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Molecular Basis of Disease > Polycystic kidney disease > Flashcards

Polycystic kidney disease Flashcards

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1
Q

What type of condition is PKD?

A

Dominant or recessive mendelian condition

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2
Q

PKD is the most common form of inherited kidney disease

TRUE or FALSE

A

TRUE

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3
Q

What makes PKD unique compared to other kidney diseases?

A

One of the only renal diseases that does not affect the glomerulus

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4
Q

What mutation leads to ADPKD?

A

PKD1 or PKD2

Genetic disease

PKD1 is the root cause for 85% of the cases

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5
Q

How many individuals are affected by PKD worldwide?

A

> 12 million people

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6
Q

What are the physiological characteristics of PKD?

A

Enlarged kidneys

Multiple cysts

Loss of renal function

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7
Q

PKD is the most common reason for life-saving dialysis or renal transplant

TRUE or FALSE

A

TRUE

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8
Q

What percentage of patients develop end-stage renal disease by age 50?

A

50%

Although onset of ESRD in APKD patients vary

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9
Q

What is ESRD?

A

Characterised by 50% loss of nephron function

By this point kidneys are not able to function by themselves

Require help by dialysis or treatment

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10
Q

What are methods for diagnosis of PKD?

A

Family history

Abdominal imaging

Genetic diagnosis

Symptoms

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11
Q

What are symptoms of PKD?

A

High blood pressure

Polyuria

Haematuria

Abdominal pain

Stones

Recurrent UTIs

Liver cysts

Intracranial pressure

Aortic aneurysms

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12
Q

Describe the morphology of a PKD kidney

A

Enormous progressive bilateral renal enlargment

Cysts form throughout the cortex and medulla

Disruption of the tight, compact structure of normal kidneys

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13
Q

What happens to renal epithelial cell function in PDK kidneys?

A

Their function is lost

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14
Q

What is the function of normal kidneys?

A

Reabsorption of fluid and nutrients

Removal of toxic waste

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15
Q

Describe the morphology of a normal kidney

A

Precise organisation in kidney cortex and medulla

Strictly regulated cell structure, function and lumen size

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16
Q

How many segments compose the epithelial tubules?

A

15

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17
Q

How many nephrons are found in a normal kidney?

A

1 000 000

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18
Q

What does ADPKD stand for?

A

Autosomal dominant PKD

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19
Q

What does ARPKD stand for?

A

Autosomal recessive PKD

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20
Q

Describe the formation of cysts in ADPKD

A

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

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21
Q

Where in the kidney are cysts found in ADPKD?

A

Any nephron segments

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22
Q

How many mutated genes are required for PKD presentation in ADPKD?

A

One mutated gene in one chromosome

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23
Q

What mutation causes ARPKD?

A

PKHD1

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24
Q

Where in the kidney are cysts found in ARPKD?

A

Collecting tubule

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25
ARPKD has more of a serious presentation than ADPKD TRUE or FALSE
TRUE
26
What must happen for ARPKD to present in individuals?
The sufferers need both copies of the chromosome to be affected by the mutated gene
27
What is the probability of dying in utero from ARPKD?
30%
28
What causes in utero death of ARPKD patients?
Pulmonary hypoplasia Lung development impeded by enlarged kidneys
29
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
30
What organ is also affected in ARPKD patients?
Liver Liver development is hindered Ductal plate malformation leads to fibrosis and often requires liver transplantation
31
Describe the morphology of cysts
Fluid-filled sacs lined by a single layer of tubule epithelium
32
What causes the progressive expansion of cysts?
Abnormal epithelial cell proliferation in tubules Ion secretion into the tubule lumen
33
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
34
What mutations leads to ADPKD?
PKD1 PKD2 Many different mutations of the genes causes the presentation of the disease
35
What mutations leads to ARPKD?
PKHD1 Many different mutations of the genes causes the presentation of the disease
36
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
37
What types of mutations cause less severe forms of the disease?
Missense In-frame deletions or insertions
38
What mutation causes the most severe presentation of the disease?
Large, N-terminal truncating mutations of PKD1 Associated with early onset ADPKD in children
39
What factors may increase the severity of PKD?
Somatic second hit mutations Modifier genes Epigenetic factors
40
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
41
Examples of cystic protein
Polycystin-1 Polycystin-2 Fibrocystin
42
In what way is the cystic protein abnormal in PKD?
Distribution Regulation Interaction with integrins Focal adhesion kinase
43
Mutated proteins involved in PKD
Polycystin-1 Polycystin-2 Fibrocystin Nephrocystin-1
44
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
45
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
46
Examples of cytokines responsible for the abnormal proliferation of endothelial cells
cAMP EGF
47
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
48
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
49
Where are the deficient proteins in PKD found?
Apical cilium Lateral adherens junctions Basal focal adhesions
50
How is apicobasal polarity maintained?
Specialised cell-cell and cell-matrix junctional complexes
51
What happens to the apicobasal polarity in ADPKD?
The epithelia in the junctional complexes are dysfunctional So polarity is hindered
52
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
53
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
54
What is the function of the polycystin complex?
Acts a mechanosensor Functions as a mechano-sensitive cation channel
55
What, in regard to calcium influx, is observed in ADPKD?
Abnormal calcium influx compared to normal collecting duct cells
56
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
57
What are the roles of the Polycystin-1 complex?
Intracellular signalling Regulation of nuclear gene transcription Morphogenesis - involved in proliferation and differentiation
58
What are the characteristics of ESRD?
Significant kidney enlargement Cystic expansion Loss of 60% of normal nephrons
59
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
60
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
61
What can we target to ail the increased tubular epithelial cell proliferation observed in PKD?
Mitogenic ligands Receptors Second messengers Signalling pathways Cell division
62
Which molecules are abnormally transported in PKD?
Sodium Chloride Calcium Potassium Water ATP
63
What underlying mechanism causes the abnormal cell differentiation and polarity observed in PKD?
Signalling pathways
64
What are targets to ail the abnormal cell-extracellular matrix structure and function observed in PKD?
Integrins Kinases Fibrotic changes
65
What protein does PKD1 code for?
Polycystin 1
66
What protein does PKD2 code for?
Polycystin 2
67
What protein does PKHD-1 code for?
FPCP

Molecular Basis of Disease (28 decks)

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