Autosomal recessive polycystic kidney disease (ARPKD) or polycystic kidney and hepatic disease 1 (PKHD1) is an often- devastating form of polycystic kidney disease. It is also known as infantile polycystic kidney disease. The incidence of ARPKD is estimated to be 1 in 20,000 live births and the fre- quency of the heterozygous carrier state 1 in 70.
GENETICS/BASIC DEFECTS
1. Inheritance: autosomal recessive
2. No clear evidence of genetic heterogeneity 3. Molecular cause
a. Mutations in the PKHD1 gene on chromosome 6p21.1-p12, encoding a putative receptor protein, fibrocystin (or polyductin)
b. The full spectrum of phenotypic variants appears to involve mutations in this gene
c. Characterization of disease-causing mutations pro- viding new insights into the molecular basis for the phenotypic variability with the recent identification of the PKHD1 gene
4. Genotype-phenotype correlations: All patients carrying two truncating mutations displayed a severe phenotype with perinatal or neonatal demise
CLINICAL FEATURES
1. The most common heritable cystic renal disease manifest- ing in infancy and childhood
2. A wide variable clinical spectrum, ranging from severe renal impairment and a high mortality rate in infancy to older children and adolescents with minimal renal disease and complications of congenital hepatic fibrosis, cholan- gitis and portal hypertension
3. Principal manifestations
a. Fusiform dilatation of renal collecting ducts and dis- tal tubuli
b. Dysgenesis of the hepatic portal triad 4. Clinical characteristics at presentation
a. 0–1 month
i. Prenatal diagnosis made ii. Positive family history iii. Pneumothorax
iv. Flank mass v. Hypertension vi. Renal insufficiency b. >1 month to 1 year
i. Frank mass ii. Hepatomegaly iii. Hypertension
iv. Urinary tract infection c. >1 year to 5 years
i. Hepatomegaly ii. Portal hypertension
d. >5 year
i. Hepatomegaly ii. Hypertension iii. Renal insufficiency
iv. Portal hypertension
e. Predominance of renal abnormalities in younger chil- dren
f. Predominance of hepatic disease in older children and adolescents
g. Tendency of inverse relative degrees of kidney and liver involvement
i. Children with severe renal disease usually with milder hepatic disease
ii. Children with severe hepatic disease with milder renal impairment
5. “Potter” phenotype developed in affected fetuses a. Pulmonary hypoplasia, often incompatible with life b. Characteristic face
i. Short and snubbed nose ii. Deep eye creases iii. Micrognathia
iv. Low-set flattened ears
c. Deformities of the spine and limbs (clubfoot) 6. Renal manifestations
a. Frequent loss of concentrating ability of the kidney b. Common recurrent urinary tract infections
c. Proteinuria d. Hematuria
e. Creatinine clearance improving early but declining progressively during adolescence
f. Hypertension early in life but usually regresses g. Enlarged kidneys
h. End-stage renal disease 7. Hepatic manifestations
a. Congenital hepatic fibrosis
i. Invariably present but only occasionally do hepatic symptoms predominate
ii. Two predominant features characterizing the liver in ARPKD
a) Bile ducts: abnormally/irregularly formed, often increased in number, and dilated intra- hepatic bile ducts
b) Portal tracts: enlarged and fibrotic iii. Normal hepatic parenchyma
iv. Hepatocellular function almost always normal in affected patients, even when they have relatively severe portal tract disease
v. Not by itself a diagnostic (not pathognomonic) sign. Congenital hepatic fibrosis has been observed in the following situations:
a) Meckel-Gruber syndrome b) Vaginal atresia
c) Tuberous sclerosis
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d) Juvenile nephronophthisis
e) Rarely autosomal dominant polycystic kid- ney disease
b. Caroli disease
i. Congenital hepatic fibrosis accompanied by a non-obstructive dilation of the intrahepatic bile ducts
ii. Clinical risk of secondary complications a) Stone formation
b) Recurrent cholangitis: may result from ectatic bile ducts
c) Hepatic abscesses d) Rare cholangiocarcinoma c. Hepatomegaly
d. Portal hypertension
i. The most common sequelae of congenital hepat- ic fibrosis
ii. Splenomegaly iii. Variceal bleeding
iv. Hypersplenism a) Leukopenia b) Thrombocytopenia c) Anemia
d) Increased susceptibility to infections result- ing from leukopenia associated with splenic sequestration
e. Ascending cholangitis
i. Presumably caused by entry of nonsterile gas- trointestinal contents into the dilated intrahepatic bile ducts
ii. Common in patients with macroscopically dilated bile ducts
iii. Clinical features a) Abdominal pain b) Fever
c) Elevation in levels of hepatic enzymes iv. Tends to recur
v. May lead to hepatic abscess formation, sepsis, and death
8. Cerebral aneurysm, a common feature of ADPKD, reported in an adult with ARPKD
9. Prognosis
a. 30–50% of affected neonates die shortly after birth in respiratory insufficiency due to pulmonary hypoplasia b. Recent trend with improved prognosis
c. 67% of children who survive the newborn period with life-sustaining renal function at 15 years of age
DIAGNOSTIC INVESTIGATIONS
1. Radiography in neonates and infants with moderate to severe renal disease
a. Smoothly enlarged kidneys because of the numerous dilated collecting ducts
b. Abdominal distension
c. Gas-filled bowel loops often deviated centrally d. Pulmonary hypoplasia and small thorax in the baby
with severe kidney disease
e. Pneumothorax common at birth following assisted ventilation
2. Ultrasonography
a. Absence of renal cysts in both parents as demonstrated by ultrasound examination
b. Neonatal ultrasonography with more marked renal cystic disease
i. Massive enlarged kidneys
ii. Increased echogenicity of entire parenchyma iii. Loss of corticomedullary differentiation
iv. Loss of central echo complex v. Small macrocysts
vi. Usually small bladder
vii. Increased hepatic echogenicity, mainly in medulla c. Ultrasonography in children with more prominent
hepatic fibrosis
i. Massive kidney enlargement
ii. Increased hepatic echogenicity, mainly in medulla
iii. Macrocysts
a) Less than 2 cm in diameter
b) Tend to become larger and more numerous over time
iv. Enlarged echogenic liver v. Hepatic cysts
vi. Pancreatic cysts
vii. Splenomegaly secondary to portal hypertension viii. Hepatofugal-flow duplex and color-flow Doppler 3. CT scan
a. Nonenhanced CT: smooth, enlarged, and low attenu- ating kidneys, likely the reflection of the large fluid volume in the dilated ducts
b. CT with contrast
i. Kidneys with a striated pattern representing accumulation of contrast material in the dilated tubules
ii. Linear opacifications representing retention of contrast medium in dilated medullary collecting ducts
iii. Macrocysts appearing as well-circumscribed rounded lucent defects
iv. Time of delay in visualizing the contrast medium in the kidneys, proportionate to the severity of renal impairment
4. Ultrasonography and magnetic resonance cholangiogra- phy to investigate the presence of an extent of Caroli dis- ease in children with autosomal recessive polycystic kidney disease
5. MRI of affected children (perinatal, neonatal and infantile course)
a. Kidney appearance
i. Enlarged, humpy but still reniform in shape ii. Homogeneously grainy parenchyma b. Signal intensity
i. Hypointense on T1-W spin-echo sequences ii. Hyperintense on T2-W turbo-spin-echo sequences c. RARE (rapid acquisition with relaxation enhance-
ment)-MR-urography
i. Hyperintense, linear radial pattern seen in the
cortex and medulla representing the characteris-
tic microcystic dilatation of collecting ducts
ii. Possible few circumscribed small subcapsular cysts
6. Histopathology of the kidney
a. Radially arranged cylindrical and fusiform ducts are present throughout renal medulla and cortex, due to a generalized dilatation of collecting ducts
b. The portal tracts of the liver are enlarged and contain abundant fibrous tissue and many cistern-like dilated bile ducts. The abnormal changes are the result of ductal plate malformation
7. Molecular diagnosis
a. Linkage analysis of the affected family using 6p21 markers demonstrating linkage to the ARPKD1 gene with the affected proband
b. 33 different mutations detected on 57 alleles (Rossetti et al., 2003)
i. 51.1% in ARPKD
ii. 32.1% in congenital hepatic fibrosis/Caroli disease) iii. Two frequent truncating mutations
a) 9689delA (9 alleles) b) 589insA (8 alleles) iv. Mutation detection rate
a) High in severely affected patients (85%) b) Lower in moderate severe ARPKD (41.9%) c) Low, but significant, in adults with congeni-
tal hepatic fibrosis/Caroli disease (323.1%) v. Complications for the prospects for gene-based
diagnostics
a) Large gene size
b) Marked allelic heterogeneity
c) Clinical diversity of the ARPKD phenotype c. Direct DNA analysis available clinically
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib: 25%
b. Patient’s offspring: not increased (theoretical risk 0.7%) 2. Prenatal diagnosis
a. Ultrasonography in most severely affected fetuses i. Enlarged, echogenic kidneys
ii. Dilated collecting ducts
iii. Characteristic hepatic ductal plate malformation iv. A small or nonvisualized bladder
v. Oligohydramnios attributable to poor fetal renal output
vi. Unreliable especially in early pregnancy b. Mutation scanning of PKHD1 is available clinically
by analysis of fetal DNA obtained from amniocente- sis or CVS. Both disease-causing alleles of an affect- ed family member must be identified or likage has been established in the family before prenatal testing can be performed. The ARPKD locus mapped to proximal chromosome 6p allowing haplotype-based prenatal diagnosis in “at-risk” family with a previous- ly affected child in whom prior family studies have identified informative linked markers. An absolute prerequisite for these studies is an accurate diagnosis of ARPKD in the previously affected sib
3. Management
a. Initial management of affected infants to focus on stabi- lization of respiratory function. Mechanical ventilation
may be necessary to treat both pulmonary hypoplasia and respiratory compromise from massively enlarged kidneys
b. Water and electrolyte balance
c. Peritoneal dialysis may be required for neonates with oliguria or anuria within the first days of life
d. Vigorous treatment of systemic hypertension with antihypertensive agents
i. ACE inhibitors
ii. Calcium channel blockers iii. Beta-blockers
iv. Judicious use of diuretics (eg, thiazides, loop diuretics)
e. Antibiotics for treatment of urinary tract infections f. Management of renal osteodystrophy in children with
ARPKD and chronic renal insufficiency i. Calcium supplements
ii. Phosphate binders
iii. 1,25-dihydroxyvitamin D3 to suppress parathy- roid hormone (PTH)
iv. Erythropoietin (EPO)
a) Increases hemoglobin levels
b) Improves the overall well-being of the child g. Potential use of recombinant human growth hor- mone therapy to improve the growth of children with uremia
h. Therapeutic options available for the treatment of portal hypertension in children
i. Conservative management ii. Control of variceal bleeding
a) Sclerotherapy effective in controlling bleeding b) Banding of varices
c) Placement of portosystemic shunts occa- sionally necessary to reduce bleeding and the formation of additional varices
iii. Prompt management with antibiotics and, when indicated, surgical drainage to help reduce mor- bidity and mortality associated with ascending cholangitis
iv. Splenectomy for hypersplenism
v. Liver transplantation in patients with severe hepatic dysfunction or chronic cholangitis i. Replacement therapy for renal failure
i. Renal dialysis ii. Renal transplant
j. Combined liver/kidney transplantation
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Fig. 1. A newborn with ARPKD showing Potter facies. The spongy appearing cut surface of a kidney from the same patient is due to gen- eralized dilatation of the collecting ducts in both cortex and medulla.
Fig. 2. Photomicrograph of a kidney of a neonate (37 weeks gestation) with ARPKD showing markedly dilated collecting ducts in the medul- la (top) and the cortex (bottom). The infant also had intrahepatic bile duct proliferation and mild cystic changes, and pulmonary hypoplasia.
Fig. 3. Photomicrograph of the liver of a 2-year-old girl with congen- ital hepatic fibrosis, consistent with ARPKD. Note the irregularly dilated branching bile ducts. There is abundant fibrous connective tis- sue in this enlarged portal tract.
Fig. 4. Two neonates with ARPKD showing markedly distended abdomen.
Fig. 5. Kidneys in another neonate with ARPKD.
