Renal Hypoplasia and Aplasia and Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)

Spectrum of malformations of the renal parenchyma and urinary tract, of monogenic, genomic or multifactorial cause, with vesicoureteric reflux and recurrent urinary tract infections.

Literature and regulatory information updated: 17 October 2026.

0. Initial Reference Table

Table 0.2. Entities within scope, genes, identifiers and reference sources.

1. Introduction

1.1. Overview and clinical importance

Congenital anomalies of the kidney and urinary tract constitute the group of malformations most frequently identified on prenatal ultrasound, with estimates of 15% of all congenital anomalies detected before birth in the Oxford Desk Reference and of about 20% in the recommendations of the Working Group on Inherited Kidney Disorders of the European Renal Association (ERA) [1, 2]. Their overall frequency lies between 3 and 6 per 1000 live births, and the spectrum ranges from an anomaly without functional consequence, such as an ectopic kidney, to a lethal condition, such as bilateral renal agenesis or bilateral multicystic dysplasia [1]. Taken together, they are the main cause of chronic kidney disease in children and the most prevalent cause of kidney disease in the first three decades of life, and a probably underestimated part of CKD of unknown cause in adults results from unrecognised CAKUT [1, 79, 80]. In a North American study cited by Kohl et al., CAKUT accounted for about 40% of children with kidney failure [81]. Renal tract anomalies occur in 250 to 300 syndromes and in about 35% of chromosomal anomalies, and a quarter of cases are associated with other malformations [2].

This article treats as its main entity renal hypoplasia and aplasia (agenesis), especially bilateral, and the spectrum of renal hypodysplasia of monogenic or genomic cause. It includes, as separate subsections, familial vesicoureteric reflux and the predisposition to recurrent urinary tract infections in the context of CAKUT. Some entities are summarised here only in what distinguishes the diagnosis of CAKUT: the 17q12 deletion and HNF1B-related disease, the branchio-oto-renal spectrum, autosomal dominant tubulointerstitial kidney disease, autosomal dominant and recessive polycystic kidney diseases and the MURCS association (Müllerian anomalies, renal aplasia and cervicothoracic somite dysplasia) with the Müllerian aplasias.

1.2. Historical milestones

The classic description of bilateral renal agenesis and the associated fetal compression phenotype is due to Edith Potter, in 1946 [82]. The designation «Potter sequence» or «oligohydramnios sequence» came to cover all causes of severe and early oligohydramnios, and Bain and Scott (1960, 50 cases) and Thomas and Smith (1974) consolidated the clinical description [83]. In 1984, Roodhooft, Birnholz and Holmes showed, by ultrasound of 71 parents and 40 siblings of 41 index cases with agenesis or severe dysgenesis of both kidneys, that 9% (10/111) of first-degree relatives had asymptomatic renal malformations, mainly unilateral agenesis (4.5% against 0.3% in 682 comparison adults), which established the familial nature of some of these malformations and the recommendation for ultrasound of relatives [84].

The molecular era began with the identification, in 1995, of the first human pathogenic variant in PAX2 in a family with optic nerve colobomas, renal hypoplasia, mild proteinuria and VUR, a single-nucleotide deletion in exon 5 causing a frameshift in the octapeptide domain, a phenotype analogous to that of the Krd mouse [85]. There followed the characterisation of the branchio-oto-renal syndrome (described clinically by Melnick in 1975 and Fraser in 1978, with EYA1 and SIX1 identified later), Townes-Brocks syndrome (described in 1972, with truncating variants in SALL1) and HNF1B-related kidney disease [21, 86, 87]. In 2007, Mefford et al. described, in a fetus with MCDK identified among 155 fetal autopsies, the recurrent 17q12 deletion mediated by segmental duplications, then measured at about 1.5 Mb, and the reciprocal duplication associated with epilepsy [88]. In 2010 biallelic HPSE2 variants were identified in the urofacial syndrome described by Ochoa, with a founder variant in Colombia, and in 2013 those in LRIG2 [7]. From 2012 onwards, next-generation sequencing and genomic arrays transformed the field. Sanna-Cherchi et al. demonstrated in 2012 that pathogenic CNVs explain about 10% of renal hypodysplasia [89]; in 2012 loss of function of FGF20 was described in fetuses with bilateral renal agenesis [90]; in 2013, DSTYK in families with dominant CAKUT [91]; in 2014, ITGA8 as the first unequivocal recessive gene for bilateral renal agenesis [17]; in 2015, TBX18 in families with pelviureteric junction obstruction [92]; in 2017, GREB1L, by three independent groups [93–95]; in 2021, GFRA1 in recessive bilateral renal agenesis [18]; and in 2022 a null founder variant in NPNT, the integrin α8 ligand, in Saudi families [96]. In 2019, Verbitsky et al. described the CNV landscape in 2824 CAKUT cases [1, 97]. In 2022, the consensus of the European Rare Kidney Disease Reference Network (ERKNet) on non-obstructive renal dysplasia set out ultrasound definitions and criteria for genetic testing and follow-up [12], and in 2026 genome sequencing of 1052 patients from the UK 100,000 Genomes Project quantified the monogenic and polygenic contribution [80].

1.3. Nomenclature and reclassifications

The nomenclature of this group has changed with the definition of each entity. GeneReviews prefers «PAX2-related disorder» to «renal-coloboma syndrome» or «papillorenal syndrome», because a growing fraction of carriers have isolated renal involvement; older names include coloboma-ureteral-renal syndrome and optic coloboma–vesicoureteral reflux–renal anomalies [20]. Parsa et al. (2001) described a family with a similar phenotype and no PAX2 variant, which they called «papillorenal syndrome», and the relationship between the two names remains unclear in GeneReviews [20]. The SIX5 gene, formerly associated with the branchio-oto-renal spectrum, has been classified as «Disputed» by the hearing loss curation group of the Clinical Genome Resource (ClinGen), although Orphanet still lists it [20, 22]. The ERA recommendations now regard as questionable the causality of several published associations, because of high allele frequency in the Genome Aggregation Database (gnomAD), lack of segregation or inheritance from a healthy parent: CDC5L, CRIM1, FOXF1, ROBO2, SOX17, SRGAP1, TRAP1, UPK3A and even DSTYK [1]. Martino et al. (2023) reclassified DSTYK loss of function as a risk factor of low penetrance and variable expressivity (43.8% on reanalysis of the original family) [10, 98]. In the ClinGen clinical validity curation, consulted in October 2026, UPK3A is «Disputed» for CAKUT, PAX2 is curated only for autosomal dominant focal segmental glomerulosclerosis, and there is no curation for RET, WNT9B, GFRA1, SIX2, BMP4, GREB1L, ITGA8, FGF20, NPNT, TBX18, NRIP1, ROBO2 or for SOX17 and TNXB in VUR; absence of curation does not equate to refutation, but requires these associations to be reported with explicit uncertainty [19]. In familial VUR, OMIM numbers eight entries (VUR1–VUR8), of which four (VUR4–VUR7) are only linkage loci without an identified gene and two (VUR3–SOX17 and VUR8–TNXB) rest on two families and one family, respectively [62, 63, 66, 67]. The old acronym REAR (renal, ear, anal, radial; Kurnit 1978) designated Townes-Brocks syndrome [23].

1.4. Definition of the entities

Renal agenesis is the absence of the kidney and ureter due to failure of the reciprocal induction between the ureteric bud and the metanephric blastema, a process that must fail before 31 days of development [83]. Renal aplasia is the presence of a rudimentary kidney, suspected at the 18–22-week ultrasound, with relative function below 5% on dimercaptosuccinic acid (DMSA) scintigraphy; in congenital solitary kidney, the consensus of the Italian Society of Paediatric Nephrology (SINePe) further distinguishes MCDK and the «undefined» solitary kidney, when the renal fossa is empty in the 3rd trimester or after birth and it is not possible to distinguish between agenesis, aplasia and involuted MCDK [99]. Dysplastic kidneys may involute before or after birth, so many diagnoses of agenesis correspond to dysplasia at the origin [2].

Renal hypoplasia is, according to the ERKNet consensus, a renal length below −2 standard deviations for age, with normal corticomedullary differentiation and without other parenchymal anomalies; the norms of Obrycki et al. (2.5th and 97.5th percentiles as an approximation of ±2 standard deviations) or renal volume relative to body surface area are used, with values below 36 mL/m² considered hypotrophic and above 96 mL/m² hypertrophic [12]. Renal dysplasia is, strictly speaking, a histological diagnosis, but the consensus accepts as an ultrasound equivalent reduced corticomedullary differentiation and/or diffuse cortical thinning without urinary tract dilatation, regardless of size and with or without cysts [12]. Hypoplasia and dysplasia should be described separately, although the registries of the European Society for Paediatric Nephrology (ESPN) with the ERA and of the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) group them together, and they frequently coexist as hypodysplasia [12]. MCDK is a kidney replaced by multiple non-communicating cysts in a lobulated outline, with no visible pelvis or parenchyma [99]. Oligomeganephronia is a histological form of hypoplasia with few enlarged glomeruli, not pathognomonic, described mainly in PAX2 and HNF1B [12, 20].

Vesicoureteric reflux is the retrograde passage of urine from the bladder into the ureter and kidney, graded I to V by the International Reflux Study Committee classification on voiding cystourethrography (VCUG) [28]. Familial VUR (ORPHA:289365) designates familial aggregation of primary VUR with dominant transmission of variable penetrance or polygenic transmission [2, 6]. Recurrent UTI, according to the National Institute for Health and Care Excellence (NICE), corresponds to two or more episodes of pyelonephritis, one episode of pyelonephritis and one or more of cystitis, or three or more episodes of cystitis [100]. Urofacial syndrome (Ochoa syndrome) is an AR disorder of bladder innervation with voiding dysfunction of prenatal or childhood onset and abnormal facial expression on smiling [2, 7]. Megacystis-microcolon-intestinal hypoperistalsis syndrome (Berdon syndrome) combines megacystis without mechanical obstruction, microcolon and hypoperistalsis, due to visceral myopathy [8]. The early urethral obstruction sequence (prune belly) designates the combination of bladder distension, hydroureter, renal dysplasia, deficiency of the abdominal musculature and cryptorchidism resulting from early urethral obstruction or non-mechanical bladder distension [101]. Congenital LUTO is fetal infravesical obstruction, mainly due to posterior urethral valves (PUV) in males, urethral atresia or stenosis, and is an obligatory differential diagnosis of megacystis and oligohydramnios [28, 102].

2. Molecular Genetics and Pathophysiology

2.1. Kidney development and molecular pathways

The definitive kidney forms from the metanephros, in the intermediate mesoderm, through reciprocal interactions between the ureteric bud, which emerges from the mesonephric duct (Wolffian duct), and the metanephric mesenchyme, which induces it to branch and is induced by it to form nephrons [11, 28]. Complete failure of ureteric bud induction produces unilateral or bilateral renal agenesis; abnormal migration between weeks 6 and 9 produces ectopia and fusion anomalies such as the horseshoe kidney [28]. Nephrogenesis continues until about 36 weeks, which allows compensatory growth of the single kidney by hyperplasia (more nephrons) and hypertrophy [103]. The mesonephric duct also gives rise to the vas deferens and seminal vesicles, and the paramesonephric (Müllerian) duct depends on it for its formation, which is why renal agenesis is associated with absence of the vas deferens in males and uterine malformations in females [99, 104].

The pathways involved include transcription factors (PAX2, EYA1, SIX1, SIX2, SALL1, HNF1B, PBX1, GATA3, WT1, LHX1), the GDNF/RET pathway (RET, GDNF, the co-receptor GFRA1 and integrin α8 with its ligand nephronectin), the WNT pathway (WNT4, WNT9B, LRP4) and the BMP/FGF pathways (BMP4, BMP7, FGF20, FGFR2) [11]. RET is a receptor tyrosine kinase that requires a GDNF family ligand and a GFRA co-receptor to be activated and is indispensable for organogenesis of the kidney and the enteric nervous system [10]. GFRA1 regulates emergence of the ureteric bud from the Wolffian duct [18]. FGF20 and FGF9 maintain the self-renewal capacity of nephron progenitors, and loss of Fgf20 with Fgf9 in the mouse, or of FGF20 in humans, causes renal agenesis [90]. GREB1L, a retinoic acid receptor coactivator, is expressed in the nephrogenic zone and in early otic and craniofacial tissues; the Greb1l−/− mouse has no kidneys and has genital tract anomalies in both sexes, and the heterozygote has a slight reduction in ureteric bud branching [10, 94]. DSTYK, a dual-specificity kinase, acts downstream of FGF receptors and colocalises with them in the ureteric bud and metanephric mesenchyme [10, 91]. Because these pathways are pleiotropic, variants frequently produce syndromic CAKUT, and the isolated form may result from milder alleles or from the location of the variant within the gene [11, 81].

The most widely accepted hypothesis links prognosis to the reduced number of nephrons (nephron endowment) and to extrarenal anomalies [1]. After birth, the estimated glomerular filtration rate (eGFR) rises in the first months to an individual baseline, linked to nephron mass, and then declines slowly, influenced by UTI, hypertension, proteinuria and developmental factors [12]. Proteinuria and focal segmental glomerulosclerosis (FSGS) secondary to hyperfiltration of the remaining nephrons explain the progression observed, for example, in carriers of PAX2 variants [1].

2.2. Pathophysiology of oligohydramnios and Potter sequence

Until 14 weeks, amniotic fluid is mainly a transudate from the fetal skin and membranes; from then on, with keratinisation of the skin, fetal urine becomes the main source, with volumes of about 250 mL at 16 weeks and 800 mL in the 3rd trimester [30]. In bilateral renal agenesis, severe oligohydramnios sets in from 14 weeks, and thoracic restriction and absence of fluid between 16 and 24 weeks, in the canalicular phase of lung development, cause lethal pulmonary hypoplasia [28, 30]. Fetal compression produces the Potter phenotype: large, flattened ears (more than 97% of cases), loose skin, characteristic facies with an infraorbital fold and micrognathia, abnormal positioning of the hands and feet with club foot, breech presentation, amnion nodosum and growth deficiency [83]. Death occurs from respiratory failure, owing to lack of late alveolar development [83]. Unilateral renal involvement does not significantly reduce the fluid, because the contralateral kidney compensates [30].

2.3. Genetic architecture and diagnostic yield

CAKUT results from rare monogenic variants, CNVs and a polygenic burden of developmental alleles, with environmental and epigenetic contributions [11]. More than 50 monogenic causes have been described, and the genetic basis is resolved in fewer than 20% of cases in unselected cohorts [11, 80]. The yield depends greatly on the phenotype and the method, as Table 2.1 shows.

The differences reflect inclusion criteria: the yield is higher when both parenchymas are involved, when there is a family history or extrarenal anomalies, and is low in unilateral or low-risk CAKUT (unilateral MCDK with a normal contralateral kidney, low-grade VUR, unilateral PUJO) and in PUV, which are essentially sporadic [1]. In the UK study, family history (odds ratio, OR, 2.2; 95% confidence interval, 95% CI, 1.1–4.4), consanguinity (OR 3.0; 95% CI 1.2–6.9) and extrarenal manifestations (OR 3.1; 95% CI 1.7–5.7) were independent predictors of a monogenic diagnosis [80]. In the same study, comparison of 813 patients with 25,205 ancestry-matched controls identified a genomic signal at 6q16.3 (rs117473527; OR 3.13; 95% CI 2.08–4.72; P = 4.8 × 10⁻⁸; minor allele frequency 0.01), not yet replicated, and estimated that common and low-frequency variants would explain 23% of the phenotypic variance, with a wide 95% CI (1–45%); a polygenic score for PUV was also constructed, validated in a European cohort of 77 cases and 2746 controls [80]. Genome-wide association studies of VUR have pointed to loci in WDPCP, VANGL1 and WNT5A (planar cell polarity pathway), and studies of PUV have named TBX5 and PTK7, according to the review by Hilger et al. [11].

The PAX2, HNF1B and EYA1 genes are the three most frequent, with 23% of cases of known cause in the Verbitsky series, and more than half of HNF1B defects correspond to the recurrent 17q12 microdeletion; each of the remaining genes explains a small percentage, and each new gene less than 0.1% of cohorts [1, 12]. The Oxford Desk Reference (2017) estimated a molecular diagnosis in 15–20% of patients with agenesis, hypoplasia or dysplasia: 5–10% with a variant in PAX2, HNF1B, DSTYK, SALL1, SIX1 or EYA1 and about 10% with a genomic imbalance [2]. The 5–10% range falls below the ESCAPE study on which the book relies, in which 17 of 99 children with hypodysplasia (17%) had variants in these genes [106]. The highest yields arise in cohorts selected for extrarenal anomalies (27.4% by exome in CAKUT+), which led the authors to prefer exome to panels in syndromic CAKUT, and in fetal cohorts CMA identifies a fraction of chromosomal anomalies that a panel does not detect [31, 109]. In the review by Hewitt and Montini (2026), a genetic cause is identified in about one fifth of patients, mainly HNF1B and PAX2 and CNVs, more often in syndromic forms [24]. In small series published between 2025 and 2026 (47 Greek children with isolated parenchymal anomalies, with candidate variants in 10.6%, including KCTD1 and GREB1L; 10 Egyptian patients with variants in RIT1, WNT9B and FRAS1; FREM2 as a candidate gene in PUV), signs of an expanding spectrum have appeared without established clinical impact [115–117].

2.4. CAKUT genes with established evidence

Table 2.2 reproduces the genes whose variants produce a renal dysplasia phenotype according to the ERKNet consensus, supplemented by the categories of the 2026 review by Hilger et al.

Source: ERKNet consensus [12]. SNV: single nucleotide variant; indel: small insertion or deletion; HDR: hypoparathyroidism, deafness and renal dysplasia; MODY: maturity-onset diabetes of the young.

Hilger et al. add to the established categories SIX1, SIX2, WT1 and LHX1 (transcription factors), RET, GDNF, GFRA1, ITGA8, BMP4, BMP7, FGF20, FGFR2, WNT4, WNT9B and LRP4 (signalling), FRAS1, FREM1, FREM2, GRIP1 and COL4A1–A5 (extracellular matrix), NPHP1, NPHP3, CEP290, VANGL1, VANGL2 and WDPCP (ciliopathies and polarity) and TBX18, FOXC1 and NR6A1 [11].

2.4.1. PAX2

PAX2 (10q24.31; OMIM gene 167409) encodes a transcription factor with an N-terminal paired domain, an octapeptide, a truncated homeodomain and a C-terminal domain rich in proline, serine and threonine [20]. It has 12 coding exons, no transcript contains all of them, and alternative splicing of exons 6, 10 and 12 generates several isoforms; the MANE Select (Matched Annotation from NCBI and EMBL-EBI) transcript is NM_000278.5 [20, 118]. The mechanism is haploinsufficiency: normal biallelic expression is required to prevent apoptosis during development (models of Porteous 2000 and Torban 2000), the gene is intolerant to loss of function and to missense variation, and ClinGen assigns it a haploinsufficiency score of 3 and a triplosensitivity score of 0, so deletion of the whole gene causes the phenotype [10, 20]. In the mouse and zebrafish, homozygous loss of function prevents closure of the optic fissure, which explains the coloboma [20]. GeneReviews estimates that pathogenic PAX2 variants explain about 8% of individuals with apparently non-syndromic renal hypodysplasia and about 4% of families with isolated autosomal dominant FSGS [20]. ClinGen classifies the relationship of PAX2 with FSGS 7 as Definitive, but has not curated the papillorenal phenotype or CAKUT, whose causality rests on the literature and on OMIM (papillorenal syndrome, OMIM 120330), which allows CAKUT without evident ocular anomaly (Negrisolo 2011) [19, 42]. The OMIM gene entry (167409) brings together the data supporting PAX2 testing in apparently isolated CAKUT [119]. In the review by Bower et al., four series of kidney disease without a known ocular sign (Nishimoto 2001, Salomon 2001, Weber 2006 and Martinovic-Bouriel 2010) totalled 13 carriers among 148 patients (9%), and targeted ophthalmological examination later found optic nerve anomalies in 10 of those 13 [119]. In 20 children and young people transplanted for CAKUT without apparent ocular change, Negrisolo et al. identified two de novo variants, and reassessment revealed bilateral optic disc excavation in one patient and myopia in the other, which indicates underdiagnosis of ocular involvement [119]. Conversely, Martinovic-Bouriel et al. found no variants in 18 fetuses with isolated kidney disease (10 with unilateral or bilateral renoureteral agenesis, 6 with enlarged dysplastic kidneys and 2 with small dysplastic kidneys), but found them in the two fetuses with associated coloboma [119]. Barua et al. (2014) detected missense variants in 7 of 85 patients with CAKUT (8%), one of them compound heterozygous in a patient with a more severe phenotype and extrarenal anomalies, and heterozygous variants in 7 families with FSGS (4% of the cohort); functional assays indicated that some act through haploinsufficiency and others through a dominant negative effect, with enhanced repressor activity of the protein [119]. The run of seven guanines where c.76dup occurs also undergoes single-guanine contractions (Schimmenti 1999), and one patient with the duplication had hydrocephalus with platybasia and Chiari type 1 malformation, which adds brain malformations to the spectrum [119]. PAX2 testing in 34 patients meeting criteria for CHARGE association was negative (Tellier 2000) [119].

About 90 pathogenic variants have been described (Bower 2012), mainly frameshift, but also nonsense, missense, splicing and in-frame duplications, clustered in the paired domain (exons 2–4), the homeodomain (exon 7) and the 5' portion of the transactivation domain (exon 8) [20]. All in-frame variants of established pathogenicity are in the paired domain; six missense variants outside it have each been described in a single individual, with weak evidence, and missense variants in exons 9–12 have no established pathogenicity [20]. The most common recurrent variant is the duplication of one guanine in a run of seven, NM_000278.5(PAX2):c.76dup p.(Val26GlyfsTer28) (NC_000010.11:g.100749778dup, GRCh38), identified in more than 25 independent families and designated in the older literature as 619insG; GeneReviews describes it on transcript NM_003987.3 as c.76dupG, and the notation is identical on NM_003987.5 after normalisation in VariantValidator [20, 118, 120]. ClinVar classifies it as pathogenic, with criteria provided by several submitters without conflict [118]. In a review of 166 affected individuals published in 2026, c.76dup was present in 27% of patients, and in the locus-specific database (277 individuals, 153 different variants, up to January 2023) it accounted for 17% of variants [121]. In 2026, a minigene assay showed that variants at the last nucleotide of exons, previously interpreted as missense, cause exon skipping in vitro: NM_000278.5:c.212G>A p.(Arg71Lys), c.212G>T p.(Arg71Met), c.212G>C p.(Arg71Thr), c.919G>A p.(Gly307Ser) and c.427G>C p.(Val143Leu), which reclassifies them as splicing variants [122].

GeneReviews found no consistent genotype-phenotype correlation, either by location or by variant type [20]. The series by Greipel et al. (2025), which brought together 104 children with CAKUT and PAX2 loss of function (7 of their own and 97 from 12 publications) and compared them with 294 without a variant, described hypo/dysplasia, frequently cystic, in 97% against 59% (P < 0.0001), more severe albuminuria and severe anomalies (cystic dysplastic kidney or agenesis) more frequent with c.76dup in exon 2, for which the authors propose a possible dominant negative effect, than with nonsense or frameshift variants in exons 3 to 7; this association comes from a retrospective analysis with literature data and has not been replicated prospectively [108]. Overall penetrance is above 99%, with a single documented carrier with normal renal and ophthalmological examinations, and in the 10 familial carriers of the Greipel series renal penetrance was complete, with parents having only albuminuria or FSGS; ocular penetrance is at least 77% (21% of carriers had no dilated fundoscopy) and renal penetrance at least 92% [20]. As an allelic phenotype, PAX2 causes isolated autosomal dominant adult FSGS (FSGS7, OMIM 616002): Barua et al. found a segregating variant in one family, rare heterozygous substitutions in 4% of a familial FSGS cohort and private missense variants in 8% of a CAKUT cohort, without evident extrarenal manifestations [10, 123]. In the OMIM entry, the 24 patients from 7 families described by Barua had onset between 8 and 68 years of age, mainly in the 2nd to 4th decade, without ocular or auditory findings, nine progressed to end-stage CKD, and ultrasound showed subtle changes (increased echogenicity, dilated pelvis, small kidneys, calyceal diverticulum) [29]. Whole-gene deletions, often with neighbouring genes, broaden the phenotype [20].

2.4.2. HNF1B and 17q12 deletion

HNF1B (17q12) encodes a transcription factor of renal, pancreatic, hepatic and genital development; intragenic variants and the recurrent 17q12 deletion cause renal cysts and diabetes syndrome (RCAD, OMIM 137920), and the deletion constitutes 17q12 deletion syndrome (OMIM 614527) [10, 21]. The recurrent deletion is about 1.4 Mb in GeneReviews 2025 (minimal GRCh38 coordinates chr17:36,458,167–37,854,616; ClinGen region ISCA-37432), was measured at about 1.5 Mb in the original description by Mefford et al. (2007) and appears as «1.2 Mb» in the MODY GeneReviews and in GeneGuidance; the difference reflects mapping conventions and reference genome versions, and the 1.2 Mb value is not supported by the primary sources [10, 21, 88, 124]. It results from non-allelic homologous recombination between segmental duplications and includes 15 genes (among them HNF1B, LHX1 and ACACA); no single gene explains the overall phenotype, and likely pathogenic LHX1 variants have been described in women with Mayer-Rokitansky-Küster-Hauser syndrome [21]. Deletion of the whole gene on a targeted test almost always corresponds to the recurrent 17q12 deletion, whereas an intragenic variant establishes HNF1B-related disease and excludes the deletion syndrome [21]. HNF1B variants explain 3–5% of hypoplasias, aplasias and dysplasias, and about 80% of carriers present at birth with a parenchymal defect (cystic kidneys, agenesis) [2]. The deletion is de novo in 75% (82/109) and inherited in 25%, with high penetrance for the renal phenotype [21]; the Oxford Desk Reference, which considers all HNF1B alterations together, reports large deletions greater than 1 Mb in about 50% and de novo variants in about 50% [125]. In the table of penetrance of recurrent CNVs reproduced by the Oxford Desk Reference (Rosenfeld et al. 2013, with the phenotype that prompted postnatal microarray, mainly neurodevelopmental, as the outcome), the 17q12 deletion appeared in 29 of 33,226 cases (0.09%) against 2 of 22,246 controls (0.01%), with an estimated penetrance of 34.4% (95% CI 13.7–70.0), and the reciprocal duplication in 0.11% against 0.02%, with a penetrance of 21.1% (95% CI 10.6–39.5); this penetrance does not refer to the renal phenotype [126].

In a retrospective cohort of adults, progression to kidney failure was 51% with the 17q12 deletion and 78% with intragenic variants, and GeneReviews summarises several studies in which intragenic variants are associated with worse kidney function and a higher risk of end-stage CKD than the deletion, owing to a possible dominant negative effect of some variants or a protective effect of the loss of other genes in the region [21]. ClinGen classifies the clinical actionability of RCAD as strong in adults and moderate in children [10]. In the paediatric CAKUT series summarised by OMIM, Nakayama et al. (2010) found pathogenic HNF1B variants in 5 of 50 Japanese children (10%; two with hypodysplastic kidneys and three with unilateral MCDK) and Thomas et al. (2011) in 4 of 73 children with CKD due to hypodysplasia; in the cohort of 86 children with cystic kidneys and an HNF1B alteration of Loirat et al. (2010), 61% had whole-gene deletion and 39% point variants [43, 44]. Among 160 patients with kidney disease of unknown cause, Edghill et al. (2006) identified 23 (14%) with an HNF1B variant: renal cysts were present in 83% and diabetes in 48%, but only 26% met the minimum criteria for MODY, so the absence of a family history of diabetes does not rule out the disease [43]. GeneGuidance and OMIM also link the gene to entries without a Mendelian relationship to CAKUT: type 2 diabetes (125853), in which a common HNF1B polymorphism (rs4430796) was associated with a protective effect in Icelandic and multiethnic case-control studies and a variant was described in two Japanese patients with late-onset type 2 diabetes, and non-papillary renal cell carcinoma (144700), in which OMIM records the susceptibility conferred by HNF1B on the basis of biallelic inactivation in 2 of 12 chromophobe carcinomas, one of them with a germline variant (Rebouissou 2005) [10, 127, 128].

2.4.3. EYA1, SIX1 and the branchio-oto-renal spectrum

EYA1 (8q13.3; OMIM 601653) and SIX1 (14q23.1; OMIM 601205) encode a transcriptional coactivator with tyrosine phosphatase activity and the transcription factor to which it binds; EYA1 converts the SIX1 complex from repressor to activator, both are expressed in the otic placode, branchial arches and metanephric mesenchyme, and the mechanism is loss of function [10, 22]. Table 2.4 reproduces the contribution of each gene according to GeneReviews 2025.

Source: GeneReviews, Table 1 [22].

Among patients with a molecular diagnosis, about 90% have variants in EYA1 or SIX1 (Cho 2024, with integration of whole genome sequencing), and CNVs or structural variants of 8q13.2–q13.3 that include EYA1 account for 10%; this 90% value is not the proportion of all patients with the spectrum explained by these genes [22]. EYA1 has a high frequency of multiexon deletions, cryptic inversions, Alu insertions and complex rearrangements that escape sequencing, panels and exome, and pericentric inversions of chromosome 8 may require high-resolution karyotype or fluorescence in situ hybridisation (FISH) [22, 129]. Smith's Recognizable Patterns of Human Malformation gives lower percentages, with a variant identified in only 50% of patients, EYA1 in about 40% (20% of these by intragenic rearrangements), SIX1 in 2% and SIX5 in 2.5%, the latter now classified as «Disputed» by ClinGen [19, 86]. Submicroscopic deletions that include EYA1 produce a broader contiguous gene phenotype, such as otofaciocervical syndrome [22, 86]. Penetrance approaches 100% in large pedigrees, with highly variable expressivity between sides, between families and within the same family, and the spectrum covers the form with renal involvement (BOR1, OMIM 113650) and the forms without (BOS1, OMIM 602588; BOS3, OMIM 608389), which coexist in the same family [22]. In OMIM, EYA1 has as allelic phenotypes BOR1 (with or without cataracts), BOS1, anterior segment anomalies with or without cataract (missense variants, Azuma 2000) and, provisionally, otofaciocervical syndrome; SIX1 is associated only with BOS3 and autosomal dominant deafness 23 (DFNA23, OMIM 605192), without its own renal phenotype entry, although the patient from the DFNA23 family in whom Ruf et al. (2004) identified a 3 bp deletion in SIX1 had a hypodysplastic single kidney with VUR and progressive renal failure [50, 130–132]. The historical distinction between BOR and BOS (Melnick 1978) has been contested since 1980 (Cremers and Fikkers-van Noord), and the BOS3 families described in Australia (more than 40 affected) and in Denmark (5 generations) had no renal anomalies in the members studied [49, 51]. The yield of EYA1 depends on clinical rigour: Orten et al. (2008) found variants in 76 of 248 families (31%) meeting the clinical criteria and in 13 of 187 (7%) with a doubtful phenotype, almost all private and without genotype-phenotype correlation, Stockley et al. (2009) in 14 of 17 probands (82%), 45% de novo, and Vervoort et al. (2002) showed that inversions and large deletions detected by Southern blot explained some of the cases negative on sequencing [49]. Non-recurrent 8q13 deletions of 2.7 to 8.7 Mb including EYA1 (Sanchez-Valle 2010) combined BOR, short stature and developmental delay, more severe with the largest deletion [49]. CAKUT occurs in 67% of patients [22].

2.4.4. SALL1, GATA3, PBX1 and other transcription factors

SALL1 (16q12.1) causes autosomal dominant Townes-Brocks syndrome, through truncating variants in 64–83% of patients and through some 16q12.1 deletions; the truncated protein interacts with negative regulators of ciliogenesis [87]. In a large monogenic kidney disease cohort, pathogenic SALL1 variants appeared in 1 in every 1592 patients (Stein 2024), and in 1 in every 2952 individuals with hearing loss (Yan 2024) [23]. Sequencing detects more than 90% of variants and deletion/duplication analysis less than 10%; the highly homologous pseudogene SALL1P1 may prevent capture-based panels and exome from distinguishing variants [23]. The variant NM_002968.3(SALL1):c.826C>T p.(Arg276Ter) was associated with the complete triad in 15 of 16 patients (94%) and with heart disease in 50%, escapes nonsense-mediated decay and acts in a dominant negative manner; variants in the 5' region of exon 2 are more severe than those in the 3' region, and deletions of SALL1 alone produce milder phenotypes (9 patients from 5 families) [10, 23]. In a series of 49 French patients and 207 from the literature, variants downstream of the glutamine-rich region were associated with more hearing loss and ear and thumb anomalies and less kidney failure, in a series of younger patients [133]. In Japan, among 1108 families studied, 14 had a SALL1 variant, and 7 of the 20 individuals had non-syndromic CAKUT, which shows that SALL1 may appear in an isolated CAKUT panel [134]. DACT1 causes Townes-Brocks syndrome 2 (OMIM 617466), with variants in families with dominant CAKUT of reduced penetrance and one family with loss of function and CAKUT, anal and/or auricular anomalies, without thumb anomalies [23]. In the original three-generation family (Webb 2017), negative for SALL1, a nonsense variant (W419X in OMIM notation, transcript not stated) segregated in six members: the proband had imperforate anus with rectovaginal fistula, crossed fused renal ectopia and VUR, her brother the same renal pattern with hypospadias, and other relatives only cup ears, microtia or bicornuate uterus [53]. Christians et al. (2023) described 11 patients from 8 families, 10 with CAKUT, and found heterozygous DACT1 variants in 8 of 209 families with CAKUT (3.8%), several inherited from an unaffected parent, with incomplete penetrance of the renal phenotype and variable expressivity of the extrarenal features (neurological and skeletal anomalies, one case of caudal regression) [53]. GATA3 (10p14) causes, through haploinsufficiency, HDR syndrome (hypoparathyroidism, sensorineural deafness and renal dysplasia, or Barakat syndrome; OMIM 146255), with a renal spectrum ranging from normal to mild dysplasia and aplasia, and ClinGen classifies the relationship as Definitive [10, 19, 129]. Haploinsufficiency was demonstrated by Van Esch et al. (2000), who delimited a 200 kb critical region in patients with partial monosomy 10p and found nonsense variants and intragenic deletions in other probands; terminal 10p deletions explain the overlap with the DiGeorge 2 phenotype, because loss of a more proximal region causes heart disease and T-cell deficiency and loss of a more distal region causes the HDR triad (Lichtner 2000) [54]. A duplication including GATA3 was associated with a similar phenotype in an isolated case (Bernardini 2009) [54]. In a Japanese CKD cohort (1254 families with absent or mild urinary abnormalities), 10 patients from 7 families had GATA3 variants, with deafness in all, renal anomalies in 90%, hypoparathyroidism in 45% and the complete triad in only 40%, which led the authors to recommend CNV analysis [135]. PBX1 (1q23.3) causes CAKUT with or without hearing impairment, abnormal ears or developmental delay (CAKUTHED, OMIM 617641), with a Definitive relationship in ClinGen and a haploinsufficiency score of 3: in a series of eight patients with a 1q23.3q24.1 microdeletion delimiting the gene (Le Tanno 2017), all had syndromic CAKUT and 75% bilateral renal hypoplasia, most have global delay, and de novo variants are frequent [10, 19, 48]. The WT1 and SIX2 genes are on the lists of established genes [11]; in the Wuhan cohort, WT1 appeared among the most prevalent causes of hypodysplasia [114].

2.4.5. Genes for bilateral renal agenesis

Bilateral renal agenesis has a relevant recessive component. Humbert et al. identified, by exome, recessive ITGA8 variants in two families with several affected fetuses: a consanguineous Roma family, originating from Serbia and Spain, with three couples who had one to four terminations of pregnancy for bilateral agenesis, homozygous for a splicing variant, and another family, compound heterozygous for two variants with demonstrated loss of function; the Itga8−/− mouse does not develop kidneys; until then, only some RET variants had been associated with this malformation [17, 37]. The ITGA8 phenotype (OMIM 191830) includes a mild extreme with two adults homozygous for loss of function with bilateral hypodysplasia and slowly progressive CKD (Gómez-Conde 2023) and an intermediate extreme with unilateral agenesis, hypoplasia, cystic dysplasia or obstructive uropathy, with intra- and interfamilial variability [10]. The FGF20 form (OMIM 615721, provisional) rests on one consanguineous family with three fetuses with isolated bilateral renoureteral agenesis and Potter sequence, homozygous for c.337delG, with a frameshift at codon 113 and a stop codon at 121, normalised in VariantValidator as NM_019851.3(FGF20):c.337del p.(Val113TrpfsTer9) (NC_000008.11:g.16995708del, GRCh38); heterozygotes were unaffected [10, 90, 120]. In 2021, GFRA1 was added as a recessive cause of non-syndromic bilateral agenesis in two patients of consanguineous parents with deceased affected siblings, both homozygous, and in a repository of 184 patients with renal agenesis (36 isolated) two had GFRA1 loss of function [18]. The variants, described in the article on transcript NM_001348097.1, are normalised on the MANE Select transcript as NM_005264.8(GFRA1):c.676C>T p.(Arg226Ter) (NC_000010.11:g.116125315G>A) and NM_005264.8(GFRA1):c.1294del p.(Thr432ProfsTer13) (NC_000010.11:g.116064503del) [18, 120]. In 2022, Al-Shamsi et al. described further families with biallelic loss of function and lethal bilateral agenesis, and OMIM created the RHDA4 entry (619887), with agenesis, oligohydramnios or anhydramnios and Potter sequence [13]. The evidence rests on few families and has no ClinGen curation [19]. In 2022, a founder nonsense variant in NPNT (nephronectin, the integrin α8 ligand), with complete nonsense-mediated decay, was identified by autozygous linkage at 4q24 in two Saudi families; at least one member had unilateral agenesis, which shows that complete loss of function is compatible with the formation of a kidney [96].

GREB1L (OMIM 617805) has dominant inheritance with markedly reduced penetrance. De Tomasi et al. found 16 heterozygous variants (4 loss-of-function and 12 missense, 14 absent from gnomAD) in 183 familial or severe CAKUT cases that included 54 fetuses with bilateral agenesis; 12 variants were in cases of bilateral agenesis, and the female fetuses also had uterine agenesis [94]. Sanna-Cherchi et al. obtained, in 195 unresolved hypodysplasia cases against 6905 controls, an exome-wide association signal with a combined p of 2.3 × 10⁻⁷ including segregation and de novo variants; greb1l knockdown in zebrafish caused pronephric defects rescued by normal human mRNA, but not by the patients' alleles [93]. Boissel et al. independently found de novo variants in two fetuses with bilateral agenesis in a cohort of 101 fetuses and stillbirths from Quebec [95]. In the same year, Brophy et al. described two unrelated families, one from Iowa (USA) and one Danish, with unilateral or bilateral agenesis and segregating heterozygous variants with incomplete penetrance, one frameshift and one missense [39]. Across the series by Sanna-Cherchi et al., 17 of 604 patients with hypodysplasia/aplasia (2.8%) had GREB1L variants: 4 loss-of-function and 13 missense, one proven de novo and 4 inherited from an apparently unaffected parent [39]. In the series by De Tomasi et al., 12 of the 54 cases of bilateral agenesis had a GREB1L variant, and in 11 of the 12 families with parental DNA the variant was of maternal origin, mostly from mothers with renal or uterine anomalies, which led the authors to propose a maternal transmission bias (imprinting or an effect on male fertility) [39]. Herlin et al. (2019) described a three-generation family with uterovaginal agenesis and unilateral renal agenesis in two 46,XX cousins (Mayer-Rokitansky-Küster-Hauser syndrome type 2) and bilateral renal agenesis in a brother, with the missense variant W235C (published designation; recorded in ClinVar as NM_001142966.3(GREB1L):c.705G>T p.(Trp235Cys), VCV001064690, single submission without assertion criteria) [136] penetrant only when inherited from the mother; Jacquinet et al. (2020) found GREB1L variants in 4 of 9 multiplex families with uterine and renal malformations, without dependence of penetrance on the sex of the transmitting parent [39]. The association with the Mayer-Rokitansky-Küster-Hauser spectrum lacks functional validation [39]. GREB1L variants also cause a distinct phenotype of profound deafness with cochlear and cochlear nerve aplasia (DFNA80) [10]. Schrauwen et al. (2020) reviewed 49 GREB1L variants and found reduced penetrance in 50% of the variants with tested relatives, maternal origin in 71% of inherited variants and ear anomalies in 14%, and Fan et al. (2024) described a nonsense variant transmitted from an unaffected grandfather to an unaffected mother and to two fetuses with bilateral agenesis; a healthy carrier parent is therefore frequent and does not rule out pathogenicity [10]. GenCC classifies the GREB1L–RHDA3 relationship from Definitive to Limited depending on the curator, without ClinGen curation [10, 19]. Orphanet also associates RET and WNT9B loss of function with bilateral agenesis, and RET, FRAS1, FREM1, FREM2, BMP4, UPK3A, DSTYK and GREB1L with unilateral agenesis [4, 40]. The human evidence for these associations is uneven. Skinner et al. (2008) found RET variants in 7 of 19 stillborn fetuses with bilateral agenesis (37%) and in 2 of 10 with unilateral agenesis (20%), and none in GFRA1 [137]; Jeanpierre et al. (2011), in 105 fetuses with severe bilateral defects, found potential coding RET variants in fewer than 7%, four inherited from a healthy father, none in GDNF and no CNVs, and concluded that the RET/GDNF pathway is not a major mechanism [138]; Chatterjee et al. (2012), in 122 living North American patients, described rare deleterious variants in the GDNF–GFRA1–RET pathway in about 5%, including combinations of rare and common variants inherited from unaffected parents [139]. The first variants in SIX2 and BMP4 were described in 2008 in five patients each with hypodysplasia, with zebrafish assays, without robust replication in the sources consulted [140]. WNT9B is essential for kidney development in animal models, but Mendelian human evidence for CAKUT is not established in the sources consulted, beyond variants in small series [116, 141]. None of these associations has ClinGen curation [19]. Biallelic missense variants in the FRAS/FREM complex genes (FRAS1, FREM1, FREM2, GRIP1) cause isolated CAKUT, whereas truncating variants cause multiorgan Fraser syndrome [81].

2.4.6. Genes with limited or questioned evidence

DSTYK was associated with dominant CAKUT (OMIM 610805) in a family with seven affected members carrying a splicing variant and in 7 of 311 unrelated patients (2.3%) with nonsense or splicing variants [91]. The reanalysis by Martino et al. (2023) estimated penetrance at 43.8% in the original family and at about 20–25% obstructive uropathy in Dstyk−/− mice of the C57BL/6J and FVB/NJ strains, rising to about 40%, of mild to moderate severity, in the C3H/HeJ strain [10, 98]. In humans, the spectrum described includes agenesis, hypodysplasia, MCDK, duplication, PUV and ureteral anomalies [10]. The ERA now regards causality as questionable, ClinGen has curated only recessive spastic paraplegia, and GeneGuidance treats heterozygous loss of function as a risk factor of incomplete penetrance, without grounds for predictive testing of relatives [1, 10, 19]. A distinct recessive entity, spastic paraplegia 23 or Lison syndrome (OMIM 270750), is associated with a homozygous intragenic deletion-insertion in DSTYK, with a founder effect, identified by Lee et al. (2017) in three consanguineous Middle Eastern families (one Kuwaiti-Jordanian, one Israeli and the Arab family from Israel described by Mukamel in 1985); GeneGuidance mentions Israeli and Palestinian-Jordanian families [10, 142]. The picture is one of childhood-onset spastic paraplegia with premature greying and vitiligo-like or hyperpigmented skin lesions, sometimes with peripheral neuropathy; one of the probands of Lee et al. had a horseshoe kidney, the only renal finding recorded in the entry [142]. TBX18 (CAKUT2, OMIM 143400) rests essentially on one study: in a dominant family with predominant PUJO, seven affected members had a truncating variant, and three other families had missense variants, with a dominant negative effect; on the MANE transcript NM_001080508.3, the variants are normalised as c.1010del p.(Gly337ValfsTer19), c.487A>G p.(Lys163Glu), which alters DNA binding, and c.1570C>T p.(His524Tyr) [92]. The mutant proteins dimerise, have a prolonged half-life and reduced repressor capacity; there is no ClinGen curation, and GenCC is divergent (from Strong to Limited), so the result should be reported with explicit uncertainty [10, 19, 46]. NRIP1 (CAKUT3, OMIM 618270, provisional entry) rests on a three-generation Yemenite Jewish family with seven affected members (six with hypodysplasia and four with VUR, without extrarenal manifestations), carrying c.279delG, and on a second family described in 2022 with a father with unilateral renal hypoplasia [10, 47, 143]. The historical notation «p.Trp93fs» corresponds, after normalisation in VariantValidator, to NM_003489.4(NRIP1):c.279del p.(Trp93Ter) (NC_000021.9:g.14967915del), because the deletion creates an immediate stop codon; the classification in the Gene Curation Coalition (GenCC) is «Limited» and the variant of the second family is present twice in gnomAD [10, 120]. ROBO2 (VUR2) behaves more like a rare risk allele than a fully Mendelian gene: Lu et al. (2007) described a de novo t(Y;3) translocation with dominant negative products and mice with reduced Robo2 dosage with CAKUT and VUR, Bertoli-Avella et al. (2008) found four cosegregating missense variants in 5.1% of familial cases, and a genome-wide scan of primary VUR (Cordell 2010) found no association with the gene [10]. The OMIM entry for VUR2 (610878; 3p12.3, AD) rests on the two families of Lu et al. with missense variants in the intracellular domain: in a British family, the daughter had bilateral VUR, hypoplastic kidneys and nephropathy, and the mother had needed ureteric reimplantation for severe VUR; in a Dutch family, the proband had bilateral VUR with duplication of the right collecting system, the mother and two aunts had urinary symptoms and CAKUT on ultrasound and the grandmother a small unilateral kidney [61]. In a Chinese registry of 379 children with primary VUR, a monogenic cause was identified in 7.39%, two of them in ROBO2 (Liu 2021) [10]. SOX17 (VUR3, OMIM 613674) rests on two families (Gimelli 2010), and its established phenotype, with Definitive ClinGen curation from October 2025, is pulmonary arterial hypertension; TNXB (VUR8, OMIM 615963) rests on a five-generation family with nine members affected by VUR and/or duplication (Gbadegesin 2013), and GeneReviews considers the evidence insufficient to support causality [10, 19, 62, 67]. Both should be treated as associations with weak evidence and not as diagnostic causes [1, 10]. VUR1 (OMIM 193000) is a locus at 1p13 without an identified gene, and VUR4–VUR7 are linkage loci at 5q14.2, 13q33.2, 18q12.3 and 12p11–q13 obtained in Caucasian and Hasidic Jewish families [60, 63–66]. BICC1 (10q21.1) confers susceptibility to cystic renal dysplasia (CYSRD, OMIM 601331): Kraus et al. (2012) studied the gene by analogy with the knockout mouse and found heterozygous loss-of-function or hypomorphic variants in 2 of 92 children (2%) with isolated renal anomalies and no HNF1B variant, both inherited from an unaffected parent, and none in 45 adults with kidney disease and early-onset diabetes; one of the boys had unilateral cystic dysplasia with hypertension as the only manifestation, and the other a non-functioning dysplastic kidney with low-grade VUR and a normalised contralateral kidney [144]. The entry also brings together older sibships with non-syndromic diffuse cystic dysplasia from parents without renal anomaly (Cole 1976; Sase 1996), in which recessive inheritance was proposed, without molecular study [144]. The review by Hilger et al. lists emerging candidate genes, summarised in Table 2.3 [11].

Source: Hilger et al. 2026, Table 2 [11]. GeneGuidance gives 19q12 as the cytoband of TSHZ3 [10], and OMIM places GFRA1 at 10q25.3 [13].

2.4.7. Bladder and smooth muscle genes: bladder dysfunction, megacystis and UTI

A group of genetic disorders of bladder innervation or smooth muscle presents in the fetus as megacystis and hydroureteronephrosis, mimicking LUTO, and after birth as voiding dysfunction with VUR, UTI and risk of kidney damage; they fall within the scope of recurrent UTI in the context of CAKUT. Urofacial syndrome is AR: biallelic variants in HPSE2 (10q24.2; OMIM 613469) explain about 64% of cases, with sequencing detecting less than 85% and deletion/duplication analysis more than 15% of variants, and variants in LRIG2 (1p13.2; OMIM 608869) about 20%, with the cause unknown in up to 16% [7]. The two proteins pattern the peripheral nerves of the fetal bladder, and biallelic LRIG2 missense variants may cause disease limited to the urinary tract, without the typical facial expression [7, 10]. On the MANE transcript NM_021828.5 of HPSE2 (numbering identical to that of NM_021828.4 used in GeneReviews), the variant c.1465_1466del p.(Asn489ProfsTer126) is common in patients of Irish ancestry and c.1516C>T p.(Arg506Ter) is a founder variant in Colombia [7, 120]. HPSE2 testing in unselected series of «non-neurogenic neurogenic» bladder without a facial sign has been largely negative (Bulum 2015), so the facial grimace is the discriminating sign for testing [10]. The OMIM entries for urofacial syndrome 1 (236730; HPSE2, 10q24.2) and 2 (615112; LRIG2, 1p13.2), both AR, document the basis of the fraction detected by deletion analysis: in a British family of Pakistani origin, the cause was a homozygous intragenic deletion of about 11 kb, including exons 8 and 9 of HPSE2 (Daly 2010) [70]. Homozygosity for the same nonsense variant in six Colombian families and for the same 2 bp deletion in two US families (Pang 2010) reflects founder effects, and haplotypes from Colombian, Irish-American and French families pointed to a single locus at 10q23–q24 [70]. Daly et al. found no HPSE2 variants in eight families, three of them consanguineous and heterozygous at the locus, which anticipated the heterogeneity later explained by LRIG2 [70]. Stuart et al. (2013) identified biallelic LRIG2 variants in two consanguineous Turkish families and a Spanish child, and, among 23 patients with «non-neurogenic neurogenic» bladder (Hinman syndrome), a man with bladder dysfunction without the facial grimace, compound heterozygous for two missense variants; there were no consistent clinical differences between the HPSE2 and LRIG2 forms [71].

Megacystis-microcolon-intestinal hypoperistalsis syndrome results from visceral myopathy: ACTG2 (AD, more severe when de novo, with parental somatic and gonadal mosaicism described) explains 44.1% of cases, and there are rare AR forms due to MYH11 (7 patients), MYL9 (4, with mydriasis), MYLK (2 families), LMOD1 (1), PDCL3 (2) and a mild AD form due to ATP2B4 (1), with the cause unknown in about 55% [8]. OMIM numbers the forms by gene: type 1 (MYLK, 3q21.1, AR), type 2 (MYH11, 16p13.11, AR), type 3 (LMOD1, 1q32.1, AR, based on a single patient), type 4 (MYL9, 20q11.23, AR, with a still provisional relationship) and type 5 (ACTG2, 2p13.1, AD) [72–76]. In a cohort of 53 families (Assia Batzir 2020), ACTG2 variants appeared in 33 (62%); the difference from the 44.1% in GeneReviews arises from the denominators, because this cohort brought together families studied in a single research programme, including the 15 positive families of Wangler et al. (2014) [8, 76]. ACTG2 carriers had more severe disease than patients without a variant, and dependence on parenteral nutrition, multiorgan transplantation and death were always associated with missense variants at arginine residues, with decreasing severity from Arg178 to Arg257 and Arg40 (OMIM protein numbering, transcript not stated) [76]. Most ACTG2 variants arise de novo (10 of 15 probands in Wangler 2014), but there is transmission over several generations: in the four families of Milunsky et al. (2017), the seven patients had chronic intestinal pseudo-obstruction and prenatal megacystis, none had microcolon, six needed lifelong bladder catheterisation and one had a multiorgan transplant at 38 years, after 35 years of parenteral nutrition [76]. Visceral myopathy 1, allelic to ACTG2, occupies the less severe end of the same spectrum [76]. In the recessive forms, heterozygosity in the parents has a particular implication, because heterozygous MYH11 and MYLK variants cause familial thoracic aortic aneurysm; no vascular disease was documented in the parents studied, and Kloth et al. (2019) suggested regular cardiovascular follow-up of a father carrying an MYH11 missense variant [72, 73]. ACTA2, through the de novo p.Arg179His variant, causes multisystemic smooth muscle dysfunction syndrome (OMIM 613834), with a hypotonic bladder and a possible prune belly-like sequence, as well as aortic and cerebrovascular disease [7, 101]. All the variants described affect codon 179: NM_001613.4(ACTA2):c.536G>A p.(Arg179His) (NC_000010.11:g.88941309C>T, GRCh38), the most frequent, and, less frequently, c.535C>T p.(Arg179Cys) (NC_000010.11:g.88941310G>A), p.Arg179Leu and p.Arg179Ser [16, 120]. In the review of 33 patients by Regalado et al. (2018), from newborn to 37 years and almost all with a de novo variant, all had congenital mydriasis and patent ductus arteriosus or aortopulmonary window in infancy, small vessel cerebrovascular disease appeared in 95%, intracranial artery stenosis in 77%, ischaemic strokes in 27%, intestinal malrotation in 30%, thoracic aortic disease was fully penetrant by 25 years and nine patients died between 6 months and 32 years [16]. The urological presentation may be the first: Brodsky et al. (2014) described a boy with congenital mydriasis and prune belly sequence (megacystis, bilateral hydroureter and hydronephrosis) with severe aortic root dilatation at 9 years, and Moreno et al. (2016), in a Brazilian series of seven children with visceral myopathy, a girl with prenatal megacystis, hydroureter and hydronephrosis, mydriasis, malrotation and hypoperistalsis, carrying p.(Arg179Cys) [16]. MYOCD causes congenital megacystis (OMIM 618719) with sex-limited inheritance: the monoallelic variant affects males, frequently lethally, and females only have disease with biallelic variants, which may be associated with cardiovascular disease [7, 10]. The OMIM entry codes only the heterozygous form (Houweling 2019): in three families, seven affected boys were heterozygous, five female carriers were healthy and one male carrier had no disease, which suggests incomplete penetrance; in a four-generation family, eight male fetuses died before birth, in another a boy was born with megacystis and right renal agenesis and went on to kidney transplantation, and male predominance is 95% [14]. In a multicentre series of fetuses with an initial suspicion of LUTO and a molecular diagnosis, none had urethral obstruction and 5 of 7 had a bladder smooth muscle defect (two MYOCD, the others ACTG2 and MYH11) [10]. CHRM3 (muscarinic M3 receptor) causes an AR prune belly-like syndrome described in only two families, with an areflexic distended bladder and mydriasis, and CHRNA3 an AR autonomic bladder dysfunction with impaired pupillary reflex, neurogenic VUR and secondary CAKUT (OMIM 191800) [7, 10]. CHRNA3 (15q25.1) encodes the α3 subunit of the nicotinic acetylcholine receptor of the autonomic ganglia; Mann et al. (2019) identified homozygous complete loss-of-function variants (abolished current in HEK293 cells) in five patients from three families (Arab, Pakistani and Macedonian, two consanguineous), with onset in utero or in infancy, hydronephrosis, VUR, thick bladder wall with post-void residual, small kidneys and recurrent UTI; most also had miosis or an impaired pupillary light reflex and, in some, orthostatic hypotension [15]. The Macedonian patient had recurrence of VUR after surgery, and OMIM records that surgical correction of VUR is not effective in this neurogenic form; the Chrna3−/− mouse reproduces megacystis with UTI, lithiasis and unreactive mydriasis [15]. The entry retains, as a historical note, the Gundrum family (1922) with bladder atony in nine members over three generations and transmission compatible with dominant inheritance, without molecular study [15]. In EBF3 neurodevelopmental disorder, about 30% of patients have lower urinary tract findings overlapping with those of urofacial syndrome [7].

2.5. Copy number variants

Recurrent CNVs explain about 3–6% of CAKUT in population series and signal neurocognitive or cardiac comorbidity; up to 16% of individuals with hypodysplasia have a diagnosis attributable to CNVs [1, 11]. In the Sanna-Cherchi series, the 17q12 (HNF1B) and 22q11.2 deletions were the most frequent, most genomic disorders appeared in a single individual, half of the CNVs were inherited from an apparently unaffected parent and most are associated with developmental delay or neuropsychiatric disease, which makes the renal malformation a sentinel manifestation of genomic imbalance [2, 89]. The 22q11.2 deletion is associated with renal developmental defects in up to one third of patients (hydronephrosis, agenesis, duplications), and the CRKL gene has been proposed as responsible for the renal phenotype [2, 11]. The 16p11.2 (TBX6/MAZ) and 1q21.1 CNVs are associated with VUR, agenesis and neurodevelopmental disorders [11]. In the Verbitsky series, large or intermediate novel CNVs were more frequent in VUR and obstructive uropathy, and there was an excess of duplications in LUTO and duplex collecting systems [1]. Among 419 North American children with CKD of any cause (CKiD cohort), 31 (7.4%) had a diagnostic genomic disorder due to CNVs, including the 17q12 deletion, with diagnostic reclassification; the Oxford Desk Reference rounds the value to 8% [2, 145]. The frequency of renal anomalies in the 22q11.2 deletion differs between sources: the Oxford Desk Reference gives structural renal tract anomalies in 36% (agenesis, MCDK, hydronephrosis, VUR) in the chapter on the syndrome and «up to one third» in the chapter on CAKUT, whereas Smith gives genitourinary anomalies in 15%; the definitions and series differ [2, 146, 147]. The 16p11.2 and 17q12 deletions appeared in 4 of 38 women (10.5%) with isolated Müllerian aplasia and, with distal 22q11.2, in 5 of 25 (20%) of the syndromic forms (Nik-Zainal 2011, according to the Oxford Desk Reference) [148]. In fetuses with renal agenesis, the most frequently reported recurrent CNVs are 16p11.2 and 22q11.21 [31].

2.6. Penetrance, expressivity and modifiers

Variable expressivity and incomplete penetrance are the rule: relatives with the same variant may have different CAKUT subphenotypes or none, and the molecular diagnosis does not distinguish dysplasia from hypoplasia, which coexist in the same family [12]. In PAX2, parents with mild kidney disease have had fetuses with severe renal failure [20]. In most children with CAKUT no monogenic cause is identified, and the explanations proposed include unidentified genes, oligogenic inheritance, mosaicism, somatic events, epigenetics and environmental factors [1, 12]. Among the environmental and teratogenic factors cited are maternal diabetes, alcohol, rubella and exposure to angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs) in the 2nd and 3rd trimesters [2, 83]. Non-coding or regulatory variants are a possible mechanism without human evidence to date [11]. In a pilot study of 195 patients with CAKUT of African ancestry (Netherlands, USA, Italy and Brazil), the 20 (10.3%) with a high-risk APOL1 genotype did not have more proteinuria, hypertension or CKD, or faster progression to kidney failure [149].

3. Clinical Spectrum and System-Specific Manifestations

3.1. Prenatal presentation

Fetal ultrasound recognises four presentations of CAKUT: parenchymal defects (agenesis, hypoplasia), cystic or hyperechogenic («bright») kidneys, oligohydramnios and urinary tract dilatation [2]. Parenchymal defects have a higher prevalence of genetic disease and worse renal and overall survival than isolated hydronephrosis, and the presence of extrarenal defects predicts worse renal survival, which is interpreted as a greater genetic burden, according to the Oxford Desk Reference, which cites Quirino 2012 and Sanna-Cherchi 2009 [2]. The study by Sanna-Cherchi et al. (312 Italian patients with anomalies of number or size) supports the first part, but did not test extrarenal defects: the risk of dialysis was higher in single kidney (HR 2.43) and in hypodysplasia with PUV (HR 5.1) than in unilateral or bilateral hypodysplasia, MCDK or horseshoe kidney, with an annual incidence of dialysis of 0.023 and 58 patients on dialysis by 30 years of age [150]. Most congenital hydronephroses (pyelectasis, PUJO, vesicoureteric junction obstruction) can be managed expectantly with appropriate postnatal imaging [2]. MCDK presents mainly as an incidental finding on prenatal ultrasound, as a large, irregularly bright kidney, with large cystic areas replacing almost all the parenchyma, and the strong association between dysplasia and obstruction makes it necessary always to assess the lower urinary tract [2]. The kidneys and bladder can be visualised from 12–14 weeks and easily from 16, but some renal findings only appear later [151]. The fetal bladder is visible from 9–10 weeks and should always be present from 12 weeks, with a longitudinal diameter below 7 mm; its visualisation confirms the existence of at least one functioning kidney [28]. Persistent non-visualisation in the 1st trimester suggests bilateral renal agenesis or bladder or cloacal exstrophy [28]. At the 18–22-week scan, the kidneys should be reniform with corticomedullary differentiation, with echogenicity equal to or lower than that of the liver; diffuse hyperechogenicity suggests dysplasia [28]. Unilateral agenesis presents with a bladder showing filling cycles and normal fluid; bilateral agenesis presents with absent bladder and kidneys and progressive anhydramnios after 20 weeks, with a universally poor prognosis without intervention [28].

According to the review by Hewitt and Montini (2026), CAKUT accounts for 20–30% of prenatal anomalies, with a pooled birth prevalence of 3.83 per 1000 [24]. Prenatal urinary tract dilatation occurs in 1–2% of pregnancies, with a male predominance of about 3:1, and up to 80% of cases are transient; mild pyelectasis, in 0.5–1% of pregnancies, is almost always incidental [2, 28]. The 2025 clinical report of the American Academy of Pediatrics (AAP) places perinatal urinary tract dilatation in about 1% of pregnancies, as the second most common prenatal congenital anomaly after cardiac anomalies, with causes that include transient dilatation, VUR and obstruction, and most cases never need surgery [152]. According to the 2026 paediatric renal imaging recommendations of the European Society of Paediatric Radiology (ESPR), only up to 30% of urinary tract dilatations need further assessment for obstruction or VUR [153].

3.2. Bilateral renal agenesis and Potter sequence

In its natural history, bilateral renal agenesis is lethal in the perinatal period due to pulmonary hypoplasia [30, 83]. Oligohydramnios appears from 14 weeks; a deepest vertical pocket (DVP) of amniotic fluid below 1 cm is associated with perinatal mortality above 95%, especially between 16 and 24 weeks [30]. The earlier the oligohydramnios, the worse the pulmonary effect; in LUTO, anhydramnios before 20 weeks is associated with survival of only 15–24%, according to the guidelines of the European Association of Urology (EAU) and the European Society for Paediatric Urology (ESPU) [28, 30]. The frequency of associated anomalies is high, and agenesis may be an isolated primary defect or part of a caudal axis anomaly [2, 83]. In oligohydramnios due to chronic fluid loss, and not due to agenesis, pulmonary hypoplasia occurs in only 50%, contractures respond to physiotherapy and survivors without central nervous system injury do well, which underlines the importance of aetiological diagnosis [83]. Survival after serial amnioinfusions, obtained only within a trial, is described in section 7.

Among syndromic causes, Fraser syndrome presents with bilateral renal agenesis in 50% and unilateral in 17% in the European EUROCAT epidemiological study of Barisic et al. (2013), which is the source of the values in Smith; the Oxford Desk Reference gives renal agenesis in 40% in a global series, without distinguishing laterality [10, 55, 154]. In that European series, cryptophthalmos appeared in 83%, syndactyly in 58%, anorectal anomalies in 42%, laryngeal anomalies in 21% and ambiguous genitalia in 13% [10]. OMIM distinguishes three AR forms by gene, Fraser syndrome 1 (FRAS1, 4q21.21), 2 (FREM2, 13q13.3) and 3 (GRIP1, 12q14.3); the FRAS1, FREM1 and FREM2 proteins form a complex in the epidermal basement membrane that is mutually stabilising, GRIP1 is required for its localisation, and the blebbed, myelencephalic blebs and eye-blebs mice reproduce the disease [56–58]. Renal agenesis dominates the fatal cases: in the four families of Lurie and Cherstvoy (1984), autopsy of 6 of the 9 affected individuals with perinatal death showed bilateral agenesis in 3 and unilateral in 3; Burn and Marwood (1982) described three siblings who presented as bilateral renal agenesis, only one with cryptophthalmos, unilateral; and there are concordant monozygotic twins [56]. In fetuses with GRIP1 variants (Vogel 2012) and FREM2 variants (Iranian family, Shafeghati 2008), bilateral renal agenesis was accompanied by a hypoplastic bladder, and one fetus had bilateral ureteral agenesis; conversely, a Chinese child with FREM2 variants had only unilateral cryptophthalmos and left renal agenesis (Yu 2018) [57, 58]. In the series of 59 patients from 40 families by van Haelst et al. (2007), 25 families were consanguineous, and anomalies of the skull, larynx, umbilicus, urinary tract and anus were more frequent than in previous reviews [56]. Anterior urethral atresia has been described, and Andiran et al. (1999) recommended confirming urethral patency in newborns with umbilical discharge or severe hydroureteronephrosis [56]. Laryngeal or tracheal obstruction retains fetal lung fluid and gives enlarged, hyperechogenic lungs, visible at 16–17 weeks (Stevens 1994), a finding that, with oligohydramnios and absent kidneys, differs from the usual pulmonary hypoplasia of Potter sequence [56, 58]. Female fetuses with bilateral agenesis and a GREB1L variant may lack a uterus [94]. In a Brazilian nested cohort from the Hospital das Clínicas of the Federal University of Minas Gerais (857 newborns with CAKUT between 1996 and 2021 and 1755 matched controls), overall early mortality was 7.2%, with an HR of 25.1 (95% CI 14.0–45.2) for perinatal and neonatal mortality compared with controls; independent factors were agenesis or hypodysplasia (HR 5.1; 95% CI 2.9–8.7), LUTO (HR 5.1; 95% CI 3.0–8.5), cystic disease (HR 3.8; 95% CI 2.3–6.4), oligohydramnios (HR 3.2; 95% CI 2.2–4.8), extrarenal malformations (HR 2.6; 95% CI 1.7–3.9), prematurity (HR 1.7) and low birth weight (HR 2.4) [155].

3.3. Unilateral agenesis, MCDK and congenital solitary kidney

Congenital solitary kidney occurs in about 1 in 2000 births and is associated with other CAKUT in about one third of cases; prenatally it is isolated in about two thirds [99]. The systematic review by Westland et al. (43 studies, 2684 patients, 63% male) estimated in unilateral agenesis associated CAKUT in 32% (VUR in 24%), extrarenal anomalies in 31%, hypertension in 16%, microalbuminuria in 21% and GFR below 60 mL/min/1.73 m² in 10%, and concluded that unilateral agenesis is not harmless [26]. The meta-analysis by Schreuder et al. on unilateral MCDK (67 cohorts, more than 3500 patients, 59% male, left side in 53.1%) found anomalies of the functioning kidney in one third (VUR in 19.7%, of which 40% grade III–V) and contralateral hypertrophy in 77% after at least 10 years of follow-up [27]. MCDK involutes in most cases before or after birth, may coexist with agenesis and, when unilateral and isolated, has a normal karyotype and a good prognosis (Lazebnik series, 1999, with 102 prenatal cases: contralateral anomaly in 33%, non-renal anomalies in 26% of unilateral and 67% of bilateral cases) [2]. In the Aubertin series (2002), among 73 apparently isolated MCDKs, one fetus had trisomy 21 and genitourinary defects later appeared in 33% and non-renal defects in 16% [2]. In a German series of 103 fetuses with MCDK (Charité, Berlin, 2005–2022), 8 (7.8%) were bilateral and, of the 95 unilateral cases, 43 (45.3%) had additional anomalies, which were associated with fewer live births, more prematurity and lower Apgar scores and gestational age; the authors recommend offering genetic counselling and invasive testing [156].

Source: SINePe consensus, Table 1 [99].

Extrarenal malformations appear in 6–31% of hospital series (about 15% of 1340 patients with MCDK and 31% of 709 with unilateral agenesis in the systematic reviews), and the solitary kidney is part of a multiorgan syndrome in up to 10%; the most frequent are cardiac, gastrointestinal, musculoskeletal and genital [99]. Female genital tract malformations appear in 11% of 502 patients with unilateral agenesis, including obstructed hemivagina and ipsilateral renal anomaly syndrome (OHVIRA or Herlyn-Werner-Wunderlich), and in males there is hypoplasia of the seminal vesicles and absence of the vas deferens [99, 103]. Congenital bilateral absence of the vas deferens with unilateral renal agenesis is not associated with CFTR variants and results from an early anomaly (before 9 weeks) of the entire mesonephric duct [104].

Hypertension and proteinuria are the main late manifestations. In the cohorts brought together by Groen in 't Woud et al. (301 children with a single kidney assessed by ambulatory blood pressure monitoring, ABPM), 65% had normal office blood pressure (BP) and ABPM, 18% masked hypertension, 4% white coat hypertension and 14% confirmed hypertension [103]. Table 3.2 details the studies.

Source: Groen in 't Woud et al. 2021, Table 2 [103].

Rates of kidney injury in congenital solitary functioning kidney range between 6% and 60% at 15 years, with few studies in adults; an isolated fall in eGFR appears in 0.3–8% of cohorts, especially at puberty [103]. In a Turkish retrospective series of 490 adults with a single kidney (337 due to congenital unilateral agenesis and 153 after nephrectomy), annual eGFR loss was 3 against 2.2 mL/min/1.73 m², creatinine doubled in 10.4%, 2.9% started KRT and 1.8% died, with lower renal survival in congenital agenesis (P = 0.043) and baseline proteinuria and creatinine as predictors [157]. In the KIMONO study, single kidney with ipsilateral CAKUT had a significantly shorter median time to signs of kidney injury [12].

3.4. Bilateral renal hypodysplasia

Bilateral dysplasia has a worse renal prognosis than unilateral dysplasia, and unilateral dysplasia, even when severe, with a normal contralateral kidney generally has a good prognosis [12]. Most children with bilateral dysplasia do not need kidney replacement therapy (KRT) in the first year of life; in the North American NAPRTCS CKD registry, about 50% progressed to kidney failure within 5 years, a figure that reflects the population of a CKD registry and not all hypodysplasia [12]. Modifying factors include contralateral hypertrophy (favourable), single kidney dysplasia, cysts, VUR and post-obstructive status [12]. In a retrospective cohort from two German tertiary centres with 229 adults with CAKUT and kidney failure, the median age at kidney failure was 22.0 years (interquartile range, IQR, 14–31; n = 81) in syndromic forms and 28.0 years (IQR 21–38; n = 145) in isolated forms, 22.0 years (IQR 15.5–30.0; n = 143) in bilateral forms and 37.0 years (IQR 28–47; n = 71) in unilateral forms, and 18.0 years (IQR 5–23; n = 9) in MCDK; because it included only patients already in kidney failure, the cohort does not estimate the risk of progression of all CAKUT [110]. In the review by Hewitt and Montini, the need for KRT peaks in adolescence, with a mean start of KRT at around 31 years, and adults with CAKUT have an increased risk of cardiovascular and metabolic disease, neurocognitive impairment and a small increase in the risk of malignancy [24].

In the single-centre Wuhan (China) cohort, with 322 children with primary hypodysplasia diagnosed by ultrasound over 10 years, 87.3% had unilateral and 12.7% bilateral disease; the bilateral form had worse function and CKD stage, and the unilateral form was more associated with other CAKUT [114]. With a median follow-up of 4.5 years, 22.4% (72/322) reached early CKD (eGFR below 75 mL/min/1.73 m²), with bilateral involvement (hazard ratio, HR, 4.40; 95% CI 2.31–8.39), urinary albumin/creatinine ratio (ACR) of 3–30 mg/mmol (HR 2.24; 95% CI 1.02–4.92) and above 30 mg/mmol (HR 2.55; 95% CI 1.32–4.93) and extra-urogenital malformations (HR 2.28; 95% CI 1.26–4.10) as independent risk factors [114]. This is a hospital cohort and not a population estimate.

In the Brazilian Belo Horizonte cohort, 822 children with prenatally diagnosed nephrouropathies followed for a median of 43 months had UTI in 29.8%, with a higher risk in females (HR 1.30; 95% CI 1.02–1.70), hypertension in 2.7%, CKD in 6%, with a higher risk when hydronephrosis was associated with another anomaly (HR 5.20; 95% CI 2.90–9.30), and 12 deaths (1.5%) [158].

3.5. Manifestations by genetic entity

3.5.1. PAX2-related disorder

In the review and series by Bower et al. (173 individuals from 86 families from the USA, France and New Zealand), 92% (159/173) had a structural or functional renal anomaly, hypodysplasia being the most common (65%, 114/173), usually bilateral but asymmetric [20, 159]. MCDK occurs in 6–10%, VUR in 14% (25/173), and there are cases of oligomeganephronia, PUJO, medullary sponge kidney, horseshoe kidney, pyeloureteral duplication and malrotation [20]. On ultrasound, hypoplasia presents as small-for-age, hyperechogenic kidneys, and on histology hypodysplasia corresponds to a reduced number of nephrons and disorganised tissue; uric acid nephrolithiasis and an intrarenal teratoma have been described [20]. Most individuals have clinically significant renal insufficiency, end-stage CKD with transplantation is not uncommon and, in rare carriers, the renal anomalies are clinically silent [20]. The mean age at diagnosis of kidney failure was 19.5 years, in a range from birth to 79 years [20]. Some families have isolated adult FSGS [20, 123]. Prenatally, 18 individuals had oligohydramnios or anhydramnios, cystic dysplasia, MCDK or hypoplasia, and seven fetuses had severe renal failure with Potter sequence [20].

Optic nerve anomalies occur in 72% (125/173), from the severe form (apparently enlarged disc, vessels emerging from the periphery, deep excavation with fibroglial tissue) to the mild form (peripheral vessels without disc malformation), and the terminology of «optic nerve coloboma» or «morning glory anomaly» is debated [20]. Retinal findings occur in 13% (retinal coloboma in six patients), and iris coloboma has not been observed [20]. Visual acuity is reduced in one or both eyes in 75% of affected individuals, from light perception to normal, with nystagmus, myopia, strabismus and risk of retinal detachment [20]. Bilateral high-frequency sensorineural hearing loss occurs in 7% in the Bower database, and there are rare reports of central nervous system malformations, developmental delay, hyperuricaemia, gout, joint laxity and soft skin without established causality [20, 159]. Intrafamilial variability is wide: renal only, ocular only or both, from asymptomatic to fetal renal failure [20]. The ERA consensus warns that heavy proteinuria due to FSGS secondary to nephron reduction may mimic steroid-resistant nephrotic syndrome [1].

3.5.2. 17q12 deletion and HNF1B disease

With methods that avoid ascertainment bias, GeneReviews estimates structural or functional renal anomalies in 85–90% of 17q12 deletion carriers, MODY5 diabetes in about 40% and some degree of developmental delay or learning difficulty in about 50% [21]. In a review of 282 individuals with the 17q12 deletion, cystic dysplasia and other structural renal anomalies appeared in 87% (167/193) of those not ascertained through kidney disease, and in 35% of cases the findings only appeared in childhood or later [21]. Hypomagnesaemia (43%), MODY5-type diabetes, genital malformations (about one third of women, including Müllerian aplasia; a quarter of men), hepatic involvement (43%), hyperparathyroidism (44%), exocrine pancreatic insufficiency (55%) and neurodevelopmental disorders complete the phenotype [21]. Hypomagnesaemia may reach 59% of children when paediatric norms are used (Kołbuc 2024), and neurodevelopmental disorders occur in about 25% of deletion carriers against 6.8% of carriers of an intragenic HNF1B variant (Nittel 2023) [21]. In a population-based phenotype-first study (Vaez 2024), the 17q12 deletion had, among the recurrent deletions studied, the strongest association with autism spectrum disorder (HR 7.79; 95% CI 2.71–22.43) and with attention deficit hyperactivity disorder (HR 4.24; 95% CI 1.29–13.92) [21]. Other findings include congenital heart disease (19%, 10/52), short stature (23%, 11/47), seizures (12%, 10/84), non-specific structural brain anomalies (27%, 10/37), neonatal cholestasis with bile duct paucity and hyperparathyroidism independent of renal failure; in MODY5 diabetes, an initial response to oral antidiabetic drugs is common, but about 80% eventually need insulin [21]. In the MODY GeneReviews, renal involvement is more frequent than diabetes, which usually appears after the childhood kidney disease, with a mean age at onset of 24 years, and sensitivity to sulfonylureas is lower than in HNF1A MODY [124]. In a Greek multicentre cohort of 20 children with HNF1B disease (CNV in 60%), cysts appeared in 95%, hypomagnesaemia in 25% and eGFR remained stable over 5 years (84.5 to 84.0 mL/min/1.73 m²), with wide individual variability [160]. The 17q12 deletion is a frequent cause of normal-sized hyperechogenic fetal kidneys [1].

3.5.3. Branchio-oto-renal spectrum

CAKUT occurs in 67% of patients, with agenesis in 29%, hypoplasia in 19%, dysplasia in 14%, PUJO in 10%, calyceal cyst or diverticulum in 10% and caliectasis, pyelectasis, hydronephrosis or VUR in 5% each, in any unilateral or bilateral combination [22]. Bilateral agenesis leads to miscarriage or neonatal death, and less severe forms progress to progressive dysfunction; FSGS, proteinuria and haematuria may contribute to kidney failure independently of CAKUT [22]. Hearing loss is present in more than 90% and preauricular pits in 82%, lop ear in 36%, preauricular tags in 13%, 2nd branchial arch anomalies in about 50% and atresia or stenosis of the external auditory canal in 29%, among more than 400 patients described [22]. An unwound cochlea (turn angle ratio, TAR, below 0.476 on CT) appeared in all EYA1 carriers studied by Juliano et al. (2022), and SIX1 carriers always have hearing loss [22]. In a family with 18 SIX1 carriers, all had hearing loss and only three had branchial cysts, and in a Tunisian family five carriers had no renal anomalies [22]. Smith estimates CKD at about 6% [86]. OMIM, citing Izzedine et al. (2004), also estimates at 6% the proportion of patients with a severe renal defect, and Fraser et al. (1980) arrived at the same value for heterozygotes with severe renal dysplasia [49]. Intrafamilial variability of the renal phenotype has direct reproductive consequences: Carmi et al. (1983) described a man with BOR and crossed renal ectopia with three children with bilateral renal agenesis and Potter sequence, and Chitayat et al. (1992) a woman with a normal renal ultrasound, renal hypoplasia only on urography and hearing loss since childhood, with two pregnancies with oligohydramnios due to renal hypoplasia and agenesis and neonatal death from pulmonary hypoplasia [49]. The less well-known otological and cervical features include stenosis or aplasia of the lacrimal ducts, gustatory lacrimation, cochlear hypoplasia with two turns, enlarged vestibular aqueduct and congenital cholesteatoma [49].

3.5.4. Townes-Brocks syndrome, HDR syndrome and PBX1

In 165 patients from 101 families with a SALL1 variant, dysplastic ears appeared in 87%, thumb anomalies in 76%, imperforate anus or anal stenosis in 70%, hearing loss in 62%, foot anomalies in 43%, renal anomalies and/or reduced renal function in 40% and genitourinary malformations in 22% [10]. The kidney may show malrotation, ectopia, horseshoe, agenesis, hypoplasia, cystic kidneys or VUR, and renal dysfunction is frequent with or without a structural anomaly and possibly underestimated because of its late onset [23, 87]. About 80% of patients have the three major signs (imperforate anus or anal stenosis, dysplastic ears, typical thumbs without radial hypoplasia) or two major and one minor, congenital heart disease occurs in 15% and developmental delay or learning difficulties in about 15% [23]. Kidney failure occurred in 39.6% of the French series of Leduc et al. and in 29.3% of patients in the literature [133]. Two presentations may reach nephrology without the triad: a form similar to the branchio-oto-renal spectrum, with dysplastic ears, hypoplastic kidneys and reduced renal function, without anal or hand malformations, in a father and two daughters (Engels 2000) and in another German family with preauricular tags, hypospadias and reduced renal function (Albrecht 2004); and overlap with hemifacial microsomia (Goldenhar syndrome), with epibulbar dermoids and mandibular hypoplasia, which justifies studying SALL1 when these signs coexist with anal anomalies (Keegan 2001; Kosaki 2007) [52]. Kidney failure may be the mode of diagnosis in adults, as in a 23-year-old man with severe hypertension and small bilateral kidneys, operated on at birth for anal stenosis (Newman 1997) [52]. Heart disease may be lethal (common arterial trunk and pulmonary atresia in a three-generation family, Surka 2001), which grounded the recommendation for cardiac assessment in all patients; some families show worsening of the phenotype from generation to generation, especially with maternal transmission (Sudo 2010) [52]. Variants that escape nonsense-mediated decay were associated with a more severe phenotype than those subject to it (Furniss 2007), consistent with the dominant negative mechanism [52]. In HDR syndrome, the triad is frequently incomplete, hypoparathyroidism (neonatal or late hypocalcaemia) is the metabolically dangerous component, and renal involvement is structural and variable (dysplasia, cysts, nephrotic disease with progression) [10]. In the review by Barakat et al. (2018), with 173 published and 7 new cases, 123 had a GATA3 variant; among these, 77 had the complete triad, 34 hypoparathyroidism and deafness, 6 deafness and kidney disease, 3 hypoparathyroidism and kidney disease, 2 kidney disease only and 1 deafness only [54]. Overall, sensorineural deafness, early, moderate to severe and usually bilateral, affected 96.7%, hypoparathyroidism 93.3% and kidney disease 72.2%, and only 40% of the latter had CAKUT, the rest having nephrotic syndrome, haematuria, proteinuria, tubular acidosis, nephrocalcinosis or CKD [54]. Female genital malformations have been described: a mother with a non-functioning right kidney and septate uterus and her daughter with right renal agenesis and uterus didelphys with septate vagina (Hernandez 2007), and a 29-year-old Portuguese woman with severe hypoparathyroidism, mild deafness and agenesis of the uterus and vagina, without renal anomaly, carrying a missense variant (Moldovan 2011) [54]. Suspected germline mosaicism in a pair of Chinese siblings with a variant absent in the parents (Sun 2009) and proliferative glomerulopathy in a Japanese man with proteinuria since 18 years of age, deafness diagnosed at 40, hypoparathyroidism at 47 and renal biopsy at 52 (Kamezaki 2017) extend the spectrum beyond dysplasia [54]. In PBX1-related CAKUT, developmental delay and ear malformations are the most common extrarenal manifestations [10].

3.5.5. Urofacial syndrome and megacystis-microcolon

In urofacial syndrome (more than 150 patients described), urinary dysfunction occurs in more than 98% and abnormal facial expression in more than 99%: on smiling or laughing, the corners of the mouth and eyes contract simultaneously, in a grimace, due to symmetric partial facial paresis [7]. The bladder has detrusor overactivity and detrusor-sphincter dyssynergia («non-neurogenic neurogenic bladder»), may be thickened and trabeculated and empties incompletely, with a patent urethra; in a series of 50 patients (Ochoa 1992, 2004) there was hydroureteronephrosis in 58% and VUR in 64%, bilateral in 36% [7]. Constipation affects about 66% and encopresis about 33% [7]. Complications include recurrent urosepsis, incontinence, bladder rupture and sepsis in infants and parenchymal damage with severe renal failure, probably significant when severe or recurrent UTIs are not treated promptly and completely; nocturnal lagophthalmos may cause keratitis, ulceration and loss of the eye, and the central nervous system and spinal cord are normal [7]. Prenatally (2nd and 3rd trimesters), the disease presents as megacystis and hydronephrosis [7]. The name «Ochoa syndrome» was proposed by Elejalde (1979), who described seven children from three families with hydronephrosis, hydroureter and the typical facial expression, in reference to the physician who had referred them; Ochoa and Gorlin later brought together 36 children seen between 1965 and 1986, all with mild neurogenic bladder and most with severe urinary tract damage, with equal sex distribution and about two thirds with moderate to severe constipation [70]. Expressivity varies within the same family: in Turkish families, one cousin had only the grimace, with normal ultrasound, DMSA, uroflowmetry and videourodynamics, and another had febrile UTIs from birth, severe incontinence, a small-capacity bladder and bilateral grade 3 VUR without facial change (Aydogdu 2010); in the LRIG2 family of Stuart et al., the 5-year-old brother of a patient who progressed to dialysis despite catheterisation, antimuscarinics and bladder augmentation had the grimace and a normal urinary tract [70, 71]. Diagnosis may be late: in the Irish family of García-Miñaur et al. (2001), one sister reached a GFR of 40 mL/min on self-catheterisation and prophylaxis, and the other, with the same grimace, was diagnosed at 25 years with normal renal function [70]. In the siblings of Daly et al., the proband presented at 2 years with acute kidney injury and urosepsis, needed urinary diversion and at 11 years had a GFR at the lower limit of normal, mild proteinuria and hypertension [70].

In megacystis-microcolon-intestinal hypoperistalsis syndrome, the newborn has abdominal distension due to the massive bladder, bilious vomiting, absence of meconium and urinary retention requiring catheterisation, and later febrile UTI, VUR, hydronephrosis, renal scarring and an acontractile bladder, with a risk of renal failure [8]. Survival rose from 12.6% (1976–2004) to 55.6% (2004–2011) in specialist centres, was 63% at 5 years and 57% at 10 years in a Japanese national survey, and 100%, 100% and 86% at 5, 10 and 20 years in a single centre with and without intestinal transplantation [8]. The original description by Berdon et al. (1976) included five female infants, two of them sisters, and subsequent series maintained a female predominance of about 4:1; the myenteric plexus ganglia are as a rule normal [72]. The recessive forms are frequently lethal early: in the North African family of Halim et al. (2017), with MYLK, one sibling died in utero at 30 weeks, one pregnancy was terminated at 15 weeks and the third died of respiratory failure after delivery at 31 weeks; the Dutch patient with LMOD1 died at 5 days with sepsis; and the patients with MYH11 died of multiorgan failure, one of them at 18 months, with mydriasis, sensorineural deafness, pulmonary hypertension and mild aortic dilatation (Yetman 2018) [72–74]. Congenital mydriasis also occurs in the MYL9 form, together with recurrent nephrolithiasis in one patient (Kandler 2020) [75]. Amniotic fluid volume does not exclude the disease: there was severe oligohydramnios in the MYH11, MYLK and MYL9 forms, with a prune belly phenotype in the MYH11 and MYL9 forms, and in the same MYL9 sibship one fetus had oligohydramnios at 19 weeks and the other polyhydramnios after 25 weeks (Moreno 2016) [72, 73, 75]. In the single-centre series of Prathapan et al. (2021), 13 of 25 patients underwent transplantation (8 multivisceral), all 11 non-transplanted patients depended on parenteral nutrition and almost all transplanted patients had full enteral feeding, with mean bilirubin, coagulation, albumin and creatinine within reference values and a median age of 9.2 years at analysis [72]. An association with trisomy 18 has been described in a fetus without ganglion cells in the colon and bladder [72].

3.5.6. Müllerian aplasia and syndromes with CAKUT

In Mayer-Rokitansky-Küster-Hauser syndrome (prevalence 1/4000–1/5000 women; 16.2% of primary amenorrhoea), there are renal malformations in 30% (unilateral agenesis or ectopia) and skeletal anomalies in 11–12%, and the MURCS association is considered a sporadic subset [148]. Although most cases are sporadic, about 4% are familial, with affected sisters, and rare point variants in WNT4 and HNF1B and CNVs at 17q12, 16p11 and 1q21 have been identified [161]. In RCAD, about 20% of women have genital tract defects (bicornuate uterus, vaginal aplasia, rudimentary uterus) [148]. In multiple malformation associations and syndromes, the renal anomaly occurs in 53% of the VACTERL association in the series of Temtamy and Miller (34 cases) reproduced by Smith, against 80% in the VATER box of the Oxford Desk Reference (from Quan and Smith 1973), with nephrolithiasis and UTI as frequent sequelae [162, 163]. In anal atresia, genitourinary anomalies make up 49% of the associated anomalies [164]. Branchio-oculo-facial syndrome (TFAP2A) has renal anomalies in 37%, with cases of agenesis and severe fetal oligohydramnios [165]. Okihiro syndrome (SALL4) is associated with crossed renal ectopia and duplex collecting system, with occasional renal agenesis and VUR and common hypertension and recurrent UTI [166]. Lacrimo-auriculo-dento-digital syndrome (FGFR2, FGFR3, FGF10) may be associated with renal agenesis, rarely bilateral and lethal [167]. Caudal dysplasia is associated with a high incidence of unilateral renal agenesis with VUR, with an association with maternal diabetes, and the sirenomelia sequence with renal agenesis and absent bladder [168, 169]. In Bardet-Biedl syndrome, there is renal malformation or declining function in more than 50%, about 8% progress to end-stage CKD, mainly before 5 years of age, and hypertension occurs in 60% [170]. In Alagille syndrome (JAG1), structural renal anomalies occur in 39% and functional anomalies in 74% [171].

3.6. Vesicoureteric reflux and urinary tract infections in the context of CAKUT

VUR occurs in about 1% of live births and is generally asymptomatic and self-limiting; the prevalence in children without symptoms is estimated at 0.4–1.8% [2, 28]. Among screened infants with prenatal hydronephrosis, the prevalence was 16.2% (7–35%), and among children with UTI it rises to 30–50%, depending on age [28]; the American Urological Association (AUA) guideline reports VUR in about 16% of newborns with prenatal hydronephrosis, more frequent in girls, of grade III or higher in two thirds, with renal anomalies in about half of grades IV–V [172]. OMIM, in the VUR1 entry, cites reflux nephropathy as a cause of up to 15% of end-stage CKD in children and young adults (Kincaid-Smith 1984) and a prevalence in siblings and offspring that may reach 50% [60]. Boys with UTI have VUR more often than girls (29% against 14%), with higher grades and earlier diagnosis, but also with a greater likelihood of resolution [28]. Spontaneous resolution is almost 80% in grades I–II and 30–50% in grades III–V within four to five years, is more likely with age below one year at presentation and low in high-grade bilateral reflux; in the Scandinavian studies, complete resolution of high-grade congenital VUR exceeds 25% [28]. Lower urinary tract dysfunction and bladder and bowel dysfunction (BBD) coexist with VUR in 40–60% of children with voiding dysfunction, and functional constipation affects almost one in three children with UTI [28].

Renal scars are present in 10–40% of children with symptomatic VUR and result from congenital dysplasia, from post-infectious injury or from both; they occur in 10% of patients with prenatal hydronephrosis and up to 30% of those with voiding dysfunction [28]. The risk of scarring increases with the number of febrile UTIs: 2.8% after the first, 25.7% after two and 28.6% after three or more [28]. Reflux nephropathy is regarded as a frequent cause of hypertension in childhood, and 10–20% of children with reflux nephropathy develop hypertension or kidney failure [28]. The Oxford Desk Reference includes chronic pyelonephritis and reflux nephropathy among the causes of kidney failure in adults and associates a poor prognosis with high-grade reflux with scars already present at birth [2]. In the PREDICT trial, 28.4% of infants with grade III–V VUR had focal congenital defects on baseline DMSA before any UTI, and 52.7% had some DMSA abnormality (diffuse hypouptake or unbalanced function) [173].

UTI is the most common bacterial infection in children. Escherichia coli is the main agent, but in fewer than half of urine cultures in a European study, with an increase in Klebsiella, Enterobacter, Enterococcus, Pseudomonas and Proteus and in beta-lactam-resistant E. coli [28]. In the first three months of life, with fever, UTI occurs in 7.5% of girls, 2.4% of circumcised boys and 20.1% of uncircumcised boys [28]. In 30% of children with urinary tract anomalies, UTI may be the first sign of the malformation [174]. Risk factors for recurrent UTI include obesity, lower urinary tract dysfunction, BBD and underlying urological conditions, especially high-grade VUR [28]. In the natural history observed in the untreated arm of the PREDICT trial, 35.6% of infants with grade III–V VUR without prior UTI had a first symptomatic UTI within 24 months and 64.4% had none [173]. The 2026 review by Standish et al. places PUV in the group at highest risk of kidney injury and febrile UTI, and the risk in vesicoureteric obstruction and duplications depends on ureteral dilatation and the presence of a ureterocele [175].

Genetic predisposition to UTI outside VUR is less well characterised. The EAU/ESPU guidelines mention differences in innate immunity and epithelial function genes in children with VUR and UTI, and abnormal development of the gut microbiota in infancy as a risk factor [28]. A systematic review with meta-analysis of 22 studies (15 paediatric) found pooled associations of paediatric UTI with variants in CXCR1, IL8, TGF, TLR4 and VDR, with weak overall epidemiological credibility [176]. A genome-wide association study (GWAS) of upper UTI in Norway and the UK Biobank identified a locus near TSN in females only [177]; in a Mendelian randomisation analysis, genetically predicted higher urinary uromodulin was associated with a lower risk of upper UTI (OR 0.80 per standard deviation; 95% CI 0.67–0.95) [178]; in the RIVUR and CUTIE cohorts, a GWAS of urinary bacterial abundance pointed to associations at or near CXCL12, ABCC1 and ROBO1, and children with VUR had lower urinary microbiota diversity [179]. A preprint from August 2026, not yet peer reviewed, describes 36 loci for recurrent UTI in more than 1.8 million individuals [180]. These data indicate a polygenic predisposition without an indicated clinical test. Some syndromes with CAKUT include recurrent UTI among their manifestations: distal 22q11.2 deletion, the VACTERL association (with nephrolithiasis), urofacial syndrome, megacystis-microcolon, the CHRM3-related prune belly-like sequence and MYOCD-related megacystis [7, 8, 10, 162]. With biallelic LRIG2 missense variants, the disease may be limited to the urinary tract, without the facial sign, which makes it a rare genetic differential diagnosis of «isolated» VUR and UTI [7]. The sources consulted describe no monogenic syndrome of isolated predisposition to UTI without a structural or functional urinary tract anomaly.

3.7. Early urethral obstruction and prune belly sequence

Early urethral obstruction results, in most cases, from valves formed during development of the prostatic urethra, and less frequently from urethral atresia, bladder neck obstruction or distal urethral obstruction; as urine is formed from 7–8 weeks, retention is progressive, with a male to female ratio of 20:1 [101]. Back pressure limits renal morphogenesis and produces tubular dilatation with cystic and dysplastic changes, the distended bladder causes secondary cryptorchidism, may prevent rotation of the colon and compress the iliac vessels, and oligohydramnios adds the deformation sequence [101]. Severe and early obstruction is frequently lethal in mid or late gestation, unless bladder rupture (through a patent urachus, the bladder wall or a ureter) decompresses the tract and leaves a «prune» abdomen; most of those who reach term have severe kidney injury, and survivors benefit from urological drainage, UTI control and an abdominal binder, with improvement of the abdominal musculature with age [101]. In females, bladder neck obstruction is rare and may result from anomalies of the cloacal plate, with genital tract and bowel anomalies [2]. The distended bladder is visible on ultrasound from 10 weeks after conception [101].

The name Eagle-Barrett syndrome was proposed in 1982 as an alternative to prune belly; Eagle and Barrett (1950) had collected nine cases, all but one male, and advocated early investigation and correction of the obstruction, even without urinary symptoms [77]. The prevailing pathogenic hypothesis regards the deficiency of the abdominal musculature as secondary to fetal distension, mainly due to PUV, which explains the male predominance, and the absence of CHRM3 expression in mature abdominal muscle was interpreted by Weber et al. (2011) in the same way [77]. In British Columbia, the incidence between 1964 and 1978 was 1 in 29,231 live births (Baird and MacDonald 1981) [77]. Familial forms suggest sex-influenced AR inheritance: in the review by Ramasamy et al. (2005), 28% of familial cases with the complete triad were female, against 5% of non-familial cases [77]. The only coded monogenic cause is CHRM3 (1q43, muscarinic M3 receptor, AR): in a consanguineous Turkish family, five siblings had PUV, two of them with a prune belly phenotype, dysfunctional or areflexic bladder, VUR and variably reduced GFR, and reassessment showed deficient pupillary constriction to light and dry mouth, with a homozygous frameshift variant (Weber 2011); in a consanguineous Malay family, two sisters with a hypocontractile bladder, hydronephrosis, recurrent UTIs, constipation and 5 mm pupils unreactive to light were homozygous for a missense variant (Beaman 2019) [77]. The pupillary abnormality, shared with the ACTA2 and MYL9 forms, points to a smooth muscle or autonomic cause and not to mechanical obstruction [16, 75, 77].

Congenital lower urinary tract obstruction has an AD monogenic form coded in OMIM (618612; BNC2, 9p22.3–p22.2) [78]. Kolvenbach et al. (2019) described a four-generation family with a nonsense variant and variable expressivity: the proband had a vesicoamniotic shunt at 13 weeks and, after birth, was diagnosed with distal urethral stenosis and bilateral grade 5 VUR; the mother had urethral stenosis diagnosed at 16 years, the maternal grandmother meatal stenosis at 47 years and a cousin of the mother meatal stenosis at 42 years [78]. On resequencing of 697 patients with LUTO, a missense variant appeared in a father and son with PUV (the son with grade 5 VUR and bilateral hypodysplasia; the father with daytime and night-time frequency, diagnosed at 38 years, with normal ultrasound and renal function) and in the paternal grandmother, an asymptomatic carrier; in three sporadic patients with PUV, the variants were benign or of uncertain significance [78]. PUV, although almost always sporadic, may thus have an AD basis with incomplete penetrance and transmission through women without the lesion, which is exclusive to males [78].

4. Clinical Recognition and Warning Signs

4.1. Prenatal period

There is no biochemical or genetic newborn screening for CAKUT; population screening is by ultrasound, and the EAU/ESPU guidelines recommend (strong recommendation) a screening ultrasound in the 1st trimester (11–14 weeks) and another in the 2nd trimester (17–22 weeks) to assess urinary tract malformations [28]. The findings that should raise suspicion of severe CAKUT are a bladder persistently not visible from 12 weeks, absence of the kidneys in the renal fossa and in an ectopic position, oligohydramnios or anhydramnios from the 2nd trimester, hyperechogenic kidneys or kidneys without corticomedullary differentiation, renal cysts and megacystis (longitudinal diameter of 7 mm or more between 11 and 14 weeks, or 15 mm or more in the 2nd trimester) [12, 28]. A visible ureter is always pathological [28]. A single umbilical artery, although non-specific, is associated with complex anomalies [28]. In the international Delphi consensus on LUTO, a longitudinal bladder diameter of 15 mm or more in the 1st trimester, with a bladder that does not empty, was considered strongly suggestive and unlikely to resolve (90.3% agreement) [181]. Megacystis with normal or increased amniotic fluid in the 2nd trimester points to megacystis-microcolon and not to LUTO, although oligohydramnios does not exclude the recessive forms [73, 75], and megacystis with hydronephrosis in the 2nd and 3rd trimesters is the prenatal presentation of urofacial syndrome [7, 8]. Hyperechogenic fetal kidneys of unknown cause justify, according to several authors cited by GeneReviews, testing for the 17q12 deletion [21].

Some extrarenal findings point to a syndrome. Congenital laryngeal obstruction (CHAOS, congenital high airway obstruction syndrome) with oligohydramnios should raise suspicion of Fraser syndrome [55]. Defects of skull ossification with early fetal anuria suggest renal tubular dysgenesis or maternal exposure to ACE inhibitors [30]. Occipital encephalocele with enlarged multicystic kidneys and postaxial polydactyly suggests Meckel-Gruber syndrome [30]. The history should include a three-generation pedigree (kidney problems, other anomalies, neuropsychiatric disease, stillbirths and neonatal deaths), consanguinity, teratogens (alcohol, diabetes, rubella, ACE inhibitors), bleeding in the first weeks and early rupture of membranes [2, 30].

4.2. Newborn, infant and child

In the newborn, the Potter phenotype (facies, flattened ears, abnormal limb positioning, respiratory distress) requires bilateral agenesis or dysplasia to be excluded [83]. Several findings justify renal ultrasound. Anomalies of the pinna, preauricular pits or tags and branchial sinuses raise the possibility of the branchio-oto-renal spectrum, although confirmed Treacher-Collins syndrome has no renal anomalies and these are rare in the oculo-auriculo-vertebral spectrum [129, 182]. A child with hearing loss needs a renal ultrasound if there are external ear anomalies, multiple congenital anomalies or low serum calcium, and a child ascertained through hearing loss with suspected HDR syndrome needs measurement of calcium and a renal ultrasound [10, 129]. It is also justified by optic nerve hypoplasia, optic disc dysplasia or morning glory anomaly (PAX2 disease), anorectal malformation with a thumb or ear anomaly (Townes-Brocks), Hirschsprung disease (renal dysplasia or agenesis in 4% of isolated cases) and the VACTERL association, with a renal anomaly in 53% [23, 162, 183, 184]. When assessing an optic nerve coloboma, one should ask about renal failure in the family and consider plasma creatinine [185]. In scalp-ear-nipple syndrome (Finlay-Marks), the frequency of urinary defects justifies investigation to prevent renal failure [186]. The branchio-oto-renal spectrum affects about 2% of children with profound hearing loss, and the Oxford Desk Reference adds, in the deaf child, a urine dipstick for glucose and blood [129]. Renal ultrasound is also justified in anal atresia, in which genitourinary anomalies are the most frequent of the associated anomalies, in the 22q11.2 deletion at initial assessment and in any component of the VACTERL association, which requires the others to be sought [146, 162, 164]. In a child with severe voiding dysfunction, VUR, hydronephrosis or recurrent UTI, a facial grimace on smiling suggests urofacial syndrome, and constipation frequently accompanies it [7, 10].

In an adolescent girl with primary amenorrhoea, Mayer-Rokitansky-Küster-Hauser syndrome requires a renal ultrasound, given renal malformations in 30% [148]. In a girl with congenital solitary kidney, ultrasound of the internal genital organs in the first months of life (under maternal oestrogen stimulation) or between thelarche and menarche allows Müllerian malformations to be detected; severe cyclical abdominal pain after menarche, or delayed menarche, suggests OHVIRA or Mayer-Rokitansky-Küster-Hauser syndrome [99, 103].

4.3. Adolescent and adult

In adults, CAKUT presents as CKD or hypertension of unexplained cause, with small, hyperechogenic kidneys without proteinuria or active sediment, a picture whose differential diagnosis includes ciliopathies and tubulointerstitial diseases [1]. The association of juvenile or young adult onset diabetes with renal cysts, renal hypoplasia, hypomagnesaemia, hyperuricaemia or genital malformation suggests HNF1B disease [11, 21]. Adult FSGS with a family history may correspond to PAX2 [123]. In a man with azoospermia and a normal karyotype, ultrasound should look for renal agenesis associated with absence of the vasa deferentia [104].

4.4. Warning and emergency signs

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Ultrasound criteria

There are no formal clinical criteria for PAX2 disease, for urofacial syndrome or for CAKUT in general; diagnosis rests on renal morphology and, when indicated, on genetic testing, and in urofacial syndrome on the association of urinary dysfunction with the typical facial expression or on biallelic variants in HPSE2 or LRIG2 [7, 12, 20]. Ultrasound is the first-choice modality before and after birth, and magnetic resonance imaging (MRI) is decided case by case [12]. The ERKNet consensus defines a minimum protocol. Prenatally, the renal length in standard deviations for gestational age, cortical thickness, corticomedullary differentiation, cysts, dilatation (at least the renal pelvis anteroposterior diameter, APD), bladder volume and amniotic fluid should be recorded. Postnatally, the length in standard deviations for length or height, cortical thickness, corticomedullary differentiation, cysts, dilatation and vascular patency by Doppler are recorded [12]. The consensus includes a flowchart of «sonotypes» with a risk of progression to KRT based on expert experience [12]. Hypoplasia is defined by a length below −2 standard deviations with normal differentiation, and dysplasia by reduced corticomedullary differentiation and/or diffuse cortical thinning without dilatation, with or without cysts [12]. Renal biopsy is not usually indicated, because it has no therapeutic consequence [12].

In the branchio-oto-renal spectrum, the clinical criteria of Chang et al. (2004) are those in Table 5.1; a molecular diagnosis is possible without the criteria being complete [22].

Source: GeneReviews, criteria of Chang 2004 [22].

In Townes-Brocks syndrome, the major suggestive findings are imperforate anus or anal stenosis, dysplastic ears and typical thumb malformations without radial hypoplasia, and the minor findings are hearing loss, foot anomalies, reduced renal function with or without malformation, genitourinary malformations and heart disease [23].

In Fraser syndrome, the criteria of Thomas et al. (1986), revised by van Haelst et al. (2007), came to count urinary tract and airway anomalies as major criteria and no longer include intellectual disability and clefts: the major criteria are syndactyly, the cryptophthalmos spectrum, urinary tract anomalies, ambiguous genitalia, laryngeal and tracheal anomalies and a positive family history, and the minor criteria are anorectal anomalies, dysplastic ears, skull ossification defects and umbilical and nasal anomalies; the diagnosis requires three major criteria, two major and two minor, or one major and three minor [56]. Cryptophthalmos is not mandatory, and the combination of acrofacial and urogenital malformations should suggest the diagnosis even without it [56]. Prenatally, Serville et al. (1989) proposed ultrasound diagnosis from 18 weeks in the presence of two of four signs: obstructive uropathy, microphthalmia, syndactyly and oligohydramnios [56].

In prenatal urinary tract dilatation, the 2024 Swiss consensus (Swiss Society of Paediatric Nephrology, Paediatric Urology and Maternal-Fetal Medicine, GRADE methodology) sets the thresholds in Table 5.2 [187].

Source: Swiss consensus, 2024 [187]. The consensus recommends at least two prenatal ultrasound scans (2nd and 3rd trimesters) and discussion with the uro-nephrological team of all cases with a bladder anomaly, ureterocele or single kidney [187].

In congenital solitary kidney, prenatal suspicion should be confirmed by neonatal ultrasound (grade B), which, performed by an experienced paediatric radiologist, is sufficient in most cases (grade B) [99]. The ultrasound should be performed 1–2 weeks after birth, because early neonatal oliguria reduces sensitivity, and the absence of hydronephrosis postnatally excludes significant obstruction but does not exclude VUR [28, 103]. A single kidney without other anomalies should show compensatory growth (grade B), the length should be measured at each ultrasound with height-related nomograms (grade C), and only at 2 years can the absence of compensatory enlargement be asserted (grade C); a length more than 2 standard deviations above the reference identifies a more favourable prognosis [99, 103].

5.2. Additional imaging

VCUG and scintigraphy are not routine tests in dysplasia without urinary tract dilatation, because high-grade VUR without dilatation or infravesical stenosis are uncommon in that context; VCUG is reserved for febrile UTI and/or dilatation, and differential function is measured only if it changes management (scintigraphy radiation dose below 1 mSv) [12]. In solitary kidney, the risk of isolated VUR is not a sufficient indication for VCUG: the sensitivity of ultrasound for high-grade VUR is 60–100%, and 14 VCUGs are needed to diagnose one dilating VUR and 43 to identify one patient who will eventually undergo ureteric reimplantation [103]. The SINePe consensus does not recommend routine imaging to exclude VUR when the kidney and tract are normal on ultrasound (grade B) and recommends VCUG if there are anomalies (grade C) [99]. Scintigraphy with DMSA or mercaptoacetyltriglycine (MAG3) is not routine when agenesis or MCDK is suspected, as the ultrasound diagnosis is accurate in more than 95%; DMSA is used for suspected rudimentary kidney, and MAG3 or MR urography when there is doubt between MCDK and severe hydronephrosis (grade C) [99, 103].

VCUG is the reference test for diagnosing and grading VUR, and contrast-enhanced voiding urosonography (ceVUS) is an alternative without ionising radiation with comparable results (weak EAU/ESPU recommendation) [28]. The 2024 ESPR update on VCUG considers both reference standards and strongly recommends ceVUS whenever indicated and possible; the Swiss consensus notes that ceVUS is less reliable for the male urethra and that the contrast agents are off-label in children in Switzerland [187, 190]. The 2026 ESPR paediatric renal imaging recommendations place ultrasound as first line, MRI in complex CAKUT where ultrasound is not sufficient and computed tomography in emergencies and lithiasis [153]. The grading is as follows.

Source: EAU/ESPU 2026, Table 2 [28].

In prenatal hydronephrosis, the EAU/ESPU recommends VCUG when ultrasound shows high-grade bilateral hydronephrosis, duplex kidney with hydronephrosis, ureterocele, ureteral dilatation or an abnormal bladder, and considers it optional in other situations; two successive normal ultrasound scans in the first one to two months make VUR rare and low grade [28]. Cortical anomalies on ultrasound (thinning, irregularity, increased echogenicity) justify VCUG [28]. The AUA recommends VCUG in Society for Fetal Urology (SFU) grade 3–4 prenatal hydronephrosis, with hydroureter, abnormal bladder or UTI during observation, and allows observation without screening in SFU grades 1–2 [172]. The 2026 AAP guideline (8 days to 5 years) recommends renal and bladder ultrasound after the first febrile UTI in all children under 5 years (strong recommendation, low certainty), to detect structural anomalies or findings associated with VUR and not VUR itself; it advises against routine VCUG after the first febrile UTI with a normal ultrasound and offers it when there are relevant ultrasound anomalies, to all children under 2 years with a second febrile UTI and to those aged 2 years or more with a second febrile UTI without another explanation (conditional recommendations), with the option of VCUG after the first UTI in subgroups (under 1 month, non-E. coli organism, circumcised boys, complicated course, unreliable follow-up) [188]. According to the Swiss consensus, MAG3 should not be performed before 4–6 weeks of life [187]. Fetal MRI is complementary and not a screening test; its performance is limited before 18–20 weeks, the optimal window is between 26 and 32 weeks, it allows lung volume to be assessed and MCDK to be distinguished from severe hydronephrosis, and gadolinium is contraindicated [28].

5.3. Laboratory assessment

In bilateral dysplasia, glomerular and tubular biochemical assessment is mandatory (creatinine and/or cystatin C, electrolytes, acid-base balance, urine biochemistry), with the first assessment between 24 and 96 hours of life, when the influence of maternal and placental renal function has dissipated [12]. In solitary kidney with anomalies on prenatal or postnatal ultrasound, the first creatinine is measured 1–2 weeks after birth; without anomalies, at 2–3 months [103]. The SINePe consensus does not require blood tests at diagnosis if the ultrasound is normal and recommends urinalysis for proteinuria in all (grade C) [99]. Estimation of GFR by combining creatinine and cystatin C is the most accurate and should be used when eGFR falls [103]. When HNF1B disease is suspected, a fractional excretion of magnesium above 2% with normal renal function confirms tubular magnesium wasting [21]. After a diagnosis of PAX2 disease, GeneReviews recommends renal ultrasound, renal function (electrolytes, urea, creatinine), urinalysis for blood and protein, investigation of VUR by VCUG, dilated ophthalmological examination and audiological assessment [20]. In newborns with high-risk or bilateral dilatation and in boys with a bilateral APD of 7 mm or more, the Swiss consensus recommends measurement of cord blood cystatin C (strong, low certainty) or, failing that, serial creatinine, because creatinine reflects the maternal value in the first 5–7 days, and considers a higher neonatal urine output, of 1.5–2 mL/kg/h, to be normal because of tubular polyuria [187]. Table 5.3 brings together the initial assessment recommended by GeneReviews in the syndromic forms.

5.4. Indications for genetic testing

KDIGO estimates that known monogenic diseases explain up to 50% of non-diabetic CKD in paediatric cohorts and 30% in adults, with more than 600 genes implicated [191]. The molecular diagnosis guides the search for extrarenal manifestations and specific follow-up (diabetes in HNF1B, risk of retinal detachment in PAX2, hearing in EYA1, neurodevelopment in the 17q12 deletion), is useful before living related kidney donation and reassures parents when the variant is de novo [1, 12]. Non-medical aspects, such as religious beliefs, insurance and the right not to know, should be respected [12]. In adults with chronic kidney disease of undetermined cause, including CAKUT recognised only in adulthood, the indications for genetic testing and its technical limitations have specific criteria.

5.5. Testing strategy

Because of heterogeneity, phenotype-directed panels, exome or genome are more efficient than sequential analysis of single genes, and testing the most frequent genes first is not necessarily easier or cheaper [1, 191]. The ERKNet consensus proposes as first line next-generation sequencing (NGS) by panel or filtered exome, prioritising the genes in Table 2.2; if the result is negative, the filter is extended to genes of human and animal renal phenotypes, because phenocopies are frequent; with high suspicion and a negative panel, trio exome or genome follows [12]. CNVs are sought by comparative genomic hybridisation (CGH) or single nucleotide polymorphism (SNP) arrays, or by multiplex ligation-dependent probe amplification (MLPA), when large CNVs are suspected [1]. The ERA prefers targeted exome with the option of whole exome as first line in unexplained kidney failure, and genome was still little used in 2022 because of costs and interpretation; the 2026 review anticipates that genome sequencing will replace exome and panels as the standard method in CAKUT [1, 11]. The criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) apply to interpretation, and many variants previously reported as causal have been reclassified as likely benign [12].

The Oxford Desk Reference recommends microarray as the first-line genetic test in the child with renal hypoplasia or dysplasia, given the diagnostic rate of 10%, and genomic analysis (array, panel or exome/genome) in parenchymal defects, especially with extrarenal defects [2]. Among the CNVs that associate CAKUT with intellectual disability and genital anomalies is the terminal 10q26 deletion, with vesicoureteric reflux, renal hypoplasia, horseshoe kidney or posterior urethral valves. In syndromic CAKUT, the yield of clinical exome (27.4%) and the low proportion of diagnoses captured by commercial panels (3.5–14.6%) favour exome, and in the fetus with renal agenesis CMA is the first test, with exome in the bilateral or non-isolated form [31, 109]. For the 17q12 deletion, CMA and exome or genome with CNV calling have a sensitivity of 100%, whereas FISH, quantitative PCR and MLPA serve to test relatives, but not the proband without CMA [21]. In the branchio-oto-renal spectrum, GeneReviews recommends a panel with deletion/duplication analysis, MLPA, CMA or genome, given the frequency of CNVs and structural variants of EYA1 [22]. In Townes-Brocks syndrome, SALL4 should be tested first if there is radial involvement or Duane syndrome [23]. In urofacial syndrome, the strategy is to sequence HPSE2, test for HPSE2 deletions and duplications if only one or no variant is found, and then study LRIG2 [7].

For PAX2 disease, GeneReviews describes the yields by method: sequencing detects about 95% of variants (136/144 probands in the locus-specific database); targeted deletion/duplication analysis identified two intragenic deletions and six whole-gene deletions; chromosomal microarray (CMA) detected six whole-gene deletions, most with additional genes and a broader phenotype; and a karyotype revealed an apparently balanced de novo t(10;13) translocation with a breakpoint in PAX2, so a karyotype is justified if the phenotype is highly suggestive and the other tests are negative [20]. These proportions refer to variants detectable by method in patients with a molecular diagnosis, and not to the clinical sensitivity of the test in a patient with CAKUT, which is much lower (Table 2.1).

5.6. Limitations of the tests

A negative result does not exclude a genetic cause. The ERA lists the causes of a negative panel or exome result [1]. Phenocopy genes may not be on the panel (for example, HNF1B mimicking polycystic kidney disease or tubulointerstitial disease). Many genes are still unknown or have only recently been identified. Large CNVs are difficult to detect without specific algorithms, and complete deletions of HNF1B and NPHP1 may be missed. GC-rich or homologous regions (exon 1 of COL4A3; PKD1 with six pseudogenes) have poor coverage. The cytosine insertion in the MUC1 VNTR is not detectable by NGS. Non-coding or deep intronic variants and imprinting defects are also not detected [1]. Low-level mosaicism, somatic events and oligogenic inheritance may explain undiagnosed cases [1, 12]. There are also gene-specific limitations: the 17q12 deletion is not visible on G-banded karyotype and might not be covered on CMA platforms predating 2007 [21]; inversions, Alu insertions and complex rearrangements of EYA1 escape sequencing and may require high-resolution karyotype or FISH [22, 129]; the SALL1P1 pseudogene compromises capture-based analysis of SALL1 [23]; and more than 15% of HPSE2 variants are deletions or duplications [7]. Periodic reanalysis of unresolved cases is a priority [191]. Incidental AR carrier status is not usually reported, and unrelated actionable findings appeared in 1.6% (34/2187) of patients with CKD studied by exome [105, 191].

The report should state the gene, the reference transcript with version (for example, NM_000278.5 for PAX2), the variant in HGVS (Human Genome Variation Society) nomenclature at DNA and protein level, zygosity, the ACMG/AMP class and, for CNVs, the genomic coordinates and the genes included [12, 118]. Variants of uncertain significance (VUS) neither confirm nor exclude the diagnosis; parental study (trio) is especially useful given the frequency of de novo variants and variable expressivity, which make segregation difficult to interpret, and parental renal ultrasound helps to recognise carriers with mild CAKUT [1, 20].

5.7. Prenatal diagnosis

Screening by cell-free fetal DNA in maternal blood detects common aneuploidies, but not structural urological anomalies; when there is a significant ultrasound finding, genetic diagnosis requires an invasive test (amniocentesis from 15 weeks or chorionic villus sampling, CVS, after 10 weeks) with CMA and, if indicated, exome [28]. The SINePe consensus recommends specialist ultrasound of the whole fetus when there is a solitary kidney (grade B), only routine obstetric follow-up in isolated solitary kidney (grade C), and CVS or amniocentesis with CMA or karyotype when there are extrarenal malformations (grade B) [99]. The ERKNet consensus does not recommend routine prenatal testing for variants in dysplasia genes, because the molecular diagnosis does not predict renal function, but allows chromosomal imbalances or ciliopathies to be studied in fetuses with syndromic features and/or hyperechogenic kidneys with oligohydramnios, after consultation with a paediatric nephrologist and a geneticist [12]. Prenatal ultrasound does not reliably distinguish dysplasia from ciliopathy [12]. The Oxford Desk Reference recommends fetal karyotype if renal involvement is bilateral or there is another finding, array if there are additional anomalies, storage of fetal and parental DNA for trio study and parental renal ultrasound before counselling on recurrence; in the case of loss or termination with abnormal renal parenchyma, DNA should be stored and a renal biopsy or full autopsy obtained [2, 30]. Karyotype is not usual in unilateral MCDK, and deletions or duplications may escape it; when there is associated heart disease, the 22q11 deletion should be sought [2]. Isolated unilateral MCDK, after detailed ultrasound, does not justify karyotype [151]. Prenatal CMA for a fetal renal anomaly may detect the 17q12 deletion, but the result does not predict the phenotype [21]. In fetuses at risk of the branchio-oto-renal spectrum, GeneReviews suggests ultrasound at 16–17 weeks for severe renal malformations and oligohydramnios, and in Townes-Brocks syndrome high-resolution 3D ultrasound can recognise the classic form from 16 weeks [22, 23]. In megacystis-microcolon, prenatal diagnosis was suspected in 26% in a systematic review, and megacystis with or without hydroureteronephrosis and normal or increased fluid in the 2nd trimester was the initial finding in 88% [8].

The ability of prenatal ultrasound to predict postnatal renal function is limited, especially in bilateral cases [192]. Fetal urine biomarkers obtained by serial vesicocentesis include sodium (favourable below 100 mEq/L), chloride (below 90 mEq/L), calcium (below 8 mg/dL), protein (below 20 mg/dL), osmolality (below 200 mOsm/L) and β2-microglobulin (below 6 mg/dL); fetal serum β2-microglobulin has a sensitivity of 80–100% and a specificity of 66–99% for predicting postnatal function, with values above 5 mg/L predictive of renal impairment [28]. A 12-peptide fetal urine signature identifies fetuses with PUV who progress to kidney failure before 2 years of age and is being validated, and amniotic fluid peptide signatures have good prognostic performance without prospective multicentre validation [28, 192]. In LUTO, the ERKNet consensus considers APD the most reliable parameter in the presence of megacystis, and the risk of fetal or neonatal death depends on oligohydramnios or anhydramnios before 20 weeks; the risk of KRT cannot be reliably predicted before birth [102]. The 2024 international Delphi consensus (168 invited experts, 80 of whom completed all three rounds, from 13 countries, predominantly European and North American; level of evidence expert opinion) defines suspected LUTO in the 1st trimester by a longitudinal bladder diameter of 7 mm or more and, in the 2nd trimester, by an enlarged bladder, keyhole sign, wall thickening, bilateral hydronephrosis or hydroureteronephrosis and male sex; diagnosis is ideally made from 16 weeks, oligohydramnios is defined by a DVP below 2 cm and not by the amniotic fluid index, and objective bladder size formulae should not be used clinically [181]. The consensus recommends offering genetic assessment to all (100%), by CVS or amniocentesis and not by vesicocentesis or cordocentesis, with FISH or PCR and microarray as first line and exome or syndromic panels as second line; fetal MRI is encouraged but not mandatory [181]. Cortical cysts, loss of corticomedullary differentiation and echogenic kidneys suggest dysplasia; in the biochemistry of a second vesicocentesis, a sodium below 100 mmol/L and a β2-microglobulin below 6 mg/dL are considered normal, without consensus for osmolality, calcium, chloride, proteins and the peptidome; without imaging evidence of dysplasia, the need for KRT cannot be predicted prenatally, the Nassr, Fontanella and Ruano scores should not be adopted (79.0%) and the best predictor of survival is the fluid volume before 24 weeks [181]. A meta-analysis of 23 studies cited in the consensus found low sensitivity and specificity of urinary calcium, sodium and β2-microglobulin [181].

5.8. Diagnosis of UTI

The EAU/ESPU guidelines recommend collecting urine by bladder catheterisation or suprapubic aspiration in the non-toilet-trained child for analysis and culture (strong), allow clean-catch voided collection for screening (weak), advise against collection bags (strong) and recommend midstream urine in the toilet-trained child (strong) [28]. The 2026 AAP guideline defines high-probability UTI, between 2 months and 5 years, as pyuria (at least 5 leucocytes per field or leucocyte esterase of +1 or more) with at least 10,000 colony-forming units (CFU)/mL of a single organism in catheter urine, or at least 100,000 CFU/mL in clean-catch midstream urine, lowering the catheter threshold of the 2011 guideline from 50,000 to 10,000 CFU/mL; before 2 months pyuria with at least 10,000 CFU/mL by catheter or suprapubic aspiration is sufficient, and sequential collection (bag for screening, catheter for confirmation) is allowed [188]. The 2024 Indian guideline considers a urine culture above 10⁴ CFU/mL significant in the infant with strong suspicion and does not recommend acute-phase DMSA [193]. The EAU/ESPU guidelines recommend renal and bladder ultrasound within 24 hours in the infant with febrile UTI or the seriously ill child (strong), consider VCUG in the follow-up of febrile UTI before 1 year of age, atypical or recurrent infections or ultrasound anomalies (weak), and DMSA at least six months after a febrile UTI to assess scarring (weak) [28]. The «top-down» approach, with acute-phase DMSA and VCUG only if there is renal involvement, misses 5–27% of VUR (presumably less significant) and avoids VCUG in more than 50% [28]. NICE NG224 does not recommend routine imaging to localise UTI or to identify VUR, and stratifies imaging by age and type of UTI, as in the following table [100].

Source: NICE NG224, Tables 4–6 [100]. Between 6 months and 3 years, VCUG is not routine, but is considered when there is dilatation on ultrasound, weak stream, non-E. coli organism or a family history of VUR; when VCUG is performed, oral prophylaxis is given for 3 days with the test on the 2nd day [100].

5.9. Practical algorithm

For a fetus with absent, small or dysplastic kidneys, the first step is a complete anomaly scan at a reference centre, with quantification of amniotic fluid and a search for extrarenal anomalies; if the anomaly is bilateral or there are extrarenal anomalies, invasive testing with CMA and, if indicated, exome is offered, with storage of fetal and parental DNA [12, 30, 99]. In the newborn, the finding is confirmed by ultrasound in the first or second week (or between 24 and 96 hours for biochemistry in bilateral disease), the anomaly is classified (agenesis, aplasia, MCDK, hypoplasia, dysplasia, dilatation), and VCUG is decided only in the presence of dilatation, anomalies of the single kidney or febrile UTI [12, 103]. Genetic testing, preferably as a trio, is done in bilateral, familial or syndromic disease, starting with a panel or exome with CNV analysis, and extended to trio exome or genome if the panel is negative with high suspicion [1, 12]. Renal ultrasound of the parents and siblings completes the family assessment, as set out in section 8 [12, 84].

6. Differential Diagnosis

6.1. Comparative table

VNTR: variable number tandem repeat.

For cystic or hyperechogenic kidneys without dilatation, the 17q12 deletion GeneReviews proposes the genetic differential diagnosis in Table 6.2, which is added to the entities above.

Source: 17q12 deletion GeneReviews, Table 3, adapted [21]; BICC1 and CRB2 rows completed with OMIM [144, 195]. The differential diagnosis also includes idiopathic and obstructive cystic dysplasia in children and acquired or simple cortical cysts in adults [21].

6.2. Main differential diagnosis

The first differential is morphological and separates agenesis (empty fossa without tissue) from aplasia (rudimentary kidney with function below 5%) and from involuted MCDK, a distinction that neonatal ultrasound, supplemented by DMSA when a rudimentary kidney is suspected, resolves in most cases [99]. The second separates non-obstructive dysplasia from dysplasia secondary to obstruction: the presence of megacystis, bladder wall thickening, dilated posterior urethra and bilateral hydroureteronephrosis points to LUTO, whose prognosis and fetal treatment are different [28, 102]. Distinguishing obstruction from non-obstruction on prenatal ultrasound is difficult, because both may have the same appearance [28]. Megacystis may also be non-obstructive (neurogenic bladder, megacystis-microcolon syndrome), which requires spinal ultrasound in the infant [2, 28]. In isolated 1st-trimester megacystis that resolved completely, chromosomal anomalies appeared in 2.4% in a multicentre series [28]. In the differential diagnosis of fetal megacystis, low obstruction (PUV, urethral atresia or stenosis) is recognised on imaging or cystoscopy; isolated prune belly sequence has no microcolon; multisystemic smooth muscle dysfunction syndrome combines mydriasis and vascular anomalies without microcolon; and megacystis-microcolon is distinguished by normal or increased amniotic fluid [8]. In urofacial syndrome, a patent urethra on VCUG or cystoscopy distinguishes it from PUV [7]. In families with more than one member affected by a prune belly-like sequence, the bladder distension is probably non-mechanical, with genetic causes such as ACTA2, ACTG2, MYH11, CHRM3 and HPSE2, whereas isolated mechanical urethral obstruction has negligible recurrence [101].

For hyperechogenic kidneys, the differential diagnosis includes the 17q12 deletion and HNF1B disease (frequently normal-sized kidneys), the polycystic diseases (markedly enlarged kidneys in the recessive form), the ciliopathies (Meckel-Gruber, Bardet-Biedl with polydactyly), Beckwith-Wiedemann syndrome and renal tubular dysgenesis [1, 2]. Prenatal ultrasound does not reliably distinguish dysplasia from ciliopathies [12]. For renal agenesis, the Oxford Desk Reference recommends considering the branchio-oto-renal spectrum in all babies, looking for branchial fistulae, asking about hearing loss and performing renal ultrasound in the parents, and also considering Fraser and MURCS syndromes, RET and HNF1B variants and exposure to ACE inhibitors [2, 30]. In the child, Fraser syndrome, the MURCS association and the branchio-oto-renal spectrum are the syndromic causes of agenesis that the Oxford Desk Reference refers to its chapters on eyelids, female infertility and ear anomalies, and the VACTERL association to its chapter on radial ray defects; the book differs from Smith in the renal frequency of the VACTERL association (80% against 53%) and in the prevalence and frequency of agenesis in Fraser syndrome (about 1/250,000 and agenesis in 40%, against 1/495,633 and 50% bilateral agenesis in the EUROCAT series), because they use different series and denominators [2, 55, 154, 162, 163]. The PAX2 disease GeneReviews recalls that isolated CAKUT (more than 20 genes, AD or AR) is distinguished by anomalies limited to the kidney and urinary tract, without ocular findings, and that two patients later diagnosed with Townes-Brocks syndrome were initially considered to have the branchio-oto-renal spectrum because of the association of dysplastic ears and renal malformation [20, 23]. Branchio-oculo-facial syndrome overlaps with the branchio-oto-renal spectrum, but is not allelic [185]. Other entities with renal agenesis include aniridia–renal agenesis–psychomotor retardation syndrome (ORPHA:1064) and the double uterus–hemivagina–renal agenesis syndrome (ORPHA:3411) [196, 197]. FREM1 phenotypes range from apparently isolated hypertelorism to a picture similar to Fraser syndrome, with a bifid nasal tip and an eyebrow configuration that guides the diagnosis, and justify renal ultrasound to look for agenesis [198]. Among teratogenic causes, fetal valproate syndrome occasionally includes renal hypoplasia, collecting system anomalies, hydronephrosis and hypospadias, together with the craniofacial pattern, heart defects and changes in cognitive development [199].

In the child with VUR and recurrent UTI, primary VUR must be distinguished from VUR secondary to infravesical obstruction (PUV), neurogenic bladder (spina bifida) and bladder and bowel dysfunction, because the initial treatment differs [28]. Urofacial syndrome, with its characteristic facial sign, and MYOCD-related megacystis are rare genetic causes of bladder dysfunction with UTI and a risk of progressive renal failure [10].

7. Treatments and Risk Management Strategies

7.1. General principles

There is no treatment directed at the cause of renal hypoplasia, aplasia or dysplasia [12]. A search of ClinicalTrials.gov in October 2026 identified no pharmacological trials targeting these conditions, only a phase 1 study of autologous cell therapy, described in section 7.9, which does not prove that others do not exist [200]. The aim is to preserve the remaining nephron mass, control hypertension and proteinuria, prevent febrile UTIs and post-infectious damage, correct the metabolic complications of CKD and prepare for dialysis and transplantation when needed [12, 28, 103]. The EAU/ESPU guidelines recommend (strong) that patients with urinary tract malformations be followed by a multidisciplinary team including maternal-fetal medicine, clinical genetics, paediatric urology and nephrology, neonatology and psychology [28]. In PAX2 disease, the team includes ophthalmology, nephrology, audiology and genetics, with the aim of preventing the complications of kidney failure and visual loss due to retinal detachment [20].

7.2. Kidney protection in hypodysplasia and congenital solitary kidney

7.2.1. Blood pressure and proteinuria

In paediatric CKD, the ERKNet consensus refers to the general recommendations: annual ABPM and a BP target at or below the 50th percentile, with ACE inhibitors or ARBs, renin-angiotensin-aldosterone system (RAAS) inhibitors, as first line [12]. The 2021 KDIGO guideline on BP in CKD suggests lowering the 24-hour mean arterial pressure (MAP) by ABPM to the 50th percentile or below for age, sex and height (recommendation 2C), performing ABPM once a year and standardised auscultatory office BP every 3 to 6 months, aiming, without ABPM, for an office systolic BP below the 90th percentile, and using ACE inhibitors or ARBs as first line for raised BP [32]. The recommendation is weak, among other reasons, because the risk of dehydration, hypotension and acute kidney injury may be greater in children with urological disease and fixed urine output during gastroenteritis, which KDIGO considers especially relevant in CAKUT with inability to concentrate urine and salt-wasting nephropathy; families should know how to recognise these signs [32]. The basis is the European ESCAPE trial (385 children aged 3 to 18 years with GFR of 15–80 mL/min/1.73 m², with one Portuguese centre), in which all received ramipril at a fixed dose of 6 mg/m² of body surface area per day and were randomised to a 24-hour MAP below the 50th percentile or between the 50th and 95th percentiles: over 5 years, a 50% decline in GFR or end-stage CKD occurred in 29.9% against 41.7% (HR 0.65; 95% CI 0.44–0.94), with no difference in adverse events, and proteinuria gradually recovered despite the ACE inhibitor [201]. The benefit was greater in glomerular diseases, with GFR below 45 and with a protein/creatinine ratio above 1.5 g/g, and in a subanalysis it was not significant with proteinuria below 0.5 g/g; the proportion of CAKUT in the cohort is not given in the trial abstract [32, 201]. The European Society of Hypertension (2016) proposes targets below the 75th percentile without proteinuria and below the 50th percentile with proteinuria, according to KDIGO [32]. For congenital solitary functioning kidney, Groen in 't Woud et al. recommend a target between the 50th and 75th percentiles and, if tolerated, below the 50th percentile for 24-hour MAP, as in Table 7.1 [103].

Source: Groen in 't Woud et al. 2021, Table 3 [103]. RAAS: renin-angiotensin-aldosterone system.

ACE inhibitors and ARBs are first line in single kidney with hypertension or albuminuria, because of their antihypertensive and antiproteinuric effect; calcium channel blockers lower BP to a similar extent [103]. A reduced eGFR is not a reason to stop the RAAS inhibitor, and paediatric data show accelerated eGFR decline after withdrawal [103]. The SINePe consensus recommends caution with RAAS inhibitors in the infant with solitary kidney (grade C), allows their use after infancy for hypertension and/or proteinuria (grade C) and contraindicates them in the presence of stenosis of the artery of the single kidney (grade C); it also mentions a retrospective study in children with bilateral hypodysplasia in which treating or not treating with an ACE inhibitor did not alter progression [99]. The labels of the US Food and Drug Administration (FDA) give the paediatric doses in Table 7.2, all for hypertension; antiproteinuric or nephroprotective use in CAKUT without hypertension is off-label, supported by the KDIGO and ERKNet recommendations [12, 32, 202–206].

Source: FDA labels consulted in October 2026 [202–206] and ESCAPE trial [201]. INN: international nonproprietary name.

All the labels carry a boxed warning of fetal toxicity: exposure in the 2nd and 3rd trimesters causes reduced fetal renal function with anuria, oligohydramnios, pulmonary hypoplasia, skeletal deformities with skull hypoplasia, hypotension and death, and the drug should be stopped as soon as pregnancy is detected; exposed newborns should be monitored for hypotension, oliguria and hyperkalaemia [202, 204]. In the European Union, ACE inhibitors and ARBs as monotherapy for hypertension are nationally authorised; the only centrally authorised paediatric ACE inhibitor, Aqumeldi® (enalapril, Proveca Pharma), is indicated in heart failure and not in hypertension or CAKUT [207]. The national summaries of product characteristics (INFARMED, Agência Nacional de Vigilância Sanitária) were not consulted, so the brand names and approved doses in Portugal and Brazil are not given in this article. In PAX2 disease, GeneReviews considers that treatment of hypertension and VUR may preserve renal function [20]. In the branchio-oto-renal spectrum, renal treatment rests on monitoring of function, control of hypertension and treatment of proteinuria in nephrology, with pyeloplasty for PUJO and antibiotic prophylaxis and/or surgical correction for VUR; for the ear, it includes canaloplasty, complete excision of infected, symptomatic or cosmetically troublesome fistulae or cysts, hearing aids and cochlear implantation in severe or profound bilateral hearing loss (contraindicated only in cochlear nerve aplasia) [22].

7.2.2. Nephrotoxic drugs

The combination of a RAAS inhibitor with a non-steroidal anti-inflammatory drug (NSAID) should be avoided, with paracetamol preferred for fever and pain; prolonged NSAIDs should be avoided with eGFR below 60 mL/min/1.73 m² and any NSAID with eGFR below 30 mL/min/1.73 m², and gentamicin requires serum level monitoring [103]. The SINePe consensus recommends paracetamol, avoidance of NSAIDs and minimisation of nephrotoxic agents (grade C) [99]. The same rule applies to PAX2 disease (avoid drugs that affect renal function, with a nephrologist), to the 17q12 deletion with renal anomalies, to the branchio-oto-renal spectrum (caution with nephrotoxic antibiotics and analgesics) and to Townes-Brocks syndrome, in which ototoxic drugs are also avoided [20–23].

7.2.3. Lifestyle and sport

The SINePe consensus recommends protein and salt intake according to the recommendations for age and sex, avoiding Western excess (grade B), and avoiding dehydration, especially in sport (grade C) [99]. Protein restriction showed no benefit in the meta-analysis of trials in children with CKD, and children may need a high protein intake [103]. Sport should not be restricted in solitary kidney (grade B): catastrophic sports-related kidney injury is estimated at 0.4 per million children per year (literature from 1966 to 2005), and most severe kidney injuries result from road traffic accidents or falls; families should be told that cycling, sledging, skiing and snowboarding, inline skating, horse riding and some contact sports carry a higher risk (grade B), and flank protectors are debated (grade C) [99]. In American football, sports-related kidney injury occurred in 9 cases per million activities, with no kidney loss [103]. The AAP imposes no restrictions in non-contact sports and recommends individual assessment in limited-contact or collision sports [99]. In PAX2 disease, GeneReviews recommends avoiding contact sports and wearing protective goggles to prevent retinal detachment [20].

7.3. Dialysis, transplantation and treatment of metabolic complications

In kidney failure, treatment is dialysis and/or transplantation [20]. In HNF1B disease, transplantation is a good option because the disease does not recur in the graft; with diabetes, simultaneous kidney-pancreas transplantation is considered, and the increased risk of post-transplant diabetes leads GeneReviews to suggest immunosuppression that avoids tacrolimus and mTOR inhibitors and reduces corticosteroids, a statement of opinion [21]. Hypomagnesaemia is treated with organic magnesium salts (aspartate, citrate, gluconate), possibly more bioavailable than inorganic salts (oxide, sulphate, glycerophosphate), with potassium-sparing diuretics and sodium-glucose cotransporter 2 (SGLT2) inhibitors as adjuncts in refractory disease; GeneReviews gives no doses [21]. No magnesium salt has an approved indication for HNF1B hypomagnesaemia, and the only dosing source consulted is the KDIGO consensus on Gitelman syndrome, whose application to HNF1B disease is an off-label extrapolation: starting dose of 300 mg/day of elemental magnesium (12.24 mmol) in adults and 5 mg/kg/day (0.2 mmol/kg) in children, preferably as modified-release tablets, divided into 2 to 4 doses with meals and titrated by levels and intestinal tolerance, with a target serum magnesium of 0.6 mmol/L (1.46 mg/dL) and no maximum dose defined in the source; the intravenous route (20% magnesium chloride, 0.1 mmol/kg per dose, repeatable every 6 hours) is reserved for tetany, arrhythmias or digestive intolerance [189]. Persistent diarrhoea may require dose reduction, and spironolactone has antiandrogenic effects [189]. The UK Kidney Association clinical information page on HNF1B considers hypomagnesaemia usually asymptomatic and rarely requiring treatment, which diverges from the supplementation proposed in other sources [208]. Genetic testing before living related donor transplantation ensures that the donor does not carry the variant, and KDIGO recommends early testing of living related donors of recipients with a known genetic disease [1, 191]; in PAX2 disease, in which carrier parents may have only albuminuria, Greipel et al. explicitly recommend PAX2 testing of living related donors [108]. In the 17q12 deletion, successful simultaneous kidney-pancreas transplantation has been described; in Müllerian aplasia, primary vaginal dilatation is effective in more than 90–96%, uterine transplantation can restore fertility and surrogacy is an alternative; exocrine pancreatic insufficiency is treated with pancreatic enzymes [21]. In patients with PUV, transplantation is safe and effective if bladder function is managed, because graft deterioration is related mainly to lower urinary tract dysfunction [28].

7.4. Fetal therapy for anhydramnios of renal cause

7.4.1. Serial amnioinfusions

The RAFT trial (Renal Anhydramnios Fetal Therapy; NCT03101891), prospective and non-randomised, took place in fetal therapy centres in the USA [33, 209]. In the isolated bilateral renal agenesis cohort (nine centres, December 2018 to July 2022; 21 maternal-fetal pairs), ultrasound-guided percutaneous amnioinfusions of isotonic fluid were started before 26 weeks, with individualised frequency to maintain a normal fluid volume for gestational age [33]. The primary outcome was postnatal survival of 14 days or more with placement of dialysis access. Recruitment was stopped after the interim analysis of 18 pairs, because of concern about neonatal morbidity and mortality beyond the primary outcome, despite efficacy [33]. Seventeen (94%) were born alive, at a median gestational age of 32 weeks and 4 days, all before 37 weeks, and 14/17 (82%; 95% CI 44–99%) achieved the primary outcome; a greater number of amnioinfusions, gestational age above 32 weeks and higher birth weight were associated with survival [33]. Only 6/17 (35%) were discharged from hospital, on peritoneal dialysis, at a median age of 24 weeks of life [33].

The fetal kidney failure arm without bilateral agenesis (13 centres, December 2018 to February 2025, follow-up of survivors until 13 February 2026), published in July 2026, included 32 participants with anhydramnios before 22 weeks treated with amnioinfusions started before 26 weeks [34]. Twenty-nine (91%) were born alive, at a median gestational age of 34 weeks and 1 day, all before 37 weeks [34]. There were no unexpected serious maternal adverse events; the commonest maternal complications were preterm prelabour rupture of membranes (PPROM) in 19 (56%) and chorioamniotic separation in 10 (29%) [34]. The primary outcome occurred in 19/29 live births (65.5%; 95% CI 45.7–82.1%) [34]. More amnioinfusions (median 14 against 7; P = 0.01), a longer interval between the first amnioinfusion and PPROM (63.5 against 29.0 days; P = 0.01), gestational age above 32 weeks (79% against 38%; P = 0.03) and higher birth weight (2029 against 1635 g; P = 0.01) were associated with survival [34]. Fourteen (48%) were discharged from hospital at a median age of 4.7 months, and of the 11 alive at the time of publication, 7 (64%) had been transplanted between 2 and 5 years of age [34]. The authors conclude that amnioinfusions mitigate lethal pulmonary hypoplasia, but significant neonatal morbidity and mortality persists independently of early lung function [34]. The PubMed Central records of the two articles provide only the abstract, so the results by aetiology and the detailed neonatal adverse events were not consulted. In a substudy of 20 pregnancies in the bilateral agenesis arm (17 with amnioinfusions and 3 with expectant management), fetal echocardiography with maternal hyperoxygenation showed a decrease in the pulmonary artery pulsatility index only in treated fetuses, and all those with clear reactivity had a favourable respiratory status at 30 days, a prenatal sign of a «rescued» pulmonary phenotype [210].

The international Delphi consensus on LUTO and the EAU/ESPU guidelines consider serial amnioinfusions an experimental procedure, to be performed only within research protocols, because the benefit has not been proven [28, 181]. At least two North American studies are recruiting: NCT06728228 (Dallas; anhydramnios before 22 weeks and first amnioinfusion before 28 weeks and 6 days; 35 participants estimated; outcomes of survival to dialysis and to transplantation at 2 years or more) and NCT03723564 (Mayo Clinic; Ringer's lactate; severe LUTO with kidney failure and bilateral agenesis; 40 participants estimated; adverse event outcome) [211, 212]. This intervention involves shared decisions about a neonatal course with peritoneal dialysis from the first month and transplantation in early childhood, and the discussion should include termination of pregnancy and perinatal palliative care where permitted by national law [28, 34].

7.4.2. Fetal intervention in LUTO

In LUTO, fetal intervention aims to improve survival and renal and bladder function; before considering it, limiting genetic or structural anomalies should be excluded (weak recommendation), and it may be considered when there are ultrasound signs of obstruction with reduced fluid in the 2nd trimester (weak) [28]. The Delphi consensus defines as criteria imaging suggestive of LUTO, absence of limiting structural or genetic anomalies, gestational age of 16 weeks or more and oligohydramnios (DVP below 2 cm), with the vesicoamniotic shunt as the primary intervention (91.9%); the peritoneoamniotic shunt, cystoscopic fulguration of the valves, serial amnioinfusion, the transurethral stent and the balloon catheter are not first line, and when fetal kidney failure is suspected serial amnioinfusion is performed only within approved research protocols, such as RAFT [181]. There was no consensus on bladder refilling, renal biochemistry or ultrasound dysplasia as candidacy criteria, on shunting in female fetuses or on the maximum gestational age (28 weeks for 64.5%); replacement of a displaced shunt was accepted even at an advanced gestational age, the stated aim is to improve perinatal survival, the route and timing of delivery follow obstetric indications, and the consensus defined a minimum set of outcomes (fetal, perinatal, neonatal and 1-year survival, procedural complications, KRT, pulmonary hypoplasia, neonatal renal function, transplantation, CKD and neurodevelopment) [181]. According to the consensus, intervention has been shown to improve perinatal survival, but not renal function, on the basis of the PLUTO trial, which was small and is more than ten years old [181]. In a meta-analysis of 10 studies of «late» intervention (16–28 weeks), perinatal survival was 57% with a shunt against 38.8% without, with benefit in fetuses with unfavourable urinary biochemistry; procedural complications reach 40% (shunt displacement or obstruction, fetal ascites, PPROM) [28]. Early shunting (before 16–17 weeks) was associated in retrospective series with overall survival of 74% and preservation of perinatal renal function in 51%, but with more complex urethral pathology and surgical removal of the shunt in more than half of newborns; the prospective IUS1st study (DRKS00017779; Germany and the Netherlands) is ongoing [28, 213]. Fetal cystoscopy with laser ablation of PUV has evidence limited to case series, with urological fistulae in up to 10% [28]. ERKNet recommends referral to a multidisciplinary tertiary obstetric centre and offers shunting in selected cases [102].

7.4.3. Postnatal treatment of PUV

The Swiss consensus recommends urgent catheterisation at birth when LUTO is strongly suspected (strong, high certainty) [187]. The strong EAU/ESPU recommendations for PUV include draining the bladder and starting antibiotic prophylaxis in the newborn with suspected infravesical obstruction, performing VCUG, attempting endoscopic valve ablation after drainage and stabilisation, offering prolonged diversion if the child is too small, using the serum creatinine nadir as a prognostic marker (above 0.85 mg/dL is associated with a poor prognosis), assessing differential renal function by DMSA or MAG3 and monitoring bladder and renal function lifelong [28]. Neonatal circumcision, combined with antibiotic prophylaxis, reduces the risk of febrile UTI in the first two years (strong recommendation) [28]. CKD develops in up to 65% of patients with PUV, and about 20% of these progress to kidney failure [28].

7.5. Urinary tract infections in the context of CAKUT

7.5.1. Treatment of febrile UTI

The EAU/ESPU guidelines recommend treating febrile UTI with courses of 4 to 7 days by the oral or parenteral route (strong), choosing the parenteral route in the seriously ill child or one who cannot tolerate oral treatment (strong), starting empirical antibiotic therapy in complicated febrile UTI (strong) and considering urinary drainage when there is no response to the antibiotic (weak) [28]. The choice of antibiotic should follow local resistance patterns, previous urine cultures and the clinical picture [28]. Early treatment of febrile UTI reduces the risk of renal scarring [28, 174]. NICE advises against repeating urine culture in asymptomatic children and does not recommend prophylaxis for asymptomatic bacteriuria [100]. The 2026 AAP guideline recommends medical assessment within 72 hours of symptom onset, expedited in children with known structural genitourinary anomalies, previous febrile UTI or loin pain (in a meta-analysis of 6 studies, assessment before 72 hours was associated with fewer scars, RR 0.68; 95% CI 0.57–0.82), and short courses of 5–7 days for pyelonephritis without an anatomical anomaly, allowing courses of more than 7 days in infants aged 8 days to 2 months and in children with anatomical genitourinary anomalies, bacteraemia or lack of response (conditional, low certainty) [188]. After 28 days, it recommends oral rather than parenteral antibiotics with admission (strong, very low certainty), with equivalent scarring and recurrence, and between 8 and 28 days parenteral treatment with early switch to oral [188]. The 2024 Indian guideline allows oral treatment for 7–10 days of pyelonephritis in the non-toxic infant [193].

7.5.2. Continuous antibiotic prophylaxis

Continuous antibiotic prophylaxis (CAP) reduces recurrent symptomatic UTI, but has not reduced new kidney damage in children after the first or second UTI and is associated with increased bacterial resistance [28]. In the RIVUR trial (19 US centres, 2007–2013; 607 children, 91.9% female, median age 12 months, range 2 to 71 months, grade I–IV VUR, 80.4% grade II–III, after a first or second febrile or symptomatic UTI, 85.8% with a febrile index UTI), daily trimethoprim-sulfamethoxazole (co-trimoxazole) suspension at a dose of 3 mg/kg of trimethoprim plus 15 mg/kg of sulfamethoxazole, against placebo for 2 years, reduced recurrent febrile or symptomatic UTI: in the abstract, 39/302 against 72/305 (relative risk, RR, 0.55; 95% CI 0.38–0.78), a value corresponding to the sensitivity analysis in which missing data count as no event; in the primary intention-to-treat analysis, which counts missing data as events, 25.5% against 37.4% (RR 0.68; 95% CI 0.53–0.87), and the HR was 0.50 (95% CI 0.34–0.74), with a number needed to treat (NNT) of 8 (95% CI 5–16) over 2 years [214]. The effect was greater when the index UTI was febrile (HR 0.41; 95% CI 0.26–0.64, against 1.28 for non-febrile) and in the presence of baseline BBD (HR 0.21; 95% CI 0.08–0.58, against 1.40 without BBD), with no difference in renal scars (11.9% against 10.2%) or new scars (8.2% against 8.4%) [214]. Among the first recurrences due to E. coli, resistance to co-trimoxazole was 63.3% in the prophylaxis group and 19.3% in the placebo group, with no difference in adverse events; at 2 years, VUR had resolved in 50.9% and worsened in 7.2% of the 428 children reassessed [214]. The authors state limited applicability to boys, to children older than 6 years and to settings with high co-trimoxazole resistance [214]. A later RIVUR analysis defined a high-risk group (uncircumcised boys, BBD and high-grade reflux) that benefits significantly from prophylaxis, and the EAU/ESPU advocates a selective risk-based approach rather than «absolute» prophylaxis in dilating VUR [28].

The European PREDICT trial (39 centres, October 2013 to January 2020) randomised 292 infants aged 1 to 5 months (77.7% male; median age 3.4 months) with grade III–V VUR without prior UTI (80.5% grade IV–V; 48.3% bilateral) to CAP or no treatment for 24 months, with the antibiotic chosen by the centre according to local resistance patterns [173]. The first symptomatic UTI occurred in 21.2% (31/146) in the prophylaxis group and in 35.6% (52/146) in the untreated group (HR 0.55; 95% CI 0.35–0.86; P = 0.008), an absolute difference of 14.4 percentage points and a number needed to treat (NNT) of 7 children for 2 years to prevent one UTI (95% CI 4–29) [173]. There was no substantial difference in new scars on DMSA (21 against 17 patients; rate ratio 1.22; 95% CI 0.69–2.18), in eGFR at 24 months (112.3 against 109.5 mL/min/1.73 m²) or in the proportion of UTIs requiring admission (27% against 30%) [173]. New scars appeared in 18.8% of infants without UTI and in 19% of those who had at least one, which suggests that part of the kidney damage in these patients is independent of infection [173]. Infections with Pseudomonas and other non-E. coli organisms were more frequent on prophylaxis, and resistance to at least two first-line antibiotics appeared in 52% of isolates in the prophylaxis group against 17% in the untreated group (rate ratio 2.98; 95% CI 1.50–5.92) [173]. In the subgroup analysis, the benefit was concentrated in girls with grade IV–V reflux (53 patients), and in the largest subgroup, the 99 boys with grade V, there was no relevant benefit [173]. The authors conclude that routine prophylaxis is not justified and should be considered only in girls with grade IV–V VUR or to prevent reinfection after a first UTI [173]. More than 95% of participants were of white European ancestry, and the results do not apply to children with prior UTI [173].

The 2026 EAU/ESPU recommendations for VUR are as follows: initially treat with CAP all symptomatic patients diagnosed in the first year of life, regardless of grade or scarring (weak); offer immediate parenteral antibiotic therapy for febrile breakthrough infections (strong); initially manage conservatively children presenting between 1 and 5 years (strong); offer close surveillance without prophylaxis to children with low-grade reflux without symptoms (strong); and investigate lower urinary tract dysfunction in all, especially after toilet training, treating it first if present (strong) [28]. CAP for symptomatic VUR diagnosed during investigation of prenatal hydronephrosis is recommended in the first year of life, but the benefit in asymptomatic VUR in the same context remains unclear [28]. There are no reliable data on duration; a practical approach is to continue CAP until toilet training without lower urinary tract dysfunction, and stopping less than a year after the last febrile UTI and bilateral reflux are associated with more recurrences [28, 215]. In megaureter, the EAU/ESPU recommends chemoprophylaxis in the first year of life, based on a study in which a ureteral diameter of 7 mm or more indicated a higher risk of UTI [28]. Co-trimoxazole prophylaxis for two years in RIVUR did not alter the full blood count, electrolytes or creatinine, so these routine tests are not mandatory [28].

The 2026 AAP guideline, which replaces the 2011 guideline and extends the scope from 8 days to 5 years in children of low medical complexity, advises against routine CAP in low-risk VUR (grades I–II without BBD), considers grade III of uncertain risk, with CAP as a reasonable option according to family values, and allows CAP in high-risk VUR (grade IV–V, intrarenal reflux, scarring or nephropathy, structural or cortical renal or ureteral anomalies, recurrent pyelonephritis, bacteraemia with intensive care admission or BBD), with referral to paediatric urology or nephrology (conditional recommendation, low certainty) [188]. The guideline states that not all nephrologists and urologists on the panel supported every aspect of this recommendation, and good practice includes shared decision-making on CAP and the assessment and treatment of BBD, including constipation, in all children with UTI [188]. The AUA (2010, amended 2017) recommends CAP in the child under 1 year with VUR and prior febrile UTI and in the child under 1 year with grade III–V VUR detected by screening, allows circumcision of the male infant with VUR, recommends treating BBD before any surgery and continuing CAP while treating it, and in the child over 1 year without BBD allows CAP or observation with prompt treatment of UTIs [172]. In the AUA meta-analysis, resolution on CAP was 31% with BBD and 61% without BBD [172]. At the other extreme, the Emilia-Romagna guideline (Italy, 2023, GRADE) does not recommend CAP after UTI, in recurrent UTI, in VUR of any grade, in isolated hydronephrosis or in neurogenic bladder, and suggests it only in significant obstructive uropathies until surgical correction [216]; the 2024 Indian guideline recommends prophylaxis in BBD and high-grade VUR and stopping it when the child is toilet trained, without BBD and without UTI for 1 year [193]; and the 2021 Swiss consensus considers CAKUT and BBD the major risk factors for sequelae and does not recommend prophylaxis in general [217]. NICE recommends against routine antibiotic prophylaxis after the first UTI [100]. For children under 16 years with recurrent UTI, it recommends treating the current UTI and then considering a trial of daily prophylaxis, with specialist advice, if behavioural and hygiene measures (or methenamine) are not effective, taking into account the uncertain evidence of benefit on recurrence and scar deterioration, reviewing it at least every 6 months and ensuring rapid access to treatment if it is stopped [218]. In congenital solitary functioning kidney, frequently excluded from trials, Groen in 't Woud et al. suggest prophylaxis and VCUG when the ureter is dilated on ultrasound or after the first UTI [103]. In prenatal hydronephrosis, two systematic reviews showed no benefit of CAP in the heterogeneous group, and the decision should be stratified by risk (ureteral dilatation, lack of circumcision, female sex, high-grade hydronephrosis) [28]. The review by Standish et al. does not recommend routine prophylaxis in isolated unilateral hydronephrosis without distal ureteral dilatation [175]. The AAP reaffirmed in 2016 its 2011 guideline on the first UTI in febrile infants aged 2 to 24 months, replaced by the 2026 guideline, and the 2025 report on perinatal urinary tract dilatation reviews the indications for prophylaxis by risk stratification with shared decision-making [152, 188, 219]. In urinary tract dilatation, the Swiss consensus does not recommend prophylaxis at low risk (strong), weighs it at high risk and suggests it with APD above 20 mm, megaureter of 7 mm or more, grade 4–5 VUR or a bladder anomaly (weak) [187].

7.5.3. Drugs and doses for prophylaxis

INN: international nonproprietary name. Below 3 months of age, NICE recommends referral to a specialist paediatrician [218]. The antibiotic should be chosen according to a recent antibiogram and be different from the one used for acute treatment, and adjustment in renal or hepatic impairment should follow the paediatric formulary [218]. The literature on CAP generally uses a quarter to a half of the daily therapeutic dose, as a single dose, and co-trimoxazole, amoxicillin and nitrofurantoin are the most used agents [28]. The sources consulted do not give brand names for these antibiotics, and trimethoprim alone is not available in Switzerland [187].

7.5.4. Non-antibiotic measures

Bladder and bowel dysfunction should be sought and treated in all toilet-trained children with febrile or recurrent UTI (strong recommendation), and treatment of constipation reduces recurrence [28]. Adequate hydration, hygiene and optimisation of bladder emptying (including clean intermittent catheterisation technique in neurogenic bladder) complete prevention; in the child with well-performed catheterisation and recurrent UTI, intravesical gentamicin has proved effective [28]. Cranberry products and probiotics reduced recurrence against placebo in children with a normal urinary tract in a meta-analysis (moderate evidence for cranberry), and the EAU/ESPU considers dietary supplementation an alternative or complement in selected cases (weak), with probiotics only as an adjunct to prophylaxis; vitamins A, D and E are not routinely indicated [28]. NICE allows cranberry with specialist advice, with uncertain benefit, and considers the evidence on probiotics inconclusive [218]. Circumcision reduces UTIs in boys with isolated hydronephrosis, VUR or PUV, and corticosteroid cream for physiological phimosis reduces recurrent UTIs, with a high number needed to treat in the absence of a urinary anomaly [28].

7.5.5. Bladder dysfunction of genetic cause

In urofacial syndrome, GeneReviews recommends prompt and complete antibiotic therapy for acute UTIs, anticholinergics to lower intravesical pressure and alpha-1 blockers to improve emptying, intermittent catheterisation via the urethra or a vesicostomy to reduce the residual, improve continence and reduce infections, nephrology for CKD and dialysis or transplantation in severe renal failure, eye lubricant by day and ointment at night for lagophthalmos and avoidance of nephrotoxic agents; there are no evidence-based guidelines or doses in GeneReviews, and botulinum toxin for the facial expression has been described in a single patient [7]. In megacystis-microcolon, clean intermittent catheterisation or vesicostomy decompresses the bladder and prevents scarring and renal failure, drugs that reduce intestinal and bladder motility are avoided, and cardiac assessment is performed in the MYH11 or ACTA2 forms [8]. In ACTA2 smooth muscle dysfunction syndrome, Regalado et al. (2018) recommend cardiovascular assessment with transthoracic echocardiography every 6 to 12 months, annual thoracic MR angiography from 10 years of age with abdominopelvic MR angiography, annual imaging of the upper limb arteries, annual ophthalmological, growth, nutritional and neurocognitive assessment in childhood and adolescence, and urological assessment according to the clinical picture; pregnancy requires prior counselling and follow-up by high-risk obstetrics and cardiology, because of the risk of aortic dissection and stroke and reduced uterine contractility [16]. In CHRNA3 autonomic bladder dysfunction, OMIM records that surgical correction of VUR is not effective, because the reflux is secondary to dysfunction of bladder and ureteral innervation [15]. In prune belly sequence, survivors benefit from urological drainage, UTI control and an abdominal binder [101].

7.6. Treatment of vesicoureteric reflux

7.6.1. Risk stratification

The EAU/ESPU stratifies VUR by risk and proposes the management in Table 7.3 [28].

Source: EAU/ESPU 2026, Table 3 [28].

The AUA recommends, in the follow-up of VUR, annual BP, height, weight and urine for proteinuria and bacteriuria, renal ultrasound every 12 months and cystography (radionuclide or low-dose fluoroscopic) between 12 and 24 months, with longer intervals when spontaneous resolution is less likely (high grades, BBD, older age), and DMSA if the ultrasound is abnormal, there is breakthrough UTI or high grade; a normal cystogram may establish resolution, and after it annual assessment continues until adolescence if either kidney is abnormal on ultrasound or DMSA [172].

7.6.2. Endoscopic and surgical treatment

The surgical recommendations of the EAU/ESPU are to offer reimplantation or endoscopic correction for frequent breakthrough infections (weak), reimplantation for persistent high-grade reflux and endoscopic correction for lower grades (strong), surgical repair over 1 year of age with high-grade reflux and abnormal parenchyma (weak) and surgical correction when parents prefer definitive therapy (strong); in high-risk patients with renal impairment, the approach should be multidisciplinary and more intensive (strong) [28]. Surgery is reserved, according to the 2023 EAU/ESPU update, for non-adherence to CAP, febrile breakthrough UTI on CAP and persistent symptomatic VUR [215]. The AUA recommends changing therapy in the event of a symptomatic breakthrough UTI, considering open reimplantation or endoscopic injection with curative intent for febrile breakthrough UTI on CAP and, with a single febrile breakthrough UTI without cortical anomalies, allows switching antibiotic before surgery; per 100 children, resolution was 98.1 (95% CI 95.1–99.1) with open surgery and 83.0 (95% CI 69.1–91.4) after one endoscopic injection, with postoperative obstruction in 0.4 per 100 (95% CI 0.2–1.2), and postoperative ultrasound is standard to exclude obstruction [172]. The Indian guideline reserves surgery in high-grade VUR for parental preference or recurrent febrile breakthrough UTIs [193].

Subureteral endoscopic injection of bulking agents elevates the ureteral orifice and lengthens the submucosal tunnel. Dextranomer/hyaluronic acid gel (Deflux®, Dexell®) and polyacrylate-polyalcohol copolymer hydrogel (Vantris®) are the current agents, and polytetrafluoroethylene is not approved in children because of particle migration [28]. In a meta-analysis of 5527 patients and 8101 renal units, resolution per ureter after one injection was 78.5% in grades I–II, 72% in grade III, 63% in grade IV and 51% in grade V, with a pooled rate of 85% after one or more injections; success was lower in duplex systems (50% against 73%) and neurogenic bladders (62% against 74%) [28]. Late vesicoureteric junction obstruction is more frequent with the polyacrylate-polyalcohol copolymer, which makes later reimplantation more difficult [28]. In the Swedish Reflux Trial (203 children aged 1–2 years with grade III–IV VUR), resolution was 71% with endoscopy, against 39% with prophylaxis and 47% with surveillance [28]. Open reimplantation techniques (Cohen, Politano-Leadbetter, Glenn-Anderson, Lich-Gregoir) have success rates of 92–98% with few complications; extravesical laparoscopic and transvesicoscopic reimplantation are good alternatives, and robotic reimplantation, especially extravesical, has more variable results, higher costs and operating times and less pain, and is recommended only in experienced centres [28, 215]. Up to 30% de novo hydronephrosis may appear after extravesical robotic reimplantation, with spontaneous resolution in the great majority [28].

7.7. Regulatory status

FDA: Food and Drug Administration; PMA: premarket approval.

7.8. Clinical trials

The trials are not comparable with one another: RIVUR included mainly older girls with low-grade reflux after UTI and normal kidneys, PREDICT mainly male infants with high-grade reflux and frequent congenital kidney damage, without prior UTI, and the conclusions of one do not transfer to the population of the other [173]. The similar relative reductions correspond to absolute reductions of 11.9 percentage points in RIVUR (primary intention-to-treat analysis) and 14.4 in PREDICT over two years, with numbers needed to treat of 8 and 7 [173, 214]. The ESCAPE trial was not designed for CAKUT, and the proportion of patients with CAKUT is not given in the abstract [201]. None of the trials showed an effect of prophylaxis on scarring or renal function, and both documented more bacterial resistance [173, 214]. PREDICT was open-label, with antibiotic varying by centre and central reading of only some of the DMSA scans [173]. The RAFT trials have no randomised control group, the first was stopped early, and the primary outcome (survival at 14 days) does not capture later mortality or the burden of neonatal dialysis [33, 34]. The shunt meta-analysis brings together small, heterogeneous studies, with level 4 evidence according to the EAU/ESPU [28].

7.9. Developments in the last 12 months and ongoing research

In the ClinicalTrials.gov registry, the phase 1 study of REACT autologous renal cell therapy in CKD due to corrected CAKUT (NCT04115345; 6 participants; completed in January 2023) has no results posted in the registry and no article was found, and the follow-up study NCT05694169 (1 participant) was terminated [200, 225]. Radiation-free imaging studies are registered: contrast-enhanced ultrasound for renal scarring (RAFTERS, NCT03653702, not yet recruiting, expected start July 2027), direct radionuclide cystography against contrast-enhanced voiding urosonography (NCT06138080, Turku, recruiting) and PIC cystogram against VCUG (NCT07334821, Turkey) [226–228]. A completed Egyptian trial compared endoscopic injection of dextranomer/hyaluronic acid with ureteric reimplantation (NCT04798443; 60 patients) [229]. Among the registered observational studies are the French study of genetic and family assessment of renal hypodysplasia (NCT00925379; 342 participants; completed in 2014, no results in the registry), endocrine and renal follow-up of children with an HNF1B variant (NCT00760331; planned until 2033), the study of standardised prenatal care in LUTO (NCT02315521), validation of the fetal urine peptide classifier in PUV (NCT03116217; 400 participants; status unknown, no results in the registry), the UK rare kidney disease registry RaDaR (NCT06065852; more than 35,000 patients), Italian studies of solitary kidney and horseshoe kidney (NCT01831141; NCT06728007) and a Philippine study of 25 patients with polyacrylate-polyalcohol copolymer (NCT01926353) [230]. A PubMed search did not find publication of the REACT results in CAKUT, which does not prove that none exists [200]. The integration of prenatal ultrasound with the amniotic fluid peptidome to predict postnatal renal function awaits prospective validation [11, 192].

7.10. Agents to avoid, pregnancy, perioperative care and transition

Fetal exposure to ACE inhibitors or ARBs in the 2nd and 3rd trimesters produces a phenocopy of renal tubular dysgenesis, with oligohydramnios and skull ossification defects, so these drugs should be avoided at that stage of pregnancy [30, 83]. NSAIDs and other nephrotoxic agents should be avoided in children and adults with CAKUT, and ototoxic agents in syndromes with hearing loss [23, 103]. In UTI prophylaxis, trimethoprim carries a teratogenic risk in the 1st trimester and nitrofurantoin should be avoided at term because of the risk of neonatal haemolysis [218]. In the 17q12 deletion, antipsychotics causing weight gain are used with caution, lithium is weighed because of its long-term renal effect, and hepatotoxic agents and alcohol are avoided if there is hepatic involvement; these recommendations rest on clinical reasoning, without efficacy studies [21]. In urofacial syndrome and megacystis-microcolon, nephrotoxic agents and drugs that reduce bladder and intestinal motility are avoided [7, 8]. In the branchio-oto-renal spectrum, GeneReviews recommends avoiding loud noise (limit of 75 dB in headphones) and considers the evidence insufficient to prohibit contact sports with an enlarged vestibular aqueduct [22].

In Townes-Brocks syndrome, renal function may deteriorate significantly during pregnancy, which justifies nephrological assessment and, given the possibility of fetal heart disease, prenatal cardiac assessment [23]. In pregnant women with the branchio-oto-renal spectrum and renal involvement, follow-up takes place in maternal-fetal medicine [22]. A woman with PAX2 disease should have a full renal assessment before pregnancy and, if she has clinical kidney disease, a joint plan with nephrology and maternal-fetal medicine [20]. Pregnancy in a woman with CKD carries a risk of decompensation and adverse outcomes, and hypertension, proteinuria and urinary tract dilatation should be screened for [12]. The risk of gestational hypertension and pre-eclampsia is 2.5 times higher in women with a single kidney due to unilateral agenesis or after donor nephrectomy [103]. Small renal scars, even bilateral, have not been shown to cause problems in pregnancy, which arise only with severe bilateral kidney damage [28]. The sources consulted describe no CAKUT-specific risks in lactation.

In the perioperative and hospital setting, gentamicin levels should be measured, nephrotoxic agents minimised and dehydration avoided, especially with a single kidney [99, 103]. There is no evidence-based end point for follow-up; puberty is the period of greatest risk for onset or progression of kidney injury in the ItalKid registry, which justifies planned transition to adult care [99, 103]. ERN eUROGEN has published transition guidelines for rare urorectogenital conditions [36].

7.11. Guideline recommendations and divergences

The 2017 Oxford Desk Reference described antibiotic prophylaxis and surgery for VUR as «equally effective»; subsequent trials and the 2023–2026 guidelines have replaced that statement with a risk-stratified approach [2, 28, 215].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

Counselling depends on whether or not there is a molecular diagnosis. When an AD variant has been identified, the risk to offspring is 50%, but severity is unpredictable, because the same variant produces different phenotypes in the same family and prognosis correlates better with renal morphology than with genotype, especially prenatally [1, 12]. When the variant is de novo, the risk to siblings is limited to germline mosaicism [1]. Without a molecular diagnosis, the ERKNet consensus estimates the risk of recurrence of dysplasia or other CAKUT at up to 20% in a subsequent pregnancy, against less than 0.1% in the general population [12]. The empirical risks of the Oxford Desk Reference and entity-specific data are brought together in Table 8.1.

The proportion of inherited cases varies by entity. In PAX2 disease, about 35% of probands have a clinically affected parent and 65% are simplex cases; among these, the variant was confirmed de novo in 41% (23/56), and the rest had no parental testing [20]. Maternal and paternal germline mosaicism has been documented, with two families in which negative parents had more than one affected child, and a parent with compatible ophthalmological findings, but without the variant in leucocytes, fibroblasts and buccal mucosa, had two carrier children [20]. The parent in whom the PAX2 variant first arose may have somatic mosaicism and be mildly or minimally affected, and when the variant appears to be de novo non-medical causes, such as alternative paternity or maternity and adoption, should be explored [20]. The 17q12 deletion is de novo in 75%; the parents should be tested, because a mildly affected parent may be unaware of the manifestations, and with a carrier parent the risk to siblings is 50%, without prediction of the phenotype, given intrafamilial variability [21]. In the branchio-oto-renal spectrum, the variant arises de novo in about 10–20%, most patients have an unrecognised affected parent, and the parents should be assessed by testing or by targeted examination (hearing loss, pits, lacrimal stenosis, fistulae, kidneys) [22]. In Townes-Brocks syndrome, about 50% have an affected relative and 50% result from a de novo variant, mainly on the paternal chromosome 16 (about 87.5%), with no paternal age effect, and four individuals with somatic and gonadal mosaicism had minimal signs [23]. In GREB1L, a healthy carrier parent is frequent and does not rule out pathogenicity, and in DSTYK heterozygous loss of function does not support predictive testing of relatives [10]. In urofacial syndrome, the variant NM_021828.5(HPSE2):c.1465_1466del p.(Asn489ProfsTer126) is common in families of Irish ancestry and NM_021828.5(HPSE2):c.1516C>T p.(Arg506Ter) is a founder variant in Colombia, which justifies testing the partner in the case of consanguinity or the same origin [7]. The CNVs associated with hypodysplasia are inherited from an apparently unaffected parent in half of cases [2].

8.2. Assessment of relatives

Apparently unaffected relatives (parents and siblings) of patients with unilateral or bilateral dysplasia may have a renal and urinary tract ultrasound, which may reveal unrecognised CAKUT, and should be screened for hypertension and proteinuria [12]. In severe bilateral agenesis or dysgenesis, or in agenesis of one kidney with dysgenesis of the other, ultrasound of parents and siblings is justified because 9% of first-degree relatives have asymptomatic renal malformations [83, 84]. In a population study from the state of Victoria, Australia (221 patients with perinatally lethal kidney disease, 1961–1980), the highest frequency of sibling recurrence (8%) occurred when the index case had bilateral agenesis with other urogenital defects; when bilateral agenesis was part of a multiple malformation syndrome, no sibling had bilateral agenesis, but 5 of 40 (12.5%) had a similar malformation pattern [37]. The same authors warned, in 1988, that a normal parental renal ultrasound does not exclude a recurrence genotype [37]. The ERA recommends parental renal ultrasound when possible, together with a detailed family history and phenotype [1]. In contrast, in unilateral MCDK, which is mainly sporadic, Belk et al. (2002) found no significant renal anomaly in 94 first-degree relatives, so formal screening of relatives is not recommended; parental ultrasound is also not indicated in mild pyelectasis [2]. In VUR, the EAU/ESPU does not recommend screening all siblings and offspring, for lack of trials on clinical outcomes, but recommends informing parents of the high prevalence (strong); VUR detected by screening is of lower grade and resolves earlier, whereas VUR discovered after UTI in a sibling is usually high grade and with reflux nephropathy, especially in boys and when the index case has high-grade reflux [28]. Renal cortical anomalies appear in 14.4% of screened asymptomatic siblings [28]. The AUA recommends VCUG or radionuclide cystography in a sibling with cortical anomalies or renal size asymmetry on ultrasound, or with UTI, and allows as options observation without screening with prompt treatment of UTIs, screening of older toilet-trained siblings and renal ultrasound of the sibling, applying the same criteria to offspring [172]. In PAX2 disease without an identified variant in the family, at-risk relatives should have a dilated ophthalmological examination, renal ultrasound, renal function, uric acid, urinalysis and BP [20]. In the branchio-oto-renal spectrum, asymptomatic relatives have molecular testing if the variant is known or, failing that, a full examination of hearing, imaging and renal function, a single major criterion in a relative of an affected person being sufficient for the diagnosis [22]. In urofacial syndrome, siblings should be examined soon after birth (facies and urinary ultrasound, or testing if the variants are known), and in megacystis-microcolon at-risk relatives may have testing or bladder ultrasound and contrast enema [7, 8]. DNA from probands without a molecular diagnosis should be stored for future studies [22].

When a variant has been identified, cascade testing of at-risk relatives, including asymptomatic children, allows early surveillance to be started in PAX2 disease and Townes-Brocks syndrome, and in a family with HNF1B disease allows early screening for diabetes and hypertension [12, 20, 23]. Testing of minors is justified in these entities because the result changes surveillance in childhood (renal function, BP, hearing, ophthalmology), and GeneReviews recommends counselling before testing under 18 years of age and considers it beneficial to test asymptomatic children in PAX2 disease [20]. Testing is also indicated before kidney donation by a relative [1].

8.3. Prenatal and preimplantation diagnosis

Once the familial variant has been identified, prenatal diagnosis and preimplantation genetic testing (PGT) are possible, and late fetal ultrasound allows the renal malformations and fluid volume to be assessed [20]. In families with an AD variant of variable expressivity, parents often opt for fetal ultrasound surveillance targeted at renal morphology rather than early molecular diagnosis by CVS, because the genotype does not predict severity; the decision is individual [1]. In AR forms, such as bilateral renal agenesis due to ITGA8, Fraser syndrome, megacystis-microcolon-intestinal hypoperistalsis syndrome or renal tubular dysgenesis, counselling supports the decision on prenatal or preimplantation diagnosis [1]. In the European EUROCAT series of Fraser syndrome, 54% of pregnancies ended in termination, 8% in stillbirth and 38% in live birth, and 82% of pregnancies with prenatal detection were terminated [10]. In the 17q12 deletion, prenatal diagnosis and preimplantation testing are possible, but the prenatal result does not predict the phenotype [21]. In pregnancies at risk of urofacial syndrome, ultrasound in the 2nd and 3rd trimesters may direct delivery to a tertiary centre, although fetal megacystis and hydroureteronephrosis are not specific [7].

Without a molecular diagnosis, the ERKNet consensus recommends, in the next pregnancy, referral to a prenatal diagnosis centre at (16–)18–20 weeks to assess amniotic fluid and renal morphology, and considering earlier assessment (for example at 16 weeks or before) if a vesicoamniotic shunt is an option, because fluid volume at that stage depends mainly on fetal urine output and correlates with postnatal prognosis [12]. In couples in which the man has congenital absence of the vasa deferentia with renal agenesis (without CFTR variants), in a series of 11 pregnancies achieved, cited by the Oxford Desk Reference, one resulted in a male fetus with bilateral renal agenesis and absent vasa deferentia, so detailed fetal ultrasound of the renal tract should be offered [104].

8.4. Content of counselling

Prenatal diagnosis of a urological anomaly imposes a considerable emotional burden, and families ask for clear and realistic prognostic information; counselling should be structured, repeated over several consultations, adapted to the family's circumstances, include the reproductive implications and ensure access to psychological support and written material [28]. The family should know that the prenatal diagnosis may not be definitive and will be confirmed and refined after birth, and counselling should respect the cultural, ethical and legal context of each country [28]. It should be explained that variable expressivity makes severity in an affected child unpredictable, that the molecular diagnosis rarely predicts renal function prenatally (except in recurrent pathogenic CNVs), and that the 17q12 deletion carries a neurodevelopmental risk, considered high by some authors and less penetrant in the cohort ascertained through renal anomalies [1]. Non-medical aspects, such as religious beliefs, implications for insurance and the right not to know, should be respected [12]. The UK resource ARC (Antenatal Results and Choices) supports parents faced with a prenatal diagnosis [30].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

Frequency estimates of renal malformations depend on the method of ascertainment (congenital anomaly registry, prenatal ultrasound series, hospital cohort or meta-analysis), on whether terminations of pregnancy are included and on the period, and therefore differ between sources. Table 9.1 brings together the available values and what each measures.

Country values for bilateral renal agenesis in the 2009–2010 EUROCAT registries range from 0.6 (Spain) to 24.1 (Malta) per 100,000 births: France 4.5; Germany 5.8; Italy 1.4; Netherlands 5.7; Ireland 10.8; Norway 3.2; Poland 1.2; Hungary 2.2; Denmark 19.0; Austria 9.7; Belgium 3.0; Croatia 13.6; United Kingdom 1.2; Ukraine 3.2 [25]. These are birth prevalences in registries, not population prevalences; the extent of the variation is not explained in the sources consulted and may reflect differences in ascertainment and recording, as well as small absolute numbers [25]. Portugal is not among the countries with a validated value in that Orphanet product. The value of 0.12 per 1000 in the Oxford Desk Reference (12 per 100,000) is about seven times higher than the European mean, and the book does not state the series or period; the difference should not be read as a difference between populations [2, 25]. Likewise, unilateral agenesis went from 0.15 per 1000 in the reference text to about 1 in 2000 in the systematic review, which brings together mainly ultrasound series [2, 26]. The prevalence of bilateral renal hypoplasia is not established, partly because the registries (ESPN/ERA, NAPRTCS) group aplasia, hypoplasia and dysplasia together [12, 25].

9.2. Data by region

In the USA, CAKUT accounted for about 40% of children with kidney failure in a study cited by Kohl et al. [81]. The exome study by Groopman et al. (3315 patients with CKD, 35.6% of non-European ancestry) and the RIVUR trial are the largest North American series [105, 214]. In the MORL laboratory (Iowa), up to January 2025, 58 of 8032 patients with hearing loss screened (0.72%) had the branchio-oto-renal spectrum [22]. In Europe, in addition to the EUROCAT registries, the data come from the UK 100,000 Genomes Project (1052 patients with CAKUT), the PREDICT trial (39 centres, with recruitment in Italy, Turkey, Poland, Lithuania, Belgium and other European countries; the author list includes a Portuguese investigator), the Dutch solitary kidney cohorts, the Italian ItalKid registry and the Leipzig centre [80, 103, 113, 173]. In Germany, the cohort of 229 adults with CAKUT and kidney failure described age at kidney failure by subtype, and the Charité series of 103 fetuses with MCDK the associated anomalies [110, 156]. The European ESCAPE blood pressure control trial included a Portuguese centre [201]. In Spain, Fraser syndrome had 0.43 per 100,000 live births, with 4 of the 7 cases of Roma ethnicity (a frequency 129 times higher) [10]. In the Global KRT Registry of the International Pediatric Nephrology Association (23,620 children from 80 countries, including the European ESPN/ERA, North American USRDS and Australian ANZDATA registries), CAKUT and inherited nephropathies predominated in the youngest children, with the cause unknown in 14% [224]. In Brazil, the Belo Horizonte cohort (822 children with prenatally diagnosed nephrouropathies) described UTI in 29.8% and CKD in 6% [158]; a nested cohort from the same university hospital (857 newborns with CAKUT, 1996–2021) quantified early mortality at 7.2% [155]; and the centre took part in the APOL1 pilot study in CAKUT of African ancestry [149]; and a Campinas cohort contributed to the description of the visceral myopathy and megacystis-microcolon spectrum (Moreno 2016, according to the Oxford Desk Reference) [2]. In Japan, SALL1 appeared in 14 of 1108 families with kidney disease and GATA3 in 7 of 1254 families with CKD [134, 135], and a 2009–2010 national survey estimated 250 patients with the branchio-oto-renal spectrum (95% CI 170–320), an apparently lower prevalence than in the West, and a series of 66 patients with severe CAKUT found variants in 30% (10/33) when MCDK or aplasia coexisted with a severe contralateral malformation [22, 99]. In China, the Wuhan cohort identified PAX2, WT1 and the 17q12 deletion as the most prevalent causes [114]. In Quebec (Canada), exome sequencing of 101 fetuses with severe anomalies gave a diagnosis in 19% [95].

9.3. Founder populations, consanguinity and ancestry

The recessive forms are concentrated in populations with consanguinity: the founder null variant in NPNT was identified in Saudi families, the FGF20 form in a consanguineous family, Fraser syndrome is frequently associated with consanguinity and, in the UK study, consanguinity tripled the probability of a monogenic diagnosis (OR 3.0) [55, 80, 90, 96]. Urofacial syndrome has a higher prevalence in regions with founder variants, such as Colombia (NM_021828.5(HPSE2):c.1516C>T p.(Arg506Ter)), and a frequent variant in patients of Irish ancestry [7, 10]. Spastic paraplegia 23, allelic and recessive to DSTYK, is due to a founder deletion-insertion shared by three consanguineous Middle Eastern families, and CHRNA3 autonomic bladder dysfunction has been described in three families (Arab, Pakistani and Macedonian), two of them consanguineous [15, 142]. The data from Portugal and Brazil in the OMIM entries consulted consist only of case reports: a Portuguese woman with HDR syndrome and uterovaginal agenesis without renal anomaly (Moldovan 2011) and a Brazilian girl with ACTA2 smooth muscle dysfunction syndrome and prenatal megacystis, identified in a series of seven children with visceral myopathy (Moreno 2016) [16, 54]. The same Brazilian series includes three children with megacystis-microcolon due to de novo ACTG2 variants and a consanguineous sibship with the MYL9 form, later explained by a deletion of about 7 kb from intron 3 to downstream of the gene (Moreno 2018) [75, 76]. There are also a large Brazilian family with PAX2 disease (Porteous 2000) and two stillborn Brazilian siblings with Fraser syndrome, homozygous for a FRAS1 splicing variant, one of them with a phenotype close to ablepharon-macrostomia syndrome (Cavalcanti 2007) [56, 119]. One of the families with the recurrent FREM2 variant of Fraser syndrome 2 was of Spanish Roma origin (Jadeja 2005) [57]. In the gnomAD analysis, predicted pathogenic variants in the six most frequent CAKUT genes were more common in African Americans (1/149) and less common in Ashkenazi Jews (1/864), and more than half were missense, many without clinical expression [223]. Fraser syndrome is associated with consanguinity in 27% in the EUROCAT series and in 41% in a review of 40 cases [10]. Spastic paraplegia 23 due to DSTYK has been described in Israeli and Palestinian-Jordanian families [10]. PAX2 disease has no known founder effect in any population [20]. More than 95% of PREDICT participants were white, which limits application to other ancestries, and the authors mention a lower incidence of VUR in black people [173]. Most genetic studies have a predominance of European ancestry, and the sources consulted provide no estimates of yield by ancestry.

9.4. Sex and special populations

Bilateral renal agenesis and MCDK show male predominance (2.45:1 and 2.4:1), but females have twice as much bilateral disease in MCDK; PUV are exclusive to males and infant VUR is more frequent and of higher grade in boys [2, 28]. In girls with solitary kidney, Müllerian malformations require gynaecological surveillance between thelarche and menarche [99]. Prematurity (less than 36 weeks), growth restriction (below the 10th percentile) and low birth weight (less than 2500 g) are risk factors considered in blood pressure surveillance of the single kidney [103]. Pregnancy in women with a single kidney or CKD carries its own risks (section 7.10). Adults with CAKUT undiagnosed in childhood may present with CKD of unknown cause, and the proportion of CAKUT among adult CKD is probably underestimated [1].

9.5. Reference networks and patient associations

ERKNet (European Rare Kidney Disease Reference Network), one of the 24 ERNs, has a working group on congenital malformations and ciliopathies, publishes consensus statements on non-obstructive renal dysplasia, fetal LUTO, genetic testing in CKD and spinal dysraphism, maintains the ERKReg registry and is preparing, with eUROGEN, recommendations on megaureter and high-grade VUR expected in the 4th quarter of 2026 [35]. ERN eUROGEN covers non-syndromic urorectogenital malformations and anorectal malformations, has published transition guidelines and has a European patient advocacy group (ePAG) [36]. The ERKNet patient portal (https://www.erknet.org/patients) includes patient representatives, organisations, patient pathways and the ERKReg registry, in partnership with the European alliance EURORDIS, and the UK RaDaR registry, with more than 35,000 patients from 109 centres, has rare disease groups that include HNF1B [35, 208, 230]. The patient resources cited in the sources include ARC (United Kingdom), the Kidney Foundation of Canada, the National Kidney Foundation (USA), the low vision programme of the National Eye Institute (USA), Unique and Chromosome Disorder Outreach (CNVs), the MMIHS Foundation and the Prune Belly Syndrome Network [8, 20–22, 30]. The sources consulted identify no CAKUT-specific patient associations in Portugal or Brazil.

10. Illustrative Clinical Case

10.1. PAX2 disease diagnosed in adulthood (Zhi et al., 2026)

Zhi et al. described a 28-year-old woman without anomalies at birth, in whom a routine examination revealed abnormal renal function, with serum creatinine of 239 µmol/L and, 20 days later, of 262.98 µmol/L, and proteinuria of 1.59 g/24 h [121]. Autoimmune antibodies and hepatitis B and tuberculosis serologies were negative, and there was no history of CKD, acute infection or drug exposure [121]. MR urography showed multiple bilateral parapelvic cystic foci, hypointense on T1 and hyperintense on T2, with sharp outlines, without pelvicalyceal dilatation (Figure 1 of the article) [121]. The initial hypotheses were glomerulonephritis and atypical polycystic disease [121].

Genetic testing identified the heterozygous variant NM_000278.5(PAX2):c.76dup p.(Val26GlyfsTer28), the most common recurrent variant in PAX2 disease, historically designated 619insG and classified as pathogenic in ClinVar [118, 121]. The parents were healthy and did not carry the variant, which was considered de novo [121]. Guided by the molecular diagnosis, scanning laser ophthalmoscopy showed small, crowded optic discs and many myelinated nerve fibres in both eyes (Figure 2 of the article), with macular optical coherence tomography (OCT) and OCT angiography without changes, a normal 24-2 visual field and corrected acuity of 1.0 in both eyes, with myopia and astigmatism (right eye −6.25 dioptres sphere and −2.25 cylinder × 166°; left eye −5.50 sphere and 2.75 cylinder × 178°) [121]. She was followed with monthly assessment of renal function and annual eye examination, and renal function remained stable without ocular deterioration [121]. The figures were consulted on the article pages in PubMed Central, through their legends, without independent interpretation of the images.

In the authors' literature review (58 articles, 166 affected individuals, 51 PAX2 variants and 5 chromosomal anomalies), c.76dup was present in 27% of patients [121]. The case illustrates three aspects of this article: PAX2 disease may present only in adulthood, with CKD and proteinuria, and be mistaken for a glomerulopathy or cystic disease; the ocular manifestations may be mild and recognised only after the molecular diagnosis; and a de novo variant reduces the recurrence risk for siblings to that of germline mosaicism, while keeping 50% for offspring [20, 121]. The monthly frequency of renal function testing used in the report does not correspond to a GeneReviews recommendation, which defines no intervals, and reflects the clinical decision in a case with reduced eGFR [20].

10.2. Complementary cases diagnosed through the family history (Hilger et al., 2026)

The review by Hilger, Westland and Hoefele describes two cases that show the value of targeted observation of relatives [11]. In the first, a 30-year-old man with diabetes since the age of 25, labelled as type 2 and insulin-dependent five years later, had bilateral renal hypoplasia on a routine ultrasound; the initial suspicion was autosomal dominant tubulointerstitial kidney disease, genetic counselling raised the possibility of HNF1B disease and a heterozygous pathogenic variant was confirmed [11]. The father had been diabetic since the age of 24, two insulin-dependent paternal uncles had received kidney transplants and the paternal grandmother, diabetic, died at 50, without segregation study [11]. In the second, a 6-year-old girl with proteinuria and bilateral renal hypoplasia had a father with CKD of unknown cause for more than 10 years; at counselling, an operated preauricular tag and bilateral triphalangeal thumbs were detected in father and daughter, and in the father hearing loss and anal canal stenosis operated in childhood, and both had a heterozygous pathogenic variant in SALL1 (Townes-Brocks syndrome) [11]. In both cases, recognition of subtle extrarenal signs in the patient and the parent guided testing and changed surveillance (diabetes in the first; hearing and annual renal function in the second) [21, 23].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

In its natural history, bilateral renal agenesis is lethal in the perinatal period due to pulmonary hypoplasia [30, 83]. With serial amnioinfusions within a trial, 82% of live births with bilateral agenesis and 65.5% of live births with fetal kidney failure of other causes survived 14 days or more with dialysis access, but only 35% and 48% were discharged from hospital, and among survivors of the second cohort 64% were transplanted between 2 and 5 years of age [33, 34]. Anhydramnios before 20 weeks is associated with survival of 15–24% in LUTO [28]. In the Brazilian cohort of 857 newborns with CAKUT, early mortality was 7.2%, with a five-fold higher risk in agenesis or hypodysplasia and in LUTO [155].

In hypodysplasia, the renal prognosis depends mainly on bilaterality, nephron mass and extrarenal anomalies. Unilateral dysplasia with a normal contralateral kidney generally has a good prognosis, and bilateral dysplasia rarely requires KRT in the first year, but about 50% of children in the NAPRTCS CKD registry progressed to kidney failure within 5 years [12]. In the Wuhan cohort, 22.4% of children with hypodysplasia reached early CKD over a median follow-up of 4.5 years, with a 4.4-fold higher risk in bilateral disease [114]. In unilateral agenesis, 16% have hypertension, 21% microalbuminuria and 10% GFR below 60 mL/min/1.73 m² [26]; in congenital solitary functioning kidney, rates of kidney injury at 15 years range between 6% and 60%, and early compensatory hypertrophy predicts a more favourable prognosis [103]. A single kidney without compensatory enlargement and/or with ipsilateral CAKUT carries a risk of reduced GFR and progression (grade B), and the prevalence of proteinuria is higher than in the paediatric population (grade B) [99]. The risk of malignancy in MCDK does not appear to be increased and does not justify ultrasound screening [103]. In the Italian series by Sanna-Cherchi et al., the risk of dialysis was higher in single kidney (HR 2.43) and in hypodysplasia with PUV (HR 5.1), and in German adults who reached kidney failure the median age was 22 years in bilateral or syndromic forms and 37 years in unilateral forms [110, 150]. In adulthood, the congenital single kidney had an annual eGFR loss of 3 mL/min/1.73 m² in a Turkish series [157], and the review by Hewitt and Montini places the mean start of KRT in CAKUT at around 31 years, with increased cardiovascular and metabolic risk [24].

By genetic entity, the mean age at diagnosis of kidney failure in PAX2 disease is 19.5 years (from birth to 79) [20]; in adult HNF1B disease, progression to kidney failure was 51% with the 17q12 deletion and 78% with intragenic variants in a retrospective cohort, and kidney failure in childhood is uncommon [21]; in the branchio-oto-renal spectrum, CKD occurs in about 6% [86]; in Townes-Brocks syndrome, kidney failure occurred in 39.6% of a French series and in 29.3% of the literature [133]; in urofacial syndrome, the proportion with severe renal failure is unknown and depends on prompt treatment of UTIs [7]; and in megacystis-microcolon, survival at 5 and 10 years was 63% and 57% in a Japanese national survey [8]. In PUV, CKD occurs in up to 65% and kidney failure in about 20% despite treatment [28]. In reflux nephropathy, 10–20% of children develop hypertension or kidney failure [28]. The 2024 update of the Spanish clinical practice guideline considers progression to CKD very unlikely in most children with UTI [231]. In isolated prenatal hydronephrosis, a nine-year follow-up found no hypertension, CKD or kidney injury in class P1 of the urinary tract dilation (UTD) classification, with higher frequencies in classes P2 and P3 [28]. In the Brazilian cohort of 822 children with prenatally diagnosed nephrouropathies, mortality was 1.5% and CKD 6% over 43 months [158]. There is no evidence-based end point for follow-up, and the risk of hypertension and loss of function persists into adulthood, with puberty as the period of greatest risk [103].

11.2. Follow-up of non-obstructive renal dysplasia

Source: ERKNet consensus [12]. In CKD, annual ABPM, office BP every 3 to 6 months and a MAP target at or below the 50th percentile apply [12, 32].

11.3. Follow-up of congenital solitary kidney

The SINePe consensus stratifies follow-up by risk (expert opinion), as shown in Table 11.2 [99]. Low risk corresponds to renal length above the 50th percentile in the first two years and at or above the 95th percentile thereafter, without ipsilateral CAKUT; medium risk, to absence of compensatory enlargement and/or ipsilateral CAKUT; and high risk, to reduced eGFR (below −1 standard deviation of the mean for age before 2 years; below 90 mL/min/1.73 m² thereafter), proteinuria and/or hypertension [99].

Source: SINePe 2022, Table 8 [99]. If there is proteinuria, the protein/creatinine ratio is quantified in the second morning urine, normal below 0.5 mg/mg until 2 years and below 0.2 mg/mg thereafter; all children with solitary kidney should be followed until adulthood according to this stratification (grade B) [99].

The Dutch proposal by Groen in 't Woud et al. differs in several intervals: ultrasound 1–2 weeks after birth, at 1 year and in the event of UTI, and then at 5, 10 and 15 years (possibly stopping after compensatory hypertrophy greater than 2 standard deviations); initial creatinine at 1–2 weeks (with anomalies) or at 2–3 months (without anomalies) and then every 5 years until puberty and every 2 years thereafter; annual urinary ACR; first BP at about 3 months and then at least annually; and ABPM to be considered in all from 5 years of age, annual if there is current or previous hypertension or CKD [103]. The SINePe consensus does not recommend routine ABPM with normal office BP (grade C), recommends it above 5 years with office BP above the 95th percentile (grade C) and strongly considers it in CKD of grade II or above, prematurity or obesity (grade C); in 10 studies with 379 children assessed by ABPM, about 22% had raised office BP before ABPM [99]. Both proposals rest on expert opinion, and the choice should be consistent within each centre.

11.4. Surveillance table

11.5. Transition to adulthood

Follow-up should continue at least into adulthood in all forms of dysplasia and in congenital solitary kidney, with planned transition to adult nephrology, because the risk of hypertension, proteinuria and loss of function persists and puberty is the period of greatest risk [12, 99, 103]. In women, surveillance before and during pregnancy follows section 7.10 [12, 20].

12. Summary and Final Considerations

Congenital anomalies of the kidney and urinary tract encompass renal agenesis, aplasia, hypoplasia and dysplasia, collecting system anomalies, vesicoureteric reflux and lower tract obstruction, and are the main cause of chronic kidney disease in children and young adults [1, 79]. Hypoplasia (length below −2 standard deviations with normal differentiation) and dysplasia (reduced corticomedullary differentiation or thin cortex, with or without cysts) are defined by ultrasound according to the ERKNet consensus, and should be described separately, although they frequently coexist [12]. Bilateral renal agenesis, lethal in its natural history due to pulmonary hypoplasia, now has initial neonatal survival within a trial with serial amnioinfusions, with significant neonatal morbidity and mortality, dialysis from the first month and transplantation in early childhood, and the intervention continues to be considered experimental outside research protocols [28, 33, 34].

The genetic architecture combines more than 50 genes, mostly of dominant inheritance with incomplete penetrance and variable expressivity (PAX2, HNF1B, EYA1, SALL1, GATA3, GREB1L, PBX1), recessive forms in bilateral agenesis (ITGA8, FGF20, GFRA1, NPNT), CNVs (17q12, 22q11.2, 16p11.2, 1q21.1) and a polygenic component [11, 12, 80]. The diagnostic yield varies between about 5% in an unselected cohort studied by genome sequencing and 15–20% in bilateral, familial or syndromic forms, and a negative result neither excludes a genetic cause nor reduces the empirical recurrence risk, which may reach 20% [1, 12, 80]. Genetic testing is recommended in familial or syndromic dysplasia and suggested in bilateral dysplasia, preferably by panel or exome with CNV analysis and as a trio; isolated sporadic solitary kidney has no routine indication [12, 99]. The evidence by gene is uneven: ClinGen confirms as definitive the relationships of PBX1, EYA1, SIX1, GATA3, HNF1B and SALL1, but has not curated most of the bilateral agenesis genes or those of familial VUR, whose SOX17 and TNXB loci rest on one or two families [19, 62, 67]. The identified variant guides the search for extrarenal manifestations (optic nerve and retina in PAX2, diabetes and magnesium in HNF1B, hearing in the branchio-oto-renal spectrum and in SALL1, calcium in GATA3, neurodevelopment in CNVs), counselling and the choice of living donor [1, 20].

Management is supportive and multidisciplinary: blood pressure control with a target at the 50th to 75th percentile, renin-angiotensin-aldosterone system inhibitors in the presence of hypertension or albuminuria, avoidance of anti-inflammatory drugs and other nephrotoxic agents, no sports restriction in solitary kidney and follow-up into adulthood, with intervals that differ between the Dutch and Italian consensus statements [12, 99, 103]. In vesicoureteric reflux, the RIVUR and PREDICT trials show that antibiotic prophylaxis reduces infections by about 12–14 percentage points over two years, with no effect on scarring or renal function and with more bacterial resistance, which has led to a selective approach based on sex, grade, bladder and bowel dysfunction and circumcision, with divergence between NICE, the 2026 AAP, the AUA and the EAU/ESPU in the first year of life [28, 100, 172, 173, 188, 214]. The paediatric doses of ACE inhibitors and ARBs labelled in the USA refer to hypertension, and their antiproteinuric use in CAKUT, like magnesium supplementation in HNF1B disease, is off-label [32, 189, 202]. The genetic bladder disorders (urofacial syndrome, megacystis-microcolon, MYOCD) mimic obstruction and require bladder drainage and prompt treatment of UTIs to protect the kidney [7, 8]. Ultrasound of parents and siblings in dysplasia and bilateral agenesis, information on the high prevalence of reflux in siblings and offspring and fetal ultrasound surveillance in subsequent pregnancies complete the care of the family [12, 28, 84].

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59. OMIM® Online Mendelian Inheritance in Man. #267430 RENAL TUBULAR DYSGENESIS; RTD. Johns Hopkins University; last edited 03/11/2025. https://omim.org/entry/267430. Accessed 30 October 2026.
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63. OMIM. 614317 VESICOURETERAL REFLUX 4; VUR4. Online Mendelian Inheritance in Man. Johns Hopkins University. Available from: https://omim.org/entry/614317. Accessed 17 Oct 2026.
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65. OMIM. 614319 VESICOURETERAL REFLUX 6; VUR6. Online Mendelian Inheritance in Man. Johns Hopkins University. Available from: https://omim.org/entry/614319. Accessed 17 Oct 2026.
66. OMIM. 615390 VESICOURETERAL REFLUX 7; VUR7. Online Mendelian Inheritance in Man. Johns Hopkins University. Available from: https://omim.org/entry/615390. Accessed 17 Oct 2026.
67. OMIM. 615963 VESICOURETERAL REFLUX 8; VUR8. Online Mendelian Inheritance in Man. Johns Hopkins University. Available from: https://omim.org/entry/615963. Accessed 17 Oct 2026.
68. OMIM® Online Mendelian Inheritance in Man. *613469 HEPARANASE 2; HPSE2. Johns Hopkins University; last edited 11/07/2024. https://omim.org/entry/613469. Accessed 28 October 2026.
69. OMIM® Online Mendelian Inheritance in Man. *608869 LEUCINE-RICH REPEATS- AND IMMUNOGLOBULIN-LIKE DOMAINS-CONTAINING PROTEIN 2; LRIG2. Johns Hopkins University; last edited 11/02/2015. https://omim.org/entry/608869. Accessed 28 October 2026.
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