Genetics: Renal Disease

Question 1

Use of which drugs during pregnancy may contribute to the development of congenital renal abnormalities?

Answer 1

In utero exposure to ACE inhibitors or angiotensin II receptor blockers → juxtaglomerular hyperplasia, absent proximal convoluted tubules, or renal fibrosis

Question 2

What is a horseshoe kidney?

How does this abnormality develop?

Answer 2

• Fusion of the left and right inferior renal pole
• Normal ascent interrupted as fused kidney gets caught on inferior mesenteric artery

Question 3

Horseshoe kidney

• is the cause genetic?
• does it require treatment?

Answer 3

Horseshoe kidney

• the cause is usually not genetic
• Usually asymptomatic; urinary tract obstruction may occur
• Rarely requires treatment

*just need to be aware of it in terms of intrabdominal surgery (vascular supply), renal stone treatment

Question 4

What happens to the kidney in cystic dysplastic syndrome?

Answer 4

• malformation of the kidney during development
• formation of the cysts varying in size

Question 5

What side usually multicystic dysplastic syndrome is and what is it associated with?

Answer 5

• bilateral in many cases
• those with bilateral disease often have other severe deformities or polysystemic malformation syndromes
• the newborn (if bilateral) has the classic characteristic of Potter’s syndrome

Question 6

What happens to the other kidney in cystic disease, if it is unilateral?

Answer 6

The contralateral kidney often undergoes hypertrophy -> compensatory mechanism

Question 7

When is multicystic dysplastic kidney disease usually diagnosed?

Answer 7

• before birth on USS (about 28 weeks old)

Question 8

Treatment approach in multicystic dysplastic kidney disease

Answer 8

• Patient is observed periodically for the first few years with ultrasounds -> to ensure the healthy kidney is functioning properly and that the unhealthy kidney is not causing adverse effects

Question 9

Genetics in polycystic ARPKD

Answer 9

• Autosomal recessive
• a defect in a gene located on chromosome 6 which encodes fibrocystin, a protein important for normal renal tubule development

*renal failure will typically develop in childhood

Question 10

What’s the most common cause of inherited kidney disease?

Answer 10

Autosomal dominant polycystic kidney disease (ADPKD)

Question 11

What is the genetic in Autosomal dominant polycystic kidney disease (ADPKD)?

Answer 11

PKD1 and PKD2, which code for polycystin-1 and polycystin-2 respectively

Type 1 (85%) -> chromosome 16

Type 2 (15%) -> chromosome 4

Question 12

What are USS diagnostic criteria for relatives of a person with PKD?

Answer 12

The screening investigation for relatives is abdominal ultrasound:

Ultrasound diagnostic criteria (in patients with positive family history)

• two cysts, unilateral or bilateral, if aged < 30 years
• two cysts in both kidneys if aged 30-59 years
• four cysts in both kidneys if aged > 60 years

Question 13

What drug may be used in selected patients of PKD?

Answer 13

Tolvaptan - vasopressin receptor antagonist -> to slow the progression of renal enlargement

In adults, to slow the progression of cyst development and renal insufficiency only if:

• they have chronic kidney disease stage 2 or 3 at the start of treatment
• there is evidence of rapidly progressing disease and
• the company provides it with the discount agreed in the patient access scheme

Question 14

Features of PKD

Answer 14

Features:

• hypertension
• recurrent UTIs
• abdominal pain
• renal stones
• haematuria
• chronic kidney disease

Question 15

Extra-renal manifestations of PKD

Answer 15

Extra-renal manifestations

• liver cysts (70%)
• berry aneurysms (8%)
• cardiovascular system: mitral valve prolapse, mitral/tricuspid incompetence, aortic root dilation, aortic dissection
• cysts in other organs: pancreas, spleen; very rarely: thyroid, oesophagus, ovary

Question 16

What is the cause of Potter’s sequence?

Answer 16

• Oligohydramnios in uterus -> Potter’s sequence
• Causes of oligohydramnios: anything that causes oliguria or anuria e.g. bilateral renal agenesis, atresia of the ureter

The fetal urine serves to cushion the fetus from being compressed by the mother’s uterus as it grows

Question 17

The appearance of Potter’s sequence

Answer 17

• flattened facies
• pulmonary hypoplasia
• micrognathia +/- cleft palate
• abnormalities of extremities

Question 18

Why there may be lung hypoplasia in oligohydramnios?

Answer 18

The fetal urine is critical to the proper development of the lungs by:

• aiding in the expansion of the airways - alveoli, by means of hydrodynamic pressure a
• supplying proline which is a critical amino acid for lung development

Question 19

What is coloboma?

Answer 19

It is a hole in one of the structures of the eye

• present before birth

*it usually presents during foetal development, but in coloboma it fails to close up

Question 20

Signs of Charge Syndrome

Answer 20

• C – Coloboma of the eye, central nervous system anomalies
• H – Heart defects
• A – Atresia of the choanae (posterior nasal structures)
• R – Retardation of growth and/or development
• G – Genital and/or urinary defects (hypogonadism, undescended testicles, besides hypospadias)
• E – Ear anomalies and/or deafness and abnormally bowl-shaped and concave ears, known as “lop ears”.

Question 21

Cause of Charge syndrome - genetics behind it

Answer 21

• mutations on the CHD7 gene (located on Chromosome 8)
• CHD7 is a member of the chromodomain helicase DNA-binding (CHD) -> protein family that plays a role in transcription regulation by chromatin remodelling

Question 22

What abnormalities are involved in branchio-oto-renal syndrome?

Answer 22

• abnormalities of the structure: kidney, ears and neck
• underdeveloped (hypoplastic) or absent kidneys with resultant renal insufficiency or renal failure
• Ear anomalies: include extra openings in front of the ears, extra pieces of skin in front of the ears (preauricular tags), or further malformation or absence of the outer ear (pinna)

* malformation or absence of the middle ear is also possible, individuals can have mild to profound hearing loss

• cysts or fistulae along the sides of their neck

Question 23

Genetics behind branchio-oto-renalsyndrome

Answer 23

• Autosomal dominant
• mutations in gene EYA1 *

*functioning EYA1 is involved in normal development of the organs and tissues/ therefore if mutated, fomation of the organs is #

Question 24

Fanconi syndrome

• what is this

Answer 24

Fanconi syndrome - generalised disorder of renal tubular transport in the proximal convoluted tubule resulting

• different molecules of metabolism being passed into the urine instead of being reabsorbed from the tubular fluid (for example, glucose, amino acids, uric acid, phosphate, and bicarbonate)

Question 25

What Fanconi syndrome can result in? (abnormalities)

Answer 25

Due to # transport in PCT in the kidney -> therefore some metabolic molecules would not be absorbed back into the body

• type 2 (proximal) renal tubular acidosis -> due to loss of bicarbonate
• polyuria
• aminoaciduria
• glycosuria
• phosphaturia
• osteomalacia -> due to loss of phosphate (other bone diseases e.g. Ricket’s may occur too)

Question 26

What is one of the inherited causes of Fanconi syndrome?

Answer 26

• cystinosis (most common cause) -> lysosomal storage disease -> abnormal accumulation of cystine and amino acid -> intracellular crystal formation

*it has AR inheritance pattern

Question 27

Potential causes of Fanconi syndrome

Answer 27

Fanconi syndrome (transport of molecules in PCT is #)

Causes

• cystinosis (most common cause in children)
• Sjogren’s syndrome
• multiple myeloma
• nephrotic syndrome
• Wilson’s disease

Question 28

Main treatment focus/ aim in children with Fanconi syndrome

Answer 28

Replacement of substances lost in the urine (mainly fluid and bicarbonate).

Question 29

Fanconi anaemia

what happens and what complications does it lead to?

Answer 29

Response to DNA damage is impaired -> increased risk of cancer development *

majority of cancers:=acute myelogenous leukemia

(bone marrow failure often develops)

Question 30

genetics of Fanconi anaemia

Answer 30

• autosomal recessive or X linked
• FANC gene

Question 31

What are the features of Fanconi anaemia?

Answer 31

Features

• aplastic anaemia
• increased risk of acute myeloid leukaemia
• neurological
• skeletal abnormalities: short stature
• cafe au lait spots

Question 32

What types of metabolic disturbance happens in Renal Tubular Acidosis?

Answer 32

All three types of renal tubular acidosis (RTA) are associated with hyperchloraemic metabolic acidosis (normal anion gap)

Question 33

Type 1 Renal Tubular Acidosis

• what ion, location
• complications
• causes

Answer 33

Type 1 RTA (distal)

• inability to generate acid urine (secrete H+) in distal tubule
• causes hypokalaemia
• complications include nephrocalcinosis and renal stones

causes include idiopathic, rheumatoid arthritis, SLE, Sjogren’s, amphotericin B toxicity, analgesic nephropathy

Question 34

Type 2 Renal Tubular Acidosis

• what ion and location
• complications
• causes

Answer 34

Type 2 RTA (proximal)

• decreased HCO3- reabsorption in proximal tubule
• causes hypokalaemia
• complications include osteomalacia
• causes include idiopathic, as part of Fanconi syndrome, Wilson’s disease, cystinosis, outdated tetracyclines, carbonic anhydrase inhibitors (acetazolamide, topiramate)

Question 35

Type 4 renal tubular acidosis

• what happens (pathophysiology)
• complications
• causes

Answer 35

Type 4 RTA (hyperkalaemic)

• reduction in aldosterone leads in turn to a reduction in proximal tubular ammonium excretion
• causes hyperkalaemia
• causes include hypoaldosteronism, diabetes

Question 36

What does the X ray show? what disease is associated with it?

Answer 36

Nephrocalcinosis = classical finding associated with Renal Tubular Acidosis type 1

Question 37

(5) features associated with metabolic syndrome

Answer 37

• central obesity
• high blood pressure
• high blood sugar
• high serum triglycerides
• low serum high-density lipoprotein (HDL)

Question 38

What are the risks for people with metabolic syndrome?

Answer 38

• cardiovascular disease
• type 2 diabetes

Question 39

Management of metabolic syndrome

Answer 39

Lifestyle: low carbs/calorie diet, exercise

Treat each of the components: high blood pressure, diabetes, high cholesterol

Question 40

What’s Wolfram’s syndrome?

Answer 40

Association of cranial Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy

and Deafness

Question 41

Pathophysiology (simple) of X -linked Nephrogenic Diabetes Insipidus

Answer 41

• failure to concentrate urine
• 90% due to mutations in vasopression V2 receptor (AVPR2)

*remaining 10% of NDI due to mutations in aquaporin-2 water channel (AQP2)

• X-linked → affected males, carrier females