Flashcards in Hereditary Kidney Disease Deck (35):
3 types of hereditary kidney disease?
Congenital nephrotic syndreom.
Familial hematuria syndromes and Alport's syndrome
Most common renal cystic disease?
Autosomal dominant polycystic kidney disease. (ADPKD)
What kinds of symptoms does ADPKD cause?
Can often be asymptomatic.
Cystic enlargement -> abdominal mass, flank or back pain.
Cyst rupture -> pain / bleeding.
What are the renal effects of ADPKD?
Hematuria (gross or micro).
Reduced GFR / CKD
Are kidney cysts ever normal?
Yes, with age it's quite common to develop the occasional cyst.
(Really shouldn't ever be > 4 in each kidney, even when over 60. Upper limit of normal increases with age.)
What are the cysts in ADPKD?
Extremely dilated tubules...
They can come from any part of the nephron tubules.
ADPKD kidneys can look pretty ugly. How can they still function?
There are still functioning nephrons between the cysts.
Other organs affected in ADPKD?
Cysts in liver (biliary), pancreas, lungs, ovaries, spleen.
GI - diverticulosis.
Vascular aneurysm - esp. bad if in brain.
Heart valves -> mitral prolapse in 25% of ADPKD patients.
What are 2 genes mutations in which can cause ADPKD?
PKD1 - polycystin 1 - a transmembrane protein of unknown function.
PDK2 - polycystin 2 - a Ca++ channel (interacts with polycystin 1)
ADPKD is, as the name implies, autosomal dominant. Why don't you see cysts being formed by every single nephron?
Two-hit hypothesis - the remaining good copy of the gene needs to be lost before a cyst will form.
(This is consistent with the observation that with age lots of people will develop a cyst if they happen to get 2 separate hits in one cell.
Interestingly, this mechanism depends on the tubule cell's capacity to regenerate and propagate that mutation....?)
What structure might be particularly important in the pathogenesis of PKD?
Primary cilia - have some sort of chemo or mechanosensory role.
What has polycystin-2 got to do with primary cilia?
Bending of primary cillium-> opens Ca++ channel (Polycystin-2) -> decreased cAMP --??--> cysts.
If polycystin-1 or polycystin-2 isn't working -> increased intracellular cAMP.
What's the molecular problem that therapies for ADPKD hope to address?
What drugs do this?
cAMP is too high in tubular cells, so if cAMP can be lowered, maybe that would help.
We know AVP increases cAMP, so AVP-antagonists ("-vaptans") can be used to lower cAMP.
Do "-vaptans" actually work for PKD? 2 problems?
Yes, they seem to slow progression, but..
- They increase LFTs.
- They make you pee like crazy. (Iatrogenic diabetes insipidus -> can't concentrate urine -> 7L/day of urine)
How, basically, is autosomal recessive PKD (ARPKD) different from ADPKD?
ARPKD affects every cell, every nephron.
Presents early (pre-natal, neonatal, juvenile) - depending on severity.
In-utero complication of ARPKD?
Kidneys don't work -> oligohydramnios (not enough amniotic fluid -> Potter's syndrome.
What's Potter's syndrome?
oligohydramnios -> facial deformity and pulmonary hypoplasia.
How does ARPKD affect the liver?
Hepatic fibrosis and enlargement.
How do ARPKD kidneys look, grossly?
"Sponge-like" (with cysts perpendicular to cortical surface)
How does the cysts appearing perpendicular to the cortical surface correspond to the histological findings of ARPKD?
The collecting tubules (which run perpendicular to cortical surface) are most affected -> "collecting tubule gigantism"
Molecular mechanism of ARPKD?
Fibrocystin mutation.... which may lead to abnormal EGFR localization... more TGF-beta in liver...
(it's pretty hazy)
What are the most common mutations in inherited nephrotic syndrome?
NPHS1 - nephrin!
NPHS2 - podicin (another slit-diaphragm protein)
WT1 - (recall - causes Wilm's Tumor - nephroblastoma)
(The first 2 should make a lot of sense, as podocyte function will be impaired.)
Congenital nephrotic syndrome of the Finnish type... is bad. What happens? What gene is defective?
Proteinuria in utero -> ESRD in 3-8 years.
Via progressive glomerulosclerosis.
This is caused by a defect in *nephrin*.
This is autosomal recessive.
What histologic pattern of nephrotic syndreome does NPHS2 / podicin mutation cause?
2 inherited hematuria syndromes?
Thin basment membrane nephropathy.
What's the deal with thin basement membrane nephropathy?
There's minimal proteinuria, but persistent proteinuria.
Natural history of Alport's syndrome?
Persistent microscopic hematuria with macroscopic episodes (often associated with URI)?
In affected males, GFR declines and proteinuria develops with 90% in ESRD by age 40.
(only 10% of female carriers have ESRD by 40).
(Other things: hearing loss, ocular defects, leiomyomatosis of GI and resp. tract, megathrombocytopenia)
What's a pathognomonic ocular sign of Alport's syndrome?
Anterior lenticonus (protrusion of anterior portion of lens)
What protein is defective in Alport's syndrome?
Type IV collagen - which is why it affects the basement membrane of many different organs (glomeruli, GI, respiratory)
What does Alport's syndrome in kidney look like on EM?
"Basket weave" pattern of thinning GBM - not a consistent, diffuse process.
How does the histology of Alport's evolve?
(early, middle, late)
Early: Normal / mild mesangial proliferation.
Middle: Mesangial sclerosis, FSGS.
Late: FSGS and global glomerulosclerosis, interstitial fibrosis, tubular atrophy, interstitial foam cells.
How does the type IV collagen monomer chain affected affect severity?
There are 3 combinations of triple helices made.
alpha-5 participates in 2 of those, so a mutation in alpha-5 will have a more severe phenotype.
Inheritance pattern of Alport's syndrome?
It depends on the Type IV collagen gene affected.
X-linked, in COL4A5 is most severe.
(Female carriers are affected, but not as severely.)
COL4A3 and A4 are usually autosomal recessive. But, if the mutation messes up the formation of normal triple helices, the mutation can be dominant.
How does thin basement membrane nephropathy relate to Alport's syndrome?
It's actually also a defect Type IV collagen - in COL4A4 - but it causes relatively minor disruptions in Type IV collagen structure.