Is Cystatin C a promising marker of renal function, at birth, in neonates prenatally diagnosed with congenital kidney anomalies?

Assessment of neonatal renal function remains a challenge. This study by Paloma et al. suggest that low-molecular weight proteins may indeed serve as promising markers of renal function at birth and in neonates prenatally diagnosed with congenital kidney anomalie

Antenatal and postnatal ultrasound in the evaluation of the risk of vesicoureteral reflux

Antenatal hydronephrosis (ANH) is a frequent anomaly detected on fetal ultrasound scans. There is no consensus recommendation for the postnatal follow-up and/or the necessity to perform a voiding cystourethrography (VCUG) to diagnose vesicoureteral reflux (VUR). We conducted a cohort/non-randomized trial of 121 patients with ANH, defined as an anterior posterior diameter (APD) ≥5mm after the 20th week of gestation, to evaluate the ability of the antenatal and postnatal ultrasonography results to predict VUR. All infants had two successive ultrasounds at 5days and 1month, respectively, after birth. A VCUG was performed at 6weeks in children with a persistent APD ≥5mm and/or an ureteral dilatation observed on at least one of two postnatal ultrasounds. In total, 88 patients had VCUG and nine had VUR, with five having high-grade reflux (>grade II). The risk of VUR increased significantly with the degree of APD detected on the postnatal ultrasound scan (p = 0.03). The odds ratios were 5.0 [95% confidence interval (CI) 0.5-51.2] for APD = 7-9mm and 9.1 (95% CI 1.0-80.9) for APD ≥10mm. The results of this study show that among our patient cohort antenatal ultrasound was not predictive of reflux. There was, however, a relation between the importance of the postnatal renal pelvis diameter and the risk of VUR. A cut-off of 7mm showed a fair ability of ultrasonography to predict VUR and a cut-off of 10mm enabled all severe refluxes in the 88 patients who had a VCUG to be diagnose

Early Urinary Biomarkers in Pediatric Autosomal Dominant Polycystic Kidney Disease (ADPKD): No Evidence in the Interest of Urinary Neutrophil Gelatinase-Associated Lipocalin (uNGAL)

Background: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is increasingly diagnosed during childhood by the presence of renal cysts in patients with a positive familial history. No curative treatment is available and early detection and diagnosis confronts pediatricians with the lack of early markers to decide whether to introduce renal-protective agents and prevent the progression of renal failure. Neutrophil Gelatinase-Associated Lipocalin (NGAL) is a tubular protein that has been recently proposed as an early biomarker of renal impairment in the ADPKD adult population.Methods: Urinary NGAL (uNGAL) levels were measured in 15 ADPKD children and compared with 15 age and gender matched controls using parametric, non-parametric, and Bayesian statistics. We also tested the association of uNGAL levels with markers of disease progression, such as proteinuria, albuminuria, blood pressure, and Total Kidney Volume (TKV) using correlation analysis. TKV was calculated by ultrasound, using the ellipsoid method.Results: No difference in mean uNGAL levels was observed between groups (ADPKD: 26.36 ng/ml; Controls: 27.24 ng/ml; P = 0.96). Moreover, no correlation was found between uNGAL and proteinuria (P = 0.51), albuminuria (P = 0.69), TKV (P = 0.68), or mean arterial pressure (P = 0.90). By contrast, TKV was positively correlated with proteinuria (P = 0.04), albuminuria (P = 0.001), and mean arterial pressure (P = 0.03).Conclusion: uNGAL did not confirm its superiority as a marker of disease progression in a pediatric ADPKD population. In the contrary, TKV appears to be an easy measurable variable and may be promising as a surrogate marker to follow ADPKD progression in children

Urinary low-molecular-weight protein excretion in pediatric idiopathic nephrotic syndrome

Background: Minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are the most common causes of idiopathic nephrotic syndrome (INS). We have evaluated the reliability of urinary neutrophil-gelatinase-associated lipocalin (uNGAL), urinary alpha1-microglobulin (uα1M) and urinary N-acetyl-beta-D-glucosaminidase (uβNAG) as markers for differentiating MCD from FSGS. We have also evaluated whether these proteins are associated to INS relapses or to glomerular filtration rate (GFR). Methods: The patient cohort comprised 35 children with MCD and nine with FSGS; 19 healthy age-matched children were included in the study as controls. Of the 35 patients, 28 were in remission (21 MCD, 7 FSGS) and 16 were in relapse (14 MCD, 2 FSGS). The prognostic accuracies of these proteins were assessed by receiver operating characteristic (ROC) curve analyses. Results: The level of uNGAL, indexed or not to urinary creatinine (uCreat), was significantly different between children with INS and healthy children (p = 0.02), between healthy children and those with FSGS (p = 0.007) and between children with MCD and those with FSGS (p = 0.01). It was not significantly correlated to proteinuria or GFR levels. The ROC curve analysis showed that a cut-off value of 17ng/mg for the uNGAL/uCreat ratio could be used to distinguish MCD from FSGS with a sensitivity of 0.77 and specificity of 0.78. uβNAG was not significantly different in patients with MCD and those with FSGS (p = 0.86). Only uα1M, indexed or not to uCreat, was significantly (p < 0.001) higher for patients in relapse compared to those in remission. Conclusions: Our results indicate that in our patient cohort uNGAL was a reliable biomarker for differentiating MCD from FSGS independently of proteinuria or GFR level

Randomised trial of oral versus sequential intravenous/oral cephalosporins in children with pyelonephritis

The hypothesis was tested that oral antibiotic treatment in children with acute pyelonephritis and scintigraphy-documented lesions is equally as efficacious as sequential intravenous/oral therapy with respect to the incidence of renal scarring. A randomised multi-centre trial was conducted in 365 children aged 6 months to 16years with bacterial growth in cultures from urine collected by catheter. The children were assigned to receive either oral ceftibuten (9mg/kg once daily) for 14days or intravenous ceftriaxone (50mg/kg once daily) for 3days followed by oral ceftibuten for 11days. Only patients with lesions detected on acute-phase dimercaptosuccinic acid (DMSA) scintigraphy underwent follow-up scintigraphy. Efficacy was evaluated by the rate of renal scarring after 6 months on follow-up scintigraphy. Of 219 children with lesions on acute-phase scintigraphy, 152 completed the study; 80 (72 females, median age 2.2 years) were given ceftibuten and 72 (62 females, median age 1.6years) were given ceftriaxone/ceftibuten. Patients in the intravenous/oral group had significantly higher C-reactive protein (CRP) concentrations at baseline and larger lesion(s) on acute-phase scintigraphy. Follow-up scintigraphy showed renal scarring in 21/80 children treated with ceftibuten and 33/72 with ceftriaxone/ceftibuten (p = 0.01). However, after adjustment for the confounding variables (CRP and size of acute-phase lesion), no significant difference was observed for renal scarring between the two groups (p = 0.2). Renal scarring correlated with the extent of the acute-phase lesion (r = 0.60, p < 0.0001) and the grade of vesico-ureteric reflux (r = 0.31, p = 0.03), and was more frequent in refluxing renal units (p = 0.04). The majority of patients, i.e. 44 in the oral group and 47 in the intravenous/oral group, were managed as out-patients. Side effects were not observed. From this study, we can conclude that once-daily oral ceftibuten for 14days yielded comparable results to sequential ceftriaxone/ceftibuten treatment in children aged 6months to 16years with DMSA-documented acute pyelonephritis and it allowed out-patient management in the majority of these childre

Balancing competing needs in kidney transplantation: does an allocation system prioritizing children affect the renal transplant function?

Children often merit priority in access to deceased donor kidneys by organ-sharing organizations. We report the impact of the new Swiss Organ Allocation System (SOAS) introduced in 2007, offering all kidney allografts from deceased donors <60 years preferentially to children. The retrospective cohort study included all paediatric transplant patients (<20 years of age) before (n = 19) and after (n = 32) the new SOAS (from 2001 to 2014). Estimated glomerular filtration rate (eGFR), urine protein-to-creatinine ratio (UPC), need for antihypertensive medication, waiting times to kidney transplantation (KTX), number of pre-emptive transplantations and rejections, and the proportion of living donor transplants were considered as outcome parameters. Patients after the new SOAS had significantly better eGFRs 2 years after KTX (Mean Difference, MD = 25.7 ml/min/1.73 m(2) , P = 0.025), lower UPC ratios (Median Difference, MeD = -14.5 g/mol, P = 0.004), decreased waiting times to KTX (MeD = -97 days, P = 0.021) and a higher proportion of pre-emptive transplantations (Odds Ratio = 9.4, 95% CI = 1.1-80.3, P = 0.018), while the need for antihypertensive medication, number of rejections and living donor transplantations remained stable. The new SOAS is associated with improved short-term clinical outcomes and more rapid access to KTX. Despite lacking long-term research, the study results should encourage other policy makers to adopt the SOAS approach

NFIA Haploinsufficiency Is Associated with a CNS Malformation Syndrome and Urinary Tract Defects

Complex central nervous system (CNS) malformations frequently coexist with other developmental abnormalities, but whether the associated defects share a common genetic basis is often unclear. We describe five individuals who share phenotypically related CNS malformations and in some cases urinary tract defects, and also haploinsufficiency for the NFIA transcription factor gene due to chromosomal translocation or deletion. Two individuals have balanced translocations that disrupt NFIA. A third individual and two half-siblings in an unrelated family have interstitial microdeletions that include NFIA. All five individuals exhibit similar CNS malformations consisting of a thin, hypoplastic, or absent corpus callosum, and hydrocephalus or ventriculomegaly. The majority of these individuals also exhibit Chiari type I malformation, tethered spinal cord, and urinary tract defects that include vesicoureteral reflux. Other genes are also broken or deleted in all five individuals, and may contribute to the phenotype. However, the only common genetic defect is NFIA haploinsufficiency. In addition, previous analyses of Nfia−/− knockout mice indicate that Nfia deficiency also results in hydrocephalus and agenesis of the corpus callosum. Further investigation of the mouse Nfia+/− and Nfia−/− phenotypes now reveals that, at reduced penetrance, Nfia is also required in a dosage-sensitive manner for ureteral and renal development. Nfia is expressed in the developing ureter and metanephric mesenchyme, and Nfia+/− and Nfia−/− mice exhibit abnormalities of the ureteropelvic and ureterovesical junctions, as well as bifid and megaureter. Collectively, the mouse Nfia mutant phenotype and the common features among these five human cases indicate that NFIA haploinsufficiency contributes to a novel human CNS malformation syndrome that can also include ureteral and renal defects

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

Congenital anomalies of the kidney and urinary tract (CAKUT): from the prenatal diagnosis to patient's care and prognosis

Congenital kidney malformations of the kidney and urinary tract (CAKUT) include a large spectrum of diseases occurring subsequently to a misdevelopement in kidney development during gestation. The majority of theses diseases are prenatally diagnosed, for this reason accurate diagnosis is needed for counseling to parents and to decide of the better management at birth. Since 2008, we create a database to establish a cohort of neonates diagnosed with CAKUT to include prospectively pre and postnatal data to improve knowledge in these diseases. CAKUT are the most frequent cause of end stage renal disease during childhood. The wide variability of these pathologies is due to the complexity of kidney development. CAKUT may be secondary to an anomaly of tissue interaction at an early stage or to a modification of a molecular pathway at different steps of nephrogenesis. Hence, nephrogenesis may lead in the majority of the cases to low renal endowment similarly to what is observed in premature and neonates borne small for age. With the first nephrons, primitive renal function appears and small amount of urine began to be produced at 10 weeks of gestation and increased progressively to reach a mature glomerular filtration rate at the age on one year. Since renal function at birth is immature, its evaluation is chief to discriminate among neonates, those who may present a possible low renal endowment and subsequently an increased risk of renal progression. However in this population, the evaluation of renal function is challenging, because of the difficulty to validate potential renal markers with a gold standard. In these work, we proposed to present a new approach for CAKUT disease with the measure of renal function since birth using Cystatin C (CysC), a renal marker, recognized to be sensible for neonates. Reference interval of Cystatin C for this age is proposed in the literature and we validate in our center a reference interval for CysC in normal term babies. When comparing CysC values of this control group, to neonates from our cohort with kidney malformation, we showed that neonates with bilateral kidney malformation had a statistically CysC increased value compared to the control group. We proposed a cut-off value for Cystatin C, above which it may indicate an increased risk to present impaired renal endowment. The majority of renal and urinary tract malformation will be revealed prenatally and the most frequent presentation is the detection on the ultrasounds of an antenatal pelvic dilatation. Many authors have proposed guidelines for the management at birth of antenatal pelvic dilatation with variable cut-off's of posterior anterior diameter. These guidelines are important to identify neonates at risk of severe obstruction or who need an imaging evaluation to rule out vesico-ureteral reflux and avoid subsequent infections and renal scars. For the future, the target will be to succeed to delay renal function. With early and multidisciplinary management of these neonates since the last decade, we already noticed a delay in renal function progression, however there is a strong need to identify predictor factors to improve long term prognosis. Indeed renal endowment increased the risk to present renal progression but also hypertension and in adulthood cardio-vascular diseases. For this purpose, we followed, our cohort of neonates with CAKUT, two years after birth to analyzed predictors of renal function progression using CysC and creatinine as markers for renal function. We found that the bilateralism of the renal malformation and or the relative renal function asymmetry detected by the initial scintigraphy were factors of renal progression. Another approach, proposed to decrease renal function progression is to target the treatment of proteinuria with ACE inhibitors. Finally, to accurately assess neonatal renal function, the validation of Cystatin C with a gold standard will be essential. Likewise, neonates with CAKUT, premature and small for age neonates, because of possible impaired renal endowment will benefit of a useful clinical tool for the measure of renal function, often undeerdiagnosed in thie population