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AGTR1-related Renal Tubular Dysgeneses May Not Be Fatal

  • Istanbul University-Cerrahpasa
  • Istanbul University-Cerrahpaşa Cerrahpaşa Faculty of Medicine
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AGTR1-related renal tubular dysgeneses may not be fatal
Ebru Burcu Demirgan, Seha Saygili, Nur Canpolat, Lale Sever, Isin Kilicaslan, Doruk
Taylan, Salim Caliskan, Fatih Ozaltin
PII: S2468-0249(20)31790-3
Reference: EKIR 1240
To appear in: Kidney International Reports
Received Date: 25 September 2020
Revised Date: 28 November 2020
Accepted Date: 30 November 2020
Please cite this article as: Demirgan EB, Saygili S, Canpolat N, Sever L, Kilicaslan I, Taylan D, Caliskan
S, Ozaltin F, AGTR1-related renal tubular dysgeneses may not be fatal, Kidney International Reports
(2021), doi:
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© 2020 Published by Elsevier Inc. on behalf of the International Society of Nephrology.
AGTR1-related renal tubular dysgeneses may not be fatal
Ebru Burcu Demirgan
, Seha Saygili
, Nur Canpolat
, Lale Sever
, Isin Kilicaslan
, Doruk Taylan
Salim Caliskan
, Fatih Ozaltin
Department of Pediatric Nephrology, Istanbul University-Cerrahpasa, Cerrahpasa Faculty of
Medicine, Istanbul, Turkey
Department of Pathology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Nephrogenetics Laboratory, Department of Pediatric Nephrology, Hacettepe University Faculty of
Medicine, Sihhiye, Ankara, Turkey
Department of Pediatric Nephrology, Hacettepe University Faculty of Medicine, Sihhiye, Ankara,
Corresponding author:
Fatih Ozaltin, M.D.
Hacettepe University Faculty of Medicine, Department of Pediatric Nephrology, 06100, Sihhiye,
Ankara, Turkey. e-mail: ORCID ID: 0000-0003-1194-0164
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Renal tubular dysgenesis (RTD) is an ultrarare disease characterized by severe developmental defects
in the proximal tubules. Absence or paucity of differentiated proximal tubules lead to persistent fetal
anuria that causes oligohydramnios and hypoplastic lung. Hypocalvaria occurs due to bone hypoxia
secondary to arterial hypotension in the early neonatal period
. These conditions mainly stem from
hereditary abnormalities in the renin-angiotensin system (RAS). Mutations in the genes encoding
angiotensinogen (AGT), renin (REN), angiotensin-converting enzyme (ACE) and angiotensin 2
receptor type 1 (AGTR1) have been associated with RTD.
4, 5
In addition to genetic abnormalities,
other conditions leading to intrauterine renal hypoperfusion such as renal artery stenosis, twin-to-twin
transfusion syndrome, cardiac malformations and exposure to RAS blocking agents in pregnancy may
also cause RTD.
In general, RTD is related to a poor prognosis as many of the individuals die early in life. Gribouval et
al. summarized 79 cases; pregnancy was terminated in 13 (16%), 9 (11%) were stillborn, 57
individuals were born alive of whom 26 (45%) died in the first 24 hours, 17 (29%) died between one
day and one week and 5 (0.8%) babies died between one week and one month.
So far, 189 patients
with RTD have been published and only 16 of them have long-term data including four children who
needed chronic dialysis or renal transplant,
twelve children who had chronic kidney disease (CKD)
in various stages.
4, 6, S1-S7
Only six unrelated patients with 4 different AGTR1 variations were reported;
pregnancy was terminated in one patient, one was stillborn, three died in the first day of life and one
lived 35 days in the neonatal intensive care unit.
Here, we present two siblings with AGTR1 related
RTD, who have longer-term survival than the previously reported individuals with AGTR1 related
RTD and also review the literature for all RTDs.
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Case Presentation
Individual II-1
The first child of a healthy consanguineous parents without family history of kidney disease was born
at 39 weeks of gestation after an uncomplicated delivery with 5
and 10
minute Apgar scores of 9
and 10, respectively (Individual II-1 in Figure 1). Medical history of the mother was uneventful for
any medications, toxic exposures or abortus. There was no information about the level of amniotic
fluid during the pregnancy at the hospital records. The birth weight, height and head circumference
were 3150 g (Standard Deviation Score (SDS) -0.14), 53 cm (SDS 1.47) and 35 cm (SDS 1.29),
respectively with wide sagittal sutures and fontanelles. Central hypotonia and joint contractures in the
wrists and ankles were noted and development of the head control was gained at the age of 3 months.
At the age of 5 months, he was admitted to the hospital due to vomiting. He was dehydrated and
malnourished; his weight, height and head circumference were 4800 g (SDS -2.97), 60 cm (SDS -
2.17) and 41 cm (SDS -1.5), respectively. Joint contractures not associated with sensory or motor
deficit were present. Laboratory evaluation showed metabolic acidosis (pH 6.9, pCO2 35.3 mmHg,
7.2 mmol/L, base excess -22), impairment of the kidney functions (by means of BUN 86
mg/dL, serum creatinine 2 mg/dL, estimated glomerular filtration rate (eGFR) 12.4 mL/min/1.73m
estimated by modified Schwartz formula
) and hyperkalemia (K
14 mmol/L) while transtubular
potassium gradient was 7.9. Repeated potassium levels were above 10 mmol/L, the heart rate was
62/min. Electrocardiography showed peaked T-waves and wide QRS complexes. After potassium
lowering therapy with sodium polystyrene sulfonate and fludrocortisone administration, its serum
level decreased to 6.0 mmol/L without requirement of dialysis. During this hospitalization period, he
had polyuria (4-5 ml/kg/hour) and propensity for dehydration, therefore serum creatinine level ranged
between 0.7 and 2 mg/dL. Urinalysis was normal. Renin-angiotensin-aldosterone system (RAAS) was
assessed by means of level of active renin and plasma renin both of which were high (2749 uIU/mL
(normal 5.3-99.1 uIU/mL) and >37 ng/mL (normal 2.40-37 ng/mL/hr), respectively) with low plasma
aldosterone level (<3.7 ng/dL, (normal 3.7-43.2 ng/dL)). Precursors of adrenal hormones were within
normal limits (17-OH progesterone 0.63 ng/ml (normal 0.07-1.53), free testosterone 0.85 pg/mL
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(normal 0.15-0.6), dehydroepiandrosterone sulfate 300ng/dL (normal 100-600) and androstenedione
1.23 ng/mL (normal 0.1-4)). Renal ultrasonography showed bilateral normal sized kidneys with
increased echogenicity; there were no signs of obstructive uropathy. Renal biopsy showed immature
glomerular and tubular structures with the infiltration of mononuclear inflammatory cells. Cystic
dilatation in the tubules and juxtaglomerular cell hyperplasia were noted (Figures 2a, b). At the time of
discharge when he was 10 months of age, his weight and height were 7400 g (SDS -2.23) and 70 cm
(SDS -1.74), respectively; neurological examination was normal. Hyperkalemia and metabolic
acidosis were under control with calcium polystyrene sulfonate and bicarbonate and serum creatinine
was 1 mg/dL. During the follow-up period between 1 and 17 years, serum creatinine increased slowly
from 1 to 1.6 mg/dL as being in serum uric acid level (maximum 9.9 mg/dL). He had polydipsia and
polyuria with a urinary pH of 5.5 and a specific gravity of 1.006 accompanied by tubular proteinuria.
At the age of 17 years, hypophosphatemia became apparent while serum creatinine level was 1.6
mg/dL. Parathormone and 25-OH vitamin D levels were 41pg/mL and 22.9 ng/mL, respectively.
Renal tubular phosphate reabsorption (TPR) slightly decreased (TPR 88% and tubular resorption of
phosphate corrected for glomerular filtration rate (TmP/GFR) 2.8). Oral sodium phosphate solution
was given. He is now 22 years old. His current weight and height are 77 kg (SDS 0.5) and 175 cm
(SDS -0.19), respectively and mean blood pressure is 125/85 mmHg. The last serum creatinine level is
1.82 mg/dL (eGFR 40mL/min/1.73m
estimated by modified Schwartz formula
). He is still under
treatment with calcium polystyrene sulfonate, bicarbonate and oral phosphorus solution. The last
kidney ultrasound showed bilateral small kidneys with increased echogenicity (left kidney 85mm
(SDS -2.39), right kidney 91 mm (SDS -1.47) without any cyst).
Individual II-2
This is the sister of the first case (Individual II-2 in Figure 1). Oligohydramnios became apparent at
the 20
week of gestation. Emergency cesarean section had to be performed at 32 weeks of gestation
due to anhydramnios and fetal distress. The birth weight, height and head circumference were 2455 g
(SDS 2.0), 45 cm (SDS -1.33) and 31 cm (SDS -1.37), respectively with a wide anterior fontanelle.
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Her 5
and 10
minutes Apgar scores were 4 and 6, respectively. She had to be intubated just after the
birth and mechanical ventilation was required for 5 days due to low breath effort and hypotonia. No
pneumothorax or congenital pneumonia or structural lung disease were detected. An echocardiography
revealed only a small patent ductus arteriosus and the ejection fraction was 64%. Although she had no
signs of sepsis or any metabolic disease, she had severe hypotension episodes (mean blood pressure
was 18-20 mmHg). Inotropic therapy was given for 20 days. She had no urine output in the first 48
hours and peritoneal dialysis was commenced at the second postpartum day that was continued until
the postnatal 24
day. Highest serum creatinine level was 3.21 mg/dL during the first month. Despite
effective peritoneal dialysis, she had hyperkalemia (the highest serum K
level was 6.6 mmol/L) and
was treated with sodium polystyrene sulfonate. Plasma active renin level and plasma renin activity
were high (>5500 uIU/mL (normal 5.3-99.1 uIU/mL) and >28 ng/mL (normal 2.40-37 ng/mL/hr),
respectively), while plasma aldosterone level was low (<4.9 ng/dL (normal 3.7-43.2 ng/dL)). Urinary
ultrasound showed normal sized kidneys with increased echogenicity. She had central hypotonia as
observed in the older sibling. Laboratory evaluation showed no finding of any metabolic disease.
Cranial magnetic resonance imaging, electromyography and muscle biopsy were normal. At the 60
postnatal day, she was discharged. The weight was normal for her age (3340 g, SDS -0.15). Urine
output was in normal range (2 mL/kg/h) with a serum creatinine level of 0.63 mg/dL. Serum
potassium level was normal with potassium lowering therapy (i.e. sodium polystyrene sulfonate). She
is now 6 years old and is still being followed up in our outpatient clinic. She was never hospitalized
again. Her lowest serum creatinine level was 0.4 mg/dL and showed slow progression up to 0.76
mg/dL (eGFR 71.5 ml/min/1.73m
estimated by modified Schwartz formula
). The highest serum
uric acid level was 7 mg/dL. Potassium lowering therapy for hyperkalemia continued and bicarbonate
was added to the treatment due to sustained metabolic acidosis. The last weight and height are 21 kg
(SDS 0.14) and 116 cm (SDS 0.21), respectively with normal blood pressure (90/64 mmHg). The last
kidney ultrasound showed bilateral small sized kidneys (i.e. right kidney 65 mm (SDS -3.61), left
kidney 72mm (SDS -1.94))
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Clinical features and laboratory findings of both cases are summarized in Table 1. Consanguinity
between parents and two siblings with the same clinical picture led us to think about an underlying
genetic etiology. We therefore performed whole exome sequencing from both siblings as well as the
parents since these findings did not suggest a specific kidney disease, after obtaining informed
consents. We identified homozygous variation in AGTR1 (i.e. NM_000685.4 c.376C>T (p.Arg126*)),
which was considered to be responsible for the phenotype in both siblings and searched the literature
for all patients with RTD. Two siblings from Pakistan with the same AGTR1 c.376C>T (p.Arg126*)
variation, both of whom had oligohydramnios and died at the first day of the life were reported.
Detailed genetic evaluation, search strategy of the literature and its results are given in the
Supplementary Material.
Here we present for the first time, two siblings with AGTR1 related RTD, who have survived for a
long period and hereby reviewed the literature for all RTDs that would be helpful for those clinicians
who involve patient care. One of the most important antenatal findings of RTD is decreased amniotic
fluid. All of the reported cases (n=157, Supplementary Table S1) including one of the siblings in the
present study with an antenatal ultrasonography had either oligo- or an-hydroamnios after the 18
week of gestation as the kidneys contribute little to amniotic fluid until 15 weeks of gestation.
Therefore, RTD should be taken into consideration in differential diagnosis of progressive decrease of
amniotic fluid without any urinary tract abnormalities that would be associated with this finding.
Clinical manifestations of the surviving RTD patients in the literature have not been well described but
would be expected to begin in the antenatal period due to defective RAS that is critical for normal
renal functions. The RAS cascade functions in human embryo at the second trimester and plays an
essential role in nephrogenesis, maintenance of peripheral vascular resistance and renal blood flow.
Renin and angiotensin-2 (ANG2) reach their maximum level right before the birth.
The vital role
of the RAS (i.e. control of the extracellular volume, renal blood flow and blood pressure) continues
after birth. Neonatal and/or fetal hypotension and hypoxia caused by an absence of a normal
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functioning RAS induces renal injury.
In accordance with this fact, we needed to overcome many life-
threatening situations in our cases. Both cases suffered from hyperkalemia and acute kidney injury due
to the low renal perfusion, but symptoms became apparent at different ages probably due to difference
in epigenetic factors that would modify the disease course. Individual II-2 had a severe hypotension at
birth requiring multiple vasopressors to keep the blood pressure within normal limits for age. She also
needed dialysis at the first day of life. Peritoneal dialysis lasted for 24 days and then serum creatinine
returned to normal range. Fourteen of all reported RTD patients in the literature needed peritoneal
dialysis, but only four of them survived beyond the first month (Supplementary Table S1). Given the
fact that release of aldosterone from the adrenal glands is regulated via the angiotensin II-AT1R
binding, hyperkalemia is a common finding in RTD, which is caused mainly due to the aldosterone
Hence the expected plasma level of aldosterone would be low in patients with AGTR1
4, S12
. No data on this is available in patients with AGTR1 mutation in the literature however in
agreement with the aforementioned expectation, both of our cases had high level of active plasma
renin and plasma renin activity and low level of plasma aldosterone. Severe metabolic acidosis is a
shared finding in both children, which is probably caused by two factors including the shortage of
aldosterone and the impaired morphology of the proximal tubules. Serum levels of RAS components
may vary depending on genetic abnormality. Pathogenic variations in ACE cause high level of active
plasma renin and plasma renin activity, whereas those in AGT result in high level of active renin
combined with a low plasma renin activity.
Both level of active plasma renin and plasma renin
activity were expected to be low in individuals with pathogenic variations in REN gene.
5, 7
Very few
reports have mentioned about low aldosterone levels in RTD,
but a compensatory increase in
serum aldosterone level can also be found as a result of residual functions in mutant proteins as
exemplified in patients with pathogenic variations of ACE gene.
Therefore, we recommend that
laboratory evaluation of RAS components should be considered in the clinical setting, which would
suggest possible diagnosis of RTD before having genetic results or help establish the diagnosis of
RTD as an alternative to genetic testing in places where genetic testing is not available.
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Membranous bones of the skull require a normal to high oxygen tension for development. Delayed
skull development may be explained by fetal hypotension combined with direct uterine pressure on the
skull due to the absence or shortage of amniotic fluid.
In agreement with this fact, in the present
and the reported other cases with RTD in the literature, large fontanels, wide sutures, calvaria
hypoplasia and contractures of the wrist and ankle joints, which would improve by regular physical
therapy are one of the most important shared findings.
Individual II-1 underwent a renal biopsy, which showed focal atrophy and cystic dilatations in
proximal tubules, immature glomeruli in some segments, hyperplasia in arterioles and peritubular
capillary and hyperplasia in juxtaglomerular apparatus. The characteristic microscopic findings of
RTD are absence or incomplete differentiation of the proximal convoluted tubules.
Renal biopsy
findings were reported in 55 cases in the literature (Supplementary Table S1). The most common
reported biopsy findings were reduced proximal tubules (n=50), crowded glomeruli (n=35) and
interstitial fibrosis (n=25). It has been shown later that the renal lesions are more diffuse namely
collapsed Henle loops and collecting ducts, thickened and disorganized muscular wall of medium-
sized arteries and arterioles.
The glomeruli may appear crowded because of deficient tubular
While RTD was initially diagnosed by biopsy and clinical features, genetic tests
largely replaced the biopsy after year 2000. Thus, seeking genetic diagnosis should be considered first
in patients with clinical findings suggesting RTD.
We observed rather slow progression of the kidney disease in our cases than the others reported in the
literature. In total, 115 affected individuals from 65 families were reported to have pathogenic
variations associated with RTD (Supplementary Table S1). Of them, ACE variants were the leading
one followed by REN, AGT and AGTR1. The AGTR1, a G-protein-coupled transmembrane receptor,
enables the functions of ANG2 by the coupling of ANG2 to its extracellular part. Because AGTR1 is
the last step of the RAS axis, it has been hypothesized that pathogenic variations leading to absence or
defect of the AGTR1 induce most likely a fatal phenotype.
Until now six cases from four unrelated
families with AGTR1 variations have been reported; one of them was stillborn, pregnancy was
terminated in one, three cases died at the first day of life and only one baby lived for 35 days on
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dialysis and showed very severe and resistant hypotension persisting for 3 weeks.
Two of the affected
individuals had compound heterozygous AGTR1 variations consisted of a T insertion leading to a
frameshift (c.110_111 insT, p.Ile38HisfsX37), and an amino acid change (c.845C>T, p.Thr282Met)
involving the highly conserved threonine located at the junction between the third extracellular loop
and the last transmembrane domain. Both variations were predicted to alter the function of AGTR1.
In other two families, homozygous truncating variations (i.e. c.251G>A (p.Trp84*) and c.376C>T
(p.Arg126*), respectively) were identified latter of which was present in our cases as well. It has been
reported that the presence of one non-truncating variant may be a favorable factor for survival.
contrast to the previous reports, our cases survived despite having homozygous truncating variations in
AGTR1, suggesting that there might be other genetic, epigenetic or environmental factors that would
be related to the inter-familial variability . Indeed, we found a homozygous PDGFD variation in both
of our cases (see Supplementary Material), which might modulate the clinical course and may explain
interfamilial variability. The classical renin-angiotensin-aldosterone system (RAAS) may cause
fibrosis in renal disease via activation of intermediary growth factors and cytokines involved in the
progression of renal disease, including transforming growth factor- ß , PDGF, endothelin, and
epidermal growth factor.
Pharmacological targeting of RAAS ameliorate renal inflammation and
fibrosis through inhibition of the production of profibrotic proteins.
Unlike the other PDGF
isoforms, the role of the D isoform of PDGF, a specific PDGF receptor ß (PDGFR-ß) ligand, in renal
development is unknown, but its upregulation has been reported to be associated with kidney fibrosis
in humans and mice.
Beneficial polymorphisms in PDGFD might modify the fibrotic effects of
classical RAAS pathway. This mechanism might be responsible for the fairly mild course in our cases
when compared to other reported patients. Modifying effects of variants of PDGFD and the other
growth factors related to tissue fibrosis in patients with RTD is intriguing and deserves further
researches. Intra-familial variability is well known concept in many genetic diseases and has been
previously reported in RTD as well (Supplementary Table S1). Variable disease course observed in
our patients despite being homozygous for both the AGTR1 and PDGFD variants may suggest the
presence of other yet undefined factors involved in the phenotype such as modifier genes, variations in
non-coding regions etc.
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RTD should be considered in a pregnant woman who has severe oligohydramnios without any
apparent fetal urinary tract defect that would explain this finding and in neonates with oligo-/an-uria
and severe arterial hypotension. RTD may also present with severe hyperkalemia accompanied with
polyuria-polydipsia in infants. Children, who survive in the neonatal and infantile period, show a slow
progressive CKD with findings of proximal tubulopathy. There is a broad phenotypic and genetic
heterogeneity of the disease (Table 2). Additional genetic/epigenetic factors might affect the course.
Despite multiple challenges, newborns with RTD can survive, even in AGTR1-related disorder that is
thought desperate, if promptly and meticulously managed.
The authors have nothing to disclose.
Patient Consent
The authors declare that they have obtained consent from the patients discussed in the report.
This work was supported by Scientific Research Projects Coordination Unit of Istanbul University-
Cerrahpasa (3736-55436).
Supplementary material
Supplementary information is available at KI Report's website.
Supplementary File: Supplementary method and supplementary references (PDF)
Supplementary Table S1: Overview of patients reported in literature with a hereditary renal tubular
dysgenesis (PDF)
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1. Gubler MC, Antignac C. Renin-angiotensin system in kidney development: renal tubular
dysgenesis. Kidney Int 2010; 77: 400-406.
2. McFadden DE, Pantzar JT, Van Allen MI, et al. Renal tubular dysgenesis with calvarial
hypoplasia: report of two additional cases and review. J Med Genet 1997; 34: 846-848.
3. Shirakawa T, Kondoh T, Takahashi R, et al. Renal tubular dysgenesis complicated with severe
cranium hypoplasia. Pediatr Int 2004; 46: 88-90.
4. Gribouval O, Gonzales M, Neuhaus T, et al. Mutations in genes in the renin-angiotensin
system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet 2005; 37:
5. Zingg-Schenk A, Bacchetta J, Corvol P, et al. Inherited renal tubular dysgenesis: the first
patients surviving the neonatal period. Eur J Pediatr 2008; 167: 311-316.
6. Gribouval O, Moriniere V, Pawtowski A, et al. Spectrum of mutations in the renin-
angiotensin system genes in autosomal recessive renal tubular dysgenesis. Hum Mutat 2012;
33: 316-326.
7. Uematsu M, Sakamoto O, Ohura T, et al. A further case of renal tubular dysgenesis surviving
the neonatal period. Eur J Pediatr 2009; 168: 207-209.
8. de Oliveira RM, Marijanovic Z, Carvalho F, et al. Impaired proteostasis contributes to renal
tubular dysgenesis. PLoS One 2011; 6: e20854.
9. Bacchetta J, Dijoud F, Bouvier R, et al. [Renal tubular dysgenesis and mutation in the renin
gene]. Arch Pediatr 2007; 14: 1084-1087.
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Figure 1. The pedigree of the family. Squares indicates males and circles indicate females. Filled
symbol indicates affected individuals. Double horizontal lines indicate consanguinity.
Figure 2. Kidney biopsy findings of individual II-1 a) juxtaglomerular hyperplasia (hematoxylin
eosin 100x) (arrow), b) juxtaglomerular hyperplasia (Masson’s trichom staining 400x) (arrow).
Sanger electropherograms of c) a healthy individual d) the affected individuals (homozygous), e) the
parents (heterozygous). Missense variation is indicated with arrow.
Table 1. Clinical and laboratory features of the patients.
SDS, standard deviation score; GA, gestational age; N/A, not available
Case 1 Case 2
Gender Male Female
Age of presentation (postnatal) 3 months Newborn
Prenatal finding
Oligohydramnios +
Newborn findings
Gestational age of birth 39 32
Birth weight/(weight-SDS for GA) 3150g/ (-0.14) 2455g/ (2.0)
Birth height/(height-SDS for GA) 53cm/ (1.47) 45cm/ (1.33)
Duration of anuria Postnatal 24 days
Lung hypoplasia - -
Multiple joint contractions + +
Central hypotonia + +
Wide sutures + +
Hypotension - +
Anuria - +
Need for dialysis - +
Laboratory findings in follow-up
Hyperkalemia + +
Metabolic acidosis + +
Hypophosphatemia + -
Plasma renin activity High High
Active renin level High High
Plasma aldosterone level Low Low
Renal ultrasonographic findings
Increased echogenity + +
Cyst + -
Kidney size Normal Normal
Kidney biopsy findings
Juxtaglomerular cellular hyperplasia + N/A
Atrophic tubules + N/A
Tubular cystic dilatation + N/A
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Table 2. Teaching points
1. RTD should be considered in a pregnant woman who has severe oligohydramnios without
any apparent fetal urinary tract defect that would explain this finding and in neonates with
oligo or an- uria and severe arterial hypotension.
2. Mutations in the genes encoding angiotensinogen, renin, angiotensin-converting enzyme
and angiotensin 2 receptor type 1 have been associated with hereditary RTD.
3. RTD can also be observed as a result of non-hereditary conditions; such as major cardiac
malformation, renal artery stenosis, severe liver disease, twin-to-twin transfusion syndrome
and exposure to RAS blockers in pregnancy.
4. There is a broad phenotypic and genetic heterogeneity of the disease. Laboratory evaluation
of RAS may give some clue for underlying genetic abnormality.
RTD, renal tubular dysgenesis; RAS, renin angiotensin system
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a) b)
Figure 2
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... Since the initial characterization, over 100 sporadic or familial cases of AR-RTD have been described in the literature (Allanson et al., 1992;Gribouval et al., 2012). While the severity of AR-RTD was initially believed to invariably result in perinatal or neonatal death due to anuria and respiratory failure, in recent years, more and more patients are being described that survive past the critical neonatal period (Bacchetta et al., 2007;Danilov et al., 2010;Demirgan et al., 2021;de Oliveira et al., 2011;Gribouval et al., 2005Gribouval et al., , 2012Hibino et al., 2015;Kim et al., 2012;Richer et al., 2015;Ruf et al., 2018;Schreiber et al., 2010;Uematsu et al., 2006Uematsu et al., , 2009Zingg-Schenk et al., 2008). Historically, treatment has been largely supportive and includes intubation and ventilation for respiratory failure, intravenous fluid and inotrope/vasopressor support for hypotension, and dialysis for anuria. ...
... They noted that at the time there were no documented cases of patients with AGT1R mutations and survival past the neonatal period. However, shortly thereafter there has been a publication describing two siblings with AR-RTD and homozygous nonsense mutations in AGT1R (Demirgan et al., 2021). We suspect that the original lack of surviving patients with AGT1R variants is more reflective of the lower incidence of AGT1R-related AR-RTD in general. ...
Full-text available
Background: Autosomal-recessive renal tubular dysgenesis (AR-RTD) is a rare genetic disorder caused by defects in the renin-angiotensin system that manifests as fetal anuria leading to oligohydramnios and Potter sequence. Although the most common outcome is neonatal death from renal failure, pulmonary hypoplasia, and/or refractory arterial hypotension; several cases have been reported that describe survival past the neonatal period. Methods: Herein, we report the first family with biallelic ACE variants and more than one affected child surviving past the neonatal period, as well as provide a review of the previously reported 18 cases with better outcomes. Results: While both siblings with identical compound heterozygous ACE variants have received different treatments, neither required renal replacement therapy. We show that both vasopressin and fludrocortisone in the neonatal period may provide survival advantages, though outcomes may also be dependent on the type of gene variant, as well as other factors. Conclusion: While AR-RTD is most often a lethal disease in the neonatal period, it is not universally so. A better understanding of the factors affecting survival will help to guide prognostication and medical decision-making.
Full-text available
Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence, associated with skull ossification defects. Early death occurs in most cases from anuria, pulmonary hypoplasia, and refractory arterial hypotension. The disease is linked to mutations in the genes encoding several components of the renin-angiotensin system (RAS): AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), and AGTR1 (angiotensin II receptor type 1). Here, we review the series of 54 distinct mutations identified in 48 unrelated families. Most of them are novel and ACE mutations are the most frequent, observed in two-thirds of families (64.6%). The severity of the clinical course was similar whatever the mutated gene, which underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during the life of a human fetus. Renal hypoperfusion, whether genetic or secondary to a variety of diseases, precludes the normal development/ differentiation of proximal tubules. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.
Full-text available
Protein conformational disorders are associated with the appearance, persistence, accumulation, and misprocessing of aberrant proteins in the cell. The etiology of renal tubular dysgenesis (RTD) is linked to mutations in the angiotensin-converting enzyme (ACE). Here, we report the identification of a novel ACE mutation (Q1069R) in an RTD patient. ACE Q1069R is found sequestered in the endoplasmic reticulum and is also subject to increased proteasomal degradation, preventing its transport to the cell surface and extracellular fluids. Modulation of cellular proteostasis by temperature shift causes an extension in the processing time and trafficking of ACE Q1069R resulting in partial rescue of the protein processing defect and an increase in plasma membrane levels. In addition, we found that temperature shifting causes the ACE Q1069R protein to be secreted in an active state, suggesting that the mutation does not affect the enzyme's catalytic properties.
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We report two cases of renal tubular dysgenesis (RTD) with calvarial hypoplasia and review the originally reported cases of RTD that came from our institution and published reports regarding the association of RTD and skull abnormalities. Although previously reported in association with RTD, calvarial hypoplasia is probably under-recognised. The cases reported here support the idea that the skull abnormalities observed in the inherited form of renal tubular dysgenesis are a common component of the disorder, as they are in the acquired form of RTD associated with maternal use of ACE inhibitors. Renewed attention to this clinical manifestation of RTD may be important in suggesting the diagnosis before death, providing more complete information to parents and physicians facing important management decisions and ensuring appropriate pathological examination postmortem.
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Autosomal recessive renal tubular dysgenesis is a severe disorder of renal tubular development characterized by persistent fetal anuria and perinatal death, probably due to pulmonary hypoplasia from early-onset oligohydramnios (Potter phenotype). Absence or paucity of differentiated proximal tubules is the histopathological hallmark of the disease and may be associated with skull ossification defects. We studied 11 individuals with renal tubular dysgenesis, belonging to nine families, and found that they had homozygous or compound heterozygous mutations in the genes encoding renin, angiotensinogen, angiotensin converting enzyme or angiotensin II receptor type 1. We propose that renal lesions and early anuria result from chronic low perfusion pressure of the fetal kidney, a consequence of renin-angiotensin system inactivity. This is the first identification to our knowledge of a renal mendelian disorder linked to genetic defects in the renin-angiotensin system, highlighting the crucial role of the renin-angiotensin system in human kidney development.
Autosomal recessive renal tubular dysgenesis (RTD) is a severe disorder of renal tubular development characterized by early onset and persistent fetal anuria leading to oligohydramnios and the Potter sequence. At birth, blood pressure is dramatically low and perinatal death occurs in most cases. Skull ossification defects are frequently associated with RTD. The disease is genetically heterogeneous and linked to mutations in the genes encoding any of the components of the renin-angiotensin system (RAS). An intense stimulation of renin production is noted in the kidneys of patients with mutations in the genes encoding angiotensinogen, angiotensin-converting enzyme, or AT1 receptor, whereas absence or increased renin production is associated with REN defects depending on the type of mutation. The severity of the disease underlines the importance of a functional RAS in the maintenance of blood pressure and renal blood flow during fetal life. The absence or poor development of proximal tubules, as well as renal vascular changes, may be attributable to renal hypoperfusion rather than to a morphogenic property of the RAS. The less severe phenotype in mice devoid of RAS may be linked to differences between mice and humans in the time of nephrogenesis and maturation of the RAS. The identification of the disease on the basis of precise clinical and histological analyses and the characterization of the genetic defects allow genetic counseling and early prenatal diagnosis.
Renal tubular dysgenesis (RTD) is a clinical disorder either acquired during fetal development or inherited as an autosomal recessive condition. Inherited RTD is caused by mutations in the genes encoding the components of the renin-angiotensin system angiotensinogen, renin, angiotensin-converting enzyme and angiotensin II receptor type 1. Inherited RTD is characterized by early onset oligohydramnios, skull ossification defects, preterm birth and neonatal pulmonary and renal failure. The histological hallmark is the absence or poor development of proximal tubules. So far, all patients died either in utero or shortly after birth. We report the first patients with inherited RTD surviving the neonatal period and still being alive. Genetic and functional analysis of the renin-angiotensin system contributes to the diagnosis of RTD. In conclusion, the clinical diagnosis of inherited RTD is easily missed after birth without renal biopsy or information on affected family members. Genetic and functional analysis of the renin-angiotensin system contributes to correct diagnosis.
Renal tubular dysgenesis is a severe and rare disorder of the renal development characterized by fetal anuria, oligohydramnios and early death from pulmonary hypoplasia and refractory arterial hypotension. We report on a female patient who presented with anuria in the neonatal period, requiring peritoneal dialysis until 5 months of age with unexpected diuresis recovery at 2 months of age. Clinical, histological and pathophysiological issues are discussed for this disease related to a mutation in the renin gene.
Renal tubular dysgenesis is a critical disorder characterized by the Potter phenotype and severe hypotension in the early neonatal period. We herein report a 3-year-old female with renal tubular dysgenesis. Endocrinological studies showed a high plasma renin activity (over 49.2 ng/ml/h; normal range 2.0-15.2), high active renin concentration (1,823.5 pg/ml; normal range 2.4-21.9), and low angiotensin-converting enzyme (ACE) concentration (1.7 U/l; normal range 8.3-21.4). Taken together, these findings suggested an abnormality of the ACE gene, ACE. Direct sequencing analysis revealed two novel deletions in the coding region of ACE. We conclude that hormonal analysis of the renin-angiotensin system can aid in identifying the responsible genes and help with efficient gene analysis and pathophysiological considerations.
  • J Bacchetta
  • F Dijoud
  • R Bouvier
Bacchetta J, Dijoud F, Bouvier R, et al. [Renal tubular dysgenesis and mutation in the renin gene]. Arch Pediatr 2007; 14: 1084-1087.