Pathology: Abnormal Development Of Kdneys And Lower Urinary Tract

Front 1

How common are Renal and UT Malformations?

How are they detected?

What else are they associated with?

Back 1

*Malformations in 3-10% neonates (shape and position).

*Prenatal detection is done by ultrasound.

*Frequent association with anomalies elsewhere:
1) Cardiovascular including single umbilical artery.
2) Genital organs especially in female.

Front 2

What are the 2 major categories of Renal and UT Malformations?

Back 2

*Abnormalities of amount of renal tissue

1) Deficient:
-Renal agenesis; unilateral or bilateral.
-Hypoplasia.

2) Excess:
-Supernumerary.
-Nephromegaly.

Front 3

What are the Renal and UT Malformations of POSITION? What about the abnormalities of differentiation?

Back 3

*Abnormalities of position or form:
-Ectopia
-Simple
-Crossed
-Fusion

*Abnormalities of differentiation:
-Cystic and/or dysplastic diseases

Front 4

Discuss UNILATERAL RENAL AGENESIS:

Back 4

*1/1000 neonates.
*M>F.
*LEFT kidney is usually affected.
*Asymptomatic.
*Discovered because of hypertrophy of unaffected kidney.
*Single umbilical artery.

Front 5

Discuss BILATERAL RENAL AGENESIS:

Back 5

*1/3000 neonates.

*Stillbirth and/or early neonatal death.

*Death due to pulmonary hypoplasia, part of oligohydramnios sequence (small amount of amniotic fluid).

Front 6

What are the genetic associations with Renal Agenesis?

Back 6

*Kidney formation is controlled in part by the RET gene (same gene associated with MEN2).

*Mutations in RET present in association with renal agenesis.

Front 7

Back 7

Bottom: bilateral renal agenesis. 19.5 WEEKS.

Front 8

What is the POTTER SEQUENCE?

What is the POTTER SYNDROME?

Back 8

SEQUENCE: A variety of renal malformations may result in oligohydramnios sequence (low set ears, beaked nose, prominent epicanthic folds, receding chin, limb deformities, growth retardation, pulmonary hypoplasia).

SYNDROME: When Potter sequence features are associated with bilateral renal agenesis.

Front 9

Back 9

NORMAL KIDNEY; compare to a photo of renal tubular dysgenesis.

Front 10

Back 10

RENAL TUBULAR DYSGENESIS. Compare to normal.

Note that you can't see any proximal convoluted tubule in renal tubular dysgenesis. In this disorder, there are either ABSENT or DEFICIENT PCTs.

Front 11

Discuss Renal Tubular Dysgenesis:

What are some associations with it?

Back 11

*AKA Primitive renal tubule syndrome.

*In utero abnormality with absence of recognizable proximal convoluted tubules.

*Recognized associations include:
-Maternal use of ACE inhibitors.
-Twin-twin transfusion syndrome.
-Others; neonatal hemochromatosis, hypocalvaria, chronic fetal hypotension, and chronic fetal hypoxia.

Front 12

Discuss the Familial form of Renal Tubular Dysgenesis:

Back 12

*Familial cases, often in consanguineous matings, have been reported.

*In a study of 11 cases in 9 families mutations were found in genes controlling renin, angiotensin, angiotensin-converting enzyme (ACE), and angiotensin II receptor type 1.

Front 13

When do you see Nephromegaly?

Back 13

*Compensatory in unilateral agenesis.

*Beckwith Wiedemann syndrome (organomegaly, hemihypertrophy, omphalocele, Wilms tumor).

*Congenital Finnish nephrosis (rare; not important).

Front 14

Absence of the ureteric bud results in?

Incomplete division of the ureteric bud results in?

Back 14

*UNILATERAL RENAL AGENESIS: absence of ureteric bud.

*DIVIDED KIDNEY: incomplete division of ureteric bud; a TERMINAL bifurcation.

Front 15

Complete division of the ureteric bud results in?

Migration of the left kidney to the right side results in?

Back 15

Complete division of the ureteric bud: bifid kidney (this diagram also shows malrotation of the right kidney).

Migration: fused kidney.

Front 16

Fusion of the kidneys results in?

Two ureteric buds on the same side results in?

Back 16

Fusion: Pelvic (discoid, horseshoe) kidney.

Two buds: Supernumerary kidney.

Front 17

Back 17

Pelvic Kidney

Front 18

Back 18

HORSESHOE KIDNEY/ 13 WEEKS

Front 19

Back 19

Horseshoe Kidney
*associated with higher incidence of Wilms tumor.

Front 20

Back 20

*FUSED KIDNEY (in horseshoe kidney).
*Affects about 1:500. You can live with this.

Front 21

Discuss Anomalous Renal Blood Vessels:

Back 21

*Additional artery is a frequent occurrence. Usually of no significance.
*25% of adult kidneys have more than one artery.
*Only 30% of adults have only one artery and one vein per kidney. 70% have LOTS of VARIATION.
*Anomalies more likely in males and involving the right kidney.

Front 22

Back 22

SIMPLE RENAL CYST

Front 23

What are the Cystic Renal Diseases?

Back 23

*Cystic renal dysplasia.

*Polycystic kidney disease:
-Autosomal recessive.
-Autosomal dominant.

*Medullary cystic disease:
-Medullary sponge kidney.
-Nephronophthisis.

*Acquired (dialysis-associated) cystic disease.

Front 24

How does diagnosis of Cystic/Dysplastic Renal Diseases happen?

Back 24

*Clinical history including family history.
*Imaging studies of patient and sometimes of relatives.
*Genetic studies.
*Gross and microscopic examination.

Front 25

Discuss Renal Dysplasia:

Back 25

*Abnormal differentiation of tissue.
*Unilateral or bilateral.
*Usually but not always with CYSTS of various size and number.

Front 26

Back 26

DIFFUSE CYSTIC DYSPLASIA:
*Kidneys are massively enlarged.
*Large number of tiny cysts bilaterally.

Front 27

Talk about the MECKEL SYNDROME:
Inheritance?
Associated features?

Back 27

*Not terrible important; just know it exists.

*Autosomal recessive.

*Occipital encephalocele, polycystic kidneys, cleft palate, pulmonary hypoplasia.

*Loci at 17q21-q24 (MES), 11q13 (MKS2), 8q24 (MKS3) (not important to know).

Front 28

Back 28

*Meckel syndrome (Meckel-Gruber syndrome).
*XS shows cystically dilated tubules.

Front 29

Back 29

*PRUNE BELLY SYNDROME (ABDOMINAL MUSCLE DEFICIENCY SYNDROME).

Front 30

Back 30

PRUNE BELLY SYNDROME; showing DIFFUSE CYSTIC RENAL DYSPLASIA.

*Key to remember: Diffuse Cystic Renal Dysplasia is UNCOMMON, and is associated with some syndromes; namely Meckel-Gruber and Prune Belly, some others.

Front 31

What are the essential features needed to make the diagnosis of Renal Dysplasia?

Back 31

*Essential feature: primitive ducts surrounded by loose mesenchyme.
*Islands of Cartilage often present.
*Glomeruli are usually present.
*Obstruction is often present.

Front 32

Back 32

Tubules surrounded by mesenchyme in Renal Dysplasia.

Front 33

Back 33

RENAL DYSPLASIA, showing poorly formed tubules surrounded by mesenchyme, and a large lobule (right) of cartilaginous tissue.

Front 34

Describe Multicystic Kidney dysplasia:

Back 34

*Prominent large cysts.
*Frequently unilateral.
*Minor dysplasia.
*Ureter may be absent, atretic, or stenotic.
*Bladder may be hypoplastic.
*May be associated with other anomalies.

Front 35

Back 35

*Multicystic Kidney.
*Reniform shape is not maintained; this is hardly recognizable.

Front 36

Back 36

*MULTICYSTIC RENAL DYSPLASIA

Front 37

Back 37

*MULTICYSTIC RENAL DYSPLASIA.
*Embryonic looking stroma.
*Large cartilage patch (right, middle).
*NORMAL glomerulus in the center.

Front 38

Back 38

A. MULTICYSTIC DYSPLASIA
B. DIFFUSE CYSTIC DYSPLASIA

Front 39

Discuss Polycystic Kidney Disease in general:
what are the two types?

Back 39

*Hereditary conditions with no dysplasia.
*Autosomal recessive – ARPKD.
*Autosomal dominant – ADPKD.
*Both are associated with hepatic and pancreatic cysts.

Front 40

Discuss ARPKD:
What characterizes it?
What genetic associations are there?

Back 40

*AKA Infantile polycystic kidney disease.
*Early neonatal death.
*Greatly enlarged smooth kidneys with cylindrical cyst-like dilatation of tubules.
*Hepatic cysts and/or fibrosis may be present.
*Less severe forms are known, in which the child may live.

*PKHD1 (KNOW THIS!) on chromosome 6 p21-p23.
*PKHD1 codes for fibrocystin, a membrane receptor protein (KNOW THIS!).
*Fibrocystin may be involved in the function of cilia in tubular epithelial cells (KNOW THIS!).

Front 41

Back 41

*Autosomal Recessive Polycystic Kidney Disease (ARPKD).
*kidneys are huge.

Front 42

Back 42

*ARPKD.
*Right shows cystically dilated tubues, a key feature.
*The tubules abut the fibrous capsule at a 90˚ angle.

Front 43

Back 43

*ARPKD.
*Dilated tubules are obvious, jutting out to the cortex.

Front 44

Discuss ADPKD:

Back 44

*AKA Adult polycystic kidney disease.
*Manifested by renal cysts, hepatic cysts, berry aneurysms.
*Becomes clinically manifest in MIDDLE AGE; rarely in fetus or neonate.
*Only a few nephrons need be involved.
*> 50% progress to end-stage renal disease.

*This is pretty common; about 50% of dialysis patients are there because of this. Much more common than ARPKD.

Front 45

Back 45

ADPKD. Enlarged cystic kidneys with multiple fluid-filled cysts.

Front 46

Back 46

*AD POLYCYSTIC KIDNEY DISEASE.
*Walls of the cysts are smooth.

Front 47

Back 47

*ADPKD.
*Flat, pink material is protein in the center of the cysts.
*Extensive fibrosis in the actual renal tissue visible. It's also enflamed. It's becoming atrophic and non-functional.

Front 48

Back 48

*LIVER CYSTS IN ADULT PKD. ADPKD.

Front 49

What are the gene origins of ADPKD?

Back 49

*Major gene, PKD-1, is responsible for ~85% of cases.
*Located on chromosome 16p.
*PKD-1 protein, polycystin-1, is a large membrane-associated glyco-protein; functions as a receptor for cell-cell and cell-matrix interactions.

*PKD-2 is responsible for ~15%.
*Located on chromosome 4.
*Gene product, polycystin-2, can act as a calcium-ion-permeable cation channel.

*Polycystin-1 and polycystin-2 are both expressed, in overlapping patterns, in the developing kidney. They're also expressed in the liver and pancreas.

Front 50

Pathophysiology of Polycystic Kidney Disease:

Back 50

*Multiple possible mutations.
*Note alterations and what they lead to.

Front 51

What are Glomerulocystic Kidneys?
What characterizes them?

What syndromic associations are there?

Back 51

*Uncommon.
*Glomerular cysts due to distended Bowman’s capsules.
*Usually bilateral; no obstruction.

*May be syndromic:
1) Zellweger syndrome
2) Orofacialdigital syndrome
3) Tuberous sclerosis
4) Trisomy 13 syndrome

Front 52

Back 52

*Gross: Enlarged, white dots represent cysts.
*µscopic: Bowman's space is enlarged (cyst space is around the glomeruli).

Front 53

What is Medullary Sponge Kidney?
Who gets it?
What are some complications?

Back 53

*Cysts formed from collecting ducts in medulla.

*A disease of adults: Normal renal function if uncomplicated.

*Complications:
-Calcifications
-Pyelonephritis
-Hematuria

Front 54

Discuss the Medullary Cystic Diseases:

What characterizes these diseases?

Back 54

*A group of childhood diseases referred to as nephronophthisis-medullary cystic disease complex.

*They are characterized by medullary cysts, tubular atrophy, and interstitial fibrosis. Renal tubular acidosis and failure result.

Front 55

Back 55

*NEPHRONOPHTHISIS MEDULLARY CYSTIC DISEASE COMPLEX
*Grossly, cysts in the medulla.
*µscopically: cystic tubules.

Front 56

What are the variants of the Nephronophthisis-Medullary Cystic Disease Complex?

Which is most common?

What other kinds of abnormalities can you see with these diseases?

Back 56

*Four variants; infantile, juvenile, adolescent, and adult.

*Familial juvenile nephronophthisis is the most common.

*15-20% of patients have extrarenal abnormalities; retinal, oculomotor disturbances, mental retardation, cerebellar abnormalities, and liver cirrhosis.

Front 57

What genes are associated with Nephronophthisis-Medullary Cystic Disease Complex?

Back 57

*Five genes, NPHP1 through 5 have been identified.

*Protein products of these genes are nephrocystins.

*Nephrocystins have been identified as components of CILIA of the epithelial cells.

*Maybe the disease is due to ciliary dysfunction.

Front 58

Discuss Dialysis-Associated Cystic Disease:

Back 58

*After prolonged dialysis for end-stage disease.

*Numerous cortical and medullary cysts.

*Probably from obstruction of tubules by fibrosis or oxalate crystals.

*Not really DUE to the dialysis; just seen in the end-stage and are associated with dialysis for that reason. The cause is the prolonged uremic state.

Front 59

Back 59

*ACQUIRED RENAL CYSTIC DISEASE WITH RENAL CELL CARCINOMA.
*Patients with acquired renal cystic disease can develop RCC.

Front 60

Summary of kidney cyst types:

Back 60

*Medullary uremic = Nephronophthisis-Medullary Cystic Disease Complex
*Hydronephrosis = NOT a cystic disease, but looks like it.

Front 61

Anomalies of the Bladder: what are the 2 kinds?

Back 61

1) Agenesis is rare. Associated with other GU anomalies.

2) Exstrophy of the bladder.

Front 62

Discuss Bladder exstrophy:

Back 62

*Occurs because of faulty migration of mesoderm to the lower abdominal wall.

*When the normal embryological event of cloacal membrane rupture occurs, the bladder and sometimes the proximal urethra lie open to the anterior abdominal wall.

*The term for the dorsally exposed urethra is epispadias.

Front 63

Back 63

*Bladder exstrophy.
*A metaplasia occurs = urothelium becomes columnar.
*Can progress to bladder cancer if this is uncorrected.

Front 64

What is Cloacal Exstrophy?

Back 64

If there is failure of migration of mesoderm to the lower abdominal wall and cloacal membrane rupture occurs before the urorectal septum has done its work, the result is cloacal exstrophy in which the urethra, bladder and lower bowel are all exposed anteriorly.

Front 65

Back 65

*Cloacal Exstrophy.
*Note 2 hemibladders; as usual an omphalocele is present.
*Arrows point to hemivaginas.
*Asterisks indicate ileum and cecum.

Front 66

What is hypospadias?

Back 66

*Hypospadias represents a failure of fusion of the urogenital folds. As a result the urethra is open ventrally in one or more locations from the perineum to the glans.