Donors' characteristics and impact on outcomes in pediatric heart transplant recipients

Organ availability and acceptability limit pediatric HTx. What characteristics define an unacceptable or high‐risk pediatric donor remains unclear. The purpose of this study was to characterize a large cohort of pediatric donors and determine the donor risk factors, including cumulative risk, that affect recipient survival. Data from the PHTS, a prospective multicenter study, were used to examine the impact of donor factors on the outcomes of patients listed <18 yr of age who received a HTx between 1993 and 2009. Donor data were available for 3149 of 3156 HTx (99.8%). Donor cause of death, need for inotropes, or CPR did not affect survival outcomes (p = 0.05). Ischemic time also did not have an impact on overall recipient survival; however, longer ischemic times negatively impacted one‐yr post‐transplant survival (p < 0.0001). There was no impact of cumulative risk factors on survival (p = 0.8). Although used in a minority of cases, hormonal therapy in the donor positively impacted survival (p = 0.03). In multivariate analysis, the only donor factor associated with decreased survival was smaller donor BSA, the other factors being related to the recipient characteristics. When analyzed by recipient age, there were no donor‐related factors that affected survival for those who received a transplant at <6 months of age. Longer ischemic time (p < 0.0001) and greater age difference between the recipient and donor (p = 0.0098) were donor‐related factors impacting early‐phase survival for recipients who received a graft at ≥10 yr of age. Factors perceived to define a marginal or high‐risk pediatric heart donor including inotrope use, CPR and donor cause of death may have less impact on outcomes than previously thought. Longer ischemic times did impact one yr, but not overall survival, and this impact was much greater with older donors. Parameters for accepting a donor heart can potentially be expanded, especially in the infant age group, but strong consideration should always be given to the interaction between ischemic time and donor age.     

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.     

Neurocognitive outcomes at kindergarten entry after liver transplantation at <3 yr of age

This prospective inception cohort study determines kindergarten‐entry neurocognitive abilities and explores their predictors following liver transplantation at age <3 yr. Of 52 children transplanted (1999–2008), 33 (89.2%) of 37 eligible survivors had psychological assessment at age 54.7 (8.4) months: 21 with biliary atresia, seven chronic cholestasis, and five acute liver failure. Neurocognitive scores (mean [s.d.], 100 [15]) as tested by a pediatric‐experienced psychologist did not differ in relation to age group at transplant (≤12 months and >12 months): FSIQ, 93.9 (17.1); verbal (VIQ), 95.3 (16.5); performance (PIQ), 94.3 (18.1); and VMI, 90.5 (15.9), with >70% having scores ≥85, average or above. Adverse predictors from the pretransplant, transplant, and post‐transplant (30 days) periods using univariate linear regressions for FSIQ were post‐transplant use of inotropes, p = 0.029; longer transplant warm ischemia time, p = 0.035; and post‐transplant highest serum creatinine, (p = 0.04). For PIQ, they were pretransplant encephalopathy, p = 0.027; post‐transplant highest serum creatinine, p = 0.034; and post‐transplant inotrope use, p = 0.037. For VMI, they were number of post‐transplant infections, p = 0.019; post‐transplant highest serum creatinine, p = 0.025; and lower family socioeconomic index, p = 0.039. Changes in care addressing modifiable predictors, including reducing acute post‐transplant illness, pretransplant encephalopathy, transplant warm ischemia times, and preserving renal function, may improve neurocognitive outcomes.     

Obesity class does not further stratify outcome in overweight and obese pediatric patients after heart transplantation

The effect of obesity stratification on pediatric heart transplant outcomes is unknown. The UNOS database was queried for patients ≥2‐<18 years listed for heart transplant and stratified by BMI: normal (BMI>5%‐≤85 percentile), overweight (BMI=86%‐95 percentile), class 1 (BMI=100%‐120% of 95 percentile), class 2 (BMI=121%‐140% of 95 percentile), and class 3 obesity (BMI>140% of 95 percentile). A total of 5056 individuals were listed for transplant, with 71% normal, 13% overweight, 10% class 1, 4% class 2, and 2% class 3 obesity. Waitlist survival was not different between groups. Post‐transplant survival was decreased in overweight and combined obese groups vs normal, with no further difference between overweight and obese classes. Overweight and obese patients had higher listing status and were more likely to have ventilator, inotrope, and mechanical circulatory support at listing. After transplant, there was an association of overweight‐obese patients with diabetes and rejection requiring hospitalization. Stricter definition of normal weight reveals overweight‐obese status was an independent risk factor for poorer post‐transplant survival, without further effect by stratification of weight class. However, because there is no difference in waitlist survival, this study does not allow the selection of absolute weight‐based criteria regarding transplant listing and suggests the need to look further for modifiable risk factors post‐transplant.     

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.     

Clinical predictors of autoimmune and severe atopic disease in pediatric heart transplant recipients

Autoimmune and allergic diseases cause morbidity and diminished quality of life in pediatric organ transplant recipients. We hypothesize that younger age at transplantation and immunosuppression regimen play a role in the development of immune‐mediated disease following heart transplant. A single institution retrospective review identified all patients undergoing heart transplant at ≤18 yr of age from 1987 to 2010 who survived ≥1 yr. Using medical record and database review, patients were evaluated for development of autoimmune or severe allergic disease. Of 129 patients who met criteria, seven patients (5.4%) with autoimmune or severe atopic disease were identified. Immune‐mediated diseases included inflammatory bowel disease (n = 3), eosinophilic esophagitis/colitis (n = 4), and chronic bullous disease of childhood (n = 1). Patients <1 yr of age at transplant were at greater risk of developing autoimmune disease than patients 1–18 yr at transplant (OR = 9.3, 95% CI 1.1–79.2, p = 0.02). All affected patients underwent thymectomy at <1 yr of age (7/71 vs. 0/58, p = 0.02). In our experience, heart transplantation in infancy is associated with the development of immune‐mediated gastrointestinal and dermatologic diseases. Further study is needed to determine risk factors for the development of immune‐mediated disease to identify best practices to decrease incidence.     

New‐onset diabetes after pediatric heart transplantation: A review of the Pediatric Heart Transplant Study

NDT is a well‐defined complication after solid organ transplantation. Little has been published describing the incidence, risk factors, and effect on outcome after pediatric heart transplantation. We performed a retrospective evaluation of pediatric patients from the PHTS registry from 2004 to 2014. Group comparison, associated factors, incidence using Kaplan‐Meier method, and risk factor and outcome analysis for NDT at 1 year post‐transplant. Of the 2185 recipients, 1756 were alive and followed at 1 year. Overall freedom from NDT was 98.9%, 94.7%, and 92.6% at 1, 5, and 10 years, respectively. Patients with NDT were more likely to be black (non‐Hispanic; P = 0.002), older at time of transplant (P < 0.0001), and have a higher BMI percentile at time of transplant (P < 0.0001). Adjusted risk factors for NDT at 1 year were older age at transplant (years; >12 years, OR: 8.8 and 5‐12 years, HR: 8.0), obese BMI percentile at time of transplant (OR: 3.8), and steroid use at 30 days after transplant (OR: 4.7). Though uncommon, NDT occurs with a constant hazard after pediatric heart transplant; it occurs more often in older patients at transplant, those who are of black race, those who are obese, and those who use steroids. Therefore, targeted weight reduction and selective steroid use in at‐risk populations could reduce the incidence of early NDT. Further data are needed to determine the risk imparted by transplantation, factors that predict late‐onset NDT, and whether NDT alters the outcome after transplant.     

Overweight,central obesity,and cardiometabolic risk factors in pediatric liver transplantation

PTMS describes the presence of ≥3 cardiometabolic risk factors that include obesity, hypertension, dyslipidemia, and IR. The prevalence of the clustering of ≥3 cardiometabolic risk factors or central obesity has not been studied in pediatric LT recipients. Single‐center, cross‐sectional study. Inclusion criteria: LT recipients 2–18 yr‐old, at least one yr post‐LT. Exclusion criteria: recipients of liver retransplants or multivisceral transplants. Eighty‐seven patients were identified. Median age was 9.8 yr (range 2–18), median time since LT was 6.9 yr (range 1–17). The most common indication for LT was biliary atresia (56%), and the most frequently used immunosuppressant was tacrolimus (80%). The prevalence of overweight and obesity was 21% and 5%, respectively. Central obesity affected 14%, hypertension 44%, IR 27%, low HDL 20%, and hypertriglyceridemia 39% of patients. The prevalence of ≥3 cardiometabolic risk factors was 19%. Fifty percent of the overweight/obese patients had ≥3 risk factors. Time since transplant, immunosuppression and renal function were not different between those with <3 or ≥3 risk factors. Clustering of cardiometabolic risk factors is prevalent in pediatric LT recipients, suggesting an increased risk of future CV events.     

Functional capacity after pediatric liver transplantation: A pilot study

The prospective cross‐sectional study investigated the 6MWT performance in pediatric group of liver transplant recipients (6–17 yr, median post‐transplantation time of 22 months) and compared to the normal values obtained in healthy children as well as evaluated the reproducibility of the 6MWT. We analyzed the relationship between walked distance and the 6MWw, distance walked × body weight) with the anthropometric, clinical, and pulmonary functions. In post‐transplanted group, the average walked distance was significantly shorter compared with control (687 ± 80 m vs. 511 ± 72 m, p < 0.001). The calculated ICC coefficient confirmed the reproducibility among tests. The Pearson correlation revealed that only walked distance in the 6MWT was moderately correlated with tidal volume. Conversely, the 6MWw was significantly correlated with age, weight, height, BMI, FVC, PEF rate, and volume expiratory. According to multiple regression analysis, age, VE and FVC factors explained 80% of the variance in the 6MWw. In conclusion, the pediatric liver transplant recipients' performance in the 6MWT is significantly lower than the values for healthy children of the same age. Notably, the 6MWw may provide relevant information, constituting an additional parameter in the determination of functional capacity.     

Tacrolimus therapeutic drug monitoring and pediatric renal transplant graft outcomes

Predose monitoring of tacrolimus levels is standard practice in the care of pediatric renal transplant patients. This is despite a paucity of data investigating the ideal target range in children, and controversy as to whether tacrolimus levels correlate with renal transplant outcomes. We performed a retrospective cohort analysis of 48 renal transplant patients at a single Canadian pediatric transplant center following the initiation of a tacrolimus–mycophenolate–prednisone‐based IS protocol. We analyzed the relationship of graft function, as defined by GFR up to five yr post‐transplant, to the preceding mean tacrolimus level. There was no significant correlation between absolute GFR and mean tacrolimus levels (r = 0.206, p = 0.38). However, a higher mean tacrolimus level, particularly ≥10 ng/mL in the first three months after transplantation, was associated with a slower rate of decline in GFR with time (r = 0.608, p = 0.004) and with a less likelihood of developing CKD five yr after transplant. We suggest that the optimal target range for tacrolimus levels may be at the upper end of what is currently practiced and that further research to validate these findings would be useful.     

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.     

Cardiovascular risk factors and cardiac disorders in long‐term survivors of pediatric liver transplantation

The MetS and cardiovascular disease are leading causes of late morbidity in adult liver transplantation recipients; however, limited data are available in pediatric liver transplantation. A single‐center retrospective review was undertaken for patients who had a liver transplantation before 18 yr of age and were >5 yr post‐transplantation, to study the prevalence of MetS, its components, and cardiac disorders. Fifty‐eight patients were included in the study with a mean age at transplantation of 6.3 ± 6.1 yr and mean follow‐up of 14.1 ± 6.0 yr. Of the study group, 41.4% were overweight or obese, with ongoing prednisone use and increased duration of follow‐up being significant risk factors. Fifty‐three patients had sufficient data for determining MetS, which was present in 17% of the patients. Although the prevalence of MetS is low in pediatric liver transplant recipients, it is associated with CKD and prednisone therapy (p < 0.05). Echocardiography data were available for 23 patients, of whom 43.4% had LVH and 13% had evidence of PH. The spectrum of cardiac disorders in this population is much wider than in adults.     

Effect of small donor weight and donor–recipient weight ratio on the outcome of liver transplantation in children

A small donor weight is a risk factor for HAT with potential for graft loss. To test this hypothesis, we evaluated outcomes of pediatric liver transplants utilizing donors <20 kg using the UNOS database from 01/2003 to 01/2012 (n = 1311). All isolated liver transplants with whole organ grafts were included. Recipients were divided into four groups based on donor weight: group 1, donor weight <5 kg (n = 34 [2%]); group 2, 5–10 kg (431 [33%]); group 3, 10–15 kg (560 [43%]); and group 4, 15–20 kg (286 [22%]). Actuarial patient survival for the first year post‐transplant was significantly lower in groups 1 and 2 compared to groups 3 and 4 (p = 0.002), similarly the one‐yr graft function (p < 0.0001). The difference was due to graft loss within the first month for groups 1 and 2. HAT was significantly higher in groups 1 and 2 compared to others (p = 0.0006). Logistic regression analysis demonstrated donor weight as the most predictive factor with analysis of the ROC curve showing a cutoff point at 7.8 kg. The donor–recipient weight ratio did, in none of the models, gain statistical significance.     

Mortality after pediatric kidney transplantation in England – a population‐based cohort study

The aim of this study was to explore mortality after pediatric kidney transplantation in England over the last decade. We used data from HES to select all kidney transplant procedures performed in England between April 2001 and March 2012. Data linkage analysis was performed with the ONS to identify all deaths occurring among this study cohort. Data for 1189 pediatric recipients were compared to 17 914 adult recipients (number of deaths, 33 vs. 2052, respectively, p < 0.001), with median follow‐up 4.4 yr (interquartile range 2.2–7.3 yr). There was no difference in mortality within the pediatric cohort; age 0–1 (n = 25, patient survival 100.0%), age 2–5 (n = 198, patient survival 96.0%), age 6–12 (n = 359, patient survival 97.5%), and age 13–18 (n = 607, patient survival 97.4%), respectively (p = 0.567). The most common causes of death were renal (n = 8, 24.2%), infection (n = 6, 18.2%), and malignancy (n = 5, 15.2%). All deaths from malignancy were secondary to PTLD. In a fully adjusted Cox regression model, only white ethnicity was significantly associated with risk of pediatric mortality post‐kidney transplantation (hazard ratio 2.7, 95% confidence interval [1.0–7.3], p = 0.047). To conclude, this population‐based cohort study confirms low mortality after pediatric kidney transplantation with short follow‐up.     

Long‐term outcome of pediatric renal transplantation: A single center study in Japan

Little is known about the risk factors for long‐term poor outcome in pediatric renal transplantation. Between 1973 and 2010, 111 renal transplants (92 living donations) were performed in 104 children (56 males, mean age, 12.5 yr) at the Social Insurance Chukyo Hospital, and followed‐up for a mean period of 13.6 yr. The patient survival at 1, 5, 10, 15, 20 (living‐ and deceased‐donor transplants), and 30 yr (living‐donor transplants only) was 98.1%, 92.8%, 87.8%, 84.9%, 82.6%, and 79.3%. The graft survival at 1, 5, 10, 15, 20, and 30 yr was 92.0%, 77.3%, 58.4%, 50.8%, 38.5%, and 33.3%. The most common cause of graft loss was CAI, AR, death with functioning, recurrent primary disease, ATN, and malignancy. Donor gender, ATN, malignancy/cardiovascular events, and eras affected patient survival. AR and CAI were the risk factors for graft loss. The evolved immunosuppression protocols improved the outcome by reducing AR episodes and ATN but not CAI, suggesting CAI as the major risk factor for graft loss. CAI was correlated with AR episodes, CMV infection, and post‐transplant hypertension. Strategies for preventing the risk factors for malignancy/cardiovascular events and CAI, including hypertension/infection, are crucial for better outcomes.     

Laparoscopic donor nephrectomy for the pediatric recipient population: Risk factors for adverse outcomes

Kidney transplantation is the optimal treatment of ESRD in children. Some studies have reported inferior outcomes in recipients of LDN allografts who are ≤5 yr of age. We performed a retrospective review of pediatric recipient outcomes of 110 LDN allografts at our institution and examined predictors of adverse outcomes. Subgroup analysis was performed by dividing recipients into three age categories: 0–5 yr, 6–17 yr, and ≥18 yr. There was no significant difference between incidences of DGF or ARE between groups. Kaplan–Meier analysis demonstrated 100% allograft survival in 0‐ to 5‐yr‐old recipients, nearly reaching statistical significance (p = 0.07) for outcome superior to that of the two older age groups. Pretransplant HD was associated with increased risk of DGF (p = 0.05). Significant risk factors for ARE were recipient weight >15 kg (p = 0.033) and multiple renal arteries (p = 0.047). Previous ARE was associated with an increased risk of allograft failure (p = 0.02). LDN is not associated with increased risk of DGF, ARE, or allograft failure in the youngest recipients. These findings support an aggressive pursuit of preemptive transplantation even in the youngest pediatric allograft recipients.     

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.     

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.     

Angiotensin II type 1 receptor antibodies in childhood kidney transplantation

Angiotensin II type 1 receptor antibodies (AT₁RAb) have emerged as non‐HLA Ab present in patients with acute AMR and risk of graft loss. Furthermore, AT₁RAb have been shown to increase angiotensin II sensitivity which may play a role in the development of CVD and hypertension. Data on AT₁RAb in stable transplant recipients are lacking. The aim of this study was to analyze the levels of AT₁RAb in a cohort of stable patients after kidney transplantation (tx) in childhood. A cross‐sectional study of 30 children (median age 14, range 3–19 yr, median time since tx five yr) and 28 adults who were transplanted in childhood (median age 26, range 20–40 yr, median time since tx 18 yr) transplanted between 1993–2006 and 1983–2002, respectively, was performed. Healthy controls were 51 healthy children (5–8 yr) and 199 healthy donors (median age 56.5 yr, range 42–83 yr). Plasma AT₁RAb were analyzed by immunoassay. Median total AT₁RAb IgG concentration was significantly higher in the pediatric‐tx group as compared to the adult‐tx group (40.0 and 10.95 U/mL, p < 0.0001). For both groups, the tx group showed higher levels: the pediatric‐tx group vs. control group (40.0 vs. 13.3 U/mL, p = 0.0006) and the adult‐tx group vs. adult control group (10.95 vs. 6.5 U/mL, p < 0.0001). Age was the strongest indicator of high levels of AT₁RAb IgG (p = 0.0003). AT₁RAb total IgG levels are significantly higher in a stable pediatric‐tx cohort as compared to adult‐tx patients and healthy controls of comparable age groups. The relevance of our findings in relation to age, time since tx, previous or future rejection, and CVD risk merits future studies.