Portal hypertension after combined liver and intestinal transplantation, a diagnostic and therapeutic challenge?

A widely accepted technique to transplant the liver-bowel bloc is first to perform a piggyback anastomosis of the donor suprahepatic vena cava to the recipient vena cava; second to restore the arterial blood supply through an aortic interposition graft; and third to ensure venous drainage of the native foregut. The venous drainage of the native foregut can be restored through an end-to-end portocaval anastomosis between the donor infrahepatic vena cava and the recipient portal vein. Stenosis of this anastomosis can lead to portal hypertension presenting with upper GI congestion, bleeding, and hypersplenism. We report the successful treatment of this complication using an e-PTFE-covered stent inserted following balloon angioplasty

Improve in-depth immunological risk assessment to optimize genetic-compatibility and clinical outcomes in child and adolescent recipients of parental donor kidney transplants: protocol for the INCEPTION study.

BACKGROUND: Parental donor kidney transplantation is the most common treatment option for children and adolescents with kidney failure. Emerging data from observational studies have reported improved short- and medium-term allograft outcomes in recipients of paternal compared to maternal donors. The INCEPTION study aims to identify potential differences in immunological compatibility between maternal and paternal donor kidneys and ascertain how this affects kidney allograft outcomes in children and adolescents with kidney failure. METHODS: This longitudinal observational study will recruit kidney transplant recipients aged ≤18 years who have received a parental donor kidney transplant across 4 countries (Australia, New Zealand, United Kingdom and the Netherlands) between 1990 and 2020. High resolution human leukocyte antigen (HLA) typing of both recipients and corresponding parental donors will be undertaken, to provide an in-depth assessment of immunological compatibility. The primary outcome is a composite of de novo donor-specific anti-HLA antibody (DSA), biopsy-proven acute rejection or allograft loss up to 60-months post-transplantation. Secondary outcomes are de novo DSA, biopsy-proven acute rejection, acute or chronic antibody mediated rejection or Chronic Allograft Damage Index (CADI) score of > 1 on allograft biopsy post-transplant, allograft function, proteinuria and allograft loss. Using principal component analysis and Cox proportional hazards regression modelling, we will determine the associations between defined sets of immunological and clinical parameters that may identify risk stratification for the primary and secondary outcome measures among young people accepting a parental donor kidney for transplantation. This study design will allow us to specifically investigate the relative importance of accepting a maternal compared to paternal donor, for families deciding on the best option for donation. DISCUSSION: The INCEPTION study findings will explore potentially differential immunological risks of maternal and paternal donor kidneys for transplantation among children and adolescents. Our study will provide the evidence base underpinning the selection of parental donor in order to achieve the best projected long-term kidney transplant and overall health outcomes for children and adolescents, a recognized vulnerable population. TRIAL REGISTRATION: The INCEPTION study has been registered with the Australian New Zealand Clinical Trials Registry, with the trial registration number of ACTRN12620000911998 (14th September 2020)

The role of short-term memory and visuo-spatial skills in numerical magnitude processing: evidence from Turner syndrome

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Catch-up growth up to ten years of age in children born very preterm or with very low birth weight

BACKGROUND: Improved survival due to advances in neonatal care has brought issues such as postnatal growth and development more to the focus of our attention. Most studies report stunting in children born very preterm and/or small for gestational age. In this article we study the growth pattern of these children and aim to identify factors associated with postnatal catch-up growth. METHODS: 1338 children born with a gestational age <32 weeks and/or a birth weight of <1500 grams were followed during a Dutch nationwide prospective study (POPS). Subgroups were classified as appropriate for gestational age and <32 weeks (AGA) or small for gestational age (<32 wks SGA and ≥32 wks SGA). Data were collected at different intervals from birth until 10 years for the 962 survivors and compared to reference values. The correlation between several factors and growth was analysed. RESULTS: At 10 years the AGA children had attained normal height, whereas the SGA group demonstrated stunting, even after correction for target height (AGA: 0.0 SDS; SGA <32 wks: -0.29SDS and ≥32 wks: -0.13SDS). Catch-up growth was especially seen in the SGA children with a fast initial weight gain. BMI was approximately 1 SD below the population reference mean. CONCLUSION: At 10 years of age, children born very preterm AGA show no stunting. However, many children born SGA, especially the very preterm, show persistent stunting. Early weight gain seems an important prognostic factor in predicting childhood growth

Pharmacogenetic Determinants of Tacrolimus Disposition and the Effects in Renal Transplant Organs and Recipients

The success of kidney transplantation is largely carried by the efficacy of CNIs. Until now no new immunosuppressive drugs have performed better than tacrolimus in large randomized trials. Because of its success, it will be difficult setting up trials with a sufficient number of patients and duration of follow-up to find new CNI-free immunosuppressive regimes with a superior long-term outcome. Nevertheless, tacrolimus is not a drug easy to use, especially because of the combination of large intra-and interindividual pharmacokinetic variation with a narrow therapeutic index, in both of which genetic variation appears to play an important role. Genetic variation also contributes to the interindividual variation in the occurrence of tacrolimus-related side effects under standard immunosuppressive treatment protocols, but little attention has been paid to the underlying mechanisms. As long as no new alternatives for tacrolimus are likely to take its place, we should put more effort in understanding the effects of this drug in the individual patient and provide a tailored treatment to optimize outcome. This entails that we have to construct an integrative approach, “from gut to kidney”, of all the potential determinants of tacrolimus pharmacokinetics and dynamics in function of the renal allograft recipient and in the renal allograft itself. In particular clinical factors that affect the functional capacity of the gut-liver axis, ischemia-reperfusion injury, systemic inflammation, altered volume of distribution, decreased protein binding and certain co-medication (e.g. corticosteroids, antivirals) have to be taken into account (Chapter 2 of thesis). In children, this also includes the consideration of significant age-related effects on tacrolimus metabolism, which appears to be regulated by the same processes involved in bone maturation during puberty (Chapter 3). However, in the background the consequences of genetic variation in our xenobiotic defence system (in particular CYP3A5) play a dominant role in determining the right tacrolimus dose to reach the desired level of systemic exposure in the blood. Despite similar systemic exposure levels important variation in long-term outcome associated with CNI nephrotoxicity remains. From a pharmacodynamics point of view systemic blood levels are not ideal and demonstrate a relatively variable correlation with tissue concentrations and pharmacodynamic parameters . We show that the in vitro exposure of proximal tubule cells to a range of concentrations associated with in vivo tissue levels (at similar systemic exposure) results in the production of profibrotic cytokines in a concentration dependent manner (Chapter 6). This profibrotic response was most pronounced in the cells with a pharmacogenetic background, associated with a lesser capacity for tacrolimus degradation and extrusion (Chapter 4 and 5).• Chapter 1 o Introduction • Background of thesis 3 • Objectives of thesis 13 • Study Hypothesis 14 • Workplan 17 • Chapter 2 o From Gut to Kidney. Transporting and Metabolizing 23 CNIs in Solid Organ Transplantation • Introduction 25 • Calcineurin Inhibitors 26 • Pharmacodynamics 26 • Cyclosporine A 29 • Tacrolimus 31 • Predicting CNI PK according to the BCS model 34 • CNIs in the Gut 36 • CNIs in the Liver 40 • CNIs in the Kidney 41 • Pharmacogenetics 43 • Other genetic determinants 55 • Pharmacokinetic CNI-Drug Interaction 56 • Dosing after organ transplantation 58 • Conclusion and future directions 65 • Chapter 3 o Tacrolimus dose requirements in pediatric renal allograft 69 recipients are characterized by a biphasic course determined by age and bone maturation • Chapter 4 o The functional implications of common genetic variation in 91 CYP3A5 and ABCB1 in human proximal tubule cells • Chapter 5 o The effect of tacrolimus exposure on CYP3A5 and P-gp 115 expression in proximal tubule cells in relation to their pharmacogenetic background. • Chapter 6 o Tacrolimus exposure in human proximal tubule cells 135 results in differentially increased CTGF expression in relation to pharmacogenetic variants of CYP3A5 and ABCB1. • Chapter 7 o General Discussion 155 • Pharmacokinetics and genetics in a broader perspective 156 • Pharmacokinetics and genetics for tacrolimus 157 • Tacrolimus dosing in practice 159 • Tacrolimus dosing in children 160 • Tacrolimus and personalized medicine 163 • Tacrolimus associated drug toxicity 164 • A human cell model for studying renal tacrolimus metabolism 166 and toxicity • Effect tacrolimus on CYP3a5 and P-gp in human PTC model 168 • CNI-associated nephrotoxicity in human PTC model 169 o Summary 171 o Conclusions 173 o Future Prospects 176 • Scientific Acknowledgements 179 • Personal contribution 179 • Conflicts of interest 180 • References 181 • Supplemental Data • S1: Primer sets 211 • S2: PK visits characteristics 212 • S3: Primer sets 213 • S4: Donor/recipient characteristics participants ciPTC study 214 • S5: Primer sets 215 • S6: Primer sets 216 • Samenvatting / Layman’s Summary 217 • Personal Acknowledgements 224 • Curriculum Vitae 230nrpages: 239status: publishe

Energy expenditure and growth failure after intestinal transplantation: A case report

We present a 12-yr-old boy who received a combined liver-pancreas small bowel transplantation at the age of two. The post-operative period was complicated by wound closure problems resulting in a large asymptomatic abdominal wall defect. Further follow-up was uneventful, with the exception of new onset growth failure not explained by extensive routine investigations. An indirect calorimetry was performed. The resting energy expenditure (REE) was significantly increased (126% of predicted), demanding a daily caloric intake of 123 kcal/kg body weight (normal for age: 80 kcal/kg). In the absence of classic reasons for increased REE, a thermal camera revealed increased dermal heat loss at the abdominal wall defect (estimated surplus in energy loss of at least 29 kcal/day: 10.4% of the elevated REE). In addition, we found lower total lung capacity due to impaired abdominal breathing. In the exploration of growth failure in children after (ITx), increased REE must be taken into account. Indirect calorimetry can serve as a valuable diagnostic tool for evaluating individual energy requirements and nutritional support. In this child, exaggerated heat loss through an aberrant abdominal wall could be a potential important contributor to the patient's increased energy requirements.status: publishe

Rituximab in children with steroid-dependent nephrotic syndrome: experience of a tertiary center and review of the literature

Rituximab (RTX) is a new treatment option in children with difficult-to-treat steroid-dependent nephrotic syndrome (SDNS). We evaluated the experience of our tertiary center and reviewed the current literature.peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=yacb20status: publishe

Cystic fibrosis and alpha-1 antitrypsin deficiency: case report and review of literature

Background: This case report describes a child born with both cystic fibrosis (CF) and alpha-1 antitrypsin deficiency (A1ATD). Both are autosomal recessive inherited diseases, mainly affecting the lungs and the liver. The combination of both diseases together is rare and may lead to a fulminant disease with limited life span. To the best of our knowledge, no case has been reported of a patient born with both diseases. Case presentation: After an uneventful pregnancy, a male baby was born with meconium ileus. The suspected diagnosis of CF was confirmed based on the sweat test and genetic analysis. The child developed persisting cholestasis, too severe to be likely caused by CF alone and indicating an associated problem. The diagnosis of A1ATD was established based on clinical suspicion (persisting cholestasis), decreased serum alpha-1 antitrypsin and genetic analysis. Supportive therapy was started, however the boy evolved to rapidly progressive liver disease leading to liver failure which necessitated an infant liver transplantation. Conclusions: This case illustrates the complexity of care in case of two severe inherited diseases as well as post solid organ transplant care

Rethinking peritubular capillary basement membrane multilayering in renal transplant pathology: a case report

Severe multilayering (ML) of the peritubular capillary basement membranes in kidney allografts is considered to be an ultrastructural hallmark of chronic antibody-mediated rejection (CAMR). We describe here the unexpected findings in a young male adolescent with underlying focal segmental glomerulosclerosis who underwent a living-related donor transplant procedure, a case which brought into question the specificity of ML.status: publishe

Body mass index is associated with hyperparathyroidism in pediatric kidney transplant recipients

Background: Hyperparathyroidism persists in up to 50% of pediatric kidney transplant recipients. The aims of this study were to describe the evolution of parathyroid hormone (PTH) in the first year after transplantation and to identify factors associated with hyperparathyroidism. Methods: This retrospective study included children who underwent kidney transplantation at the University Hospitals of Ghent, Leuven, Rotterdam, or Amsterdam. Data from 149 patients were collected before and up to 12 months after transplantation. Severe hyperparathyroidism was defined as PTH 2-fold above the reference value. Factors associated with hyperparathyroidism and severe hyperparathyroidism were identified using multivariate logistic regression analysis. Results: Before transplantation, 97 out of 137 patients (71%) had hyperparathyroidism. The probability of hyperparathyroidism and severe hyperparathyroidism declined from 0.49 and 0.17 to 0.29 and 0.09 at 3 and 12 months after transplantation, respectively. BMI SDS (β: 0.509; p = 0.011; 95% CI: 1.122–2.468), eGFR (β: − 0.227; p = 0.030; 95% CI: 0.649–0.978), and pre-transplant hyperparathyroidism (β: 1.149; p = 0.039; 95% CI: 1.062–9.369) were associated with hyperparathyroidism 12 months after transplantation. Pre-transplant hyperparathyroidism (β: 2.115; p = 0.044; 95% CI: 1.055–65.084), defined as intact parathormone (iPTH) levels > 65 ng/l (6.9 pmol/l) or 1-84 PTH > 58 ng/l (6.2 pmol/l), was associated with severe hyperparathyroidism at 3 months. Only eGFR (β: − 0.488; p = 0.010; 95% CI: 0.425–0.888) was inversely associated with severe hyperparathyroidism at 9 months after transplantation. Conclusions: Allograft function remains the main determinant of severe hyperparathyroidism after transplantation. Our findings emphasize the importance of BMI and pre-transplant PTH control