Tacrolimus is a crucial immunosuppressant for organ transplant patients, requiring therapeutic drug monitoring due to its variable exposure after oral intake. Physiologically based pharmacokinetic (PBPK) modelling has provided insights into tacrolimus disposition in adults but has limited application in paediatrics. This study investigated age dependency in tacrolimus exposure at the levels of absorption, metabolism, and distribution. Based on the literature data, a PBPK model was developed to predict tacrolimus exposure in adults after intravenous and oral administration. This model was then extrapolated to the paediatric population, using a unique reference dataset of kidney transplant patients. Selecting adequate ontogeny profiles for hepatic and intestinal CYP3A4 appeared critical to using the model in children. The best model performance was achieved by using the Upreti ontogeny in both the liver and intestines. To mechanistically evaluate the impact of absorption on tacrolimus exposure, biorelevant in vitro solubility and dissolution data were obtained. A relatively fast and complete release of tacrolimus from its amorphous formulation was observed when mimicking adult or paediatric dissolution conditions (dose, fluid volume). In both the adult and paediatric PBPK models, the in vitro dissolution profiles could be adequately substituted by diffusion-layer-based dissolution modelling. At the level of distribution, sensitivity analysis suggested that differences in blood plasma partitioning of tacrolimus may contribute to the variability in exposure in paediatric patients.

BACKGROUND:Little is known about the time-varying determinants of kidney graft failure in children. METHODS:We performed a retrospective study of primary pediatric kidney transplant recipients (younger than 18 years) from the Eurotransplant registry (1990-2020). Piece-wise exponential additive mixed models were applied to analyze time-varying recipient, donor, and transplant risk factors. Primary outcome was death-censored graft failure. RESULTS:We report on 4528 kidney transplantations, of which 68% with deceased and 32% with living donor. One thousand six hundred and thirty-eight recipients experienced graft failure, and 168 died with a functioning graft. Between 2011 and 2020, the 5-year graft failure risk was 10% for deceased donor and 4% for living donor kidney transplant recipients. Risk of graft failure decreased five-fold from 1990 to 2020. The association between living donor transplantation and the lower risk of graft failure was strongest in the first month post-transplant (adjusted hazard ratio, 0.58; 95% confidence interval, 0.46 to 0.73) and remained statistically significant until 12 years post-transplant. Risk factors for graft failure in the first 2 years were deceased donor younger than 12 years or older than 46 years, potentially recurrent kidney disease, and panel-reactive antibody >0%. Other determinants of graft failure included dialysis before transplantation (until 5 years post-transplant), human leukocyte antigen mismatch 2-4 (0-15 years post-transplant), human leukocyte antigen mismatch 5-6 (2-12 years post-transplant), and hemodialysis (8-14 years post-transplant). Recipients older than 11 years at transplantation had a higher risk of graft failure 1-8 years post-transplant compared with other age groups, whereas young recipients had a lower risk throughout follow-up. Analysis of the combined effect of post-transplant time and recipient age showed a higher rate of graft failure during the first 5 years post-transplant in adolescents compared with young transplant recipients. In contrast to deceased donor younger than 12 years, deceased donor older than 46 years was consistently associated with a higher graft failure risk. CONCLUSIONS:We report a long-term inverse association between living donor kidney transplantation and the risk of graft failure. The determinants of graft failure varied with time. There was a significant cumulative effect of adolescence and time post-transplant. The ideal donor age window was dependent on time post-transplant.

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. 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. 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. 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.

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.

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.

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. 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. 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. 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.

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 com-bined liver-kidney transplantation (LKTx) have been suggested. However, the impact of these different trans -plant 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 & PLUSMN; 1101 mu mol/L) was 7.8-fold higher than in LTx (176 & PLUSMN; 103 mu mol/L; P < 0.001) and 6.4-fold higher than in LKTx (215 & PLUSMN; 110 mu mol/L; P < 0.001). Comparable data were observed at month 24. At time of transplan-tation, mean eGFR in KTx was 18.1 & PLUSMN; 24.3 mL/min/1.73 m2, in LTx 99.8 & PLUSMN; 29.9 mL/min/1.73 m2, and in LKTx 31.5 & PLUSMN; 21.2 mL/min/1.73 m2. At month 12 posttransplant, mean eGFR in KTx (62.3 & PLUSMN; 30.3 mL/min/1.73 m2) was 33.4% lower than in LTx (93.5 & PLUSMN; 18.3 mL/min/1.73 m2; P = 0.0053) and 25.4% lower than in LKTx (83.5 & PLUSMN; 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.(c) 2022 Elsevier Inc. All rights reserved.

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.

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). 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. 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). 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

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. 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. 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

ABSTRACT Introduction The aim of our study was to evaluate the factors influencing the choice between a deceased donor (DD) and living donor kidney transplantation (LD KT) for children and adolescents with chronic kidney disease (CKD) from the perspective of parents and physicians. Methods Patients with CKD stages 4 and 5 at the University Hospitals of Ghent, Leuven and Antwerp were included. Between February 2019 and March 2020, the corresponding questionnaires were distributed among parents and physicians in order to evaluate the potential differences between the medical recommendation and parental choice. Results Twenty-eight patients (median age 11 yr, range 2–19 yr), 10 girls and 18 boys were included. Three patients had undergone kidney transplantation in the past. Parents of 13 children opted for DD and 13 LD, and in two cases, there was no preference. Physicians recommended DD in 14 cases and LD in 14 cases. Parental choice corresponded with physician’s recommendation in 22 cases. Parental reasons for choosing DD were medical (n = 7), socio-economic (n = 1), combination of both (n = 1) or no reason (n = 4). Pediatric nephrologists advised against LD for medical (n = 6) or socio-economic (n = 6) reasons or a combination of both (n = 2). Conclusion In our cohort, the treating physicians regarded the family’s socio-economic factors more important for not actively promoting LD than the parents. A better understanding and communication regarding perceived socio-economic hurdles between caretakers and families might contribute to a higher incidence of living kidney donation in Belgium.

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.

Background The Flemish Collaborative Glomerulonephritis Group (FCGG) registry is the first population-based native kidney biopsy registry in Flanders, Belgium. In this first analysis, we report on patient demographics, frequency distribution and incidence rate of biopsied kidney disease in adults in Flanders. Methods From January 2017 to December 2019, a total of 2054 adult first native kidney biopsies were included. A 'double diagnostic coding' strategy was used, in which every biopsy sample received a histopathological and final clinical diagnosis. Frequency distribution and incidence rate of both diagnoses were reported and compared with other European registries. Results The median age at biopsy was 61.1 years (interquartile range, 46.1-71.7); male patients were more prevalent (62.1%) and biopsy incidence rate was 129.3 per million persons per year. Immunoglobulin A nephropathy was the most frequently diagnosed kidney disease (355 biopsies, 17.3% of total) with a similar frequency as in previously published European registries. The frequency of tubulointerstitial nephritis (220 biopsies, 10.7%) and diabetic kidney disease (154 biopsies, 7.5%) was remarkably higher, which may be attributed to changes in disease incidence as well as biopsy practices. Discordances between histopathological and final clinical diagnoses were noted and indicate areas for improvement in diagnostic coding systems. Conclusions The FCGG registry, with its 'double diagnostic coding' strategy, provides useful population-based epidemiological data on a large Western European population and allows subgroup selection for future research.