Polycystic kidney disease Flashcards
What type of condition is PKD?
Dominant or recessive mendelian condition
PKD is the most common form of inherited kidney disease
TRUE or FALSE
TRUE
What makes PKD unique compared to other kidney diseases?
One of the only renal diseases that does not affect the glomerulus
What mutation leads to ADPKD?
PKD1 or PKD2
Genetic disease
PKD1 is the root cause for 85% of the cases
How many individuals are affected by PKD worldwide?
> 12 million people
What are the physiological characteristics of PKD?
Enlarged kidneys
Multiple cysts
Loss of renal function
PKD is the most common reason for life-saving dialysis or renal transplant
TRUE or FALSE
TRUE
What percentage of patients develop end-stage renal disease by age 50?
50%
Although onset of ESRD in APKD patients vary
What is ESRD?
Characterised by 50% loss of nephron function
By this point kidneys are not able to function by themselves
Require help by dialysis or treatment
What are methods for diagnosis of PKD?
Family history
Abdominal imaging
Genetic diagnosis
Symptoms
What are symptoms of PKD?
High blood pressure
Polyuria
Haematuria
Abdominal pain
Stones
Recurrent UTIs
Liver cysts
Intracranial pressure
Aortic aneurysms
Describe the morphology of a PKD kidney
Enormous progressive bilateral renal enlargment
Cysts form throughout the cortex and medulla
Disruption of the tight, compact structure of normal kidneys
What happens to renal epithelial cell function in PDK kidneys?
Their function is lost
What is the function of normal kidneys?
Reabsorption of fluid and nutrients
Removal of toxic waste
Describe the morphology of a normal kidney
Precise organisation in kidney cortex and medulla
Strictly regulated cell structure, function and lumen size
How many segments compose the epithelial tubules?
15
How many nephrons are found in a normal kidney?
1 000 000
What does ADPKD stand for?
Autosomal dominant PKD
What does ARPKD stand for?
Autosomal recessive PKD
Describe the formation of cysts in ADPKD
Mutated proteins attach to the cell wall more strongly
Dont allow the flexibility for the nephrons to settle appropriately in the kidneys
This leads to abnromal out-pushings of the epithelial wall
Where in the kidney are cysts found in ADPKD?
Any nephron segments
How many mutated genes are required for PKD presentation in ADPKD?
One mutated gene in one chromosome
What mutation causes ARPKD?
PKHD1
Where in the kidney are cysts found in ARPKD?
Collecting tubule
ARPKD has more of a serious presentation than ADPKD
TRUE or FALSE
TRUE
What must happen for ARPKD to present in individuals?
The sufferers need both copies of the chromosome to be affected by the mutated gene
What is the probability of dying in utero from ARPKD?
30%
What causes in utero death of ARPKD patients?
Pulmonary hypoplasia
Lung development impeded by enlarged kidneys
ARPKD is rarely a cause of endstage renal failure in children
TRUE or FALSE
FALSE
It is a common cause of endstage renal failure in children
Will need dialysis or transplantation
What organ is also affected in ARPKD patients?
Liver
Liver development is hindered
Ductal plate malformation leads to fibrosis and often requires liver transplantation
Describe the morphology of cysts
Fluid-filled sacs lined by a single layer of tubule epithelium
What causes the progressive expansion of cysts?
Abnormal epithelial cell proliferation in tubules
Ion secretion into the tubule lumen
What are the differences of cyst appearance between ARPKD and ADPKD?
ARPKD affects the collecting duct, ADPKD affects the whole tubule
ARPKD cysts remain in contact with their nephron of origin, this does not happen in ADPKD
What mutations leads to ADPKD?
PKD1
PKD2
Many different mutations of the genes causes the presentation of the disease
What mutations leads to ARPKD?
PKHD1
Many different mutations of the genes causes the presentation of the disease
What types of mutations cause the most serious versions of the disease?
Frameshift
Nonsense
Splice
Cause large rearrangements of the genes resulting in stops or truncation of the proteins
What types of mutations cause less severe forms of the disease?
Missense
In-frame deletions or insertions
What mutation causes the most severe presentation of the disease?
Large, N-terminal truncating mutations of PKD1
Associated with early onset ADPKD in children
What factors may increase the severity of PKD?
Somatic second hit mutations
Modifier genes
Epigenetic factors
Examples of cellular abnormalities that cause tubular abnormalities in PKD
Increased tubular epithelial cell proliferation
Increase epithelial cell apoptosis
Abnormal cell ion and fluid secretion
Abnormal cell-extracellular matrix structure and functional interactions
Persistent foetal gene expression
Abnormal cystic protein
Examples of cystic protein
Polycystin-1
Polycystin-2
Fibrocystin
In what way is the cystic protein abnormal in PKD?
Distribution
Regulation
Interaction with integrins
Focal adhesion kinase
Mutated proteins involved in PKD
Polycystin-1
Polycystin-2
Fibrocystin
Nephrocystin-1
What causes the abnormal fluid secretion into the lumen that leads to cyst formation?
Dysfunctional sodium pump causes the gradient to favour water to accumulate into the interstitial space
Pumps that determine the movement of water are located in the apical side of the barrier instead of their normal placement on the basal side
This is caused by fetal gene expression of Erb-B2 and B2
What causes the abnormal proliferation of endothelial cells that leads to cyst formation?
Autocrine and paracrine loops
Different proliferation rates leads to tension, changes in cell shape and changes in division orientation
Examples of cytokines responsible for the abnormal proliferation of endothelial cells
cAMP
EGF
What happens if different proliferation rates occur to endothelial cells in the kidneys?
Tension
Changes in cell shape
Changes in division orientation
Leads to cyst formation
Why do changes in division orientation lead to cyst formation in the endothelial cell lining of kidneys?
Mis-orientation of cell divisions leads to cystic outpushings
Where are the deficient proteins in PKD found?
Apical cilium
Lateral adherens junctions
Basal focal adhesions
How is apicobasal polarity maintained?
Specialised cell-cell and cell-matrix junctional complexes
What happens to the apicobasal polarity in ADPKD?
The epithelia in the junctional complexes are dysfunctional
So polarity is hindered
What causes the abnormal apicobasal polarity of endothelial cells in PKD?
EGFR and NaK-ATPase is mispolarized and found on the apical membrane of epithelial cells
What causes the mispolarization of EGFR and NaK-ATPase?
Fetal gene expression of Erb-B2 and B2 subunits
So morphology of the epithelial cells mimics that of normal fetal cells
What is the function of the polycystin complex?
Acts a mechanosensor
Functions as a mechano-sensitive cation channel
What, in regard to calcium influx, is observed in ADPKD?
Abnormal calcium influx compared to normal collecting duct cells
How are the focal adhesions of the basal membrane abnormal in ADPKD?
They have increased length
Causes cells to become more firmly attached to one another
Increases rate of cyst formation as there is increased tension
What are the roles of the Polycystin-1 complex?
Intracellular signalling
Regulation of nuclear gene transcription
Morphogenesis - involved in proliferation and differentiation
What are the characteristics of ESRD?
Significant kidney enlargement
Cystic expansion
Loss of 60% of normal nephrons
When is a good time to start treating PKD?
Before the development of ESRD
This presents a large window of opportunity to inhibit cystic expansion
What are the targets for PKD therapy?
Increased tubular epithelial proliferation
Ion transport and fluid secretion
Cell differentiation, planar and apico-basal polarity
Cell-cell matrix structure and function
Cystic gene expression, distribution and function
What can we target to ail the increased tubular epithelial cell proliferation observed in PKD?
Mitogenic ligands
Receptors
Second messengers
Signalling pathways
Cell division
Which molecules are abnormally transported in PKD?
Sodium
Chloride
Calcium
Potassium
Water
ATP
What underlying mechanism causes the abnormal cell differentiation and polarity observed in PKD?
Signalling pathways
What are targets to ail the abnormal cell-extracellular matrix structure and function observed in PKD?
Integrins
Kinases
Fibrotic changes
What protein does PKD1 code for?
Polycystin 1
What protein does PKD2 code for?
Polycystin 2
What protein does PKHD-1 code for?
FPCP
