Page 1 of 10

Congenital Anomalies of the Urinary Tract Dr. Noel Binayas December 11, 2014

Group 8

Audio – italicized Blue box/Red text – Book notes Embryopathies/Developmental Abnormalities are significant in the first few years of life (pedia patients); It has an impact in adulthood, hence, it is emphasized by the request of the nephrologist to address the problem of vesicoureteral reflux; It has a significant impact with the proliferation of dialysis centers and increasing ESRD in the adult population that requires subsequent dialysis

GU TRACT ANOMALIES

1. 10% of population 2. 30% when other anomalies are present

3. a second anomaly is common 4. part of an association of manifestations:

VATER/VACTERL - vertebral anomalies, anorectal malformation, cardiac anomalies, tracheoesophageal anomalies, esophageal anomalies, renal anomalies, limb defect (absent ulna, radius, polydactyly, syndactyly)

5. if 1 anomaly is present, look for the possibility that another is present

EMBRYOLOGY

Urogenital Ridge - where the genitourinary system originates; major and only derivative of the intermediate mesoderm

6. nephric primordium 7. gonadal primordium 8. genital duct primordium

Notochord – primary organizer Induction is from the center towards the

periphery so midline structures develop first

3 Stages of Renal Development Stage is not a proper term since they do not follow 1 after another; However, one should be present before another is induced to development but the structures that arise may be dependent from prior structures in the previous stage

1. Pronephros

Primitive kidneys

functions only in the first 4 weeks and degenerates - nothing is derived from this stage

2. Mesonephros

replaces the pronephros at 4th week

Three slightly overlapping kidney systems are formed in a cranial to caudal sequence during intrauterine life in humans. The first of these systems is rudimentary and nonfunctional; the second may function for a short time during the early fetal period; the third forms the permanent kidney.

Page 2 of 10

mesonephric tubules join the pronephric duct to form the mesonephric or Wolffian duct

3. Metanephros

develops and differentiates with the inductive influence of the cranial growth of the ureteric bud (starts 5th week from the mesonephric duct), which it envelopes to form the renal cortex

This is the main anlage where your TRUE KIDNEYS come from.

It is an entirely different structure that develops from the ureteric bud as a result of stimulation or inductive influence of factors present at the tips of the ureteric bud which is derived from around the cloaca

With the elongation and formation of the ureteric bud and the subsequent confluence, canalization and interconnection of the metanephric component which develops into the nephrons, distal collecting duct which interconnect with the ureteric portion of the ureteric bud

The ureteric bud defines the collecting system; the collecting system and kidneys starts from the distal limb of the convuluted tubules - interconnections between the ureteric bud and the metanephric tubules occur

The 2 components of the development of the kidneys: metanephros and ureteric bud

GENE INDUCTIONS

As the ureteric bud develops, they ascend. There are inductors/induction that influence the surrounding tissues of the metanephric caps which proceed to create the developing renal tubules; Those are the so called gene evocators or inductors

Genes involved in the differentiation of the kidney a. WT1

Wilm's tumor gene; Wilm's tumor is characterized by primitive nephrogenic structures - metanephric and ureteric bud

The mesonephros and mesonephric ducts are derived from intermediate mesoderm from upper thoracic to upper lumbar (L3) segments. They lengthen rapidly, form an S-shaped loop, and acquire a tuft of capillaries that will form a glomerulus at their medial extremity. Around the glomerulus the tubules form Bowman’s capsule, and together these structures constitute a renal corpuscle. Laterally the tubule enters the longitudinal collecting duct known as the mesonephric or wolffian duct.

A. Relationship of the intermediate mesoderm of the pronephric, mesonephric,and metanephric systems. In cervical and upper thoracic regions intermediate mesoderm is segmented; in lower thoracic, lumbar, and sacral regions it forms a solid, unsegmented mass of tissue, the nephrogenic cord. Note the longitudinal collecting duct, formed initially by the pronephros but later by the mesonephros.

B. Excretory tubules of the pronephric and mesonephric systems in a 5-week-old embryo.

Page 3 of 10

structures; if these primitive structres remain in the newborn/child it results to Wilm's Tumor or Nephroblastoma

expressed by the mesenchyme

enables the tissue to respond to induction by the ureteric bud (from the distal hindgut and cloaca)

GDNF and HGF, also produced by the mesenchyme, interact through their receptors - RET and MET, respectively, in the ureteric bud epithelium, to stimulate growth of the bud and maintain the interactions. - very dynamic exchange of signals between the ureteric buds and the metanephric tissue

The growth factors FGF2 and BMP7 stimulate the proliferation of the mesenchyme and maintain (the induction of) WTI expression.

b. PAX2 and WNT4

produced by the ureteric bud, cause the mesenchyme to epithelialize in preparation for excretory tubule differentiation.

Laminin and type IV collagen form a basement membrane for the epithelial cells.

METANEPHRIC SYSTEM

It gives rise to the kidney proper

The metanephros as it develops around the

ureteric bud - The ureteric bud arises from the distal mesophric bud is not inducted in itself, so it has got to be connected to the hind gut.

The metanephric tissue develops around the tip of the ascending ureteric bud

9th to 12th weeks

Development of a metanephric excretory unit. Arrows, the place where the excretory unit (blue) establishes an open communication with the collecting system (yellow), allowing flow of urine from the glomerulus into the collecting ducts. The collecting ducts of the permanent kidney develop from the ureteric bud, an outgrowth of the mesonephric duct close to its entrance to the cloaca. The bud penetrates the metanephric tissue, which is molded over its distal end as a cap. Subsequently the bud dilates, forming the primitive renal pelvis, and splits into cranial and caudal portions, the future major calyces. The ureteric bud gives rise to the ureter, the renal pelvis, the major and minor calyces, and approximately 1 million to 3 million collecting tubules. Each newly formed collecting tubule is covered at its distal end by a metanephric tissue cap . Under the inductive influence of the tubule, cells of the tissue cap form small vesicles, the renal vesicles, which in turn give rise to small S-shaped tubules . Capillaries grow into the pocket at one end of the S and differentiate into glomeruli. These tubules, together with their glomeruli, form nephrons, or excretory units. The proximal end of each nephron forms Bowman’s capsule, which is deeply indented by a glomerulus . The distal end forms an open connection with one of the collecting tubules, establishing a passageway from Bowman’s capsule to the collecting unit. Continuous lengthening of the excretory tubule results in formation of the proximal convoluted tubule, loop of Henle, and distal convoluted tubule .

Page 4 of 10

Metanephros ascends, rotates and revascularizes (to assume its renal vascular supply).

It takes out its own vascular supply, because if it stays in this position, the kidney will be pelvic rather than lumbar.

ASCENT OF THE KIDNEYS

There is elongation of the ureterc bud, ascent of kidneys and revascularization; The long ureter connects to the metanephric tissue, collecting tubes, ducts and drains into the distal hindgut(the anterior urogenital sinus). The cloaca divides into the anterior urogenital sinus and the posterior rectum. The urogenital sinus becomes the future urinary bladder.

Ectopic kidneys – unascended kidneys

EMBRYOPATHY

Developmental abnormalities from abnormal

processes of development Failure of any of these steps to occur results in anomalies of

9. Form - shape 10. Number 11. Position - ectopy/ wrong position 12. Volume

ABNORMALITIES IN FORM

Cystic Abnormalities

1. Autosomal recessive polycystic kidney disease (ARPKD)

2. Austosomal dominant polycystic kidney disease (ADPKD)

3. Multicystic dysplastic kidney (MCDK) 4. Multilocular cystic nephroma 5. Simple cysts - 1 or 2 of us will have this ***usually seen in ultrasound: multicystic/polycystic kidneys and simple cysts (1 cm in size and usually of no significance)

In the pelvis the metanephros receives its arterial supply from a pelvic branch of the aorta. During its ascent to the abdominal level, it is vascularized by arteries that originate from the aorta at continuously higher levels. The lower vessels usually degenerate, but some may remain.

The kidney, initially in the pelvic region, later shifts to a more cranial position in the abdomen. This ascent of the kidney is caused by diminution of body curvature and by growth of the body in the lumbar and sacral regions.

Hence, the kidney develops from two sources: (a) metanephric mesoderm - which provides excretory units (b) the ureteric bud - which gives rise to the collecting system.

Page 5 of 10

CYSTIC DISEASE OF THE KIDNEY

GENETIC (always work up the genetic background)

Congenital Anomaly Inheritance

Infantile polycystic kidneys AR Adult polycystic kidneys AD Juvenile nephronophthisis AR Juvenile nephronophthisis-medullary cystic disease complex (Medullary sponge kidneys)

-

Medullary cystic disease AD Congenital nephrosis AR Familial hypoplastic glomerulocystic kidney disease

AD

Cysts associated with multiple malformation syndrome

-

NONGENETIC

Multicystic kidney (multicystic dysplasia)

Multilocular cyst (mulilocular cystic adenoma)

Simple cyst/ (Simple) medullary sponge kidneys (<5% inherited)

Sporadic glomerulocystic kidney disease

Acquired renal cystic disease

Calyceal diverticulum (pyelogenic cyst)

Comparison of Autosomal Recessive and Dominant Polycystic Kidney Disease

These are the 2 most important polycystic

kidney disease; the histologic features are done by biopsy but can be differentiated by cytogenetic studies

ARPKD ADPKD

Incidence 1 in 6,000-40,000 1 in 1000 Inheritance Autosomal

recessive Autosomal dominant, 100% penetrance, variable expression

Age at diagnosis 0 to late adolescence diagnosed earlier but can also be diagnosed at a later age

0-35 yrs

Imaging US is the 1st screening test which can show

US: enlarged kidneys with increased echogenecity

US: multiple, large, echolucent cysts

IVP: poor

what type of polycystic kidney disease is present

IVP: poor function, contrast streaks extend to cortex

CT: evaluate other organs

function, distorted col. system

Other organs affected CT is also useful in detection

Liver: Congenital hepatic fibrosis (with late onset)

Vascular: Circle of Willis aneurysms

Cysts: liver, spleen, thyroid, ovary, endometrium, epididymis, seminal vesicle

If there are cysts suspect AD instead of AR

Presentation Younger: renal failure Older: liver disease

Renal failure

Histologic features

Kidney: Collecting duct ectasia

Liver: periportal fibrosis

Any portion of nephron involved, multiple cysts of varying size

ABNORMALITIES IN NUMBER

A. Renal Agenesis - less than normal in number

13. Unilateral – usually associated with vascular accidents during the development of the kidneys or failure of one anlage to develop.

14. Bilateral

ex. A baby with bilateral renal agenesis presents with dyspnea, tachypnea; Carried by an oligyhydramniotic pregnancy and delivered CS; Xray showed compressed

In congenital polycystic kidney numerous cysts form. It may be inherited as an autosomal recessive or autosomal dominant disorder or may be caused by other factors. Autosomal recessive polycystic kidney disease, which occurs in 1/5,000 births, is a progressive disorder in which cysts form from collecting ducts. The kidneys become very large, and renal failure occurs in infancy or childhood. Autosomal dominant polycystic kidney disease, cysts form from all segments of the nephron and usually do not cause renal failure until adulthood. The autosomal dominant disease is more common (1/500 to 1/1,000 births) but less progressive than the autosomal recessive disease.

Page 6 of 10

thoracic structures and chest unexpanded. There are excessive creases in the feet and cheeks. Dx: Potter Syndrome - incompatible with life; sustained by neonatal dialysis while waiting for renal transplant so that it can survive

Congenital hydronephrosis in infant - US: hydrnephrotic kidney in 1 side usually caused by uretero-pelvic obstruction, congenital stenosis

1 absent kidney in a child is undetectable since the other compensates

OLIGOHYDRAMNIOS develops due to anuria. Because of the low volume of amniotic fluid the fetus is all cramped up inside the uterus and the muscles become atonic. Atonic muscles causes deep creases to develop in the skin such as the deep transverse creases on the face which is a characteristic finding of the syndrome. The lungs are also unable to expand becoming hypoplastic at birth.

B. Supernumerary Kidneys

Caveat: hydronephrosis sec to obstruction of ureteropelvic junction at the outlet of the calyxes, a congenital stricture is present - a common cause

Common Associations with Renal Agenesis

The kidneys are mesodermal in origin, hence, it

is associated with other mesodermal problems which is distributed in general areas of the body

Unilateral Bilateral

Urologic -urethral absence or atresia -asymmetric or hemitrigone -contralateral renal ectopia

-ureteral atresia -absence or hypoplastic bladder -malrotation

Genital( Male) -absent vas deferens, seminal vesicle

-hypospadias -penile agenesis -undescended testis

Genital (Female)

-unicornuate or didelphic uterus -duplicate or absent vagina

-rudimentary, anomalous or absent uterus, vagina -hypoplastic or absent ovaries

Pulmonary -pulmonary hypoplasia

CV -septal, valvular defects

-present

GI -imperforate anus

- imperforate anus

Esophageal -stricture, atresia Orthopedic -vertebral,

phalangeal anomalies

-club feet -spina bifida

Others Syndromes -VATER, Poland, Turner’s

-characteristic (Potter) facies

ABNORMALITIES IN POSITION

Ectopia and Fusion Anomalies 1. Simple renal ectopia - lower than usual position 2. Crossed renal ectopia - Right kidney drained by

left draining ureter - right renal ectopia, left kidney drained by right draining ureter- left renal ectopi.

3. Horseshoe kidney

Potter sequence, characterized by anuria, oligohydramnios (decreased volume of amniotic fluid) and hypoplastic lungs secondary to the oligohydramnios.

Page 7 of 10

Common Associations with Ectopic Kidney

1st thing to ask yourself - what other abnormalities are present

A. Musculoskeletal

Vertebral (as in VATER), rib anomalies

Cranial Asymmetry

Absent bones - absent ulna, missing cervical spine, extra ribs

B. Urologic

Vesicoureteral reflux - common

UPJ obstruction

Contralateral agenesis C. Genital

Male patients:

Undescended testis

Hypospadias

Urethral duplication

Female patients:

Uterine or vaginal anomalies, atresia, agenesis

D. Others

Cardiovascular

Gastrointestinal

General rule: when you have an abnormal kidney, look for associated abnormality- VATER/VACTERL

URETER DUPLEX SYSTEM

complete or partial

usually associated with an ectopic opening in the bladder

usually the abnormal one is the superior ureter in the duplex system; the superior pole becomes hydronephrotic

the ureter drains in the bladder or in the vagina or vestibule -usually in females

URETERAL OBSTRUCTIONS AND MALFORMATIONS

1. Ureteropelvic junction obstruction in children (UPJ)

- most common cause of hydrnephrosis; in infancy

The kidneys are pushed so close together during their passage through the arterial fork that the lower poles fuse. The horseshoe kidney is usually at the level of the lower lumbar vertebrae, since its ascent is prevented by the root of the inferior mesenteric artery. The ureters arise from the anterior surface of the kidney and pass ventral to the isthmus in a caudal direction. Horseshoe kidney is found in 1/600 people.

Duplication of the ureter results from early splitting of the ureteric bud. Splitting may be partial or complete, and metanephric tissue maybe divided into two parts, each with its own renal pelvis and ureter. More frequently, however, the two parts have a number of lobes in common as a result of intermingling of collecting tubules. In rare cases one ureter opens into thebladder, and the other is ectopic, entering the vagina, urethra, or vestibule. This abnormality results from development of two ureteric buds.One of the buds usually has a normal position, while the abnormal bud moves down together with the mesonephric duct. Thus it has a low, abnormal entrance in the bladder, urethra, vagina, or epididymal region.

Page 8 of 10

there is dilated calyxeal system and enlarged kidneys

2. Ureteral duplication 3. Triplication, Quadriplication 4. Retrocaval Ureter - the ureter passes behind the

vena cava 5. Megaureter – associated with a megabladder and

megacolon (hirschsprung disease); Megacystic hypoganglionic syndrome can be seen also in Eagle Barrett syndrome/prune belly syndrome - obstruction of the bladder neck enlarges the abdomen in the intrauterine life (pot belly fetus) and form the prune belly of the newborn because of the extra folds in the abdomen because of the deficiency of abdominal wall

6. Ectopic Ureter 7. Ureterocoeles Prune belly syndrome or abdominal muscle wall

agenesis occurs due to the failure of the lateral mesoderm to develop.

It is usually associated with megacystis and hydronephrosis.

Babies with PBS are prone to respiratory infections since the abdomen cannot participate in respiration and the diaphragm is lax. They could not expectorate phlegm. It is usually the cause of death for these children.

Uropathies Detectable by Prenatal Sonography US - very good in screening; useful in detecting

urogenital abnormalities) Do not simmply request for hepatobiliary or

renal ultrasound, request for ultrasound of the whole abdomen to eval other organs most important abdominal studies in detecting congenital anomalies even in the neonatal period

Condition Frequency

Ureteropelvic junction obstruction 1: 2,000

Multicystic dysplastic kidney 1: 3,000

Primary ureterovesical junction obstruction

1: 10,000

Ectopic Uterocoele or ureter 1: 10,000

Posterior urethral valves - in boys 1: 8,000

Prune belly syndrome (rarest) 1: 40,000

Vesicoureteral reflux 1: 100

VESICOURETERAL REFLUX (VUR)

denotes the retrograde flow of urine from the urinary bladder to the upper urinary tract

Primary VUR (true congenital) vs Secondary VUR (associated with adult HPN or permanent renl injury that starts during infancy)

Primary VUR Secondary VUR

Congenital anomaly of the UVJ - more common

Altered physiology in: ﹠ increased intravesical

pressure ﹠ obstructed, poorly

compliant bladders ﹠ lower tract anomalies:

4. ureteral ectopia 5. ureterocoeles 6. bladder extrophy 7. prune belly

syndrome diagnosed by imaging, voiding cystourethrogram

VUR = Reflux Nephropathy

Renal damage secondary to chronic pyelonephritis - kidneys are destroyed; seen in adults but may be properly dealt with during childhood

VUR increases the morbidity of UTI (pyelonephritis) by involving the upper urinary tract

Renal scarring is the most important pathology in renal infections that can lead to VUR

VUR Incidence and Morbidity

97% of children with renal scarring showed VUR.

Renal failure is the most ominous sequelae of VUR.

threefold increase in risk of hypertension

reduced somatic growth in childhood

pregnancy complications in adulthood

VUR is the most significant factor you want to eliminate if you want to decrease the incidence of adult renal disease

Childhood UTI and VUR

40% are found to have VUR

inverse correlation with age

average age of diagnosis: 2-3 years upon work-up following a febrile UTI - sometimes there is a low rate of diagnosing UTI in children; achild not growing properly may have recurring UTI

75% - 80% discovered to have primary VUR are girls.

Males predominate in newborn worked-up for VUR.

increased prevalence among siblings of children with VUR

Page 9 of 10

more common in fair-skinned children of Northern European descent - recently the incidence is already the same, they just had better means of diagnosing and awareness

VOIDING CYSTOURETHROGRAM (VCUG)

- a means to diagnose VUR

iodinated contrast instillation, or

radionuclide cystography

Indications:

an evaluation following UTI in children

postnatal evaluation of newborns with prenatally diagnosed hydronephrosis

high risk children: o with renal anomalies o lower tract anomalies

o siblings with history of VUR

International Reflux Study Classification, 1992 - depends on how much reflux occurs

Grade Characteristics

Grade I Reflux into the ureter only Grade II Reflux into the ureter, renal pelvis and

calyxes Grade III Mild or moderate dilation of the ureter

and renal pelvis with no or minimal forniceal blunting

Grade IV Moderate dilation and tortuosity of the ureter with blunting of the fornices but maintenance of the papillary impressions

Grade V Gross dilation and tortuosity of the ureters and pelvis with absence of papillary impressions smoothens out the calyxes

Hydronephrosis is a late manifestation of

obstruction Prognosis and treatment Most cases of primary VUR ()some weakness in the

junction) in children will resolve spontaneously. Expectant Management

Sterilize urine until reflux is resolved (Nitrofurantoin, Cotrimoxazole) - more common in our setting in adults

Monitoring of UTI episodes (fever, urine cultures), reflux (VCUG) and kidneys (scans) - all should undergo VCUG but it is time consuming

Growth profile

Blood pressure - as early as possible to detect HPN

Surgery

Goal of surgery is to create an adequate

intravesical segment of the ureter to prevent reflux. (change the angulation or ball valve mechanism)

Intravesical or extravesical route

90-100% success rates

STING (endoscopic subureteric injection technique) using a bulking agent (PTFE, Teflon, etc.)

close the ureter and transplant to another area in the bladder

BLADDER AND URETHRA

Bladder is derived from the hindgut and

urogenital sinus

During the fourth to seventh weeks of development the cloaca divides into the urogenital sinus anteriorly and the anal canal posteriorly

Page 10 of 10

Urethral valves - in boys, the posterior urethral

valves creates a ball valve mechanism; shaft of the urethra - anterior portion is mobile

Bladder exstrophy

Epispadias Hypospadias - Failure of fusion of the urethral folds

If you want to evaluate the bladder or ureter or kidney, scan the whole abdomen

“The important thing to remember in the surgical

correction of any congenital anomaly… whatever this may be… The first surgery must be right! Subsequent

operations must advance… Or else… be definitive.”

Increase in suicide rates in patients with congenital anomalies of the external genitalia

These surgeries, especially in children, disrupt their psychosexual development. As physicians, you should also become sensitive to these issues.

Notetakers: C1, C2, rV, pyolo Editor: C1 Sources: Slides, Lecture Audio, Jax Notes, Langman’s Embryology

Divisions of the cloaca into the urogenital sinus and anorectal canal. The mesonephric duct is gradually absorbed into the wall of the urogenital sinus, and the ureters enter separately. A. At the end of the fifth week. B. 7 weeks. C. 8 weeks.

Bladder exstrophy is a ventral body wall defect in which the bladder mucosa is exposed. o Epispadias is a constant feature, and the open

urinary tract extends along the dorsal aspect of the penis through the bladder to the umbilicus.

o Exstrophy of the bladder may be caused by a lack of mesodermal migration into the region between the umbilicus and genital tubercle, followed by rupture of the thin layer of ectoderm. This anomaly is rare, occurring in 2/100,000 live births.