Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of polycystic kidney disease with an estimated incidence of approximately 1/400 to 1/1000 individ- uals worldwide. It roughly accounts for 10% of patients with chronic renal failure requiring hemodialysis or transplantation.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant with almost complete penetrance b. Negative family history in 40% of cases
2. Genetically heterogeneous with at least three different genes now known to cause ADPKD. All three types of ADPKD present with an identical profile of extrarenal manifestations (including liver cysts and aneurysms) a. Type I (85–90% of cases): caused by mutations in
PKD1 gene, which is:
i. Mapped on chromosome 16p13.3
ii. The most severe form with a lower median sur- vival and a higher risk of progressing to end- stage renal disease
iii. Closely linked to TSC2, a gene responsible for a major form of tuberous sclerosis
b. Type II (most of the remaining cases): caused by mutations in PKD2 gene, which is:
i. Mapped on chromosome 4q21-q23 ii. Identified by positional cloning
iii. Producing milder disease but otherwise pheno- typically identical with the PKD1 disease c. A small number of familial cases reported to be
unlinked to both the PKD1 and PKD2 loci, suggest- ing the existence of at least one more proposed gene (PKD3) which has not been identified
d. Patients with mutations in both the PKD1 and PKD2 genes (transheterozygotes) have a more severe clini- cal course than those with mutations in only one of the genes
3. Mechanism of cyst formation: somatic second-hit model a. A germline mutation in one PKD allele in all cells in
ADPKD
b. A random somatic mutation (second hit) occurring in the normal allele causing increased cell proliferation, leading to cyst formation
4. Molecular basis of ADPKD
a. Protein products of the disease gene forming a macro- molecular signaling structure, the polycystin complex, that regulates fundamental aspects of renal epithelial development and cell biology
b. Protein products of PKD1 and PKD2 (polycystin-1 and polycystin-2, respectively)
i. Share sequence homology
ii. May form components of a receptor/channel complex
c. Polycstin-1
i. Predicted to have a receptor-like structure ii. May be involved in cell-cell/matrix interactions iii. May have a regulatory role over a polycystin
channel d. Polycystin-2
i. Similar to and functioning as an ion channel subunit
ii. Causes nonselective cation permeability e. Basic defect in ADPKD: could be in polycystin-
regulated intracellular Ca
++levels 5. Disease characteristics
a. Principal ductal organs with cyst formation i. Kidneys
ii. Liver
b. Consequences of cyst enlargement
i. Progressive destruction of normal renal tissue ii. End-stage renal failure in >50% of patients by
age 60
c. Systemic involvement
i. Arterial hypertension developing early and observed in >50% of patients
ii. Vascular aneurysms iii. Cardiac valve defects
iv. Colonic diverticula
CLINICAL FEATURES
1. Intrafamilial and interfamilial variability in the onset, phenotype, and progression of the disease
a. Due to genetic heterogeneity
i. More common PKD1 (accounting for approxi- mately 85% of cases associated with more severe disease)
ii. Evidence of significant intrafamilial phenotypic variation suggesting modifying factors (such as the angiotensin-converting enzyme insertion/dele- tion polymorphism) as well as environmental fac- tors that influence the clinical course
iii. Association of the position of the PKD1 muta- tion with earlier end-stage renal disease
b. Age of onset
i. Presenting at any age
ii. Generally presenting in the 4th and 5th decades of life
iii. Occasionally presenting in the fetal or neonatal period
2. Onset of disease in the childhood in children who carry PKD1 gene
a. Frequency of children with renal cysts detectable by ultrasound
i. 60% by five years of age
ii. 75–80% among children aged 5–18 years
797
b. Number of renal cysts at 11 years i. 1–10 in 60% of children
ii. More than 10 cysts in 40% of children
3. Age at the time of diagnosis and progression of the disease a. Diagnosis in utero or in the first year of life (intrauter-
ine or infantile onset)
i. Manifesting unusually severe disease
ii. End-stage renal disease during childhood in 18%
of cases
b. Diagnosis after the first year of life
i. Increase in the number of cysts over a mean interval of 3.7 years
ii. Systolic hypertension in 9% of cases iii. None with decreased renal function 4. Renal manifestations
a. Development of bilateral renal cysts i. Primary renal manifestation
ii. Leading to functional changes (impaired renal concentrating capacity, hypertension)
iii. Leading to various clinical manifestations b. Flank or back pain (about 60%)
c. Acute pain i. Infected cyst
ii. Ruptured cyst (associated with gross hematuria) iii. Nephrolithiasis (20–36%)
d. Urinary tract infection (40–68%) e. Hematuria
f. Mild proteinuria g. End-stage renal disease 5. Extrarenal manifestations
a. Liver involvement
i. Most common extrarenal manifestation ii. Liver cysts uncommon before 16 years of age iii. Liver cysts observed in about 75% of patients
older than 60 years
iv. No liver symptoms in most patients with ADPKD v. Occasionally encountered liver changes
a) Congenital hepatic fibrosis
b) Segmental dilation of the biliary tract vi. Liver cysts responsible for most of the hepatic
complications vii. Acute complications
a) Cyst infection b) Cyst hemorrhage c) Cyst rupture d) Cyst torsion
viii. Chronic complications related to progressive increase of the polycystic liver
a) Abdominal mass b) Ascites
c) Hepatic venous outflow obstruction (Budd- Chiari syndrome)
d) Portal hypertension with variceal bleeding e) Inferior vena cava compression
f) Bile duct compression g) Jaundice
ix. Intrahepatic biliary cysts a) More common in women b) Exacerbated by pregnancy b. Other rare cystic involvement
i. Pancreatic cysts (10%)
ii. Arachnoid cysts (5%) iii. Ovarian cysts
c. Cardiovascular manifestations not uncommon i. Intracranial berry aneurysms (5–10%) ii. Dolichoectatic arteries
iii. Aortic root dilatation
iv. Dissections of intracerebral, coronary, thoracic, iliac, aortic, and splenic arteries reported v. Cardiac valve defects
d. Other noncystic involvement
i. Colonic diverticula (80% of patients with end- stage renal disease)
ii. Hernias (25%) 6. Clinical course in children
a. Clinical spectrum ranging from severe neonatal man- ifestations mimicking autosomal recessive polycystic kidney disease to renal cysts noted on ultrasound in asymptomatic children
b. Diagnosis made in utero by ultrasound: massively enlarged cystic kidneys
c. Newborn presenting with Potter phenotype and death from pulmonary hypoplasia
d. Newborn with large abdominal masses e. After neonatal period
i. Hypertension ii. Abdominal pain
iii. Palpable abdominal mass iv. Hematuria
v. Renal insufficiency only rarely vi. Renal infections
f. Rare extrarenal manifestations i. Liver cysts
ii. Cerebral vessel aneurysms g. Prognosis
i. Severe symptoms in neonatal or infantile cases ii. Milder symptoms in late childhood cases 7. Risk factors precipitating faster progression of the disease
a. The PKD-1 gene b. Male gender
c. Earlier onset of symptoms i. Renal enlargement ii. Hematuria iii. Proteinuria
iv. Incipient renal failure v. Hypertension
d. Having >10 renal cysts before age 12 years
e. Having blood pressures above the 75th percentile for age, height, and gender
f. Polycystic liver disease
i. Frequently associated with autosomal dominant polycystic kidney disease
ii. Develops later than renal cysts
iii. Develops earlier and more severe in women than in men
DIAGNOSTIC INVESTIGATIONS
1. Urinalysis
a. Hematuria
b. Mild proteinuria
c. Evidence of infection
2. Sonography
a. Prenatal presentation
i. Large hyperechogenic kidneys ii. Variable size
iii. Mixtures of small and large cysts
iv. Exceptionally uncommon oligohydramnios b. Postnatal presentation: invariably large cysts 3. Renal ultrasound and IVP
a. Enlarged kidneys
b. Macrocysts and distortion of the collecting system 4. CT scan and/or MRI for renal, hepatic, pancreatic and
ovarian cysts
5. CT scan and/or MRI angiography for intracranial aneurysm
6. Renal function tests
7. Renal ultrasound to assess carrier status
a. A painless and relatively noninvasive procedure b. Detection rate in asymptomatic subjects from fami-
lies with known ADPKD
i. 22% of cases in the first decade ii. 66% of cases by the second decade iii. 86% by age 25
8. Molecular genetic testing a. Linkage analysis
i. Linkage analysis with microsatellite markers ii. Requires a relatively large number of affected
family members in order to establish which one of the two possible genes is responsible within each family
b. Direct DNA analysis difficult to perform due to:
i. Large size and complexity of PKD1 and PKD2 genes
ii. Marked allelic heterogeneity
c. Mutation screening in the research laboratory i. Mutation detection rates of 50–70% for PKD1 ii. Mutation detection rates of about 75% for PKD2 d. Mutation screening of entire coding region by dena- turing high-performance liquid chromatography recently available clinically
9. Screening for mutations of PKD1 gene: complicated by the genomic structure of the 5 ′-duplicated region encod- ing 75% of the gene
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Not increased in de novo case ii. 50% if one of the parent is affected b. Patient’s offspring
i. 50% risk of acquiring the disease ii. Both sexes of offspring affected equally 2. Carrier testing for family members at risk
a. Ultrasound and radiography
b. Molecular mutation analysis of PKD1 and PKD2 genes
3. Prenatal diagnosis
a. Prenatal ultrasonography
i. Enlarged kidneys with or without cysts ii. Absence of urine in the bladder
iii. May not be evident until the third trimester
b. Molecular mutation analysis of PKD1 and PKD2 genes on fetal DNA obtained from amniocentesis or CVS, provided the mutation has been identified in the affected family members or linkage has been estab- lished in the family
4. Management
a. No treatment currently directed at the disease process
b. Monitoring of presymptomatic patients with ADPKD i. Monitor blood pressure
ii. Test renal function iii. Advantages
a) Prevent or control hypertension b) Prevent or control infection
c) Identify potential kidney donors from among the family
d) Offer advise on reproduction e) Provide prenatal diagnosis c. Treatment of polycystic kidney disease
i. Narcotic analgesics for pain ii. Antibiotics for infection iii. Treatment of nephrolithiasis
a) Potassium citrate for uric acid lithiasis, hypocitric calcium oxalate nephrolithiasis, and distal acidification defects
b) Extracorporeal shock-wave lithotripsy c) Percutaneous nephrostolithotomy iv. Needle aspiration of dominant cysts
v. Laparoscopic cyst decortication vi. Open renal cyst decortication
vii. Therapeutic intervention aimed at slowing the progression of renal failure
a) Control of hypertension b) Control of hyperlipidemia c) Dietary protein restriction d) Control of acidosis
e) Prevention of hyperphosphatemia viii. Renal dialysis
ix. Renal transplantation for end stage renal disease d. Treatment of massive polycystic liver disease
i. Aspiration of cyst fluid ii. Stenting
iii. Cyst fenestration iv. Liver resection
v. Liver transplantation
e. Treatment of intracranial aneurysms i. Asymptomatic aneurysm
a) Observation and yearly follow-up b) Surgery for enlarging aneurysm
ii. Ruptured or symptomatic aneurysm: surgical clipping at its neck
f. Management of aortic dissection i. Aortic root dilatation
a) Yearly follow-up
b) Strict blood pressure control with β-blockade ii. Surgery for aortic root greater than 55–60 mm
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Fig. 1. A lady (A) with autosomal dominant polycystic kidney disease and with family history of multiple affected family members. Her liver was markedly enlarged as shown by a pencil mark on the patient’s photo. The ultrasonography of the kidney (B) showed numerous cysts with minimal residual normal appearing cortex. The right kidney (shown on ultrasound image) measured 11 cm with the largest cyst measuring 2.9 cm. The left kidney measured 13.3 cm in length with the largest cyst measuring 3.8 cm. The abdominal CT scan (C) showed marked hepatomegaly \which occupies the entire abdomen. Numerous hepatic cysts and renal cysts were evident. Numerous cysts of differ- ent sizes were also detected in her brother’s enlarged kidneys by ultra- sonography (the left kidney is shown here).
Fig. 2. Three CT scans of an adult patient with polycystic kidney dis- ease with and without contrast showing multiple cysts in the kidneys and liver.
Fig. 3. Appearance of the gross and cut section of a kidney (745 gm) surgically removed from in a 43-year-old female with autosomal dom- inant polycystic kidney disease.
Fig. 4. Multiple hepatic cysts of a patient with autosomal dominant polycystic kidney disease.
