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Background The etiology of congenital solitary functioning kidney (CSFK) is largely unknown but likely includes various risk factors. We performed a case-control study to compare exposure to environmental and parental risk factors during embryonic kidney development between children with CSFK and healthy controls. Methods We included 434 children with CSFK and 1302 healthy controls from the AGORA data- and biobank matched on year of birth. Exposure to potential risk factors was investigated using parental questionnaire data. Crude and adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were estimated for each potential risk factor. Multiple imputation was used to deal with missing values. Confounders for each potential risk factor were selected using directed acyclic graphs. Results Maternal stress was newly identified as a risk factor for CSFK (aOR 2.1, 95% CI 1.2-3.5). Known associations with conception using in vitro fertilization/intracytoplasmic sperm injection (aOR 1.8, 95% CI 1.0-3.2), maternal infections during pregnancy (aOR 2.5, 95% CI 1.4-4.7), smoking during pregnancy (aOR 1.4, 95% CI 1.0-2.0), and parental CAKUT (aOR 6.6, 95% CI 2.9-15.1) were confirmed, but previous associations with diabetes and obesity could not be replicated. Folic acid supplement use and younger maternal age seemed to reduce the risk of CSFK (aORs 0.7, 95% CI 0.5-1.0, and 0.8, 95% CI 0.6-1.0, respectively). Conclusions Environmental and parental risk factors are likely to be involved in the development of CSFK and future studies should combine genetic, environmental, and gene-environment interaction analyses. Women wanting to become pregnant should consider optimizing their health and lifestyle. Graphical abstract, Author(s): Sander Groen in 't Woud [sup.1] [sup.2] , Nel Roeleveld [sup.1] , Iris A. L. M. van Rooij [sup.1] , Wout F. J. Feitz [sup.3] , Michiel F. Schreuder [...]

Background C3 glomerulopathy (C3G) is a rare kidney disorder characterized by predominant glomerular depositions of complement C3. C3G can be subdivided into dense deposit disease (DDD) and C3 glomerulonephritis (C3GN). This study describes the long-term follow-up with extensive complement analysis of 29 Dutch children with C3G. Methods Twenty-nine C3G patients (19 DDD, 10 C3GN) diagnosed between 1992 and 2014 were included. Clinical and laboratory findings were collected at presentation and during follow-up. Specialized assays were used to detect rare variants in complement genes and measure complement-directed autoantibodies and biomarkers in blood. Results DDD patients presented with lower estimated glomerular filtration rate (eGFR). C3 nephritic factors (C3NeFs) were detected in 20 patients and remained detectable over time despite immunosuppressive treatment. At presentation, low serum C3 levels were detected in 84% of all patients. During follow-up, in about 50% of patients, all of them C3NeF-positive, C3 levels remained low. Linear mixed model analysis showed that C3GN patients had higher soluble C5b-9 (sC5b-9) and lower properdin levels compared to DDD patients. With a median follow-up of 52 months, an overall benign outcome was observed with only six patients with eGFR below 90 ml/min/1.73 m.sup.2 at last follow-up. Conclusions We extensively described clinical and laboratory findings including complement features of an exclusively pediatric C3G cohort. Outcome was relatively benign, persistent low C3 correlated with C3NeF presence, and C3GN was associated with higher sC5b-9 and lower properdin levels. Prospective studies are needed to further elucidate the pathogenic mechanisms underlying C3G and guide personalized medicine with complement therapeutics. Graphical abstract, Author(s): Marloes A. H. M. Michels [sup.1] , Kioa L. Wijnsma [sup.1] , Roel A. J. Kurvers [sup.2] , Dineke Westra [sup.1] , Michiel F. Schreuder [sup.1] , Joanna A. [...]

Author(s): Sander Groen in't Woud [sup.1] [sup.2] , Loes F. M. van der Zanden [sup.2] , Michiel F. Schreuder [sup.1] Author Affiliations: (1) grid.461578.9, Department of Pediatric Nephrology, 804, Radboud [...]

Prematurity and perinatal stress, such as intrauterine growth restriction (IUGR) and chorioamnionitis, are pathological processes creating an impaired intrauterine environment. These intrauterine factors are associated with the development of proteinuria, hypertension, and chronic kidney disease (CKD) later in life. Initially, this was thought to be secondary to oligonephropathy, subsequent glomerular hypertrophy, and hyperfiltration, leading to glomerulosclerosis, a further decrease in nephron number, and finally CKD. Nowadays, there is increasing evidence that prematurity and perinatal stress affect not only nephron endowment but also the maturation of podocytes and vasculogenesis. IUGR is associated with podocyte damage and an aggravated course of nephrotic syndrome. Moreover, preterm birth and IUGR are known to cause upregulation of the postnatal renin-angiotensin system, resulting in hypertension. Chorioamnionitis causes damage to the glomeruli, thereby predisposing to the development of glomerulosclerosis. This review aims to summarize current knowledge on the influence of prematurity, IUGR, and chorioamnionitis on the development of different glomerular structures. After summarizing human and experimental data on low nephron number in general, a specific focus on the current understanding of podocyte and glomerular capillary formation in relation to prematurity and different causes of perinatal stress is presented., Author(s): Lieke A. Hoogenboom [sup.1] [sup.2] , Tim G. A. M. Wolfs [sup.1] [sup.3] [sup.4] , Matthias C. Hütten [sup.3] [sup.5] , Carine J. Peutz-Kootstra [sup.6] , Michiel F. Schreuder [...]

Nephrotic syndrome is a heterogeneous disease, and one of the most frequent glomerular disorders among children. Depending on the etiology, it may result in end-stage renal disease and the need for renal replacement therapy. A dysfunctional glomerular filtration barrier, comprising of endothelial cells, the glomerular basement membrane and podocytes, characterizes nephrotic syndrome. Podocytes are often the primary target cells in the pathogenesis, in which not only the podocyte function but also their crosstalk with other glomerular cell types can be disturbed due to a myriad of factors. The pathophysiology of nephrotic syndrome is highly complex and studying molecular mechanisms in vitro requires state-of-the-art cell-based models resembling the in vivo situation and preferably a fully functional glomerular filtration barrier. Current advances in stem cell biology and microfluidic platforms have heralded a new era of three-dimensional (3D) cultures that might have the potential to recapitulate the glomerular filtration barrier in vitro. Here, we highlight the molecular basis of nephrotic syndrome and discuss requirements to accurately study nephrotic syndrome in vitro, including an overview of specific podocyte markers, cutting-edge stem cell organoids, and the implementation of microfluidic platforms. The development of (patho) physiologically relevant glomerular models will accelerate the identification of molecular targets involved in nephrotic syndrome and may be the harbinger of a new era of therapeutic avenues., Author(s): Susan Veissi [sup.1] , Bart Smeets [sup.2] , Lambertus P. van den Heuvel [sup.1] [sup.3] [sup.4] , Michiel F. Schreuder [sup.1] , Jitske Jansen [sup.1] [sup.2] Author Affiliations: (1) [...]

In children, the main causes of chronic kidney disease (CKD) are congenital diseases and glomerular disorders. CKD is associated with multiple physiological changes and may therefore influence various pharmacokinetic (PK) parameters. A well-known consequence of CKD on pharmacokinetics is a reduction in renal clearance due to a decrease in the glomerular filtration rate. The impact of renal impairment on pharmacokinetics is, however, not limited to a decreased elimination of drugs excreted by the kidney. In fact, renal dysfunction may lead to modifications in absorption, distribution, transport, and metabolism as well. Currently, insufficient evidence is available to guide dosing decisions on many commonly used drugs. Moreover, the impact of maturation on drug disposition and action should be taken into account when selecting and dosing drugs in the pediatric population. Clinicians should take PK changes into consideration when selecting and dosing drugs in pediatric CKD patients in order to avoid toxicity and increase efficiency of drugs in this population. The aim of this review is to summarize known PK changes in relation to CKD and to extrapolate available knowledge to the pediatric CKD population to provide guidance for clinical practice., Author(s): Anne M. Schijvens [sup.1] , Saskia N. de Wildt [sup.2] [sup.3] , Michiel F. Schreuder [sup.1] Author Affiliations: (1) grid.461578.9, Radboud Institute for Molecular Life Sciences, Department of Pediatric [...]

Aims: Prednisolone is the cornerstone of treatment for idiopathic nephrotic syndrome in children, but is associated with marked side‐effects. Therapeutic drug monitoring using saliva would be a patient‐friendly option to monitor prednisolone treatment. To assess the feasibility of saliva monitoring, we described the pharmacokinetics (PK) of unbound prednisolone in plasma and saliva of children with first onset steroid‐sensitive nephrotic syndrome (SSNS). Methods: Children (age 2–16 years) with SSNS participating in a randomized, placebo‐controlled trial with levamisole were treated with an 18‐week tapering schedule of prednisolone. Five serial samples were collected at 4 (saliva) and 8 weeks (saliva and plasma) after first onset. A nonlinear mixed‐effects model was used to estimate the PK parameters of unbound prednisolone and the saliva‐to‐plasma ratio. Monte Carlo simulations were performed to assess the predictive performance of saliva monitoring. Results: From 39 children, 109 plasma and 275 saliva samples were available. Estimates (relative squared error) of unbound plasma clearance and volume of distribution were 93 (5%) L h−1 70 kg−1 and 158 (7%) L 70 kg−1, respectively. Typical saliva‐to‐plasma ratio was 1.30 (8%). Monte Carlo simulations demonstrated that on basis of 4 saliva samples and a single plasma sample unbound plasma area‐under‐the‐concentration–time curve can be predicted within 20% imprecision in 79% of the patients compared to 87% based on 4 plasma samples. Conclusion: Saliva proved to be a reliable and patient‐friendly option to determine prednisolone plasma exposure in children with SSNS. This opens opportunities for further PK and pharmacodynamics studies of prednisolone in a variety of paediatric conditions. [ABSTRACT FROM AUTHOR]

Nephrotic syndrome is one of the most common glomerular disorders in childhood. Glucocorticoids have been the cornerstone of the treatment of childhood nephrotic syndrome for several decades, as the majority of children achieves complete remission after prednisone or prednisolone treatment. Currently, treatment guidelines for the first manifestation and relapse of nephrotic syndrome are mostly standardized, while large inter-individual variation is present in the clinical course of disease and side effects of glucocorticoid treatment. This review describes the mechanisms of glucocorticoid action and clinical pharmacokinetics and pharmacodynamics of prednisone and prednisolone in nephrotic syndrome patients. However, these mechanisms do not account for the large inter-individual variability in the response to glucocorticoid treatment. Previous research has shown that genetic factors can have a major influence on the pharmacokinetic and dynamic profile of the individual patient. Therefore, pharmacogenetics may have a promising role in personalized medicine for patients with nephrotic syndrome. Currently, little is known about the impact of genetic polymorphisms on glucocorticoid response and steroid-related toxicities in children with nephrotic syndrome. Although the evidence is limited, the data summarized in this study do suggest a role for pharmacogenetics to improve individualization of glucocorticoid therapy. Therefore, studies in larger cohorts with nephrotic syndrome patients are necessary to draw final conclusions about the influence of genetic polymorphisms on the glucocorticoid response and steroid-related toxicities to ultimately implement pharmacogenetics in clinical practice., Author(s): Anne M. Schijvens [sup.1] , Rob ter Heine [sup.2] , Saskia N. de Wildt [sup.3] [sup.4] , Michiel F. Schreuder [sup.1] Author Affiliations: (Aff1) grid.461578.9, Department of Pediatric Nephrology, [...]

Background Congenital solitary functioning kidney (CSFK) is an anomaly predisposing to hypertension, albuminuria and chronic kidney disease. Its aetiology is complex and includes genetic and environmental factors. The role of gene–environment interactions (G×E), although relevant for other congenital anomalies, has not yet been investigated. Therefore, we performed a genome-wide G×E analysis with six preselected environmental factors to explore the role of these interactions in the aetiology of CSFK. Methods In the AGORA (Aetiologic research into Genetic and Occupational/environmental Risk factors for Anomalies in children) data- and biobank, genome-wide single-nucleotide variant (SNV) data and questionnaire data on prenatal exposure to environmental risk factors were available for 381 CSFK patients and 598 healthy controls. Using a two-step strategy, we first selected independent significant SNVs associated with one of the six environmental risk factors. These SNVs were subsequently tested in G×E analyses using logistic regression models, with Bonferroni-corrected P -value thresholds based on the number of SNVs selected in step one. Results In step one, 7–40 SNVs were selected per environmental factor, of which only rs3098698 reached statistical significance (P  = .0016, Bonferroni-corrected threshold 0.0045) for interaction in step two. The interaction between maternal overweight and this SNV, which results in lower expression of the Arylsulfatase B (ARSB) gene, could be explained by lower insulin receptor activity in children heterozygous for rs3098698. Eight other G×E interactions had a P -value <.05, of which two were biologically plausible and warrant further study. Conclusions Interactions between genetic and environmental factors may contribute to the aetiology of CSFK. To better determine their role, large studies combining data on genetic and environmental risk factors are warranted. [ABSTRACT FROM AUTHOR]

Life with a solitary functioning kidney (SFK) may be different from that when born with two kidneys. Based on the hyperfiltration hypothesis, a SFK may lead to glomerular damage with hypertension, albuminuria and progression towards end-stage renal disease. As the prognosis of kidney donors was considered to be very good, having a SFK has been considered to be a benign condition. In contrast, our research group has demonstrated that being born with or acquiring a SFK in childhood results in renal injury before adulthood in over 50% of those affected. Most congenital cases will be detected during antenatal ultrasound screening, but up to 38% of cases of unilateral renal agenesis are missed. In about 25-50% of cases of antenatally detected SFK there will be signs of hypertrophy, which could indicate additional nephron formation and is associated with a somewhat reduced risk of renal injury. Additional renal and extrarenal anomalies are frequently detected and may denote a genetic cause for the SFK, even though for the majority of cases no explanation can (yet) be found. The ongoing glomerular hyperfiltration results in renal injury, for which early markers are lacking. Individuals with SFK should avoid obesity and excessive salt intake to limit additional hyperfiltration. As conditions like hypertension, albuminuria and a mildly reduced glomerular filtration rate generally do not result in specific complaints but may pose a threat to long-term health, screening for renal injury in any individual with a SFK would appear to be imperative, starting from infancy. With early treatment, secondary consequences may be diminished, thereby providing the optimal life for anyone born with a SFK., Author(s): Michiel F. Schreuder [sup.1] Author Affiliations: (Aff1) 0000 0004 0444 9382, grid.10417.33, Department of Pediatric Nephrology, Amalia Children's Hospital, Radboud University Medical Center, , PO Box 9101, 6500 HB, [...]

Background Hemolytic uremic syndrome (HUS) is one of the most common causes of acute renal failure in children, with the majority of cases caused by an infection with Shiga toxin-producing Escherichia coli (STEC). Whereas O157 is still the predominant STEC serotype, non-O157 serotypes are increasingly associated with STEC-HUS. However, little is known about this emerging and highly diverse group of non-O157 serotypes. With supportive therapy, STEC-HUS is often self-limiting, with occurrence of chronic sequelae in just a small proportion of patients. Case diagnosis/treatment In this case report, we describe a 16-month-old boy with a highly severe and atypical presentation of STEC-HUS. Despite the presentation with multi-organ failure and extensive involvement of central nervous system due to extensive thrombotic microangiopathy (suggestive of atypical HUS), fecal diagnostics revealed an infection with the rare serotype: shiga toxin 2d-producing STEC O80:H2. Conclusions This report underlines the importance of STEC diagnostic tests in all children with HUS, including those with an atypical presentation, and emphasizes the importance of molecular and serotyping assays to estimate the virulence of an STEC strain., Author(s): Kioa L. Wijnsma [sup.1] , Anne M. Schijvens [sup.1] , John W. A. Rossen [sup.2] , A. M. D. (Mirjam) Kooistra-Smid [sup.3] , Michiel F. Schreuder [sup.1] , Nicole [...]