Hereditary Glomerulopathy and Cystic Disease

Hereditary Conditions:

Alport’s Syndrome

Thin Basement Membrane Disease

Congenital Nephrotic Syndrome (Finnish & French types)

Storage Diseases

• Fabry’s Disease
• Familial Lecithin-Cholesterol-Acyltransferase (LCAT) Deficiency

Nail-Patella Syndrome

Cystinosis

Alport’s Syndrome

Genetics:

• Sex-linked à most common occurring in 80 – 85% of cases
  • Usually a defect in the a5 isomer (gene – Xq22/Col4A5/a5)
  • In about 1 – 2% there can be a defect in the a6 isomer (gene – Xq22/Col4A6/a6)
  • The disease is heterogeneous from a genetic standpoint
• Autosomal Recessive à occurs in 10% of cases
• Autosomal Dominant à very few cases
• Occurs more commonly in males rather than females

Clinical Features:

• Starts somewhere in the 1^st or 2^nd year of life although its not noticed

• Progressive glomerulonephritis à complete renal failure around 20 to 30 years of age – will need a kidney transplant
• Hearing defect à not seen at birth but progresses with age
  • Usually have high tone loss (~30 db) à most marked in 1000 – 8000 Hz frequency range
  • Bilateral defect but the amount of loss can be different in both ears
• Ocular abnormalities
  • Anterior lenticonus à lens is angular instead of concave & there’s a problem with refraction
  • Retinal dots & flecks and corneal erosions
• Platelet abnormalities à tend to be very large but there’s no bleeding or coagulation defects
• Leiomyomatosis
• Kidneys à glomeruli are asymmetrical, have 3 – 4 lobules of capillaries (normally you should have 6 – 8), & have an abnormal mesangial response
  • Can present as acute nephritic syndrome (more common) or nephritic syndrome (bad prognosis)

Diagnostic Feature:

• In electron microscopy in young children the basement membrane is thin & diffuse à thickness is ~ 260 (normal is ~ 300) – this feature is also seen in another disease so it’s not as diagnostic for this syndrome
• As the patient ages (7 – 12 years old) the basement membrane becomes thick & laminated à very diagnostic for this syndrome

Thin Basement Membrane Disease (Benign Familial Hematuria)

Most common cause of asymptomatic hematuria in the US (~ 1% of the population) à there’s normal renal function

·         Hematuria worsens after exercise or infection

·         Proteinuria is less common (children < adults)

·         No extrarenal manifestations

·         Occurs more commonly in females rather than males

·         Basement membrane is < 300 Å thick

Autosomal dominant inheritance à genetically heterogeneous (genes – Col4A3 & Col4A4 mutation)

More common than Alport’s Syndrome and you can’t make a diagnosis of Alport’s just by seeing a thin basement membrane

Immunofluorescence à can see the absence of a3 in the basement membrane by using an anti-a3 antibody

Fabry’s Disease

Also called Angiokeratoma Corporis Diffusum à very small capillaries in the dermis become degraded – patient looks like they have diffuse purpura over their body

Rare familial phospholipid storage disease à it’s a sex-linked recessive disease

Deficiency of a-galactosidase A à causes there to be accumulation & storage of glycosphingolipids in all areas of the body (heart, kidney, skin, GI tract, lungs, etc)

Starts from childhood à will go see a doctor around 14 – 15 years old when they become symptomatic

• Complete renal failure around 30 – 40 years old

Death usually results from chronic renal failure or CHF

Diagnostic Feature à myelin figures (aka zebra bodies)

Familial LCAT Deficiency

Genetics à autosomal recessive disease but is uncommon

There’s a defect in the esterification of cholesterol leading to increased cholesterol levels

Patients will present in their 40s- 50s

Clinical manifestations:

• Hyperlipidemia
• Accelerated atherosclerosis
• Lipid deposition (foam cells) in tissues
• Proteinuria à nephritic syndrome à renal failure
• Corneal opacities (lipoid arcus, grayish spots)
• Hemolytic anemia
• HTN

Cystic Renal Diseases

Autosomal dominant polycystic disease (most common)

Autosomal recessive polycystic disease

Medullary cystic diseases

• Medullary sponge kidney
• Uremic medullary cystic disease (nephronophthisis-UMCD complex)

Cystic renal dysplasia

Acquired cystic disease

Genetics of Polycystic Renal Diseases

Autosomal dominant disease

·         PKD1 gene (also called polycystine gene) à most common mutation (85% of cases) – located on chromosome 16p13.3

·         PKD2 gene mutation (12% of cases) – located on chromosome 4q13-23

·         PKD3 gene mutation (, 1% of cases) – don’t know what chromosome it’s located on

Autosomal recessive disease

• PKHD1 gene à mutation occurs here in 99% of cases – located on chromosome 6p12

Autosomal Dominant Polycystic Disease

Almost always bilateral but may be unilateral

Generally asymmetrical – one kidney may be less cystic than the other

Cysts start from birth but they’re not noticed because they are so small

·         They are point mutations within different parts of the nephron & as the defects cause obstruction to the tubules they then dilate – patients can go 40 – 50 years before this manifests & they will live for a long time without symptoms

Patients will experience hematuria, infection, HTN, defects in small blood vessels, & renal failure

Associates lesions à liver cysts (60% of cases), congenital intracranial aneurysms (15%), aortic aneurysm/aortic dissection, cardiac valve abnormalities especially the mitral valve (20 – 30%), cysts in various other organs (pancreas, spleen, arachnoid, seminal vesicles), colonic diverticuosis, & inguinal hernia

·         The whole liver becomes filled with cysts & you can develop portal HTN & eventual end stage liver disease

Autosomal Recessive Polycystic Disease

Each neprhon has the same problem & is completely defective à the kidney looks like a sponge – see dilated tubules from top to bottom

·         Can’t make out the cortex from the medulla due to the dilated tubules

Develop congenital hepatic “fibrosis” (biliary ductular dysgenesis) à there’s a problem with the development of the bile ducts

·         There’s disjunction between communication of the bile ducts

·         Ducts become large, irregular, & intertwined with one another

·         Can develop portal HTN, which may lead to death

Does not present itself clinically during childhood or younger age

Medullary Cystic Disease

Medullary Sponge Kidney à benign type of disease

·         Some people may develop infection, hematuria, or hemorrhage which then needs surgical intervention

Nephronopthisis-UMCD complex à serious disease

·         Corticomedullary cysts AND progressive cortical tubulointerstitial fibrosis

o        Genetically determined & is a vital component of the disease

o        Most common cause of tubulointerstitial nephritis in children

·         Large cysts are visible in the parenchyma & the cortex is completely fibrotic

Cystic Dysplasia

The cystic transformation is due to some kind of congenital defect in the lower urinary tract.

The obstruction causes the kidneys to undergo fribronecrosis, and eventually cystic transformation

Progression of Inflammatory Glomerular Disease

Kidney disease is not cured it’s managed

·         Post-strep GN & minimal change kidney disease may recover/resolve spontaneously

·         Usually it will progress: acute GN à subacute/chronic GN à ESRD

o        Rapidly progressive GN will most likely develop into ESRD

Progression of renal disease:

·         Persistent/recurrent primary disease

·         Glomerular hemodynamic adaptations à increased capillary pressure/GFR

·         Systemic HTN

·         High protein diet & hyperlipidemia

·         Platelet/coagulation factors

·         Cytokines à TGF, PDGF, FGF

·         Interstitial disease

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