SM 216a - Genetic Cystic Disease Flashcards
Why is adequate fluid intake important for the treatment of ADPKD?
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
What mutation causes Autosomal-Dominant Polycystic Kidney Disease (ADPKD)?
Mutations in either PDK1 or PKD2
Encode fro proteins polycystin 1 or polycystin 2
These proteins are necessary for maintaining ciliary function, which contributes to normal intracellular Ca2+ and cAMP
What causes autosomal recessive polycystic kidney disease (ARPKD)?
Genetic mutation in PKHD1
Encodes for fibrocystin
Describe the clinical manifestation of a patient with ARPKD
- Kidney dysfunction
- Usually before age 10
- Liver involvement (always)
- Biliary dysgenesis
- Congenital hepatic fibrosis -> portal hypertension
- Risk for cholangitis (inflammation of the biliary duct)
Describe the clinical presentation of ADPKD
- 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
What causes medullary cystic kidney disease?
Mutations in one of the following genes
- MUC1 (encodes mucin 1)
- UMOD (encodes uromodulin)
- REN (Endodes renin)
Describe the clinical manifestation of medullary cystic kidney disease
- Commonly associated with hyperuricemia and gout
- Progressive CKD
- ESRD by the 3rd-6th decade
- No extrarenal manifestations
Describe the histologic changes seen in ADPKD
Very little normal kidney tissue between cysts
Cysts are round
Describe the pathophysiology of Autosomal-Dominant Polycystic Kidney Disease (ADPKD)?
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
- Increased ADH casues cysts to grow faster
-
-> Cyst growth
- Normal parenchyma is replaced by nonfunctional cysts
- Compression and distortion of renal vasculature
- Activation of RAAs
- Obstruction, decreased tubular flow
Describe the histologic changes seen in ARPKD
Cysts are longitudinal
Not much functional kidney in between cysts
Describe the treatment approach to ADPKD
- Blood pressure control
- Goal = 130/80, maybe even lower
- 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
Describe the pathophysiology of Autosomal Recessive PKD (ARPKD)
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
What proteins are encoded by PKD1 and PKD2?
What do they do?
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 diminant polycystic kidney disease
