Publications by authors named "Detlef Bockenhauer"

177 Publications

100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care - Preliminary Report.

N Engl J Med 2021 11;385(20):1868-1880

From Genomics England (D.S., K.R.S., A.M., E.A.T., E.M.M., A.T., G.C., K.I., L.M., M. Wielscher, A.N., M. Bale, E.B., C.B., H.B., M. Bleda, A. Devereau, D.H., E. Haraldsdottir, Z.H., D.K., C. Patch, D.P., A.M., R. Sultana, M.R., A.L.T.T., C. Tregidgo, C. Turnbull, M. Welland, S. Wood, C.S., E.W., S.L., R.E.F., L.C.D., O.N., I.U.S.L., C.F.W., J.C., R.H.S., T.F., A.R., M.C.), the William Harvey Research Institute, Queen Mary University of London (D.S., K.R.S., V.C., A.T., L.M., M.R.B., D.K., S. Wood, P.C., J.O.J., T.F., M.C.), University College London (UCL) Institute of Ophthalmology (V.C., G.A., M.M., A.T.M., S. Malka, N.P., P.Y.-W.-M., A.R.W.), UCL Genetics Institute (V.C., N.W.W.), GOSgene (H.J.W.), Genetics and Genomic Medicine Programme (L.V., M.R., M.D., L.C., P. Beales, M.B.-G.), National Institute for Health Research (NIHR) Great Ormond Street Hospital Biomedical Research Centre (BRC) (M.R., S. Grunewald, S.C.-L., F.M., C. Pilkington, L.R.W., L.C., P. Beales, M.B.-G.), Infection, Immunity, and Inflammation Research and Teaching Department (P.A., L.R.W.), Stem Cells and Regenerative Medicine (N.T.), and Mitochondrial Research Group (S. Rahman), UCL Great Ormond Street Institute of Child Health, UCL Ear Institute (L.V.), the Department of Renal Medicine (D. Bockenhauer), and Institute of Cardiovascular Science (P.E.), UCL, Moorfields Eye Hospital National Health Service (NHS) Foundation Trust (V.C., G.A., M.M., A.T.M., S. Malka, N.P., A.R.W.), the National Hospital for Neurology and Neurosurgery (J.V., E.O., J.Y., K. Newland, H.R.M., J.P., N.W.W., H.H.), the Metabolic Unit (L.A., S. Grunewald, S. Rahman), London Centre for Paediatric Endocrinology and Diabetes (M.D.), and the Department of Gastroenterology (N.T.), Great Ormond Street Hospital for Children NHS Foundation Trust (L.V., D. Bockenhauer, A. Broomfield, M.A.C., T. Lam, E.F., V.G., S.C.-L., F.M., C. Pilkington, R. Quinlivan, C.W., L.R.W., A. Worth, L.C., P. Beales, M.B.-G., R.H.S.), the Clinical Genetics Department (M.R., T.B., C. Compton, C.D., E. Haque, L.I., D.J., S. Mohammed, L.R., S. Rose, D.R., G.S., A.C.S., F.F., M.I.) and St. John's Institute of Dermatology (H.F., R. Sarkany), Guy's and St. Thomas' NHS Foundation Trust, the Division of Genetics and Epidemiology, Institute of Cancer Research (C. Turnbull), Florence Nightingale Faculty of Nursing, Midwifery, and Palliative Care (T.B.), Division of Genetics and Molecular Medicine (M.A.S.), and Division of Medical and Molecular Genetics (M.I.), King's College London, NIHR BRC at Moorfields Eye Hospital (P.Y.-W.-M.), NHS England and NHS Improvement, Skipton House (V.D., A. Douglas, S. Hill), and Imperial College Healthcare NHS Trust, Hammersmith Hospital (K. Naresh), London, Open Targets and European Molecular Biology Laboratory-European Bioinformatics Institute, Wellcome Genome Campus, Hinxton (E.M.M.), the Division of Evolution and Genomic Sciences, Faculty of Biology, Medicine, and Health, University of Manchester (J.M.E., S.B., J.C.-S., S.D., G.H., H.B.T., R.T.O., G. Black, W.N.), and the Manchester Centre for Genomic Medicine, St. Mary's Hospital, Manchester University NHS Foundation Trust (J.M.E., Z.H., S.B., J.C.-S., S.D., G.H., G. Black, W.N.), Manchester, the Department of Genetic and Genomic Medicine, Institute of Medical Genetics, Cardiff University, Cardiff (H.J.W.), the Department of Clinical Neurosciences (T.R., W.W., R.H., P.F.C.), the Medical Research Council (MRC) Mitochondrial Biology Unit (T.R., W.W., P.Y.-W.-M., P.F.C.), the Department of Paediatrics (T.R.), the Department of Haematology (K.S., C. Penkett, S. Gräf, R.M., W.H.O., A.R.), the School of Clinical Medicine (K.R., E.L., R.A.F., K.P., F.L.R.), the Department of Medicine (S. Gräf), and Cambridge Centre for Brain Repair, Department of Clinical Neurosciences (P.Y.-W.-M.), University of Cambridge, NIHR BioResource, Cambridge University Hospitals (K.S., S.A., R.J., C. Penkett, E.D., S. Gräf, R.M., M.K., J.R.B., P.F.C., W.H.O., F.L.R.), and Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust (G.F., P.T., O.S.-B., S. Halsall, K.P., A. Wagner, S.G.M., N.B., M.K.), Cambridge Biomedical Campus, Wellcome-MRC Institute of Metabolic Science and NIHR Cambridge BRC (M.G.), Congenica (A.H., H.S.), Illumina Cambridge (A. Wolejko, B.H., G. Burns, S. Hunter, R.J.G., S.J.H., D. Bentley), NHS Blood and Transplant (W.H.O.), and Wellcome Sanger Institute (W.H.O.), Cambridge, the Health Economics Research Centre (J. Buchanan, S. Wordsworth) and the Wellcome Centre for Human Genetics (C. Camps, J.C.T.), University of Oxford, NIHR Oxford BRC (J. Buchanan, S. Wordsworth, J.D., C. Crichton, J.W., K.W., C. Camps, S.P., N.B.A.R., A.S., J.T., J.C.T.), the Oxford Centre for Genomic Medicine (A. de Burca, A.H.N.), and the Departments of Haematology (N.B.A.R.) and Neurology (A.S.), Oxford University Hospitals NHS Foundation Trust, Oxford Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, Churchill Hospital (C. Campbell, K.G., T. Lester, J.T.), the MRC Weatherall Institute of Molecular Medicine (N.K., N.B.A.R., A.O.M.W.) and the Oxford Epilepsy Research Group (A.S.), Nuffield Department of Clinical Neurosciences (A.H.N.), University of Oxford, and the Department of Clinical Immunology (S.P.), John Radcliffe Hospital, Oxford, Peninsula Clinical Genetics Service, Royal Devon and Exeter NHS Foundation Trust (E.B.), and the University of Exeter Medical School (E.B., C.F.W.), Royal Devon and Exeter Hospital (S.E.), Exeter, Newcastle Eye Centre, Royal Victoria Infirmary (A.C.B.), the Institute of Genetic Medicine, Newcastle University, International Centre for Life (V.S., P. Brennan), Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University (G.S.G., R.H., A.M.S., D.M.T., R. Quinton, R.M., R.W.T., J.A.S.), Highly Specialised Mitochondrial Service (G.S.G., A.M.S., D.M.T., R.M., R.W.T.) and Northern Genetics Service (J. Burn), Newcastle upon Tyne Hospitals NHS Foundation Trust (J.A.S.), and NIHR Newcastle BRC (G.S.G., D.M.T., J.A.S.), Newcastle upon Tyne, the Institute of Cancer and Genomic Sciences, Institute of Biomedical Research, University of Birmingham (C. Palles), and Birmingham Women's Hospital (D.M.), Birmingham, the Genomic Informatics Group (E.G.S.), University Hospital Southampton (I.K.T.), and the University of Southampton (I.K.T.), Southampton, Liverpool Women's NHS Foundation Trust, Liverpool (A. Douglas), the School of Cellular and Molecular Medicine, University of Bristol, Bristol (A.D.M.), and Yorkshire and Humber, Sheffield Children's Hospital, Sheffield (G.W.) - all in the United Kingdom; Fabric Genomics, Oakland (M. Babcock, M.G.R.), and the Ophthalmology Department, University of California, San Francisco School of Medicine, San Francisco (A.T.M.) - both in California; the Jackson Laboratory for Genomic Medicine, Farmington, CT (P.N.R.); and the Center for Genome Research and Biocomputing, Environmental and Molecular Toxicology, Oregon State University, Corvallis (M.H.).

Background: The U.K. 100,000 Genomes Project is in the process of investigating the role of genome sequencing in patients with undiagnosed rare diseases after usual care and the alignment of this research with health care implementation in the U.K. National Health Service. Other parts of this project focus on patients with cancer and infection.

Methods: We conducted a pilot study involving 4660 participants from 2183 families, among whom 161 disorders covering a broad spectrum of rare diseases were present. We collected data on clinical features with the use of Human Phenotype Ontology terms, undertook genome sequencing, applied automated variant prioritization on the basis of applied virtual gene panels and phenotypes, and identified novel pathogenic variants through research analysis.

Results: Diagnostic yields varied among family structures and were highest in family trios (both parents and a proband) and families with larger pedigrees. Diagnostic yields were much higher for disorders likely to have a monogenic cause (35%) than for disorders likely to have a complex cause (11%). Diagnostic yields for intellectual disability, hearing disorders, and vision disorders ranged from 40 to 55%. We made genetic diagnoses in 25% of the probands. A total of 14% of the diagnoses were made by means of the combination of research and automated approaches, which was critical for cases in which we found etiologic noncoding, structural, and mitochondrial genome variants and coding variants poorly covered by exome sequencing. Cohortwide burden testing across 57,000 genomes enabled the discovery of three new disease genes and 19 new associations. Of the genetic diagnoses that we made, 25% had immediate ramifications for clinical decision making for the patients or their relatives.

Conclusions: Our pilot study of genome sequencing in a national health care system showed an increase in diagnostic yield across a range of rare diseases. (Funded by the National Institute for Health Research and others.).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa2035790DOI Listing
November 2021

Long-term kidney function in children with Wilms tumour and constitutional WT1 pathogenic variant.

Pediatr Nephrol 2021 Oct 4. Epub 2021 Oct 4.

Department of Paediatric Oncology Great Ormond Street Hospital, UCL Institute of Child Health, NIHR Great Ormond Street Hospital Biomedical Research Centre, London, UK.

Background: Wilms tumour (WT) survivors, especially patients with associated syndromes or genitourinary anomalies due to constitutional WT1 pathogenic variant, have increased risk of kidney failure. We describe the long-term kidney function in children with WT and WT1 pathogenic variant to inform the surgical strategy and oncological management of such complex children.

Methods: Retrospective analysis of patients with WT and constitutional WT1 pathogenic variant treated at a single centre between 1993 and 2016, reviewing genotype, phenotype, tumour histology, laterality, treatment, patient survival, and kidney outcome.

Results: We identified 25 patients (60% male, median age at diagnosis 14 months, range 4-74 months) with WT1 deletion (4), missense (2), nonsense (8), frameshift (7), or splice site (4) pathogenic variant. Thirteen (52%) had bilateral disease, 3 (12%) had WT-aniridia, 1 had incomplete Denys-Drash syndrome, 11 (44%) had genitourinary malformation, and 10 (40%) had no phenotypic anomalies. Patient survival was 100% and 3 patients were in remission after relapse at median follow-up of 9 years. Seven patients (28%) commenced chronic dialysis of which 3 were after bilateral nephrectomies. The overall kidney survival for this cohort as mean time to start of dialysis was 13.38 years (95% CI: 10.3-16.4), where 7 patients experienced kidney failure at a median of 5.6 years. All of these 7 patients were subsequently transplanted. In addition, 2 patients have stage III and stage IV chronic kidney disease and 12 patients have albuminuria and/or treatment with ACE inhibitors. Four patients (3 frameshift; 1 WT1 deletion) had normal blood pressure and kidney function without proteinuria at follow-up from 1.5 to 12 years.

Conclusions: Despite the known high risk of kidney disease in patients with WT and constitutional WT1 pathogenic variant, nearly two-thirds of patients had sustained native kidney function, suggesting that nephron-sparing surgery (NSS) should be attempted when possible without compromising oncological risk. Larger international studies are needed for accurate assessment of WT1genotype-kidney function phenotype correlation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-021-05125-5DOI Listing
October 2021

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.

J Am Soc Nephrol 2021 Oct 4. Epub 2021 Oct 4.

J de Baaij, Department of Physiology, Radboud University Radboud Institute for Molecular Life Sciences, Nijmegen, Netherlands

Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. GS is caused by biallelic pathogenic variants in , encoding the Na-Cl cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of , , , or may result in the same renal phenotype of GS, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a GS phenotype, the genotype is unknown. We identified mitochondrial DNA (mtDNA) variants in three families with GS-like electrolyte abnormalities, then investigated 156 families for variants in and , which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced In NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive Na transport. Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (=7), m.616T>C (=1), m.643A>G (=1) (all in ) and m.4291T>C (=4, in ). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV reduced maximal mitochondrial respiratory capacity in patient fibroblasts. pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Pathogenic mtDNA variants in and can cause a GS-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained GS-like tubulopathies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2021050596DOI Listing
October 2021

An international cohort study spanning five decades assessed outcomes of nephropathic cystinosis.

Kidney Int 2021 11 6;100(5):1112-1123. Epub 2021 Jul 6.

Department of Pediatric Nephrology and Development and Regeneration, University Hospitals Leuven, Leuven, Belgium.

Nephropathic cystinosis is a rare disease secondary to recessive mutations of the CTNS gene encoding the lysosomal cystine transporter cystinosin, causing accumulation of cystine in multiple organs. Over the years, the disease has evolved from being a fatal condition during early childhood into a treatable condition, with patients surviving into adulthood. Data on cystinosis are limited by the rarity of the disease. Here, we have investigated factors associated with kidney and growth outcome in a very large cohort of 453 patients born between 1964 and 2016 and followed in Belgium, Germany, Austria, France, Italy, Spain, The Netherlands, Turkey and United Kingdom. From the 1970s to the 1990s, the median increase in kidney survival was 9.1 years. During these years, cysteamine, a cystine-depleting agent, was introduced for the treatment of cystinosis. Significant risk factors associated with early progression to end-stage kidney disease assessed by Cox proportional multivariable analysis included delayed initiation of cysteamine therapy and higher mean leucocyte cystine levels. No significant effect on kidney function was observed for gender, pathogenic variant of the CTNS gene, and the prescription of indomethacin or renin angiotensin system blockers. Significantly improved linear growth was associated with early use of cysteamine and lower leukocyte cystine levels. Thus, our study provides strong evidence in favor of early diagnosis and optimization of cystine depletion therapy in nephropathic cystinosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2021.06.019DOI Listing
November 2021

Epidemiology of Distal Renal Tubular Acidosis: A Study Using Linked UK Primary Care and Hospital Data.

Nephron 2021 1;145(5):486-495. Epub 2021 Jul 1.

Great Ormond Street Hospital, London, United Kingdom.

Introduction: Distal renal tubular acidosis (dRTA), or RTA type 1, a rare inherited or acquired disease, is a disorder of the distal tubule caused by impaired urinary acid secretion. Due to associated conditions and nonspecific symptoms, dRTA may go undetected. This analysis aims to estimate the prevalence of dRTA in the UK Clinical Practice Research Datalink (CPRD) databases and extrapolate it to European Union Five (EU5) populations.

Methods: A retrospective analysis was conducted using the CPRD GOLD database and linked Hospital Episode Statistics (HES) data to identify diagnosed and potentially undiagnosed or miscoded patients (suspected patients). Patients' records with at least one diagnosis code for dRTA, RTA, specific autoimmune diseases, or renal disorders recorded between January 1987 and November 2017 were obtained and analyzed. An algorithm was developed to detect potentially undiagnosed/miscoded dRTA, based on associated conditions and prescriptions.

Results: A total of 216 patients with diagnosis of RTA or dRTA were identified (with 98 linked to hospital data), and 447 patients were identified as having suspected dRTA. dRTA prevalence for 2017 was estimated between 0.46 (recorded cases, of which 22.1% were considered primary) and 1.60 when including suspected cases (7.6% primary) per 10,000 people. Prescription and clinical records of diagnosed patients revealed a wide range of comorbidities and a need for pharmacological treatment to manage associated symptoms.

Conclusion: The study provides new estimates of dRTA prevalence in Europe and suggests that patients may often be unreported or miscoded, potentially confounding appropriate disease management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000516876DOI Listing
July 2021

Identification of a Locus on the X Chromosome Linked to Familial Membranous Nephropathy.

Kidney Int Rep 2021 Jun 3;6(6):1669-1676. Epub 2021 Mar 3.

Department of Renal Medicine, University College London, London, UK.

Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults and is a leading cause of end-stage renal disease due to glomerulonephritis. Primary MN has a strong male predominance, accounting for approximately 65% of cases; yet, currently associated genetic loci are all located on autosomes. Previous reports of familial MN have suggested the existence of a potential X-linked susceptibility locus. Identification of such risk locus may provide clues to the etiology of MN.

Methods: We identified 3 families with 8 members affected by primary MN. Genotyping was performed using single-nucleotide polymorphism microarrays, and serum was sent for anti-phospholipase A2 receptor (PLA2R) antibody testing. All affected members were male and connected through the maternal line, consistent with X-linked inheritance. Genome-wide multipoint parametric linkage analysis using a model of X-linked recessive inheritance was conducted, and genetic risk scores (GRSs) based on known MN-associated variants were determined.

Results: Anti-PLA2R testing was negative in all affected family members. Linkage analysis revealed a significant logarithm of the odds score (3.260) on the short arm of the X chromosome at a locus of approximately 11 megabases (Mb). Haplotype reconstruction further uncovered a shared haplotype spanning 2 Mb present in all affected individuals from the 3 families. GRSs in familial MN were significantly lower than in anti-PLA2R-associated MN and were not different from controls.

Conclusions: Our study identifies linkage of familial membranous nephropathy to chromosome Xp11.3-11.22. Family members affected with MN have a significantly lower GRS than individuals with anti-PLA2R-associated MN, suggesting that X-linked familial MN represents a separate etiologic entity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ekir.2021.02.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8207324PMC
June 2021

Tubulopathy meets Sherlock Holmes: biochemical fingerprinting of disorders of altered kidney tubular salt handling.

Pediatr Nephrol 2021 08 18;36(8):2553-2561. Epub 2021 Jun 18.

Department of Renal Medicine, University College London, NW3 2PF, London, UK.

Evolution moves in mysterious ways. Excretion of waste products by glomerular filtration made perfect sense when life evolved in the ocean. Yet, the associated loss of water and solutes became a problem when life moved onto land: a serious design change was needed and this occurred in the form of ever more powerful tubules that attached to the glomerulus. By reabsorbing typically more than 99% of the glomerular filtrate, the tubules not only minimise urinary losses, but, crucially, also maintain homeostasis: tubular reabsorption and secretion are adjusted so as to maintain an overall balance, in which urine volume and composition matches intake and environmental stressors. A whole orchestra of highly specialised tubular transport proteins is involved in this process and dysfunction of one or more of these results in the so-called kidney tubulopathies, characterised by specific patterns of clinical and biochemical abnormalities. In turn, recognition of these patterns helps establish a specific diagnosis and pinpoints the defective transport pathway. In this review, we will discuss these clinical and biochemical "fingerprints" of tubular disorders of salt-handling and how sodium handling affects volume homeostasis but also handling of other solutes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-021-05098-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260524PMC
August 2021

Patient and caregiver perspectives on blood pressure in children with chronic kidney disease.

Nephrol Dial Transplant 2021 Jun 4. Epub 2021 Jun 4.

College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Background: Over 50% of children with chronic kidney disease (CKD) have uncontrolled hypertension, increasing their long-term risk of cardiovascular disease and progression to kidney failure. Children receiving medications or dialysis may also experience acute blood pressure fluctuations accompanied by debilitating symptoms. We aimed to describe the perspectives of children with CKD and their parental caregivers on blood pressure, to inform patient-centered care.

Methods: Secondary thematic analysis was conducted on qualitative data from the Standardized Outcomes in Nephrology-Children and Adolescents initiative, encompassing 16 focus groups, an international Delphi survey, and two consensus workshops. We analyzed responses from children with CKD (aged 8-21 years) and caregivers (of children aged 0-21 years) pertaining to blood pressure.

Results: Overall, 120 patients and 250 caregivers from 22 countries participated. We identified five themes: invisibility and normalization (reassured by apparent normotension, absence of symptoms, expected links with CKD); confused by ambiguity (hypertension indistinguishable from cardiovascular disease, questioning need for prophylactic intervention, frustrated by inconsistent messages, struggling with technical skills in measurement); enabling monitoring and maintaining health (gauging wellbeing, preventing vascular complications); debilitating and constraining daily living (provoking anxiety and agitation, helpless and powerless, limiting life activities); and burden of medications (overwhelmed by quantity of tablets, distress from unexpected side effects).

Conclusions: For children with CKD and their caregivers, blood pressure was an important heath indicator, but uncertainty around its implications and treatment hampered management. Providing educational resources to track blood pressure, and minimizing symptoms and treatment burden, may improve outcomes in children with CKD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfab194DOI Listing
June 2021

The European Rare Kidney Disease Registry (ERKReg): objectives, design and initial results.

Orphanet J Rare Dis 2021 06 2;16(1):251. Epub 2021 Jun 2.

Department of Renal Medicine, University College London and Paediatric Nephrology Unit, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.

Background: The European Rare Kidney Disease Reference Network (ERKNet) recently established ERKReg, a Web-based registry for all patients with rare kidney diseases. The main objectives of this core registry are to generate epidemiological information, identify current patient cohort for clinical research, explore diagnostic and therapeutic management practices, and monitor treatment performance and patient's outcomes. The registry has a modular design that allows to integrate comprehensive disease-specific registries as extensions to the core database. The diagnosis (Orphacode) and diagnostic information (clinical, imaging, histopathological, biochemical, immunological and genetic) are recorded. Anthropometric, kidney function, and disease-specific management and outcome items informing a set of 61 key performance indicators (KPIs) are obtained annually. Data quality is ensured by automated plausibility checks upon data entry and regular offline database checks prompting queries. Centre KPI statistics and benchmarking are calculated automatically.

Results: Within the first 24 months since its launch, 7607 patients were enrolled to the registry at 45 pediatric and 12 specialized adult nephrology units from 21 countries. A kidney disease diagnosis had been established in 97.1% of these patients at time of enrolment. While 199 individual disease entities were reported by Orphacode, 50% of the cohort could be classified with 11, 80% with 43 and 95% with 92 codes. Two kidney diagnoses were assigned in 6.5% of patients; 5.9% suffered from syndromic disease. Whereas glomerulopathies (54.8%) and ciliopathies including autosomal dominant polycystic kidney disease (ADPKD) (31.5%) were the predominant disease groups among adults, the pediatric disease spectrum encompassed congenital anomalies of the kidney and urinary tract (CAKUT) (33.7%), glomerulopathies (30.7%), ciliopathies (14.0%), tubulopathies (9.2%), thrombotic microangiopathies (5.6%), and metabolic nephropathies (4.1%). Genetically confirmed diagnoses were reported in 24% of all pediatric and 12% adult patients, whereas glomerulopathies had been confirmed by kidney biopsy in 80.4% adult versus 38.5% pediatric glomerulopathy cases.

Conclusions: ERKReg is a rapidly growing source of epidemiological information and patient cohorts for clinical research, and an innovative tool to monitor management quality and patient outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-021-01872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173879PMC
June 2021

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

Nat Rev Nephrol 2021 Jun;17(6):434

Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41581-021-00431-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8329697PMC
June 2021

Distal renal tubular acidosis: ERKNet/ESPN clinical practice points.

Nephrol Dial Transplant 2021 08;36(9):1585-1596

Department of Renal Medicine, University College London, London, UK.

Distal renal tubular acidosis (dRTA) is characterized by an impaired ability of the distal tubule to excrete acid, leading to metabolic acidosis. Associated complications include bone disease, growth failure, urolithiasis and hypokalaemia. Due to its rarity, there is limited evidence to guide diagnosis and management; however, available data strongly suggest that metabolic control of the acidosis by alkali supplementation can halt or revert almost all complications. Despite this, cohort studies show that adequate metabolic control is present in only about half of patients, highlighting problems with treatment provision or adherence. With these clinical practice points the authors, part of the working groups tubulopathies in the European Rare Kidney Disease Reference network and inherited kidney diseases of the European Society for Paediatric Nephrology, aim to provide guidance for the management of patients with dRTA to facilitate adequate treatment and establish an initial best practice standard against which treatment of patients can be audited.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfab171DOI Listing
August 2021

Founder mutation in the PMM2 promotor causes hyperinsulinemic hypoglycaemia/polycystic kidney disease (HIPKD).

Mol Genet Genomic Med 2021 Apr 3:e1674. Epub 2021 Apr 3.

Department Renal Medicine, University College London, London, UK.

Background: Polycystic kidney disease with hyperinsulinaemic hypoglycaemia (HIPKD) is a recently described disease caused by a single nucleotide variant, c.-167G>T, in the promoter region of PMM2 (encoding phosphomannomutase 2), either in homozygosity or compound heterozygosity with a pathogenic coding variant in trans. All patients identified so far are of European descent, suggesting a possible founder effect.

Methods: We generated high density genotyping data from 11 patients from seven unrelated families, and used this information to identify a common haplotype that included the promoter variant. We estimated the age of the promoter mutation with DMLE+ software, using demographic parameters corresponding to the European population.

Results: All patients shared a 0.312 Mb haplotype which was absent in 503 European controls available in the 1000 Genomes Project. The age of this mutation was estimated as 105-110 generations, indicating its occurrence around 600 BC, a time of intense migration, which might explain the presence of the same mutations in Europeans around the globe.

Conclusion: The shared unique haplotype among seemingly unrelated patients is consistent with a founder effect in Europeans.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/mgg3.1674DOI Listing
April 2021

Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness.

J Am Soc Nephrol 2021 06 2;32(6):1498-1512. Epub 2021 Apr 2.

Department of Neuroscience, Physiology and Pharmacology, University College London, London, United Kingdom.

Background: The transepithelial transport of electrolytes, solutes, and water in the kidney is a well-orchestrated process involving numerous membrane transport systems. Basolateral potassium channels in tubular cells not only mediate potassium recycling for proper Na,K-ATPase function but are also involved in potassium and pH sensing. Genetic defects in cause EAST/SeSAME syndrome, characterized by renal salt wasting with hypokalemic alkalosis associated with epilepsy, ataxia, and sensorineural deafness.

Methods: A candidate gene approach and whole-exome sequencing determined the underlying genetic defect in eight patients with a novel disease phenotype comprising a hypokalemic tubulopathy with renal salt wasting, disturbed acid-base homeostasis, and sensorineural deafness. Electrophysiologic studies and surface expression experiments investigated the functional consequences of newly identified gene variants.

Results: We identified mutations in the gene encoding KCNJ16, which along with KCNJ15 and KCNJ10, constitutes the major basolateral potassium channel of the proximal and distal tubules, respectively. Coexpression of mutant KCNJ16 together with KCNJ15 or KCNJ10 in oocytes significantly reduced currents.

Conclusions: Biallelic variants in were identified in patients with a novel disease phenotype comprising a variable proximal and distal tubulopathy associated with deafness. Variants affect the function of heteromeric potassium channels, disturbing proximal tubular bicarbonate handling as well as distal tubular salt reabsorption.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1681/ASN.2020111587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259640PMC
June 2021

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

Nat Rev Nephrol 2021 04 29;17(4):277-289. Epub 2021 Jan 29.

Division of Nephrology and Dialysis, Department of Pediatric Subspecialties, Bambino Gesù Pediatric Hospital Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS), Rome, Italy.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41581-020-00384-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8128706PMC
April 2021

Diagnosis and management of Bartter syndrome: executive summary of the consensus and recommendations from the European Rare Kidney Disease Reference Network Working Group for Tubular Disorders.

Kidney Int 2021 02;99(2):324-335

Department of Renal Medicine, University College London, London, United Kingdom; Department of Pediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Bartter syndrome is a rare inherited salt-losing renal tubular disorder characterized by secondary hyperaldosteronism with hypokalemic and hypochloremic metabolic alkalosis and low to normal blood pressure. The primary pathogenic mechanism is defective salt reabsorption predominantly in the thick ascending limb of the loop of Henle. There is significant variability in the clinical expression of the disease, which is genetically heterogenous with 5 different genes described to date. Despite considerable phenotypic overlap, correlations of specific clinical characteristics with the underlying molecular defects have been demonstrated, generating gene-specific phenotypes. As with many other rare disease conditions, there is a paucity of clinical studies that could guide diagnosis and therapeutic interventions. In this expert consensus document, the authors have summarized the currently available knowledge and propose clinical indicators to assess and improve quality of care.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.10.035DOI Listing
February 2021

Erratum: Long-term outcome in inherited nephrogenic diabetes insipidus.

Clin Kidney J 2020 Dec 7;13(6):1111. Epub 2020 Dec 7.

[This corrects the article DOI: 10.1093/ckj/sfy027.][This corrects the article DOI: 10.1093/ckj/sfy027.].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ckj/sfaa223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769540PMC
December 2020

Treatment and long-term outcome in primary nephrogenic diabetes insipidus.

Nephrol Dial Transplant 2020 Dec 26. Epub 2020 Dec 26.

Department of Paediatrics, Division of Nephrology, Erciyes University Faculty of Medicine, Kayseri,Turkey.

Background: Primary nephrogenic diabetes insipidus (NDI) is a rare disorder and little is known about treatment practices and long-term outcome.

Methods: Paediatric and adult nephrologists contacted through European professional organizations entered data in an online form.

Results: Data were collected on 315 patients (22 countries, male 84%, adults 35%). Mutation testing had been performed in 270 (86%); pathogenic variants were identified in 258 (96%). The median (range) age at diagnosis was 0.6 (0.0-60) years and at last follow-up 14.0 (0.1-70) years. In adults, height was normal with a mean (standard deviation) score of -0.39 (±1.0), yet there was increased prevalence of obesity (body mass index >30 kg/m2; 41% versus 16% European average; P < 0.001). There was also increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (32%) and adults (48%). Evidence of flow uropathy was present in 38%. A higher proportion of children than adults (85% versus 54%; P < 0.001) received medications to reduce urine output. Patients ≥25 years were less likely to have a university degree than the European average (21% versus 35%; P = 0.003) but full-time employment was similar. Mental health problems, predominantly attention-deficit hyperactivity disorder (16%), were reported in 36% of patients.

Conclusion: This large NDI cohort shows an overall favourable outcome with normal adult height and only mild to moderate CKD in most. Yet, while full-time employment was similar to the European average, educational achievement was lower, and more than half had urological and/or mental health problems.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfaa243DOI Listing
December 2020

A Rare Cause of Chronic Hypokalemia with Metabolic Alkalosis: Case Report and Differential Diagnosis.

Children (Basel) 2020 Nov 5;7(11). Epub 2020 Nov 5.

Nephrology and Dialysis Unit, Department of Pediatrics, Azienda Ospedaliero Universitaria Sant'Orsola-Malpighi, 40138 Bologna, Italy.

Hypokalemia and metabolic alkalosis can be present in different rare diseases, and the differential diagnosis of these forms is challenging. Apparent mineralcorticoid (AME) excess syndrome is one of these conditions. Characterized by increased blood pressure due to excessive sodium retention and plasma volume, it is caused by a mutation in the gene encoding the oxydoreductase enzyme 11β-hydroxysteroide dehydrogenase type 2. We report the case of a child presenting with failure to thrive associated with early detection of hypokalemia, metabolic alkalosis, nephrocalcinosis and hypertension in which AME syndrome was detected. A novel mutation in the gene was identified in this patient. In clinical pictures characterized by metabolic alkalosis and hypokalemia, the evaluation of renin, aldosterone and blood pressure is crucial for accurate diagnosis. AME syndrome is a rare disorder that can be an insidious but lethal disease, if untreated. With clinical signs appearing during the first days of life. Early diagnosis is imperative in order to enable prompt and adequate treatment to improve the outcome of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/children7110212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7694404PMC
November 2020

Hyponatraemia despite isotonic maintenance fluid therapy: a time series intervention study.

Arch Dis Child 2020 Oct 28. Epub 2020 Oct 28.

Paediatric Nephrology, Paediatric Surgery, Paediatric Intensive Care, and Neonatal Care, Lund University, Skane University Hospital, Lund, Sweden

Objective: To examine the prevalence of dysnatraemias among children admitted for paediatric surgery before and after a change from hypotonic to isotonic intravenous maintenance fluid therapy.

Design: Retrospective consecutive time series intervention study.

Setting: Paediatric surgery ward at the Children's Hospital in Lund, during a 7-year period, 2010-2017.

Patients: All children with a blood sodium concentration measurement during the study period were included. Hypotonic maintenance fluid (40 mmol/L NaCl and 20 mmol/L KCl) was used during the first 3 years of the study (646 patients), and isotonic solution (140 mmol/L NaCl and 20 mmol/L KCl) was used during the following period (807 patients).

Main Outcome Measures: Primary outcomes were sodium concentration and occurrence of hyponatraemia (<135 mmol/L) or hypernatraemia (>145 mmol/L).

Results: Overall, the change from hypotonic to isotonic intravenous maintenance fluid therapy was associated with a decreased prevalence of hyponatraemia from 29% to 22% (adjusted OR 0.65 (0.51-0.82)) without a significantly increased odds for hypernatraemia (from 3.4% to 4.3%, adjusted OR 1.2 (0.71-2.1)). Hyponatraemia <130 mmol/L decreased from 6.2% to 2.6%, and hyponatraemia <125 mmol/L decreased from 2.0% to 0.5%.

Conclusions: Routine use of intravenous isotonic maintenance fluids was associated with lower prevalence of hyponatraemia, although hyponatraemia still occurred in over 20% of patients. We propose that the composition and the volume of administered fluid need to be addressed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/archdischild-2019-318555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070620PMC
October 2020

Novel insights in the genetics of steroid-sensitive nephrotic syndrome in childhood.

Pediatr Nephrol 2021 08 21;36(8):2165-2175. Epub 2020 Oct 21.

Department of Renal Medicine, University College London, London, UK.

Steroid-sensitive nephrotic syndrome (SSNS) is the most common form of nephrotic syndrome in childhood and there is growing evidence that genetics play a role in the susceptibility for the disease. Familial clustering has been observed and has led to several studies on familial SSNS trying to identify a monogenic cause of the disease. Until now, however, none of these have provided convincing evidence for Mendelian inheritance. This and the phenotypic variability within SSNS suggest a complex inheritance pattern, where multiple variants and interactions between those and the environment play roles in disease development. Genome-wide association studies (GWASs) have been used to investigate this complex disease. We herein highlight new insights in the genetics of the disease provided by GWAS and identify how these insights fit into our understanding of the pathogenesis of SSNS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-020-04780-4DOI Listing
August 2021

Genetics of renovascular hypertension in children.

J Hypertens 2020 10;38(10):1964-1970

Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust.

Objective: In most cases of renovascular hypertension in children, the cause is unclear. The aim of this study was to investigate genetic variation as a factor in the development of renovascular hypertension in children.

Methods: In a cohort of 37 unrelated children from a single tertiary referral center, exome sequencing was performed. We assessed variants in recognized and suspected disease genes and searched for novel ones with a gene-based variant-burden analysis.

Results: In the majority of patients, exome sequencing could not identify causative variants. We found a pathogenic variant in a recognized associated disease gene in five patients (three pathogenic variants in NF1, one in ELN and a deletion of chromosome 7q11.23, consistent with Williams syndrome). In two other patients, (likely) pathogenic variants were found in putative renovascular hypertension genes (SMAD6 and GLA), with clinical implications for both. Ten additional patients carried variants of uncertain significance (VUS) in known (n = 4) or putative (n = 6) renovascular hypertension disease genes. Rare variant burden analysis yielded no further candidate genes.

Conclusion: Genetic contributors, such as germline mutations in NF1, ELN, 7q11.23del were present in only 5 out of 37 (14%) children with renovascular hypertension. Twelve other children (32%) had potentially causal variants identified, including a pathogenic variant in SMAD6; a vasculopathy gene hitherto unknown to link with renovascular hypertension. Most importantly, our data show that exome sequencing can rarely identify the cause of renovascular hypertension in nonsyndromic children. We suggest that nongenetic factors or somatic genetic variation will play a more important role.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HJH.0000000000002491DOI Listing
October 2020

Developing Consensus-Based Outcome Domains for Trials in Children and Adolescents With CKD: An International Delphi Survey.

Am J Kidney Dis 2020 10 10;76(4):533-545. Epub 2020 Jul 10.

Khoo Teck Puat-National University Children's Medical Institute, National University Hospital, Singapore.

Rationale & Objective: The inconsistency in outcomes reported and lack of patient-reported outcomes across trials in children with chronic kidney disease (CKD) limits shared decision making. As part of the Standardized Outcomes in Nephrology (SONG)-Kids initiative, we aimed to generate a consensus-based prioritized list of critically important outcomes to be reported in all trials in children with CKD.

Study Design: An online 2-round Delphi survey in English, French, and Hindi languages.

Settings & Participants: Patients (aged 8-21 years), caregivers/family, and health care professionals (HCPs) rated the importance of outcomes using a 9-point Likert scale (7-9 indicating critical importance) and completed a Best-Worst Scale.

Analytical Approach: We assessed the absolute and relative importance of outcomes. Comments were analyzed thematically.

Results: 557 participants (72 [13%] patients, 132 [24%] caregivers, and 353 [63%] HCPs) from 48 countries completed round 1 and 312 (56%) participants (28 [40%] patients, 64 [46%] caregivers, and 220 [56%] HCPs) completed round 2. Five outcomes were common in the top 10 for each group: mortality, kidney function, life participation, blood pressure, and infection. Caregivers and HCPs rated cardiovascular disease higher than patients. Patients gave lower ratings to all outcomes compared with caregivers/HCPs except they rated life participation (round 2 mean difference, 0.1), academic performance (0.1), mobility (0.4), and ability to travel (0.4) higher than caregivers and rated ability to travel (0.4) higher than HCPs. We identified 3 themes: alleviating disease and treatment burden, focusing on the whole child, and resolving fluctuating and conflicting goals.

Limitations: Most participants completed the survey in English.

Conclusions: Mortality, life participation, kidney function, and blood pressure were consistently highly prioritized by patients, caregivers, and HCPs. Patients gave higher priority to some lifestyle-related outcomes compared with caregivers/HCPs. Establishing critically important outcomes for all trials in children with CKD may improve consistent reporting of survival, kidney health, and clinical and life impact outcomes that are meaningful for decision making.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.ajkd.2020.03.014DOI Listing
October 2020

Establishing core outcome domains in pediatric kidney disease: report of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-KIDS) consensus workshops.

Kidney Int 2020 09 4;98(3):553-565. Epub 2020 Jul 4.

Department of Nephrology and Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia.

Trials in children with chronic kidney disease do not consistently report outcomes that are critically important to patients and caregivers. This can diminish the relevance and reliability of evidence for decision making, limiting the implementation of results into practice and policy. As part of the Standardized Outcomes in Nephrology-Children and Adolescents (SONG-Kids) initiative, we convened 2 consensus workshops in San Diego, California (7 patients, 24 caregivers, 43 health professionals) and Melbourne, Australia (7 patients, 23 caregivers, 49 health professionals). This report summarizes the discussions on the identification and implementation of the SONG-Kids core outcomes set. Four themes were identified; survival and life participation are common high priority goals, capturing the whole child and family, ensuring broad relevance across the patient journey, and requiring feasible and valid measures. Stakeholders supported the inclusion of mortality, infection, life participation, and kidney function as the core outcomes domains for children with chronic kidney disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.05.054DOI Listing
September 2020

Pseudouridylation defect due to and mutations causes nephrotic syndrome with cataracts, hearing impairment, and enterocolitis.

Proc Natl Acad Sci U S A 2020 06 17;117(26):15137-15147. Epub 2020 Jun 17.

Département des Sciences Biologiques, Université du Québec à Montréal, Montréal, QC H2X 1Y4, Canada.

RNA modifications play a fundamental role in cellular function. Pseudouridylation, the most abundant RNA modification, is catalyzed by the H/ACA small ribonucleoprotein (snoRNP) complex that shares four core proteins, dyskerin (DKC1), NOP10, NHP2, and GAR1. Mutations in , , or cause dyskeratosis congenita (DC), a disorder characterized by telomere attrition. Here, we report a phenotype comprising nephrotic syndrome, cataracts, sensorineural deafness, enterocolitis, and early lethality in two pedigrees: males with p.Glu206Lys and two children with homozygous p.Thr16Met. Females with heterozygous p.Glu206Lys developed cataracts and sensorineural deafness, but nephrotic syndrome in only one case of skewed X-inactivation. We found telomere attrition in both pedigrees, but no mucocutaneous abnormalities suggestive of DC. Both mutations fall at the dyskerin-NOP10 binding interface in a region distinct from those implicated in DC, impair the dyskerin-NOP10 interaction, and disrupt the catalytic pseudouridylation site. Accordingly, we found reduced pseudouridine levels in the ribosomal RNA (rRNA) of the patients. Zebrafish mutants recapitulate the human phenotype and show reduced 18S pseudouridylation, ribosomal dysregulation, and a cell-cycle defect in the absence of telomere attrition. We therefore propose that this human disorder is the consequence of defective snoRNP pseudouridylation and ribosomal dysfunction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1073/pnas.2002328117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334496PMC
June 2020

Co-Existence of Congenital Adrenal Hyperplasia and Bartter Syndrome due to Maternal Uniparental Isodisomy of HSD3B2 and CLCNKB Mutations.

Horm Res Paediatr 2020 5;93(2):137-142. Epub 2020 Jun 5.

Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom.

Introduction: We present a patient with co-existence of 3β-hydroxysteroid dehydrogenase type 2 (HSD3B2) deficiency and Bartter syndrome, a unique dual combination of opposing pathologies that has not been reported previously in the literature.

Case: A female infant (46,XX) born at 34/40 weeks' gestation, weighing 2.67 kg (-1.54 standard deviation score) to non-consanguineous parents presented on day 4 of life with significant weight loss. Subsequent investigations revealed hyponatraemia, hypochloraemia, metabolic alkalosis, elevated 17-hydroxyprogesterone, ACTH, and renin. Urine steroid profile suggested HSD3B2 deficiency, which was confirmed by the identification of a homozygous HSD3B2 mutation. Due to the persistence of the hypochlo-raemic and hypokalemic alkalosis, an underlying renal tubulopathy was suspected. Sequence analysis of a targeted tubulopathy gene panel revealed a homozygous deletion in CLCNKB, consistent with Bartter syndrome type 3. The mother was found to be heterozygous for both mutations in -HSD3B2 and CLCNKB, and the father was negative for both. Single-nucleotide polymorphism microarray analysis confirmed 2 segments of homozygosity on chromosome 1 of maternal ancestry, encompassing both HSD3B2 and CLCKNB.

Discussion: Identification of a homozygous rare mutation in an offspring of non-consanguineous parents should raise suspicion of uniparental disomy, especially if the phenotype is unusual, potentially encompassing more than one disorder. The persistence of hypokalemic alkalosis, the biochemical fingerprint of hyperaldosteronism in a child with a form of CAH in which aldosterone production is severely impaired, challenges our current understanding of mineralocorticoid-mediated effects in the collecting duct.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000507577DOI Listing
July 2021

The hypokalemia mystery: distinguishing Gitelman and Bartter syndromes from 'pseudo-Bartter syndrome'.

Nephrol Dial Transplant 2020 Jun 3. Epub 2020 Jun 3.

Division of Nephrology and Hypertension, Department of Internal Medicine, American University of Beirut, Beirut, Lebanon.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfaa100DOI Listing
June 2020

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

Eur J Hum Genet 2020 10 28;28(10):1368-1378. Epub 2020 May 28.

Department of Pediatric Nephrology, Reference Center for Hereditary Kidney Diseases (MARHEA), Necker Hospital, APHP, 75015, Paris, France.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41431-020-0642-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608398PMC
October 2020

Nomenclature for kidney function and disease: report of a Kidney Disease: Improving Global Outcomes (KDIGO) Consensus Conference.

Kidney Int 2020 06 9;97(6):1117-1129. Epub 2020 Mar 9.

Executive Managing Editor, Kidney International.

The worldwide burden of kidney disease is rising, but public awareness remains limited, underscoring the need for more effective communication by stakeholders in the kidney health community. Despite this need for clarity, the nomenclature for describing kidney function and disease lacks uniformity. In June 2019, Kidney Disease: Improving Global Outcomes (KDIGO) convened a Consensus Conference with the goal of standardizing and refining the nomenclature used in the English language to describe kidney function and disease, and of developing a glossary that could be used in scientific publications. Guiding principles of the conference were that the revised nomenclature should be patient-centered, precise, and consistent with nomenclature used in the KDIGO guidelines. Conference attendees reached general consensus on the following recommendations: (i) to use "kidney" rather than "renal" or "nephro-" when referring to kidney disease and kidney function; (ii) to use "kidney failure" with appropriate descriptions of presence or absence of symptoms, signs, and treatment, rather than "end-stage kidney disease"; (iii) to use the KDIGO definition and classification of acute kidney diseases and disorders (AKD) and acute kidney injury (AKI), rather than alternative descriptions, to define and classify severity of AKD and AKI; (iv) to use the KDIGO definition and classification of chronic kidney disease (CKD) rather than alternative descriptions to define and classify severity of CKD; and (v) to use specific kidney measures, such as albuminuria or decreased glomerular filtration rate (GFR), rather than "abnormal" or "reduced" kidney function to describe alterations in kidney structure and function. A proposed 5-part glossary contains specific items for which there was general agreement. Conference attendees acknowledged limitations of the recommendations and glossary, but they considered standardization of scientific nomenclature to be essential for improving communication.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.kint.2020.02.010DOI Listing
June 2020

Rituximab versus cyclophosphamide as first steroid-sparing agent in childhood frequently relapsing and steroid-dependent nephrotic syndrome.

Pediatr Nephrol 2020 08 27;35(8):1445-1453. Epub 2020 Apr 27.

Faculty of Medicine, King Abduaziz University, PO Box 80215, Jeddah, 21589, Kingdom of Saudi Arabia.

Background: Approximately 50% of children with steroid-sensitive nephrotic syndrome (SSNS) will suffer from frequent relapses or steroid dependency, prompting the use of so-called steroid-sparing drugs. In this pilot study, we compare the efficacy and safety of rituximab to oral cyclophosphamide as first-line steroid-sparing medications.

Methods: A prospective open-label non-randomized study of children with frequent relapsing or steroid-dependant SSNS. Exclusion criteria were steroid-resistant disease, prescription of immunosuppressive agents other than prednisolone or levamisole, evidence of impaired kidney function, leucopenia, or active infection. The recruited children were allocated either to the oral cyclophosphamide (3 mg/kg/day for 8 weeks) or intravenous rituximab treatment (two doses of 375 mg/m/dose, 2 weeks apart) and were monitored for relapses and side effects for 12 months.

Results: Forty-six subjects were included from two centers; 27 received cyclophosphamide and 19 received rituximab. One-year relapse-free survival was reached in 17 (58.6%) patients treated with cyclophosphamide compared to 16 (84.2%) with rituximab (adjusted HR 0.36; 95% CI 0.09-1.45; p = 0.151). The mean interval to relapse was 6.9 months in the cyclophosphamide group (N = 10) and 6.3 months in the rituximab group (N = 3). Both treatments were associated with a significant (p < 0.001) reduction in prescribed dose of oral alternate-day steroid from 1.02 to 0.36 mg/kg (cyclophosphamide) and 0.86 to 0.08 mg/kg (rituximab). Importantly, a significantly (p = 0.003) higher percentage of patients achieved complete withdrawal of steroid within 3 months of commencing study treatment in the rituximab (73.7%) versus cyclophosphamide (29.6%) group. Transient leucopenia was the most frequent adverse effect observed in the cyclophosphamide group (18.5%) and one patient (3.4%) had acute hepatotoxicity besides severe leucopenia and neutropenia in the 7th week of treatment with complete recovery with the withdrawal of cyclophosphamide and maintenance of remission. A minor infusion-related reaction in the form of a generalized macular skin rash was observed in one patient (5%) in the rituximab group.

Conclusions: Rituximab is non-inferior to cyclophosphamide and safe as a first-line steroid-sparing agent in children with SSNS. A larger multicenter study is required to assess superiority over cyclophosphamide. Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00467-020-04570-yDOI Listing
August 2020

Diagnoses of uncertain significance: kidney genetics in the 21st century.

Nat Rev Nephrol 2020 11;16(11):616-618

Department of Renal Medicine, University College London, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41581-020-0277-6DOI Listing
November 2020
-->