Autosomal Dominant Polycystic Kidney Disease

Question 1

Autosomal dominant polycystic kidney disease is a common genetic disorder characterised by multiple …

Answer 1

Autosomal dominant polycystic kidney disease is a common genetic disorder characterised by multiple renal cysts.

Question 2

Autosomal dominant polycystic kidney disease (ADPKD) is due to inheritance of the abnormal genes … or … that is thought to occur in around 1 in 1000 live births.

Answer 2

Autosomal dominant polycystic kidney disease (ADPKD) is due to inheritance of the abnormal genes PKD1 or PKD2 that is thought to occur in around 1 in 1000 live births.

Question 3

Autosomal dominant polycystic kidney disease (ADPKD)
The disease is characterised by development of multiple renal cyst and progressive renal impairment, which leads to end-stage renal disease (ESRD) in around …% of patients by 60 years of age. It accounts for up to 10% of patients with ESRD.

Answer 3

The disease is characterised by development of multiple renal cyst and progressive renal impairment, which leads to end-stage renal disease (ESRD) in around 50% of patients by 60 years of age. It accounts for up to 10% of patients with ESRD.

Question 4

ADPKD is generally a condition of adults and rarely presents in childhood. The estimated median age of developing ESRD is in 6th decade for PKD1 and 8th decade for PKD2.

Answer 4

ADPKD is generally a condition of adults and rarely presents in childhood. The estimated median age of developing ESRD is in 6th decade for PKD1 and 8th decade for PKD2.

Question 5

Aetiology - ADPKD

Answer 5

The majority of cases of ADPKD are due to PKD1 or PKD2 mutations.

Question 6

The majority of cases of ADPKD are due to PKD1 or PKD2 mutations.
What is chance of passing on to offspring?

Answer 6

As the name suggests, ADPKD is an autosomal dominant inherited condition due to a mutation within the PKD1 or PKD2 gene. Autosomal dominant means only a single abnormal copy of the gene is needed to express the phenotypes (i.e. the clinical features of the disease). If one parent has the condition, there is a 50% chance of passing it to their offspring.

Question 7

PDK3

Answer 7

The majority of cases of ADPKD are due to PKD1 or PKD2 mutations.

Question 8

Polycystic kidney disease type 1

Answer 8

The gene PKD1 is located on chromosome 16 and encodes the protein polycystin-1. This protein is involved in cell adhesion through protein-protein, cell-cell, and/or cell-matrix interactions thought to be due to regulation of calcium influx.

PKD1 accounts for the majority of cases (74-96%; depending on study) and has a more severe phenotype associated with earlier onset renal impairment.

Question 9

Polycystic kidney disease type 2

Answer 9

The gene PKD2 is located on chromosome 4 and encodes the protein polycystin-2. It is a type of calcium-permeable channel transmembrane proteins, which co-localises with polycystin-1.

PKD2 accounts for approximately 15% of ADPKD and has a less severe phenotype.

Question 10

PKD1 vs PKD2 - which has a more severe phenotype?

Answer 10

PKD1 - also more common

PDK2 is about 15%

Question 11

In ADPKD, all cells contain the inherited genetic mutation in PKD1 or PKD2. However, < …% of nephrons within the kidneys become abnormally cystic. This means that further genetic alterations (e.g. somatic mutation) need to occur within tubular cells of nephrons, which lead to the development of cysts.

Answer 11

In ADPKD, all cells contain the inherited genetic mutation in PKD1 or PKD2. However, < 1% of nephrons within the kidneys become abnormally cystic. This means that further genetic alterations (e.g. somatic mutation) need to occur within tubular cells of nephrons, which lead to the development of cysts.

Question 12

ADKPD pathophysiology overview

Answer 12

In ADPKD, all cells contain the inherited genetic mutation in PKD1 or PKD2. However, < 1% of nephrons within the kidneys become abnormally cystic. This means that further genetic alterations (e.g. somatic mutation) need to occur within tubular cells of nephrons, which lead to the development of cysts.

Early cyst development can occur in any aspect of the nephron, but usually distal regions. There is dilatation and out-pouching of the tubule wall, which leads to the development of cysts with fluid from the glomerular filtration.

Overtime, these cysts separate from the nephron, which leads an isolated sac. Ongoing fluid accumulation is achieved through secretion of fluid into the cysts by transepithelial transport and autonomous growth. There is continued epithelial hyperpalsia, fluid secretion, membrane alterations and fibrosis of the interstitium. Collectively, this leads to massive cystic disease and impaired renal function.

The proteins polycystin-1 and polycystin-2 can be found in a variety of other tissues including hepatic ducts and pancreatic ducts. Therefore, it is unsurprising that ADKPD can present with extra-renal cystic disease affecting the liver and pancreas.

Question 13

Symptoms of ADPKD

Answer 13

ADPKD may be asymptomatic for many years until picked up on screening or abnormal blood tests.

Abdominal, flank or back pain: due to large size or cyst complications (rupture/infection)
Haematuria: typically occurs in association with ruptured cyst
Dysuria and fever: suggestive of urinary tract infection or infected cyst
Renal colic: nephrolithiasis (i.e. stones) more common
Constitutional features of chronic kidney disease: fatigue, weakness, reduced energy
Polyuria, polydipsia, nocturia: excess urine due to poor concentrating ability of kidneys (i.e. not responding to anti-diuretic hormone)

Question 14

Signs of ADPKD

Answer 14

Bilateral flank masses: due to large polycystic kidneys
Hepatomegaly: if polycystic liver disease
Hypertension: seen in most patients by 4th decade of life (even if normal renal function)

Question 15

ADPKD - cyst complications?

Answer 15

Ruptured cyst: common cause of loin pain, usually self-limiting
Haemorrhagic cyst: describes a ruptured cyst with haemorrhage. If occurs into the collecting system can be associated with visible haematuria. Loin pain common as with ruptured cysts. Most self-limiting within 7 days.
Infected cyst: many occur in relation to rupture. Typical features include fever, pain, dysuria.

Question 16

Extra-renal manifestations of ADPKD (6)

Answer 16

Polycystic liver disease: seen in > 80% of patients on MRI imaging. Poor correlation with renal cysts. Women generally affected at younger age and more severely.
Pancreatic cysts: seen in up to 36% of patients.
Cerebral aneurysms: four times higher compared to general population. 8-12% of patients. Rupture most serious complication of ADPKD.
Cardiac valve disease: seen in 25-30%. Most commonly mitral valve prolapse and aortic regurgitation.
Gastrointestinal abnormalities: diverticulosis and hernias (abdominal/inguinal) occur at higher frequency
Seminal vesicle cysts and infertility: vesicle cysts in up to 40% of males. Rarely causes infertility. ADPKD also associated with poor sperm motility.

Question 17

Cardiac valve disease in ADPKD

Answer 17

Cardiac valve disease: seen in 25-30%. Most commonly mitral valve prolapse and aortic regurgitation.

Question 18

Gastrointestinal abnormalities in ADPKD

Answer 18

Gastrointestinal abnormalities: diverticulosis and hernias (abdominal/inguinal) occur at higher frequency

Question 19

Seminal vesicle cysts and infertility in ADPKD

Answer 19

Seminal vesicle cysts and infertility: vesicle cysts in up to 40% of males. Rarely causes infertility. ADPKD also associated with poor sperm motility

Question 20

Cerebral aneurysms - ADPKD

Answer 20

four times higher compared to general population. 8-12% of patients. Rupture most serious complication of ADPKD.

Question 21

Polycystic liver disease + ADPKD : seen in > …% of patients on MRI imaging. Poor correlation with renal cysts. Women generally affected at younger age and more severely.

Answer 21

Polycystic liver disease + ADPKD : seen in > 80% of patients on MRI imaging. Poor correlation with renal cysts. Women generally affected at younger age and more severely.

Question 22

The diagnosis of ADPKD is primarily made on …

Answer 22

The diagnosis of ADPKD is primarily made on imaging with identification of multiple bilateral renal cysts. The principle imaging modality is ultrasound, but MRI and CT have an increasing role. Most newer ultrasound machines can detect cysts down to 0.5cm.

Question 23

The principle imaging modality for ADPKD?

Answer 23

The principle imaging modality is ultrasound, but MRI and CT have an increasing role. Most newer ultrasound machines can detect cysts down to 0.5cm

Question 24

A definitive diagnosis of ADPKD?

Answer 24

A definitive diagnosis can be made with genetic testing, but this is usually reserved for atypical cases (e.g. early severe disease, no family history) and up to 8% will not have an identified mutation (current genetic testing not sensitive to detect all mutation types).

Question 25

Screening - ADPKD

Answer 25

Patients with a family history of ADPKD should be identified and offered screening. This involves investigating asymptomatic patients.

Ultrasound is main investigation used in screening. If ultrasound is equivocal, MRI can be used. Screening usually begins in adulthood.

Question 26

Ultrasonographic diagnostic criteria

If positive family history

< 30 years: ≥… cysts (unilateral or bilateral)
30-39 years: ≥…. cysts (unilateral or bilateral)
40-59 years: ≥… cysts in each kidney

Answer 26

If positive family history

< 30 years: ≥3 cysts (unilateral or bilateral)
30-39 years: ≥3 cysts (unilateral or bilateral)
40-59 years: ≥2 cysts in each kidney

Question 27

If no family history is present, there is no established imaging based criteria. Generally, a diagnosis can be made in the presence of multiple bilateral renal cysts (e.g. ≥10 and ≥5mm in size) or bilateral renal enlargement with cysts. Diagnosis in this context is supported by presence of hepatic cysts. (ADPKD)

Answer 27

If no family history is present, there is no established imaging based criteria. Generally, a diagnosis can be made in the presence of multiple bilateral renal cysts (e.g. ≥10 and ≥5mm in size) or bilateral renal enlargement with cysts. Diagnosis in this context is supported by presence of hepatic cysts.

Question 28

Differential diagnosis

Several conditions may lead to cystic kidneys, which need to be excluded as part of the work-up.

Answer 28

Multiple benign cysts: cysts more common as we age
Localised cystic benign: unilateral disease
Acquired renal cystic disease: may be seen in patients with CKD on dialysis
Medullary sponge kidney: congenital disorder of collecting ducts and calyceal system
Other genetic conditions: e.g. autosomal recessive polycystic kidney disease, tuberous sclerosis, others

Question 29

Bedside ADPKD tests

Answer 29

Bedside

Protein:creatinine ratio (ACR)
Urinalysis and MC&S: infection or haemorrhage

Question 30

Bloods in ADPKD

Answer 30

Bloods

Full blood count: anaemia if CKD or haemorrhagic cysts
Urea & electrolytes: assessment of renal function
Liver function tests: any hepatic impairment from cysts
Bone profile: calcium/phosphate handling in CKD
CRP: infected cysts

Question 31

Imaging in suspected ADPKD

Answer 31

Ultrasound: principle investigations, especially in screening
CT KUB: if presenting with suspected renal stone
Renal MRI/CT: high sensitivity and good for assessing progression (e.g. kidney size). Useful if concern regarding renal cell carcinoma (RCC)
Cerebral imaging (e.g. MRA): screening for cerebral aneurysms

Question 32

The core aspect of ADPKD management is good …

Answer 32

The core aspect of ADPKD management is good blood pressure control and disease monitoring. Acute complications may develop that need management and as the disease progresses patients need input for CKD +/- transplant consideration.

Question 33

Blood pressure treatment in ADPKD

Answer 33

General treatment: blood pressure control essential (<130/80 mmHg). Slows disease progression. ACE inhibitors most effective. Regular follow-up including renal function assessment and ultrasound to look for progression. Maintain adequate hydration (3+ litres/day) unless significant CKD and dietary sodium restriction.

Question 34

Treatment for high-risk patients (ADPKD)

Answer 34

Treatment for high-risk patients: vasopressin (V2) receptor antagonists may be used in patients high-risk of progression. Specialist area with specific indications. At risk of hypernatraemia.

Question 35

Managing complications in ADPKD

Answer 35

Managing complications: treat urinary tract infections and infected cysts. Analgesia for abdominal pain or cyst rupture (avoid NSAIDs). Rarely, cyst decompression and/or nephrectomy may be needed if recurrent infections or pain that significantly impacts on quality of life. Haematuria managed conservatively where possible. If concerns, needs work-up for RCC.

Question 36

ADPKD -
Screening for … aneurysms is generally reserved for patients with a personal or family history of intracerebral haemorrhage, patients who require … (e.g. develop deep vein thrombosis), patients with high-risk occupations or patients needing major surgery (e.g. renal transplant).

Answer 36

ADPKD -
Screening for cerebral aneurysms is generally reserved for patients with a personal or family history of intracerebral haemorrhage, patients who require anticoagulation (e.g. develop deep vein thrombosis), patients with high-risk occupations or patients needing major surgery (e.g. renal transplant).

Question 37

ADPKD -
Screening for cerebral aneurysms is generally reserved for patients with a personal or family history of intracerebral haemorrhage, patients who require anticoagulation (e.g. develop deep vein thrombosis), patients with high-risk occupations or patients needing major surgery (e.g. renal transplant).
what is the principle imaging tool for this?

Answer 37

MR angiography is the principle imaging tool (CT angiography if MRI contraindicated). Patients with small aneurysms may have sequential screening 2-3 yearly and those with no aneurysm 5-yearly.

Question 38

Aneurysm in ADPKD

Answer 38

Indications for intervention on asymptomatic aneurysms is completed on a case-by-case basis, which depends on aneurysm size, aneurysm location, and family history. Most common treatments are endovascular coiling or surgical clipping.

Question 39

All patients with ADPKD should be advised:

Answer 39

Good BP control
Smoking cessation
Reduce alcohol
No elicit drugs
Avoid excessive straining

Question 40

Patients with ADPKD are at risk of progressive …

Answer 40

Patients with ADPKD are at risk of progressive renal impairment.

Question 41

Complications
Patients with ADPKD are at risk of progressive renal impairment.

The spectrum of disease is variable among patients with ADPKD. Major risk factors for progressive disease include

Answer 41

The spectrum of disease is variable among patients with ADPKD. Major risk factors for progressive disease include PKD1 mutation, large kidneys, recurrent visible haematuria, frequency kidney infections, Afro-Caribbean ancestry, hypertension, male gender.

Question 42

Complications of ADPKD

Answer 42

ESRD
Massive cyst haemorrhage
Cerebral haemorrhage (e.g. aneurysm rupture)
Sepsis
Progressive liver disease

Question 43

The gene PKD1, which accounts for polycystic disease type 1, is located on chromosome … and encodes the protein polycystin-1.

Answer 43

The gene PKD1, which accounts for polycystic disease type 1, is located on chromosome 16 and encodes the protein polycystin-1.

Question 44

The presence of ≥… cysts unilaterally or bilaterally is consistent with ADPKD in patients with a positive family history who are 15-39 years of age.

Answer 44

The presence of ≥3 cysts unilaterally or bilaterally is consistent with ADPKD in patients with a positive family history who are 15-39 years of age.

Question 45

An abdominal ultrasound is a quick, non-invasive and inexpensive way of screening for … and should be offered first line.

Answer 45

An abdominal ultrasound is a quick, non-invasive and inexpensive way of screening for ADPKD and should be offered first line.

Question 46

Which of the following extrarenal manifestations is most commonly seen in autosomal dominant polycystic kidney disease (ADPKD)?

	Mitral valve prolapse
B	Berry aneurysm
C	Splenic cysts
D	Hepatic cysts
E	Tricuspid regurgitation

Answer 46

Hepatic cysts may be seen in up to 80% of patients ADPKD on MRI, which makes it one of the most common extrarenal manifestations.

Question 47

Which of the following cardiac manifestations is most commonly associated with autosomal dominant polycystic kidney disease (ADPKD)?

A	Pulmonary regurgitation
B	Mitral valve prolapse
C	Aortic stenosis
D	Tricuspid stenosis
E	Tricuspid regurgitation

Answer 47

Valvular abnormalities may be identified in 25-30% of patients with ADPKD, of which mitral valve prolapse and aortic regurgitation are most common.

Question 48

Question 8.
What is the mechanism of action of Tolvaptan?
A Angiotensin converting enzyme inhibitor
B Mineralcorticoid receptor antagonist
C Vasopressin receptor antagonist
D Calcium receptor antagonist
E Potentiates the action of anti-diuretic hormone

Answer 48

Tolvaptan is a vasopressin receptor antagonist, which has been shown to suppress the progression of ADPKD.
In vitro, vasopressin has been shown to increase intracellular level of cAMP, which drive cyst formation. In addition, elevated levels of vasopressin have been associated with disease severity and progression in some studies.

In the UK, Tolvaptan is recommended as an option for treating ADPKD to slow disease progression if:

• CKD stage 2/3 at start of treatment
• Evidence of rapidly progressive disease, AND
• Patient access scheme available (to do with financial implications of drug)

Question 49

In the UK, Tolvaptan is recommended as an option for treating ADPKD to slow disease progression if:

Answer 49

• CKD stage 2/3 at start of treatment
• Evidence of rapidly progressive disease, AND
• Patient access scheme available (to do with financial implications of drug)

Question 50

Which of the following is the most serious complication of ADKPD?

A	Polycystic liver disease
B	Haemorrhagic cyst
C	Pyelonephritis
D	Ruptured berry aneurysm
E	Seminal vesicle cyst

Answer 50

Berry aneurysms occurs in 8-12% of patients with ADPKD (depending on study), which can rupture and lead to a life-threatening subarachnoid haemorrhage.
A berry aneurysm refers to a vascular malformation of the cerebral circulation. They are the most common type of aneurysm that occurs within the brain and is four times more common in patients with ADPKD. The majority are located in the anterior circulation and rupture can lead to subarachnoid haemorrhage, which may be life-threatening.

Consequently, screening is usually recommended for berry aneurysms in patients with ADPKD who fulfil any of the following criteria:

• Personal or family history of intracerebral haemorrhage
• Patients who require anticoagulation (e.g. develop deep vein thrombosis)
• Patients with high-risk occupations
• Patients needing major surgery (e.g. renal transplant).

Question 51

A 45 year old man is admitted to accident emergency with severe flank pain. The pain came on suddenly this morning and feel like a constant dull ache on the left side. He also noticed visible blood in his urine. He denies any fevers or rigors and has otherwise been well over the last few weeks. He was diagnosed with hypertension five years ago and started on ramipril by his GP, but he intermittently takes it. He has no allergies and lives with his husband and adopted son. He works in finance and does not smoke or drink. He notes that his mother died from renal disease in her 50’s but is unsure why. On examination, there is evidence of bilateral ballottable masses in both flanks with tenderness and guarding on the left side. The urine dip at the bedside shows blood (3+) and protein (2+).
Most likely diagnosis?

Answer 51

The history of hypertension, suspected family history of renal disease and bilateral renal masses is highly suggestive of autosomal dominant polycystic kidney disease (ADPKD).