic artery thrombosis (HAT). Thrombosis in children occurred significantly early (mean 5.4 days) compared with adults (mean 418.7 days, P = 0.0001). Nonthrombotic complications occurred in 30 patients (29 adults, one child). Overall, 13-year patient survival after HAT was 43.2% (72.7% children, 32.9% adults). For nonthrombotic complications, 54.3% of adults died and 69.4% grafts were lost. An overall incidence of 4.2% thrombotic and 3.2% nonthrombotic complications was observed. Rate of HAT was higher in children, but survival was better compared with adults.
