Congenital Renal Disease

8/2/2019 Congenital Renal Disease

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Congenital Renal and Genital

Abnormalities

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 MultipleCongenital 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

• 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 toWilms tumors (WT1 inhibits Pax2 expression)

• PAX2 enhances transcription of WT1, E-cadherin,GDFa and several BMP and FGF genes

• PAX2 inhibits transcription of vimentin gene

Molecular Genetics

• RET and GDFa involved in uteric bud growth andbranching, and thus metanephric induction

• GDFa 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, andvas 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

Renal Agenesis• Absence of kidneys

– Unilateral (compatible with life)

• Affects 1 in every 800-1500 people

• May occasionally present with genitalia anomolies• Trisomy of 18

• Addition or partial trisomy of 13

• Prenatal rubella infection

– Bilateral (incompatible with life)• 40% stillborn

• Of those born alive 95% die within 24 hours of birth

• Potter syndrome and associated oligohydramnios

Renal hypoplasia

• Incomplete development of kidneys

– Unilateral (compatible with life)

– Bilateral (incompatible with life) if condition is

severe

• Kidneys are small

– Decreased functional parenchyma

• 10% incidence of asymptomatic renal anomalies foundin 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

Hereditary Urogenital Adysplasia

• 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 inblastema, 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 (thickennedCD w/ undifferentiated renal blastema

• mouse model Pax2 transgenic

Congenital cystic kidneys

• Type 1

– Polycystic kidneys found in infants

• Bilateral and results in early death• AKA giant or sponge kidneys

• Large renal pelvis and calyces

• Type 2

– Cysts are variable in size and shape

– Usually unilateral

– Affected kidney non functional

Congenital cystic kidneys (cont.)

• Type 3 – Affected kidneys contain both normal and abnormal

tissue

– Both kidneys involved – Autosomal dominant gene

• Trisomy of 13-15, 18, 21, 22

• Type 4

– Caused by urethral obstruction – If severe early death

• Type 5 – Manifests during adult life, death by 50.

– Autosomal dominant

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 ?)

• 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 (defectof metanephric and paramesonephric ducts)

• Epoophoron / Paroopheron (mesonephric ductremnant near oviduct)

Horseshoe (fused) kidney

• Fusion of two kidneys at their lower end

– Tissue that connects kidneys = isthmus

• 1:400

• Trisomy 13-15; 18, 21, Turner’s syndrome,

mosaicism

• In rats horseshoe kidney can be produced

experimentally by creating vitamin A

deficiency

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 lowset ears, deficiency of cartilage

• due to oligohydramnios of any cause

Eagle-Barrett Syndrome

• More commonly known as Prune Belly

Syndrome

• Characterized by:

– deficiency of abdominal wall musculature

– a dilated, non-obstructed urinary tract

– bilateral cryptorchidism

– talipes equinovarus and hip dislocation

• Incidence is 1/35-50,000

• >95% occur in males

• Believed to be caused by in-utero urinary

tract obstruction and a specific mesodermal

injury between the 4th and 10th week of

gestation.

• Associated with renal dysplasia or agenesis.

• Often presents with a large-capacity, poorly

contractile bladder.

• Heart, pulmonary, GI and orthopedic

anomalies occur in a large percentage of PBS

patients.

Management:

• Neonatal Period

– Optimize urinary tract drainage

– Monitor and treat renal insufficiency

– Antibiotic prophylaxis if reflux is present

• Children

– Surgical repair of reflux

– Orchiopexy

– Reconstruction of the abdominal wall

– Renal transplant

Prune Belly Syndrome -

Prognosis• Prognosis varies from stillbirth to minimal

abdominal laxity.

• Long-term prognosis depends on renalfunction and pulmonary status.

• Psychological issues stemming from

abdominal wall laxity and infertility.

Renal Coloboma Syndrome

• Renal failure, coloboma, high frequency hearing loss

• Extreme variability of phenotype: VU reflux only tooligomeganephronia (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 toepithelialization

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 anomaliesAnal atresiaCardiac abnormalitiesTracheoesophageal fistulaEsophageal dysmotilityRenal anomaliesLimb 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

Development of the reproductive

system• Makes its appearance during 5th & 6th week

– Indifferent stage-sex cannot be determined

• Gonads (testes & ovaries) develop from

– Coelomic epithelium

– Inner mesenchyme tissue

– Primordial germ cells

• Thickening of ventromedial surface of urogenital

ridge forming genital ridge

Genital ridge

• Covered by coelomic epithelium

– Primary sex cords

• Grow into underlying mesenchyme

• Inner mass is composed of mesenchyme

• Outer layer called cortex

• Inner layer called medulla

– Males- medulla differentiates, cortex regresses

– Females-cortex develops, medulla regresses

Primordial Germ Cells (PGC)

• Differentiate in the neck of the yolk sac

– Early in the 4th week

• Migrate to genital ridge

– Amoeboid movement

– By end of 6th week the PGC become

incorporated into the primary sex cords – migration of primordial germ cells

Development of testes

• Primary sex cords of testes containing theprimordial germ cells = testes cords

– Well defined cords within the medulla

– Contain two types of cells

• Epithelial cells Sertoli cells• Primordial germ cells spermatoblasts

– development of testes

• Testes cords remain solid until puberty

– Canalize to form seminiferous tubules (ST), tubulirecti, rete testis

• ST seperated from each other by mesenchyme that givesrise to interstitial cells (Cells of Leydig)

Development of the Ovaries

• Primary sex cords are not well defined

– Extend into the medulla but later dissappear

• PGC migrate near the cortex (surface epithelium

– Forms cortical cords

– At about 16th week cortical cords break up into

isolated clusters called primordial follicles

– development of ovary

Primordial Follicles

• Follicle contains

– Ooblast (oogonium)

• Derived from the primordial germ cell

• Undergoes mitosis during fetal life – Results in development of primary oocyte

– A number of follicular cells

• Derived from the cortical cords

– Each primary oocyte surrounded by follicular cells

= primary follicle

• follicular development

Development of Genital Ducts• Indifferent stage

– Both male and female genital ducts present

• Male develop from mesonephric/wolffian ducts

• Female develop from paramesonephric/mullerian duct

– Undifferentiated gonad

• Males:Mesonephric ducts form epididymis,

ductus deferens, ejaculatory duct

– Cranial mesonephric tubules efferent ducts• Open into epididymis

– Process begins about the 3rd month

Development of Genital Ducts

• Females: Paramesonephric duct/Mullerian duct

develops on each side of the body

– Longitudinal invagination of coelomic epithelium

on the lateral surface of mesonephros

– Ducts open into coelom

– Runs along side of mesonephric duct

– Fuse at caudal end• Y shaped uterovaginal complex uterus & vagina

– uterovaginal complex

Fetal testes

• Produce androgens

– Stimulate development of mesonephric ducts

– Suppress formation of paramesonephric ducts

• If testes fail to develop or removed

– Paramesonephric ducts will develop

• Removal of fetal ovaries

– Has no effect on fetal sexual development

Development of external genitalia

• Indifferent stage – Genital tubercle

• Develops at upper end of cloacal membrane

• Elongates to form the Phallus

– Labioscrotal swellings appear – Urogenital folds appear

– Cloacal membrane divided into two

• Development of urorectal septum

– Upper urogenital membrane

– Lower anal membrane

» These membranes rupture around week 7 formingurogenital and anal openings

Development of external genitalia

• Male genitalia

– Phallus elongates to form the penis

• Enlongation pulls the urogenital folds together

• When folds start to fuse they enclose the urethra – Urethral opening moves progressively towards end of penis

– Labioscrotal swellings fuse forming scrotum

• Female genitalia – Phallus becomes clitoris (relatively small)

– Urogenital folds do not fuse labia minora

– Labioscrotal fuse only at ends

labia majora

Accessory sex glands

• Male

– Highly developed

• Seminal vesicles• Prostate

• Bulbourethral glands

• Female – Minimal

• Major vestibular glands (homologous to

bulbouretharal glands in male)

Congenital Malformations• Ovarian hypoplasia

• Pure gonadal dysgenesis

• Testicular feminization syndrome

• Hermaphroditism

– true

– Female pseudohermaphroditism

– Male pseudohermaphroditism• Hypospadias

• Epispadia

Ovarian hypoplasia

• Small overies

• Poor breast development

• Small uterus

• Found in Turner’s syndrome

– Incomplete or partial X chromasome

• Can be unilateral or bilateral

– Unilateral fertile

– Bilateral infertile

Pure Gonadal Dysgenesis

• Normal karyotypes (46, XX or 46, XY)

• Primordial germ cells do not migrate from

the yolk sac – No development of the ovaries or testes

Jacob’s syndrome

• XYY

• No abnormal appearance/behavior• fertile

Jacob’s Syndrome

1 in 1,800 births

47 chromosomes

XYY only

#23 Trisomy

Nondisjunction

Jacob’s Syndrome

Normal physically

Normal mentally

Increase in testosteronePerhaps more aggressive

Normal lifespan

Testicular Feminization Syndrome

• Occurs at rate of 1:50,000

• Appears to be a normal female despite the

presence of testes in either abdomen oringuinal region

– Testes produce normal levels of testosterone

• Tissues unresponsive to androgens

• External genitalia are normal

• Shallow blind ending vagina

Hermaphroditism

• True hermphrodite

– Both ovaries and testicular tissue present

• Masculine form

• Feminine form

• Intermediate form (more common) – 46, XX/ 46, XY or 46, XX/ 47, XXY

Hermaphroditism• Female pseudohermaphroditism (46, XX)

– AKA congenital adrenogenital syndrome

• Masculinization due to high level of androgens fromadrenal cortex

• Male pseudohermaphroditism

– Testes and ambiguous female genitalia

• Many types, most common is of unknown etiology

• Often considered females at a young age because penisis absent

– Raised as girls until puberty when male secondary sexcharacteristics appear via endocrine activities of testes

Klinefelter’s Syndrome

• XXY, male

1 in 1,100 births

47 chromosomes

XXY only

47, XXY

#23 Trisomy

Nondisjunction

Scarce beard

Longer fingers and arms

Sterile

Delicate skinLow mental ability

Normal lifespan

Down Syndrome • 47, XY, +21

1 in 1,250 births

47 chromosomes

XY or XX

#21 Trisomy

Nondisjunction

Down Syndrome

Short, broad hands

Stubby fingers

Rough skin

Impotency in malesMentally retarded

Small round face

Protruding tongue

Short lifespan

Turners Syndrome

• 45, X

Wolf Hirshhorn Syndrome

• 4p- • Very rare. Affected children are small, with

microcephaly and abnormal facies. There are

cardiac, renal, and genital abnormalities. Mostare stillborn or die in infancy.

A i idi Wil T

Aniridia-Wilms Tumor

Syndrome

1 in 50,000,000 births

46 chromosomes

XY or XX

#11 Deletion of upper arm

Aniridia-Wilms Tumor Syndrome

Mentally retarded

Growth retarded

Blindness

Tumors on kidneysShort lifespan

Four-Ring Syndrome

Cleft palate

Club feet

Testes don’t descend

Short lifespan

Triple X Syndrome

1 in 2,500 births

47 chromosomes

XXX only

#23 Trisomy

Nondisjunction

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 & RenalUltrasounds. Pedi. 108:e32, Aug 2001.

4) OMIM 191830, 267430.

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