Impeccable management of immunosuppression is required to ensure the best longterm outcomes for liver transplant recipients. This is particularly challenging for children who arguably need 8 decades ...of graft and patient survival. Too little risks chronic, often subclinical allo‐immune injury while too much risks insidious and cumulative toxicities. Historically, immunosuppression minimization or withdrawal has been a strategy to optimize the longevity of liver transplant recipients. The literature is sprinkled with single‐center reports of operationally tolerant patients ‐ those with apparently normal liver function and liver tests. However, without biopsy evidence of immunological quiescence, confidence in the phenotypic assignment of tolerance is shaky. More recently, multicenter trials of immunosuppression withdrawal for highly selected, stable, longterm adult and pediatric liver recipients have shown tolerance rates, based on both biochemical and histological assessment, of 40% and 60%, respectively. Extended biochemical and histologic follow‐up of children over 8 years, equivalent to 7+ years off of drug, suggests that operational tolerance is robust. Therefore, clearly, immunosuppression can be completely and safety withdrawn from highly‐selected subsets of adults and children. However, these trials have also confirmed that clinically ideal recipients ‐ those eligible for immunosuppression withdrawal trial ‐ can harbor significant and worrisome inflammation and/or fibrosis. Although the etiology and prognosis of these findings remain unknown, it is reasonable to surmise that they may reflect an anti‐donor immune response that is insufficiently controlled. To achieve the outcomes that we are seeking and that our patients are demanding, we desperately need noninvasive but accurate biomarkers that identify whether immunosuppression is neither too much nor too little but “just right.” Until these are available, liver histology remains the gold standard to assess allograft health and guide immunosuppression management. Liver Transplantation 23 1601–1614 2017 AASLD.
Physical frailty after liver transplantation Lai, Jennifer C.; Segev, Dorry L.; McCulloch, Charles E. ...
American journal of transplantation,
August 2018, Volume:
18, Issue:
8
Journal Article
Peer reviewed
Open access
Frailty is prevalent in liver transplant candidates, but little is known of what happens to frailty after liver transplantation. We analyzed data for 214 adult liver transplant recipients who had ≥1 ...frailty assessment using the Liver Frailty Index (LFI) at 3‐ (n = 178), 6‐ (n = 139), or 12‐ (n = 107) months posttransplant (higher values=more frail). “Frail” and “robust” were defined as LFI ≥4.5 and <3.2. Median pre–liver transplant LFI was 3.7, and was worse at 3 months (3.9; P = .02), similar at 6 months (3.7; P = .07), and improved at 12 months (3.4; P < .001). The percentage who were robust pre‐ and 3‐, 6‐, and 12‐months posttransplant were 25%, 14%, 28%, and 37%; the percentage frail were 21%, 21%, 10%, and 7%. In univariable analysis, each 0.1 pretransplant LFI point more frail was associated with a decreased odds of being robust at 3‐ (odds ratio OR 0.75), 6‐ (OR 0.77), and 12‐months (OR 0.90) posttransplant (P ≤ .001), which did not change substantially with multivariable adjustment. In conclusion, frailty worsens 3 months posttransplant and improves modestly by 12 months, but fewer than 2 of 5 patients achieve robustness. Pretransplant LFI was a potent predictor of posttransplant robustness. Aggressive interventions aimed at preventing frailty pretransplant are urgently needed to maximize physical health after liver transplantation.
Physical frailty only modestly improves after liver transplantation and is most strongly predicted by pretransplant physical frailty status, suggesting the need for structured interventions aimed at preventing pretransplant physical frailty to maximize physical health after liver transplantation. See Maddur and Levitsky's editorial on page 1841.
The development of human leukocyte antigen (HLA) donor‐specific antibody/antibodies (DSA) is not well described in liver transplant (LT) patients undergoing immunosuppression (IS) withdrawal ...protocols despite the allograft risk associated with de novo DSA (dnDSA). We analyzed the development of dnDSA in 69 LT patients who received calcineurin inhibitor monotherapy and were enrolled in the ITN030ST study. Of these 69 patients, 40 stable patients were randomized to IS maintenance (n = 9) or IS minimization (n = 31). Nine of the 31 IS minimization patients achieved complete withdrawal and were free of IS. Among patients who achieved stable IS monotherapy 1 year after transplantation, the prevalence of dnDSA was 18.8%. Acute rejections and the biopsy‐proven findings disqualifying patients from IS withdrawal attempt were factors associated with dnDSA development (P = 0.011 and P = 0.041, respectively). Among randomized patients, dnDSA prevalence was 51.7% after IS minimization and 66.7% in IS‐free patients. dnDSA prevalence in patients on IS maintenance was 44.4%. dnDSA development during IS minimization was a risk factor for acute rejection (P = 0.015). The majority of dnDSA were against HLA‐DQ antigens (78.7%). Conclusion. During the first year following transplantation, acute rejections increase the risk of developing dnDSA, so dnDSA positivity should be considered for IS withdrawal eligibility; during IS minimization, dnDSA development was associated with acute rejection, which prevented further IS withdrawal attempts.
A substantial proportion of pediatric liver transplant recipients develop subclinical chronic allograft injury. We studied whether there are distinct patterns of injury based on histopathologic ...features and identified associated immunologic profiles.
We conducted a cross-sectional study of 157 stable, long-term pediatric recipients of transplanted livers (70 boys; > 6 years old at time of transplantation; mean, 8.9 ± 3.46 years after liver transplantation) who underwent liver biopsy analysis from August 13, 2012, through May 1, 2014. Participants had received livers from a living or deceased donor and had consistently normal results from liver tests. Liver biopsy specimens were scored by a central pathologist; an unsupervised hierarchical cluster analysis of histologic features was used to sort biopsy samples into 3 clusters. We conducted transcriptional and cytometric analyses of liver tissue samples and performed a systems biology analysis that incorporated clinical, serologic, histologic, and transcriptional data.
The mean level of alanine aminotransferase in participants was 27.6 ± 14.57 U/L, and the mean level of γ-glutamyl transferase was 17.4 ± 7.93 U/L. Cluster 1 was characterized by interface activity (n = 34), cluster 2 was characterized by periportal or perivenular fibrosis without interface activity (n = 45), and cluster 3 had neither feature (n = 78). We identified a module of genes whose expression correlated with levels of alanine aminotransferase, class II donor-specific antibody, portal inflammation, interface activity, perivenular inflammation, portal and perivenular fibrosis, and cluster assignment. The module was enriched in genes that regulate T-cell–mediated rejection (TCMR) of liver and other transplanted organs. Functional pathway analysis showed overrepresentation of TCMR gene sets for cluster 1 but not clusters 2 or 3.
In an analysis of biopsies from an apparently homogeneous group of stable, long-term pediatric liver transplant recipients with consistently normal liver test results, we found evidence of chronic graft injury (inflammation and/or fibrosis). Biopsy samples with interface activity had a gene expression pattern associated with TCMR.
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Pediatric liver transplant recipients arguably have the most to gain and the most to lose from discontinuing immunosuppression (IS). Whereas IS undoubtedly exerts a cumulative toll, there is concern ...that insufficient or no IS may contribute to allograft deterioration. Twelve pediatric recipients of parental living donor liver grafts, identified as operationally tolerant through complete IS withdrawal (WISP‐R; NCT00320606), were followed for a total of 5 years (1 year of IS withdrawal and 4 years off IS) with serial liver tests and autoantibody and alloantibody assessments. Liver biopsies were performed 2 and 4 years off IS, and, at these time points, immunoglobulin G (IgG) subclass and C1q binding activity for donor‐specific antibodies (DSAs) were determined. There were no cases of chronic rejection, graft loss, or death. Allografts did not exhibit progressive increase in inflammation or fibrosis. Smooth‐muscle actin expression by stellate cells and CD34 expression by liver sinusoidal endothelial cells remained stable, consistent with the absence of progressive graft injury. Three subjects never exhibited DSA. However, 3 subjects showed intermittent de novo class I DSA, 4 subjects showed persistent de novo class II DSA, and 5 subjects showed persistent preexisting class II DSA. Class II DSA was predominantly against donor DQ antigens, often of high mean fluorescence intensity, rarely of the IgG3 subclass, and often capable of binding C1q. Conclusion: Operationally tolerant pediatric liver transplant recipients maintain generally stable allograft histology in spite of apparently active humoral allo‐immune responses. The absence of increased inflammation or progressive fibrosis suggests that a subset of liver allografts seem resistant to the chronic injury that is characteristic of antibody‐mediated damage. (Hepatology 2017;65:647‐660)
Background and Aims
Tolerance is transplantation’s holy grail, as it denotes allograft health without immunosuppression and its toxicities. Our aim was to determine, among stable long‐term pediatric ...liver transplant recipients, the efficacy and safety of immunosuppression withdrawal to identify operational tolerance.
Approach and Results
We conducted a multicenter, single‐arm trial of immunosuppression withdrawal over 36‐48 weeks. Liver tests were monitored biweekly (year 1), monthly (year 2), and bimonthly (years 3‐4). For‐cause biopsies were done at investigators’ discretion but mandated when alanine aminotransferase or gamma glutamyltransferase exceeded 100 U/L. All subjects underwent final liver biopsy at trial end. The primary efficacy endpoint was operational tolerance, defined by strict biochemical and histological criteria 1 year after stopping immunosuppression. Among 88 subjects (median age 11 years; 39 boys; 57 deceased donor grafts), 33 (37.5%; 95% confidence interval CI 27.4%, 48.5%) were operationally tolerant, 16 were nontolerant by histology (met biochemical but failed histological criteria), and 39 were nontolerant by rejection. Rejection, predicted by subtle liver inflammation in trial entry biopsies, typically (n = 32) occurred at ≤32% of the trial‐entry immunosuppression dose and was treated with corticosteroids (n = 32) and/or tacrolimus (n = 38) with resolution (liver tests within 1.5 times the baseline) for all but 1 subject. No death, graft loss, or chronic, severe, or refractory rejection occurred. Neither fibrosis stage nor the expression level of a rejection gene set increased over 4 years for either tolerant or nontolerant subjects.
Conclusions
Immunosuppression withdrawal showed that 37.5% of selected pediatric liver‐transplant recipients were operationally tolerant. Allograft histology did not deteriorate for either tolerant or nontolerant subjects. The timing and reversibility of failed withdrawal justifies future trials exploring the efficacy, safety, and potential benefits of immunosuppression minimization.
We previously reported encouraging results of down‐staging of hepatocellular carcinoma (HCC) to meet conventional T2 criteria (one lesion 2–5 cm or two to three lesions <3 cm) for orthotopic liver ...transplantation (OLT) in 30 patients as a test of concept. In this ongoing prospective study, we analyzed longer‐term outcome data on HCC down‐staging in a larger cohort of 61 patients with tumor stage exceeding T2 criteria who were enrolled between June 2002 and January 2007. Eligibility criteria for down‐staging included: (1) one lesion >5 cm and up to 8 cm; (2) two to three lesions with at least one lesion >3 cm and not exceeding 5 cm, with total tumor diameter up to 8 cm; or (3) four to five lesions with none >3 cm, with total tumor diameter up to 8 cm. A minimum observation period of 3 months after down‐staging was required before OLT. Tumor down‐staging was successful in 43 patients (70.5%). Thirty‐five patients (57.4%) had received OLT, including two who had undergone live‐donor liver transplantation. Treatment failure was observed in 18 patients (29.5%), primarily due to tumor progression. In the explant of 35 patients who underwent OLT, 13 had complete tumor necrosis, 17 met T2 criteria, and five exceeded T2 criteria. The Kaplan‐Meier intention‐to‐treat survival at 1 and 4 years after down‐staging were 87.5% and 69.3%, respectively. The 1‐year and 4‐year posttransplantation survival rates were 96.2% and 92.1%, respectively. No patient had HCC recurrence after a median posttransplantation follow‐up of 25 months. The only factor predicting treatment failure was pretreatment alpha‐fetoprotein >1,000 ng/mL. Conclusion: Successful down‐staging of HCC can be achieved in the majority of carefully selected patients and is associated with excellent posttransplantation outcome. (HEPATOLOGY 2008.)
Expanded criteria donors Feng, Sandy; Lai, Jennifer C
Clinics in liver disease,
08/2014, Volume:
18, Issue:
3
Journal Article
Peer reviewed
Open access
The greatest challenge facing liver transplantation today is the shortage of donor livers. Demand far exceeds supply, and this deficit has driven expansion of what is considered an acceptable organ. ...The evolving standard has not come without costs, however, as each new frontier of expanded donor quality (i.e., advancing donor age, donation after cardiac death, and split liver) may have traded wait-list for post-transplant morbidity and mortality. This article delineates the nature and severity of risk associated with specific deceased donor liver characteristics and recommends strategies to maximally mitigate these risks.
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