Predictors of survival following liver transplantation for pediatric hepatoblastoma and hepatocellular carcinoma: Experience from the Society of Pediatric Liver Transplantation (SPLIT).

Management of unresectable pediatric hepatoblastoma (HB) and hepatocellular carcinoma (HCC) remains challenging. The Society of Pediatric Liver Transplantation (SPLIT) database was used to study survival predictors in pediatric liver transplantation (LT) for HB and HCC. Event-free survival (EFS), associated risk factors, and postoperative complications were studied in children requiring LT for HB/HCC at 16 SPLIT centers. Three-year EFS was 81% for HB (n = 157) and 62% for HCC (n = 18) transplants. Of HB transplants, 6.9% were PRETEXT II and 15.3% were POST-TEXT I/II. Tumor extent did not impact survival (p = NS). Salvage (n = 13) and primary HB transplants had similar 3-year EFS (62% versus 78%, p = NS). Among HCC transplants, 3-year EFS was poorer in older patients (38% in ≥8-year-olds vs 86% <8-year-olds) and those with larger tumors (48% for those beyond versus 83% within Milan criteria, p = NS). Risk of infection (HR 1.5, 95% CI 1.1-2.2, p = .02) and renal injury (HR 2.4, 95% CI 1.7-3.3, p < .001) were higher in malignant versus nonmalignant LT. Survival is favorable for pediatric HB and HCC LT, including outcomes after salvage transplant. Unexpected numbers of LTs occurred in PRE/POST-TEXT I/II tumors. Judicious patient selection is critical to distinguish tumors that are potentially resectable; simultaneously, we must advocate for patients with unresectable malignancies to receive organs.

Non-HLA AT1R antibodies are highly prevalent after pediatric intestinal transplantation.

The role of angiotensin II type-1 receptor (AT1R) antibodies in intestinal transplantation (ITx) is unclear. The aims were 1) to identify the prevalence of AT1R antibodies in pediatric ITx, compared to pediatric intestinal failure (IF), and 2) to determine whether AT1R antibodies were associated with graft dysfunction. 46 serum samples from 25 ITx patients (3 isolated ITx, 22 liver-inclusive ITx) were collected during routine visits >6 months apart and during episodes of graft dysfunction as a result of infectious enteritis or rejection. For comparison, samples were collected from 7 IF control patients. AT1R antibodies were considered positive for levels >17 U/mL. The median (range) AT1R antibody level for ITx patients was 40.0 U/mL (7.2-40.0), compared to 7.0 U/mL (5.7-40.0) for IF patients (p = .02). There was a trend toward higher prevalence of AT1R antibodies in ITx compared with IF patients (68% versus 29%, p = .09). Among ITx patients, the prevalence of AT1R antibodies was not different between periods of active graft dysfunction and normal health (83% versus 67%, p = .31). For 16 patients with >2 samples, AT1R antibodies remained positive in 67% cases, developed in 14% cases, disappeared in 10% cases, and remained negative in 10% cases. The changes in AT1R antibodies did not correlate with de/sensitizing events. This is the first study of AT1R antibodies in pediatric ITx. AT1R antibodies are highly prevalent after ITx and may be triggered by immune activation associated with the transplant. However, their pathogenicity and clinical utility remain in question.

Characterization of T cell immunophenotypes in intestinal transplantation: A pilot study.

Immunophenotyping of peripheral blood mononuclear cells has been shown to be a useful, non-invasive method of predicting acute cellular rejection (ACR) following intestinal transplantation (ITx). Our objectives were to characterize differences in the T cell immunophenotype of ITx recipients in peripheral blood samples (1) collected late versus early after ITx and (1) associated with episodes of ACR and infectious enteritis. An IRB-approved, cross-sectional study of ITx recipients was performed. Peripheral blood samples were collected during normal visits and episodes of allograft dysfunction. A total of 38 patients were included in the analysis: 31 ITx recipients (87% liver-inclusive allografts) and 7 intestinal failure control patients. Of the ITx patients, 26 patients were pediatric patients (<21 years). A total of 70 samples were analyzed from ITx recipients, including 51 during normal visits and 19 during episodes of allograft dysfunction (median of 2 samples per patient; range of 1-6 samples per patient). In the late (n = 32) versus early post-ITx (n = 19) normal samples, there was a significantly higher percentage of central memory CD4 T cells (p = .001). In the ACR (n = 5) versus infectious enteritis (n = 14) samples, there was a higher percentage of CD8 T cells expressing HLA-DR (p = .002), CD57 (p < .001), and KLRG1 (p < .001) and a higher percentage of CD4 T cells expressing CD57 (p = .03). Additional studies are needed with larger cohorts to validate these changes in the T cell immunophenotype. Further elucidating T cell immunophenotypes in ITx will lead to a better understanding of immune mechanisms of allograft dysfunction, identification of potential biomarkers in ITx, and optimized selection of immunosuppressive therapies.

Prevalence and Clinical Impact of Donor-Specific Alloantibody Among Intestinal Transplant Recipients.

BACKGROUND: Rejection remains the leading cause of allograft loss, and a major barrier to improving long-term outcomes after intestinal transplantation. Our aim is to define the prevalence and investigate the role of donor-specific antibody (DSA) on intestinal graft outcomes. METHODS: The study includes 109 transplants performed in 95 recipients at a single center. Patients were screened for DSA pretransplant, monitored regularly posttransplant and when clinically indicated using the single-antigen bead Luminex assay. Standard induction immunosuppression was with interleukin-2 receptor antagonists, and antithymocyte globulin in high-risk recipients. Maintenance regimens were tacrolimus-based. RESULTS: Pretransplant DSA was detected in 12 (11%) recipients with 50% continuing to have circulating antibodies posttransplant. An additional 24 (25%) patients developed de novo DSA, and of these, 71% had persistent antibodies. Recipients with preformed DSA demonstrated elevated risks of early graft failure, whereas those with de novo DSA experienced accelerated graft loss once DSA was detected, reaching a 28% failure rate within 2 years. HLA-DQ mismatch is a significant risk factor for de novo DSA emergence, whereas the persistence of antibodies is predicted by DSA strength and specificity. Although inclusion of the liver in the intestinal allograft imparts an immunological advantage against rejection-related graft loss, this protective effect was lost among recipients with persistent DSA. CONCLUSIONS: The presence of DSA is associated with inferior graft outcomes among intestinal transplant recipients. An enhanced understanding of the mechanisms by which DSA causes allograft injury, and effective strategies targeting humoral immune reactivity are needed to improve long-term intestinal graft outcomes.

Incidence, timing, and significance of early hypogammaglobulinemia after intestinal transplantation.

BACKGROUND: Despite recent advances in intestinal transplantation (ITx), infection (INF) and acute cellular rejection (ACR) remain major causes of patient and graft loss. Studies in other solid-organ transplantations indicate that low levels of serum immunoglobulin G (IgG) negatively impact outcomes. To date, there have been no studies on IgG after ITx. METHODS: A retrospective review of an IgG measurement protocol in primary ITx recipients between 2007 and 2011 was undertaken. IgG levels were measured at the time of evaluation, transplantation, and at weekly intervals for 2 months. Hypogammaglobulinemia (HGG) was defined as IgG levels below the lower limit of the 95% confidence interval for age. Associations between HGG, INF, and ACR were tested, and the incidence and timing of INF and ACR were compared. RESULTS: Thirty-four patients were transplanted at a mean (SD) age of 12.4 (17.2) years. Most were Latino children with gastroschisis who received multivisceral grafts. Relative to pre-ITx levels, a statistically significant decrease in IgG levels was observed after ITx (P<0.05). Twenty patients (59%) developed HGG during the post-ITx period at a mean (SD) of 9.8 days. No significant associations were identified between HGG and INF or ACR. CONCLUSIONS: This is the first study to describe serum IgG levels after ITx. A marked decrease in serum IgG levels was observed early on, in most patients. The etiology is potentially related to immunotherapy. HGG was not associated with INF or ACR, possibly related to the sample size and our practice of exogenous intravenous immunoglobulin replacement.

Pretransplant predictors of survival after intestinal transplantation: analysis of a single-center experience of more than 100 transplants.

INTRODUCTION: Outcomes after intestinal transplantation (ITx) have steadily improved. There are few studies that assess factors associated with these enhanced results. The purpose of this study was to examine peri-ITx variables and survival. METHODS: A review of a prospectively maintained database was undertaken and included all patients undergoing ITx from 1991 to 2010. The study endpoints were patient and graft survival. Data collection included 44 variables. Survival was computed using Kaplan-Meier methods. Univariate analysis was conducted (log-rank test) with significance set at P less than or equal to 0.20. Multivariate analysis of significant variables was conducted using model reduction by backward elimination variable selection method with significance set at P less than 0.05. RESULTS: Eighty-eight patients received 106 ITx. The majority of recipients were male, Latino, and children. The leading causes of intestinal and liver failure were gastroschisis and parenteral nutrition. Grafts transplanted were isolated intestine (24%), liver-intestine (62%), and multivisceral (14%). Overall 1- and 5-year patient and graft survival were 80% and 65%, and 74% and 64%, respectively. Significant univariate survival predictors were weight less than 20 kg, children, liver-inclusive allograft, panel reactive antibody less than 20%, absence of donor-specific antibody, negative crossmatch, warm ischemia time less than 60 min, absence of recipient splenectomy, interleukin-2 receptor antagonist induction, and era. Significant multivariate survival predictors were absence of donor-specific antibody, absence of recipient splenectomy, and liver-inclusive graft type. CONCLUSION: This large, single-center ITx experience confirms a marked improvement in outcome over time. Several important factors were associated with survival, and these factors can potentially be adjusted before ITx. These findings should refocus future efforts on strategies to improve treatment and prevent graft loss.

Immunosuppression and the risk of post-transplant malignancy among cadaveric first kidney transplant recipients.

The success of renal transplantation may be counterbalanced by serious adverse medical events. The effect of immunosuppression on the incidence of de novo neoplasms among kidney recipients should be monitored continuously. Using data from the Scientific Registry of Transplant Recipients, we studied the association of induction therapy by immunosuppression with antilymphocyte antibodies, with the development of de novo neoplasms. The study population included more than 41 000 recipients who received a cadaveric first kidney transplant after December 31, 1995, and were followed through February 28, 2002. Using Cox regression models, we estimated time to development of two types of malignancy: de novo solid tumors and post-transplant lymphoproliferative disorder (PTLD). We made adjustments for several patient demographic factors and comorbidities. Induction therapy was significantly associated with a higher relative risk (RR) of PTLD (RR = 1.78, p < 0.001), but not with a greater likelihood of de novo tumors (RR = 1.07, p = 0.42). Treatment with maintenance tacrolimus vs. cyclosporine showed a significantly different RR of developing de novo tumors for recipients with induction than for those not receiving induction (p = 0.024). These new estimates of the magnitude of malignancy risk associated with induction therapy may be useful for clinical practice.

One hundred in situ split-liver transplantations: a single-center experience.

OBJECTIVE: To identify predictors of graft and recipient survival from a single-institution series of in situ split-liver transplantations and compare outcomes to living donor and whole organs for adults and children. SUMMARY BACKGROUND DATA: Split-liver transplantation is a surgical technique that creates 2 allografts from a single cadaver donor. We have applied split-liver transplantation to all indications and categories of medical urgency for initial as well as retransplantation to expand the current donor pool and decrease reliance upon living donation. METHODS: A retrospective analysis was conducted of 100 consecutive in situ split-liver transplantations yielding a left lateral segment and right trisegment graft that were performed at the University of California Los Angeles between 9/91 and 02/03. These 100 transplantations generated 190 allografts for transplantation into 105 children and 60 adults, with the sharing of 25 allografts among transplant centers across the United States. Outcomes and incidence of complications were compared with living donor and whole organ recipients receiving liver transplantation during the same time period with independent predictors of split-liver graft and recipient survival identified by multivariate analysis. RESULTS: The incidence of biliary and vascular complications observed in recipients of left lateral segment grafts created by split-liver transplantation was not statistically different from recipients of left lateral segment grafts created from living donation or children receiving whole-organ grafts from pediatric donors. Kaplan-Meier survival estimations of left lateral segment graft and recipient survival also demonstrated no statistical difference among split-liver, living donor, and whole-organ recipients. Right trisegment grafts from split-liver transplantation demonstrated a 10% incidence of biliary and 7% incidence of vascular complications. Long-term graft function was excellent with patient and graft survival equal to 1086 recipients of cadaver whole-organ grafts from donors ages 10-40 years who underwent transplant operations during the same time period. Predictors of split-liver transplantation graft and recipient survival included United Network for Organ Sharing status at transplantation, indication, occurrence of a complication, donor creatinine, and donor length of hospitalization. CONCLUSIONS: Split-liver transplantation is an effective mechanism for immediate expansion of the cadaver donor pool that can reduce dependence upon living donation in adults and children.

Liver transplantation for fulminant hepatic failure: experience with more than 200 patients over a 17-year period.

OBJECTIVE: To analyze outcomes after liver transplantation (LT) in patients with fulminant hepatic failure (FHF) with emphasis on pretransplant variables that can potentially help predict posttransplant outcome. SUMMARY BACKGROUND DATA: FHF is a formidable clinical problem associated with a high mortality rate. While LT is the treatment of choice for irreversible FHF, few investigations have examined pretransplant variables that can potentially predict outcome after LT. METHODS: A retrospective review was undertaken of all patients undergoing LT for FHF at a single transplant center. The median follow-up was 41 months. Thirty-five variables were analyzed by univariate and multivariate analysis to determine their impact on patient and graft survival. RESULTS: Two hundred four patients (60% female, median age 20.2 years) required urgent LT for FHF. Before LT, the majority of patients were comatose (76%), on hemodialysis (16%), and ICU-bound. The 1- and 5-year survival rates were 73% and 67% (patient) and 63% and 57% (graft). The primary cause of patient death was sepsis, and the primary cause of graft failure was primary graft nonfunction. Univariate analysis of pre-LT variables revealed that 19 variables predicted survival. From these results, multivariate analysis determined that the serum creatinine was the single most important prognosticator of patient survival. CONCLUSIONS: This study, representing one of the largest published series on LT for FHF, demonstrates a long-term survival of nearly 70% and develops a clinically applicable and readily measurable set of pretransplant factors that determine posttransplant outcome.