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Molecular Basis of Disease > Polycystic kidney disease > Flashcards

Polycystic kidney disease Flashcards

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
Q

ARPKD has more of a serious presentation than ADPKD

TRUE or FALSE

A

TRUE

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26
Q

What must happen for ARPKD to present in individuals?

A

The sufferers need both copies of the chromosome to be affected by the mutated gene

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27
Q

What is the probability of dying in utero from ARPKD?

A

30%

28
Q

What causes in utero death of ARPKD patients?

A

Pulmonary hypoplasia

Lung development impeded by enlarged kidneys

29
Q

ARPKD is rarely a cause of endstage renal failure in children

TRUE or FALSE

A

FALSE

It is a common cause of endstage renal failure in children

Will need dialysis or transplantation

30
Q

What organ is also affected in ARPKD patients?

A

Liver

Liver development is hindered

Ductal plate malformation leads to fibrosis and often requires liver transplantation

31
Q

Describe the morphology of cysts

A

Fluid-filled sacs lined by a single layer of tubule epithelium

32
Q

What causes the progressive expansion of cysts?

A

Abnormal epithelial cell proliferation in tubules

Ion secretion into the tubule lumen

33
Q

What are the differences of cyst appearance between ARPKD and ADPKD?

A

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
Q

What mutations leads to ADPKD?

A

PKD1

PKD2

Many different mutations of the genes causes the presentation of the disease

35
Q

What mutations leads to ARPKD?

A

PKHD1

Many different mutations of the genes causes the presentation of the disease

36
Q

What types of mutations cause the most serious versions of the disease?

A

Frameshift

Nonsense

Splice

Cause large rearrangements of the genes resulting in stops or truncation of the proteins

37
Q

What types of mutations cause less severe forms of the disease?

A

Missense

In-frame deletions or insertions

38
Q

What mutation causes the most severe presentation of the disease?

A

Large, N-terminal truncating mutations of PKD1

Associated with early onset ADPKD in children

39
Q

What factors may increase the severity of PKD?

A

Somatic second hit mutations

Modifier genes

Epigenetic factors

40
Q

Examples of cellular abnormalities that cause tubular abnormalities in PKD

A

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
Q

Examples of cystic protein

A

Polycystin-1

Polycystin-2

Fibrocystin

42
Q

In what way is the cystic protein abnormal in PKD?

A

Distribution

Regulation

Interaction with integrins

Focal adhesion kinase

43
Q

Mutated proteins involved in PKD

A

Polycystin-1

Polycystin-2

Fibrocystin

Nephrocystin-1

44
Q

What causes the abnormal fluid secretion into the lumen that leads to cyst formation?

A

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
Q

What causes the abnormal proliferation of endothelial cells that leads to cyst formation?

A

Autocrine and paracrine loops

Different proliferation rates leads to tension, changes in cell shape and changes in division orientation

46
Q

Examples of cytokines responsible for the abnormal proliferation of endothelial cells

A

cAMP

EGF

47
Q

What happens if different proliferation rates occur to endothelial cells in the kidneys?

A

Tension

Changes in cell shape

Changes in division orientation

Leads to cyst formation

48
Q

Why do changes in division orientation lead to cyst formation in the endothelial cell lining of kidneys?

A

Mis-orientation of cell divisions leads to cystic outpushings

49
Q

Where are the deficient proteins in PKD found?

A

Apical cilium

Lateral adherens junctions

Basal focal adhesions

50
Q

How is apicobasal polarity maintained?

A

Specialised cell-cell and cell-matrix junctional complexes

51
Q

What happens to the apicobasal polarity in ADPKD?

A

The epithelia in the junctional complexes are dysfunctional

So polarity is hindered

52
Q

What causes the abnormal apicobasal polarity of endothelial cells in PKD?

A

EGFR and NaK-ATPase is mispolarized and found on the apical membrane of epithelial cells

53
Q

What causes the mispolarization of EGFR and NaK-ATPase?

A

Fetal gene expression of Erb-B2 and B2 subunits

So morphology of the epithelial cells mimics that of normal fetal cells

54
Q

What is the function of the polycystin complex?

A

Acts a mechanosensor

Functions as a mechano-sensitive cation channel

55
Q

What, in regard to calcium influx, is observed in ADPKD?

A

Abnormal calcium influx compared to normal collecting duct cells

56
Q

How are the focal adhesions of the basal membrane abnormal in ADPKD?

A

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
Q

What are the roles of the Polycystin-1 complex?

A

Intracellular signalling

Regulation of nuclear gene transcription

Morphogenesis - involved in proliferation and differentiation

58
Q

What are the characteristics of ESRD?

A

Significant kidney enlargement

Cystic expansion

Loss of 60% of normal nephrons

59
Q

When is a good time to start treating PKD?

A

Before the development of ESRD

This presents a large window of opportunity to inhibit cystic expansion

60
Q

What are the targets for PKD therapy?

A

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
Q

What can we target to ail the increased tubular epithelial cell proliferation observed in PKD?

A

Mitogenic ligands

Receptors

Second messengers

Signalling pathways

Cell division

62
Q

Which molecules are abnormally transported in PKD?

A

Sodium

Chloride

Calcium

Potassium

Water

ATP

63
Q

What underlying mechanism causes the abnormal cell differentiation and polarity observed in PKD?

A

Signalling pathways

64
Q

What are targets to ail the abnormal cell-extracellular matrix structure and function observed in PKD?

A

Integrins

Kinases

Fibrotic changes

65
Q

What protein does PKD1 code for?

A

Polycystin 1

66
Q

What protein does PKD2 code for?

A

Polycystin 2

67
Q

What protein does PKHD-1 code for?

A

FPCP

Molecular Basis of Disease (28 decks)

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