Publications by authors named "Stephane Decramer"

99 Publications

Hepatocyte nuclear factor-1β shapes the energetic homeostasis of kidney tubule cells.

FASEB J 2021 Nov;35(11):e21931

Institut National de la Santé et de la Recherche Médicale, UMR 1297, Institut des Maladies Métaboliques et Cardiovasculaires, Hôpital Rangueil, Toulouse, France.

Energetic metabolism controls key steps of kidney development, homeostasis, and epithelial repair following acute kidney injury (AKI). Hepatocyte nuclear factor-1β (HNF-1β) is a master transcription factor that controls mitochondrial function in proximal tubule (PT) cells. Patients with HNF1B pathogenic variant display a wide range of kidney developmental abnormalities and progressive kidney fibrosis. Characterizing the metabolic changes in PT cells with HNF-1β deficiency may help to identify new targetable molecular hubs involved in HNF1B-related kidney phenotypes and AKI. Here, we combined H-NMR-based metabolomic analysis in a murine PT cell line with CrispR/Cas9-induced Hnf1b invalidation (Hnf1b ), clustering analysis, targeted metabolic assays, and datamining of published RNA-seq and ChIP-seq dataset to identify the role of HNF-1β in metabolism. Hnf1b cells grown in normoxic conditions display intracellular ATP depletion, increased cytosolic lactate concentration, increased lipid droplet content, failure to use pyruvate for energetic purposes, increased levels of tricarboxylic acid (TCA) cycle intermediates and oxidized glutathione, and a reduction of TCA cycle byproducts, all features consistent with mitochondrial dysfunction and an irreversible switch toward glycolysis. Unsupervised clustering analysis showed that Hnf1b cells mimic a hypoxic signature and that they cannot furthermore increase glycolysis-dependent energetic supply during hypoxic challenge. Metabolome analysis also showed alteration of phospholipid biosynthesis in Hnf1b cells leading to the identification of Chka, the gene coding for choline kinase α, as a new putative target of HNF-1β. HNF-1β shapes the energetic metabolism of PT cells and HNF1B deficiency in patients could lead to a hypoxia-like metabolic state precluding further adaptation to ATP depletion following AKI.
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http://dx.doi.org/10.1096/fj.202100782RRDOI Listing
November 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.
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http://dx.doi.org/10.1681/ASN.2021050596DOI Listing
October 2021

To biopsy or not to biopsy: Henoch-Schönlein nephritis in children, a 5-year follow-up study.

Pediatr Nephrol 2021 Jul 5. Epub 2021 Jul 5.

Néphrologie Pédiatrique, CHU Reims, 45 rue Cognacq Jay, 51092, Reims CEDEX, France.

Background: The prognosis of Henoch-Schönlein purpura (HSP), IgA vasculitis, depends on kidney involvement. There is no consensus on the initiation of treatment for HSP nephritis (HSPN). Some centres start treatment before performing a kidney biopsy (KB) while in others, treatment is dictated by the importance of the clinical, biological and histological signs. The aim of this study was to evaluate which of these two approaches is associated with a better kidney outcome at 5-year follow-up.

Methods: This multicentre, retrospective, nonrandomised study included children treated for HSPN between 2006 and 2010 in a French paediatric nephrology unit. One group had an early KB at diagnosis (before starting treatment or in the 15 following days). In the second group, initial treatment was decided without performing a KB.

Results: Among the 107 children included, 63.5% had an early KB at diagnosis. Follow-up at 5 years was completed in 44 children (28 KB at diagnosis, 16 no KB at diagnosis). Median urine protein/creatinine at 5 years was 2.5 mg/mmol in the early biopsy diagnosis group and 12.5 mg/mmol in the non-biopsy group. An antiproteinuric treatment was given, at 5 years, to 35.7% of the early biopsy at diagnosis children and in 62.5% of the non-biopsied children.

Conclusions: Children with early KB at diagnosis seem to have a better renal outcome at 5 years compared to those without an early biopsy at diagnosis or biopsied later. However, this is a small patient cohort and data are missing. Further work is needed to build consensual guidelines on the management of HSPN in children.
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http://dx.doi.org/10.1007/s00467-021-05086-9DOI Listing
July 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.
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http://dx.doi.org/10.1186/s13023-021-01872-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8173879PMC
June 2021

Mapping of the amniotic fluid proteome of fetuses with congenital anomalies of the kidney and urinary tract identifies plastin 3 as a protein involved in glomerular integrity.

J Pathol 2021 Aug 16;254(5):575-588. Epub 2021 Jun 16.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1297, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.

Congenital anomalies of the kidney and the urinary tract (CAKUT) are the first cause of chronic kidney disease in childhood. Several genetic and environmental origins are associated with CAKUT, but most pathogenic pathways remain elusive. Considering the amniotic fluid (AF) composition as a proxy for fetal kidney development, we analyzed the AF proteome from non-severe CAKUT (n = 19), severe CAKUT (n = 14), and healthy control (n = 22) fetuses using LC-MS/MS. We identified 471 significant proteins that discriminated the three AF groups with 81% precision. Among them, eight proteins independent of gestational age (CSPG4, LMAN2, ENDOD1, ANGPTL2, PRSS8, NGFR, ROBO4, PLS3) were associated with both the presence and the severity of CAKUT. Among those, five were part of a protein-protein interaction network involving proteins previously identified as being potentially associated with CAKUT. The actin-bundling protein PLS3 (plastin 3) was the only protein displaying a gradually increased AF abundance from control, via non-severe, to severe CAKUT. Immunohistochemistry experiments showed that PLS3 was expressed in the human fetal as well as in both the fetal and the postnatal mouse kidney. In zebrafish embryos, depletion of PLS3 led to a general disruption of embryonic growth including reduced pronephros development. In postnatal Pls3-knockout mice, kidneys were macroscopically normal, but the glomerular ultrastructure showed thickening of the basement membrane and fusion of podocyte foot processes. These structural changes were associated with albuminuria and decreased expression of podocyte markers including Wilms' tumor-1 protein, nephrin, and podocalyxin. In conclusion, we provide the first map of the CAKUT AF proteome that will serve as a reference for future studies. Among the proteins strongly associated with CAKUT, PLS3 did surprisingly not specifically affect nephrogenesis but was found as a new contributor in the maintenance of normal kidney function, at least in part through the control of glomerular integrity. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5703DOI Listing
August 2021

Association of kidney biopsy findings with short- and medium-term outcomes in children with moderate-to-severe IgA vasculitis nephritis.

Eur J Pediatr 2021 Oct 2;180(10):3209-3218. Epub 2021 May 2.

Department of Multidisciplinary Pediatrics, Pediatric Nephrology Unit, Assistance Publique des Hôpitaux de Marseille, Marseille, France.

Assessing the initial severity of immunoglobulin A vasculitis nephritis (IgAV-N) is important due to its determining effect on kidney management and outcomes. This paper describes a multicentre paediatric cohort of IgAV-N patients and discusses relationships among clinical presentation, histological features, and kidney outcome. We retrospectively studied a cohort of 170 children with biopsy-proven IgAV-N, diagnosed between 2007 and 2017. One-quarter of the cohort (27%) presented with initial nephrotic syndrome (NS). Kidney biopsy revealed International Study of Kidney Disease (ISKDC) grade II or grade III in 83% of cases. Endocapillary proliferation was observed in 73% of patients, and chronic lesions were observed in 25%. Data analysis showed a significant association between NS at onset and endocapillary proliferation and cellular crescents. After a median follow-up of 21 months (IQR 12-39), 30% of patients had persistent proteinuria or decreased eGFR. At the end of follow-up, kidney impairment was more often observed in patients with NS at onset and those with cellular crescents and chronic lesions on initial kidney biopsy.Conclusion: This study highlights the relationship between the clinical and histological presentation of IgAV-N and the factors that affect kidney outcome. The ISKDC classification may be improved by including lesions that are more discriminating for disease severity and prognosis. What is Known: • Nephrotic syndrome (NS) or kidney failure at diagnosis and cellular crescents in more than 50% of the glomeruli are recognized as risk factors for poor kidney outcome in immunoglobulin A vasculitis nephritis (IgAV-N). • The reference histological classification of the International Study of Kidney Disease in Children (ISKDC) is primarily based on the presence and number of affected glomeruli (mesangial proliferation, cellular crescents). The updated Oxford classification, which emphasizes tubular atrophy and interstitial fibrosis, is also used to group pathological features of IgAV-N. Both classifications have limitations. What is New: • Medical treatment should not be postponed in patients with IgAV-N and NS until after biopsy, as NS at diagnosis is associated with initial histological severity and poorer kidney outcome. This proposal needs to be verified in further studies. • Endocapillary proliferation is associated with the initial severity of IgAV-N at diagnosis, while chronic glomerular changes and interstitial fibrosis are associated with poorer short- and medium-term kidney outcomes.
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http://dx.doi.org/10.1007/s00431-021-04065-4DOI Listing
October 2021

Preemptive Kidney Transplantation is Associated With Transplantation Outcomes in Children: Results From the French Kidney Replacement Therapy Registry.

Transplantation 2021 Mar 18. Epub 2021 Mar 18.

1 University of Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR1219, Bordeaux, France. 2 Pediatric Nephrology Unit, Pellegrin-Enfants Hospital, Bordeaux University Hospital, Centre de Référence Maladies Rénales Rares Sorare, Bordeaux, France. 3 Pediatric Nephrology Unit, Robert Debré Hospital, Centre de Référence Maladies Rénales Rares Marhea, APHP, Paris, France. 4 Agence de la Biomédecine, REIN Registry, La Plaine-Saint Denis, France. 5 Pediatric Nephrology Unit, Necker Enfants-Malades Hospital, Centre de Référence Maladies Rénales Rares Marhea, APHP, Paris Descartes University, Paris, France. 6 Pediatric Nephrology Unit, Femme-Mère-Enfant Hospital, Lyon University Hospital, Centre de Référence Maladies Rénales Rares Nephrogones, Bron, France. 7 France Pediatric Nephrology Unit, Femme-Enfant-Adolescent Hospital, Nantes University Hospital, Nantes, France. 8 Pediatric Nephrology Unit, Jeanne de Flandre Hospital, Lille University Hospital, Lille, France. 9 Pediatric Nephrology Unit, Timone-Enfants Hospital, Marseille University Hospital, Marseille, France. 10 Pediatric Nephrology Unit, Children's Hospital, Toulouse University Hospital, Centre de Référence Maladies Rénales Rares Sorare, Toulouse, France. 11 Pediatric Nephrology Unit, Trousseau Hospital, Centre de Référence Maladies Rénales Rares Marhea, APHP, Paris, France. 12Pediatric Nephrology Unit, Arnaud de Villeneuve Hospital, Montpellier University Hospital, Centre de Référence Maladies Rénales Rares Sorare, Montpellier, France. 13 Pediatric Nephrology Unit, Felix Guyon Hospital, La Réunion University Hospital, Saint Denis, France. 14 Pediatric Nephrology Unit, Clocheville Hospital, Tours University Hospital, Tours, France. 15 Pediatric Nephrology Unit, Brabois Hospital, Nancy University Hospital, Vandoeuvre-les-Nancy, France. 15Pediatric Nephrology Unit, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France. 17 Pediatric Nephrology Unit, Archet Hospital, Nice University Hospital, Nice, France. 18 INSERM, Clinical Investigation Center-Clinical Epidemiology-CIC-1401, Bordeaux, France.

Background: Kidney transplantation (KT) is the optimal treatment for children with end-stage kidney disease (ESKD). The aim of this study was to evaluate the impact of PKT and of pretransplant dialysis duration on graft survival among French pediatric kidney transplant recipients.

Methods: We analyzed all first pediatric kidney-only transplantations performed in France between 1993 and 2012. A Cox multivariable model was used to investigate the association of PKT and pretransplant dialysis time with the hazard of graft failure defined as death, return to dialysis or retransplant, whichever occurred first.

Results: 1911 patients were included, of which 380 (19.8%) received a PKT. Median time of follow-up was 7.0 years. PKT was associated with a 55% reduction of the hazard of graft failure at any time after KT compared to patients transplanted after dialysis (HR 0.45; 95%CI 0.33-0.62), after adjustment for recipient sex and age, primary kidney disease, donor age and type (living or deceased donor), number of HLA mismatches, cold ischemia time and year of transplantation. A reduction of the hazard of graft failure was found in PKT whatever the compared duration of dialysis, even when less than 6 months and whatever the dialysis modality. Results were similar in multiple sensitivity analyses.

Conclusions: In France, PKT among pediatric patients is associated with a better graft survival when compared to KT after dialysis, even when less than 6 months. Based on these findings, we suggest that PKT should be considered as the treatment of choice for children with ESKD.
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http://dx.doi.org/10.1097/TP.0000000000003757DOI Listing
March 2021

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

Comparison of the amniotic fluid and fetal urine peptidome for biomarker discovery in renal developmental disease.

Sci Rep 2020 12 10;10(1):21706. Epub 2020 Dec 10.

Institut National de La Santé Et de La Recherche Médicale (INSERM), U1048/I2MC-Equipe 12, Institut of Cardiovascular and Metabolic Disease, 1 Avenue Jean Poulhès, BP 84225, 31432, Toulouse Cedex 4, France.

Production of amniotic fluid (AF) is view as predominately driven by excretion of fetal urine (FU). However, the origin of AF peptides, often considered as potential biomarkers of developmental diseases, has never been investigated. Here, we evaluated the FU origin of AF peptides and if the AF peptide content can be used as a surrogate of FU. The abundance of endogenous peptides was analyzed by capillary electrophoresis coupled to mass spectrometry in 216 AF and 64 FU samples. A total of 2668 and 3257 peptides was found in AF and FU respectively. The AF peptidome largely overlapped with the FU peptidome, ranging from 54% in the second pregnancy trimester to 65% in the third trimester. Examination of a subset of 16 paired AF and FU samples revealed that 67 peptides displayed a significant positively correlated abundance in AF and FU, strongly suggesting that their presence in AF was directly associated to FU excretion. As proof-of-concept we showed that measuring the AF abundance of these 67 peptides of FU origin allowed prediction of postnatal renal survival in fetuses with posterior urethral valves. These results demonstrate that the AF peptidome can be considered as a good surrogate of the FU peptidome.
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http://dx.doi.org/10.1038/s41598-020-78730-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729974PMC
December 2020

The low affinity p75 neurotrophin receptor is down-regulated in congenital anomalies of the kidney and the urinary tract: Possible involvement in early nephrogenesis.

Biochem Biophys Res Commun 2020 12 26;533(4):786-791. Epub 2020 Sep 26.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France. Electronic address:

Congenital Anomalies of the Kidney and of the Urinary Tract (CAKUT) cover a broad range of disorders including abnormal kidney development caused by defective nephrogenesis. Here we explored the possible involvement of the low affinity p75 neurotrophin receptor (p75NTR) in CAKUT and nephrogenesis. In mouse, p75NTR was highly expressed in fetal kidney, located within cortical early nephrogenic bodies, and decreased rapidly after birth. In human control fetal kidney, p75NTR was also located within the early nephrogenic bodies as well as in the mature glomeruli, presumably in the mesangium. In CAKUT fetal kidneys, the kidney cortical structure and the localization of p75NTR were often disorganized, and quantification of p75NTR in amniotic fluid revealed a significant reduction in CAKUT compared to control. Finally, invalidation of p75NTR in zebrafish embryo with an antisense morpholino significantly altered pronephros development. Our results indicate that renal p75NTR is altered in CAKUT fetuses, and could participate to early nephrogenesis.
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http://dx.doi.org/10.1016/j.bbrc.2020.09.084DOI Listing
December 2020

Mycophenolic acid area under the concentration-time curve is associated with therapeutic response in childhood-onset lupus nephritis.

Pediatr Nephrol 2021 02 27;36(2):341-347. Epub 2020 Aug 27.

Centre Hospitalier Universitaire de Bordeaux, Service de Pédiatrie, Centre de référence Maladies Rénales Rares du Sud-Ouest (SORARE), Bordeaux, France.

Background: Mycophenolic acid (MPA), the active compound of mycophenolate mofetil (MMF), is widely used in lupus nephritis treatment. Therapeutic drug monitoring of adults suggests that area under the concentration-time curve (AUC) of MPA (MPA-AUC) is associated with clinical outcomes, but childhood data are scarce.

Methods: Retrospective study of 27 children with biopsy-proven lupus nephritis treated with MMF between 2008 and 2016. In 25 children, MPA-AUC was performed within 6 months after kidney biopsy and MMF initiation. Treatment response at 6 months was defined as normal or improved GFR by 25% compared with baseline, 50% reduction of proteinuria to < 0.5 g/day or 50 mg/mmol, and no hematuria.

Results: A total of 62 MPA-AUC were analyzed in 27 patients. Overall median was 44 mg h/L (interquartile range [IQR] 33-54). Individual dose adaptation was required in 32 cases (52%) to achieve target AUC of 30-60 mg h/L. At 6 months, 14/25 patients were defined as responders (56%, median MPA-AUC 49 mg h/L (40-59)) and 11/25 as non-responders (44%, 29 mg h/L (24-38)). Patients with MPA-AUC levels > 45, 30-45, and < 30 mg h/L had 6-month response rates of 89% (8/9), 60% (6/10), and 0% (0/6), respectively. In a logistic regression model adjusted for age, sex, lupus nephritis classification, and time since MMF initiation, an MPA-AUC > 45 mg h/L was significantly associated with therapeutic response (OR 3.6, 95% CI 2.4-9.5, p = 0.03).

Conclusions: Therapeutic drug monitoring leading to individualized dosing may improve efficacy of MMF. MPA-AUC > 45 mg h/L is associated with better response rate and may be considered as a target value in pediatric lupus nephritis.
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http://dx.doi.org/10.1007/s00467-020-04733-xDOI Listing
February 2021

Mutation affecting the conserved acidic WNK1 motif causes inherited hyperkalemic hyperchloremic acidosis.

J Clin Invest 2020 12;130(12):6379-6394

Université de Paris, INSERM, PARCC, F-75006, Paris, France.

Gain-of-function mutations in with no lysine (K) 1 (WNK1) and WNK4 genes are responsible for familial hyperkalemic hypertension (FHHt), a rare, inherited disorder characterized by arterial hypertension and hyperkalemia with metabolic acidosis. More recently, FHHt-causing mutations in the Kelch-like 3-Cullin 3 (KLHL3-CUL3) E3 ubiquitin ligase complex have shed light on the importance of WNK's cellular degradation on renal ion transport. Using full exome sequencing for a 4-generation family and then targeted sequencing in other suspected cases, we have identified new missense variants in the WNK1 gene clustering in the short conserved acidic motif known to interact with the KLHL3-CUL3 ubiquitin complex. Affected subjects had an early onset of a hyperkalemic hyperchloremic phenotype, but normal blood pressure values"Functional experiments in Xenopus laevis oocytes and HEK293T cells demonstrated that these mutations strongly decrease the ubiquitination of the kidney-specific isoform KS-WNK1 by the KLHL3-CUL3 complex rather than the long ubiquitous catalytically active L-WNK1 isoform. A corresponding CRISPR/Cas9 engineered mouse model recapitulated both the clinical and biological phenotypes. Renal investigations showed increased activation of the Ste20 proline alanine-rich kinase-Na+-Cl- cotransporter (SPAK-NCC) phosphorylation cascade, associated with impaired ROMK apical expression in the distal part of the renal tubule. Together, these new WNK1 genetic variants highlight the importance of the KS-WNK1 isoform abundance on potassium homeostasis.
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http://dx.doi.org/10.1172/JCI94171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7685730PMC
December 2020

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes.

Kidney Int 2020 12 1;98(6):1589-1604. Epub 2020 Aug 1.

Exeter Kidney Unit, Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, UK.

There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.
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http://dx.doi.org/10.1016/j.kint.2020.06.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719087PMC
December 2020

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease.

Kidney Int 2021 03 1;99(3):737-749. Epub 2020 Aug 1.

Department of Pediatrics, Hôpital Nord, CHU de Saint Etienne, Saint Etienne, France.

Although a rare disease, bilateral congenital anomalies of the kidney and urinary tract (CAKUT) are the leading cause of end stage kidney disease in children. Ultrasound-based prenatal prediction of postnatal kidney survival in CAKUT pregnancies is far from accurate. To improve prediction, we conducted a prospective multicenter peptidome analysis of amniotic fluid spanning 140 evaluable fetuses with CAKUT. We identified a signature of 98 endogenous amniotic fluid peptides, mainly composed of fragments from extracellular matrix proteins and from the actin binding protein thymosin-β4. The peptide signature predicted postnatal kidney outcome with an area under the curve of 0.96 in the holdout validation set of patients with CAKUT with definite endpoint data. Additionally, this peptide signature was validated in a geographically independent sub-cohort of 12 patients (area under the curve 1.00) and displayed high specificity in non-CAKUT pregnancies (82 and 94% in 22 healthy fetuses and in 47 fetuses with congenital cytomegalovirus infection respectively). Change in amniotic fluid thymosin-β4 abundance was confirmed with ELISA. Knockout of thymosin-β4 in zebrafish altered proximal and distal tubule pronephros growth suggesting a possible role of thymosin β4 in fetal kidney development. Thus, recognition of the 98-peptide signature in amniotic fluid during diagnostic workup of prenatally detected fetuses with CAKUT can provide a long-sought evidence base for accurate management of the CAKUT disorder that is currently unavailable.
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http://dx.doi.org/10.1016/j.kint.2020.06.043DOI Listing
March 2021

The ANTENATAL multicentre study to predict postnatal renal outcome in fetuses with posterior urethral valves: objectives and design.

Clin Kidney J 2020 Jun 26;13(3):371-379. Epub 2019 Sep 26.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.

Background: Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature.

Methods: Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1-β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature.

Results: In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment.

Conclusions: Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV.
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http://dx.doi.org/10.1093/ckj/sfz107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7367108PMC
June 2020

Unusual fetal ascites and spontaneous bladder rupture in a female fetus: a case report.

J Med Case Rep 2020 Jul 19;14(1):115. Epub 2020 Jul 19.

CHU Toulouse, Pole de Gynécologie Obstétrique, Hôpital Paule de Viguier, 31059, Toulouse, France.

Background: Fetal bladder rupture causing urinary ascites is uncommon. It is generally related to invasive fetal medicine procedures or obstructive disorders such as in posterior urethral valves in male fetuses. An exceptional case of spontaneous bladder rupture in a female fetus occurred in a pregnant woman treated with high doses of opiates in an intensive care unit. This unusual obstetric situation leads to discussion of the possible causes of fetal bladder rupture, its management, and the pediatric prognosis.

Case Presentation: We report the case of a 30-year-old nulliparous black woman with a history of mesenteric cystic lymphangioma and multiple bowel resections leading to chronic malabsorption. During her pregnancy, our patient presented with an occlusive syndrome and major bilateral renal dilation. Urinary derivation resulted in iatrogenic bilateral ureteral perforation. Our patient thus presented with major uroperitoneum, bilateral pleural effusion and acute renal failure, treated by thoracic drainage and bilateral nephrostomy. Postoperative pain required treatment with level III analgesics. In this context, 5 days after morphine treatment introduction an enlarged fetal bladder was observed, followed 3 days later by voluminous fetal ascites. The diagnosis of spontaneous bladder rupture was suspected. After multidisciplinary discussion, expectant management was decided. At 31 weeks and 4 days gestation, our patient went into spontaneous labor with a subsequent vaginal delivery. The infant required resuscitation and paracentesis of ascites at birth. Her neonatal course was favorable with a simple urethral bladder drainage. Cystography at day 9 was normal. At 2 years of follow-up, the mother and the child have a normal course.

Conclusions: An iatrogenic origin of megacystis in a female fetus must be evoked in the event of maternal administration of high doses of opiates in the second part of her pregnancy. In our case, the megacystis was followed by spontaneous bladder rupture at 30 weeks of gestation, with a favorable maternal fetal issue.
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http://dx.doi.org/10.1186/s13256-020-02425-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7370489PMC
July 2020

Ofatumumab treatment for nephrotic syndrome recurrence after pediatric renal transplantation.

Pediatr Nephrol 2020 08 18;35(8):1499-1506. Epub 2020 Apr 18.

Pediatric Department, University Hospital of Nantes, Nantes, France.

Background: Relapsing nephrotic syndrome (NS) after transplantation can be a challenge to treat. The result of the consequent long-lasting proteinuria is the loss of the graft. Disease recurrence after renal transplantation occurs in around half of cases, and the efficacy of therapeutic strategies is often limited. Recently, ofatumumab, a second-generation and fully human anti-CD20 monoclonal antibody, has been shown to be effective in severe situations.

Methods: We retrospectively collected data from the medical records of children with recurrence of NS after renal transplantation treated with ofatumumab in France, after failure of previous treatments.

Results: Six patients were included in this study in five centers with a median duration of follow-up of 10.5 months. Two different ofatumumab regimens were administered. The primary outcome was proteinuria at 6 months after the last dose of ofatumumab. No patient achieved a complete remission, 3/6 had a partial remission, and 3/6 had no response to ofatumumab. Four patients exhibited a minor allergic reaction with the first infusion. One patient died of infection, as a consequence of multiple factors. No malignancies were observed; however, the time of follow-up was not sufficient to see such disease.

Conclusions: Altogether, these results suggest ofatumumab has a poor efficacy in treating recurrence of NS after renal transplantation. However, it could be discussed in multidrug-resistant refractory NS, but infectious complications and overimmunosuppression have to be balanced. There is a need for further studies to confirm these findings and safety and to determine a standardized protocol in this indication.
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http://dx.doi.org/10.1007/s00467-020-04567-7DOI Listing
August 2020

Immunoglobulin serum levels in rituximab-treated patients with steroid-dependent nephrotic syndrome.

Pediatr Nephrol 2020 03 8;35(3):455-462. Epub 2019 Nov 8.

Pediatric Nephrology Unit, Armand Trousseau Hospital, APHP.6, 75012, Paris, France.

Background: Rituximab (RTX) is efficient in steroid-dependent nephrotic syndrome (SDNS) in pediatric and adult patients. The aim of this study is to describe hypogammaglobulinemia as a side effect of RTX treatment.

Methods: All pediatric patients (< 18 years old) of four French pediatric nephrology centers who received RTX for SDNS between 2010 and 2015 have been included. Clinical and biological data have been analyzed retrospectively before, during, and after RTX treatment. Hypogammaglobulinemia was defined as an IgG level < - 2 standard deviations for patient age.

Results: A total of 107 pediatric patients have been included, 65.9% were boys, median age at nephrotic syndrome diagnosis was 3.1 interquartile range [IQ 2.24-5.45] years and age at RTX introduction was 11.7 [IQ 8.6-14.2] years. Twenty-one patients had hypogammaglobulinemia before the initiation of RTX. Of the patients, 25/86 had at least one hypogammaglobulinemia during B cell depletion or after B cell recovery while IgG levels at initiation were normal with a persisting hypogammaglobulinemia for 13 patients 1 year after B cell recovery. Patients who developed hypogammaglobulinemia were younger at RTX initiation with a median age of 8.2 years [IQ 6.3-12.4]. Among all the 46 patients with hypogammaglobulinemia during follow-up, 13 had a concomitant infection.

Conclusions: Hypogammaglobulinemia is a frequent complication of RTX treatment in younger children treated for SDNS. The use of RTX in children has to be carefully evaluated and their clinical and biological follow-up should be adapted to the age-dependent risk profile for hypogammaglobulinemia.
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http://dx.doi.org/10.1007/s00467-019-04398-1DOI Listing
March 2020

A single-center study to evaluate the efficacy of a fetal urine peptide signature predicting postnatal renal outcome in fetuses with posterior urethral valves.

Pediatr Nephrol 2020 03 7;35(3):469-475. Epub 2019 Nov 7.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France.

Background: Posterior urethral valves (PUVs) account for 17% of pediatric renal failure. The management of pregnancies involving fetuses with PUV is hampered by the fact that current clinical parameters obtained from fetal ultrasound and/or fetal urine biochemistry are insufficient to predict postnatal renal function. We previously have developed a fetal urine peptide signature (12PUV) that predicted with high precision postnatal renal failure at 2 years of age in fetuses with PUV. Here, we evaluated the accuracy of this signature to predict postnatal renal outcome in fetuses with PUV in an independent single-center study.

Methods: Thirty-three women carrying fetuses with suspected PUV were included. Twenty-five fetuses received vesicoamniotic shunts during pregnancy. PUV was confirmed postnatally in 23 patients. Of those 23 fetuses, 2 were lost in follow-up. Four and 3 patients died in the pre- and perinatal periods, respectively. Follow-up renal function at 6 months of age was obtained for the remaining 14 patients. The primary outcome was early renal failure, defined by an eGFR < 60 mL/min/1.73 m before 6 months of age or pre- or perinatal death.

Results: The peptide signature predicted postnatal renal outcome in postnatally confirmed PUV fetuses with an AUC of 0.94 (95%CI 0.74-1.0) and an accuracy of 90% (95%CI 78-100). The signature predicted postnatal renal outcome for the suspected PUV cases with an AUC of 0.89 (95%CI 0.72-0.97) and an accuracy of 84% (95%CI 71-97).

Conclusions: This single-center study confirms the predictive power of the previously identified 12PUV fetal urinary peptide signature.
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http://dx.doi.org/10.1007/s00467-019-04390-9DOI Listing
March 2020

School level of children carrying a HNF1B variant or a deletion.

Eur J Hum Genet 2020 01 3;28(1):56-63. Epub 2019 Sep 3.

Service de Pédiatrie, CHU de Limoges, Limoges, France.

The prevalence of neurological involvement in patients with a deletion of or a variant in the HNF1B gene remains discussed. The aim of this study was to investigate the neuropsychological outcomes in a large cohort of children carrying either a HNF1B whole-gene deletion or a disease-associated variant, revealed by the presence of kidney anomalies. The neuropsychological development-based on school level-of 223 children included in this prospective cohort was studied. Data from 180 children were available for analysis. Patients mean age was 9.6 years, with 39.9% of girls. Among these patients, 119 carried a HNF1B deletion and 61 a disease-associated variant. In the school-aged population, 12.7 and 3.6% of patients carrying a HNF1B deletion and a disease-associated variant had special educational needs, respectively. Therefore, the presence of a HNF1B deletion increases the risk to present with a neuropsychiatric involvement when compared with the general population. On the other hand, almost 90% of patients carrying a HNF1B disease-associated variant or deletion have a normal schooling in a general educational environment. Even if these findings do not predict the risk of neuropsychiatric disease at adulthood, most patients diagnosed secondary to kidney anomalies do not show a neurological outcome severe enough to impede standard schooling at elementary school. These results should be taken into account in prenatal counseling.
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http://dx.doi.org/10.1038/s41431-019-0490-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6906503PMC
January 2020

Defects in tA tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome.

Nat Commun 2019 09 3;10(1):3967. Epub 2019 Sep 3.

Service de Néphrologie, Rhumatologie et Dermatologie pédiatriques, Hospices Civils de Lyon, Hôpital Femme-Mère-Enfant, Centre de référence de maladies rénales rares, Université de Lyon, Bron, France.

N-threonyl-carbamoylation of adenosine 37 of ANN-type tRNAs (tA) is a universal modification essential for translational accuracy and efficiency. The tA pathway uses two sequentially acting enzymes, YRDC and OSGEP, the latter being a subunit of the multiprotein KEOPS complex. We recently identified mutations in genes encoding four out of the five KEOPS subunits in children with Galloway-Mowat syndrome (GAMOS), a clinically heterogeneous autosomal recessive disease characterized by early-onset steroid-resistant nephrotic syndrome and microcephaly. Here we show that mutations in YRDC cause an extremely severe form of GAMOS whereas mutations in GON7, encoding the fifth KEOPS subunit, lead to a milder form of the disease. The crystal structure of the GON7/LAGE3/OSGEP subcomplex shows that the intrinsically disordered GON7 protein becomes partially structured upon binding to LAGE3. The structure and cellular characterization of GON7 suggest its involvement in the cellular stability and quaternary arrangement of the KEOPS complex.
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http://dx.doi.org/10.1038/s41467-019-11951-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722078PMC
September 2019

Social deprivation is associated with poor kidney transplantation outcome in children.

Kidney Int 2019 09 28;96(3):769-776. Epub 2019 May 28.

University of Bordeaux, ISPED, Centre INSERM U1219-Bordeaux Population Health Research, Bordeaux, France; INSERM, Clinical Investigation Center-Clinical Epidemiology-CIC-1401, Bordeaux, France; Pediatric Nephrology Unit, Pellegrin-Enfants Hospital, Bordeaux University Hospital, Centre de Référence Maladies rénales rares Sorare, Bordeaux, France. Electronic address:

Socioeconomic status is an important determinant of health. Its impact on kidney transplantation outcome has been studied among adults but data in children are scarce, especially in Europe. Here, we investigate the association between the level of social deprivation (determined by the continuous score European Deprivation Index) and graft failure risk in pediatric kidney transplant recipients. All patients listed under 18 years of age who received a first kidney transplant between 2002 and 2014 in France were included. Of 1050 kidney transplant recipients (males 59%, median age at transplantation 13.2 years, preemptive transplantation 23%), 211 graft failures occurred within a median followup of 5.9 years. Thirty-seven percent of these patients belong to the most deprived quintile, suggesting that deprivation is more frequent in pediatric patients with end-stage kidney disease (ESKD) than in the general population. Five- and ten-year graft survival were 85% and 69%, respectively, in the most deprived quintile vs. 90% and 83%, respectively, in the least deprived quintile. At any time after transplantation, patients in the most deprived quintile had almost a two-fold higher hazard of graft failure compared with the least deprived quintile, after adjustment for age at renal replacement therapy, duration of dialysis, primary kidney disease, and rural/urban living environment (hazard ratio 1.99; 95% confidence interval 1.20-3.28). The hazard of graft failure did not differ significantly between girls and boys. Thus, our findings suggest a lower socioeconomic status is independently associated with poor graft outcome in pediatric kidney transplantation.
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http://dx.doi.org/10.1016/j.kint.2019.05.011DOI Listing
September 2019

Quality of life in children with severe forms of idiopathic nephrotic syndrome in stable remission-A cross-sectional study.

Acta Paediatr 2019 12 15;108(12):2267-2273. Epub 2019 Jul 15.

Service de Néphrologie et Dialyse Pédiatrique, Hôpital Trousseau, APHP.6, and DHU i2b, Paris, France.

Aim: Severe forms of idiopathic nephrotic syndrome (INS) require immunosuppressive therapy: oral treatment or intravenous therapy (rituximab, RTX). The main objective was to describe quality of life (QOL) in these specific patients.

Methods: Cross-sectional, multicentre, observational study analysed QOL using a standardised questionnaire in children from 7 to 17 years, with a steroid-dependent or steroid-resistant INS in stable remission. The questionnaire consisted of 30 questions concerning physical and emotional well-being, self-esteem, family, friends, school and disease resulting in a global score of 0-100.

Results: A total of 110 patients with a mean age of 11.6 years from three French paediatric nephrology centres were included. A total of 71 patients had oral immunosuppressive treatment, 27 had RTX, and 12 had both. 13.6% of patients had a steroid-resistant INS. The mean number of relapses was 5.8. Seventy-eight patients answered the questionnaire. The global score in the whole study population was 74.7; 72.6 in the RTX group, 76.2 in the oral drugs group, (P = 0.49). The results of sub-dimension 'school' were statistically lower in RTX group (61.6 ± 19.5) compared with oral drugs group (71.4 ± 16; P = 0.02).

Conclusion: Global QOL score was high in 'difficult-to-treat' patients with INS in stable remission on oral immunosuppressive or RTX treatment.
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http://dx.doi.org/10.1111/apa.14912DOI Listing
December 2019

Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients.

Clin Genet 2019 08 6;96(2):107-117. Epub 2019 Jun 6.

Department of Medical Genetics, CHU Bordeaux INSERM U1211, Université de Bordeaux, Bordeaux, France.

Fabry disease (FD), a rare X-linked disease, can be treated with bi-monthly infusion of enzyme replacement therapy (ERT) to replace deficient α-galactosidase A (AGAL-A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12-15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood.
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http://dx.doi.org/10.1111/cge.13546DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6852597PMC
August 2019

Adverse events associated with currently used medical treatments for cystinuria and treatment goals: results from a series of 442 patients in France.

BJU Int 2019 11 25;124(5):849-861. Epub 2019 Mar 25.

Department of Urology, Strasbourg University Hospital, Strasbourg University, Strasbourg, France.

Objective: To evaluate medical treatments, in terms of adverse events (AEs) and therapeutic goals, in a large series of patients with cystinuria.

Patients And Methods: Data from 442 patients with cystinuria were recorded retrospectively. Crystalluria was studied in 89 patients. A mixed-effects logistic regression model was used to estimate how urine pH, specific gravity and cysteine-binding thiols (CBT) correlate with risk of cystine crystalluria.

Results: Alkalizing agents and CBT agents were given to 88.8% (n = 381) and 55.3% (n = 238) of patients, respectively. Gastrointestinal AEs were reported in 12.3%, 10.4% and 2.6% of patients treated with potassium bicarbonate, potassium citrate and sodium bicarbonate, respectively (P = 0.008). The percentages of patients who experienced at least one AE with tiopronin (24.6%) and with D-penicillamine (29.5%) were similar (P = 0.45). Increasing urine pH and decreasing urine specific gravity significantly reduced the risk of cystine crystalluria, whereas D-penicillamine and tiopronin treatments did not reduce this risk (odds ratio [OR] 1 for pH ≤6.5; OR 0.52 [95% confidence interval {95% CI} 0.28-0.95] for 7.0 8.0, P <0.001).

Conclusion: Adverse events were frequent with D-penicillamine and tiopronin. Alkaline hyperdiuresis was well tolerated and reduced cystine crystalluria. Urine specific gravity ≤1.005 and urine pH >7.5, while warning about calcium-phosphate crystallization, should be the goals of medical therapy.
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http://dx.doi.org/10.1111/bju.14721DOI Listing
November 2019

Urinary proteome signature of Renal Cysts and Diabetes syndrome in children.

Sci Rep 2019 02 18;9(1):2225. Epub 2019 Feb 18.

Mosaiques Diagnostics GmbH, Hannover, Germany.

Renal Cysts and Diabetes Syndrome (RCAD) is an autosomal dominant disorder caused by mutations in the HNF1B gene encoding for the transcriptional factor hepatocyte nuclear factor-1B. RCAD is characterized as a multi-organ disease, with a broad spectrum of symptoms including kidney abnormalities (renal cysts, renal hypodysplasia, single kidney, horseshoe kidneys, hydronephrosis), early-onset diabetes mellitus, abnormal liver function, pancreatic hypoplasia and genital tract malformations. In the present study, using capillary electrophoresis coupled to mass spectrometry (CE-MS), we investigated the urinary proteome of a pediatric cohort of RCAD patients and different controls to identify peptide biomarkers and obtain further insights into the pathophysiology of this disorder. As a result, 146 peptides were found to be associated with RCAD in 22 pediatric patients when compared to 22 healthy age-matched controls. A classifier based on these peptides was generated and further tested on an independent cohort, clearly discriminating RCAD patients from different groups of controls. This study demonstrates that the urinary proteome of pediatric RCAD patients differs from autosomal dominant polycystic kidney disease (PKD1, PKD2), congenital nephrotic syndrome (NPHS1, NPHS2, NPHS4, NPHS9) as well as from chronic kidney disease conditions, suggesting differences between the pathophysiology behind these disorders.
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http://dx.doi.org/10.1038/s41598-019-38713-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379363PMC
February 2019

Treatment and long-term outcome in primary distal renal tubular acidosis.

Nephrol Dial Transplant 2019 06;34(6):981-991

Nephrology Unit Azienda Ospedaliera, Papa Giovani XXIII, Bergamo, Italy.

Background: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome.

Methods: We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form.

Results: Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%); pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate.

Conclusion: Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.
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http://dx.doi.org/10.1093/ndt/gfy409DOI Listing
June 2019

Combination of the fetal urinary metabolome and peptidome for the prediction of postnatal renal outcome in fetuses with PUV.

J Proteomics 2018 07 19;184:1-9. Epub 2018 Jun 19.

Institut National de la Santé et de la Recherche Médicale (INSERM), U1048, Institut of Cardiovascular and Metabolic Disease, Toulouse, France; Université Toulouse III Paul-Sabatier, Toulouse, France. Electronic address:

Most of biomarker panels, extracted from single omics traits, still need improvement since they display a gray zone where prediction is uncertain. Here we verified whether a combination of omics traits, fetal urinary metabolites and peptides analyzed in the same sample, improved prediction of postnatal renal function in fetuses with posterior urethral valves (PUV) compared to individual omics traits. Using CE-MS, we explored the urinary metabolome of 13 PUV fetuses with end stage renal disease (ESRD) and 12 PUV fetuses without postnatal ESRD at 2 years postnatally. This allowed the selection of 24 differentially abundant metabolite features which were modelled into predictive classifiers, alone or in combination with 12 peptides previously identified as predictive of ESRD. Validation in 35 new fetuses showed that the combination of peptides and metabolites significantly outperformed the 24 metabolite features with increased AUC (0.987 vs 0.905), net reclassification improvement (36%) and better sensitivity accuracy (86% vs 60%). In addition, the two trait combination tended to improve, but without reaching statistical significance, the already high performances of the 12 peptide biomarkers (AUC 0.967, accuracy 80%). In conclusion, this study demonstrates the potential of cumulating different omics traits in biomarker research where single omics traits fall short.

Significance: Although increasingly proposed in disease-diagnosis and -prognosis because of their improved efficacy over single markers, panels of body fluid biomarkers based on single omics analysis still fail to display perfect accuracy, probably due to biological variability. Here, we hypothesized that combination of different omics traits allowed to better capture this biological variability. As proof of concept, we studied the added value of fetal urine metabolites and peptides using CE-MS, starting from the same urine sample, to predict postnatal renal outcome in fetuses with posterior urethral valves. We observed that the prognostic power of combined metabolite and peptide markers was clearly higher than that of metabolites alone and slightly, but non-significantly, improved compared to the peptides alone. To our knowledge, this report is the first to demonstrate that combining multiomics traits extracted from (fetal) urine samples displays clear promise for kidney disease stratification.
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http://dx.doi.org/10.1016/j.jprot.2018.06.012DOI Listing
July 2018

Patterns of Clinical Response to Eculizumab in Patients With C3 Glomerulopathy.

Am J Kidney Dis 2018 07 9;72(1):84-92. Epub 2018 Feb 9.

Department of Nephrology and Immunology, Centre Hospitalier Universitaire de Nantes, Nantes, France. Electronic address:

Background: Cases reports and small series of patients with C3 glomerulopathy have reported variable efficacy of eculizumab.

Study Design: Case series of C3 glomerulopathy.

Setting & Participants: Pediatric and adult patients with C3 glomerulopathy treated with eculizumab between 2010 and 2016 were identified through the C3 glomerulopathy French registry database, and a questionnaire was sent to participating French pediatric and adult nephrology centers, as well as one pediatric referral center in Québec, Canada.

Outcomes: Global or partial clinical renal response.

Measurements: Evolution of serum creatinine and proteinuria values.

Results: 26 patients (13 children/adolescents) were included. 22 (85%) patients had received steroids, plasma exchange, or immunosuppressive therapy before eculizumab, and 3 of them had rapid progression of their kidney disease despite treatment. At the initiation of eculizumab therapy, 11 (42%) patients had chronic kidney disease, 7 (27%) had rapidly progressive disease, and 3 (12%) required dialysis. After eculizumab treatment (median duration, 14 months), 6 (23%) patients had a global clinical response; 6 (23%), a partial clinical response; and 14 (54%), no response. Compared with those who had a partial clinical or no response, patients who had a global clinical response had lower estimated glomerular filtration rates, a more rapidly progressive course, and more extracapillary proliferation on kidney biopsy. Age, extent of renal fibrosis, frequency of nephrotic syndrome, low serum C3 and C3 nephritic factor and elevated soluble C5b-9 concentrations, or complement gene variants did not differ between responders and nonresponders.

Limitations: Retrospective design without a control group, relatively small number of cases, inclusion of pediatric and adult cases.

Conclusions: Eculizumab appears to be a potential treatment for patients with crescentic rapidly progressive C3 glomerulopathy. Its benefit in patients with non-rapidly progressing forms seems to be limited.
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http://dx.doi.org/10.1053/j.ajkd.2017.11.019DOI Listing
July 2018

Prevalence of Novel Mutations in Antenatal Bartter Syndrome.

Clin J Am Soc Nephrol 2018 02 16;13(2):242-250. Epub 2017 Nov 16.

Due to the number of contributing authors, the affiliations are provided in the Supplemental Material.

Background And Objectives: Mutations in the gene, located on the X chromosome, have been recently detected in males with a transient form of antenatal Bartter syndrome or with idiopathic polyhydramnios. The aim of this study is to analyze the proportion of the population with mutations in this gene in a French cohort of patients with antenatal Bartter syndrome.

Design, Setting, Participants, & Measurements: The French cohort of patients with antenatal Bartter syndrome encompasses 171 families. Mutations in genes responsible for types 1-4 have been detected in 75% of cases. In patients without identified genetic cause (=42), transient antenatal Bartter syndrome was reported in 12 cases. We analyzed the gene in the entire cohort of negative cases by Sanger sequencing and retrospectively collected clinical data regarding pregnancy as well as the postnatal outcome for positive cases.

Results: We detected mutations in in 17 patients, including the 12 with transient antenatal Bartter syndrome, from 16 families. Fifteen different mutations were detected (one whole deletion, three frameshift, three splicing, three nonsense, two inframe deletions, and three missense); 13 of these mutations had not been previously described. Interestingly, two patients are females; in one of these patients our data are consistent with selective inactivation of chromosome X explaining the severity. The phenotypic presentation in our patients was variable and less severe than that of the originally described cases.

Conclusions: mutations explained 9% of cases of antenatal Bartter syndrome in a French cohort, and accounted for 38% of patients without other characterized mutations and for 44% of male probands of negative cases. Our study confirmed previously published data and showed that females can be affected. As a result, this gene must be included in the screening of the most severe clinical form of Bartter syndrome.
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http://dx.doi.org/10.2215/CJN.05670517DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5967426PMC
February 2018
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