ABO‐incompatible pediatric liver transplantation in very small recipients: Birmingham’s experience

Gelas T, McKiernan PJ, Kelly DA, Mayer DA, Mirza DF, Sharif K. ABO‐incompatible pediatric liver transplantation in very small recipients: Birmingham’s experience.
Pediatr Transplantation 2011: 15: 706–711. © 2011 John Wiley & Sons A/S. Abstract: Liver transplantation (LT) for very small recipients is challenging but in experienced centres, good results can be achieved. Despite the risk of antibody‐mediated acute rejection, some studies have demonstrated the safety of ABO incompatible liver transplantation (ILT) in children and particularly in infants. The aim of our study was to describe the outcome of liver transplantation in infants <5 kg and the safety of using ILT in this group. All LT performed between 1991 and 2010 in children <5 kg were reviewed. Twenty‐nine patients were included, five of whom had an ILT. Acute liver failure was encountered in 20 cases. The recipient age and weight at transplantation were respectively 63 days (range: 14–268 days) and 4 kg (range: 2.4–5 kg). The graft‐to‐recipient ratio was 6.1% (range 2.3–9%). An aortic conduit and delayed abdominal closure were used respectively in 76% and 81% of the procedures. The ABO compatible liver transplantation (CLT) and ILT groups were similar regarding recipient’s demographics, graft types or technical transplantation data. The one‐ and five‐yr patient and graft survival were respectively 62%, 62% and 62%, 57.9% with a median follow‐up of 95 months. Vascular complications occurred in six cases (21.4%) and biliary complications were encountered in five patients (17%). Acute and chronic rejection developed respectively in 37% and 26% of the recipients. The five patients undergoing ILT are all alive without graft lost after a median follow‐up of 34 months (range 7–55 months). When compared with the CLT group, no significant differences were found regarding patient or graft survival, vascular or biliary complications and rejection rates. In our experience, ILT in small infants has short and long term outcomes comparable to ABO‐compatible grafts and excellent results can be achieved with a standard immunosuppressive protocol. To avoid mortality on the waiting list for neonatal recipients, ABO‐incompatible liver grafts can be used safely.     

The impact of rituximab in ABO‐incompatible pediatric living donor liver transplantation: The experience of a single center

Previous studies have demonstrated the safety of ABO‐incompatible pediatric LDLT using preoperative plasmapheresis and rituximab; however, no reports have described the timing and dosage of rituximab administration for pediatric LDLT. This study aimed to describe a safe and effective dosage and timing of rituximab for patients undergoing pediatric ABO‐incompatible LDLT based on the experience of our single center. A total of 192 LDLTs in 187 patients were examined. These cases included 29 ABO‐incompatible LDLTs in 28 patients. Rituximab was used beginning in January 2004 in recipients older than two yr of age (first period: 375 mg/m² in two cases; second period: 50 mg/m² in two cases; and 200 mg/m² in eight cases). Two patients who received 375 mg/m² rituximab died of Pneumocystis carinii pneumonia and hemophagocytic syndrome. One patient who received 50 mg/m² rituximab required retransplantation as a consequence of antibody‐mediated complications. All eight patients administered 200 mg/m² survived, and the mean CD20⁺ lymphocyte count was 0.1% at the time of LDLT. In the preoperative management of patients undergoing pediatric ABO‐incompatible LDLT, the administration of 200 mg/m² rituximab three wk prior to LDLT was safe and effective.     

Outcomes in pediatric cardiac transplantation with a positive HLA cross-match

Richmond ME, Hsu DT, Mosca RS, Chen J, Quaegebeur JM, Addonizio LJ, Lamour JM. Outcomes in pediatric cardiac transplantation with a positive HLA cross‐match.
Pediatr Transplantation 2012: 16: 29–35. © 2011 John Wiley & Sons A/S. Abstract: Previous studies have shown poor outcomes in pediatric heart transplant recipients with a high PRA or a positive direct donor–recipient cross‐match. This study describes outcomes in patients with a positive cross‐match at a large pediatric program. Pediatric heart transplant patients at a large single center between January 1993 and July 2009 were reviewed; those with cross‐match data were analyzed. Cross‐match data were available in 242/262 (92.4%) patients. Indications for transplant were cardiomyopathy (58%), CHD (32%), and retransplant (7%). PRA was ≥10% in 31/213 (14.6%) patients. A retrospective cross‐match was positive in 17/31 (55%) patients with PRA ≥10% and 0/182 with PRA <10%. In positive cross‐match patients, rejection frequency in the first year post‐transplant was higher than negative cross‐match patients (1.69 vs. 0.96 episodes/pt year, p = 0.014). There was no difference in rejection frequency after the first year post‐transplant (0.18 vs. 0.12 episodes/pt year, p = 0.14). Overall survival was not significantly different between the groups with a median follow‐up time of 4.5 yr. Heart transplantation in patients with a positive cross‐match may result in good medium‐term survival but a higher frequency of early rejection. Further investigation is warranted to define which patients with a positive cross‐match will do poorly.     

HLA antibodies in pediatric heart transplantation

We have analyzed the impact of anti-HLA antibodies present in the patients' circulation prior and/or following heart transplantation in a population of 108 pediatric recipients. Anti-HLA class I and class II antibodies were monitored by traditional CDC using donor and panel T and B lymphocytes and by SPA for detection of DSA. There was a highly significant correlation between the development of AMR and presence of CDC- or SPA-detected DSA. However, the fraction of the transplant population which remained AMR-free was much higher among patients with SPA-detected compared to CDC-detected DSA. Furthermore, long-term graft survival was negatively affected only by cytotoxic, complement-fixing anti-HLA class I antibodies developing following transplantation. Anti-HLA class I or class II antibodies detected by SPA had no effect on long-term survival rates.     

Antibody depletion for the treatment of crossmatch‐positive pediatric heart transplant recipients

Sensitization to HLA is a risk factor for adverse outcomes after heart transplantation. Requiring a negative prospective CM results in longer waiting times and increased waitlist mortality. We report outcomes in a cohort of sensitized children who underwent transplant despite a positive CDC CM+ using a protocol of antibody depletion at time of transplant, followed by serial IVIG administration. All patients <21 yrs old who underwent heart transplantation at Boston Children's Hospital from 1/1998 to 1/2011 were included. We compared freedom from allograft loss, allograft rejection, and serious infection between CM+ and CM? recipients. Of 134 patients in the cohort, 33 (25%) were sensitized prior to transplantation and 12 (9%) received a CM+ heart transplant. Serious infection in the first post‐transplant year was more prevalent in the CM+ patients compared with CM? patients (50% vs. 16%; p = 0.005), as was HD‐AMR (50% vs. 2%; p < 0.001). There was no difference in freedom from allograft loss or any rejection. At our center, children transplanted despite a positive CM had acceptable allograft survival and risk of any rejection, but a higher risk of HD‐AMR and serious infection.     

Successful ABO incompatible heart transplantation after desensitization therapy in an older child

Background

ABO-incompatible heart transplantation (HTx) has become a standard procedure for children below 2 years of age due to an immunologically immature immune system and associated low isohemagglutinin titers.

Methods

We report a case of an ABO-incompatible HTx (recipient blood group O, donor blood group A) at the age of 5 years and 11 months with a fully matured immune system and previously high isohemagglutinin titers that diminished as a result of human leucocyte antigen (HLA) desensitization therapy with rituximab and immunoglobulins.

Results

The anti-A titer at the time of HTx was 1:16 with post-transplant isoagglutinin titers never exceeding 1:4 without any signs of rejection with now 3 years of post-HTx follow-up.

Conclusions

ABO isohemagglutinin titers should be routinely assessed in children undergoing desensitization therapy since ABOi transplantation can be considered in selected cases to expand the donor pool with the option of crossing the ABO barrier to find a better-matched allograft.     

ABO‐incompatible liver transplantation for children under 2 years of age: A case report and a single‐center review

Desensitization with RTX has been broadly introduced in adult LT across the ABO blood type barrier. For pediatric LT, the prophylactic use of RTX has not been standardized, especially for children under 2 years of age. A 20‐month‐old girl with BA underwent living donor LT from her ABO‐I mother. On POD 6, she developed combined T cell‐mediated and AMRs. Steroid bolus injection was immediately introduced, followed by antibody‐depleting therapy with PE and IVIG. Based on a peripheral blood lymphocyte analysis by fluorescence‐activated cell sorting, ATG and RTX were introduced for refractory rejection. Although she recovered from the combined rejections, IHBCs were inevitable as a consequence. We recommend extending the desensitization protocol to cover children under 2 years of age in order to prevent life‐threatening complications.     

Hospital readmission following pediatric heart transplantation

The frequency, indications, and outcomes for readmission following pediatric heart transplantation are poorly characterized. A better understanding of this phenomenon will help guide strategies to address the causes of readmission. Data from the Clinical Trials in Organ Transplantation for Children (CTOTC‐04) multi‐institutional collaborative study were utilized to determine incidence of, and risk factors for, hospital readmission within 30 days and 1 year from initial hospital discharge. Among 240 transplants at 8 centers, 227 subjects were discharged and had follow‐up. 129 subjects (56.8%) were readmitted within one year; 71 had two or more readmissions. The 30‐day and 1‐year freedom from readmission were 70.5% (CI: 64.1%, 76.0%) and 42.2% (CI: 35.7%, 48.7%), respectively. The most common indications for readmissions were infection followed by rejection and fever without confirmed infection, accounting for 25.0%, 10.6%, and 6.2% of readmissions, respectively. Factors independently associated with increased risk of first readmission within 1 year (Cox proportional hazard model) were as follows: transplant in infancy (P = .05), longer transplant hospitalization (P = .04), lower UNOS urgency status (2/IB vs 1A) at transplant (P = .04), and Hispanic ethnicity (P = .05). Hospital readmission occurs frequently in the first year following discharge after heart transplantation with highest risk in the first 30 days. Infection is more common than rejection as cause for readmission, with death during readmission being rare. A number of patient factors are associated with higher risk of readmission. A fuller understanding of these risk factors may help tailor strategies to reduce unnecessary hospital readmission.     

Evaluation of the current post‐transplantation Human Leukocyte Antigen antibody screening in pediatric renal transplant recipients

The necessity of post‐transplant monitoring for donor‐specific antibodies (DSAs) is unclear. This study evaluates the clinical relevance of post‐transplantation donor‐specific HLA antibodies in pediatric renal transplant recipients, aiming at better stratification of patients at risk of graft dysfunction and better recommendations for post‐transplant monitoring. A cohort of 68 pediatric kidney recipients, involving 76 transplantations between 2004 and 2014, was studied retrospectively. All patients were screened for HLA antibodies at 1, 3, 6, and 12 months after transplantation and yearly thereafter. Samples testing positive were further analyzed to detect DSA. A biopsy was performed on clinical indication. We studied the baseline characteristics of the patients with biopsy, with DSA, and with rejection. We assessed the effect of post‐transplant DSA on clinical outcome, including antibody‐mediated acute rejection and GFR decrease. In our cohort, the prevalence of DSA was 19% (13/68 transplantations). Most patients with HLA antibodies after transplantation were DSA‐positive (76%; 13/17). A clear association between DSA and subsequent rejection was found. At the end of the study period, a significantly lower GFR was found in patients with biopsy, DSA, or rejection. Based on our observations, we recommend routine post‐transplantation screening for HLA and DSA. The presence of DSA justifies a renal biopsy even in the absence of clinical signs of rejection.     

Donor‐specific antibodies in a pediatric kidney transplant population—Prevalence and association with antiproliferative drug dosing

Prevalence and implications of anti‐HLA class I and class II antibodies are beginning to be better characterized in pediatric kidney transplant recipients. dnDSA formation is predictive of AMR and downstream diminished graft function and survival. However, risk factors for the development of dnDSA are not well defined in this patient population. After introducing DSA surveillance into our pediatric kidney transplant program, we are reporting the prevalence of class I and class II DSA in 67 otherwise stable recipients. Secondary end‐points included risk factors for DSA development and assessment of graft function. Significantly, lower median daily MMF doses were observed in patients with DSAs compared to patients without DSAs (371 vs 617 mg/m²/d, respectively; P = 0.035). Class II DSA formation was more common, with a prevalence of 17.9%, as compared to 10.4% for class I DSA. Estimated glomerular filtration rate was also decreased in patients with positive DSA vs those with negative titers (71, SD 25 vs 78, SD 29 mL/min/1.73 m², respectively; P = 0.034). We conclude that reduced‐dose MMF is associated with dnDSA and DSA is associated with diminished graft function in stable pediatric kidney transplant recipients.     

Effects of an acute,outpatient physiotherapy exercise program following pediatric heart or lung transplantation

This prospective interventional study investigated the impact of a three‐month, ambulatory HA or HB, semi‐individualized, PT‐prescribed exercise program following pediatric HTx or LTx. SMW distance, strength, and flexibility were assessed at start and completion of the program and one yr after enrollment. Subjects received either an HB or HA exercise program three times per week. The cohort demonstrated clinically and statistically significant improvements in SMW distances at three months (425.7 ± 109.4–500.6 ± 93.6 m, p < 0.001) and at one yr (528.5 ± 66.6 m, p = 0.001), although there was no difference between the two groups at any time. Similar improvements were also observed in strength and flexibility measures. Correlates with higher SMW distance at three months and one yr included older age, male gender, and underlying diagnosis other than CHD. Male gender and diagnosis other than CHD were associated with a slower improvement in the SMW distance. This is the first report of institutionally based, outpatient exercise rehabilitation in the recovery following pediatric thoracic transplantation. We found similar improvements to HB interventions up to one yr after surgery. Further study of the role of exercise rehabilitation and long‐term fitness outcomes is needed.     

B‐type natriuretic peptide trends after pediatric heart transplantation

BNP is increasingly utilized in the management of pediatric HT recipients. Performing a retrospective single‐center chart review, we sought to describe BNP changes during the first year after HT and identify factors that affect its trend. After exclusion for rejection, 316 BNP levels from 50 patients were evaluated. BNP underwent an exponential decline 120 days after HT followed by a plateau. Log₁₀BNP decline strongly correlated with time (r = ?0.70, p < 0.0001). Initial BNP was less in pretransplant VAD (p = 0.0016) and lower post‐HT inotrope use (p = 0.0043). Infant recipients, IT >4 h, and those bridged medically were associated with higher plateau BNP. Multivariable logistic regression demonstrated IT >4 h independently predicted plateau BNP in the upper quartile (OR 7.1, p = 0.02). No significant change in BNP coincided with rejection (N = 6 patients) without severe hemodynamic compromise. BNP correlated modestly with right atrial pressure (r = 0.4652, p < 0.0001) and pulmonary capillary wedge pressure (r = 0.2660, p < 0.001), but poorly with echocardiogram (r = ?0.18, p = 0.003). Trending BNP could help provide insight into how the graft recovers after HT and IT >4 h independently predicted higher plateau BNP and may reflect subtle changes in graft performance.     

Clinical significance of anti‐HLA antibodies associated with ventricular assist device use in pediatric patients: A United Network for Organ Sharing database analysis

While VAD use in pediatric patients has previously been associated with anti‐HLA antibody production, the clinical significance of these antibodies is unclear. We investigated the clinical impact of anti‐HLA antibodies associated with VAD use in a large cohort of pediatric HTx recipients. From 2004 to 2011, pediatric cardiomyopathy patients post‐HTx (N=1288) with pre‐HTx PRA levels were identified from the United Network for Organ Sharing database. PRA levels were compared between VAD patients and those with no history of MCS. Incidence of rejection and overall survival were compared between VAD and non‐MCS groups after stratification by PRA and age. VAD recipients were more likely to produce anti‐HLA antibodies than non‐MCS patients (25.5% vs 10.5% had PRA>10%, P<.0001). Sensitized VAD patients (PRA>10%) had a higher incidence of rejection within 15 months of HTx compared to sensitized non‐MCS patients (57.1% vs 35.9%, P=.02). There was no intergroup difference in 15‐month mortality. Among pediatric cardiomyopathy patients supported with a VAD, the presence of anti‐HLA antibodies prior to HTx is associated with an increased risk of rejection. The mechanism of the association between VAD‐associated antibodies and early rejection is unclear and warrants further investigation.     

Outcome of antibody‐mediated rejection compared to acute cellular rejection after pediatric heart transplantation

Outcomes of ACR after pediatric HTx have been well described, but less has been reported on outcomes of AMR. We compared the clinical characteristics and cardiovascular outcomes (composite end‐point of death, retransplantation, or allograft vasculopathy) of pediatric HTx recipients with AMR, ACR, and no rejection in a retrospective single‐center study of 104 recipients. Twenty were treated for AMR; 15 were treated for ACR. Recipients with AMR had an increased frequency of congenital heart disease (90% vs ACR 67% vs no rejection 59%, P = .03), homograft (68% vs 7% vs 18%, P < .001), HLA sensitization (45% vs 13% vs 13%, P = .008), and positive cross‐match (30% vs 7% vs 9%, P = .046). AMR caused hemodynamic compromise more often than ACR (39% vs 4%, P = .02). AMR recipients had worse cardiovascular outcome than recipients with ACR or no rejection (40% vs 20% vs 8.6%, P = .003). In bivariate Cox analysis, AMR (HR 4.1, CI 1.4‐12.0, P = .009) and ischemic time (HR 1.6, CI 1.1‐2.3, P = .02) were associated with worse cardiovascular outcome; ACR was not. In summary, pediatric HTx recipients who develop AMR have worse cardiovascular outcome than recipients who develop only ACR or experience no rejection at all.     

Association of post‐transplant donor‐specific HLA antibody with liver graft fibrosis during long‐term follow‐up after pediatric liver transplantation

The aim of this study was to evaluate the significance of post‐transplant DSA as a predictor of liver fibrosis during long‐term follow‐up after pediatric LT. We evaluated the histological findings in 18 LT recipients who underwent liver biopsy after DSA screening. Liver fibrosis was scored based on the METAVIR fibrosis staging. Patients were divided into 2 groups based on histological findings, and clinical characteristics among patients with liver fibrosis were assessed. Of 18 patients, 7 were included in the fibrosis group. No significant between‐group differences were found regarding peritransplant characteristics, including age, sex, primary disease, ABO incompatibility, and immunosuppressive regimen. Episodes of acute rejection and non‐adherence to immunosuppressive drugs were comparable between both groups. The MFI for anti‐DR DSA and positive rate were significantly higher in the fibrosis group (1655 vs 216; P = .019, 86% vs 27%; P = .012, respectively). MFI for anti‐DQ DSA was higher in the fibrosis group, but non‐significantly (2052 vs 384; P = .46). Post‐transplant anti‐DR DSA is associated with graft fibrosis during long‐term follow‐up. This finding seems useful for the implementation of valid histological examinations of liver grafts for patients with higher MFI, especially for anti‐DR DSA, after pediatric LT.     

Post-transplant lymphoproliferative disorder following pediatric heart transplantation

Immunosuppression after heart transplantation is implicated in development of post-transplant lymphoproliferative disorder (PTLD). Despite a higher prevalence of PTLD in children, there is scarce knowledge about incidence, pathophysiologic mechanisms and risk factors for PTLD in pediatric recipients of cardiac allografts. We examined retrospectively the medical records of all 143 pediatric patients (mean age 9.2 +/- 6.1 yr) who received donor allografts between 1984 and 2002 and survived over 30 days. Five children (3.5%) developed PTLD over a mean follow-up period of 41.1 +/- 46.0 months. Time from transplant to diagnosis of PTLD ranged from 3.9 to 112 months (mean 48.0 +/- 41.9 months). Excluding PTLD, no other malignancies were found in this population. Actuarial freedom from PTLD was 99.2%, 99.2% and 96.2% at 1, 2, and 5 yr, respectively. Children who developed PTLD were more likely (by univariate analysis) to have been Rh negative (p = 0.01), Rh mismatched (p = 0.003), Epstein-Barr virus (EBV) seronegative (p = 0.001) and transplanted for congenital heart disease (p < 0.02). PTLD was associated with significant morbidity and mortality with a mean survival following diagnosis of 21.2 months. PTLD is a serious complicating outcome of cardiac transplantation that occurs in approximately 3.5% of children. Aside of immunosuppression, risk factors in this series for developing PTLD include EBV seronegativity and Rh negative status and mismatch. Non-hematogenous malignancies are rare in light of short allograft half-life.     

IGG3 anti‐HLA donor‐specific antibodies and graft function in pediatric kidney transplant recipients

Anti‐HLA DSAs are associated with ABMR and graft loss in KT recipients, yet the influence of DSA IgG subclass on outcomes in pediatric KT recipients is not completely understood. We performed a single‐center retrospective chart review of pediatric KT recipients with anti‐HLA DSAs, aiming to study the association between specific DSA IgG subclasses and graft outcomes, including ABMR and significant graft dysfunction (graft loss or 50% decrease in eGFR). Thirty‐six patients (mean age 15.4y) with DSAs initially detected 1 month‐14.3 years post‐transplantation were followed for a median of 2.8 years. Rates of IgG1, 2, 3, and 4 subclass detection were 92%, 33%, 58%, and 25%, respectively. Twenty‐two patients (61%) had clinical ABMR, whereas 19% had subclinical ABMR, and 13 (36%) experienced significant graft dysfunction. Patients with IgG3+ DSAs had a higher risk of graft dysfunction compared with IgG3‐ patients (52% vs 13%, P = .03). In a multiple Cox proportional regression analysis, the presence of IgG3+ DSA was independently associated with significant graft dysfunction (HR 10.45, 95% CI 1.97‐55.55, P = .006). In conclusion, IgG3 subclass DSAs are associated with graft dysfunction and may be useful for risk stratification and treatment decisions in DSA‐positive pediatric KT recipients.     

Changes in left ventricular strain parameters following pediatric heart transplantation

STE is increasingly utilized to assess strain in a variety of pathologies. Strain measurements have demonstrated utility following HT x and may aid in the detection of rejection and CAV . Strain parameters have not been well defined in the pediatric HT x population. This study aimed to describe strain in pediatric HT x recipients compared to controls and assess changes over time. All pediatric HT x recipients with available echocardiograms (2004‐2015) without rejection or CAV were identified. Longitudinal and circumferential strain was measured at <1 month, 1 year, 3 years, and 5 years post‐transplant and compared to controls. A total of 218 echocardiograms were analyzed in 79 HT x recipients. At <1 month post‐transplant, there was a significant decrement in longitudinal strain (GLS ?14.6 vs ?19.2, P  < .001) with concurrent augmentation of circumferential strain (GCS ?27.3 vs ?24.3, P  = .005). By 1 year post‐HT x, all strain parameters normalized and were not significantly different from the control population. In the absence of graft complications, strain parameters did not change up to 5 years post‐transplant. Abnormal longitudinal strain parameters are present in the early post‐HT x period with a compensatory increase in circumferential strain. These changes normalize by 1 year post‐transplant and do not change over time in the absence of graft complications.