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Renal > Polycystic Kidney Disease > Flashcards

Polycystic Kidney Disease Flashcards

1
Q

What gene is associated with autosomal dominant PCKD?

A

PKD1 (chromosome 16) and PKD2 (chromosome 4) - normally encode for proteins that regulate differentiation and proliferation of renal TUBULAR epithelial cells

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2
Q

What gene is associated with autosomal recessive PCKD?

A

PKHD1

Chromosome 6

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3
Q

Is PKD1 or PKD2 more severe?

A

PKD1 leads to a more severe phenotype
PKD1 and truncating mutations are more severe
PKD1 has larger kidneys and more cysts

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4
Q

Renal manifestations of PCKD

A
  • HTN (can precede diagnosis)
  • Haematuria: indicates cyst rupture
    into the collecting system and is commonly self-limited
    Hemorrhage into a cyst typically presents with pain rather
    than hematuria
  • Proteinuria (less common)
  • Flank pain secondary to kidney stones, cyst rupture, haemorrhage or infection - use quinolones, calculi, UTI
  • Renal failure
  • Chronic pain syndrome due to large kidneys/cysts
  • 50% develop ESKD by age 60
  • Early stage: minimal symptoms and hypertension
  • Late stage: kidney failure + kidney pain
  • Systemic symptoms: e.g. ICAs, liver cysts
  • Diagnosis by family history and renal ultrasound (Pei Ravine criteria)
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5
Q

Extrarenal manifestations

A
  • Hepatic cysts (most common extrarenal manifestation)
  • Other cysts including pancreatic, seminal
  • Cerebral aneurysms
  • Cardiac valve disease - normally MVP or AR due to aortic root dilation
    Cardiomyopathy, aortic dissection/aneurysm
    Colonic/duodenal diverticulae
    Abdominal/inguinal hernia

Risk factors for severe polycystic liver disease

  • Female
  • Number of pregnancies
  • Exposure to HRT
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6
Q

Common artery associated with cerebral aneurysm in PCKD

A

MCA

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7
Q

When to screen for cerebral aneurysms in PCKD and how

A

Indications for Screening
- Symptoms or previous history of ruptured aneurysm
- Family hx of ich/aneurysm
- Neurological symptoms
- High risk jobs, eg: airline pilot
- Prior to operations - undergoing major surgery
Can use MRA without gadolinium or CTA

Investigation: Cerebral CT with contrast or MRA

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8
Q

When are hepatic cysts most severe in PCKD

A

Can be most severe post-menopausal

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9
Q

Diagnosis of PCKD

A
  • Family hx +
    >3 cysts total in age 15-39 or >2 cysts in each kidney (40-59) or at least 4 cysts in each kidney age>60
  • No family history - will require >10 cysts in each kidney and bilateral renal enlargement +/- genetic testing
  • Exclusion criteria:
    no cysts on US by age 40 or <5 cysts on MRI (<40)
    Negative MRI at 18 almost always exclude PCKD

Tips:

  1. Up to 10% family history is negative
  2. Diagnosis not excluded if renal ultrasound negative in at-risk <40 years old
  3. No mutation detected in 10% of patients and diagnostic accuracy 60-90%
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10
Q

Indications for genetic testing for PCKD

A
  • Disconcordance between renal imaging and GFR
  • Atypical presentations (e.g. early onset, mild PKD, atypical radiology presentation)
  • Living related transplant donor (e.g. to clarify diagnosis if cysts on imaging)
  • Negative family history (10-15%)
  • Family planning
  • Prognostic information to select pts for Rx and clinical trials
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11
Q

Tuberous sclerosis - what genes increases the risk of early ESRF

A

PKD1 and TSC2

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12
Q

Characteristics of tuberous sclerosis

A

Autosomal dominant
Mutations in TSC1/2 - allows for abnormal proliferation of cells in different tissues
- Renal Manifestations: renal cysts, renal angiomyolipoma (AML) - can use everolimus mTOR inhibitor
Can have renal cysts, other features: AML in kidneys (angiomyolipoma benign kidney tumour), skin angiofibroma, cortical tubers, astrocytomas , seizures, LAM (lymphangioleiomyomatosis), cardiac rhabdomyoma, sclerotic bone lesions

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13
Q

Pharm management of PCKD

A

Tolvaptan
Vasopressin V2 (ADH) receptor antagonist
Earlier Rx is started = more benefit
For every 4 years on the Rx, delay dialysis by ~1 year
Reduce the rate of increase in total kidney size and rate of eGFR decline
Want to keep urine osm < 280, want hypotonic urine

There are no specific therapies for ADPKD. The vasopressin antagonist tolvaptan has been shown to Vasopressin receptor antagonist (tolvaptan) reduce the rate of increase in total kidney size/volume and the rate of glomerular filtration rate loss in early stage ADPKD, likely from blockade of intracellular adenosine monophosphate, which is overproduced in cysts; however, poor tolerance, hepatotoxicity, and expense are barriers to use

  • Patients with hypertension respond well to an ACE inhibitor or angiotensin receptor blocker (ARB).
    Target BP : <130/80 mm Hg (<110/75 if eGFR > 60 ml/min and can tolerate)
  • Treatment of cyst infection and pyelonephritis requires antibiotics capable of penetrating the cysts, which include fluoroquinolones (eg: ciprofloxacin) and trimethoprim- sulfamethoxazole.
  • Treat CVD risk factors
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14
Q

Why do patient die from PCKD

A

Due to cardiac causes - Cardiovascular disease
is the most common cause of death in patients with
ADPKD
50% reach ESKD by age 60 - especially PKD1

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15
Q

What chromosome does PKD1 and PKD2 lie on

A

PKD1 - chromosome 16

PKD2 - chromosome 4

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16
Q

Cardiac manifestations of PCKD

A

• Cardiac valve disease (MVP and AR most common due to aortic root dilation, less freq MR and TR)
• Other cardiac manifestations: cardiomyopathy, LVH, diastolic dysfunction, AF, coronary aneurysms / artery dissection, pericardial effusion ( aSx)
○ Consider beta blockers (in addition to RAAS blocker)
Aortic dissection / aneurysm

17
Q

Characteristics of recessive PCKD

A

PKHD1
more severe disease (30% fatal at birth), usually older children / young adults, congenital hepatic fibrosis and portal HTN

18
Q

In PCKD, where do the cysts normally originate from?

A

most cysts originating in the renal collecting duct

19
Q

The different types of cystic kidney diseases and associated genes.

  • ADPKD
  • ARPKD
  • Tuberous sclerosis
  • Nephronophthisis
A
  • ADPKD: autosomal dominant, PKD1, PKD2
    Most common inherited kidney disorder (5% of ESKD cases);
    intracranial cerebral aneurysm; mitral valve prolapse; hepatic cysts; diverticulosis
  • ARPKD: autosomal recessive, PKHD1
    Pediatric; ESKD; hepatic fibrosis; portal hypertension; homozygous mutations cause complete loss of function: severe cystic kidney disease, oligohydramnios, pulmonary hypoplasia, Potter syndrome; no specific therapies
  • Tuberous sclerosis: autosomal dominant, TSC1 (Ch9), TSC2 (Ch16)
    Characterized by benign hamartomas (kidney, brain, skin, other organs); epilepsy, brain tumors, developmental delay, autism, and lung disease may also occur; renal angiomyolipomas are common; kidney cysts may develop
  • Nephronophthisis: autosomal recessive, multiple (13)
    Most common genetic cause of ESKD in childhood/adolescence; interstitial fibrosis; renal medullary cysts; a renal concentrating defect and/or salt wasting; retinitis pigmentosa; no specific therapies
20
Q

Tuberous Sclerosis

A

Tuberous sclerosis (TS) is a genetic condition of autosomal dominant inheritance. Like neurofibromatosis, the majority of features seen in TS are neurocutaneous.

Cutaneous features
- depigmented ‘ash-leaf’ spots which fluoresce under UV light
- roughened patches of skin over lumbar spine (Shagreen patches)
- adenoma sebaceum (angiofibromas): butterfly distribution over nose
fibromata beneath nails (subungual fibromata)
- café-au-lait spots* may be seen

Neurological features

  • developmental delay
  • epilepsy (infantile spasms or partial)
  • intellectual impairment

Also; hamartomas, renal cysts, renal angiomyolipomas

  • retinal hamartomas: dense white areas on retina (phakomata)
  • rhabdomyomas of the heart
  • gliomatous changes can occur in the brain lesions
  • polycystic kidneys, renal angiomyolipomata
  • lymphangioleiomyomatosis: multiple lung cysts

Renal Angiomyolipomas (AMLs) are seen in 75% of patients with tuberous sclerosis

  • are the most common benign tumour of the kidney.
  • Although regarded as benign, angiomyolipomas may grow such that kidney function is impaired or the blood vessels may dilate and burst, leading to bleeding.

Tuberous sclerosis results from mutations of the TSC1 or TSC2 gene, upregulation of TOR
- Encode for proteins that have a tumour suppressing effect and disruption of these gene products allows for abnormal cell proliferation in different tissues
- Kidney Manifestations: renal angiomyolipoma, renal cyst
-Renal angiomyolipoma occur in 75% of patients
RCC is less common occurring in 1-2% of adults with TSC

Everolimus (mTOR inhibitor) can be used for the management of TSC-associated brain tumours and AMLS
Surgery or embolization may be required for large AMLS or haemorrhage AMLS

21
Q

Alport Syndrome

A
  • Caused by mutation in a3/4/5 (a5 most common) chains of type IV collagen
  • There are three genetic variants: X-linked
    (80%), autosomal recessive (15%), and autosomal dominant
    (5%). Female carriers variably develop kidney disease
  • Characterised by sensorineural hearing loss and lenticonus (conical deformation of the lens).
  • Proteinuria, hypertension, and CKD usually develop over time.
  • ESKD occurs between the late teenage years and the fourth decade of life.
  • Diagnosis is confirmed by kidney biopsy.
  • There are no specific therapies for hereditary nephritis.
  • Antiproteinuric therapy with RAAS inhibitors is a mainstay
    of management.
  • Kidney transplantation is the optimal treatment for ESKD, with no recurrence in the transplanted kidney.
22
Q

Stages of CKD

A 
Stage 1: GFR >90
Stage 2: GFR: 60-89
Stage 3: GFR 30-59
3a: 45-59
3b: 30-44
Stage 4: GFR 15-29
Stage 5: GFR < 15
23
Q

What are the stages of diabetic nephropathy?

A

Stage 1: hyperfiltration (increase in GFR), may be reversible

Stage 2 (silent or latent phase): most patients do not develop microalbuminuria for 10 years, GFR remains elevated

Stage 3: microalbuminuria (albumin excretion 30-300mg/day, dipstick negative)

Stage 4 (overt nephropathy): persistent proteinuria (albumin excretion >300mg/day, dipstick positive), HTN present, histology shows glomerulosclerosis and focal glomerulosclerosis (Kimmelstiel-wilson nodules)

Stage 5: end stage renal disease GFR< 10ml/min

24
Q

Autosomal Recessive Polycystic Kidney Disease

A

PKHD1

  • Incidence: 1:50 000 live births
  • Characteristic feature: childhood disease consisting of cystic kidney with congenital hepatic fibrosis

Manifestations

  • majority present in utero or newborn with kidney enlargement and biliary dysgenesis
  • less common present with late-onset portal hypertension or cholangitis

• Less common AR-inherited cystic kidney diseases

  • Nephronophthisis (NPHP)
  • Bardet-Biedl syndrome (BBS): a rare monogenic hereditary disease characterized by short stature, obesity, retinitis pigmentosa, intellectual disability, and polydactyly
  • Joubert syndrome (JBTS)
  • Meckel-Gruber syndrome (MKS)

Renal (12 decks)

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