A longitudinal study of long-term renal outcome after pediatric liver transplantation in relation to CNI exposure.

BACKGROUND: Chronic kidney disease (CKD) is reported in 20%-30% of children after liver transplantation (LT). One of the proposed underlying causes is the long-term exposure to tacrolimus, a calcineurin inhibitor (CNI), which is the main immunosuppressive drug used after LT. Variation in tacrolimus absolute exposure and relative dose requirements are believed to be important risk factors for developing CNI-associated nephrotoxicity. AIM: To describe the long-term renal outcome of pediatric LT recipients and determine the effects of tacrolimus exposure on renal outcome parameters. METHODS: Retrospective single center study of renal function (GFR, proteinuria) and pharmacokinetic parameters (C0 , AUC0-12h ) obtained during annual follow-up in children after liver transplantation, between 1998 and 2019. Relevant pharmacogenetic variants for tacrolimus disposition (CYP3A5 and ABCB1) were determined in recipients and donors. The evolution of individual renal function and tacrolimus exposure was evaluated using linear mixed models for repeated measurements. RESULTS: Twenty-six children were included (mean follow-up: 10.4 years (range 2-18.9)). Mean estimated GFR was 109.3 (SE: 7.4), vs. measured: 91.3 mL/min/1.73 m2 (SE: 6.3), which remained stable during follow-up. CKD stage ≥2 was observed in 32.8% of the visits based on eGFR versus 50.0% on mGFR. CKD stage ≥3 was uncommon (4.1% and 6.2% resp.). Mean tacrolimus C0 was 5.3 ng/mL (SE: 2.5) with a AUC0-12h of 72.7 ng*h/mL (SE: 30.3), which demonstrated a small decrease during follow-up. There was a negative correlation between C0 and mGFR (rS = -0.3; p < .001). We found no correlation between GFR and tacrolimus dose requirements ((ng/mL)/(mg/kg)) or pharmacogenetic background. CONCLUSION: Renal function during long-term follow-up after pediatric LT remained stable for the majority of our cohort. However, mild CKD was relatively common, warranting follow-up into adulthood. Although absolute tacrolimus exposure has a small depressing effect on concurrent GFR, there is no progressive deterioration of GFR due to long-term exposure, dose requirements or genetic background under the current target levels. These findings should be confirmed in a larger sample set, ideally including data from multiple centers.

Effects of fecal microbiota transplantation for recurrent Clostridium difficile infection in children on kidney replacement therapy: a pilot study.

BACKGROUND: Recurrent Clostridium difficile infection (rCDI) is a rising problem in children with chronic diseases. Fecal microbiota transplantation (FMT) is a recent alternative for rCDI patients who do not respond to conventional treatment. FMT could have an additional positive effect on the intestinal dysbiosis and accumulation of uremic retention molecules (URM) associated with chronic kidney disease (CKD). Our aim was to investigate the clinical efficacy of FMT for rCDI in children with CKD together with the effect on dysbiosis and URM levels. METHODS: We analyzed stool and blood samples before and until 3 months after FMT in 3 children between 4 and 8 years old with CKD and rCDI. The microbiome was analyzed by 16 s rRNA sequencing. URM were analyzed with ultra-performance liquid chromatography-tandem mass spectrometry. CRP and fecal calprotectin were analyzed as parameters for systemic and gut inflammation, respectively. RESULTS: CDI resolved after FMT in all three without adverse events; one patient needed a second FMT. No significant effect on CRP and calprotectin was observed. Stool samples demonstrated a reduced richness and bacterial diversity which did not improve after FMT. We did observe a trend in the decrease of specific URM up to 3 months after FMT. CONCLUSION: FMT is an effective treatment for rCDI in patients with CKD. Analysis of the microbiome showed an important intestinal dysbiosis that, besides a significant reduction in Clostridium difficile, did not significantly change after FMT. A trend for reduction was seen in some of the measured URM after FMT.

Tacrolimus induces a pro-fibrotic response in donor-derived human proximal tubule cells dependent on common variants of the CYP3A5 and ABCB1 genes.

BACKGROUND: Common genetic variants of the enzymes and efflux pump involved in tacrolimus disposition have been associated with calcineurin inhibitor nephrotoxicity, but their importance is unclear because of the multifactorial background of renal fibrosis. This study explores the pro-fibrotic response of tacrolimus exposure in relation to the differential capacity for tacrolimus metabolism in proximal tubule cells (PTCs) with a variable (pharmaco)genetic background. METHODS: PTCs were obtained from protocol allograft biopsies with different combinations of CYP3A5 and ABCB1 variants and were incubated with tacrolimus within the concentration range found in vivo. Gene and protein expression, CYP3A5 and P-glycoprotein function, and tacrolimus metabolites were measured in PTC. Connective tissue growth factor (CTGF) expression was assessed in protocol biopsies of kidney allograft recipients. RESULTS: PTCs produce CTGF in response to escalating tacrolimus exposure, which is approximately 2-fold higher in cells with the CYP3A5*1 and ABCB1 TT combination in vitro. Increasing tacrolimus exposure results in relative higher generation of the main tacrolimus metabolite {13-O-desmethyl tacrolimus [M1]} in cells with this same genetic background. Protocol biopsies show a larger increase in in vivo CTGF tissue expression over time in TT vs. CC/CT but was not affected by the CYP3A5 genotype. CONCLUSIONS: Tacrolimus exposure induces a pro-fibrotic response in a PTC model in function of the donor pharmacogenetic background associated with tacrolimus metabolism. This finding provides a mechanistic insight into the nephrotoxicity associated with tacrolimus treatment and offers opportunities for a tailored immunosuppressive treatment.

Early corticosteroid withdrawal is associated with improved adult height in pediatric kidney transplant recipients.

BACKGROUND: Catch-up growth after pediatric kidney transplantation (kTx) is usually insufficient to reach normal adult height. We aimed to analyze the effect of pre-transplant recombinant human growth hormone (rhGH) and corticosteroid withdrawal on linear growth in the first year after kidney transplantation and identify factors associated with final height (FH). METHODS: Patients who underwent kTx between 1996 and 2018 at below 18 years old in five Belgian and Dutch centers were included. We analyzed the differences between height Z-scores at kTx and 1 year post-transplant (Δ height Z-score) in children with and without corticosteroids at 1 year (CS + /CS -) and with and without rhGH treatment before kTx (rhGH + /rhGH -). Univariable and multivariable linear regression analysis was applied to identify factors associated with height Z-score at 1 year post-kTx, Δ height Z-score, and FH Z-score. RESULTS: A total of 177 patients were included, with median age 9.3 years at kTx. Median height Z-scores pre-kTx and 1 year later in the CS - /rhGH - , CS + /rhGH - , CS - /rhGH + , and CS + /rhGH + groups were - 1.42/ - 0.80, - 0.90/ - 0.62, - 1.35/ - 1.20, and - 1.30/ - 1.60 (p = 0.001). CS use 1 year post-kTx was the only factor associated with Δ height (p = 0.003) on multivariable analysis. CS use at 1 year was the only variable associated with FH (p = 0.014) in children with pre-transplant height Z-score below - 1 (n = 52). CONCLUSIONS: Increase in height Z-score in the first year post-kTx was highest in the CS - /rhGH - group and lowest in the CS + /rhGH + group. The use of corticosteroids at 1 year post-kTx is associated with catch-up growth and in children with pre-transplant height Z-score below - 1 also with final height. A higher resolution version of the Graphical abstract is available as Supplementary information.

Epidemiology and clinicopathological characteristics of native kidney disease in children in Flanders, Belgium.

BACKGROUND: The Flemish Collaborative Glomerulonephritis Group (FCGG) registry is a population-based kidney biopsy registry that has been including all native kidney biopsies performed in children in Flanders (Belgium), since 2017. METHODS: From 2017 to 2020, 148 pediatric (< 18 years) native kidney biopsies were included. Each biopsy received a histopathological and final nephrological diagnosis, and concordance between both was assessed. Disease chronicity, summarized by the Mayo Clinic Chronicity Score, was determined on 122 biopsies with > 5 glomeruli. RESULTS: Kidney biopsy rate was high (29.0 biopsies per million children per year), median age was 10.0 years (IQR 5.8-14.7), and boys predominated (56.1% males). A total of 140 biopsies (94.6%) showed a representative pathology result. Glomerular disease was most prevalent, with IgA nephropathy/IgA vasculitis (43 biopsies, 29.1%) and minimal change disease (MCD) (29 biopsies, 19.6%) being the overall most frequent diagnoses. In general, diagnostic concordance was high (80.7%). In Alport syndrome and focal segmental glomerulosclerosis (FSGS), concordance was lower, as the nephrological diagnosis was often determined by results of genetic analysis. Nephrotic syndrome was the most frequent indication for kidney biopsy (31.8%) and was mainly caused by MCD and FSGS. The degree of disease chronicity on kidney biopsies was generally low, although 27.3% of biopsies with a diagnosis of FSGS showed moderate-to-severe chronic damage. CONCLUSIONS: The presented epidemiological findings validate data from previous European registry studies and may inspire kidney biopsy registries worldwide to implement novel features such as clinicopathological concordance and chronicity grading. A higher resolution version of the Graphical abstract is available as Supplementary information.

Illness-related parental stress and quality of life in children with kidney diseases.

BACKGROUND: This cross-sectional study investigated quality of life (QoL) and illness-related parental stress in children with kidney diseases by (1) comparing mean levels of these two variables between several kidney disease categories; (2) exploring correlations between QoL and parental stress; and (3) describing which disease category reports lowest QoL and highest parental stress. METHODS: We included 295 patients with a kidney disease (0-18 years) and their parents, followed at 6 reference centers for pediatric nephrology. Children's QoL was assessed by the PedsQL™ 4.0 Generic Core Scales, and illness-related stress by the Pediatric Inventory for Parents. All patients were divided into 5 kidney disease categories according to the multidisciplinary care program criteria prescribed by the Belgian authorities: (1) structural kidney diseases, (2) tubulopathies and metabolic diseases, (3) nephrotic syndrome, (4) acquired diseases with proteinuria and hypertension, and (5) kidney transplantation. RESULTS: Child self-reports showed no differences in QoL between kidney disease categories, in contrast to parent proxy reports. Parents of transplant patients reported lower QoL in their child and more parental stress compared with the 4 non-transplant categories. QoL and parental stress were negatively correlated. Lowest QoL and highest parental stress scores were mainly found in transplant patients. CONCLUSIONS: This study showed lower QoL and higher parental stress in pediatric transplant patients compared with non-transplants, based on parent reports. Higher parental stress is associated with worse QoL in the child. These results highlight the importance of multidisciplinary care for children with kidney diseases, with special attention to transplant patients and their parents. A higher resolution version of the Graphical abstract is available as Supplementary information.

Renal outcome and plasma methylmalonic acid levels after isolated or combined liver or kidney transplantation in patients with methylmalonic acidemia: A multicenter analysis.

BACKGROUND: Methylmalonic acidemia (MMAemia) is characterized by accumulation of methylmalonic acid (MMA) in all body tissues. To minimize disease-related complications, isolated kidney (KTx), liver (LTx) or combined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different transplant strategies on outcome are unclear. METHODS: In this multicenter retrospective observational study, we compared plasma MMA levels and estimated glomerular filtration rate (eGFR) data of 83 patients. Sixty-eight patients (82%) had a mut0-type MMAemia, one patient had a mut--type MMAemia, and seven (7.3%) had an inherited defect in cobalamin metabolism (cblA- or cblB-type MMAemia). Median observation period was 3.7 years (0-15.1 years). RESULTS: Twenty-six (31%) patients underwent KTx, 24 (29%) LTx and 33 (40%) LKTx. Posttransplant, mean plasma MMA concentration significantly decreased in all three cohorts; but at month 12, plasma MMA in KTx (1372 ± 1101 µmol/L) was 7.8-fold higher than in LTx (176 ± 103 µmol/L; P < 0.001) and 6.4-fold higher than in LKTx (215 ± 110 µmol/L; P < 0.001). Comparable data were observed at month 24. At time of transplantation, mean eGFR in KTx was 18.1 ± 24.3 mL/min/1.73 m2, in LTx 99.8 ± 29.9 mL/min/1.73 m2, and in LKTx 31.5 ± 21.2 mL/min/1.73 m2. At month 12 posttransplant, mean eGFR in KTx (62.3 ± 30.3 mL/min/1.73 m2) was 33.4% lower than in LTx (93.5 ± 18.3 mL/min/1.73 m2; P = 0.0053) and 25.4% lower than in LKTx (83.5 ± 26.9 mL/min/1.73 m2; P = 0.0403). CONCLUSIONS: In patients with isolated MMAemia, LTx and LKTx lead to markedly lower plasma MMA levels during the first 2 years posttransplant than KTx and are associated with a better preservation of kidney function. LTx should therefore be part of the transplant strategy in MMAemia.

A study of the 20-year evolution of antimicrobial resistance patterns of pediatric urinary tract infections in a single center.

Febrile urinary tract infections (UTIs) are important bacterial infections in children but increasingly difficult to treat due to antimicrobial resistance. We performed a retrospective analysis of the prevalence of uropathogens in hospitalized children with a febrile UTI between 2000 and 2019 in our university hospital to get more insight into trend and determinants of antimicrobial resistance over time. There were 1010 hospitalizations in children with a median age of 1.1 years. Thirty-six percent had an abnormal ultrasound and/or the presence of vesico-ureteral reflux, defined as CAKUT. Escherichia coli was the most prevalent pathogen (76%). However, there was an increasing prevalence towards other gram-negative organisms over time, and these pathogens were more common in children with congenital anomalies of kidney and urinary tract (CAKUT) (OR 4.26 (3.14-5.78), p < 0.001). E. coli strains demonstrated an increase in resistance against amoxicillin clavulanic acid (AMC) over time from 16% (2000-2004) to 36% (2015-2019) with an average increase of 2.0%/year; this was + 1.1%/year for third-generation cephalosporin. Multivariate analysis demonstrated that prior antibiotic use was an additional risk factor for antimicrobial resistance in E. coli. Nevertheless, increasing resistance was also observed in children without reported previous antibiotic treatment (+ 1.9%/year, p = 0.04).    Conclusion: We observed a significant pattern of increasing antimicrobial resistance of E. coli within a relatively short period of time, making it increasingly difficult to treat pediatric UTIs. This pattern was also seen in children without underlying risk factors (recent antibiotic treatment or structural urological disease). This is indicative for a larger problem in the general population and an important threat to our current standard of health care. What is Known: • Escherichia coli is the most frequent pathogen in pediatric urinary tract infections. • There is an increasing antimicrobial resistance against commonly used antibiotics in urinary tract infections. What is New: • The first 20-year retrospective, longitudinal study on characteristics of the microorganisms of pediatric urinary tract infections in a single center. • A 1-2% yearly increase in antimicrobial resistance, not only in children with congenital anomalies of the kidneys or recent antibiotic treatment but also in children without risk factors.

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.

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 (ß: 0.509; p = 0.011; 95% CI: 1.122-2.468), eGFR (ß: - 0.227; p = 0.030; 95% CI: 0.649-0.978), and pre-transplant hyperparathyroidism (ß: 1.149; p = 0.039; 95% CI: 1.062-9.369) were associated with hyperparathyroidism 12 months after transplantation. Pre-transplant hyperparathyroidism (ß: 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 (ß: - 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.

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).

Repeated kidney re-transplantation-the Eurotransplant experience: a retrospective multicenter outcome analysis.

In Eurotransplant kidney allocation system (ETKAS), candidates can be considered unlimitedly for repeated re-transplantation. Data on outcome and benefit are indeterminate. We performed a retrospective 15-year patient and graft outcome data analysis from 1464 recipients of a third or fourth or higher sequential deceased donor renal transplantation (DDRT) from 42 transplant centers. Repeated re-DDRT recipients were younger (mean 43.0 vs. 50.2 years) compared to first DDRT recipients. They received grafts with more favorable HLA matches (89.0% vs. 84.5%) but thereby no statistically significant improvement of patient and graft outcome was found as comparatively demonstrated in 1st DDRT. In the multivariate modeling accounting for confounding factors, mortality and graft loss after 3rd and ≥4th DDRT (P < 0.001 each) and death with functioning graft (DwFG) after 3rd DDRT (P = 0.001) were higher as compared to 1st DDRT. The incidence of primary nonfunction (PNF) was also significantly higher in re-DDRT (12.7%) than in 1st DDRT (7.1%; P < 0.001). Facing organ shortage, increasing waiting time, and considerable mortality on dialysis, we question the current policy of repeated re-DDRT. The data from this survey propose better HLA matching in first DDRT and second DDRT and careful selection of candidates, especially for ≥4th DDRT.

Bortezomib for autoimmune hemolytic anemia after intestinal transplantation.

AIHA is rare in the general population and associated with a mortality of 8%. In contrast, AIHA occurs in up to 12.2% of cases after intestinal transplantation and is associated with mortality up to 50%. Treatment entails a "step-up" approach including corticosteroids, IvIg, plasmapheresis, and rituximab. However, AIHA after transplantation often is refractory to this strategy, contributing to a poor outcome. We describe a child with microvillous inclusion disease who developed AIHA 1 year after multivisceral transplantation that was refractory to standard therapy and was subsequently treated with bortezomib.We observed remission of AIHA within 1 week after the start of bortezomib. Bortezomib was associated with transient diarrhea, leucopenia, and elevated liver enzymes. Three years later, he remains in remission without important complications. Published data on bortezomib for autoimmune cytopenias outside SOT are discussed. This is the first report to support bortezomib as an important therapeutic alternative for AIHA after SOT. The occurrence and treatment of AIHA after SOT, and specifically intestinal transplantation, should be the subject of future registry studies to collect additional experience and explore the optimal therapeutic approach.

Outcomes of kidney transplantations in children weighing 15 kilograms or less: a retrospective cohort study.

Kidney transplantation (KT) is often delayed in small children because of fear of postoperative complications. We report early- and long-term outcomes in children transplanted at ≤15 kg in the two largest Belgian pediatric transplant centers. Outcomes before (period 1) and since the introduction of basiliximab and mycophenolate-mofetil in 2000 (period 2) were compared. Seventy-two KTs were realized between 1978 and 2016: 38 in period 1 and 34 in period 2. Organs came from deceased donors in 48 (67%) cases. Surgical complications occurred in 25 KTs (35%) with no significant difference between the two periods. At least one acute rejection (AR) occurred in 24 (33%) KTs with significantly less patients experiencing AR during period 2: 53% and 12% in period 1 and, period 2 respectively (P < 0.001). Graft survival free of AR improved significantly in period 2 compared with period 1: 97% vs. 50% at 1 year; 87% vs. 50% at 10 years post-KT (P = 0.003). Graft survival tended to increase over time (period 1: 74% and 63% at 1 and 5 years; period 2: 94% and 86% at 1 and 5 years; P = 0.07), as well as patient survival. Kidney transplantation in children ≤15 kg remains a challenging procedure with 35% of surgical complications. However, outcomes improved and are nowadays excellent in terms of prevention of AR, patient and graft survival.

Renal Replacement Therapy in children with severe developmental disability: guiding questions for decision-making.

Whether to initiate or to withhold Renal Replacement Therapy (RRT) in children with severe developmental disability (DD) remains a topic of intense debate. The present study investigated the opinion of professionals on this difficult issue and proposed a checklist with guiding questions for decision-making. Clinicians affiliated to different organizations involved in pediatric nephrology worldwide were invited to respond to a web-based survey. This survey focused on the collection of demographic data of the respondents together with their opinion concerning the decision-making regarding RRT in a particular case and for children with severe DD in general. A total of 286 professionals responded to the survey. Sixty-six percent supported initiating RRT in the child of the case report, with pre-emptive transplantation being the preferred modality. Important arguments pro RRT initiation in children with severe DD in general were parental preference, decrease of suffering, and improvement of survival and quality of life. Important contraindications included low IQ, severe comorbidities, and inability of the patient to take medication or for the family to provide sufficient care.Conclusion: The present study presents an inventory on the opinions of health care professionals involved in RRT in children regarding the treatment of children with DD and assists in the decision-making process by identifying important medical and psychosocial arguments for initiating or withholding RRT in severe DD patients. What is Known: •Renal Replacement Therapy (RRT) in children with severe developmental disability (DD) is a topic of intense debate. •Previous studies on the opinion of professionals mainly focused on the use of IQ as an argument in the decision-making whether or not starting RRT. What is New: •The present study investigated the opinion of professionals with regard to considering initiation or withholding RRT in children with severe DD and identified medical and psychosocial arguments playing a role in the decision-making process. •Based on these arguments, a checklist with guiding questions for decision-making is proposed.

Tacrolimus dose requirements in paediatric renal allograft recipients are characterized by a biphasic course determined by age and bone maturation.

AIMS: Despite longstanding recognition of significant age-dependent differences in drug disposition during childhood, the exact course and the underlying mechanisms are not known. Our aim was to determine the course and determinants of individual relative dose requirements, during long-term follow-up in children on tacrolimus. METHODS: This was a cohort study in a tertiary hospital with standardized annual pharmacokinetic (PK) follow-up (AUC0-12hr ) in recipients of a renal allograft (≤19 years), between 1998 and 2015. In addition, the presence of relevant pharmacogenetic variants was determined. The evolution of dose-corrected exposure was evaluated using mixed models. RESULTS: A total of 184 PK visits by 43 children were included in the study (median age: 14.6). AUC0-12h corrected for dose per kg demonstrated a biphasic course: annual increase 4.4% (CI: 0.3-8.7%) until ±14 years of age, followed by 13.4% increase (CI 8.7-18.3%). Moreover, exposure corrected for dose per m2 proved stable until 14 years (+0.8% annually; CI: -3.0 to +4.8%), followed by a steep increase ≥14 years (+11%; CI: 7.0-16.0%). Analysis according to bone maturation instead of age demonstrated a similar course with a distinct divergence at TW2: 800 (P = 0.01). Genetic variation in CYP3A4, CYP3A5, and CYP3A7 was associated with altered dose requirements, independent of age. CONCLUSIONS: Children exhibit a biphasic course in tacrolimus disposition characterized by a high and stable drug clearance until a specific phase in pubertal development (TW2: 800 at age: ±14 years), followed by an important decline in relative dose requirements thereafter. Pharmacogenetic variation demonstrated an age/puberty independent effect. We suggest a critical reappraisal of current paediatric dosing algorithms for tacrolimus and drugs with a similar disposition.

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

BACKGROUND: 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. METHODS: The patient received a kidney from his mother, whose donor screening was unremarkable. He developed nephrotic-range proteinuria shortly after the procedure. Biopsies performed within the first 6 months after transplantation demonstrated ML (5-6 layers). RESULTS: Since there were no other criteria for CAMR, electron microscopic analysis of the baseline biopsy was performed, which in retrospect also demonstrated ML. The donor is still asymptomatic after 7 years of follow-up, with normal renal function and no proteinuria. CONCLUSIONS: We discuss the phenomenon of ML in renal disease and together with the findings in our case would like to draw attention to the fact that ML in the setting of renal transplantation is not specific to CAMR, as it can exist in several kidney diseases and even in asymptomatic donors.

High-urgency kidney transplantation in the Eurotransplant Kidney Allocation System: success or waste of organs? The Eurotransplant 15-year all-centre survey.

BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.