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.

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

“…Reference Networks on rare diseases over a period of 4 years and with a patient follow-up until the child's age of 2 years [20]. The ANTENATAL study will also be an excellent opportunity to evaluate the potential of adding other fetal urinary omics traits to peptide markers for kidney disease stratification, including proteins, metabolites and miRNAs, as we observed in a recent study [21] based on a recently developed urinary metabolome analysis pipeline [22].…”

“…However, it should be kept in mind that PUV is a rare disease (ORPHA:93110) with a prevalence of 1-9/100 000. Such limitations should be removed in the future by the ongoing multicenter ANTENATAL study [20]. In addition, although fetal biochemistry was performed (sodium and chloride), fetal urine β2-microglobulin, known to be also associated to postnatal renal outcome in PUV [24], was not available for comparison.…”

Postnatal Management in Congenital Lower Urinary Tract Obstruction With and Without Prenatal Vesicoamniotic Shunt

“…Currently, European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet) support such a study to generate reliable data (22). The status of amnion fluid, the renal ultrasound as well as the fetal urine biochemistry could be helpful in counseling prospective parents.…”

Definition, diagnosis and management of fetal lower urinary tract obstruction: consensus of the ERKNet CAKUT-Obstructive Uropathy Work Group

“…The final validation of the 12PUV signature is currently ongoing in the first clinical proteomics study in prenatal medicine (NCT03116217 (ref. 49 )), which aims to include 400 patients with PUV. In conclusion, fetal biomarkers showed promising results…”