Autosomal Recessive Renal Tubular Dysgenesis

Disorder of renal tubular development due to biallelic defects of the renin-angiotensin system (AGT, REN, ACE and AGTR1)

Literature and regulatory information updated: 1 November 2026.

0. Initial Reference Table

1. Introduction

1.1. Definition and scope

Autosomal recessive renal tubular dysgenesis is a disorder of fetal kidney development in which the proximal convoluted tubules fail to differentiate, although the kidneys are of normal size and shape. The functional consequence is anuria that begins in fetal life and persists, with progressive oligohydramnios, Potter sequence, pulmonary hypoplasia and, after birth, arterial hypotension that responds poorly to the usual vasopressors, and renal failure [6, 24, 25]. A defect of ossification of the membranous bones of the skull vault is frequently associated, manifesting as wide sutures and fontanelles or as hypocalvaria [1, 26]. The genetic form results from biallelic variants in any one of four genes encoding components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin I-converting enzyme, ACE) and AGTR1 (angiotensin II type 1 receptor) [1]. Because severity does not differ consistently between genes and the mechanism is failure of the common pathway, the disease is treated as a single class defined by the pathway rather than by the gene [6, 18].

The same histological lesion arises when the fetal kidney is hypoperfused for another reason. Orphanet therefore recognises a parent entity, "Renal tubular dysgenesis" (ORPHA:3033), with three aetiological subtypes: the form of genetic origin (ORPHA:97369, corresponding to OMIM #267430), the drug-related form (ORPHA:97368), mainly ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), and the donor form in twin-twin transfusion (ORPHA:97367) [2–5]. The acquired forms are treated as differential diagnoses, including fetopathy due to pharmacological blockade of the RAS; tubular dysgenesis also features among the congenital anomalies of the kidney and urinary tract.

1.2. Historical overview

The entity was described as a familial pathological finding by Allanson, Pantzar and MacLeod in 1983: two stillborn sisters, consecutive children of a non-consanguineous Chinese couple, with Potter sequence and kidneys in which normal proximal convoluted tubules were lacking and all tubules had a primitive appearance, resembling collecting ducts [1]. In 1986 Swinford and colleagues described a second family, of northern European and American ancestry, with three children who died from oligohydramnios sequence and pulmonary hypoplasia, and Schwartz and colleagues reported siblings with "isolated congenital renal tubular immaturity" [1]. MacMahon and colleagues reviewed twelve cases from five families in 1990, and Allanson and colleagues added nine cases from a single paediatric centre in 1992, stressing that amniotic fluid volume could be normal before 22 weeks and that the disease might not be as rare as had been assumed [1, 12].

The link with the skull came from comparison with ACEI fetopathy. Barr and Cohen had proposed in 1991 that fetal hypotension explained the hypocalvaria in those exposed to these drugs, because the membranous bone of the skull vault is highly vascularised and depends on a high oxygen tension, unlike endochondral bone, which is spared [1]. McFadden and colleagues described two cases of tubular dysgenesis with hypoplasia of the skull vault in 1997 and noted that six of the 24 cases in Allanson's series had microcephaly, poorly developed cranial bones or widely open fontanelles, proposing that the skull anomalies were a common component of the inherited form [1, 26]. In 1995 Ariel and colleagues showed by nephron microdissection, in a consanguineous Palestinian family, that the hypoplasia affected all segments, from the glomerulus to the collecting duct [1].

The founding paper of the Mendelian form is that of Gribouval and colleagues, published in Nature Genetics in 2005: in eleven individuals from nine families they found homozygous or compound heterozygous variants in REN, AGT, ACE or AGTR1, and proposed that the renal lesion and early anuria resulted from the chronically low perfusion pressure of the fetal kidney caused by inactivity of the RAS [24]. It was the first Mendelian kidney disease attributed to RAS defects [24]. The following year Lacoste and colleagues described the pathology and RAS expression in 29 fetuses and newborns from 18 families [11], and in 2012 Gribouval and colleagues brought together 54 distinct variants in 48 unrelated families [6]. The idea of a uniformly lethal disease was revised from 2006–2008, with the first survivors beyond the neonatal period [22, 27, 28], and from 2020 with the description of attenuated forms presenting as chronic kidney disease in childhood or adolescence [13, 14].

1.3. Nomenclature and associated entities

OMIM entry #267430 has the title "Renal tubular dysgenesis; RTD", with the synonym "primitive renal tubule syndrome", and includes an entity without a known molecular basis, "renal tubular dysgenesis with choanal atresia and athelia" [1]. The latter was described by Hisama and colleagues in 1998 in three siblings who died in the neonatal period with tubular dysgenesis, absent nipples, preauricular pits and tags, branchial clefts, choanal atresia, abnormal lung lobulation, ventricular septal defect, type IIB interrupted aortic arch, absent gallbladder, thymus and parathyroid, accessory spleen and imperforate anus; the inheritance remained undetermined (X-linked recessive, dominant with gonadal mosaicism or subtle deletion) [1]. Horvath and Armstrong reported in 2007 a girl with a similar picture, renal magnesium wasting, renal function that improved in the first weeks, adrenal insufficiency, cerebral calcifications and death at 13 weeks, and defined as core features choanal atresia or stenosis, athelia, renal tubular dysfunction and a history of cervical cysts or branchial clefts [1]. Given the syndromic phenotype and the absence of a demonstrated RAS defect, this is probably a distinct entity, which should be considered in the differential diagnosis.

In the literature, the genetic form appears with the abbreviations RTD, ARRTD or AR-RTD and, in some papers, as "tubular dysplasia" [16]. In this article, RTD denotes the lesion in general and AR RTD the genetic form.

2. Molecular Genetics and Pathophysiology

2.1. The renin-angiotensin system and the fetal kidney

The RAS is a cascade in which renin, an aspartic protease synthesised by the juxtaglomerular cells of the kidney and secreted after removal of a signal peptide and a prosegment, cleaves hepatic angiotensinogen into angiotensin I; this is the rate-limiting step, and angiotensinogen is the only known substrate of renin [29, 30]. ACE, a dipeptidyl carboxypeptidase with two catalytic domains that exists in membrane-bound and circulating forms, converts angiotensin I into angiotensin II and inactivates bradykinin [9]. Angiotensin II acts mainly through the AT1 receptor, encoded by AGTR1, a Gq protein-coupled receptor that mediates vasoconstriction, aldosterone release and renal sodium retention [31]. Angiotensin II also stimulates vasopressin secretion by the neurohypophysis [18]. In the fetus, the system maintains arterial pressure and renal blood flow, and is essential for the normal differentiation of the proximal tubules [6, 30].

Any biallelic variant that abolishes the production of angiotensin II (loss of renin, angiotensinogen or ACE) or its action (loss of the AT1 receptor) produces the same result: low systemic arterial pressure and renal blood flow during fetal life, which prevent development of the proximal tubules [6, 15]. The same lesion arises in renal hypoperfusion of other causes — the donor in twin-twin transfusion, major heart defects, congenital haemochromatosis or exposure to RAS blockers — which supports the hypothesis that the determinant is haemodynamic [1, 15]. Fetal hypotension also explains the hypocalvaria, through the vulnerability of membranous bone to hypoxia [1].

2.2. Pathology and expression of the renin-angiotensin system

In the series of Lacoste and colleagues (29 fetuses and newborns from 18 families), severe proximal tubular defects were present in all fetuses from 18 weeks of gestation and the lesions extended to other tubular segments; there was thickening of the arterial wall from the arcuate arteries to the afferent arterioles [11]. Immunohistochemistry separated two patterns: renal renin was markedly increased, with hyperplasia of the producing cells, in 19 of 24 patients from 13 families (defects downstream of renin, in AGT, ACE or AGTR1), and was undetectable in four patients from three families (REN defects) [11, 31]. Angiotensinogen and ACE were absent or scarce in the proximal tubule, in proportion to the severity of the lesion, and expression of angiotensin II receptors showed no specific changes [11]. This renin pattern has diagnostic value because it points towards the gene before the molecular result.

The exact mechanism by which hypoperfusion prevents tubular differentiation is still under study. Kidney organoids derived from induced pluripotent stem cells with ACE or AGTR1 knocked out formed proximal tubules indistinguishable from controls in vitro; however, organoids lacking AGTR1 did not engraft under the renal capsule of immunodeficient mice because of insufficient VEGF-A production, a defect corrected by hypoxia at 2% oxygen or by ectopic expression of VEGF-A, which led the authors to propose delayed angiogenesis as a non-autonomous cause of the dysgenesis [32]. Another group showed in human organoids that AT1 receptor signalling modulates the fate of nephron progenitors [33]. These data are preclinical.

2.3. The four genes and the variant spectrum

In the 2012 series, ACE was the most frequent gene, present in two thirds of families (64.6%), followed by REN (about one fifth of families, 20% in OMIM), AGT (four families) and AGTR1 (three families); most of the 54 variants were novel [1, 6]. OMIM gives 64.4% for ACE; the value in the original paper is 64.6% [1, 6]. The variants include nonsense substitutions, small frameshifting deletions and insertions, splicing variants, missense variants and multi-exon deletions [6, 16]. The gene-disease relationship of ACE with AR RTD was classified by ClinGen as "Definitive" on 11 December 2024, and is the only curated relationship for this gene [9].

The following table brings together variants described in the sources, normalised in VariantValidator with the MANE transcript (GRCh38) where indicated; historical nomenclature (one-letter amino acid numbering or mature protein numbering) appears in brackets [34–38].

Two nomenclature discrepancies deserve mention. OMIM records the AGT variant c.604C>T as "Glu202Ter", but VariantValidator, with the MANE transcript, returns p.(Gln202Ter), consistent with the cytosine-to-thymine change that turns a CAG codon into TAG [34, 35]. In a Vietnamese report, the ACE variant NM_000789.4:c.2503G>T appears as p.Glu853Ter (published designation), whereas VariantValidator gives p.(Glu835Ter) [43]. The large AGT delins is described with different coordinates in the two papers that report it, and the two notations have not been harmonised in the sources consulted [10, 16].

2.4. Molecular mechanisms by gene

Renin. The REN variants found in AR RTD are null (nonsense, such as NM_000537.4:c.145C>T p.(Arg49Ter) and c.127C>T p.(Arg43Ter)) or missense variants that prevent secretion. Michaud and colleagues studied the tyrosine duplication Y15dup, the substitution of the catalytic aspartate D38N and S69Y (mature renin numbering, = NM_000537.4:c.404C>A p.(Ser135Tyr)), next to the "flap" (a β-hairpin structure covering the substrate-binding site): all produced misfolded, enzymatically inactive prorenin with abnormal intracellular trafficking, and S69Y was not secreted; secretion could be partially restored by lowering the temperature or by inhibiting the proteasome [36, 40]. Renal immunohistochemistry without renin is the tissue counterpart of these defects [11].

Angiotensin-converting enzyme. The most relevant functional finding is that what matters is membrane-anchored ACE, not plasma activity. The truncated mutant R762X was enzymatically active and secreted, but was not inserted into the plasma membrane, and was associated with neonatal death; the R1180P mutant reached the membrane and was rapidly secreted, and was compatible with life after transient neonatal renal failure; W594R, R828H, Q1136X and G1145AX were neither inserted nor secreted [44]. These designations use the historical numbering of mature ACE, without the 29 residues of the signal peptide; in the reference sequence NP_000780.1 (MANE transcript NM_000789.4) they correspond to residues Arg791, Arg1209, Trp623, Arg857, Gln1165 and Gly1174, and Q1069R corresponds to Gln1098 [44, 45]. The authors concluded that total absence of ACE at the cell surface is incompatible with life [44]. The Q1069R variant was retained in the endoplasmic reticulum and degraded by the proteasome; lowering the temperature allowed secretion of active enzyme, which characterises a conformational disease [45]. For these reasons, plasma ACE activity cannot be used to exclude the disease [9].

Angiotensinogen. The lack of substrate produces a compensatory rise in renin: in an adolescent homozygous for AGT p.(Arg375Gln), blood angiotensinogen was low and plasma renin and renin expression in vascular and tubular cells of the renal biopsy were markedly increased, without elevation of angiotensin II or aldosterone [14]. The authors noted the parallel with hepatic silencing of angiotensinogen under study for hypertension [14]. This is the only form in which fresh frozen plasma can supply the missing molecule [18, 22].

AT1 receptor. AGTR1 variants are the least frequent; those described include truncations (NM_000685.5:c.251G>A p.(Trp84Ter), c.376C>T p.(Arg126Ter), c.415C>T p.(Arg139Ter) and p.Ile38HisfsTer37, published designation) and the missense variant c.845C>T p.(Thr282Met) [23, 38]. In RTD due to defects downstream of renin, renal renin is increased [31].

2.5. Genotype-phenotype correlations

The 2012 series found no differences in severity between genes [6], and in an analysis of 78 cases with known genotype, survival did not differ between genes (chi-squared, p=0.27) [18]. It was hypothesised that the disease was more severe when the affected protein is more distal in the pathway, supported by the lack of survivors with AGTR1 variants; the description of surviving siblings with nonsense variants in AGTR1 and of a 28-year-old adult homozygous for AGTR1 p.(Arg216*) (published designation; in NP_000676.1, from the MANE transcript NM_000685.5, residue 216 is a threonine, so the numbering does not map), treated with high doses of fludrocortisone, weakened that hypothesis [18, 23].

Variant type carries more weight. Fourteen of the 18 families with survivors reviewed by Vincent and colleagues had at least one non-truncating variant, compared with nine of 39 families without survivors in the 2012 series (p=0.016) [18]. In a review of 61 genetically confirmed cases of ACE-related RTD (terminations of pregnancy excluded), overall survival was 24.6% (15/61): 8.6% (3/35) with two truncating variants, 44.4% (4/9) with one truncating and one non-truncating variant and 47.1% (8/17) with two non-truncating variants [20]. Variants lie more towards the 3' end of the gene, and 5' variants tend to be associated with greater severity, with exceptions; location or type alone do not predict the individual outcome [20]. Eight of the families with survivors had affected siblings who died in utero or in the neonatal period, which points to a contribution from modifier genes and from neonatal treatment [18].

2.6. Penetrance, expressivity and attenuated forms

Penetrance in homozygotes and compound heterozygotes is complete for the tubular lesion, but clinical expressivity ranges from fetal death to chronic kidney disease recognised late. Fila and colleagues identified biallelic loss-of-function variants in ACE in three patients with progressive chronic renal failure, referred for investigation of suspected juvenile hyperuricaemic nephropathy, nephronophthisis and cystic disease; all had anaemia disproportionate to the degree of renal failure and marked polyuria-polydipsia [13]. The German adolescent with AGT p.(Arg375Gln) was born preterm after oligohydramnios, recovered from grade 3 acute kidney injury and progressed to chronic kidney disease G3b [14]. These cases show that the diagnosis of AR RTD can be reached through "agnostic" sequencing in chronic kidney disease of unknown cause [13, 14].

2.7. Allelic disorders and common variation

ADTKD-REN. Heterozygous REN variants in the signal peptide (62% of variants, exon 1), the prosegment (27%) or mature renin (15%, exons 2, 8, 9 and 10) cause autosomal dominant tubulointerstitial kidney disease, REN type (ADTKD-REN, formerly familial juvenile hyperuricaemic nephropathy type 2, OMIM 613092) [7]. The mechanism differs from that of AR RTD: the mutant preprorenin does not enter the endoplasmic reticulum correctly or fails to fold, accumulates in the juxtaglomerular cells and causes cellular stress, early death of these cells, tubular atrophy and interstitial fibrosis [7]. Clinically, the childhood- or adolescent-onset form presents with hypoproliferative anaemia, hyperkalaemia, acidosis, hyperuricaemia with gout and slowly progressive chronic kidney disease, and the adult form with gout and mild chronic kidney disease [7, 29]. One of the families in the original description was of Portuguese origin, with the signal peptide variant NM_000537.4:c.47T>G p.(Leu16Arg) [36]. In parents of children with AR RTD due to null REN variants, heterozygosity for a null variant does not correspond to the mechanism of ADTKD-REN, which requires missense variants or small indels that disturb biosynthesis [7].

Common variation. AGT has an extensive literature on the association between the M235T variant (historical numbering, = NM_000029.4:c.803T>C p.(Met268Thr)) and promoter variants and plasma angiotensinogen, essential hypertension and pre-eclampsia; ACE has the intron 16 insertion/deletion polymorphism (rs4646994) associated with ACE activity; and AGTR1 has associations with hypertension [30, 31, 35, 37]. These are population associations of small effect, without a Mendelian relationship; a heterozygous variant in these genes is not diagnostic of hypertension, and this literature should not interfere with the interpretation of a diagnostic result [30, 31].

Mitochondrial mimic. Biallelic variants in RMND1, the gene for an autosomal recessive mitochondrial disease, were identified in two cases of severe fetal nephropathy with an RTD-like phenotype and low renin expression, without variants in the RAS genes, with severe reduction of subunits of complexes I and IV of oxidative phosphorylation [46].

3. Clinical Spectrum and Manifestations by System

3.1. Fetal period

Clinical expression begins in the fetus. The proximal tubular lesion is present from 18 weeks, and early and persistent fetal anuria leads to oligohydramnios or anhydramnios [6, 11]. The timing of oligohydramnios varies: Allanson and colleagues observed normal amniotic fluid volumes before 22 weeks in affected pregnancies, and oligohydramnios at the end of the second trimester with structurally normal kidneys was the finding that suggested the diagnosis [1, 12]. In recent series, oligohydramnios was detected between 23 and 31 weeks, with an amniotic fluid index (AFI) of 0.93 to 5.3 cm, an absent or poorly filled fetal bladder and normal-sized or slightly enlarged kidneys, sometimes with an echogenic cortex and blurred corticomedullary junction [16, 18, 47]. In one fetus at 27 weeks, increased renal vascular resistance with reversed diastolic flow on Doppler and a small pleural effusion were observed [16]. Fetal growth restriction accompanies some cases [20, 23, 48].

Oligohydramnios that sets in during the canalicular phase of lung development (16 to 24 weeks) is the cause of the pulmonary hypoplasia; the earlier it occurs, the more severe the effect on the lung [49]. Fetal compression produces the Potter sequence: flattened facies, large, low-set ears flattened against the head, redundant skin, joint contractures and club feet [47, 50]. Delivery is frequently preterm, between 27 and 36 weeks in published cases, because of oligohydramnios, rupture of membranes, growth restriction or fetal distress [18, 19, 23, 51].

3.2. Neonatal period: the respiratory, haemodynamic and renal triad

In the series of Lacoste and colleagues, of 29 fetuses and newborns, the disease was uniformly severe and all died in the perinatal period, from persistent anuria and hypoxia related to pulmonary hypoplasia [11]. The triad that defines the neonatal period is respiratory failure (pulmonary hypoplasia, pneumothorax, persistent pulmonary hypertension), refractory arterial hypotension and anuric renal failure [6, 23, 52].

Lung. Unilateral or bilateral pneumothoraces are frequent, as is the need for high-frequency ventilation and inhaled nitric oxide for persistent pulmonary hypertension and, in one case, venoarterial extracorporeal membrane oxygenation [8, 20, 23, 51].

Circulation. Hypotension is profound (mean arterial pressure below 15–20 mmHg in some reports) and resists fluid boluses, catecholamines (dopamine, dobutamine, adrenaline, noradrenaline) and hydrocortisone [8, 20, 23, 53]. The response to vasopressin, documented in several cases, is consistent with the mechanism, because vasopressin bypasses the angiotensin II pathway [8, 18, 51]. Patent ductus arteriosus and ventricular septal defect were seen in survivors [18].

Kidney. Ultrasound shows normal-sized, echogenic, non-cystic kidneys with reduced corticomedullary differentiation and normal blood flow on Doppler [20, 52]. The anuria does not respond to furosemide, even at doses of 14 mg/kg/day [18, 20]. In one newborn, MAG-3 scintigraphy showed good renal uptake without excretion into the collecting system [18]. Serum creatinine rises progressively (up to 1018 µmol/L in one case), with hyperkalaemia, non-anion-gap metabolic acidosis and hyponatraemia [18, 20, 47].

Skull and skeleton. Wide sutures and fontanelles and hypocalvaria are signs of great diagnostic value, and RTD features in the differential diagnosis of a large fontanelle [54]; at autopsy, markedly reduced mineralisation of the skull vault can be documented [20, 23, 26]. Not all cases have them: in one family, one sister had no hypoplasia of the skull vault and the other did [18]. Arthrogryposis and foot deformities are a consequence of compression [20, 47].

Other organs. Idiopathic neonatal intestinal perforation, necrotising enterocolitis, microcolon with perforation of the terminal ileum in three patients from two families with ACE variants, and oesophageal atresia in one case with an ACE variant have been described [18, 19, 48, 55]. Systemic hypoperfusion is the proposed explanation for the intestinal lesions [19]. Intracranial haemorrhage with hydrocephalus, cryptorchidism and micropenis occurred in isolated cases [20, 53]. Hypoproliferative anaemia, with low reticulocytes, may appear in the first weeks without response to erythropoietin [20].

3.3. Treated disease: survivors beyond the neonatal period

The number of survivors has grown since 2006. The authors of a 2022 paper counted more than 100 published cases and 18 survivors beyond the neonatal period, to which they added two sisters [18]; in 2025, a review restricted to ACE counted 15 survivors among 61 cases, aged between 10 months and 19 years, six with and five without kidney replacement therapy [20]. In an Israeli series of five newborns with a prenatal diagnosis who survived the neonatal period, four from an extended Bedouin family and four with ACE variants, presentation ranged from peritoneal dialysis with extreme hypotension to absence of symptoms, and the patients were aged between 5 and 20 years with chronic kidney disease of variable stage [56].

In survivors, anuria generally lasts from days to weeks: 15 and 16 days in the cases of Schreiber and Uematsu, 10 days in the first sister of the Canadian family, 29 days until spontaneous diuresis in the infant with an AGT variant [18, 22, 28]. Once diuresis is established, the picture becomes that of a tubulopathy with hyperreninaemic hypoaldosteronism: polyuria (sometimes described as nephrogenic diabetes insipidus), episodes of dehydration and prerenal acute kidney injury triggered by infections, hyperkalaemia, type 4 hyperchloraemic metabolic acidosis and hyponatraemia [8, 19, 51]. In the Japanese patient followed up to 10 years of age, renin was markedly raised (18.5 ng/mL/h; reference 0.2–3.9) with inappropriately low aldosterone (51 pg/mL), very low serum ACE (0.9 U/L) and appropriate antidiuretic hormone (1.7 pg/mL), and polyuria reached 7.8 mL/kg/h during an episode of dehydration [19]. Arterial pressure remains at the lower limit of normal [18]. Renal function stabilises at chronic kidney disease stage 2 to 4 in most cases (glomerular filtration rate of 19 to 60 mL/min/1.73 m² in the reports), and some patients needed chronic dialysis and kidney transplantation (one at 4 years, with the REN variant NM_000537.4:c.404C>A p.(Ser135Tyr)) [8, 18, 27, 28, 36]. In one infant treated with continuous kidney replacement therapy, renal function and ultrasound were normal at 27 months [57]. Renal anaemia may require erythropoietin or darbepoetin [18].

Neurodevelopment is normal in most survivors described in detail, including the patient with a REN variant at 10 years, Schreiber's child at 3 years and the Japanese patient at 10 years [19, 28, 36]. The exceptions relate to neonatal complications, such as intracranial haemorrhage with hydrocephalus in a girl born preterm at 27 weeks, or to unexplained findings, such as T2 signal changes in the globus pallidus in one of the Canadian sisters [18, 53].

3.4. Late-onset attenuated forms

Forms without a severe neonatal picture or with an unrecognised neonatal picture present as progressive chronic kidney disease in childhood or adolescence, with disproportionate anaemia and polyuria-polydipsia, and can be confused with juvenile hyperuricaemic nephropathy, nephronophthisis or cystic disease [13]. The adolescent with AGT p.(Arg375Gln) had oligohydramnios, preterm birth and severe acute kidney injury in the neonatal period, and only exome sequencing in adolescence made the diagnosis [14]. A man homozygous for AGTR1 p.(Arg216*) was alive at 28 years on high doses of fludrocortisone [23].

4. Clinical Recognition and Warning Signs

4.1. In pregnancy

Prenatal suspicion rests on a combination: oligohydramnios or anhydramnios without rupture of membranes, an empty or poorly filled fetal bladder and kidneys of normal morphology or merely echogenic [16, 58]. Increased renal vascular resistance with reversed diastolic flow reinforces suspicion even without structural anomalies [16]. Additional warning signs are a history of fetal or neonatal deaths with oligohydramnios, consanguinity and a sibling with a diagnosis of RTD [16, 41, 49]. A history of exposure to ACEIs, ARBs, renin inhibitors or non-steroidal anti-inflammatory drugs (NSAIDs), and of monochorionic twin pregnancy, points towards the acquired forms [15, 47, 49, 59].

4.2. In the newborn

The diagnosis should be considered in any newborn with Potter sequence or pulmonary hypoplasia, arterial hypotension refractory to catecholamines, anuric renal failure and normal-sized, echogenic, non-cystic kidneys, especially if there are wide sutures and fontanelles [9, 47, 52]. The combination of hypotension, respiratory failure and skull ossification defects with a normal renal ultrasound points towards RTD among the causes of neonatal renal failure with oligohydramnios [47]. The clinical diagnosis is easily missed without a renal biopsy or without information on affected relatives [27]. In one case, the initial signs were attributed to septic shock and intestinal perforation, and only the contractures and the large anterior fontanelle led to the hypothesis of RTD [19].

Emergency signs. Persistently very low mean arterial pressure despite catecholamines, total absence of urine output, hyperkalaemia above 7 mmol/L and hypoxaemia due to pulmonary hypoplasia or pulmonary hypertension require neonatal intensive care with access to advanced ventilation and kidney replacement therapy [20, 23, 47].

4.3. In the child and adolescent

In the child or adolescent, suspicion arises in the presence of chronic kidney disease of unknown cause with disproportionate anaemia, polyuria and polydipsia, hyperkalaemia, acidosis and episodes of acute kidney injury during infections, particularly if there is a history of oligohydramnios, prematurity or neonatal renal failure [13, 14, 19]. The hormonal pattern of high renin with low or inappropriately normal aldosterone suggests a defect downstream of renin; low renin with loss of tubular function suggests another diagnosis, including ADTKD-REN [7, 19].

4.4. Newborn screening

There is no newborn screening for AR RTD. Angiotensinogen is included in reproductive carrier screening panels in Australia [30], and in Taiwan a rapid test for the AGT founder variant has been validated [10].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Criteria

There are no formal published diagnostic criteria. In the sources consulted, the diagnosis rests on three pillars: the clinical phenotype (persistent fetal anuria with oligohydramnios, Potter sequence, refractory hypotension, renal failure with normal-sized kidneys and skull ossification defects), renal histology with absent or scarce differentiated proximal tubules, and the identification of biallelic pathogenic or likely pathogenic variants in one of the four RAS genes [6, 9, 15]. Histology establishes tubular dysgenesis, but does not distinguish the gene or the cause; only the molecular test assigns the disease to the genetic form and allows prenatal diagnosis in a subsequent pregnancy [9, 30].

5.2. Tests in order

Ultrasound and Doppler. In pregnancy, ultrasound documents the oligohydramnios, the bladder and renal morphology, and renal artery Doppler may show increased resistance [16]. If the ultrasound images are inadequate because of the lack of fluid, fetal magnetic resonance imaging may help [49]. In the newborn, renal ultrasound shows normal-sized, echogenic kidneys, and radiography or examination of the skull documents the deficient ossification [9, 52].

Hormonal study of the RAS. Functional analysis of the RAS contributes to the diagnosis and can point towards the gene: in the patient with ACE variants, plasma renin activity above 49.2 ng/mL/h (reference 2.0–15.2), active renin of 1823.5 pg/mL (2.4–21.9) and ACE of 1.7 U/L (8.3–21.4) pointed to ACE [60]. In the AGT form, absent or low circulating angiotensinogen with raised renin points towards this gene [14, 30]. Normal plasma ACE activity does not exclude the disease, because there are lethal variants that produce active secreted enzyme but without membrane expression [9, 44].

Histology. Renal biopsy or autopsy shows crowded glomeruli separated by small tubules with distal tubule morphology, without proximal tubules; absence of the brush border on periodic acid-Schiff (PAS) staining and absence of CD10 staining confirm the lack of proximal tubules, and epithelial membrane antigen marks the distal tubules [23, 47]. Renin immunohistochemistry distinguishes the REN forms (renin absent) from the others (renin increased) [11]. When the patient survives and there is no tissue, the tissue of a deceased sibling can be reviewed [28]. Perinatal autopsy and the study of surgical specimens have a central role in the diagnosis and prognosis of anomalies with insufficient nephron development [61].

Genetic testing. The first-line test is sequencing of the four genes, by panel with copy number variant analysis, exome or genome, preferably as a trio [16, 18, 48]. The European recommendation for renal failure of unknown cause is targeted exome sequencing, with analysis of the whole exome as a second step, and the turnaround time for urgent indications (prenatal and neonatal) should not exceed two weeks [17]. In anhydramnios, amniocentesis may be impossible; amnioinfusion allowed fluid to be obtained for clinical exome sequencing in two fetuses with ACE variants, and in other series cord blood obtained by cordocentesis was used [16, 43]. Chorionic villus sampling, placental biopsy and fetal blood are alternatives, and DNA from the fetus and parents should be stored [23, 49].

5.3. Algorithm

5.4. Limitations of the tests

Exome sequencing and panels detect point variants and small indels well, but can miss deletions and large rearrangements: the AGT founder delins, of about 2.9 kb, was detected by copy number variant analysis of the exome and confirmed by Sanger sequencing, and in one family it appeared in compound heterozygosity with a point variant [16]. In one report, only one ACE variant was found in a pair of affected siblings [37]; in these situations the second variant should be sought (CNV, deep intronic, splicing). Splicing variants require functional proof or a robust prediction, such as ACE NM_000789.4:c.1487G>A p.(Arg496Gln), predicted to destroy the splice donor of intron 9 [18]. A negative test for the four genes does not exclude RTD, which may be secondary or due to another gene, such as RMND1 [46]. The proportion of families with variants in the RAS genes measures what was detected in series selected by histology and is not equivalent to the clinical sensitivity of the test [6].

5.5. Report, variants of uncertain significance and segregation

The report should state the gene, the transcript with version (for example NM_000789.4 for ACE), the HGVS c. and p. nomenclature, zygosity and class according to the ACMG/AMP criteria. Variants of uncertain significance are frequent in these genes: in an Egyptian study, the variants ACE p.(Leu13_Leu16del) and AGT p.(Tyr37Cys), found in parents of fetuses who died with RTD, were classified as of uncertain significance [41]. Segregation in the parents confirms the phase (trans) in compound heterozygotes and is essential before prenatal diagnosis [16, 23]. The policy on reporting variants of uncertain significance varies between centres [17].

5.6. Prenatal and preimplantation diagnosis

Once the two familial variants have been identified, early prenatal diagnosis, by chorionic villus sampling, and preimplantation genetic testing become available [6, 11, 17, 23]. In the absence of a molecular diagnosis, serial ultrasound surveillance of amniotic fluid volume and the bladder in an at-risk pregnancy is the only resource, with the limitation that oligohydramnios may only appear after 22 weeks [12].

6. Differential Diagnosis

6.1. Comparative table

6.2. Acquired forms

The most important distinction is between the genetic form and the acquired forms, because the recurrence risk changes from 25% to that determined by the underlying cause [50]. Histology is identical in both [15, 30]. Exposure to drugs acting on the RAS during the second and third trimesters reproduces the phenotype (anuria, hypotension, hypocalvaria, pulmonary hypoplasia, patent ductus arteriosus, growth restriction) [62]. The fetal RAS becomes functional at around 26 weeks, and the toxicity is attributed to fetal hypotension with oligohydramnios and compression [62]. In twin-twin transfusion, the oliguric donor has increased renal renin secretion, and RTD in the donor is the natural model of hypoperfusion [1, 63]. Congenital haemochromatosis, major heart defects, severe fetal renal artery stenosis, maternal exposure to NSAIDs and ischaemic placental necrosis complete the list of secondary causes [15, 47].

A case from the Centro Materno-Infantil do Norte, in Porto, illustrates the limits of this classification: a female newborn of 35 weeks with oligohydramnios, Potter sequence, anuric renal failure, transient hypotension responsive to fluids and skull ossification defects had a histological diagnosis of RTD (glomeruli and distal tubules, without a brush border on PAS and without CD10 staining), but without variants in the RAS genes, with a de novo 9.3 Mb 1q24.1q25.1 duplication that did not include those genes, normal active renin (47 pg/mL) and ferritin (80 µg/L) and a small area of ischaemic placental necrosis; she died on day 20 despite peritoneal dialysis [47]. The authors interpreted the case as suggestive of alternative mechanisms [47].

6.3. Other causes of oligohydramnios with renal failure

In the presence of oligohydramnios with neonatal renal failure, the main differential diagnosis includes RTD, bilateral renal agenesis, renal hypoplasia or dysplasia, obstructive uropathy and autosomal recessive polycystic kidney disease [47]. RTD is distinguished by kidneys of normal size and structure, absence of cysts and of collecting system dilatation, severe hypotension and skull ossification defects [47, 52]. Bilateral agenesis causes severe oligohydramnios from 14 weeks, earlier than RTD [49]. Renal ultrasound of parents and siblings is indicated in bilateral agenesis or dysgenesis, because 9% of first-degree relatives had asymptomatic renal malformations in a classical series [50].

6.4. Differential of the attenuated forms and ADTKD-REN

In children or adults, attenuated ACE-related RTD has been confused with juvenile hyperuricaemic nephropathy, nephronophthisis and cystic disease, and is distinguished by disproportionate anaemia and marked polyuria [13]. ADTKD-REN shares the REN gene, anaemia, hyperkalaemia and acidosis, but is dominant, has no oligohydramnios or neonatal picture and has low or low-normal renin and aldosterone, whereas RTD due to defects downstream of renin has markedly raised renin [7, 19]. Renal biopsy is not recommended for the diagnosis of ADTKD-REN, because the findings are non-specific [29].

7. Treatments and Risk Management Strategies

7.1. Principles and level of evidence

There is no disease-modifying therapy or specific clinical guideline for AR RTD; the available evidence consists of case reports and series, and there are no registered clinical trials (ClinicalTrials.gov search with no studies for "renal tubular dysgenesis" on 1 November 2026) [9, 30]. The following recommendations derive from these series, from the pathophysiological mechanism and, for fludrocortisone, from analogous conditions treated with the same drug, as indicated in each case. Management has three phases: pregnancy with suspicion or a diagnosis, the neonatal period, in which survival is decided, and follow-up of survivors, whose picture is that of hyperreninaemic hypoaldosteronism with tubulopathy and chronic kidney disease.

7.2. Pregnancy with an affected fetus

Once the prenatal diagnosis has been made, the family receives counselling on the prognosis and the options, which include termination of pregnancy, chosen by several couples in the published series, and continuation with delivery planned in a centre with neonatal intensive care, advanced ventilation and kidney replacement therapy [9, 16, 43]. Xu and colleagues emphasise symptomatic treatment of oligohydramnios and interventions to promote fetal maturation before a preterm delivery [57]; in the reports, the mothers received antenatal corticosteroids for lung maturation (betamethasone) [18, 47]. Amnioinfusion was used to obtain fluid for diagnosis and to facilitate morphological assessment, without data on its effect on the pulmonary prognosis [43]. Drugs that block the RAS are contraindicated in an at-risk pregnancy, because they reproduce the phenotype [9, 64].

7.3. Neonatal period

Respiratory support. Pulmonary hypoplasia and persistent pulmonary hypertension require mechanical ventilation, often high-frequency, surfactant in preterm infants, inhaled nitric oxide and drainage of pneumothoraces; in one case venoarterial extracorporeal membrane oxygenation was used, without survival [18, 20, 23, 51].

Hypotension: vasopressin. The hypotension of AR RTD is refractory to fluid boluses, catecholamines and hydrocortisone [8, 18]. Vasopressin, by acting on V1 receptors independently of angiotensin II, bypasses the defect; it raises pressure through direct vasoconstriction and may improve renal blood flow [8, 18]. In three of the nine survivors without kidney replacement therapy reviewed by Vincent and colleagues, vasopressin normalised arterial pressure, and in two diuresis began almost immediately [18]. The doses described were 0.001 IU/kg/min started at 36 hours of life, with stabilisation of pressure and immediate diuresis but difficult weaning over three weeks [8]; an infusion of up to 0.0007 µg/kg/min (unit as published) with dobutamine up to 10 µg/kg/min, withdrawn on day 4 [18]; and, in a preterm infant of 34 weeks, mean arterial pressure rose from less than 20 to 35–45 mmHg after it was started on day 2, although anuria persisted [20]. In a preterm infant of 27 weeks, desmopressin was described as effective in maintaining arterial pressure and diuresis [51]. The FDA label for vasopressin (Vasostrict®) indicates it only to raise arterial pressure in adults with vasodilatory shock refractory to fluids and catecholamines (0.03–0.1 U/min in post-cardiotomy shock; 0.01–0.07 U/min in septic shock) and states that safety and efficacy in paediatric patients have not been established; neonatal use in RTD is off-label and the doses above come from individual reports, not from a guideline [65].

Hypotension: fresh frozen plasma in the AGT form. Infusions of fresh frozen plasma, as an exogenous source of angiotensinogen, raised and maintained arterial pressure in two newborns with AGT variants, who still required peritoneal dialysis [18, 22]. The same benefit is not to be expected in the REN, ACE and AGTR1 forms, in which angiotensinogen is normal [18]. In the Israeli series, extreme hypotension was treated with vasopressors and plasma infusions, and the authors consider intensive treatment of postnatal hypotension critical for survival and prognosis [56].

Neonatal fludrocortisone. Vasopressin does not correct the hypoaldosteronism. In a female newborn of 33 weeks, fludrocortisone 0.1 mg twice daily was started on day 2 of life together with vasopressin, which could be withdrawn on day 4, whereas in the two previous cases treated with vasopressin alone weaning took three and nine weeks [18]. The dose had to be reduced to 0.1 mg daily on day 9 because of hypernatraemia (147 mmol/L) and hypokalaemia (2.9 mmol/L), and at 4.5 months the patient was admitted with hypernatraemia of 174 mmol/L and hypertension, which led to discontinuation of the drug [18]. The efficacy of fludrocortisone was also described at 6 days and at 1 month of life, according to the authors of a 2026 report [19].

Renal failure. Kidney replacement therapy is, as a rule, peritoneal dialysis, started in the first days, until spontaneous diuresis appears; complications include catheter leaks and peritonitis [22, 47, 56, 66]. Continuous kidney replacement therapy was used in one case with complete recovery and was stopped in another because of hypotension [23, 57]. Furosemide does not induce diuresis [18, 20]. Strict fluid and electrolyte restriction from the first day, correction of hyperkalaemia with glucose and insulin or cation-exchange resins and, in one case without dialysis, enteral lactulose to increase faecal excretion of nitrogenous compounds prolonged survival [18, 20]. Lactulose is not a first-line treatment for neonatal uraemia [20]. The course of diuresis in the first weeks is the factor that most guides the decision to continue dialysis and the counselling of the family [66]. Diuresis may appear late and spontaneously even after a decision for palliative care, as happened on day 10 of life in one female newborn [18].

Shared decisions and palliative care. In cases with complete anuria and biallelic truncating variants, the probability of survival is low (8.6% in the ACE review), and the decision not to start dialysis was taken by some parents after counselling; early genetic diagnosis gives time for that decision and for the family's contact with the child [20]. Rapid genetic diagnosis also supported the continuation of intensive care in one case that survived [66].

7.4. Survivors: fludrocortisone and treatment of the tubulopathy

Rationale. Survivors have persistent hypoaldosteronism, with markedly raised renin and low or inappropriately normal aldosterone, and distal tubular immaturity that reduces the response to aldosterone; polyuria, hyperkalaemia, acidosis and volume depletion with prerenal acute kidney injury during intercurrent illness result [8, 19]. Fludrocortisone, a synthetic mineralocorticoid, replaces the missing aldosterone [18, 19].

Results described. In Schreiber's child, hypotension and hyperkalaemia normalised with fludrocortisone [28]. In Ruf's infant, discontinuation of fludrocortisone through non-adherence caused hyperkalaemia and a rise in creatinine, and with fludrocortisone and bicarbonate the electrolytes normalised [8]. In the Japanese patient, fludrocortisone started at 4 years of age (0.025 mg/day, then 0.04 mg/day) ended the episodes of acute kidney injury and hyperkalaemia, reduced polyuria and raised the glomerular filtration rate from about 35 to about 45 mL/min/1.73 m², with 48.47 mL/min/1.73 m² at 10 years [19]. In a preterm infant, fludrocortisone started at 2 years for persistently high creatinine attributed to nephrogenic diabetes insipidus reduced urine output and maintained renal function [51]. In a child compound heterozygous for ACE variants, fludrocortisone achieved electrolyte and acid-base balance without kidney replacement therapy [67]. An adult with an AGTR1 variant was alive at 28 years on high doses [23].

Dose: reference and comparison. There is no guideline with a fludrocortisone dose for AR RTD. By declared extrapolation, the reference dose is that for primary adrenal insufficiency in children, according to the Endocrine Society: typical dose of 100 µg daily, without adjustment for body surface area, with sodium chloride supplementation of 1 to 2 g daily in infants under 6 months, monitoring by renin (target at the upper limit of normal) and blood pressure surveillance, because mineralocorticoid excess causes hypertension and renin suppression [68]. In RTD, renin is chronically raised by the pathway defect itself, so the renin target for adrenal insufficiency cannot be transposed directly; in the reports, titration was guided by potassium, sodium, urine output and arterial pressure [18, 19]. In the allelic disease ADTKD-REN, a condition with hyporeninaemic hypoaldosteronism and the same REN gene, GeneReviews indicates fludrocortisone (0.1 mg tablet) to correct hypotension, hyperkalaemia and acidosis, to be started before stage 3 chronic kidney disease because it increases the glomerular filtration rate, with a risk of fluid retention and hypertension when the rate is below 60 mL/min/1.73 m² [7].

The doses used in RTD lie within the paediatric range of the Portuguese SmPC, except for the 0.2 mg/day in an 8-year-old child and the initial neonatal dose of 0.2 mg/day, which exceed that range and the dose of the analogous guideline; in both cases the use is off-label [18, 53, 68, 69]. The adverse effects to monitor are hypernatraemia, hypokalaemia, fluid retention and hypertension, observed in one infant [7, 18].

Other measures. Survivors frequently need sodium chloride and sodium bicarbonate supplements (3.6 g/day and 1.5 g/day of NaCl in the Japanese patient at 10 years), cation-exchange resins for hyperkalaemia, active vitamin D (alfacalcidol), iron and erythropoietin or darbepoetin for renal anaemia [18, 19]. Desmopressin (360 µg/day) was added in a patient with nephrogenic diabetes insipidus and polyuria to optimise volume status [53]. By analogy with ADTKD-REN, the low-salt diet usual in chronic kidney disease should not be applied, and a salt intake of 3 to 4 g daily corrects hypotension in that disease [7]. Gastrostomy was required in patients with poor weight gain and to manage fluids [18, 53].

End-stage chronic kidney disease. Chronic peritoneal dialysis and kidney transplantation are the options in end-stage disease; the patient with REN p.Ser135Tyr was transplanted at 4 years and had normal development at 10 years, and another patient with ACE p.Gln1069Arg (historical numbering; residue Gln1098 in NP_000780.1) underwent peritoneal dialysis and deceased-donor transplantation at 4 years [18, 36].

7.5. Agents and circumstances to avoid

Dehydration and volume depletion should be avoided, as should NSAIDs (which precipitated acute renal failure in a febrile child with ADTKD-REN, a disease with low RAS activity), ACEIs and ARBs, which aggravate the deficit of the system, and nephrotoxic agents [7]. Intercurrent infections with vomiting or food refusal warrant early hydration, because they were the usual cause of admissions for acute kidney injury, hyperkalaemia and hyponatraemia [8, 18, 19].

7.6. Anaesthesia and the perioperative period

A 7-year-old child with AR RTD due to ACE variants had circulatory arrest four minutes after inhalational induction with 8% sevoflurane and 40% nitrous oxide, requiring resuscitation, adrenaline boluses of 10 µg/kg and an infusion of 0.10 to 0.25 µg/kg/min, abandonment of surgery and transient acute kidney injury [53]. One year later, the same operation proceeded without incident with: prior correction of dehydration (desmopressin 360 µg/day started after the first event and an intravenous infusion of 80 mL/h during fasting), intravenous hydrocortisone 100 mg/m² before surgery, an arterial line and central venous access, titrated intravenous induction with midazolam 0.3 mg/kg, ketamine 2–3 mg/kg and fentanyl 3 µg/kg to preserve sympathetic tone, and maintenance with propofol and remifentanil, adrenaline 0.03–0.05 µg/kg/min and vasopressin 0.33 mU/kg/min [53]. The authors stress that preoperative arterial pressure may not reflect dehydration, and that urine output, urine specific gravity, urea and the ratio of inferior vena cava to aortic diameter are useful indicators [53]. These measures describe a single case and do not constitute a validated protocol; the pre-anaesthetic assessment of these patients should anticipate profound hypotension.

7.7. Pregnancy and breastfeeding in affected or carrier women

There are no reports of pregnancy in women with AR RTD in the sources consulted. RAS blockers (ACEIs, ARBs, sacubitril/valsartan and renin inhibitors) are fetotoxic in the second and third trimesters and are contraindicated in pregnancy, according to the 2025 European and American guidelines, which is relevant to any woman of childbearing age, including carriers [64, 71]. In ADTKD-REN, high doses of fludrocortisone in pregnancy are associated with a risk of clinical hyperaldosteronism in the newborn, according to GeneReviews, which refers to the label [7].

7.8. Regulatory status of the drugs used

7.9. Available evidence

There are no clinical trials. The table summarises the observational studies with treatment or outcome data.

These data have limitations that prevent conclusions on efficacy: they are retrospective series and reports with publication bias in favour of survivors, treatments changed over time, the variant type conditions the prognosis independently of treatment, and there are no comparison groups [18, 20]. The association between vasopressin, fludrocortisone and survival is observational, and families with the same genotype had different outcomes [18].

7.10. Developments in the last 12 months

Between November 2025 and October 2026 the following contributions were published, all observational or preclinical: stabilisation of renal function over six years with fludrocortisone in a child with ACE variants (case report, published online in November 2025) [19]; the description of haemodynamic collapse under general anaesthesia and of the protocol that allowed a safe second anaesthetic (case report, December 2025) [53]; a rapid real-time PCR test for the AGT founder variant and a heterozygote frequency of 1% in 5000 healthy Taiwanese people (validation and frequency study, October 2025) [10]; ACE and AGT variants of uncertain significance in Egyptian families with fetal deaths (cohort, November 2025) [41]; and a preterm newborn with ACE-related RTD who survived beyond the neonatal period with early peritoneal dialysis (report, October 2026, read in abstract form) [66]. In the same period there were no marketing applications or trials for RTD. Zilebesiran, an interfering RNA that silences hepatic angiotensinogen, is in a phase 3 trial in hypertension (NCT07181109, recruiting since September 2025, 11,000 participants) and is not authorised; its mechanism is the opposite of what is needed in this disease and it is not a therapy for RTD [30, 73].

7.11. Transition

Survivors reach adolescence and adulthood with chronic kidney disease, tubulopathy and mineralocorticoid therapy, and the oldest patient described was 28 years old [23, 56]. Transition from paediatric to adult nephrology should convey the molecular diagnosis, the dependence on salt and fludrocortisone, the risk of severe hypotension during anaesthesia and dehydration and the contraindication of RAS blockers and NSAIDs [7, 53]. At reproductive age, genetic counselling and discussion of contraception and pregnancy are part of transition [17].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

AR RTD is transmitted in an autosomal recessive manner. When both parents are heterozygous carriers, each pregnancy has a 25% probability of an affected fetus, 50% of a healthy carrier and 25% of a non-carrier [9, 50]. The series show actual recurrence in sibships: two stillborn sisters in the original description, three affected siblings in a Palestinian family, two and three successive pregnancies with oligohydramnios in Chinese families, and surviving Canadian sisters with the same genotype [1, 16, 18]. In the acquired forms, the risk depends on the cause (drug exposure, twin-twin transfusion, heart disease) and is not that of a recessive disease [50]. The distinction between the genetic and the acquired form, with molecular study of the index case or, if this is not available, of the parents, is therefore the central step in counselling [6, 49].

In one case with biallelic ACE variants, one of the variants was presumed de novo and the other inherited from the mother [48]; in this scenario the risk for siblings is low, but not zero, because of the possibility of germline mosaicism. In one report, only one ACE variant was found in two affected siblings, which shows that the absence of the second variant should not be interpreted as dominant inheritance [37].

8.2. Cascade testing and carriers

After the variants have been identified, the parents should be tested to confirm the phase, and adult siblings and other relatives can learn their carrier status for reproductive planning [17, 23]. Consanguinity is frequent in the families described (Maghreb, Turkey, Pakistan, Middle East, Egypt), and carrier screening in consanguineous populations has been proposed as a preventive measure [1, 23, 41]. In Taiwan, a rapid real-time PCR test for the AGT founder variant, validated against Sanger sequencing, allows screening of carriers, whose frequency was 1% in 5000 healthy adults [10]. AGT is included in expanded reproductive carrier screening panels in Australia [30]. Heterozygous carriers of the AGT founder variant had higher serum angiotensinogen than non-carriers, with no difference in arterial pressure [10]. Carriers of null REN variants do not, by mechanism, have the risk of ADTKD-REN, which depends on specific missense variants or small indels [7].

8.3. Prenatal and preimplantation diagnosis

With the familial variants known, early prenatal diagnosis by chorionic villus sampling and preimplantation genetic testing are possible [6, 11, 23]. Without a prior molecular diagnosis, oligohydramnios and anhydramnios make amniocentesis difficult, and amnioinfusion or cordocentesis allow material to be obtained [16, 43]. The European recommendation is that the prenatal result should be available within two weeks [17]. In the Chinese family in which two pregnancies had been terminated, the third resulted in a healthy term newborn without the variant [16]. Ultrasound surveillance of amniotic fluid, without a molecular test, does not exclude the disease before 22 weeks [12].

8.4. Counselling and family support

Counselling should explain that the disease is in most cases lethal in the perinatal period, but not universally so, and that the prognosis depends on the variant type, the degree of pulmonary hypoplasia and the response to neonatal treatment [18, 20, 28]. Rapid genetic diagnosis supports both the decision to continue intensive care and the decision to limit it, and gives the family time for bonding with the child [20, 66]. The involvement of a clinical geneticist or genetic counsellor to discuss recurrence, family screening and reproductive options is recommended in genetic kidney disease [17]. Carrier testing in healthy minors has no immediate clinical benefit and, as a rule, is deferred until the person can decide for themselves.

9. Special Considerations: Population Diversity and Epidemiology

9.1. Frequency

There is no estimate of the prevalence or incidence of AR RTD. Orphanet publishes no prevalence for ORPHA:3033 or ORPHA:97369, and the sources count families and cases, not rates [3, 9]. The 1992 description already suggested that the disease might be underdiagnosed, and the title of the 2006 paper described it as "not uncommon" [11, 12]. The published totals were about 150 cases in 2018 and in 2025, with 18 survivors beyond the neonatal period according to the 2025 authors [8, 53]. Any rate calculated for RTD in general would include the acquired forms and would not be a rate for the genetic form [9]. The lack of histological and genetic diagnosis in many fetal and neonatal deaths with oligohydramnios contributes to underestimation [12, 27].

9.2. Geographical distribution and founder populations

The families described are of very varied origin: China, Japan, Taiwan, Korea, Vietnam, Turkey, the Maghreb (Algeria, Morocco, Tunisia), the Middle East (Palestinian and Bedouin families, Qatar), Pakistan, Egypt, Europe (France, Italy, Switzerland, Slovenia, Germany) and North America [1, 14, 18, 23, 36–38, 41, 43, 52, 56, 74]. Parental consanguinity is common, which explains the frequency of homozygosity [1, 6].

The only quantified founder variant is the AGT delins in Taiwan, with 1% heterozygotes among 5000 healthy individuals; the authors conclude that AR RTD is probably more frequent in Taiwan than was thought [10]. The same delins was found in the homozygous and compound heterozygous state in families from Shenzhen, in southern China [16]. A carrier frequency of 1% corresponds, if matings are random, to about 1 in 40,000 pregnancies with two alleles of this variant; this is a theoretical estimate from the carrier frequency, not an observed incidence.

9.3. Europe, Portugal and Brazil

The large genetic series came from the French network of fetal pathology and paediatric nephrology (Paris), with European, Maghrebi and other families [6, 11, 24]. In Portugal, the most recent published case is an RTD confirmed by histology, without variants in the RAS genes, at the Centro Materno-Infantil do Norte, in Porto [47]; a Portuguese family underlies the description of ADTKD-REN, the dominant allelic disease [36]. The sources consulted include no Brazilian cases of AR RTD; absence from the sources does not demonstrate absence of cases.

9.4. Special populations

Extremely preterm infants accumulate the complications of prematurity (intracranial haemorrhage, necrotising enterocolitis) and those of the disease [18, 53]. Surviving children are vulnerable to intercurrent illness with dehydration and to general anaesthesia [19, 53].

9.5. European networks and resources

ERKNet, the European reference network for rare kidney diseases (https://www.erknet.org), and ERN ITHACA, for congenital anomalies and intellectual disability (https://ern-ithaca.eu), are the relevant networks [21]. The sources consulted did not identify a patient organisation specific to RTD; the resources are those of rare kidney disease and perinatal loss organisations.

10. Illustrative Clinical Case

In 2026 Sugita and colleagues, from the Department of Paediatrics of the University of Tokyo Hospital, described a 10-year-old girl with AR RTD due to a homozygous ACE variant [19]. She was the first child of parents without known consanguinity and was born by emergency caesarean section at 35 weeks and 5 days, because of severe oligohydramnios, weighing 2336 g; there was no maternal exposure to ACEIs or ARBs [19]. Immediately after birth she had hypotension (pressure of about 30/20 mmHg) and respiratory distress, and underwent emergency surgery for idiopathic gastrointestinal perforation; after surgery she had acute kidney injury, with persistent creatinine of about 0.70 mg/dL, interpreted as chronic kidney disease [19]. She had bilateral joint contractures and a large anterior fontanelle, signs that, in retrospect, suggested RTD [19].

At 7 months she was admitted with creatinine of 1.32 mg/dL and potassium of 6.1 mEq/L, which improved with hydration; the transtubular potassium gradient of 5.9 suggested type 4 renal tubular acidosis, and she was started on sodium chloride and sodium bicarbonate [19]. Genetic testing at 14 months identified NM_000789.4:c.1454dup, p.(Ser486PhefsTer29), in the homozygous state, a variant not previously described [19, 34]. At 2 years and 9 months, the estimated glomerular filtration rate was 48.23 mL/min/1.73 m², and ultrasound showed kidneys of about 7.0 cm, with increased echogenicity and reduced corticomedullary differentiation [19].

At 3 years, after a cold, she had acute kidney injury with hyponatraemia, potassium of 6.3 mEq/L, bicarbonate of 18.8 mEq/L and glomerular filtration of 31.2 mL/min/1.73 m², with polyuria of about 7.8 mL/kg/h (more than 2000 mL per day) that contributed to the dehydration [19]. Renin was 18.5 ng/mL/h (reference 0.2–3.9), aldosterone 51 pg/mL, within the reference range but inappropriately low for the renin, serum ACE 0.9 U/L (8.3–21.4) and antidiuretic hormone 1.7 pg/mL [19]. At 4 years the episode recurred, with polyuria of about 6.6 mL/kg/h, and, after recovery, she was started on oral fludrocortisone 0.025 mg daily [19].

After fludrocortisone there were no further episodes of acute kidney injury or hyperkalaemia; potassium, previously between 5 and 6 mEq/L, normalised, hyponatraemia became rare, the family noticed a reduction in urine output and glomerular filtration rose from about 35 to about 45 mL/min/1.73 m², with a stable fractional excretion of sodium between 1.7% and 2.2% [19]. At 10 years, glomerular filtration was 48.47 mL/min/1.73 m², without admissions, on sodium bicarbonate 3.6 g/day, sodium chloride 1.5 g/day and fludrocortisone 0.04 mg/day, with normal weight and height and age-appropriate neurodevelopment [19]. Figure 1 of the paper shows the course of sodium, potassium and glomerular filtration after the start of fludrocortisone (https://pmc.ncbi.nlm.nih.gov/articles/PMC12852240/figure/Fig1/) [19].

The case shows the survivor phenotype, with hyperreninaemic hypoaldosteronism, polyuria and prerenal acute kidney injury triggered by infections, and the clinical response to mineralocorticoid replacement. It is an individual observation, with off-label use of fludrocortisone at doses below the typical paediatric dose of the adrenal insufficiency guideline [68]; it does not demonstrate that fludrocortisone alters the course of chronic kidney disease in all patients. For comparison, the typical histology of RTD (crowded glomeruli between distal-type tubules, without proximal tubules and without CD10 staining) is illustrated in figure 1 of the AGTR1 case published by Al-Maraghi and colleagues (https://pmc.ncbi.nlm.nih.gov/articles/PMC11034062/figure/Fig1/) [23].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

The overall prognosis is poor: in the 2006 histological and genetic series, all 29 fetuses and newborns died in the perinatal period [11], and in the 2025 review survival of the cases with ACE variants was 24.6%, with 8.6% in carriers of two truncating variants and 44.4–47.1% when there was at least one non-truncating variant [20]. These values come from published cases, with a bias in favour of exceptional cases, and exclude terminated pregnancies [20]. The causes of death are pulmonary hypoplasia with respiratory failure, refractory hypotension and anuric renal failure [6, 11]. In survivors, renal function generally stabilises at chronic kidney disease stage 2 to 4, with a risk of progression, and some need chronic dialysis and transplantation; others reach adolescence or adulthood with chronic kidney disease, and the oldest described was 28 years old [14, 18, 23, 56]. In one infant, renal function was normal at 27 months [57]. Neurodevelopment is generally normal when there are no severe neonatal complications [19, 28, 36].

11.2. Surveillance

There is no published surveillance protocol for AR RTD. The table combines the parameters followed in reports of survivors with the intervals for the allelic disease ADTKD-REN and for adrenal insufficiency on fludrocortisone, declared as extrapolation.

11.3. Follow-up

Follow-up is the responsibility of paediatric nephrology, with clinical genetics for family counselling and anaesthesiology whenever there is surgery [9, 53]. The key points are maintenance of volume status and salt, titration of fludrocortisone by electrolytes and arterial pressure, treatment of anaemia and acidosis, preparation for kidney replacement therapy if function deteriorates, and avoidance of NSAIDs, RAS blockers and dehydration [7, 18, 19].

12. Summary and Final Considerations

Autosomal recessive renal tubular dysgenesis is the expression, in the fetal kidney, of loss of function of the renin-angiotensin system: biallelic variants in ACE (about two thirds of families), REN, AGT or AGTR1 prevent the production or action of angiotensin II, the perfusion pressure of the fetal kidney remains low and the proximal tubules fail to differentiate. The result is persistent fetal anuria, oligohydramnios, Potter sequence with pulmonary hypoplasia, hypocalvaria and, after birth, refractory hypotension and renal failure, with normal-sized kidneys on ultrasound. The histology is identical to that of the acquired forms due to hypoperfusion, mainly exposure to ACEIs or ARBs and twin-twin transfusion, so only genetic testing establishes the hereditary form and the 25% recurrence risk.

The diagnosis should be considered in any fetus with oligohydramnios, an empty bladder and structurally normal kidneys, and in any newborn with hypotension resistant to catecholamines, anuria and wide fontanelles; hormonal study of the RAS points towards the gene, normal plasma ACE activity does not exclude the disease and a negative test does not exclude secondary RTD or another gene, such as RMND1. The disease is no longer considered universally lethal: about a quarter of published cases with ACE variants survived, especially when there was at least one non-truncating variant. The reports suggest benefit from vasopressin for neonatal hypotension, from fresh frozen plasma in the AGT form, from peritoneal dialysis until spontaneous diuresis and from fludrocortisone for the hypoaldosteronism of survivors, but the evidence is observational and there are no specific trials or guidelines. Survivors live with chronic kidney disease, polyuria and a risk of dehydration, acute kidney injury and haemodynamic collapse during anaesthesia, and need nephrological follow-up with planned transition. Molecular diagnosis of the index case allows the family to be offered prenatal and preimplantation diagnosis and, in populations with founder variants or high consanguinity, carrier screening.

13. References

1. Online Mendelian Inheritance in Man, OMIM®. #267430 Renal tubular dysgenesis; RTD. Johns Hopkins University; last edited 2025-11-03. https://www.omim.org/entry/267430
2. Orphanet. Renal tubular dysgenesis of genetic origin (ORPHA:97369). https://www.orpha.net/en/disease/detail/97369
3. Orphanet. Renal tubular dysgenesis (ORPHA:3033). https://www.orpha.net/en/disease/detail/3033
4. Orphanet. Drug-related renal tubular dysgenesis (ORPHA:97368). https://www.orpha.net/en/disease/detail/97368
5. Orphanet. Renal tubular dysgenesis due to twin-twin transfusion (ORPHA:97367). https://www.orpha.net/en/disease/detail/97367
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