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Renal by Minnie: AH Version > 207: Genetic Cystic Disease > Flashcards

207: Genetic Cystic Disease Flashcards

1
Q

Why is adequate fluid intake important for the treatment of ADPKD?

A

The goal is to reduce ADH secretion - adequate fluid intake (>3L/day) prevents ADH secretion by keeping plasma Osm low

  • When ADH binds to its V2 receptor, it increases intracellular cAMP
  • In patients with ADPKD, this is bad because
  • *increased cAMP -> increased fluid secretion into cysts
  • > cyst growth**
  • Preventing ADH from binding to its receptor prevents this increase in cAMP, thus reducing fluid secretion into cysts and cyst growth
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2
Q

Which polycystic kidney disease is characterized by kidneys that get progressively larger?

A

ADPKD

In ARPKD, cysts develop then stabilize

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3
Q

How is ADPKD diagnosed?

A

Count the cysts on ultrasound; you can predict teh number of cysts that a person with ADPKD would have at each age

More cysts = higher liklihood of ADPKD

If there is a family history, you know what to look for. If no family history, genetic testing may be useful

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4
Q

Why is total kidney volume often reported in patients with ADPKD?

A

Total kidney volume is an accurate prognostic factor that predicts the rate of GFR decline

Bigger kidneys–> lower GFR

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5
Q

What mutation causes Autosomal-Dominant Polycystic Kidney Disease (ADPKD)?

A

Mutations in either PKD1 or PKD2

Encode for proteins polycystin 1 or polycystin 2

These proteins are necessary for maintaining ciliary function, which contributes to normal intracellular Ca2+ and cAMP

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6
Q

What causes autosomal recessive polycystic kidney disease (ARPKD)?

A

Genetic mutation in PKHD1

Encodes for fibrocystin

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7
Q

What is the inheritance pattern for ADPKD?

A

Autosomal dominant, but ~5% of cases are caused by de novo mutations

2nd hit hypothesis - Patients usually dont’ develop disease until later in life, when their functional copy of PDK1 or PDK2 is presumably compromised

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8
Q

A mutation in PKD1 or PKD2 leads to which genetic kidney disease?

A

Autosomal dominant polycystic kidney disease (ADPKD)

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9
Q

Describe the clinical manifestation of a patient with ARPKD

A
  • Kidney dysfunction
    • Usually before age 10
  • Liver involvement (always)
    • Biliary dysgenesis
    • Congenital hepatic fibrosis -> portal hypertension
  • Risk for cholangitis (inflammation of the biliary duct)
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10
Q

A mutation in UMOD will lead to which genetic kidney disease?

A

Medullary cycstic kidney disease

(UMOD encodes uromodulin)

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11
Q

Describe the clinical presentation of ADPKD

A
  • Usually adult onset
  • Renal manifestations
    • Hypertension
    • Proteinuria
    • Hematuria
    • Abdominal/flant pain
    • Kiney stones
    • UTI/kidney infections
  • Extrarenal
    • Hepatic cysts
    • Intracranial aneurysm
    • Mitral valve prolapse
    • Aortic aneurysm
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12
Q

What causes medullary cystic kidney disease?

A

Mutations in one of the following genes

  • MUC1 (encodes mucin 1)
  • UMOD (encodes uromodulin)
  • REN (Endodes renin)
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13
Q

A mutation in REN will lead to which genetic kidney disease?

A

Medullary polycystic kidney disease

(REN encodes renin)

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14
Q

Describe the clinical manifestation of medullary cystic kidney disease

A
  • Commonly associated with hyperuricemia and gout
  • Progressive CKD
    • ESRD by the 3rd-6th decade
  • No extrarenal manifestations
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15
Q

What are the common extrarenal clinical manifestations of ADPKD?

A

Hepatic cysts

Intracranial aneurysms (10%, clusters in families)

Mitral valve prolapse

Aortic aneurysm

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16
Q

Describe the histologic changes seen in ADPKD

A

Very little normal kidney tissue between cysts

Cysts are round

17
Q

What is medullary cystic kidney disease (MCKD)?

A

A kidney disease characterized by tubular fibrosis and interstitial fibrosis, but the clinical manifestation is not severe

18
Q

Describe the pathophysiology of Autosomal-Dominant Polycystic Kidney Disease (ADPKD)?

A

Mutations in either PKD1 or PDK2

  • -> Abnormal ciliary function
  • -> Decreased intracellular Ca2+, increased cAMP
  • -> Deranged cellular signaling
  • -> Cell proliferation & fluid secretion into the expanding cyst
    • Increased ADH casues cysts to grow faster
      • Binding of ADH to V2 receptors stimulates cAMP
      • -> Increased proliferation and fluid secretion
  • -> Cyst growth
    • Normal parenchyma is replaced by nonfunctional cysts
    • Compression and distortion of renal vasculature
    • Activation of RAAs
    • Obstruction, decreased tubular flow
19
Q

Describe the histologic changes seen in ARPKD

A

Cysts are longitudinal

Not much functional kidney in between cysts

20
Q

Describe the treatment approach to ADPKD

A

Basically, CDK management + trying to preserve remaining kidney tissue

  • Blood pressure control
    • Goal = 130/80, maybe even lower for young patients
    • Use ACE inhibitro OR ARB
  • Low Na+ intake
  • Low caffeine intake
  • Avoid contact sports
  • Adequate water intake (at lease 3L/day)
    • Goal is to minimize ADH secretion
    • Increased ADH -> Increased cAMP -> Increased fluid secretion into cysts
  • Transplant
21
Q

Describe the pathophysiology of Autosomal Recessive PKD (ARPKD)

A

Genetic mutation in PKHD1 -> Abnormal fibrocystin

Normally, fibrocystin is found in primary cilia, tubular epithelial cells, and bile duct epithelial celsl

Mutation in PKHD1 -> Cystic kidney and liver

  • Oligohydramnios
    • Pulmonary hypoplasia
    • Limb defects
  • If the baby survives the neonatal period, the child will develop ESRD by age 10

Much more severe than ADPKD

22
Q

What proteins are encoded by PKD1 and PKD2?

What do they do?

A

Polycystin 1 and Polycistin 2

  • Co-localize to the primary cillum of kidny tubular epithelial cells
  • Important for maintaining normal ciliary function
    • Ciliary function is important for normal intracellular cAMP and Ca2+ levels
    • These are important for cellular signaling

Mutations = autosomal dominant polycystic kidney disease

23
Q

A mutation in MUC1 will lead to which genetic kidney disease?

A

Medullary cystic kidney disease (MCKD)

MUC1 encodes mucin 1

24
Q

What is the role of V2 receptor antagonists in treating ADPKD?

A

When ADH binds to its V2 receptor, it increases intracellular cAMP

In patients with ADPKD, this is bad because increased cAMP -> increased fluid secretion into cysts -> cyst growth

Preventing ADH from binding to its receptor prevents this increase in cAMP, thus reducing fluid secretion into cysts and cyst growth

25
Q

A mutation in PKHD1 causes which genetic kidney disease?

A

Autosomal recessive polycystic kidney disease (ARPKD)

Renal by Minnie: AH Version (27 decks)

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