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24 Cards in this Set
- Front
- Back
Genetic pleiotropism
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1 gene has many effects
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Genetic (locus) heterogeneity
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Mutation of different genes can give the same disorder.
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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 --- 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
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GFR in polycystic kidney disease (PKD)
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throw out thios fc
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Types of polycystic kidney diseases
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AD (chrom 16 or 4) and AR (barely touched on today)
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proteins busted in AD PKD
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polycystin-1 and 2.
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Causes of multiple cysts in both kidneys
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AD PKD, AR PKD, multiple simple cysts, von hippel lindau, tuberous sclerosis.
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AD PKD epidem
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it is serious and fairly common.
sx present after reproductive age. |
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Dx of AD PKD with known fam hx
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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. |
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DX of AD PKD without known fam hx
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bilateral renal enlargement and multiple cysts and ruled out vHL, tuberous sclerosis.
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PKD-1 gene
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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. |
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Can you tell different btwn mutation in PKD-1 or 2?
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not from appearance, signs, sx of the pt.
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AD PKD vs AR PKD cyst locations
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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. |
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PKD-2 gene
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Chrom 4.
Calcium channel in the cell membrane. Probably transports polycystin-1 in some way into the membrane. |
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Elements of AD inheritance
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Vertical transmission of phenotype
M:F ratio is 1 M-->M transmission is present |
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Presenting sx of AD PKD
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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 |
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Natural history of AD PKD
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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. |
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Clinical features of AD PKD
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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. |
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Pleiotropic effects of AD PKD
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Kidney, GI (hepatic cysts and diverticuli), cerebrovasc aneurysms, CV valvular abnormalities
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Monitoring disease progression
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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. |
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Tx of signs and sx
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HTN and LVHypertrophy
Hematuria UTIs Renal stones Renal pain Renal insuff. |
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Which mutation typically has teh disease hit later in life?
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PKD2. So pt are "in the safe of not getting AD PKD" at a later age.
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AR PKD
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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. |
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Conclusions
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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 |