High prevalence of hepatitis A and B nonimmunity in pediatric liver transplant recipients.

BACKGROUND: Pediatric liver transplant recipients are at increased risk of post-transplant infections. The purpose of this study was to quantify hepatitis A and B non-immunity based on antibody titers in liver transplant recipients. METHODS: We conducted a retrospective chart review of 107 pediatric liver transplant recipients at a single medical center from 2000 to 2017. We compared hepatitis immune patients to non-immune patients and studied response to vaccination in patients immunized post-transplantation. RESULTS: Eighty-one percent of patients had pre-transplant immunity to hepatitis A whereas 68% had pre-transplant immunity to hepatitis B. Post-transplant hepatitis B immunity decreased to 33% whereas post-transplant hepatitis A immunity remained high at 82%. Older age and time since transplantation were significantly associated with hepatitis B non-immunity. Most patients responded to doses post-transplantation with 78% seroconversion following hepatitis A re-immunization and 83% seroconversion following hepatitis B re-immunization. CONCLUSIONS: Pediatric liver transplant recipients are at risk of hepatitis A and B non-immunity, particularly with respect to hepatitis B. Boosters post-transplant may improve immunity to hepatitis viruses.

The role of donor-specific HLA alloantibodies in liver transplantation.

The impact of donor-specific HLA alloantibodies (DSA) on short- and long-term liver transplant outcome is not clearly defined. While it is clear that not all levels of allosensitization produce overt clinical injury, and that liver allografts possess some degree of alloantibody resistance, alloantibody-mediated adverse consequences are increasingly being recognized. To better define the current state of this topic, we assembled experts to provide insights, explore controversies and develop recommendations for future research on the consequences of DSA in liver transplantation. This article summarizes the proceedings of this inaugural meeting. Several insights emerged. Acute antibody-mediated rejection (AMR), although rarely diagnosed, is increasingly understood to overlap with T cell-mediated rejection. Isolated liver allograft recipients are at increased risk of early allograft immunologic injury when preformed DSA are high titer and persist posttransplantation. Persons who undergo simultaneous liver-kidney transplantation are at risk of renal AMR when Class II DSA persist posttransplantation. Other under-appreciated DSA associations include ductopenia and fibrosis, plasma cell hepatitis, biliary strictures and accelerated fibrosis associated with recurrent liver disease. Standardized DSA testing and diagnostic criteria for both acute and chronic AMR are needed to distil existing associations into etiological processes in order to develop responsive therapeutic strategies.

A common peripheral blood gene set for diagnosis of operational tolerance in pediatric and adult liver transplantation.

To identify biomarkers of operational tolerance in pediatric and adult liver transplant recipients, transcriptional profiles were examined from 300 samples by microarrays and Q-PCR measurements of blood specimens from pediatric and adult liver transplant recipients and normal tissues. Tolerance-specific genes were validated in independent samples across two different transplant programs and validated by Q-PCR. A minimal set of 13 unique genes, highly expressed in natural killer cells (p = 0.03), were significantly expressed in both pediatric and adult liver tolerance, irrespective of different clinical and demographic confounders. The performance of this gene set by microarray in independent samples was 100% sensitivity and 83% specificity and the AUC was 0.988 for only three genes by Q-PCR. 26% of adults and 64% of children with excellent liver allograft function, on minimal or dual immunosuppression, showed high prediction scores for tolerance. Novel peripheral transcriptional profiles can be identified in operational tolerance in pediatric and adult recipients of liver allografts, suggesting a high incidence of a pro-tolerogenic phenotype in stable patients on chronic immunosuppression. Given the high incidence of viral infections and malignancies in liver transplant recipients, this gene set provides an important monitoring tool that can move the field toward personalized and predictive medicine in organ transplantation.

Pediatric health-related quality of life after intestinal transplantation.

As outcomes after ITx improve, greater emphasis is needed on HRQOL. The primary aims of this study were to (i) assess the feasibility of measuring HRQOL in pediatric ITx recipients, (ii) measure HRQOL using validated instruments, and (iii) compare HRQOL in ITx recipients to healthy normal (NL) children. The CHQ and Pediatric Quality of Life (PedsQL4.0) instruments were administered to both patients and parents at outpatient visits. All 24 eligible patients were enrolled. The median age at study enrollment was 6.0 yr (range: 2-18 yr), and the median time from transplant to study enrollment was 2.8 yr (range: 0.5-11.8 yr). The majority of subjects were male (58%), Latino (58%), and liver-inclusive (92%) recipients. For CHQ and PedsQL4.0, parental responses were significantly lower in multiple categories including physical health and social functioning compared to healthy norms. Patient responses were not different from NL using CHQ but using PedsQL4.0 were significantly lower in the school functioning subcategory and psychosocial health summary score. HRQOL as reported by children and families after ITx is significantly lower in multiple categories compared to NL.

Differential cytokine and chemokine expression during rejection and infection following intestinal transplantation.

BACKGROUND/OBJECTIVES: Rejection and infectious enteritis in intestinal transplant (ITx) patients present with virtually identical symptoms. Currently, the gold standard for differentiating between these two conditions is endoscopy, which is invasive and costly. Our primary aim was to identify differences in peripheral blood cytokines during episodes of acute cellular rejection (ACR) and infectious enteritis in patients with intestinal transplants. METHODS: This was a prospective, cross-sectional study involving ITx patients transplanted between 2000 and 2016. We studied 63 blood samples collected from 29 ITx patients during periods of normal (n = 24) and abnormal (n = 17) allograft function. PBMCs from whole blood samples were cultured under unstimulated or stimulated conditions with phytohemagglutinin (PHA). The supernatant from these cultures were collected to measure cytokine and chemokine levels using a 38-plex luminex panel. RESULTS: Our study found that cytokines and chemokines are differentially expressed in normal, ACR, and infectious enteritis samples under unstimulated conditions based on heatmap analysis. Although each cohort displayed distinctive signatures, only MDC (p = 0.037) was found to be significantly different between ACR and infectious enteritis. Upon stimulation of PBMCs, patients with ACR demonstrated increased immune reactivity compared to infectious enteritis; though this did not reach statistical significance. CONCLUSIONS: To our knowledge, this is the first comprehensive study comparing cytokine expression during acute rejection and infectious enteritis in intestinal transplant recipients. Our results suggest that cytokines have the potential to be used as clinical markers for risk stratification and/or diagnosis of ACR and infectious enteritis.

The oversight of solid organ transplantation in the United States.

The publication of the Organ Procurement and Transplantation Network (OPTN) Final Rule in 2000 resulted in a new and different regulatory environment for solid organ transplantation in the United States. In this review the role of the OPTN in providing oversight is clarified, differentiating the powers of enforcement the OPTN and HHS possess compared to the importance of confidential peer review in promoting compliance with OPTN policies. The function of the OPTN's Membership and Professional Standards Committee (MPSC) in adjudicating center performance and investigating alleged violations is described as well as the type and impact of adverse actions that the MPSC can recommend. The role of the OPTN Board compared to that of the Secretary of HHS in determining adverse actions is differentiated. We describe MPSC's broad scope of work in the ongoing evaluation of performance of all transplant centers. Finally, the relationship between the OPTN oversight and other entities charged with safe health care practices in the United States is considered.

Preventable death: children on the transplant waiting list.

Children, especially those under 5 years of age, have the highest death rate on the transplant waiting list compared to any other age range. This article discusses the concept, supported by OPTN data, that there is an age range of small pediatric donors, which are almost exclusively transplanted into small pediatric transplant candidates. Allocation policies that allow broader sharing of small pediatric donors into small pediatric candidates are likely to decrease death rates of children on the waiting list. As well, although the number of pediatric deceased donors continues to decline, improving consent rates for eligible pediatric donors, and judicious use of pediatric donors after cardiac death, can enhance the pediatric deceased donor supply.

Risk factors for rejection and infection in pediatric liver transplantation.

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.

Renal event outcomes in intestinal transplantation: results from a single-center experience.

BACKGROUND: Poor patient outcomes have been closely linked with perioperative renal function after most solid organ transplants, except intestinal transplantation (ITx). This study examined the effect of peri-ITx renal function on outcome. PATIENTS AND METHODS: A retrospective review of all patients undergoing ITx since 1991 was completed and included 43 patients and 49 transplants. Serum creatinine (sCr) and calculated glomerular filtration rate were compared with peri-ITx and out to 5 years. A renal event (RE) was defined as acute renal failure, immunotherapeutic change driven by poor renal function, or hemodialysis. Comparisons were made based on primary immunotherapeutic regimens-induction interleukin-2 receptor antagonist (IL-2RA; n=31) or standard tacrolimus-based therapy (STD; n=18). Data was analyzed using standard statistical analysis. RESULTS: The frequency of RE was: 60% (STD) versus 31% (IL-2RA) P<.05. RE-associated mortality was 63% (STD) and 27% (IL-2RA) P<.05. Overall mortality was associated with a RE in 50% (STD) and 37% (IL-2RA) of patients. Average sCr across all timepoints was 1.05 (STD) and 0.78 (IL-2RA) P<.003. Surviving patients with RE in STD tended to suffer prolonged renal insufficiency, whereas those in IL-2RA did not. CONCLUSION: This is the first study examining outcomes after ITx related to renal function. Clearly, renal function and RE impacted outcomes. Obtaining RE-free survival and lessening the impact of RE when they do occur is of paramount importance. It appears that IL-2RA immunotherapy reduces RE and their associated morbidity.

Nutritional outcomes following pediatric intestinal transplantation.

BACKGROUND: This study sought to describe the long-term nutritional outcomes of children after intestinal transplant (SBT). METHODS: Between 1991 and March 2005, 30 children received 33 SBT at a single center. Eligibility criteria included patient and graft survival >6 months. Weight, height, albumin, prealbumin, zinc (Zn), and essential fatty acid (EFA) levels were reviewed retrospectively. RESULTS: The 19 patients who met inclusion criteria had a median age at SBT of 2.9 years. The majority of patients were male, Latino, transplanted for necrotizing enterocolitis and received combined liver-SBT. All patients were weaned off total parenteral nutrition to elemental formula at a mean of 39 days post-SBT. Seventeen of 19 patients were Zn deficient and four patients were EFA deficient post-SBT. CONCLUSIONS: Pre-SBT most subjects were significantly deficient in anthropometric and biochemical parameters. Post-SBT the mean Z score for weight and height improved significantly at year 1, then leveled off in year 2. Serum protein levels improved from pre-SBT, yet remained low-normal. Zn deficiency was seen frequently after SBT and is under investigation. Children who developed EFA deficiency were on the same formula, receiving inadequate EFA supplementation. Successful SBT was associated with growth and maintenance of serum nutritional parameters but not with significant catch-up growth.

Improved graft survival of pediatric liver recipients transplanted with pediatric-aged liver donors.

BACKGROUND: Improving graft survival after liver transplantation is an important goal for the transplant community, particularly given the increasing donor shortage. We have examined graft survivals of livers procured from pediatric donors compared to adult donors. METHODS: The effect of donor age (<18 years or > or =18 years) on graft survivals for both pediatric and adult liver recipients was analyzed using data reported to the UNOS Scientific Registry from January 1, 1992 through December 31, 1997. Graft survival, stratified by age, status at listing, and type of transplant was computed using the Kaplan-Meier method. In addition, odds ratios of graft failure at 3 months, 1 year, and 3 years posttransplant were calculated using a multivariate logistic regression analysis controlling for several donor and recipient factors. Modeling, using the UNOS Liver Allocation Model investigated the impact of a proposed policy giving pediatric patients preference to pediatric donors. RESULTS: Between 1992 and 1997 pediatric recipients received 35.6% of pediatric aged donor livers. In 1998 the percent of children dying on the list was 7.4%, compared with 7.3% of adults. Kaplan-Meier graft survivals showed that pediatric patients receiving livers from pediatric aged donors had an 81% 3-year graft survival compared with 63% if children received livers from donors > or =18 years (P<0.001). In contrast, adult recipients had similar 3-year graft survivals irrespective of donor age. In the multivariate analysis, the odds of graft failure were reduced to 0.66 if pediatric recipients received livers from pediatric aged donors (P<0.01). The odds of graft failure were not affected at any time point for adults whether they received an adult or pediatric- aged donor. The modeling results showed that the number of pediatric patients trans planted increased by at most 59 transplants per year. This had no significant effect on the probability of pretransplant death for adults on the waiting list. Waiting time for children at status 2B was reduced by as much as 160 days whereas adult waiting time at status 2B was increased by at most 20 days. CONCLUSION: A policy that would direct some livers procured from pediatric- aged donors to children improves the graft survival of children after liver transplantation. The effect of this policy does not increase mortality of adults waiting. Such a policy should increase the practice of split liver transplantation, which remains an important method to increase the cadaveric donor supply.

Serial decrease in glomerular filtration rate in long-term pediatric liver transplantation survivors treated with cyclosporine.

Serial calculations of glomerular filtration rate were made in 31 pediatric liver transplant recipients surviving more than 1 year. GFR was computed from the Schwartz formula, (cGFR = KL/S Cr), before orthotopic liver transplantation, and at 3-6 monthly intervals thereafter. At the same time points, CsA dose/kg, CsA level, blood pressure, and liver functions were recorded. The mean difference between the pre-OLT cGFR and the most-current cGFR for all patients was -50 ml/min/1.73 m2 (P = less than 0.005). In 17/31 (55%), the current cGFR was less than 80 ml/min/1.73 m2, indicative of renal impairment. The cGFR continued to decrease in 24 patients followed beyond 1 year (26.8 ml/min/1.73 m2 per year decrease, P less than 0.005). More patients with a cGFR less than 80 ml/min/1.73 m2 had outpatient hypertension. There was no correlation of cGFR with CsA levels, CsA dose, or liver function. We conclude that a significant decrease in cGFR is seen in children treated with CsA for more than 1 year, which is progressive in the majority.

A comparison of renal function in cyclosporine- and FK-506-treated patients after primary orthotopic liver transplantation.

In this randomized controlled trial comparing FK-506 to CsA, we report parameters of nephrotoxicity in adult patients surviving > 90 days after orthotopic liver transplant (OLT). Patients randomized to FK-506 first received 0.15 mg/kg IV/day followed by 0.3 mg/kg PO/day. Doses were modified to avoid toxicity and to achieve FK-506 levels of 0.5 to 1.5 ng/ml. CsA was administered in the usual manner with dose adjustments to whole blood HPLC levels. A pre-OLT glomerular filtration rate (GFR) of > or = 30 ml/min/1.73/m2 and/or serum creatinine < or = 2.0 mg/dl were required for inclusion in the study. GFRs were obtained at post OLT days 28, 180, and 360. Other parameters of renal function evaluated were creatinine, magnesium, serum electrolytes, blood pressure, use of antihypertensives, and magnesium supplements. There were 38 patients in the FK-506 group and 34 in the CsA group. The mean days of follow up for each group was similar: 456 +/- 135 days for the FK-506 group and 451 +/- 112 days for the CsA group. The mean oral dose for the FK-506 group ranged from 0.13-0.16 mg/kg/day with mean FK-506 levels of 0.6-0.8 ng/ml. In the FK-506 group, there was a significant fall in the pre-transplant GFR from 89 +/- 31 ml/min/173 m2 to 43 +/- 15 ml/min/173 m2 at day 360. Similarly, for the CsA group, the pre-transplant GFR of 75 +/- 31 ml/min/1.73 m2 fell to 49 +/- 17 ml/min/1.73 m2 at day 360. At each time point studied, there was no significant difference in mean GFR between the two groups. There were no significant differences in the monthly mean values for creatinine, electrolytes, magnesium, or blood pressure between the two groups. Magnesium levels were in the low normal range (1.4-1.6 mEq/L), and the mean potassium levels in the high normal range (4.4-4.7 mEq/L). In both groups, a similar number of patients required magnesium supplementation or hypertensive medications. The nephrotoxicity of FK-506 given at low oral doses and with concomitant low levels was comparable to that of CsA. The two drugs were remarkably similar in their spectrum of electrolyte disturbances and incidence of hypertension.

Red cell aplasia in children on tacrolimus after liver transplantation.

Hematological toxicity of tacrolimus has been rarely reported. We report two pediatric recipients of liver transplantation with anemia. They were treated with tacrolimus for 8 and 47 months, respectively, before developing pure red cell aplasia (PRCA) confirmed by bone marrow biopsy. The children recovered quickly on withdrawal of tacrolimus. The clinical profile of these children is compared with the only other patient reported in the literature with PRCA due to tacrolimus. All three patients had similar hematological findings. However, the mechanism of the tacrolimus-induced PRCA in these children appears to be different from that reported in the adult patient.

Differences in oral FK506 dose requirements between adult and pediatric liver transplant patients.

The oral dose recommendation for FK506 (Fujisawa Pharmaceutical, Deerfield, IL) after liver transplantation has, to date, made no distinction between adult and pediatric patients. Sixteen pediatric and 33 adult liver transplant patients treated long term with oral FK506 were studied. Initial FK506 doses were 0.3 mg/kg/day p.o. or 0.15 mg/kg/day i.v. Thereafter, doses were adjusted to achieve therapeutic FK506 serum levels (0.5-3.0 ng/ml, ELISA liquid/liquid separation) and to maintain an acceptable serum creatinine. FK506 (in mg/kg/day), FK506 levels, and liver function were assessed at monthly intervals on outpatient visits. The mean age of 16 pediatric patients was 5.3 +/- 3.5 years and of 33 adult patients was 49 +/- 12 years. Mean days of FK506 therapy were 284 +/- 136 for pediatric patients and 239 +/- 112 for adult patients. For each time period, pediatric patients required a significantly higher dose of FK506 compared to adult patients (P < 0.001). The overall mean pediatric dose for the first year was 0.46 +/- 0.4 mg/kg/day compared to the mean adult dose of 0.13 +/- 0.01 mg/kg/day. The ratio of pediatric to adult oral FK506 dose requirements ranged from 2.7 to 4.4 over the 1 year of followup. FK506 levels monitored at the same time points showed no significant differences at any month between pediatric and adult patients. We conclude that the oral dose per kilogram per day of FK506 required to maintain similar FK506 levels is significantly greater in pediatric patients compared to adult recipients during the first year of follow-up. Pediatric recipients require substantially more, and adult recipients substantially less, than the recommended oral FK506 dose to achieve a therapeutic effect.

Liver transplantation in polysplenia syndrome: use of a living-related donor.

Congenital anatomic anomalies often present technical obstacles during liver transplants. Biliary atresia is the most common indication for liver transplants in children, and approximately 7-10% of these patients have congenital anomalies comprising the "polysplenia syndrome." The polysplenia syndrome, which often includes abdominal situs inversus, is of particular concern in liver transplants because these anatomic anomalies result in a more complex hepatectomy, alterations in the placement of the donor grafts, and the need for additional vascular reconstruction. Earlier reports have shown mixed results for these patients who have undergone orthotopic liver transplants, reporting a high rate of postoperative complications and poor survival. The use of living-related donor grafts has produced excellent results in the general pediatric population. This is the first report of the successful use of a living-related donor graft for an orthotopic liver transplant to treat end-stage liver disease secondary to biliary atresia in a child with polysplenia syndrome.

Liver transplantation in the first three months of life.

BACKGROUND: Pediatric liver transplant recipients have traditionally been grouped according to age. Age-based classification schemes are useful in identifying clinical problems in selected age groups and also for developing solutions to these problems. Although infants in the first 3 months of life have not traditionally been considered a distinct age group, several features of these infants may distinguish them from other pediatric liver transplant recipients. METHODS: The experience with liver transplantation in infants during the first 3 months of life in three large pediatric liver transplant programs (University of Chicago, Stanford University, and UCLA) was analyzed in order to characterize this group. RESULTS: A total of 23 liver transplants were performed at these three centers in children younger than 3 months of age. This group of patients comprised approximately 37% of the U.S. experience between 1988 and 1994 according to United Network for Organ Sharing statistics. Age distribution at the time of transplantation included the following: <1 month, 28%; 1-2 months, 35%; and 2-3 months, 36%. Median age at the time of transplantation was 37 days (range, 7-90 days), and mean age was 57+/-30 days. Mean weight at the time of transplantation was 3.8+/-1.0 kg. Etiology of liver disease included idiopathic hepatitis, 52%; iron storage disease, 17%; and other causes, 31%. Types of liver allografts used included cadaveric, 85% (reduced size, 60%, and full-size, 25%); living donor, 15%; ABO-identical, 65%; and ABO-compatible, 35%. Actuarial patient and graft survival rates were 60% and 60% at 1 year and 60% and 42% at 2 years, respectively. Median follow-up was 1.5 years. Rejection occurred in 42% of patients, with a median time to first rejection of 13 days. Of these patients, 28% required steroids only and 14% required OKT3. Three patients (14%) were retransplanted at a median time to retransplantation of 1.6 years. Vascular thrombosis occurred in three patients (14%). CONCLUSIONS: Liver transplantation performed in infants younger than 3 months of age (1) provides acceptable short- and long-term patient and graft survival, (2) is associated with significant rates of rejection, and (3) is not associated with excessive rates of vascular thrombosis. The etiology of end-stage liver disease occurring in the first 3 months of life is distinct from that in other pediatric liver transplant recipient age groups. These infants should be referred promptly for liver transplantation as reasonable survival can be expected.

De novo hepatitis C in children after liver transplantation.

BACKGROUND: We describe the incidence, results of interferon therapy, and outcome of hepatitis C virus (HCV) hepatitis occurring de novo after pediatric orthotopic liver transplantation (OLT). METHODS AND RESULTS: Of children undergoing OLT between 1984 and September 1996, 321 children survived for more than 1 year. Of these, 13 (4.0%) developed previously undiagnosed HCV disease, as suggested by HCV antibody testing and HCV polymerase chain reaction and confirmed by liver biopsy. Of the 117 children who received transplants before HCV screening of blood products or donors, 10.2% developed de novo HCV disease. The mean age at diagnosis of HCV hepatitis was 13.2+/-5.0 years, and the mean time to diagnosis after OLT was 8.1 years (range, 4-11 years). The mean alanine aminotransferase (ALT) level at diagnosis was 108 IU/ml, and the liver biopsy specimen showed chronic active or chronic persistent hepatitis in 11 children, cirrhosis in 1 child, and nonspecific changes in 1 child. Twelve children were treated with interferon-2alpha; children who weighed > or =20 kg received 3 x 10(6) units every other day, and those who weighed <20 kg received 1.5 x 10(6) units every other day. Four patients developed rapidly progressive liver failure while receiving interferon therapy and required urgent re-transplantation. Three of the four children again developed histologic evidence of recurrent HCV 4-6 months after the second OLT, and all three subsequently died of HCV-induced liver failure. One patient remains alive and well with no evidence of HCV recurrence and a negative HCV RNA. Of the remaining eight children treated with interferon, only two have had a sustained response (normal ALT) and one is now HCV RNA negative. HCV RNA levels did not correlate with outcome or disease severity. HCV antibody levels were unreliable, with two patients having negative HCV antibody but a positive HCV RNA at diagnosis. Six patients were able to be genotyped: four were la and two were 1b. CONCLUSION: Overall mortality for de novo HCV hepatitis was 23%. Seventy-five percent of children who received a second transplant for HCV hepatitis had early histologic recurrence that led to liver failure and death. Interferon therapy resulted in a sustained improvement in ALT in only 15% of children. The time to onset and progression of clinical disease both in the original graft and the retransplant graft were accelerated compared with nonimmunosuppressed individuals.