Congenital Renal Abnormalities

Scott Wenderfer, MD/PhD

February 2002
 Congenital Renal Abnormalities
• Isolated Renal Agenesis
• Bilateral Renal Agenesis
• Hypoplastic Kidney
• Ectopic Ureter
• Bifid Ureter
• Megaureter
• Vesicourinary Reflux
• Hydronephrosis
• Cystic Kidney
• Renal Tubular Dysgenesis
• Accessory Renal Artery
• Ectopic (Pelvic) Kidney
• Horseshoe Kidney
• Mayer-Rokitansky-Kuster-
Hauser syndrome
• Gartner’s Cyst
• Epoophoron / Paroopheron
• Dysplastic Kidney
 Renal Involvement in Multiple
Congenital Anomaly Syndromes
• Potter’s Syndrome
• RCS: Renal Coloboma Syndrome
• BOR: Brachio-oto-renal Syndrome
• TBS: Townes-Brocks Syndrome
• Nagar Syndrome
• CHARGE Syndrome
• VACTERL Syndrome
• DiGeorge Sequence

• association with preauricular pits and tags?

• association with single umbilical artery?
 Urogenital Development
Intermediate mesoderm
• nephrotomes
– cervical, regress @ 4 wks

• mesonephroi - Wolffian ducts - vas deferens

- urogenital sinus - bladder, urethra
– thoracolumbar, regress @ 10 wks

• metanephroi - ureteric buds & kidney blastema

– sacral, arise @ 4 wks
 Urogenital Development
Metanephros induced by uteric buds
• renal corpuscle induces Bowman’s capsule
• as uteric bud branches, blastema bifurcates
• reciprocal induction of branching
• renal calyces form from 2o bud fusion
• uteric buds form collecting tubules
• blastema forms PCT, LoH, DCT
• DCT fuses with CD @ 10 wks
Kidneys ascend from sacral to lumbar
• differential growth of segments
• new vessel growth from more proximal aorta
 Molecular Genetics
• PAX2 expressed in CNS, optic placode, kidney
• PAX2 prevents apoptosis, supporting proliferation
• PAX2 autophagy dependent on HSP73, LGP96 and
inhibited by EGF receptor signalling
• PAX2 phosphorylated by MAPK pathway (JNK)
• PAX2 expressed in nephrogenic rests adjacent to
Wilms tumors (WT1 inhibits Pax2 expression)
• PAX2 enhances transcription of WT1, E-cadherin,
GDF and several BMP and FGF genes
• PAX2 inhibits transcription of vimentin gene
 Molecular Genetics
• RET and GDF involved in uteric bud growth and
branching, and thus metanephric induction
• GDF is absent in PAX2null mice
• BMP4 inhibits GDF
• EYA1 expressed in kidney blastema
• PAX8 expressed in early renal tubular epithelium
called S-shaped body
Hereditary Urogenital Adysplasia
• Isolated renal agenesis 1/2,000
• Bilateral renal agenesis 1/3,000
• Renal aplasia (non-functional tissue capping ureter)
• true agenesis = absent ureter, bladder hemitrigone, and
vas deferens
• defects in mesonephric / paramesonephric ducts
• can get 2o regression of hypoplastic / dysplastic kidney
• nuclear medicine scan can rule out ectopic kidney
• autosomal dominant
• 50-90% penetrance, variable expression
• Vancouver family with 5q11.2 - q13.3 aberration
Hereditary Urogenital Adysplasia
• 10% incidence of asymptomatic renal anomalies found
in parents / sibs of 41 index cases of B renal agenesis
• 8% incidence in sibs of 221 perinatal lethal renal dz
• Parental renal US does not predict recurrance risk

Recommendations:
• prenatal US @ 15-18 weeks PMA
• no contact sports for ptns with unilateral renal
agenesis
• increased risk for HTN, ESRD
Congenital Renal Abnormalities
• Hypoplastic Kidney (paucity of uteric bud bifurcation,
or renal vascular formation <brachyrrhine mouse>)
• Ectopic Ureter (formation 3 uteric buds)
• Bifid Ureter (premature uteric bud bifurcation)
• Hydronephrosis (failure of programmed cell death in
blastema, spontaneously or 2o to obstruction)
• Megaureter
• Vesicourinary Reflux (familial, QTL at 1p13)
 Cystic Kidney Diseases
• Failure of collecting duct to fuse w/ metanephros
• Autosomal dominant polycystic kidney disease
• PKD1, mutant polycystin gene, 16p13.3
• PKD2, polycystin interacting protein, 4q13-p23
• PKD3, locus not mapped
• Autosomal recessive polycystic kidney disease
• disease gene maps to 6p, incidence 1/40,000
• mouse model Pax2null in cpk background
• Multicystic dysplastic kidney
• multifocal microcystic tubular dilation (thickenned
CD w/ undifferentiated renal blastema
• mouse model Pax2 transgenic
 Renal Tubular Dysgenesis
• Hereditary less common than acquired (ACEi)
• Hypoplasia of tubules, absense of PCTs
• Associated with paternal minimal change disease
• Normal amniotic fluid volume before 22 weeks
(because of mesonephroi ?)
Congenital Renal Abnormalities
• Accessory renal artery (no sacral vessel regression)
• Ectopic (Pelvic) Kidney (no migration of kidney)
• Horseshoe Kidney (fusion of inferior pole of kidneys)
• Gartner’s Cyst (mesonephric duct remnant near
vagina)
• Mayer-Rokitansky-Kuster-Hauser syndrome (defect
of metanephric and paramesonephric ducts)
• Epoophoron / Paroopheron (mesonephric duct
remnant near oviduct)
 Potter’s Syndrome
• 1946 Edith Potter - Chicago pathologist
• “flattened ears & bilateral renal agenesis”
• incompatible with life
• incidence 1/3,000 live births
• Potter’s facies only 20% Potter’s syndrome
• wide set eyes, squashed nose, receding chin, large low
set ears, deficiency of cartilage
• due to oligohydramnios of any cause
 Renal Coloboma Syndrome
• Renal failure, coloboma, high frequency hearing loss
• Extreme variability of phenotype: VU reflux only to
oligomeganephronia (bilateral renal hypoplasia)
• Pax2 Gene Mutation on 10q22.1-q24.3
• Two alternatively spliced transcripts known
• Multiple mutations / polymorphisms identified
• mouse model made by transgene insertion into Pax2
• 2nd mouse model Pax2(1Neu) frameshift mutant
• Zebrafish model “no isthmus”
Brachio-oto-renal Syndrome
Brachial cysts / fistulas 60%
Ear malformations (cup, lop, microtia)30%
Preauricular pits 70%
Hearing loss 75%
Renal anomalies 15%

• autosomal dominant, seen in 1/40,000 live births

• EYA1 gene mutation
• EYA1 expressed in condensing blastema prior to
epithelialization
 Townes-Brocks Syndrome
Ear defects (satyr, lop, cup, pits, tags) 70%
Hearing loss 50%
Hand malformation 50%
Imperforate anus / rectourinary fistula 50%
Renal anomalies 25%

• autosomal dominant transcription factor defect

• SALL1 gene mutation
• SALL1 expressed in excretory organs, ear, limbs
 Nagar Syndrome
Craniofacial anomalies (mandibular hypoplasia)
Preaxial limb defects (noradii, hypoplastic hallices)
Hearing loss 95%
Renal anomalies 10%

• unknown mode of inheritance

CHARGE Syndrome
Coloboma of iris / retina 80%
Heart defects 75%
Atresia of choanae 50%
Retarded growth 70%
Developmental delay 100%
Genital hypoplasia 70%
Ear Defects / hearing loss 90%

Renal abnormalities 15%

Cleft lip / palate 20%
Tracheo-esophageal fistula 20%
 VACTERL
Vertebral anomalies
Anal atresia
Cardiac abnormalities
Tracheoesophageal fistula
Esophageal dysmotility
Renal anomalies
Limb defects
 DiGeorge Sequence
thymic aplasia / hypoplasia and immunodeficiency
developmental delay
cleft lip / palate
colobomas
parathyroid hypoplasia
cardiac malformations
renal agenesis

• Autosomal dominant, recessive, or X-linked

• Microdeletion in 22q11 most common
 Preauricular Pits and Tags
• Incidence 5/1000 live births
• 2 studies: 4-9% associated w/ renal disease
• hydronephrosis, or undiagnosed MCA
• Mainz Congenital Birth Defect Monitoring System
• association with cup ears, preauricular pits
• no association with ear tags
• Embryology: Ear & Kidney Arise Separate Times
• UCLA recommendations for Renal US:
• FHx deafness, renal or auricular disease
• maternal gestational diabetes
 References:
1) Development of the Urogenital System. In Human Embryology
1st Ed. W.J. Larsen, Ed. Churchill Livingstone, New York, 1993.

2) Renal Agenesis. In Nelson Textbook of Pediatrics 16Ed.,

Behrman, Ed., W.B. Saunders Company, 2000.

3) R.Y. Wang et al. Syndromic Ear Anomalies & Renal

Ultrasounds. Pedi. 108:e32, Aug 2001.

4) OMIM 191830, 267430.