Hereditary Kidney Disease

Question 1

3 types of hereditary kidney disease?

Answer 1

Cystic diseases.
Congenital nephrotic syndreom.
Familial hematuria syndromes and Alport’s syndrome

Question 2

Most common renal cystic disease?

Answer 2

Autosomal dominant polycystic kidney disease. (ADPKD)

Question 3

What kinds of symptoms does ADPKD cause?

Answer 3

Can often be asymptomatic.
Cystic enlargement -> abdominal mass, flank or back pain.
Cyst rupture -> pain / bleeding.
Renal things..

Question 4

What are the renal effects of ADPKD?

Answer 4

Hematuria (gross or micro).
Mild proteinuria.
HTN
UTI
Stones
Reduced GFR / CKD

Question 5

Are kidney cysts ever normal?

Answer 5

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.)

Question 6

What are the cysts in ADPKD?

Answer 6

Extremely dilated tubules…

They can come from any part of the nephron tubules.

Question 7

ADPKD kidneys can look pretty ugly. How can they still function?

Answer 7

There are still functioning nephrons between the cysts.

Question 8

Other organs affected in ADPKD?

Answer 8

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.

Question 9

What are 2 genes mutations in which can cause ADPKD?

Answer 9

PKD1 - polycystin 1 - a transmembrane protein of unknown function.
PDK2 - polycystin 2 - a Ca++ channel (interacts with polycystin 1)

Question 10

ADPKD is, as the name implies, autosomal dominant. Why don’t you see cysts being formed by every single nephron?

Answer 10

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….?)

Question 11

What structure might be particularly important in the pathogenesis of PKD?

Answer 11

Primary cilia - have some sort of chemo or mechanosensory role.

Question 12

What has polycystin-2 got to do with primary cilia?

Signaling pathway?

Answer 12

Bending of primary cillium-> opens Ca++ channel (Polycystin-2) -> decreased cAMP –??–> cysts.

If polycystin-1 or polycystin-2 isn’t working -> increased intracellular cAMP.

Question 13

What’s the molecular problem that therapies for ADPKD hope to address?
What drugs do this?

Answer 13

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.

Question 14

Do “-vaptans” actually work for PKD? 2 problems?

Answer 14

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)

Question 15

How, basically, is autosomal recessive PKD (ARPKD) different from ADPKD?

Answer 15

ARPKD affects every cell, every nephron.
Presents early (pre-natal, neonatal, juvenile) - depending on severity.

Question 16

In-utero complication of ARPKD?

Answer 16

Kidneys don’t work -> oligohydramnios (not enough amniotic fluid -> Potter’s syndrome.

Question 17

What’s Potter’s syndrome?

Answer 17

oligohydramnios -> facial deformity and pulmonary hypoplasia.

Question 18

How does ARPKD affect the liver?

Answer 18

Hepatic fibrosis and enlargement.

Question 19

How do ARPKD kidneys look, grossly?

Answer 19

“Sponge-like” (with cysts perpendicular to cortical surface)

Question 20

How does the cysts appearing perpendicular to the cortical surface correspond to the histological findings of ARPKD?

Answer 20

The collecting tubules (which run perpendicular to cortical surface) are most affected -> “collecting tubule gigantism”

Question 21

Molecular mechanism of ARPKD?

Answer 21

Fibrocystin mutation…. which may lead to abnormal EGFR localization… more TGF-beta in liver…
(it’s pretty hazy)

Question 22

What are the most common mutations in inherited nephrotic syndrome?

Answer 22

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.)

Question 23

Congenital nephrotic syndrome of the Finnish type… is bad. What happens? What gene is defective?
Inheritance pattern?

Answer 23

Proteinuria in utero -> ESRD in 3-8 years.
Via progressive glomerulosclerosis.

This is caused by a defect in nephrin.
This is autosomal recessive.

Question 24

What histologic pattern of nephrotic syndreome does NPHS2 / podicin mutation cause?

Answer 24

FSGS

Question 25

2 inherited hematuria syndromes?

Answer 25

Thin basment membrane nephropathy.

Alport’s syndrome.

Question 26

What’s the deal with thin basement membrane nephropathy?
Inheritance pattern?
Prognosis?

Answer 26

Autosomal dominant.
There’s minimal proteinuria, but persistent proteinuria.
It’s benign.

Question 27

Natural history of Alport’s syndrome?

Answer 27

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)

Question 28

What’s a pathognomonic ocular sign of Alport’s syndrome?

Answer 28

Anterior lenticonus (protrusion of anterior portion of lens)

Question 29

What protein is defective in Alport’s syndrome?

Answer 29

Type IV collagen - which is why it affects the basement membrane of many different organs (glomeruli, GI, respiratory)

Question 30

What does Alport’s syndrome in kidney look like on EM?

Answer 30

“Basket weave” pattern of thinning GBM - not a consistent, diffuse process.

Question 31

How does the histology of Alport’s evolve?

early, middle, late

Answer 31

Early: Normal / mild mesangial proliferation.
Middle: Mesangial sclerosis, FSGS.
Late: FSGS and global glomerulosclerosis, interstitial fibrosis, tubular atrophy, interstitial foam cells.

Question 32

How does the type IV collagen monomer chain affected affect severity?

Answer 32

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.

Question 33

Inheritance pattern of Alport’s syndrome?

Answer 33

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.

Question 34

How does thin basement membrane nephropathy relate to Alport’s syndrome?

Answer 34

It’s actually also a defect Type IV collagen - in COL4A4 - but it causes relatively minor disruptions in Type IV collagen structure.

Question 35

How can transplant in Alport’s fail, particularly?

Answer 35

If the patient never made a particular flavor of Type IV protamer, that protamer in the donated kidney will be a foreign antigen.
Antibodies can be developed against it -> Goodpasture’s syndrome.