SM 215: Genetic Cystic Disease

Question 1

Genetics of ADPKD

Answer 1

Most common monogenic cause of ESRD (4th leading cause of ESRD alone!)
80% mutations in PKD1 = ligand receptor (more severe disease)
15% mutations in PKD2 = V-gated Ca Channel (more mild disease)
AD inheritance, 5% cases are de novo
Huge phenotypic variability - many possible mutations
2 Hit Hypothesis: mutation exists everywhere, but cysts are not - suggests need for a second trigger

Question 2

Pathogenesis of ADPKD

Answer 2

Mutation + 2nd hit = Deficiency of PC1/2 = dysfunctional tubule cilia = loss of intracellular inhibitory signalling (low Ca, high cAMP) = cystogenesis = compress normal kidney = renal dysfunction (tubule obstruction and vessel compression) = inflammation
Inflammation = more ADH = more cAMP = more cystogenesis
Fluid secreted into cysts makes them grow

Question 3

Pathology and Histology of ADPKD

Answer 3

Pathology: Innumerable Cysts, loss of normal tissue, enlarged size, seen throughout renal parenchyma
Histology: Large Cysts causing glomerular compression, very little normal functional tissue between cysts

Question 4

What is a biomarker for ADPKD

Answer 4

Total Kidney Volume - good prognostic for predicting rate of GFR decline
As TKV increases, GFR decreases
Calculated through radiology

Question 5

Clinical Manifestations of ADPKD

Answer 5

Renal: renal HTN, Abd/flank pain, proteinuria, hematuria, nephrolithiasis/UTI/infection due to poor tubular flow
Extra-renal: hepatic cysts (most common extrarenal manifestation), intracranial aneurysms, MV prolapse, Aortic Aneurysm

IT IS A SYSTEMIC DISEASE

Question 6

Treatment of ADPKD

Answer 6

1. BP Control <130/80 with ACE-i/ARB (lower glom hyperfiltration due to nephron loss)
2. Low Na/caffeine intake
3. Avoid contact sports
4. 3L+ water intake (keep low plasma osM to lower ADH to keep cAMP down)

Meds

1. V2R Antagonists = low ADH = low cAMP = less cystogenesis
2. mTOR inhibition - ineffective
3. Somatostatin analogs? unsure

Question 7

Features and abnormalities and genetics of ARPKD

Answer 7

More rare and severe phenotype than ADPK, abnormalities present in utero or at birth
Fetal Abnormalities = oligohydramnios (poor kidney fx) = pulmonary hypoplasia (no urine, no surfactant) + limb defects
50% of neonates who survive have ESRD by age 10
Mutation: PKHD1 gene for fibrocystin - in cilia of tubular epithelial cells AND bile duct epithelial cells (LIVER EQUALLY AFFECTED)

Question 8

Pathology, Histology, Extrarenal sx of ARPKD

Answer 8

Pathology: relatively small cysts throughout renal parenchyma (less growth), cysts are longitudinal and perpendicular to cortical surface, less kidney enlargement than ADPKD
Histology: longitudinal cysts
Extrarenal: Liver involvement and dysfunction, biliary dysgenesis + congenital hepatic fibrosis - causes portal HTN - leads to cirrhosis and risk for cholangitis

Question 9

Medullary Cystic Kidney Disease

Histology, Pathology, Genetics, Presentation

Answer 9

Histology: Tubular + Interstitial Fibrosis
Assoc with minimal abnormalities in urine
50% have cysts - small in corticomedullary junction (kidney size is small to normal)
Genetics 3 genes - MUC1 (mucin 1), UMOD (uromodulin), REN (renin)
Presentation: Hyperuricemia and gout, progressive CKD with ESRD early (3-6th decade), no extra renal manifestations)

Question 10

Medullary Sponge Kidney

Answer 10

small cysts in medulla that spare the cortex (seen on imaging), renal function remains normal, associated with nephrocalcinosis and nephrolithiasis (only at risk for kidney stones)