SM 215: Genetic Cystic Kidney Disease

Question 1

What is Autosomal Dominant Polycystic Kidney Disease?

Answer 1

ADPKD is the most common monogenic cause of ESRD and due to mutations in the PKD 1 and PKD 2 genes

Question 2

What genes are responsible for the development of ADPKD?

Answer 2

PKD 1 and PKD 2 cause ADPKD

Question 3

What is the mode of inheritance of ADPKD?

Answer 3

Autosomal Dominant Polycystic Kidney Disease is inherited via autosomal dominant

Question 4

Can ADPKD be acquired from the environment?

Answer 4

No, but it can arise from a de novo mutation

Question 5

Why is there significant phenotypic variability in ADPKD?

Answer 5

The severity depends on the type of 100’s of mutations in the PKD 1 and PKD 2 genes and the amount of functional protein that gets made

Question 6

Why do some people who have the PKD 1/2 mutations that cause ADPKD not experience illness?

Answer 6

Second-hit hypothesis

Question 7

Which gene mutation causes worse ADPKD?

Answer 7

PKD 1 mutations are worse than PKD 2

Question 8

What factors account for the variability in the severity of symptoms in ADPKD?

Answer 8

Variable severity in defects of: trafficking, altered post-translational modification, decreased protein production, etc.

Question 9

What hormone worsens ADPKD?

Answer 9

ADH worsens ADPKD by causing cysts to grow faster

Question 10

How does hypertension occur in ADPKD?

Answer 10

Cysts in ADPKD expand and compress cause activation of the RAAS system

Question 11

What signaling changes cause ADPKD?

Answer 11

Decreases in Ca and increases in cAMP

Question 12

How do Ca, cAMP, and ADH cause cystic growth in ADPKD?

Answer 12

Ca + cAMP + ADH = cell proliferation that causes fluid secretion, leading to cyst growth

Question 13

How many cysts are formed in ADPKD?

Answer 13

Innumerable

Question 14

Does ADPKD cause monoliteral or bilateral kidney enlargement?

Answer 14

ADPKD causes bilateral enlargement

Question 15

Which parts of the kidney are effected by cysts in ADPKD?

Answer 15

Cysts are variable in size throughout the entire kidney

Question 16

What biomarker is a predictor of the rate of decline in GFR in ADPKD?

Answer 16

Total Kidney Volume (TKV) is a good biomarker to predict the decline in GFR in ADPKD

Question 17

How does TKV predict the progression of ADPKD?

Answer 17

Faster rises in TKV = greater decline in cGFR = faster losses in Kidney

Question 18

How is ADPKD diagnosed?

Answer 18

ADPKD is diagnosed with cysts on Ultrasound based on a person’s age and with a family history of ADPKD

Question 19

Does ADPKD cause renal or extrarenal manifestations?

Answer 19

ADPKD causes both renal and extrarenal manifestations

Question 20

What are Renal manifestations of ADPKD?

Answer 20

Hypertension, flank pain, proteinuria, neprolithiasis

Question 21

How does ADPKD cause Hypertension?

Answer 21

Cysts in ADPKD compress healthy glomeruli, decreasing GFR to that glomeruli and triggering the RAAS system

Question 22

How does ADPKD cause Nephrolithiasis?

Answer 22

Lower GFR causes urine stasis which promotes stone formation

Question 23

What are Extrarenal manifestations of ADPKD?

Answer 23

Hepatic cysts and intracranial aneurysms

Question 24

Do extrarenal manifestations resolve after kidney transplant in ADPKD?

Answer 24

Nope - still have a risk for cirrhosis from Hepatic cysts and sudden death from intracranial aneurysms

Question 25

Why does the Liver develop cysts in ADPKD?

Answer 25

The PKD 1 and PKD 2 genes are effecting multiple organs

Question 26

What are the current therapies for ADPKD?

Answer 26

Blood pressure control to < 130/80 Low sodium intake Lots of water intake > 3L

Question 27

What is the first line therapy for ADPKD?

Answer 27

ACEi/ARB to lower hypertension

Question 28

What is the novel therapy for ADPKD?

Answer 28

V2R antagonists like Tolvapatan

Question 29

How do V2R antagonists treat ADPKD?

Answer 29

V2R antagonists prevent ADH from growing cysts

Question 30

Why is high water intake recommended in ADPKD?

Answer 30

Increasing water intake lowers ADH release, slowing cysts from growing

Question 31

Can a transplant cure ADPKD?

Answer 31

Yes and no - fix the kidney, but not the extrarenal effects

Question 32

What is ARPKD?

Answer 32

Autosomal Recessive Polycystic Kidney Disease

Question 33

Which is more severe, ARPKD or ADPKD?

Answer 33

ARPKD - higher mortality and rapid progression to ESRD

Question 34

When do ARPKD abnormalities present?

Answer 34

ARPKD presents in utero and at birth

Question 35

Which gene leads to ARPKD?

Answer 35

Mutations in PKHD1 leads to ARPKD

Question 36

What other organ is effected by ARPKD?

Answer 36

The Liver, which is seriously dysfunctional

Question 37

Explain Liver dysfunction in ARPKD?

Answer 37

Portal Hypertension arises from biliary dysgenesis and hepatic fibrosis, because the PKHD1 gene encodes epithelial cells

Question 38

Which disease predisposes Cholangitis, ARPKD or ADPKD?

Answer 38

ARPKD

Question 39

What is Medullary Cystic Kidney Disease?

Answer 39

A disease characterized by evidence of tubular and interstitial fibrosis associated with minimal urinary abnormalities

Question 40

Are the abnormalities in Medullary Cystic Kidney Disease severe?

Answer 40

Nope, minimal proteinuria and hematuria

Question 41

Describe the cysts in Medullary Cystic Kidney Disease?

Answer 41

Cysts are small

Question 42

What gene is associated with MCKD?

Answer 42

3 genes: MUC1, UMOD, REN

Question 43

What is MCKD associated with?

Answer 43

Hyperuricemia and gout

Question 44

What is MCKD?

Answer 44

Medullary Cystic Kidney Disease

Question 45

What are the extrarenal manifestations of MCKD?

Answer 45

None

Question 46

How does Medullary Sponge Kidney effect renal function?

Answer 46

Renal function is normal, since only small cysts form

Question 47

What is Medullary Sponge Kidney associated with?

Answer 47

Kidney stones