A pre-transplantation risk assessment tool for graft survival in Dutch pediatric kidney recipients.

Background: A prediction model for graft survival including donor and recipient characteristics could help clinical decision-making and optimize outcomes. The aim of this study was to develop a risk assessment tool for graft survival based on essential pre-transplantation parameters. Methods: The data originated from the national Dutch registry (NOTR; Nederlandse OrgaanTransplantatie Registratie). A multivariable binary logistic model was used to predict graft survival, corrected for the transplantation era and time after transplantation. Subsequently, a prediction score was calculated from the ß-coefficients. For internal validation, derivation (80%) and validation (20%) cohorts were defined. Model performance was assessed with the area under the curve (AUC) of the receiver operating characteristics curve, Hosmer-Lemeshow test and calibration plots. Results: In total, 1428 transplantations were performed. Ten-year graft survival was 42% for transplantations before 1990, which has improved to the current value of 92%. Over time, significantly more living and pre-emptive transplantations have been performed and overall donor age has increased (P < .05).The prediction model included 71 829 observations of 554 transplantations between 1990 and 2021. Other variables incorporated in the model were recipient age, re-transplantation, number of human leucocyte antigen (HLA) mismatches and cause of kidney failure. The predictive capacity of this model had AUCs of 0.89, 0.79, 0.76 and 0.74 after 1, 5, 10 and 20 years, respectively (P < .01). Calibration plots showed an excellent fit. Conclusions: This pediatric pre-transplantation risk assessment tool exhibits good performance for predicting graft survival within the Dutch pediatric population. This model might support decision-making regarding donor selection to optimize graft outcomes. Trial registration: ClinicalTrials.gov Identifier: NCT05388955.

Diagnosing, discarding, or de-VUSsing: A practical guide to (un)targeted metabolomics as variant-transcending functional tests.

PURPOSE: For patients with inherited metabolic disorders (IMDs), any diagnostic delay should be avoided because early initiation of personalized treatment could prevent irreversible health damage. To improve diagnostic interpretation of genetic data, gene function tests can be valuable assets. For IMDs, variant-transcending functional tests are readily available through (un)targeted metabolomics assays. To support the application of metabolomics for this purpose, we developed a gene-based guide to select functional tests to either confirm or exclude an IMD diagnosis. METHODS: Using information from a diagnostic IMD exome panel, Kyoto Encyclopedia of Genes and Genomes, and Inborn Errors of Metabolism Knowledgebase, we compiled a guide for metabolomics-based gene function tests. From our practical experience with this guide, we retrospectively selected illustrative cases for whom combined metabolomic/genomic testing improved diagnostic success and evaluated the effect hereof on clinical management. RESULTS: The guide contains 2047 metabolism-associated genes for which a validated or putative variant-transcending gene function test is available. We present 16 patients for whom metabolomic testing either confirmed or ruled out the presence of a second pathogenic variant, validated or ruled out pathogenicity of variants of uncertain significance, or identified a diagnosis initially missed by genetic analysis. CONCLUSION: Metabolomics-based gene function tests provide additional value in the diagnostic trajectory of patients with suspected IMD by enhancing and accelerating diagnostic success.

Perioperative anesthesia care for the pediatric patient undergoing a kidney transplantation: An educational review.

Living-donor kidney transplantation is the first choice therapy for children with end-stage renal disease and shows good long-term outcome. Etiology of renal failure, co-morbidities, and hemodynamic effects, due to donor-recipient size mismatch, differs significantly from those in adult patients. Despite the complexities related to both patient and surgery, there is a lack of evidence-based anesthesia guidelines for pediatric kidney transplantation. This educational review summarizes the pathophysiological changes to consider and suggests recommendations for perioperative anesthesia care, based on recent research papers.

Prognostic Factors on Graft Function in Pediatric Kidney Recipients.

BACKGROUND: Graft survival in pediatric kidney transplant recipients has increased in the last decades. Determining prognostic factors for graft function over time allows the identification of patients at risk for graft loss and could lead to improvement of current guidelines. METHODS: Data were collected among pediatric kidney transplant recipients in a single center during the first 5 years after transplantation. Mixed model analysis was used to indicate possible prognostic factors for the loss of graft function. RESULTS: A total of 100 pediatric kidney transplant recipients were analyzed. Negative prognostics of graft function are higher donor age and higher recipient age, presence of obstructive uropathology, re-transplant, and occurrence of BK viremia. The negative influence on graft function of both donor age and presence of obstructive uropathology increased over time. In this study, the factors that did not influence graft function over time were the number of HLA mismatches, pre-transplant dialysis, intra-abdominal graft placement, ischemia time, occurrence of acute rejection, presence of lower urinary tract dysfunction, occurrence of urinary tract infections, and infections with cytomegalovirus and Epstein-Barr virus. CONCLUSIONS: This study showed that a higher donor age and higher recipient age, presence of obstructive uropathology, a re-transplant, and the occurrence of BK viremia were negative prognostic factors of graft function over time, in the first 5 years after transplant. Graft function was comparable between steroid-sparing regimens (preferable in low-risk patients) and regimens including steroids (for special reasons).

Chitotriosidase as a Novel Biomarker for Therapeutic Monitoring of Nephropathic Cystinosis.

BACKGROUND: Nephropathic cystinosis, a hereditary lysosomal storage disorder caused by dysfunction of the lysosomal cotransporter cystinosin, leads to cystine accumulation and cellular damage in various organs, particularly in the kidney. Close therapeutic monitoring of cysteamine, the only available disease-modifying treatment, is recommended. White blood cell cystine concentration is the current gold standard for therapeutic monitoring, but the assay is technically demanding and is available only on a limited basis. Because macrophage-mediated inflammation plays an important role in the pathogenesis of cystinosis, biomarkers of macrophage activation could have potential for the therapeutic monitoring of cystinosis. METHODS: We conducted a 2-year prospective, longitudinal study in which 61 patients with cystinosis who were receiving cysteamine therapy were recruited from three European reference centers. Each regular care visit included measuring four biomarkers of macrophage activation: IL-1ß, IL-6, IL-18, and chitotriosidase enzyme activity. RESULTS: A multivariate linear regression analysis of the longitudinal data for 57 analyzable patients found chitotriosidase enzyme activity and IL-6 to be significant independent predictors for white blood cell cystine levels in patients of all ages with cystinosis; a receiver operating characteristic analysis ranked chitotriosidase as superior to IL-6 in distinguishing good from poor therapeutic control (on the basis of white blood cell cystine levels of <2 nmol 1/2 cystine/mg protein or ≥2 nmol 1/2 cystine/mg protein, respectively). Moreover, in patients with at least one extrarenal complication, chitotriosidase significantly correlated with the number of extrarenal complications and was superior to white blood cell cystine levels in predicting the presence of multiple extrarenal complications. CONCLUSIONS: Chitotriosidase enzyme activity holds promise as a biomarker for use in therapeutic monitoring of nephropathic cystinosis.

Preparing for a kidney transplant: Medical nephrectomy in children with nephrotic syndrome.

Nephrotic syndrome is characterized by proteinuria, hypoalbuminemia, and general edema. These symptoms may persist in children who reach ESRD, which is unfavorable for the patient's allograft outcome. In addition, this may hamper early diagnosis of a relapse after transplantation. Surgical bilateral nephrectomy is often considered for that reason, but medical nephrectomy may be a less invasive alternative. In this retrospective single-center case series, we identified all children on dialysis with ESRD due to nephrotic syndrome in which a medical nephrectomy was attempted before kidney transplantation between 2013 and 2018. Outcome was measured by urine output and serum albumin levels. Eight patients with either congenital nephrotic syndrome or focal segmental glomerular sclerosis were included in the study. All patients received an ACE inhibitor as drug of first choice for medical nephrectomy, to which 5 patients responded with oligoanuria and a significant rise in serum albumin, and 3 patients responded insufficiently. In 1 of these 3 patients, diclofenac was added to the ACE inhibitor, with good result. In the other 2 patients, indomethacin was initiated without success, and surgical bilateral nephrectomy was performed. Overall, 6/8 patients had a successful medical nephrectomy and did not need surgical nephrectomy. No recurrence of nephrotic syndrome was found after kidney transplantation in all but one. Medical nephrectomy with ACE inhibitors and/or non-steroidal anti-inflammatory drugs is a safe and non-invasive therapy to minimize proteinuria in children with ESRD due to nephrotic syndrome before kidney transplantation. We suggest that this strategy should be considered as therapy before proceeding with surgical nephrectomy.

A Population Pharmacokinetic Model Does Not Predict the Optimal Starting Dose of Tacrolimus in Pediatric Renal Transplant Recipients in a Prospective Study: Lessons Learned and Model Improvement.

BACKGROUND AND OBJECTIVE: Bodyweight-based dosing of tacrolimus is considered standard care. Currently, at first steady state, a third of pediatric kidney transplant recipients has a tacrolimus pre-dose concentration within the target range. We investigated whether adaptation of the starting dose according to a validated dosing algorithm could increase this proportion. METHODS: This was a multi-center, single-arm, prospective trial with a planned interim analysis after 16 patients, in which the tacrolimus starting dose was based on bodyweight, cytochrome P450 3A5 genotype, and donor status (living vs. deceased donor). RESULTS: At the interim analysis, 31% of children had a tacrolimus pre-dose concentration within the target range. As the original dosing algorithm was poorly predictive of tacrolimus exposure, the clinical trial was terminated prematurely. Next, the original model was improved by including the data of the children included in this trial, thereby doubling the number of children in the model building cohort. Data were best described with a two-compartment model with inter-individual variability, allometric scaling, and inter-occasion variability on clearance. Cytochrome P450 3A5 genotype, hematocrit, and creatinine influenced the tacrolimus clearance. A new starting dose model was developed in which the cytochrome P450 3A5 genotype was incorporated. Both models were successfully internally and externally validated. CONCLUSIONS: The weight-normalized starting dose of tacrolimus should be higher in patients with a lower bodyweight and in those who are cytochrome P450 3A5 expressers.

Oscillometric and intra-arterial blood pressure in children post-kidney transplantation: Is invasive blood pressure measurement always needed?

OBJECTIVE: Blood pressure (BP) monitoring in children immediately after kidney transplantation is ideally performed with an arterial line. Accurate measurement of BP is necessary for optimal management. However, during the first days postoperative, the arterial line is removed and BP measurement is switched to a non-invasive device. The aim of this study was to determine the accuracy and reliability of the automated oscillometric device compared to invasive arterial BP (IBP) monitoring in patients after renal transplantation in pediatric intensive care unit (PICU). METHOD: We analyzed all simultaneously measured BPs in children with a kidney transplant in the Amalia Children's Hospital Radboud University Medical Center between January 1, 2012, and January 1, 2016. BP measurements were performed according to the hospital protocol. Agreement between invasive and non-invasive methods was assessed using Bland-Altman plots. RESULTS: A total of 29 patients were included in this retrospective study. The majority of children were male (59%), and median age was 11 years (range 1-17 years). Totally, 80 BP measurements were recorded during the first days post-kidney transplantation. The correlation coefficients (R) of systolic, diastolic, and MAP of non-invasive (NIBP) and IBP measurements were 0.84, 0.76, and 0.77, respectively (P < 0.01). Overall, the average MAP (7.5 ± 1.2 mm Hg; P < 0.05) NIBP values were lower compared to IBP. In hypertensive patients, MAP (10.4 ± 10.0 mm Hg; P < 0.05) BP values were significantly lower using the NIBP device. Clinically relevant difference of >10 mm Hg was found in 51% (41/80) of measurements and mainly observed in hypertensive measurements. CONCLUSIONS: IBP measurement is considered the golden standard for monitoring BP in patients immediately after kidney transplantation. NIBP values showed a good agreement with invasive reading, but the variability of NIBP mainly in hypertensive patients is high as it is the number of clinically relevant differences to IBP. We conclude that IBP remains the golden standard to monitor BP in children directly postoperatively.

The potential impact of hematocrit correction on evaluation of tacrolimus target exposure in pediatric kidney transplant patients.

BACKGROUND: Tacrolimus is an important immunosuppressive agent with high intra- and inter-individual pharmacokinetic variability and a narrow therapeutic index. As tacrolimus extensively accumulates in erythrocytes, hematocrit is a key factor in the interpretation of tacrolimus whole blood concentrations. However, as hematocrit values in pediatric kidney transplant patients are highly variable after kidney transplantation, translating whole blood concentration targets without taking hematocrit into consideration is theoretically incorrect. The aim of this study is to evaluate the potential impact of hematocrit correction on tacrolimus target exposure in pediatric kidney transplant patients. METHODS: Data were obtained from 36 pediatric kidney transplant patients. Two hundred fifty-five tacrolimus whole blood samples were available, together responsible for 36 area under the concentration-time curves (AUCs) and trough concentrations. First, hematocrit corrected concentrations were derived using a formula describing the relationship between whole blood concentrations, hematocrit, and plasma concentrations. Subsequently, target exposure was evaluated using the converted plasma target concentrations. Ultimately, differences in interpretation of target exposure were identified and evaluated. RESULTS: In total, 92% of our patients had lower hematocrit (median 0.29) than the reference value of adult kidney transplant patients. A different evaluation of target exposure for either trough level, AUC, or both was defined in 42% of our patients, when applying hematocrit corrected concentrations. CONCLUSION: A critical role for hematocrit in therapeutic drug monitoring of tacrolimus in pediatric kidney transplant patients is suggested in this study. Therefore, we believe that hematocrit correction could be a step towards improvement of tacrolimus dose individualization.

Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer-Saldino syndrome diagnosis.

BACKGROUND: Mainzer-Saldino syndrome (MZSDS) is a skeletal ciliopathy and part of the short-rib thoracic dysplasia (SRTD) group of ciliary disorders. The main characteristics of MZSDS are short limbs, mild narrow thorax, blindness, and renal failure. Thus far, variants in two genes are associated with MZSDS: IFT140, and IFT172. In this study, we describe a 1-year-old girl presenting with mild skeletal abnormalities, Leber congenital amaurosis, and bilateral hearing difficulties. For establishing an accurate diagnosis, we combined clinical, molecular, and functional analyses. METHODS: We performed diagnostic whole-exome sequencing (WES) analysis to determine the genetic cause of the disease and analyzed two gene panels, containing all currently known genes in vision disorders, and in hearing impairment. Upon detection of the likely causative variants, ciliary phenotyping was performed in patient urine-derived renal epithelial cells (URECs) and rescue experiments were performed in CRISPR/Cas9-derived Ift140 knock out cells to determine the pathogenicity of the detected variants in vitro. Cilium morphology, cilium length, and intraflagellar transport (IFT) were evaluated by immunocytochemistry. RESULTS: Diagnostic WES revealed two novel compound heterozygous variants in IFT140, encoding IFT140. Thorough investigation of WES data did not reveal any variants in candidate genes associated with hearing impairment. Patient-derived URECs revealed an accumulation of IFT-B protein IFT88 at the ciliary tip in 41% of the cells indicative of impaired retrograde IFT, while this was absent in cilia from control URECs. Furthermore, transfection of CRISPR/Cas9-derived Ift140 knock out cells with an IFT140 construct containing the patient mutation p.Tyr923Asp resulted in a significantly higher percentage of IFT88 tip accumulation than transfection with the wild-type IFT140 construct. CONCLUSIONS: By combining the clinical, genetic, and functional data from this study, we could conclude that the patient has SRTD9, also called Mainzer-Saldino syndrome, caused by variants in IFT140. We suggest the possibility that variants in IFT140 may underlie hearing impairment. Moreover, we show that urine provides an excellent source to obtain patient-derived cells in a non-invasive manner to study the pathogenicity of variants detected by genetic testing.

A randomized clinical trial indicates that levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome.

Levamisole has been considered the least toxic and least expensive steroid-sparing drug for preventing relapses of steroid-sensitive idiopathic nephrotic syndrome (SSINS). However, evidence for this is limited as previous randomized clinical trials were found to have methodological limitations. Therefore, we conducted an international multicenter, placebo-controlled, double-blind, randomized clinical trial to reassess its usefulness in prevention of relapses in children with SSINS. The efficacy and safety of one year of levamisole treatment in children with SSINS and frequent relapses were evaluated. The primary analysis cohort consisted of 99 patients from 6 countries. Between 100 days and 12 months after the start of study medication, the time to relapse (primary endpoint) was significantly increased in the levamisole compared to the placebo group (hazard ratio 0.22 [95% confidence interval 0.11-0.43]). Significantly, after 12 months of treatment, six percent of placebo patients versus 26 percent of levamisole patients were still in remission. During this period, the most frequent serious adverse event (four of 50 patients) possibly related to levamisole was asymptomatic moderate neutropenia, which was reversible spontaneously or after treatment discontinuation. Thus, in children with SSINS and frequent relapses, levamisole prolonged the time to relapse and also prevented recurrence during one year of treatment compared to prednisone alone. However, regular blood controls are necessary for safety issues.

A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation.

BACKGROUND: Multiple clinical, demographic, and genetic factors affect the pharmacokinetics of tacrolimus in children, yet in daily practice, a uniform body-weight based starting dose is used. It can take weeks to reach the target tacrolimus pre-dose concentration. OBJECTIVES: The objectives of this study were to determine the pharmacokinetics of tacrolimus immediately after kidney transplantation and to find relevant parameters for dose individualization using a population pharmacokinetic analysis. METHODS: A total of 722 blood samples were collected from 46 children treated with tacrolimus over the first 6 weeks after renal transplantation. Non-linear mixed-effects modeling (NONMEM®) was used to develop a population pharmacokinetic model and perform a covariate analysis. Simulations were performed to determine the optimal starting dose and to develop dosing guidelines. RESULTS: The data were accurately described by a two-compartment model with allometric scaling for bodyweight. Mean tacrolimus apparent clearance was 50.5 L/h, with an inter-patient variability of 25%. Higher bodyweight, lower estimated glomerular filtration rate, and higher hematocrit levels resulted in lower total tacrolimus clearance. Cytochrome P450 3A5 expressers and recipients who received a kidney from a deceased donor had a significantly higher tacrolimus clearance. The model was successfully externally validated. In total, these covariates explained 41% of the variability in clearance. From the significant covariates, the cytochrome P450 3A5 genotype, bodyweight, and donor type were useful to adjust the starting dose to reach the target pre-dose concentration. Dosing guidelines range from 0.27 to 1.33 mg/kg/day. CONCLUSION: During the first 6 weeks after transplantation, the tacrolimus weight-normalized starting dose should be higher in pediatric kidney transplant recipients with a lower bodyweight, those who express the cytochrome P450 3A5 genotype, and those who receive a kidney from a deceased donor.

A Novel Hypokalemic-Alkalotic Salt-Losing Tubulopathy in Patients with CLDN10 Mutations.

Mice lacking distal tubular expression of CLDN10, the gene encoding the tight junction protein Claudin-10, show enhanced paracellular magnesium and calcium permeability and reduced sodium permeability in the thick ascending limb (TAL), leading to a urine concentrating defect. However, the function of renal Claudin-10 in humans remains undetermined. We identified and characterized CLDN10 mutations in two patients with a hypokalemic-alkalotic salt-losing nephropathy. The first patient was diagnosed with Bartter syndrome (BS) >30 years ago. At re-evaluation, we observed hypocalciuria and hypercalcemia, suggesting Gitelman syndrome (GS). However, serum magnesium was in the upper normal to hypermagnesemic range, thiazide responsiveness was not blunted, and genetic analyses did not show mutations in genes associated with GS or BS. Whole-exome sequencing revealed compound heterozygous CLDN10 sequence variants [c.446C>G (p.Pro149Arg) and c.465-1G>A (p.Glu157_Tyr192del)]. The patient had reduced urinary concentrating ability, with a preserved aquaporin-2 response to desmopressin and an intact response to furosemide. These findings were not in line with any other known salt-losing nephropathy. Subsequently, we identified a second unrelated patient showing a similar phenotype, in whom we detected compound heterozygous CLDN10 sequence variants [c.446C>G (p.(Pro149Arg) and c.217G>A (p.Asp73Asn)]. Cell surface biotinylation and immunofluorescence experiments in cells expressing the encoded mutants showed that only one mutation caused significant differences in Claudin-10 membrane localization and tight junction strand formation, indicating that these alterations do not fully explain the phenotype. These data suggest that pathogenic CLDN10 mutations affect TAL paracellular ion transport and cause a novel tight junction disease characterized by a non-BS, non-GS autosomal recessive hypokalemic-alkalotic salt-losing phenotype.

Mortality risk disparities in children receiving chronic renal replacement therapy for the treatment of end-stage renal disease across Europe: an ESPN-ERA/EDTA registry analysis.

BACKGROUND: We explored the variation in country mortality rates in the paediatric population receiving renal replacement therapy across Europe, and estimated how much of this variation could be explained by patient-level and country-level factors. METHODS: In this registry analysis, we extracted patient data from the European Society for Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association (ESPN/ERA-EDTA) Registry for 32 European countries. We included incident patients younger than 19 years receiving renal replacement therapy. Adjusted hazard ratios (aHR) and the explained variation were modelled for patient-level and country-level factors with multilevel Cox regression. The primary outcome studied was all-cause mortality while on renal replacement therapy. FINDINGS: Between Jan 1, 2000, and Dec 31, 2013, the overall 5 year renal replacement therapy mortality rate was 15·8 deaths per 1000 patient-years (IQR 6·4-16·4). France had a mortality rate (9·2) of more than 3 SDs better, and Russia (35·2), Poland (39·9), Romania (47·4), and Bulgaria (68·6) had mortality rates more than 3 SDs worse than the European average. Public health expenditure was inversely associated with mortality risk (per SD increase, aHR 0·69, 95% CI 0·52-0·91) and explained 67% of the variation in renal replacement therapy mortality rates between countries. Child mortality rates showed a significant association with renal replacement therapy mortality, albeit mediated by macroeconomics (eg, neonatal mortality reduced from 1·31 [95% CI 1·13-1·53], p=0·0005, to 1·21 [0·97-1·51], p=0·10). After accounting for country distributions of patient age, the variation in renal replacement therapy mortality rates between countries increased by 21%. INTERPRETATION: Substantial international variation exists in paediatric renal replacement therapy mortality rates across Europe, most of which was explained by disparities in public health expenditure, which seems to limit the availability and quality of paediatric renal care. Differences between countries in their ability to accept and treat the youngest patients, who are the most complex and costly to treat, form an important source of disparity within this population. Our findings can be used by policy makers and health-care providers to explore potential strategies to help reduce these health disparities. FUNDING: ERA-EDTA and ESPN.

A preliminary study searching for the right dose of tacrolimus in very young (≤4 years) renal transplant patients.

OBJECTIVES: The Radboudumc Amalia Children's hospital in the Netherlands has a programme for renal transplantation in children aged ≤4 years. Children receive chronic corticosteroid sparing immunosuppressive therapy that consists of tacrolimus and mycophenolate mofetil. This work aimed to describe the PK of tacrolimus in children ≤4 years with renal transplants. METHODS: Paediatric renal transplant patients aged ≤4 years were included in this analysis. A PK curve of tacrolimus recorded ≤3 weeks after transplantation has been standard of care in our institution and aided in adjusting the dose in each patient to attain a target AUC0-12h of 210 µg h/l early after transplantation. KEY FINDINGS: Eight patients were included. The first two patients received an initial twice-daily regimen and the subsequent six patients a three-times daily regimen. Median dose-corrected AUCtau was 63 µg h/l. AUC target attainment was 37.5%. Of the remaining patients, two had an AUC very close to (around 10% below) the target. CONCLUSIONS: Large interindividual variability of tacrolimus was observed and showed suboptimal AUC target attainment. In this population, an even more aggressive approach of higher doses (e.g. 0.4 mg/kg per day) and more early AUC determination should be considered. This should be evaluated prospectively in a larger group of patients.

AGORA, a data- and biobank for birth defects and childhood cancer.

BACKGROUND: Research regarding the etiology of birth defects and childhood cancer is essential to develop preventive measures, but often requires large study populations. Therefore, we established the AGORA data- and biobank in the Netherlands. In this study, we describe its rationale, design, and ongoing data collection. METHODS: Children diagnosed with and/or treated for a structural birth defect or childhood cancer and their parents are invited to participate in the AGORA data- and biobank. Controls are recruited through random sampling from municipal registries. The parents receive questionnaires about demographics, family and pregnancy history, health status, prescribed medication, lifestyle, and occupational exposures before and during the index pregnancy. In addition, blood or saliva is collected from children and parents, while medical records are reviewed for diagnostic information. RESULTS: So far, we have collected data from over 6,860 families (3,747 birth defects, 905 childhood cancers, and 2,208 controls). The types of birth defects vary widely and comprise malformations of the digestive, respiratory, and urogenital tracts as well as facial, cardiovascular, kidney, skeletal, and central nervous system anomalies. The most frequently occurring childhood cancer types are acute lymphatic leukemia, Hodgkin and non-Hodgkin lymphoma, Wilms' tumor, and brain and spinal cord tumors. Our genetic and/or epidemiologic studies have been focused on hypospadias, anorectal malformations, congenital anomalies of the kidney and urinary tract (CAKUT), and orofacial clefts. CONCLUSION: The large AGORA data- and biobank offers great opportunities for investigating genetic and nongenetic risk factors for disorders in children and is open to collaborative initiatives. Birth Defects Research (Part A) 106:675-684, 2016. © 2016 Wiley Periodicals, Inc.