Genetics: Renal Disease Flashcards
Use of which drugs during pregnancy may contribute to the development of congenital renal abnormalities?
In utero exposure to ACE inhibitors or angiotensin II receptor blockers → juxtaglomerular hyperplasia, absent proximal convoluted tubules, or renal fibrosis
What is a horseshoe kidney?
How does this abnormality develop?
- Fusion of the left and right inferior renal pole
- Normal ascent interrupted as fused kidney gets caught on inferior mesenteric artery
Horseshoe kidney
- is the cause genetic?
- does it require treatment?
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
What happens to the kidney in cystic dysplastic syndrome?
- malformation of the kidney during development
- formation of the cysts varying in size
What side usually multicystic dysplastic syndrome is and what is it associated with?
- 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
What happens to the other kidney in cystic disease, if it is unilateral?
The contralateral kidney often undergoes hypertrophy -> compensatory mechanism
When is multicystic dysplastic kidney disease usually diagnosed?
- before birth on USS (about 28 weeks old)
Treatment approach in multicystic dysplastic kidney disease
- 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
Genetics in polycystic ARPKD
- 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
What’s the most common cause of inherited kidney disease?
Autosomal dominant polycystic kidney disease (ADPKD)
What is the genetic in Autosomal dominant polycystic kidney disease (ADPKD)?
PKD1 and PKD2, which code for polycystin-1 and polycystin-2 respectively
Type 1 (85%) -> chromosome 16
Type 2 (15%) -> chromosome 4
What are USS diagnostic criteria for relatives of a person with PKD?
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
What drug may be used in selected patients of PKD?
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
Features of PKD
Features:
- hypertension
- recurrent UTIs
- abdominal pain
- renal stones
- haematuria
- chronic kidney disease
Extra-renal manifestations of PKD
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
What is the cause of Potter’s sequence?
- 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
The appearance of Potter’s sequence
- flattened facies
- pulmonary hypoplasia
- micrognathia +/- cleft palate
- abnormalities of extremities
Why there may be lung hypoplasia in oligohydramnios?
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
What is coloboma?
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
Signs of Charge Syndrome
- 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”.
Cause of Charge syndrome - genetics behind it
- 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
What abnormalities are involved in branchio-oto-renal syndrome?
- 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
Genetics behind branchio-oto-renalsyndrome
- 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 #
Fanconi syndrome
- what is this
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)
What Fanconi syndrome can result in? (abnormalities)
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)
What is one of the inherited causes of Fanconi syndrome?
- cystinosis (most common cause) -> lysosomal storage disease -> abnormal accumulation of cystine and amino acid -> intracellular crystal formation
*it has AR inheritance pattern
Potential causes of Fanconi syndrome
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
Main treatment focus/ aim in children with Fanconi syndrome
Replacement of substances lost in the urine (mainly fluid and bicarbonate).
Fanconi anaemia
what happens and what complications does it lead to?
Response to DNA damage is impaired -> increased risk of cancer development *
majority of cancers:=acute myelogenous leukemia
(bone marrow failure often develops)
genetics of Fanconi anaemia
- autosomal recessive or X linked
- FANC gene
What are the features of Fanconi anaemia?
Features
- aplastic anaemia
- increased risk of acute myeloid leukaemia
- neurological
- skeletal abnormalities: short stature
- cafe au lait spots
What types of metabolic disturbance happens in Renal Tubular Acidosis?
All three types of renal tubular acidosis (RTA) are associated with hyperchloraemic metabolic acidosis (normal anion gap)
Type 1 Renal Tubular Acidosis
- what ion, location
- complications
- causes
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
Type 2 Renal Tubular Acidosis
- what ion and location
- complications
- causes
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)
Type 4 renal tubular acidosis
- what happens (pathophysiology)
- complications
- causes
Type 4 RTA (hyperkalaemic)
- reduction in aldosterone leads in turn to a reduction in proximal tubular ammonium excretion
- causes hyperkalaemia
- causes include hypoaldosteronism, diabetes
What does the X ray show? what disease is associated with it?
Nephrocalcinosis = classical finding associated with Renal Tubular Acidosis type 1
(5) features associated with metabolic syndrome
What are the risks for people with metabolic syndrome?
- cardiovascular disease
- type 2 diabetes
Management of metabolic syndrome
Lifestyle: low carbs/calorie diet, exercise
Treat each of the components: high blood pressure, diabetes, high cholesterol
What’s Wolfram’s syndrome?
Association of cranial Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy
and Deafness
Pathophysiology (simple) of X -linked Nephrogenic Diabetes Insipidus
- 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
