Genetic Diseases Affecting the Kidneys

Question 1

Is congenital cystic disease more common in childhood or adulthood?

Answer 1

Rarely presents in childhood

Commonly presents in adulthood

Question 2

What is a cyst?

Answer 2

Sac like structure containing fluid

In the kidneys these arise from the tubules

Question 3

What are the complications of a cyst?

Answer 3

Compression of other structures 
Replacing useful tissue 
Becoming infected
Bleeding 
Pain

Question 4

Describe the genetics of adult polycystic kidney disease.

Answer 4

Most common inherited kidney disorder
5-10% of patients with end stage renal failure
Autosomal dominant
Either PKD 1 (chr 16) or PKD 2 (chr 4) gene mutation
25% have no known family history

Question 5

Which gene mutation most commonly causes APKD?

Answer 5

PKD1 - 85%

PKD2 - 15%

Question 6

How do PKD1 and 2 gene mutations cause APKD?

Answer 6

The genes code for polycystin 1 and 2

• these are located in the renal tubular epithelia (and liver and pancreas ducts)
• overexpressed in cyst cells
• membrane proteins involved in intracellular calcium regulation

Question 7

What is the natural history of APKD?

Answer 7

Cysts gradually enlarge
Kidney volume increases
Some compensation
eGFR falls (10yrs before kidneys fail)

Question 8

How can you diagnose APKD on ultrasound?

Answer 8

Differentiate between simple renal cysts (common in the general population)
Family history
- age 15-30 - 2 unilateral or bilateral cysts
- age 30-59 - 2 cysts in each kidney
- over 60 - 4 cysts in each kidney
No family history
- 10 or more cysts in both kidneys, renal enlargement and liver cysts

Question 9

When should someone be given an US for APKD?

Answer 9

Symptoms
Family history
- scanned at 21
- again at 30 if negative

Question 10

What are the clinical consequences of APKD?

Answer 10

Renal complications
- ESRD by 55 (PKD1) or 74 (PKD2)
Hypertension
Intracranial aneurysms
- berry aneurysm common
Mitral valve prolapse
Aortic incompetence 
Colonic diverticular disease
Liver/pancreas cysts
Hernia

Question 11

How is APKD managed?

Answer 11

Supportive (no cure)
Early detection and management of blood pressure (delays progression)
Treat complications
Manage extra-renal associations 
Renal replacement therapy 
- e.g. dialysis

Question 12

What is Tolvaptan treatment?

Answer 12

Vasopressin V2 receptor antagonist

Helps reduce speed of progression to ESRF

Question 13

What are the implications of Tolvaptan treatment?

Answer 13

Delays onset of renal replacement therapy by 4-5 years 
Heavy monitoring 
Side effects
- hepatotoxicity
- hypernatraemia 
- dehydration 
Very expensive (lifelong drug)

Question 14

What is Von Hippel Lindau?

Answer 14

Autosomal dominant condition cause multiple benign and malignant neoplasms (not just in the kidneys)

Question 15

What neoplasms can Von Hippel Lindau form?

Answer 15

Can cause renal cysts and multifocal renal cell carcinomas

Can also cause phaechromocytoma, haemangioblastoma, clear cell carcinoma of the CNS

Question 16

What is tuberous sclerosis?

Answer 16

An autosomal dominant genetic condition
Causes benign hamartomas of multiple systems
- brain
- eyes
- heart
- lung
- liver 
- kidney (prone to bleeding)
- skin

Question 17

What are the main complications of tuberous sclerosis?

Answer 17

Multiple renal cysts
Renal angiomyolipomas - high risk of bleeding 
Renal cell carcinoma
Epilepsy 
Learning difficulties

Question 18

What is medullary cystic kidney disease?

Answer 18

Autosomal dominant

Cyst formation at the cortico-medullary junction (cortex mostly)

Question 19

What are the complications of medullary cystic disease?

Answer 19

Small to normal sized kidneys
Hyperuriecaemia
Gout

Question 20

What is Alport’s syndrome?

Answer 20

X-linked, so normally affects men (but women can be a carrier)
Second most common inherited disease
Collagen 4 abnormalities
- due to alpha 3, 4 or 5 gene mutations

Question 21

What are the complications of Alport’s syndrome?

Answer 21

Deafness and renal failure
- affects basement membranes such as cochlear and kidney GBM
- split, thin and laminated GBM
Can also affect the eyes

Question 22

What are the clinical consequences of Alport’s syndrome?

Answer 22

Microscopic haematuria, proteinuria and ESRF
- 90% on dialysis by 40 years
Sensorineural hearing loss in late childhood
Carriers
- 12% ESRF by 40years

Question 23

What is Fabry’s disease?

Answer 23

X-linked storage disorder
Alpha galactosidase A deficiency resulting in accumulation of globotriaosylceramide (Gb3)
- Gb3 accumulates in glomeruli, particularly podocytes

Question 24

What are the complications associated with Fabry’s disease?

Answer 24

Proteinuria 
ESRF (34 years average)
Neuropathy (fingers and feet)
Cardiac and skin features
- angiokeratoma

Question 25

How is Fabry’s disease diagnosed?

Answer 25

Measurement of alpha-gal A activity in leukocytes

Renal biopsy - inclusion bodies of G3b

Question 26

How is Favry’s disease managed?

Answer 26

Enzyme replacement therapy

- early diagnosis needed