Lymphocyte subset reconstitution in pediatric liver recipients induced with steroid-free rabbit anti-human thymocyte globulin

Multiple measurements of lymphocyte subsets in 91 children treated with steroid-free tacrolimus, and rabbit anti-human thymocyte globulin induction demonstrate early reconstitution of T-cytotoxic cells, and gradual reconstitution of all other subsets, which is complete after one yr. Rejection-prone children demonstrate significantly higher counts of lymphocytes and all subsets prior to liver transplantation, and may exemplify one basis for enhanced baseline immunocompetence.     

Incidence of bloodstream infections in small bowel transplant recipients receiving selective decontamination of the digestive tract: A single‐center experience

Pediatric patients undergoing small bowel transplantation are susceptible to postoperative CLABSI. SDD directed against enteric microbes is a strategy for reducing CLABSI. We hypothesized that SDD reduces the frequency of CLABSI, infections outside the bloodstream, and allograft rejection during the first 30 days following transplant. A retrospective chart review of 38 pediatric small bowel transplant recipients at CCHMC from 2003 to 2011 was conducted. SDD antimicrobials were oral colistin, tobramycin, and amphotericin B. The incidence of CLABSI, infections outside the bloodstream, and rejection episodes were compared between study periods. The incidence of CLABSI did not differ between study periods (6.9 CLABSI vs. 4.6 CLABSI per 1000 catheter days; p = 0.727), but gram positives and Candida predominated in the first 30 days. Incidence of bacterial infections outside the bloodstream did not differ (p = 0.227). Rejection occurred more frequently during the first month following transplant (p = 0.302). SDD does not alter the incidence of CLABSI, bacterial infections outside the bloodstream, or allograft rejection in the immediate 30 days post‐transplantation. However, SDD does influence CLABSI organism types (favoring gram positives and Candida) and Candidal infections outside the bloodstream.     

Current status of small bowel transplantation in children

Small bowel transplantation is gradually changing from an experimental procedure to a very desirable and viable treatment option in children with irreversible intestinal failure due to either short bowel syndrome or functional impairment. Long term total parenteral nutrition and home parenteral nutrition would be necessary to manage these children in the absence of a small bowel transplant programme. Parenteral nutrition is also associated with complications which can result in chronic liver disease. In India, there is no infrastructure for this treatment option and even if it was there the cost of this method of treatment is likely to be more than the cost of post-operative immunosuppression. Small bowel can be transplanted as an isolated graft, in combination with the liver or as part of a multiviscera! transplant. The operative techniques have been standardised. Major post-operative complications result from sepsis and lymphoproliferative diseases. The best results have been obtained with a combined liver and small bowel transplant.     

Analysis of rabbit anti‐thymocyte globulin vs basiliximab induction in pediatric liver transplant recipients

Literature is limited comparing induction immunosuppression in pediatric liver transplant (LTx) recipients. This is a single‐center, retrospective cohort study of primary pediatric liver transplants at our center between 2005 and 2016 who received either basiliximab (BSX) or rabbit anti‐thymocyte globulin (rATG) induction. Maintenance immunosuppression consisted of tacrolimus ± a corticosteroid taper. Exclusions included receipt of an ABO‐incompatible graft, retransplantation, and multi‐organ transplantation. Primary outcomes were incidence of treated biopsy‐proven acute rejection (tBPAR) and PTLD within the first year and infections within 90 days of LTx. Secondary outcomes included graft and patient survival, time to first tBPAR, and incidence of steroid‐resistant rejection (SRR) within the first year post‐LTx. A total of 136 patients were included in the final analysis of which 57 patients (42%) received BSX induction. Patients who received rATG induction with or without a 2‐week corticosteroid taper experienced significantly more tBPAR compared to those who received BSX induction with a 6‐month corticosteroid taper (55.7% vs 33.3%, P = .01). There were no differences in the incidence of PTLD, infections, SRR, graft or patient survival, or time to first tBPAR between the two groups . Induction with rATG either with or without a short corticosteroid taper was associated with significantly more tBPAR in primary pediatric LTx recipients when compared to BSX induction with a prolonged corticosteroid taper in the setting of maintenance immunosuppression with tacrolimus.     

Sirolimus for solid organ transplantation in children

Sirolimus represents a major advancement in the field of solid organ transplantation and is being used as a rescue agent for acute and chronic rejection as well as for primary immunosuppression with good graft outcome. Although initial studies with sirolimus were in adults, now significant data have accumulated on the role of sirolimus in pediatric solid organ transplantation. This article reviews the current status of sirolimus in pediatric transplantation.     

Anellovirus loads are associated with outcomes in pediatric lung transplantation

Anelloviruses are DNA viruses ubiquitously present in human blood. Due to their elevated levels in immunosuppressed patients, anellovirus levels have been proposed as a marker of immune status. We hypothesized that low anellovirus levels, reflecting relative immunocompetence, would be associated with adverse outcomes in pediatric lung transplantation. We assayed blood samples from 57 patients in a multicenter study for alpha‐ and betatorquevirus, two anellovirus genera. The primary short‐term outcome of interest was acute rejection, and longer‐term outcomes were analyzed individually and as “composite” (death, chronic rejection, or retransplant within 2 years). Patients with low alphatorquevirus levels at 2 weeks post‐transplantation were more likely to develop acute rejection within 3 months after transplant (P = .013). Low betatorquevirus levels at 6 weeks and 6 months after transplant were associated with death (P = .047) and the composite outcome (P = .017), respectively. There was an association between low anellovirus levels and adverse outcomes in pediatric lung transplantation. Alphatorquevirus levels were associated with short‐term outcomes (ie, acute rejection), while betatorquevirus levels were associated with longer‐term outcomes (ie, death, or composite outcome within 2 years). These observations suggest that anelloviruses may serve as useful biomarkers of immune status and predictors of adverse outcomes.     

Pattern of growth after pediatric living-donor small bowel transplantation

The aim of our study was to analyze growth in children who underwent LDSB. The question was whether these children obtain linear growth and improvement of the Z-score for height and weight after the transplant. Three children with a mean age of 24 months underwent living-donor intestinal transplantation with 150 cm of terminal ileum. At a mean follow-up of 27 months height increased from 82.5 to 97.5 cm although Z-score for height did not improve, -2.679 to -2.675. Mean weight increased from 11.4 to 14.2 kg while Z-score for weight went from -1.916 to -2.409. Although these data are pertinent to only three children and the follow-up is slightly longer than two yr, it appears that while long-term survival and independency from TPN is achieved, only linear growth might be expected and catch-up growth does not occur.     

Renal function and histology in children after small bowel transplantation

Boyer O, Noto C, Patey‐Mariaud De Serre N, Gubler M‐C, Dechaux M, Goulet O, Niaudet P, Lacaille F. Renal function and histology in children after small bowel transplantation. Abstract: CKD is a frequent long‐term complication after SBTx. CNIs are a well‐known factor, but probably not the only cause. We assessed the incidence, risk factors, and severity of CKD in 27 children with SBTx (15 combined liver/SBTx) and prednisone/TAC‐based maintenance immunosuppression. Median follow‐up was seven yr (3–21). A renal biopsy was performed in 14 patients, 1–18 yr post‐SBTx. A reduced GFR was observed in 17 children (63%) during the follow‐up with none requiring dialysis. CNI toxicity was observed in 11/14 biopsies, as early as two yr post‐transplant, and could occur with a normal mGFR. The dose of TAC was reduced by 50% in 13 patients with CKD and/or significant kidney histological lesions, and six were also given MMF. This led to a significant improvement in renal function: mGFR normalized in eight patients and improved or stabilized in five. No rejection occurred. At last follow‐up, 37% had CKD stage 2 and 15% had CKD stage 3. In conclusion, CKD is frequent in children after SBTx and probably multifactorial. Less nephrotoxic immunosuppressive protocols may improve mGFR and should be further considered. The kidney histology helps in designing personalized immunosuppression strategies for patients.     

Current status of immunosuppressive agents for solid organ transplantation in children

Immunosuppression after organ transplantation is complex and ever evolving. Over the past two decades, newer immunosuppressive agents have been introduced with an aim to provide better patient and graft survival. Improved therapeutic strategies have been developed offering the option to use combinations of drugs with non-overlapping toxicities. There are, however, only a few clinical studies with robust data to rationalize the use of these agents in children. This review will discuss the newer immunosuppressive agents used for solid organ transplant, their current status in post-transplant management and prevention of allograft rejection.     

Impaired cellular immune response to diphtheria and tetanus vaccines in children after thoracic transplantation

Safety and immunogenicity of diphtheria and tetanus booster vaccination were evaluated in 28 children after thoracic transplantation. Adverse events were documented in a patient diary. Blood was collected prior to and four wk after vaccination. Specific antibody concentrations were measured by ELISA. Lymphocytes were investigated for expression of activation markers (CD25, HLA-DR) by flow cytometry and proliferation assays with and without stimulation. Post-vaccination antibody titers were higher than prevaccination (p < 0.001), with more patients having protective antibody levels against diphtheria (p < 0.02) and tetanus (p < 0.001). There was no increased proliferation in non-stimulated or stimulated cultures after vaccination. The number of T-lymphocytes activated by the vaccination antigens was similar pre- and post-vaccination, whereas HLA-DR-expression on stimulated and non-stimulated CD4(+) T-cells increased significantly. Increase in antibodies was negatively correlated with tacrolimus dose, and impaired cellular immunity was associated with higher tacrolimus dose and steroid use. Adverse events were similar to the general population; serious adverse events and rejection did not occur. Vaccination with inactivated vaccines can be performed safely in immunosuppressed children after thoracic transplantation and induces protective antibody levels in the majority of patients. Impaired induction of specific cellular immunity is correlated with intensity of immunosuppression and may explain reduced sustainability of antibodies.     

Immunosuppression in infants with short bowel syndrome undergoing isolated liver transplantation

BACKGROUND: Little data exist on immunosuppressive drug absorption in children with short bowel syndrome and intestinal failure associated liver disease (SBS-IFALD). AIM: To evaluate the absorption of immunosuppressive medications in children with SBS-IFALD undergoing isolated liver transplantation (iLTx). METHODS: A retrospective review was performed in children with SBS-IFALD undergoing LTx and comparison made with weight, age-matched children undergoing iLTX (extra-hepatic biliary atresia (EHBA) and normal intestinal length and function). RESULTS: Seven children with SBS-IFALD undergoing iLTx (median residual bowel length, 60 cm, range 40-80) were compared with 15 children undergoing LTx for EHBA. SBS-IFALD children had significantly lower trough tacrolimus levels at three months (5.8 vs. 7.9 ng/mL, p<0.05) and six months (5.0 vs. 8.0 ng/mL, p<0.05), but equivalent levels at 12 months after iLTx. The median calculated dose-normalized concentrations indicated that systemic availability of tacrolimus was comparable in two groups at 3, 6, 12 months (33.1 vs. 23.3; 42.4 vs. 36; 51 vs. 52.9) despite the differences in enteral function. The incidence of acute rejection was 1/7 (SBS-IFALD) and 10/15 (EHBA) group (p = 0.06). CONCLUSION: Children with SBS-IFALD demonstrated adequate absorption of oral tacrolimus without significant acute rejection rate after iLTx suggesting that modification of immunosuppression is not necessary.     

Evaluation of the immune function assay in pediatric living donor liver transplantation

The immune function (ImmuKnow) assay is a measure of cell‐mediated immunity based on the peripheral CD4+ T cell ATP activity. The efficacy of ImmuKnow in pediatric LDLT is not well documented. The aim of this study was to assess the correlations between the ImmuKnow and the clinical status in pediatric LDLT recipients. A total of 716 blood samples were obtained from 60 pediatric LDLT recipients (one month to 16 yr of age). The recipient's status was classified as follows: stable, infection, or rejection. The ImmuKnow values in the pediatric LDLT recipients with a clinically stable status had a lower immune response (IQR 85–297 ATP ng/mL) than that previously reported in adults. Meanwhile, the ImmuKnow values of the stable patients were not correlated with age. Furthermore, a significant difference was found in the ImmuKnow values between the bacterial or fungal infection and stable groups, but not between the CMV or EBV infection and stable groups. The ImmuKnow levels in the pediatric LDLT were lower than those observed in the adult LDLT. The proposed reference value is between 85 and 297 ATP ng/mL in pediatric LDLT recipients. We conclude that the ImmuKnow assay could be helpful for monitoring pediatric LDLT recipients with bacterial or fungal infections.     

Kidney transplantation in children with posterior urethral valves

Abstract:  There is controversy about the outcome of renal transplantation in patients with PUV. The objective of this study was to analyze the outcome of renal transplantation in children with PUV. Fifteen patients had a history of PUV as the etiology of their ESRD. Forty-five patients comprised a control group without lower urinary tract anomalies. Mean age and follow-up duration were not significantly different between the case and the control group (p = 0.1). The immunosuppressive protocol and the year of transplantation were similar in these two groups (p = 0.2, 0.4, respectively). Among patients with PUV, 37.5% had acute rejection; and 56.2% had chronic rejection. Among the controls, 22.2% had acute rejection and 28.8% had chronic rejection. None of these differences was significant. Mean survival time was seven yr in affected patients and 6.2 yr in the control group (p = 0.9). Among patients with PUV, the rate of graft survival in the first year after transplantation was 95%; and those in the third, fifth, and seventh yr, 91%, 65%, and 50%, respectively. For the controls, the graft survival was 83% at one yr; 80% at three yr; 71% at five yr; and 60% at seven yr after transplantation (p = 0.9). Conclusively, this study showed that a history of PUV had no effect on graft function. Graft survival was not different among these patients compared with patients free of these anomalies. We also showed that urological complications were few in these patients.     

Excellent outcome in infants and small children with thrombophilias undergoing kidney transplantation

One of the most common causes of early graft failure in children undergoing renal transplantation is vascular thrombosis. Numerous risk factors for graft thrombosis have been previously described. Children with various types of thrombophilias such as protein C, protein S and factor V Leiden deficiencies are at an increased risk for vascular thrombosis. Infants and small children with these disorders undergoing renal transplantation have not been well documented in the literature. We reviewed our experience in the diagnosis, peri-operative management and follow up of these patients at our institution. A retrospective analysis of all children undergoing renal transplantation at our institution, using data obtained from the Pediatric Transplant Registry at our institution since May 2000 was performed. The indications for renal transplant included focal segmental glomerulosclerosis, renal dysplasia and reflux nephropathy. One patient had factor V Leiden mutation and two patients had protein S deficiency. Patients were anticoagulated in the peri-operative and post-transplant period. All index transplants were performed with living donor kidneys. There were no adverse outcomes in children with thrombophilias despite having significantly lower weight at the time of transplant vs. children without thrombophilia. The incidence of graft thrombosis in the pediatric renal transplant recipients is high. We identify a potential cause of thrombosis in children not well documented in the literature. A high index of suspicion combined with preoperative screening and diagnosis of thrombophilias and an appropriate treatment plan may decrease the incidence of graft thrombosis in infants and small children undergoing renal transplantation.     

Better renal function with enhanced immunosuppression and protocol biopsies after kidney transplantation in children

Subclinical rejection may be associated with decreased graft function after renal transplantation (Tx). Detection by protocol biopsies and treatment could thus be important for the long-term prognosis. We have earlier discovered that glomerular filtration rate (GFR) declined in young children during the first 18 months. Consequently, we slightly enhanced and individualized each patient's immunosuppression. This was a retrospective study of 59 pediatric renal Tx patients between 1995 and 2001. The 35 historical controls received triple-therapy of azathioprine, methylprednisolone and cyclosporine. GFR was measured by protocol at discharge, 6 and 18 months, and a core biopsy was obtained at 18 months. The 24 study patients in addition received basiliximab, had GFR measured at 3 and 12 months, and a biopsy taken at 3 months. Based on histology and function, immunosuppression was individually adjusted. The groups were compared for GFR and histology at 18 months after Tx. There were less acute rejection episodes in the study group (0.38 vs. 1.23 per patient) and serum creatinine concentrations were lower. Subclinical rejection was detected and treated in 39% at 3 months. There were more chronic changes in the control (47%) than in the study group (29%) at 18 months. GFR was significantly higher in the study group at 18 months (87 vs. 68 mL/min/1.73 m(2)), most remarkably in patients < or =2 yr of age (99 vs. 68 mL/min/1.73 m(2)). Detection of subclinical rejection and slightly enhanced and individualized immunosuppression improved GFR 18 months after renal Tx, especially in the youngest patients.     

Early bacterial and fungal infection in children receiving allogeneic stem cell transplantation for acute lymphoblastic leukemia in Argentina

Infections are important complications associated with allogeneic HSCT. Describing infection rates in low‐ and middle‐income countries provides data to infer efficacy of supportive care practices in these settings. In this retrospective cohort study, we included patients (age ≤ 18 years) who underwent a first allogeneic HSCT for ALL in a single center in Argentina between 1998 and 2016. The primary outcome was sterile site bacterial infection. Secondary outcomes were proven or probable invasive fungal infection, TRM, and infectious deaths. There were 68 allogeneic HSCT recipients with ALL included in this analysis. Overall, 17 (25.0%) experienced at least one sterile site bacterial infection and 10 (14.7%) experienced at least one proven or probable invasive fungal infection. The TRM rate was 19.1%, and 3 (4.4%) patients died of infection. In a middle‐income country center in Argentina, pediatric allogeneic HSCT infection rates, TRM, and infection‐related mortality were comparable to high‐income countries. These data support continuation of allogeneic HSCT programs in similar resource‐limited settings provided that adequate supportive care and monitoring of outcomes can be performed.     

Basiliximab with delayed introduction of calcineurin inhibitors as a renal‐sparing protocol following liver transplantation in children with renal impairment

Renal impairment is frequently compromised in patients with end‐stage liver disease and is associated with increased long‐term mortality post‐LT. In contrast to CNI, basiliximab is an immunosuppressive agent with minimal nephrotoxic potential. This study reviews the experience of a single pediatric liver transplant center's renal‐sparing approach with the use of basiliximab and MMF to compensate for delayed entry of CNI in children with renal impairment at the time of organ availability. There were no differences in renal function between pediatric patients with and without pre‐LT renal impairment within the first year (cGFR: 135 mL/min/1.73 m² vs. 144 mL/min/1.73 m²; p = 0.56) or at 5–8 yr following LT, (129 mL/min/1.73 m² vs. 130 mL/min/1.73 m²; p = 0.97). In addition, there was no difference in ACR rates (50% vs. 43%, p = 0.62) between patients in the basiliximab group and those patients receiving standard CNI and steroid strategies. The utilization of a renal‐sparing approach with basiliximab alongside delayed entry and lower early target trough levels of CNI in children with renal impairment at the time of LT is safe and maintains excellent long‐term kidney function.     

Use of organs from increased infectious risk deceased donors in pediatric kidney transplantation

Living donors are the main source of transplanted kidneys for children and young people in many countries, but there still remains a significant need for deceased donor kidney transplantation. Given the waiting times associated with deceased donor kidney transplantation and the morbidity or mortality that can occur in those on the waiting list, it is essential that the utilization of kidneys from deceased donors is optimized. The use of organs from deceased donors at increased risk of transmitting human immunodeficiency virus, hepatitis B virus, or hepatitis C virus is relatively common in adults, but far less so in children. The risks and benefits of the use of kidneys from increased infectious risk donors (IIRD) are discussed. The variation of definitions of IIRD between countries is explored as is the need for pediatric nephrologists and transplant surgeons to have an understanding of the prevalence of viral diseases within the country in which they work. The role of screening tests such as nucleic acid tests is examined, along with the concept of residual risk. Finally, considerations in acquiring informed consent in the use of kidneys from IIRDs in children and young people are discussed.     

Outcome after kidney transplantation in children with thrombotic risk factors

BACKGROUND: According to the data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), vascular thrombosis accounts for 11.6% of graft losses in pediatric renal transplantation. In adults, inherited and acquired thrombophilic risk factors, e.g. factor V Leiden mutation, have been associated with early graft loss and increased rejection episodes. Data on the impact of these factors on the outcome of children after renal transplantation are rare. METHODS/PATIENTS: Sixty-six pediatric patients awaiting renal transplantation (mean age 10.1 yr) were screened for inherited and acquired risk factors for hypercoagulable disorders (protein C, S, and antithrombin III deficiency, antiphospholipid antibodies, factor V Leiden, prothrombin, and MTHFR mutation) in order to intensify anticoagulation in those with an increased risk for thrombophilia: intravenous heparin was administered with a partial prothrombin time (PTT) prolongation of 50 s for 14 days and switched to low-molecular-weight heparin for another 8 wk before aspirin was introduced for the first year. Patients without hypercoagulable risk factors were treated with heparin without PTT prolongation for 14 days and switched to aspirin immediately afterwards. The results on graft survival, incidence of acute rejection episodes, and long-term renal graft function were analyzed between recipients with and without hypercoagulable risk factors. RESULTS: Thrombophilic risk factors were identified in 27.3% of our patients. No thrombosis occurred. One serious bleeding complication led to a second surgical intervention. The rate of acute rejection episodes was not increased in patients with and without thrombotic risk factors after 90 days (16.7 vs. 25%), 1 yr (22.2 vs. 33.3%), and 3 yr (38.9 vs. 41.7%) of follow-up, respectively (p = n.s.). After a mean follow-up of 3 yr the kidney function was comparable in both groups, with 63.1 in recipients with and 69.8 mL/min/1.73 m(2) in recipients without hypercoagulable risk (p = n.s.). At latest follow-up, three graft losses were found not to be attributed to thrombotic risk factors. INTERPRETATION: Children with thrombophilic risk factors were identified and treated with an intensified anticoagulation regimen after renal transplantation. An increased risk for graft failure, acute rejection episodes, or impaired renal function for pediatric renal transplant recipients with hypercoagulable status was not found.