Renal Development Renal Development & Dysplasia& Dysplasia

Part IPart IHsiao Lai, MDHsiao Lai, MDFeb 19, 2010Feb 19, 2010

ECU, Brody School of MedicineECU, Brody School of MedicineNephrology and HypertensionNephrology and Hypertension

Pediatric Nephrology Core CurriculumPediatric Nephrology Core Curriculum

Where will you encounter Where will you encounter Renal Dysplasia?Renal Dysplasia?

Ob-Gyn referal prenatal screening ultrasound Ob-Gyn referal prenatal screening ultrasound at 20wksat 20wks

Neonatal nursery/NICUNeonatal nursery/NICU Abnormal RUSAbnormal RUS Congenital malformation syndrome with renal Congenital malformation syndrome with renal

anomaliesanomalies Primary renal failure/insufficiencyPrimary renal failure/insufficiency

Childhood: Childhood: Frequent UTI’sFrequent UTI’s Incidental finding on abdominal imagingIncidental finding on abdominal imaging Hypertensive childHypertensive child

AdolescentAdolescent Present in renal failure/ESRD requiring dialysis or Present in renal failure/ESRD requiring dialysis or

transplantationtransplantation

Congenital Anomalies of Congenital Anomalies of Kidney and Urinary tract Kidney and Urinary tract

(CAKUT)(CAKUT)

Account for:Account for: Diverse non-syndromic renal and Diverse non-syndromic renal and

lower urinary tract malformationslower urinary tract malformations Most common congenital anomalyMost common congenital anomaly 1/3 of all anomalies detected by 1/3 of all anomalies detected by

routine fetal ultrasound (18-22 wk)routine fetal ultrasound (18-22 wk) 40% of childhood ESRD40% of childhood ESRDWoolf et. Al: in Renal Dysplasia

Birth Defects Monitoring Program

Causes of Pediatric Causes of Pediatric ESRDESRD

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CAKUTCAKUT 4040

Acquired GNAcquired GN 1818

Congenital Nephrotic SyndromeCongenital Nephrotic Syndrome 88

NephronophthisesNephronophthises 55

CystinosisCystinosis 33

PKDPKD 33

OtherOther 2323

Common Congenital Renal Common Congenital Renal AnomaliesAnomalies

Cystic Dysplastic KidneysCystic Dysplastic Kidneys Renal agenesisRenal agenesis Horseshoe KidneyHorseshoe Kidney Ectopic Kidneys Ectopic Kidneys Duplicated Kidneys and UretersDuplicated Kidneys and Ureters

Common Urogenital Common Urogenital AnomaliesAnomalies

Urinary Outlet ObstructionUrinary Outlet Obstruction Ureteropelvic Junction Obstruction UPJUreteropelvic Junction Obstruction UPJ Ureterovesicle Junction Obstruction Ureterovesicle Junction Obstruction

UVJUVJ Posterior Urethral ValvesPosterior Urethral Valves Anterior Urethral ValvesAnterior Urethral Valves Congenital MegaureterCongenital Megaureter

Primary Vesicoureteral RefluxPrimary Vesicoureteral Reflux UreteroceleUreterocele

Congenital Renal Congenital Renal AnomaliesAnomalies

Present at birthPresent at birth Occur during the process of Occur during the process of

organogenesisorganogenesis Involves defects:Involves defects:

Tissue InductionTissue Induction Reciprocal feedback between tissue Reciprocal feedback between tissue

precursorsprecursors MorphogenesisMorphogenesis MigrationMigration

Intermediate mesoderm

Renal DevelopmentRenal Development

Intermediate Intermediate mesodermmesoderm

PronephrosPronephros Mesonephros Mesonephros Nephric (Wolffian) Nephric (Wolffian)

Duct formationDuct formation Metanephros = Metanephros =

Fetal KidneyFetal Kidney

Formation of Fetal Formation of Fetal KidneyKidney

Wk 4: appearance of Wolffian or Wk 4: appearance of Wolffian or Mesonephric Duct Mesonephric Duct

D28: formation of Ureteric Bud D28: formation of Ureteric Bud (UB)(UB)

Wk 4-8: Initial MM induction and Wk 4-8: Initial MM induction and UB branchingUB branching

Week 8: First nephrons are formedWeek 8: First nephrons are formed Week 4-8 kidneys ascend from Week 4-8 kidneys ascend from

pelvis to lumbar locationpelvis to lumbar location Wk 10 filtration beginsWk 10 filtration begins

Renal and Urogenital Renal and Urogenital DevelopmentDevelopment

11stst 6-10 UB 6-10 UB branches coalesce branches coalesce to form renal to form renal pelvis and calycespelvis and calyces

Wk 5 implantation Wk 5 implantation of distal UB into of distal UB into posterior posterior urogenital sinusurogenital sinus

Wk 5-7 ureter Wk 5-7 ureter becomes occludedbecomes occluded

Wk 7-8 Wk 7-8 recanalization of recanalization of ureterureter

Urogenital DevelopmentUrogenital Development Wk 4-6: cloaca separates into anterior Wk 4-6: cloaca separates into anterior

and posterior portionand posterior portion Anterior cloaca develops into urogenital Anterior cloaca develops into urogenital

sinus which gives rise to the bladder and sinus which gives rise to the bladder and urethraurethra

Posterior cloaca gives rise to the rectumPosterior cloaca gives rise to the rectum Urogenital sinus continuous superiorly Urogenital sinus continuous superiorly

with allantois which later regresses. with allantois which later regresses. Expanded superior portion of urogenital Expanded superior portion of urogenital

sinus becomes the bladdersinus becomes the bladder Inferior portion gives rise to pelvic Inferior portion gives rise to pelvic

urethra and also the penile urethra in urethra and also the penile urethra in males and the vestibule of the vagina in males and the vestibule of the vagina in femalesfemales

Later Stages of Later Stages of NephrogenesisNephrogenesis

In humans the early UB divisions are not In humans the early UB divisions are not associated with nephrogenesisassociated with nephrogenesis

Wk 8-15 Period of UB branching with stochastic Wk 8-15 Period of UB branching with stochastic formation of UB ampulla and nephron unitsformation of UB ampulla and nephron units

UB branching decelerates after 15 wks, however UB branching decelerates after 15 wks, however nephron induction continues up until 32-26 nephron induction continues up until 32-26 weeksweeks

Wk 15-20 Arcade induction of 5-7 nephrons per Wk 15-20 Arcade induction of 5-7 nephrons per ampulla ampulla

Wk 20-36 Serial induction of without UB Wk 20-36 Serial induction of without UB branchingbranching

Wk 32-36 End of NephrogenesisWk 32-36 End of Nephrogenesis

Late NephrogenesisLate Nephrogenesis

Mechanisms of Mechanisms of Maldevelopment Maldevelopment

UB Agenesis UB Agenesis UB Duplication UB Duplication Disruption of Renal MesenchymeDisruption of Renal Mesenchyme Interrupted Cross-talk between Interrupted Cross-talk between

UB and MMUB and MM Abnormal apoptosis/proliferationAbnormal apoptosis/proliferation Abnormal UB implantationAbnormal UB implantation Abnormal UB recanalizationAbnormal UB recanalization Abnormal renal migrationAbnormal renal migration

Edith Louise PotterEdith Louise Potter 1901-19931901-1993 Early training in Early training in

MinnesotaMinnesota Chicago Lying-In HospitalChicago Lying-In Hospital Pioneer in understanding Pioneer in understanding

perinatal pathology of perinatal pathology of congenital malformationscongenital malformations

Rh Factor and congenital Rh Factor and congenital hemolytic anemiahemolytic anemia

Pioneer in renal Pioneer in renal developmentdevelopment

Euro J Pediatrics 1994

Potter’s SyndromePotter’s Syndrome

Bilateral renal agenesisBilateral renal agenesis Syndrome of findings: Syndrome of findings:

Oligohydramnios, Potter’s facies, Oligohydramnios, Potter’s facies, skeletomuscular abnormalities, skeletomuscular abnormalities, pulmonary hypoplasia resulting from pulmonary hypoplasia resulting from a particular series of developmental a particular series of developmental events stemming fromevents stemming from

Death usually from respiratory failure Death usually from respiratory failure within minutes to hours of birthwithin minutes to hours of birth

Normal KidneysNormal Kidneys

““Dysplastic” KidneysDysplastic” Kidneys Small or large abnormally shaped kidneysSmall or large abnormally shaped kidneys Immature/undifferentiated or metaplastic Immature/undifferentiated or metaplastic

(abnormal) renal structures (abnormal) renal structures May be associated with cysts in case of cystic May be associated with cysts in case of cystic

dysplastic kidneys or complete agenesis of dysplastic kidneys or complete agenesis of kidneyskidneys

If dysplasia is extensive, renal dysfunction may If dysplasia is extensive, renal dysfunction may necessitate nephrologic care, including renal necessitate nephrologic care, including renal replacement therapyreplacement therapy

Very little or no excretory functionVery little or no excretory function Often associated with urogenital anomalies Often associated with urogenital anomalies

and refluxand reflux

Multicystic Dysplastic Multicystic Dysplastic KidneyKidney

Minimal to no functional Minimal to no functional renal parenchyma renal parenchyma usually with primitive usually with primitive tubules and foci of tubules and foci of cartilage cartilage

Kidney consists of Kidney consists of groups of groups of noncommunicating noncommunicating cysts with fibrous cysts with fibrous connective tissueconnective tissue

““Bunches of grapes” Bunches of grapes” appearanceappearance

Multicystic Dysplastic Multicystic Dysplastic KidneyKidney

1/2400 live births1/2400 live births Usually unilateral with ureteral atresiaUsually unilateral with ureteral atresia Increase incidence of reflux Increase incidence of reflux

incontralateral kidneyincontralateral kidney Often regress over several months to Often regress over several months to

years and may account for many cases of years and may account for many cases of unilateral “renal agenesis”unilateral “renal agenesis”

Uncommonly, the kidney develops tumors Uncommonly, the kidney develops tumors or infection, and hypertension may or infection, and hypertension may developdevelop

Most experts recommend observation, Most experts recommend observation, although some advocate removing these although some advocate removing these kidneys, especially if solid tissue is kidneys, especially if solid tissue is extensive or unusual appearing on extensive or unusual appearing on ultrasonographyultrasonography

MCDKMCDK

ARPKDARPKD

1 in 20,000 individuals1 in 20,000 individuals Cysts in Kidneys and LiverCysts in Kidneys and Liver PKD1 gene – polycystinPKD1 gene – polycystin Variable severity and presentation, Variable severity and presentation,

but severe cases usually present in but severe cases usually present in neonatal/infantile period with renal neonatal/infantile period with renal symptoms later cases present with symptoms later cases present with liver-related symptomsliver-related symptoms

ARPKDARPKD

30-50% mortality in newborn period 30-50% mortality in newborn period mainly from in-utero oligohydramnios mainly from in-utero oligohydramnios leading to pulmonary hypoplasia leading to pulmonary hypoplasia

If survive newborn period 1/3 need If survive newborn period 1/3 need dialysis or transplantation by age 10dialysis or transplantation by age 10

Kidneys can have rapid growth over the Kidneys can have rapid growth over the first few monthsfirst few months

Mild cases present in late childhood or Mild cases present in late childhood or adolescent with symptoms of periportal adolescent with symptoms of periportal fibrosis with gastric varicele bleeding fibrosis with gastric varicele bleeding and mild renal insufficiencyand mild renal insufficiency

ARPKDARPKD

Cortical cysts form in collectng duct

ADPKD on Fetal USADPKD on Fetal US

Radiographic Appearance Radiographic Appearance of ARPKD vs ADPKDof ARPKD vs ADPKD

kennythekidney.com

ADPKDADPKD

Renal HypoplasiaRenal Hypoplasia

Inadequate ureteral bud Inadequate ureteral bud branching causes an branching causes an underdeveloped, small kidney with underdeveloped, small kidney with histologically normal nephrons histologically normal nephrons Small well formed kidneysSmall well formed kidneys

Functional on renogramFunctional on renogram If hypoplasia is segmental, If hypoplasia is segmental,

hypertension can occur, and hypertension can occur, and ablative surgery may be neededablative surgery may be needed

Decreased Nephron Decreased Nephron NumberNumber

Number of nephrons more than Number of nephrons more than doubles between 20 and 40 weeksdoubles between 20 and 40 weeks

Majority of nephrons form during Majority of nephrons form during final third of gestationfinal third of gestation

Final nephron number can be highly Final nephron number can be highly variable between 230,000 to 1800,000 variable between 230,000 to 1800,000

One branching generation may result One branching generation may result in 30-35% less nephrons than wild in 30-35% less nephrons than wild type- usually undetectable phenotypestype- usually undetectable phenotypes

Decreased nephron number is related Decreased nephron number is related to increased risk of hypertension and to increased risk of hypertension and chronic kidney diseasechronic kidney disease

Duplex Kidney and Duplex Kidney and UretersUreters

~15% of all live births~15% of all live births Incomplete fusion of upper and Incomplete fusion of upper and

lower pole moieties can result lower pole moieties can result incomplete or incomplete incomplete or incomplete duplication of the collecting systemduplication of the collecting system

Two ureteric buds arise from the Two ureteric buds arise from the mesonephric duct, or if a single UB mesonephric duct, or if a single UB divides into two branches before it divides into two branches before it invades into the metanephrogenic invades into the metanephrogenic blastemablastema

Weigert-Meyer LawWeigert-Meyer Law

Upper Pole Moiety: obstructed

Lower Pole Moiety: refluxes

Weigert-Meyer LawWeigert-Meyer Law Upper pole moiety: ureter inserts Upper pole moiety: ureter inserts

ectopically, inferomedial to normal ectopically, inferomedial to normal sitesite

Lower pole moiety: ureter inserts Lower pole moiety: ureter inserts orthotopically-posterio-lateral orthotopically-posterio-lateral insertion into bladder trigoneinsertion into bladder trigone

Ectopic insertion often has a Ectopic insertion often has a urethrocele which obstructs its own urethrocele which obstructs its own collecting system and can distort the collecting system and can distort the lower moiety insertion and cause lower moiety insertion and cause reflux into lower pole moietyreflux into lower pole moiety

Duplex Kidney and Duplex Kidney and UretersUreters

Complete duplicationComplete duplication results results when two entirely separate when two entirely separate ureters drain separate upper and ureters drain separate upper and lower pole or two individual lower pole or two individual kidneys kidneys

Partial duplicationPartial duplication occurs when occurs when the two ureters join before the two ureters join before reaching the bladderreaching the bladder

Duplication of the renal pelvis Duplication of the renal pelvis alone can also occuralone can also occur

Abnormalities of Renal Abnormalities of Renal Fusion, Ascent and Rotation Fusion, Ascent and Rotation Horseshoe KidneyHorseshoe Kidney Cross-fused EctopiaCross-fused Ectopia Pelvic KidneyPelvic Kidney Pancake KidneyPancake Kidney

Abnormalities of Ascent Abnormalities of Ascent and Rotationand Rotation

Horseshoe kidney

Cross fused ectopia

Horseshoe KidneyHorseshoe Kidney 1 in 400 live births1 in 400 live births Kidneys fuse together early during Kidneys fuse together early during

ascent usually at lower polesascent usually at lower poles Connecting isthmus can be renal Connecting isthmus can be renal

parencyhmal or fibrous tissueparencyhmal or fibrous tissue Ureters usually drain medially and Ureters usually drain medially and

anteriorly to isthmusanteriorly to isthmus Asymptomatic in the majority of casesAsymptomatic in the majority of cases May be associated with reflux May be associated with reflux

nephropathy if ureters implant more nephropathy if ureters implant more superiorly that causes CKD, or with superiorly that causes CKD, or with more complex developmental syndromesmore complex developmental syndromes

Crossed-Fused EctopiaCrossed-Fused Ectopia

Kidneys fuse early in developmentKidneys fuse early in development Both fused kidneys lie on one side Both fused kidneys lie on one side

of the spine, and the ureters cross of the spine, and the ureters cross the midline in order to enter the the midline in order to enter the bladder with upper ureter bladder with upper ureter implanting posteriorlyimplanting posteriorly

Often the upper kidney is Often the upper kidney is obstructed, while the lower ureter obstructed, while the lower ureter refluxesrefluxes

Pelvic/Ectopic KidneyPelvic/Ectopic Kidney

Kidney fails to ascend to normal location Kidney fails to ascend to normal location in the renal fossain the renal fossa

Predominantly pelvic location, rarely Predominantly pelvic location, rarely thoracic thoracic

Incidence is 1/900 live births, more Incidence is 1/900 live births, more commonly on left commonly on left

Usually clinically asymptomatic and Usually clinically asymptomatic and found coincidentallyfound coincidentally

Often associated with genital anomalies, Often associated with genital anomalies, but cardiovascular and skeletal but cardiovascular and skeletal anomalies are also commonanomalies are also common

1/3 of siblings affected1/3 of siblings affected Likely AD inheritance with widely variable penetranceLikely AD inheritance with widely variable penetrance Structural abnormality of vesicoureteral junction with Structural abnormality of vesicoureteral junction with

abnormally short submucosal segment of the ureter abnormally short submucosal segment of the ureter or deficiency in the musculature of the intravesical or deficiency in the musculature of the intravesical ureterureter

Bladder Outlet Bladder Outlet ObstructionObstruction

UPJ UPJ UVJUVJ PUVPUV Ureteral DuplicationUreteral Duplication Ectopic UretersEctopic Ureters Congenital MegaureterCongenital Megaureter

UPJ ObstructionUPJ Obstruction

Most common upper urinary tract Most common upper urinary tract obstruction in children obstruction in children

Incidence 1/1000-1/2000 newbornsIncidence 1/1000-1/2000 newborns Most common cause of pediatric Most common cause of pediatric

hydronephrosishydronephrosis Account for 50% of hydronephrosis on Account for 50% of hydronephrosis on

prenatal ultrasoundprenatal ultrasound More commonly on left, 20-30% bilateralMore commonly on left, 20-30% bilateral Often associated with other congenital Often associated with other congenital

anomalies especially MCDKanomalies especially MCDK

UPJ ObstructionUPJ Obstruction

UPJ is formed during Wk 5 of UPJ is formed during Wk 5 of gestationgestation

The UPJ is the last area of the UB to The UPJ is the last area of the UB to recanalizerecanalize

Abnormal or incomplete Abnormal or incomplete recanalization of the UB during recanalization of the UB during development leads to UPJ obstructiondevelopment leads to UPJ obstruction

UPJ functional obstruction can also UPJ functional obstruction can also result from an aperistaltic portion of result from an aperistaltic portion of UPJUPJ

UPJ ObstructionUPJ Obstruction

Posterior Urethral ValvesPosterior Urethral Valves Occurs only in malesOccurs only in males 1/5000 male births1/5000 male births Most common cause of urinary tract Most common cause of urinary tract

obstruction in malesobstruction in males Accounts for 20% of all childhood Accounts for 20% of all childhood

ESRDESRD Wide range of severity with mild Wide range of severity with mild

disease often missed until disease often missed until presentation with renal failure in presentation with renal failure in adolescence, severe disease can adolescence, severe disease can present with Eagle Barrett Syndromepresent with Eagle Barrett Syndrome

Posterior Urethral ValvesPosterior Urethral Valves

Results from persistent obstructing Results from persistent obstructing urogenital membraneurogenital membrane

Disrupted embryological Disrupted embryological development of male urethra development of male urethra between Wk 9-14between Wk 9-14

There seems to a also a component There seems to a also a component of renal dysplasia along with of renal dysplasia along with obstruction that does not necessarily obstruction that does not necessarily resolve with correction of resolve with correction of obstructionobstruction

PUVPUV

Management PUVManagement PUV

Foley catheter decompression at birthFoley catheter decompression at birth Management of associated renal Management of associated renal

dysfunctiondysfunction Valve ablation within weeks of birthValve ablation within weeks of birth Management of post ablation urinary Management of post ablation urinary

incontinenceincontinence Monitor for VUR and CKDMonitor for VUR and CKD Supravesical diversion prior to 21 Supravesical diversion prior to 21

wks, has not proved very successfulwks, has not proved very successful

Congenital Syndromes with Congenital Syndromes with Renal AnomaliesRenal Anomalies

Many widely diverse syndromesMany widely diverse syndromes Not enough time to summarize Not enough time to summarize

herehere Maybe a later presentation?Maybe a later presentation? Enjoy your weekend!Enjoy your weekend!