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24 Cards in this Set

  • Front
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Genetic pleiotropism
1 gene has many effects
Genetic (locus) heterogeneity
Mutation of different genes can give the same disorder.
17 year old male with gross hematuria after high school soccer game. He complained of flank pain after being hit in game (no foul, no card). Pain resolved during game and he played on. Later that evening he had blood in urine went to ED.

PE normal. Vitals nl, including BP.
UA showed gross blood (RBC’s) only (no proteinuria). BUN, creatinine, electrolytes, etc. all normal.

Renal US abnormal CT both: many cysts of varying size both kidneys, some filled with ?cells; large kidneys bilaterally. Normal liver and pancreas.

Dx: PKD
Family history: no renal disease

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J.T. is a 26-year old male medical student who presented to the ED one night with sudden onset severe flank pain.
ED made diagnosis of “renal colic”; thought to be renal stone passing. Microscopic hematuria, UA otherwise normal. BP 140/90 when medicated for pain. Creatinine and BUN normal.
Ultrasound: Multiple cysts varying in size in both kidneys; bilateral renal enlargement; several cysts in the liver
Abdominal CT: same findings; “good parenchyma” in kidneys.
Diagnosis: Polycystic Kidney Disease
Family History: Patient is adopted.
Patient started on antihypertensive and referred to Renal Service for initiation of long-term care.
vignettes
GFR in polycystic kidney disease (PKD)
throw out thios fc
Types of polycystic kidney diseases
AD (chrom 16 or 4) and AR (barely touched on today)
proteins busted in AD PKD
polycystin-1 and 2.
Causes of multiple cysts in both kidneys
AD PKD, AR PKD, multiple simple cysts, von hippel lindau, tuberous sclerosis.
AD PKD epidem
it is serious and fairly common.

sx present after reproductive age.
Dx of AD PKD with known fam hx
At least 2 cysts (uni or bilat) before age 30

2 cysts in each kidney in pts 30-59 years

or 4 cysts in each kidney after age 60.
DX of AD PKD without known fam hx
bilateral renal enlargement and multiple cysts and ruled out vHL, tuberous sclerosis.
PKD-1 gene
most AD PKD is due to busted PKD-1 gene.

chrom 16.

polycystin 1.

probably a signaling protein (spans the membrane) - regulates gene txpn and interacts with cytoskeleton.
Can you tell different btwn mutation in PKD-1 or 2?
not from appearance, signs, sx of the pt.
AD PKD vs AR PKD cyst locations
AD - in every tubule segment and rapidly closes off the nephron of origin.

AR - cysts from collecting tubules only, which remain connected to the nephron of origin.
PKD-2 gene
Chrom 4.

Calcium channel in the cell membrane. Probably transports polycystin-1 in some way into the membrane.
Elements of AD inheritance
Vertical transmission of phenotype

M:F ratio is 1

M-->M transmission is present
Presenting sx of AD PKD
Abd or flank pain (colic) - due to mechanical effect of cysts/stones
HTN - before decline in filtration. normal to high renin.
UTIs
Hematuria (gross or microscopic)
Fatigue
Natural history of AD PKD
Highly penetrant gene (almost everyone gets cysts...)

Loss of renal func in 30s and 1/2 have ESRD by age 60.

Even wwins do not have identical courses. Will have different timing of sx, ESRD, non-renal complications, etc.
Clinical features of AD PKD
Renal function abnormalities.

HTN, renal pain

Cyst hemorrhage (pain, hematuria, fever, etc.)

Stones in about 20% of pts. Urinary stasis and metabolic alterations.

Renal cell carcinoma risk is elevated.
Pleiotropic effects of AD PKD
Kidney, GI (hepatic cysts and diverticuli), cerebrovasc aneurysms, CV valvular abnormalities
Monitoring disease progression
HTN should be tx aggressively.

Sequential creatinine measurements.

Imaging to estimate kidney volume. (gives a clue abt onset of kidney disease)

MRAngiography for pts who have a family history of aneurysm or stroke.
Tx of signs and sx
HTN and LVHypertrophy
Hematuria
UTIs
Renal stones
Renal pain
Renal insuff.
Which mutation typically has teh disease hit later in life?
PKD2. So pt are "in the safe of not getting AD PKD" at a later age.
AR PKD
More rare than AD.

Fetal or neonatal death is common (whereas AD presents much later in life)

Huge enlargement of kidneys, lung compression, respiratory failure.
Conclusions
AD PKD offers example of:
Genetic heterogeneity of disease (or, locus heterogeneity PKD-1, PKD-2)
Genetic pleiotropism (one gene, many effects– e.g., brain aneurysms)
Common and significant autosomal dominant condition

AR PKD reviewed
Different gene, protein;
Different clinical presentation and course