Genetic aspects of congenital nephrotic syndrome : a consensus statement from the ERKNet-ESPN inherited glomerulopathy working group

Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders presenting with massive proteinuria within the first 3 months of life almost inevitably leading to end-stage kidney disease. The Work Group for the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Pediatric Nephrology (ESPN) has developed consensus statement on genetic aspects of CNS diagnosis and management. The presented expert opinion recommends genetic diagnostics as the key diagnostic test to be ordered already during the initial evaluation of the patient, discusses which phenotyping workup should be performed and presents known genotype-phenotype correlations.Peer reviewe

Management of congenital nephrotic syndrome : consensus recommendations of the ERKNet-ESPN Working Group

Publisher Copyright: © 2021, The Author(s).Congenital nephrotic syndrome (CNS) is a heterogeneous group of disorders characterized by nephrotic-range proteinuria, hypoalbuminaemia and oedema, which manifest in utero or during the first 3 months of life. The main cause of CNS is genetic defects in podocytes; however, it can also be caused, in rare cases, by congenital infections or maternal allo-immune disease. Management of CNS is very challenging because patients are prone to severe complications, such as haemodynamic compromise, infections, thromboses, impaired growth and kidney failure. In this consensus statement, experts from the European Reference Network for Kidney Diseases (ERKNet) and the European Society for Paediatric Nephrology (ESPN) summarize the current evidence and present recommendations for the management of CNS, including the use of renin–angiotensin system inhibitors, diuretics, anticoagulation and infection prophylaxis. Therapeutic management should be adapted to the clinical severity of the condition with the aim of maintaining intravascular euvolaemia and adequate nutrition, while preventing complications and preserving central and peripheral vessels. We do not recommend performing routine early nephrectomies but suggest that they are considered in patients with severe complications despite optimal conservative treatment, and before transplantation in patients with persisting nephrotic syndrome and/or a WT1-dominant pathogenic variant.Peer reviewe

FGF23 and its role in X-linked hypophosphatemia-related morbidity

Background: X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood. Methods: The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH. Results: The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations. Conclusions: By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.Peer reviewe

NPHS2 mutation associated with recurrence of proteinuria after transplantation

Mutations in the NPHS2 gene encoding podocin are associated with steroid-resistant nephrotic syndrome (SRNS) in childhood. Patients usually present with focal segmental glomerulosclerosis (FSGS). It is unclear to what extent SRNS due to NPHS2 mutations predisposes to recurrence of proteinuria/FSGS after renal transplantation (RTx). A 4-year-old girl with infantile SRNS was started on peritoneal dialysis because of end-stage renal disease due to FSGS. Mutational screening of the patient and her parents revealed a novel single nucleotide deletion in exon 8 of the NHPS2 gene (948delT), for which the patient was homozygous and her parents confirmed heterozygous asymptomatic carriers. At the age of 4.5 years the patient received a renal graft from her mother. On day 7 after RTx, the patient developed progressive proteinuria (urine protein/creatinine ratio 2.4 g/g), which responded within 1 week to prednisone pulse therapy, an increased cyclosporin A dosage, and ramipril therapy. The patient has maintained stable graft function and no further recurrence of proteinuria has been observed. In conclusion, patients with SRNS due to NPHS2 mutations are not protected from recurrence of proteinuria after RTx. The quick response to increased immunosuppression in our patient suggests an immune-mediated pathomechanism for recurrence of proteinuria.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47824/1/467_2003_Article_1408.pd

Promoting breastfeeding and interaction of pediatric associations with providers of nutritional products

Pediatric associations have been urged not to interact with and not to accept support from commercial providers of breast milk substitutes (BMSs), based on the assumption that such interaction would lead to diminished promotion and support of breastfeeding. The leadership of seven European pediatric learned societies reviewed the issue and share their position and policy conclusions here. We consider breastfeeding as the best way of infant feeding and strongly encourage its active promotion, protection, and support. We support the World Health Organization (WHO) Code of Marketing of BMSs. Infant formula and follow-on formula for older infants should not be advertised to families or the public, to avoid undermining breastfeeding. With consistently restricted marketing of BMSs, families need counseling on infant feeding choices by well-informed pediatricians. Current and trustworthy information is shared through congresses and other medical education directed and supervised by independent pediatric organizations or public bodies. Financial support from commercial organizations for congresses, educational, and scientific activities of pediatric organizations is an acceptable option if scientific, ethical, societal, and legal standards are followed; any influence of commercial organizations on the program is excluded, and transparency is ensured. Public–private research collaborations for improving and evaluating pharmaceuticals, vaccines, medical devices, dietetic products, and other products and services for children are actively encouraged, provided they are guided by the goal of enhancing child health and are performed following established high standards. We support increasing investment of public funding for research aiming at promoting child health, as well as for medical education.BK is the Else Kröner - Senior Professor of Paediatrics at LMU co-funded by Else Kröner-Fresenius Foundation and LM

CHD1L: a new candidate gene for congenital anomalies of the kidneys and urinary tract (CAKUT)

Background. Recently, we identified a microduplication in chromosomal band 1q21.1 encompassing the CHD1L/ALC1 gene encoding a chromatin-remodelling enzyme in congenital anomalies of the kidneys and urinary tract (CAKUT) patient. Methods. To explore the role of CHD1L in CAKUT, we screened 85 CAKUT patients for mutations in the CHD1L gene and performed functional analyses of the three heterozygous missense variants detected. In addition, we quantitatively determined CHD1L expression in multiple human fetal and adult tissues and analysed expression of CHD1L protein in human embryonal, adult and hydronephrotic kidney sections. Results. Two of three novel heterozygous missense variants identified in three patients were not found in >400 control chromosomes. All variants lead to amino acid substitutions in or near the CHD1L macro domain, a poly-ADP-ribose (PAR)-binding module interacting with PAR polymerase 1 (PARP1), and showed decreased interaction with PARP1 by pull-down assay of transfected cell lysates. Quantitative messenger RNA analysis demonstrated high CHD1L expression in human fetal kidneys, and levels were four times higher than in adult kidneys. In the human embryo at 7-11 weeks gestation, CHD1L immunolocalized in the early ureteric bud and the S- and comma-shaped bodies, critical stages of kidney development. In normal postnatal sections, CHD1L was expressed in the cytoplasm of tubular cells in all tubule segments. CHD1L expression appeared higher in the hydronephrotic kidney of one patient with a hypofunctional CHD1L variant than in normal kidneys, recapitulating high fetal levels. Conclusion. Our data suggest that CHD1L plays a role in kidney development and may be a new candidate gene for CAKU

Energy and protein requirements for children with CKD stages 2-5 and on dialysis-clinical practice recommendations from the Pediatric Renal Nutrition Taskforce

Dietary management in pediatric chronic kidney disease (CKD) is an area fraught with uncertainties and wide variations in practice. Even in tertiary pediatric nephrology centers, expert dietetic input is often lacking. The Pediatric Renal Nutrition Taskforce (PRNT), an international team of pediatric renal dietitians and pediatric nephrologists, was established to develop clinical practice recommendations (CPRs) to address these challenges and to serve as a resource for nutritional care. We present CPRs for energy and protein requirements for children with CKD stages 2-5 and those on dialysis (CKD2-5D). We address energy requirements in the context of poor growth, obesity, and different levels of physical activity, together with the additional protein needs to compensate for dialysate losses. We describe how to achieve the dietary prescription for energy and protein using breastmilk, formulas, food, and dietary supplements, which can be incorporated into everyday practice. Statements with a low grade of evidence, or based on opinion, must be considered and adapted for the individual patient by the treating physician and dietitian according to their clinical judgment. Research recommendations have been suggested. The CPRs will be regularly audited and updated by the PRNT.Peer reviewe

Nutritional management of the infant with chronic kidney disease stages 2-5 and on dialysis

The nutritional management of children with chronic kidney disease (CKD) is of prime importance in meeting the challenge of maintaining normal growth and development in this population. The objective of this review is to integrate the Pediatric Renal Nutrition Taskforce clinical practice recommendations for children with CKD stages 2-5 and on dialysis, as they relate to the infant from full term birth up to 1 year of age, for healthcare professionals, including dietitians, physicians, and nurses. It addresses nutritional assessment, energy and protein requirements, delivery of the nutritional prescription, and necessary dietary modifications in the case of abnormal serum levels of calcium, phosphate, and potassium. We focus on the particular nutritional needs of infants with CKD for whom dietary recommendations for energy and protein, based on body weight, are higher compared with children over 1 year of age in order to support both linear and brain growth, which are normally maximal in the first 6 months of life. Attention to nutrition during infancy is important given that growth is predominantly nutrition dependent in the infantile phase and the growth of infants is acutely impaired by disruption to their nutritional intake, particularly during the first 6 months. Inadequate nutritional intake can result in the failure to achieve full adult height potential and an increased risk for abnormal neurodevelopment. We strongly suggest that physicians work closely with pediatric renal dietitians to ensure that the infant with CKD receives the best possible nutritional management to optimize their growth and development.Peer reviewe

Non-small cell lung carcinoma in an adolescent manifested by acute paraplegia due to spinal metastases: a case report

<p>Abstract</p> <p>Introduction</p> <p>Bronchial carcinomas in childhood and adolescence are extremely rare; only individual cases have been reported previously.</p> <p>Case presentation</p> <p>We report on a 16-year-old Caucasian German boy with non-small cell lung carcinoma (squamous cell non-small cell lung carcinoma) stage IV, T4N2M1, without epidermal growth factor receptor overexpression and/or mutation or k-ras mutation. He presented with paraplegia due to spinal metastases of the bronchial carcinoma. No familial predisposition or toxin exposure was identified. Treatment following adult protocols consisted of surgical intervention for spinal metastases, first-line cisplatinum and gemcitabine, irradiation and second-line docetaxel. After a transient response our patient experienced disease progression and died about 10 months later.</p> <p>Conclusion</p> <p>Response and survival in our 16-year-old patient were similar to adult patients with stage IV non-small cell lung carcinoma.</p