Outcomes in pediatric hepatitis C transplant recipients: Analysis of the UNOS database

HCV may lead to the development of ESLD in late childhood and, consequently, contributes to the need for liver transplantation. The aim of this study was to examine post‐transplant outcomes in HCV‐positive pediatric patients with ESLD from any cause and to determine the impact of the PELD scoring system, introduced in February 2002, on post‐transplant patient and graft survival. A retrospective analysis of the UNOS database from 1994 to 2010 was performed to assess graft and patient survival in pediatric HCV‐seropositive liver transplant recipients. Graft survival and patient survival comparing subjects in the pre‐PELD era and post‐PELD era were analyzed using Kaplan–Meier statistics. Factors associated with survival were identified using Cox regression analysis. Of 120 pediatric HCV transplant recipients, 80 were transplanted in the pre‐PELD era and 40 were transplanted post‐PELD. Median serum total bilirubin, INR, and creatinine were 4.8 mg/dL, 1.6, and 0.7 mg/dL in the pre‐PELD era vs. 5.5 mg/dL, 1.7, and 0.6 mg/mL, respectively, in the post‐PELD era (p NS). One‐yr graft survival in the pre‐PELD vs. post‐PELD era was 65.0% and 89.7%, respectively (p < 0.01); corresponding three‐yr graft survival was 57.3% vs. 76.2% (p = 0.04). One‐yr patient survival in the pre‐PELD vs. post‐PELD era was 79.0% and 97.5%, respectively (p < 0.01); corresponding three‐yr survival was 79.0% vs. 89.4% (p = 0.17). Twenty‐eight patients (23.3%) were retransplanted: 24 (30%) in the pre‐PELD era (median time to retransplant 272 days) and four (10%) in the post‐PELD era (median time to retransplant 586 days). Early follow‐up demonstrates a trend toward improved pediatric HCV liver transplant graft and patient survival in the post‐PELD era. Superior outcomes may be attributed to pretransplant factors, improved surgical technique and better treatment options for HCV infection.     

Pretransplant six‐minute walk test predicts peri‐ and post‐operative outcomes after pediatric lung transplantation

The purpose of the pretransplant assessment in lung transplantation is to determine a patient's need for transplant as well as their potential survival post‐procedure. In 2005, the UNOS introduced the LAS, a calculation based on multiple physiologic measures to determine need and likelihood for survival. Measures include NYHA class and the 6‐MWT. Some adult studies indicate a positive correlation with 6‐MWT and waiting list survival. In pediatric/adolescent patients, there are minimal data regarding the predictive value of physiologic markers in either wait list survival or post‐transplant outcome. A retrospective cohort study of 60 consecutive lung transplantations from 1990 to 2008 was performed at a pediatric tertiary care facility. Functional pretransplant assessments were abstracted from the medical record and compared with outcomes after transplantation. Results: a 6‐MWT of >1000 ft (305 m) prior to transplantation correlated with a shorter ICU stay (7 vs. 11 days, p = 0.046) and fewer days of mechanical ventilation (2 vs. 4, p = 0.04). A pretransplant 6‐MWT greater than 750 ft (229 m) correlated with shorter overall hospitalization (37 vs. 20 days, p = 0.03). Measuring pretransplant 6‐MWT tests for pediatric patients is valuable in predicting peri‐operative outcomes after lung transplantation.     

Pretransplant trends in α‐fetoprotein levels as a predictor of recurrence after living donor liver transplantation for unresectable hepatoblastoma: A single‐institution experience

LT is a practical therapeutic alternative for unresectable hepatoblastoma; however, deciding when to perform LT is difficult. The aim of this study was to optimize the timing of LT for hepatoblastoma using pretransplant trends in AFP levels. Trends in pretransplant AFP levels and their influence on post‐transplant outcomes were retrospectively evaluated. All patients who underwent living donor LT for hepatoblastoma in our institution since 2002 were included. Variables analyzed included history of prior tumor resection, pretransplant AFP responses to chemotherapy, metastatic disease at diagnosis, and post‐transplant chemotherapy. Eight patients (seven boys and one girl; median age, 35 months; range, 15 months‐12 years) were transplanted. The overall post‐transplant recurrence‐free survival rate was 62.5% (5/8) with a mean follow‐up of 77 months. Patients with post‐transplant recurrence showed a 0.573 log increase in AFP levels after the last chemotherapy session before LT. This was significantly higher than the 0.279 log decrease observed in patients without post‐transplant recurrence (P = .024). Because the AFP response cannot be accurately predicted before each cycle of chemotherapy, it may be appropriate to perform LT when AFP levels do not decrease after the last cycle and before they are found to be elevated again.     

Comparison of outcomes of hand‐assisted laparoscopic to open donor nephrectomy for pediatric recipients

The purpose of this study is to compare the outcome of pediatric recipients of kidneys procured using a hand‐assisted laparoscopic (HALDN group) to an open technique (ODN group). Twenty‐eight patients ≤18 yr old (HALDN group) were compared with 17 patients (ODN group). The serum creatinine for HALDN and ODN groups at discharge were 0.93 ± 0.48 and 0.94 ± 0.54 mg/dL (p = 0.917), respectively. The serum creatinine for HALDN and ODN groups at six and 12 months was 1.01 ± 0.44 and 1.11 ± 0.55, and 1.04 ± 0.52 and 1.14 ± 0.46 mg/dL (p = 0.516, p = 0.554), respectively. The eGFR for HALDN and ODN groups at discharge was 108.66 ± 37.23 and 106.1 ± 50.55 mL/min/1.73 m² (p = 0.845), respectively. The eGFR for HALDN and ODN groups at six and 12 months was 97.77 ± 28.25 and 81.73 ± 27.46, and 94.56 ± 28.3 and 85.74 ± 30.1 mL/min/1.73 m2 (p = 0.085, p = 0.344), respectively. The patient and graft survival for both groups were 100% at 12 months post‐transplant. In conclusion, the short‐term outcome of recipients of kidneys procured via HALDN is comparable to that of kidneys procured via ODN in pediatric patients.     

High‐risk age window for mortality in children with cystic fibrosis after lung transplantation

LTx in children with CF remains controversial. The UNOS database was queried from 1987 to 2013 for CF patients <18 yr of age at time of transplant. PCHR model was used to quantify hazard of mortality. 489 recipients were included in the survival analysis. The hazard function of post‐transplant mortality was plotted over attained age to identify age window of highest risk, which was 16–20 yr. Unadjusted PCHR model revealed ages immediately after the high‐risk window were characterized by lower hazard of mortality (HR = 0.472; 95% CI = 0.302, 0.738; p = 0.001). After adjusting for potential confounders, the decline in mortality hazard immediately after the high‐risk window remained statistically significant (HR = 0.394; 95% CI: 0.211, 0.737; p = 0.004). Hazard of mortality in children with CF after LTx was highest between 16 and 20 yr of attained age and declined thereafter.     

Risk factors for neurological complications and their correlation with survival following pediatric liver transplantation

Despite the improved outcomes of LT, post‐operative NCs remain a significant cause of morbidity and mortality. The aim of the study was to identify the incidence of and risk factors for NCs in children who underwent LT. The medical records of pediatric patients who underwent LT at Asan Medical Center Children's Hospital between January 1994 and December 2010 were retrospectively analyzed. The onset and types of NC and pretransplant variables associated with NC were evaluated. We identified 190 children (85 boys [44.7%], 105 girls [55.3%]) of mean age 4.1 ± 4.7 yr, who underwent LT. Forty‐six NCs occurred in 41 (21.6%) patients after LT, the most common being seizures (n = 13, 28.3%) and encephalopathy (n = 10, 21.7%). Of the 46 NCs, 24 (52.2%) occurred within three months after LT. Multivariate analysis showed that primary liver disease, preoperative neurological problems, preoperatively higher serum creatinine concentration, and graft failure were significant risk factors for NCs. The survival rate was significantly lower for patients with NCs than for those without (p < 0.001). NCs after pediatric LTs were common and associated with a higher mortality rate in our study. Close monitoring and appropriate risk management may improve the long‐term outcomes of pediatric patients who undergo LT.     

Treatment of BK virus‐associated nephropathy with CMX001 after kidney transplantation in a young child

NC, with renal failure secondary to bilateral dysplastic kidneys, received an LRD renal transplant (tx) at 17 months of age. Her early post‐tx course was complicated by persistently elevated blood polyoma BK virus DNA loads. A protocol biopsy at six months post‐transplant revealed BKVAN. Blood viral loads did not respond to decreased immunosuppression or treatment with ciprofloxacin and leflunomide. Six months post‐tx, her serum creatinine began to rise and we sought experimental therapy to prevent the loss of her graft. At seven months post‐tx, with FDA approval under an eIND, the patient was started on a 36‐wk course of treatment with the investigational drug. The patient is now more than 24 months after stopping treatment with CMX. BKV viral DNA loads remain at low, but still detectable levels. Urine viral loads have declined, but remain elevated. EBV DNA loads become undetectable. The patient's serum creatinine has declined back to a baseline of 0.5–0.7 mg/dL and has been stable for two yr. Renal function was preserved in association with the use of CMX001 to treat BKV nephropathy in a young pediatric kidney transplant recipient. There were no serious adverse events associated with the use of CMX001. This novel medication may be of value in the treatment of BKVAN in pediatric renal transplant recipients.     

Utility of thrombophilia screening in pediatric renal transplant recipients

Thrombosis after kidney transplantation may result in catastrophic outcomes, including graft loss. Thrombophilia has been implicated in post‐transplant thrombosis; data, however, are inconclusive on the impact of acquired and inherited thrombophilia and resultant thrombosis in renal graft recipients. We aimed to evaluate whether identifying children with thrombophilia during the pretransplant evaluation predicted post‐transplant outcomes. We reviewed 100 kidney transplants performed in 100 children, aged 1‐18 years, in a single‐center retrospective study. Routine pretransplant comprehensive thrombophilia evaluation was completed. Thrombophilia was demonstrated in 36% patients (N = 36). TEs occurred in 11 patients before kidney transplant. Low PS and antithrombin were found in 9/86 (10.5%) and 2/89 (2.2%) children, respectively. Heterozygosity for FLV and PGM were found in 5/81 (6.2%) and 1/93(1.1%) children, respectively. A post‐transplant thrombotic event occurred in 10 children (10%); six involved the renal transplant. The association between a history of a pretransplant thrombotic event and post‐operative renal graft thrombosis approached, but did not reach significance (P = 0.071). There was no association between preoperative screening abnormalities and post‐operative TEs. Graft loss due to a thrombotic event occurred in two patients; none had underlying thrombophilia. Our data suggest that the utility of universal, comprehensive preoperative thrombophilia testing is not beneficial in determining risk of post‐operative graft thrombosis. Thrombophilia testing may be considered in a select population with a history of pretransplant thrombotic event.     

Late acute rejection: Incidence,risk factors,and effect on graft survival and function

Long‐term graft survival and function has not kept pace with short‐term success in kidney transplant (Tx) recipients. LAR ≥6 months post‐Tx may contribute to lack of improvement; risk factors for LAR are not well known. Of 64 Tx recipients followed over six yr, 23 (35.9%) had LAR (LAR group) and 41 had no LAR (no LAR group). Of all variables, significant risk factors for LAR included DGF, (43.4% LAR vs. 14.6% in no LAR group, p = 0.0096); de novo DSA (65.2% vs. 26.8%, p = 0.003); mean COV% of TAC (41.8% vs. 34.6%, p = 0.03); and non‐adherence (34.8% vs. 7.3%, p = 0.0043). DGF and DSA remained statistically significant (p = 0.002 and 0.003, respectively); COV% TAC had borderline significance (p = 0.057), and non‐adherence was not significant on multivariate regression analysis. Patients with LAR had inferior graft survival and function, whereas graft function was stable in the no LAR group over a mean follow‐up of 31.2 months. Patients with de novo DSA and DGF should be considered at risk of LAR; an early diagnosis and treatment of LAR may improve graft survival and function.     

Post‐transplant lymphoproliferative disorder: No relationship to recombinant human growth hormone use in Australian and New Zealand pediatric kidney transplant recipients

PTLD is a potentially life‐limiting complication of pediatric transplantation. Previous registry‐based studies in renal transplantation have suggested a link between rhGH use and PTLD. In this study, demographic and transplant data on those aged <18 yr and transplanted between 1991 and 2008 were collected from the ANZDATA Registry. Associations between gender, age at time of transplant, recipient CMV and EBV status, use of monoclonal antibody therapy, and use of rhGH were studied as potential predictors of PTLD. Among 650 transplants, there were 20 cases (3.1%) of PTLD, with half presenting within two yr post‐transplant. Eight patients exposed to rhGH at any time developed PTLD, and this association was not statistically significant (RR = 1.5[0.6–3.4], p = 0.36). On multivariate analysis, there were no significant predictors for PTLD. In this study, previously identified potential risk factors were not identified as significant predictors for the development of PTLD. Although limited sample size may affect our ability to infer safety, this large retrospective cohort study does not suggest an increased risk of PTLD in pediatric kidney transplant recipients who received rhGH treatment.     

Pediatric solid organ transplant recipients: Transition to home and chronic illness care

Pediatric SOT recipients are medically fragile and present with complex care issues requiring high‐level management at home. Parents of hospitalized children have reported inadequate preparation for discharge, resulting in problems transitioning from hospital to home and independently self‐managing their child's complex care needs. The aim of this study was to investigate factors associated with the transition from hospital to home and chronic illness care for parents of heart, kidney, liver, lung, or multivisceral recipients. Fifty‐one parents from five pediatric transplant centers completed questionnaires on the day of hospital discharge and telephone interviews at three wk, three months, and six months following discharge from the hospital. Care coordination (p = 0.02) and quality of discharge teaching (p < 0.01) was significantly associated with parent readiness for discharge. Readiness for hospital discharge was subsequently significantly associated with post‐discharge coping difficulty (p = 0.02) at three wk, adherence with medication administration (p = 0.03) at three months, and post‐discharge coping difficulty (p = 0.04) and family management (p = 0.02) at six months post‐discharge. The results underscore the important aspect of education and care coordination in preparing patients and families to successfully self‐manage after hospital discharge. Assessing parental readiness for hospital discharge is another critical component for identifying risk of difficulties in managing post‐discharge care.     

Parental functioning improves the developmental quotient of pediatric liver transplant recipients

Psychomotor development in pediatric liver transplant (LT) recipients depends on several factors. Our aim was to evaluate the importance of parental involvement and family dynamics on psychomotor development by assessing (i) children and parents individually, (ii) the parent–child relationship, and (iii) the correlation between parental functioning and patient outcome, all before and after LT. Age‐appropriate scales were used before and after LT. Twenty‐one patients, 19 mothers, and 16 fathers were evaluated. Developmental quotient (DQ): No subjects scored in the “very good” range. The proportion of children with deficits increased from LT to two yr: 17.6% vs. 28.6%. Subjects 0–2 yr were more likely to have normal DQ at transplant (66.7% vs. 50% for older children). Abnormal DQ was more prevalent two yr post‐LT in children older at LT (p = 0.02). The mother–child relationship was normal in 59% of families pre‐LT and in 67% at two yr. The relationship was more favorable when the child received a transplant as an infant (p = 0.014 at 12 months post‐LT). Normal DQ was associated with higher maternal global functioning score pre‐LT (p = 0.03). Paternal performance scores were higher than maternal scores. Children transplanted after two yr of age suffer greater long‐term deficits than those transplanted as infants.     

De novo development of antibodies to kidney‐associated self‐antigens angiotensin II receptor type I,collagen IV,and fibronectin occurs at early time points after kidney transplantation in children

Chronic rejection is the leading cause of graft loss following pediatric kidney transplantation. Our group and others have demonstrated an association between the development of Abs to self‐antigens and chronic rejection following adult lung and heart transplantation. The goal of this study was to determine whether Abs to kidney‐associated self‐antigens develop following pediatric renal transplantation. We investigated post‐transplant development of Abs to kidney‐associated self‐antigens angiotensin II receptor type I, Fn, and collagen IV in a pediatric cohort. Using ELISA, we measured Abs to kidney‐associated self‐antigens in serum. Our cohort included 29 subjects with samples collected pretransplant and for 12 months post‐transplant. No samples had Abs to kidney‐associated self‐antigen pretransplant. In contrast, 50% (10/20) of subjects developed Abs to one or more kidney‐associated self‐antigen post‐transplantation. The median time to antibody appearance and duration of persistence were 103 and 61 days, respectively. Development of Abs did not correlate with graft function. Half of subjects developed Abs to kidney‐associated self‐antigens angiotensin II receptor type I, Fn, or collagen IV in the first year after kidney transplantation—a higher rate of early antibody development than expected. In this small study, Abs did not correlate with worse clinical outcomes.     

Post‐renal transplant erythrocytosis: A case report

PTE is defined as hematocrit >51% or hemoglobin >17 g/dL after renal transplantation. Risk factors include native kidneys with adequate erythropoiesis pretransplant, smoking, renal artery stenosis, and cyclosporine treatment. We report the case of a 14‐yr‐old female kidney transplant patient, with triple therapy immunosuppression and stable graft function who developed PTE at 12 months post‐transplant with hemoglobin 17.3 g/dL, hematocrit 54.2%, stable graft function, and normotensive with normal cardiac echocardiogram and erythropoietin levels. The only risk factor found was tobacco use. As she had no spontaneous improvement, enalapril treatment was started at 19 months post‐transplant with a hemoglobin level of 17.5 g/dL and hematocrit 53%; by 23 months post‐transplant, hemoglobin lowered to 15 g/dL and hematocrit to 44.5% and continued to be in normal range thereafter. PTE is a rare condition in childhood and can be successfully treated with enalapril.     

Non‐invasive staging of chronic kidney allograft damage using urine metabolomic profiling

Chronic kidney allograft damage is characterized by IFTA and GS. We sought to identify urinary metabolite signatures associated with severity of IFTA and GS in pediatric kidney transplant recipients. Urine samples (n = 396) from 60 pediatric transplant recipients were obtained at the time of kidney biopsy and assayed for 133 metabolites by mass spectrometry. Metabolite profiles were quantified via PLS‐DA. We used mixed‐effects regression to identify laboratory and clinical predictors of histopathology. Urine samples (n = 174) without rejection or AKI were divided into training/validation sets (75:25%). Metabolite classifiers trained on IFTA severity and %GS showed strong statistical correlation (r = .73, P < .001 and r = .72; P < .001, respectively) and remained significant on the validation sets. Regression analysis identified additional clinical features that improved prediction: months post‐transplant (GS, IFTA); and proteinuria, GFR, and age (GS only). Addition of clinical variables improved performance of the %GS classifier (AUC = 0.9; 95% CI = 0.85‐0.96) but not for IFTA (AUC = 0.82; 95% CI = 0.71‐0.92). Despite the presence of potentially confounding phenotypes, these findings were further validated in samples withheld for rejection or AKI. We identify urine metabolite classifiers for IFTA and GS, which may prove useful for non‐invasive assessment of histopathological damage.     

Survival in children on extracorporeal membrane oxygenation at the time of lung transplantation

Limited data exist on ECMO at the time of LTx in children. The UNOS database was queried from 2000 to 2013 for pediatric lung transplant recipients (<18 yr) to assess post‐transplant survival of patients on ECMO at the time of LTx. Of 587 pediatric recipients with 17 on ECMO, 585 were used for univariate and Kaplan–Meier function analysis, 535 for multivariate Cox models, and 24 for propensity score matching. Univariate Cox (HR = 1.777; 95% CI: 0.658, 4.803; p = 0.257) and Kaplan–Meier function (log‐rank test: chi‐square (df = 1): 1.32, p = 0.250) analyses did not identify a survival difference between ECMO and non‐ECMO, while multivariate Cox models (HR = 1.821; 95% CI: 0.654, 5.065; p = 0.251) did not demonstrate an increased risk for death. Propensity score matching analysis (HR = 1.500; 95% CI: 0.251, 8.977; p = 0.657) also failed to demonstrate a significantly increased hazard ratio. Using a contemporary cohort of pediatric lung transplant recipients, the use of ECMO at the time of lung transplantation did not negatively impact survival.     

Lung transplant waitlist mortality: Height as a predictor of poor outcomes

The LAS was designed to minimize pretransplant mortality while maximizing post‐transplant outcome. Recipients <12 are not allocated lungs based on LAS. Waitlist mortality has decreased for those >12, but not <12, suggesting this population may be disadvantaged. To identify predictors of waitlist mortality, a retrospective analysis of the UNOS database was performed since implementation of the LAS. There were 16 973 patients listed for lung transplant in the United States; 12 070 (71.1%) were transplanted, and 2498 (14.7%) patients died or were removed from the wait list. Significantly more pediatric patients died or were removed compared with adults (22.0% vs. 14.4%, p < 0.01). In multivariate analysis, in addition to higher LAS at time of listing (adj. HR1.058, 1.055–1.060), shorter height (1.008, 1.006–1.010), male gender (1.210, 1.110–1.319), and requiring ECMO (1.613, 1.202–2.163) were associated with pretransplant mortality. Post‐transplant survival was not affected by height. The current age cutoff may impose limitations within the current lung allocation system in the United States. Height is an independent predictor of waitlist mortality and may be a valuable factor for the development of a comprehensive lung allocation system.     

Outcome of duct‐to‐duct vs. Roux‐en‐Y hepaticojejunostomy biliary anastomoses in below 15‐kg pediatric liver transplant recipients

The best type of biliary anastomosis to use in lower weight pediatric liver transplant recipients is debatable. In this study, we share a single center's experience comparing the rate of anastomotic biliary complications based on the type of biliary anastomosis performed in this population of patients. A retrospective review of pediatric liver transplants for recipients weighing <15 kg from 11/2003 till 12/2011 was performed. Patients were grouped based on the type of biliary anastomosis into two groups: duct‐to‐duct (d‐d) and Roux‐en‐Y hepaticojejunostomy (h‐j) anastomoses. A total of 24 patients (12 males, 12 females) with a mean age of 26 ± 20 months and a mean weight of 9.27 ± 2.63 kg (range = 5.3–13.9 kg) were studied. All anastomotic complications occurred in patients who received left lateral segments. No statistical differences were found in the post‐operative biliary (p = 0.86) or vascular (p = 0.99) complications between the two groups. Acknowledging the limited sample size, our data suggest that duct‐to‐duct anastomosis can be performed safely in pediatric liver transplantation recipients weighing below 15 kg.     

Outcome of heart transplantation in pediatric cancer survivors

The aim of this study is to evaluate the outcome of heart transplantation in children surviving malignancies. Pediatric heart transplant recipients were identified using the UNOS database. Follow‐up data including survival and rate of malignancy were analyzed. A total of 7169 children received heart transplants between 1987 and 2011. Of these, 107 (1.5%) survived previous malignancy treatment (group I) and 7062 (98.5%) did not have prior malignancy (group II). Survival after transplant was 92.5%, 90.6%, 80.3%, and 65% at three months, one, five, and 10 yr in group I, similar to the rate in group II (90.1%, 84.4%, 73.8%, and 57.7%). Survival after transplantation was similar between group I and children who underwent OHT secondary to cardiomyopathy in group II. The rate of post‐OHT malignancy in group I was higher than that in group II (14/107(13%) vs. 386/7062 (5.4%), p = 0.001). Children who developed malignancy in group I had similar survival as children who developed malignancy in group II. Post‐transplant survival is similar in children with and without pretransplant malignancy in spite of higher rate of malignancy in children with pretransplant malignancy. OHT appears to be a reasonable treatment option in children who develop end‐stage heart disease after malignancy treatment.