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

Abstract 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 in utero 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

Comparison of clinical and ultrasonographic evaluations for peripheral synovitis in juvenile idiopathic arthritis.

International audienceOBJECTIVES: The characteristics of synovitis in juvenile idiopathic arthritis (JIA) are important to evaluate, as they define several clinical categories. The metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints are frequently involved. Few studies have investigated peripheral joint evaluation using ultrasonography, a sensitive tool for detecting subclinical synovitis. Our objectives here were to compare clinical and ultrasound evaluations of MCP and MTP joint synovitis and to determine the prevalence of predefined ultrasound abnormalities in JIA patients and healthy controls. METHODS: Standardized physical and ultrasound assessments of the same joints were done in 31 consecutive patients with JIA and 41 healthy volunteers. Joint pain, motion limitation, and swelling were recorded. Ultrasonography was performed on the same joints by 2 trained sonographers who recorded synovial fluid, synovial hypertrophy, erosion, and power Doppler signal. Intraobserver reproducibility of ultrasonography was assessed. RESULTS: Of 558 peripheral joints examined in JIA patients, 69 (12.5%) had ultrasonographic synovitis and 83 (15%) had abnormal physical findings. All the physical abnormalities were significantly associated with ultrasonographic synovitis (P < 0.0001) but agreement was low between ultrasonographic and physical findings. Ultrasonographic synovitis was most common at the feet (59.4%), where it was detected clinically in only 25% of cases. Ultrasonographic synovitis was associated with the presence of synovial fluid. Cartilage vascularization was found in 2 (4.2%) healthy controls. CONCLUSION: Ultrasonography is useful for monitoring synovitis in JIA. Subclinical involvement of the MTP joints is common. Clinicians should be aware of the specific ultrasonographic findings in children

Normal sonoanatomy of the paediatric entheses including echostructure and vascularisation changes during growth

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Ultrasonography for detecting enthesitis in juvenile idiopathic arthritis.

International audienceOBJECTIVE: Enthesitis is a major feature of juvenile idiopathic arthritis (JIA) but is difficult to diagnose clinically. Our objective was to compare the accuracy of ultrasonography with power Doppler (US-PD) versus clinical examination for diagnosing enthesitis in patients with JIA and healthy controls. METHODS: Twenty-six consecutive patients with JIA and 41 healthy volunteers underwent standardized clinical and US-PD examinations of 5 entheseal sites (proximal and distal quadricepital tendon insertions, Achilles tendon, and plantar fascia). US-PD reproducibility was evaluated. US-PD enthesitis was defined as a PD signal at the enthesis insertion. Bursitis, erosions, and cartilage vascularization were recorded. RESULTS: In the JIA group, 27 (12.5%) of the entheseal sites exhibited clinical enthesitis (distal patellar ligament in 45% of cases) and 20 (9.4%) exhibited US-PD enthesitis (distal patellar tendon in 30%), including 10 clinically normal sites (50%). US-PD enthesitis was found in several patients with oligoarthritis or polyarthritis. Clinical enthesitis (P < 0.0001) and HLA-B27-positive (P = 0.05) status were significantly associated with US-PD enthesitis. Erosion and bursitis, but not tendon thickening, were associated with US-PD enthesitis. US-PD enthesitis was not found at any of the 410 entheseal sites in controls; grade 1 cartilage vascularization was noted at 6% of the control sites. CONCLUSION: Enthesitis is a rare phenomenon in JIA. Clinically silent enthesitis is detected by US-PD and can be found in JIA categories other than enthesitis-related arthritis. Tendon thickening and cartilage vascularization can be detected in healthy controls. These findings may have implications for patient classification of the use of US-PD

P570 : Exploration moléculaire des gènes CYP24A1, SLC34A1 et SLC34A3 dans une cohorte de patients avechypersensibilité à la vitamine D

International audienceIntroduction : L’hypersensibilité à la vitamine D correspond sur le plan biologique à l’association d’une hypercalcémie transitoireavec PTH basse (adaptée), d’une hypercalciurie et d’une 1,25-(OH)2D (calcitriol) augmentée (inappropriée).En dehors des formes néonatales transitoires, des formes génétiques récessives autosomiques (MIM143880, 616963) ont étédécrites, associées à des mutation perte de fonction de CYP24A1 (20q13.2, MIM126065), le gène codant l’enzyme vitamine D24-hydroxylase responsable du catabolisme de la vitamine D. Le déficit enzymatique est responsable d’une accumulation devitamine D active, d’où une dérégulation de l’absorption intestinale de calcium avec tendance à l’hypercalcémie/hypercalciuriechronique. En cas de prise de vitamine D ou d’exposition solaire (favorisant la synthèse cutanée de vitamine D), unedécompensation est possible sous la forme de complications aigües de l’hypercalcémie (désydratation, difficultés alimentaires,troubles du rythme et de la conduction) ou chroniques de l’hypercalciurie (lithiase rénale, néphrocalcinose, insuffisance rénalechronique).Plus récemment, un autre mécanisme physiopathologique a été identifié chez des patients présentant un phénotype similaireassocié à des anomalies du phosphate (hypophosphatémie et hyperphosphaturie modérées transitoires). Il s’agit de mutationsperte de fonction dans les gènes SLC34A1 (5q35.3, MIM182309) et SLC34A3 (9q34.3, MIM609826) codant les cotransporteurs sodium-phosphate NPT2a/NaPiIIa et NPT2c/NaPiIIc. Ces mutations ont précédemment été associées aurachitisme hypophosphatémique avec hypercalciurie (MIM612286, 241530).Elles sont responsables d’une fuite urinaire de phosphate, d’où une diminution de la sécrétion de FGF23, hormonehyperphosphaturiante inhibant la synthèse de calcitriol, et une dérégulation de la production de calcitriol.Matériel et méthode : Nous rapportons l’étude des régions codantes et des jonctions introns-exons par séquençage haut-débit(Ion Personal Genome Machine, Thermofisher Scientific, Waltham, Massachusetts, États-Unis) des gènes CYP24A1, SLC34A1et SLC34A3 dans une cohorte de 90 patients porteurs d’un phénotype d’hypersensibilité à la vitamine D.Résultats : Nous identifions 22 (24.4%) patients avec mutation biallélique de CYP24A1, 2 (2.2%) patients avec mutationbiallélique de SLC34A1 et 3 (3.3%) patients avec mutation biallélique de SLC34A3. Le phénotype biologique est identique àl’exception de phosphatémies fréquemment rapportées à la limite inférieure de la normale.Conclusion : Nous confirmons l’implication des gènes codant les transporteurs de phosphates NPT2a/NaPiIIa et NPT2c/NaPiIIcdans le phénotype d’hypersensibilité à la vitamine D, en moidre proportion que les mutation de CYP24A1. S’agissantessentiellement de mutations faux-sens, une étude attentive du phénotype, et en particulier du bilan phosphocalcique sanguinet urinaire, est nécessaire pour l’interprétation des variants

Pneumocystis primary infection in infancy: Additional French data and review of the literature

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Impact of rotavirus vaccination on hospitalizations for rotavirus diarrhea: the IVANHOE study.

International audienceThe aim of the IVANHOE study was to determine the real-world impact of the rotavirus vaccine, controlling for epidemic-to-epidemic variation in disease burden. A population-based prospective cohort study was conducted in Brest City and 7 suburban districts (CUB area), North-western Brittany, France (210,000 inhabitants; 5500 births per year). The vaccination program started in May 2007 for a 2-year period for all infants born in the Brest birth zone through pediatricians, public outpatient clinics and general practitioners. To determine vaccine impact we monitored trends in hospitalizations for rotavirus-specific diarrhea using an active hospital-based surveillance system initiated 5 years before vaccine introduction. The number of hospitalizations for rotavirus-specific diarrhea during the 2008/2009 epidemic in infants less than 2 years of age whose parents lived within the CUB area was modelled as a function of (1) the number of hospitalizations in infants 2-5 years of age to control for epidemic-to-epidemic variation and (2) vaccine introduction. A total of 4684 infants received at least one dose. Of these, 2635 lived within the CUB area. Vaccine coverage for a complete schedule in the CUB area was 47.1%. Poisson modelling revealed a reduction by a factor of 2.04 (1.56-2.66) in the number of hospitalizations during the last epidemic season (2008/2009), the number of observed cases being equal to 30, against an expected number of 61. Relative risk reduction for hospitalizations for rotavirus diarrhea was 98% (95% CI: 83-100%). We observed a noticeable impact of vaccination on rotavirus diarrhea hospitalizations within 2 years of vaccine introduction integrating for the first time rotavirus epidemics variation. The trial is registered with ClinicalTrials.gov, number, NCT00740935

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease

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.</p

Amniotic fluid peptides predict postnatal kidney survival in developmental kidney disease

International audienceAlthough 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