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.

Keywords: development; kidney disease; obstructive uropathy; prediction; prenatal biomarkers.

FIGURE 1

Performance of a panel of 12 fetal urinary peptides (12PUV classifier) in predicting postnatal renal outcome in fetuses with PUV (proof of concept study). (A) Receiver operator characteristic curve for prediction of postnatal renal survival using the 12PUV classifier (38 fetuses, 16 with early ESRD, 22 without ESRD at 2 years postnatally). Adapted from Klein et al. [9] with permission. (B) Predictive accuracy of the 12PUV classifier compared with the clinical parameters including routinely ultrasound-measured characteristics of the fetal kidneys and amniotic fluid volume (oligoamnios or anhydramnios) as well as fetal urine biochemistry. *P < 0.05, **P < 0.01, ***P < 0.001 versus the 12PUV classifier using the McNemar test for paired proportions. Adapted from Klein et al. [9] with permission.

FIGURE 2

ANTENATAL study setup. Four hundred patients recruited in >30 centres will enter the ANTENATAL study with a confirmed presence of a megabladder in the prenatal period. Fetal urine and/or amniotic fluid will be sampled. Fetal urine will be scored with the previously identified peptide-based 12PUV classifier and then compared with renal outcome at 2 years, and renal function at a number of time-points after birth. Fetal urine content in additional omics traits, including proteins, miRNAs and metabolites, will be explored to determine the added value of combining those traits with the peptide-based 12PUV classifier. Amniotic fluid samples will be screened for omics biomarkers of postnatal function in PUV to eventually move the analysis into a less invasive body fluid. Follow-up of all patients will be performed according to local standard care, which can be with or without intervention (vesicoamniotic shunt/laser ablation of valves).

FIGURE 3

ANTENATAL study flow chart. The inclusion period will last for 48 months. The participation of each patient will carry on for 30 months, thereby resulting in a total duration of 78 months for the ANTENATAL trial.