Cystic Diseases of the Kidney

A useful classification of renal cysts is as follows:[9]

1. Cystic renal dysplasia

2. Polycystic kidney disease
a. Autosomal-dominant (adult) polycystic disease
b. Autosomal-recessive (childhood) polycystic disease
3. Medullary cystic disease
a. Medullary sponge kidney
b. Nephronophthisis
4. Acquired (dialysis-associated) cystic disease
5. Localized (simple) renal cysts
6. Renal cysts in hereditary malformation syndromes (e.g., tuberous sclerosis)
7. Glomerulocystic disease
8. Extraparenchymal renal cysts (pyelocalyceal cysts, hilar lymphangitic cysts)

Table 20-2 -- Summary of Renal Cystic Diseases

Pathologic Clinical Features Typical Diagrammatic
Inheritance
Features or Complications Outcome Representation
Hematuria, flank
Chronic renal
Large multicystic pain, urinary tract
Adult polycystic Autosomal failure
kidneys, liver cysts, infection, renal
kidney disease dominant beginning at
berry aneurysms stones,
age 40–60 yr
hypertension
Variable,
Childhood
Autosomal Enlarged, cystic death in
polycystic kidney Hepatic fibrosis
recessive kidneys at birth infancy or
disease
childhood
Hematuria, urinary
Medullary sponge Medullary cysts on tract infection,
None Benign
kidney excretory urography recurrent renal
stones
Progressive
Corticomedullary Salt wasting,
Familial juvenile Autosomal renal failure
cysts, shrunken polyuria, growth
nephronophthisis recessive beginning in
kidneys retardation, anemia
childhood
Chronic renal
Adult-onset Corticomedullary
Autosomal Salt wasting, failure
medullary cystic cysts, shrunken
dominant polyuria beginning in
disease kidneys
adulthood
Single or multiple
Microscopic
Simple cysts None cysts in normal- Benign
hematuria
sized kidneys

Cystic degeneration Hemorrhage,

Acquired renal Dependence
None in end-stage kidney erythrocytosis,
cystic disease on dialysis
disease neoplasia

AUTOSOMAL-DOMINANT (ADULT) POLYCYSTIC KIDNEY DISEASE

 • hereditary disorder characterized by multiple expanding cysts of both kidneys that ultimately
destroy the renal parenchyma and cause renal failure.
• a common condition affecting roughly 1 of every 400 to 1000 live births and accounting for about
5% to 10% of cases of chronic renal failure requiring transplantation or dialysis.
• The pattern of inheritance  autosomal dominant, with high penetrance.
• universally bilateral; reported unilateral cases probably represent multicystic dysplasia.
• initially involve only portions of the nephrons, so renal function is retained until about the fourth
or fifth decade of life.
• genetically heterogeneous.
• caused by mutations in genes located on chromosome 16p13.3 (PKD1) and 4q21 (PKD2), and
rare unlinked families suggest the presence of at least one additional disease-associated gene.
• Mutations of PKD1  about 85% of cases (most of the remainder involving PKD2)
•  associated with a more severe disease, end-stage renal disease or
• death occurring at an average age of 53 years, compared to 69
• years for PKD2.
• is a systemic disorder in which cysts and other anomalies also arise in other organs (discussed
later).

Genetics and Pathogenesis.

• The PKD1 gene encodes a large (460-kDa) integral membrane protein named polycystin-1, which has
a large extracellular region, multiple transmembrane domains, and a short cytoplasmic tail.It has been
localized to tubular epithelial cells, particularly those of the distal nephron . it involved in cell-cell
and cell-matrix interactions.
• The PKD2 gene product polycystin-2 is an integral membrane protein.[15] It has been localized to all
segments of the renal tubules and is also expressed in many extrarenal tissues. Recent evidence
indicates that polycystin-2 may act as a Ca2+-permeable cation channel and that a basic defect in
ADPKD is a disruption in the regulation of intracellular Ca2+ levels.Another leading possibility is that
polycystin-2 may also occupy a plasma membrane position, where it may form a complex with
polycystin-1.[17]

• focused on links between the polycystins and cell-cell and cell-matrix interactions important in
tubular epithelial cell growth and differentiation.
• epithelial cells lining the cysts of ADPKD have a high proliferation rate, and that the
nonproliferating cells in cysts exhibit abnormally simplified structure, with a relatively immature
phenotype.
• Cysts are frequently detached from adjacent tubules and enlarge by active fluid secretion from the
lining epithelial cells.
• the extracellular matrix (ECM) produced by cyst-lining cells is abnormal.
• cysts develop as a result of an abnormality in cell differentiation, associated with sustained cellular
proliferation and some degree of increased apoptosis, transepithelial fluid secretion, and
remodeling of the ECM.[10]
• The increase in cells caused by abnormal proliferation, and the expanding volume of intraluminal
fluid caused by abnormal secretion from epithelial cells lining the cysts, result in progressive cyst
enlargement.
• cyst fluids harbor mediators, derived from epithelial cells, that enhance fluid secretion and induce
inflammation  contribute to further enlargement of cysts and the interstitial fibrosis
characteristic of progressive polycystic kidney disease.[11]
 • PKD1 gene serves a suppressor function: its loss leads to hyperplasia of epithelial cells.[
• polycystin-1 and polycystin-2 form components of a polycystin complex  acts to regulate
intracellular Ca
• The extracellular region of polycystin-1 may be the binding site for one or more ligands that
modulate the activity of the channel.
• Mutation of either of these genes  lead to loss of the polycystin complex or the formation of an
aberrant complex.
• The consequent disruption of normal polycystin activity may lead to changes in intracellular Ca2+
levels and, given the second messenger effects of Ca2+, to changes in cellular proliferation,
abnormal extracellular matrix, and the secretory function of the epithelia that together result in the
characteristic features of ADPKD.

Mutations in polycystin 1, 2 or fibrocystin

Defects in cell-cell & cell-matrix interactions

Altered tubular epithelial growth & differentiation

Abnormal extracellular matrix cell proliferation fluid secretion

Vascular damage CYST interstitial inflammation/fibrosis

Morphology.
In gross appearance :  the kidneys are usually bilaterally enlarged and may achieve
enormous sizes;
 weights up to 4 kg for each kidney
 The external surface appears to be composed solely of a mass of
cysts, up to 3 to 4 cm in diameter, with no intervening
parenchyma .
microscopic examination: reveals functioning nephrons dispersed between the cysts.
 cysts may be filled with a clear, serous fluid or, more usually,
with turbid, red to brown, sometimes hemorrhagic fluid.
 As these cysts enlarge, they may encroach on the calyces and
pelvis to produce pressure defects.
 cysts arise from the tubules throughout the nephron and therefore have
variable lining epithelia.
 papillary epithelial formations and polyps project into the lumen.
 Bowman capsules are occasionally involved in cyst formation, and
glomerular tufts may be seen within the cystic space.

Clinical Features.

 remain asymptomatic until indications of renal insufficiency announce the presence of the underlying
kidney disease.
 In others, hemorrhage or progressive dilation of cysts may produce pain.
 Excretion of blood clots causes renal colic.
 The larger masses, usually apparent on abdominal palpation, may induce a dragging sensation.
 occasionally begins with the insidious onset of hematuria, followed by other features of progressive
chronic renal disease, such as proteinuria (rarely more than 2 gm/day), polyuria, and hypertension.
 Patients with PKD2 mutations tend to have an older age at onset and later development of renal failure.
 Progression is accelerated in blacks (largely correlated with sickle cell trait), in males compared with
females, and in the presence of hypertension.
 Tend to have extrarenal congenital anomalies.
 About 40% have one to several cysts in the liver (polycystic liver disease) that are usually
asymptomatic. The cysts are derived from biliary epithelium.
 occur much less frequently in the spleen, pancreas, and lungs. Intracranial berry aneurysms,
presumably from altered expression of polycystin in vascular smooth muscle, arise in the circle of
Willis, and subarachnoid hemorrhages from these[21] account for death in about 4% to 10% of patients
with polycystic kidney disease.
 Mitral valve prolapse and other cardiac valvular anomalies occur in 20% to 25% of patients, but most
are asymptomatic.
 The clinical diagnosis is made by radiologic imaging techniques.

AUTOSOMAL-RECESSIVE (CHILDHOOD) POLYCYSTIC KIDNEY DISEASE

 having an autosomal-recessive type of inheritance.

 Perinatal, neonatal, infantile, and juvenile subcategories have been defined, depending on the time of
presentation and presence of associated hepatic lesions.
 The first two are the most common; serious manifestations are usually present at birth, and the young
infant might succumb rapidly to renal failure.
 genetically homogeneous, being associated with a gene, PKHD1, that maps to chromosome region
6p21-23.
 PKHD1 gene encodes a large novel protein, fibrocystin.[22] The gene is highly expressed in adult and
fetal kidney and also in liver and pancreas.
 Fibrocystin is a 447-kDa integral membrane protein with a large extracellular region, a single
transmembrane component and a short cytoplasmic tail.
 The extracellular region contains multiple copies of a domain forming an immunoglobulin-like fold.[14]
 The function of fibrocystin is unknown but its putative conformational structure indicates it may be a
cell surface receptor with a role in collecting-duct and biliary differentiation.
 Patients who survive infancy (infantile and juvenile forms) may develop a peculiar type of hepatic
fibrosis characterized by bland periportal fibrosis and proliferation of well-differentiated biliary
ductules, a condition now termed congenital hepatic fibrosis.
 In older children, the hepatic picture in fact predominates. Such patients may develop portal
hypertension with splenomegaly.
 congenital hepatic fibrosis sometimes occurs in the absence of polycystic kidneys and has been
reported occasionally in the presence of adult polycystic kidney disease.

Morphology.

1. The kidneys are enlarged and have a smooth external appearance.

2. On cut section, numerous small cysts in the cortex and medulla give the kidney a spongelike
appearance.
3. Dilated elongated channels are present at right angles to the cortical surface, completely replacing the
medulla and cortex ( Fig. 20-8C
4. On microscopic examination : cylindrical or, less commonly, saccular dilation of all collecting
tubules.The cysts have a uniform lining of cuboidal cells, reflecting their origin from the collecting
tubules.The disease is invariably bilateral. In almost all cases, the liver has cysts with portal fibrosis (
Fig. 20-8D ) as well as proliferation of portal bile ducts.