Kymora Scotland, MD, PhD
T. Ernesto Figueroa, MD, FAAP, FACS
BASICS
DESCRIPTION
• A group of inherited disorders involving cystic dilatation of the renal collecting ducts and varying degrees of biliary dysgenesis and periportal fibrosis
• Formerly known as infantile polycystic kidney disease
• An overlap in the spectrum of renal and liver involvement precludes use of the Blyth and Orkenden classification (perinatal, neonatal, infantile, and juvenile subtypes)
• Best grouped as polycystic disease of newborn and young infant, polycystic disease of childhood, and congenital hepatic fibrosis
EPIDEMIOLOGY
Incidence
• Most common inherited cystic renal disease in infancy and childhood
• Incidence: 1–2 in 10,000 live births
• Males = females
• Severely affected neonates usually die hours after birth; overall survival is much improved if they live beyond the neonatal period
Prevalence
• Commonly discovered in perinatal period; can present early in childhood or adolescence
• Survival: For patients living to 1 mo: 86% alive at 1 yr, 67% alive at 15 yr
RISK FACTORS
• Definite risk factor: Heterozygous parents
• The cause of ARPKD remains poorly understood
• Genetic and/or epigenetic factors may promote aberrant epithelial hyperplasia that causes cystic expansion of the collecting ducts and fluid accumulation
• Less is known about hepatobiliary changes; however, epithelial hyperplasia may have role
Genetics
• Associated with mutations of the PKHD1 gene (1 – 3)
• Autosomal recessive, heterozygotes unaffected, gene locus at chromosome 6p21
• Gene located at 6p21 produces a protein called fibrocystin which has been identified at the renal collecting ducts and the hepatic bile duct; possible involvement in renal cilia function
• Multiple allelism is likely responsible for variable phenotypic presentation
• Offspring of heterozygotes: 25% risk of disease, 50% carriers
PATHOPHYSIOLOGY
• Clinical course (renal):
– Severely affected neonates commonly die of pulmonary complications hours after birth
– Patients surviving the neonatal period have a better prognosis; they can have some renal maturation
– Progressive renal cyst enlargement, fibrosis, and renal insufficiency
– Eventually, most develop renal failure
– Later presentation: Less severe renal component
• Clinical course (hepatobiliary):
– Development of hepatosplenomegaly, portal HTN, extrahepatic bile duct dilation, gall bladder enlargement, occasional choledochal cyst formation, and hepatic dysfunction
– Liver failure ultimately develops later in childhood
ASSOCIATED CONDITIONS
• Ehlers–Danlos syndrome
• Potter syndrome
GENERAL PREVENTION
Genetic counseling for families with proven ARPKD (linkage studies with polymorphic DNA markers)
DIAGNOSIS
HISTORY
• Age of the patient:
– Other cystic renal disorders rarely present in the pediatric population:
Younger, more respiratory and renal issues;
Older, more hepatobiliary issues
– ∼1/3 are diagnosed before age 1; 1/3 between ages 1 and 20 yr; and 1/3 beyond 20 yr
• Prenatal care
– Characteristic changes on prenatal US after week 30, abnormal uterine growth measurements, maternal α-fetoprotein levels, amniocentesis results, history of stillbirth
• Birth history:
– Difficult delivery suggests possible flank or abdominal mass
• Family history:
– Normal parents with a normal renal US suggests recessive disease
• Medical history:
– For older patient, may suggest evolution of disease
• Present illness:
– Polydipsia, polyuria, fatigue, unexplained fever, hematuria, pyuria, edema, difficult feeding, recent GI bleed or vague GI symptoms
PHYSICAL EXAM
• HTN, respiratory rate, temperature
• General appearance:
– Potter phenotype, pallor
• Palpable kidneys: Hepatosplenomegaly
• Extremities: Joint contractures, edema
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Electrolytes, blood chemistry, urine analysis, urine culture
• CBC (exclude anemia, hypersplenism)
• Coagulation profile
• Liver function tests (usually normal)
• High maternal α-fetoprotein (associated with ARPKD), high amniotic fluid release (possible correlation)
Imaging
• Renal ultrasound is best initial test (4):
– Prenatal: Enlarged kidneys, oligohydramnios, normal liver, no bladder filling (more reliable after 30-wk gestation)
– Infancy: Enlarged reniform kidneys, cortical echogenicity
– Older children: Macrocysts (<2-cm diameter), decreased size, medullary echogenicity, hepatosplenomegaly
– Loss of corticomedullary differentiation: The kidneys typically have a homogeneous appearance
• CT may be used in confusing cases: More sensitive to inhomogeneity of cysts
Diagnostic Procedures/Surgery
• Renal biopsy
• Liver biopsy
Pathologic Findings
• Renal
– Bilateral enlarged kidneys with reniform shape
– Pinpoint opalescent dots on capsule (cortical collecting duct cysts)
– Cut surface with sponge-like quality due to linear distention of nephrons in radial pattern
– Normal pelvicaliceal system and renal vessels
– In neonates, kidneys at least 10% of body weight
– Microscopic pathology: Fusiform cysts (<2 mm + diameter) lined by low columnar or cuboidal epithelium
– No normal parenchyma
• Hepatobiliary
– All children with ARPKD have lesions in the periportal areas of the liver
– Can have hepatosplenomegaly at presentation; frequently normal
– Elongated, hyperplastic biliary ducts with ectasia
– Periportal fibrosis with normal hepatocellular histology
DIFFERENTIAL DIAGNOSIS
• Autosomal dominant polycystic kidney disease (ADPKD)
• Bardet–Biedl syndrome
• Caroli disease
• Chondrodysplasia syndrome
• Congenital hypernephronia nephromegaly with tubular dysgenesis
• Glutaric aciduria type II
• Ivemark syndrome
• Jeune syndrome
• Juvenile nephronophthisis
• Meckel–Gruber syndrome
• Renal dysplasia
• Trisomy 9 and 13
• Zellweger syndrome
TREATMENT
GENERAL MEASURES
• No specific therapy for ARPKD. Treatments are supportive
• Pulmonary issues 1st priority initially; survival better with advances in perinatology
• Goals: Delay progression to renal failure, liver failure, and portal HTN
• Avoid nephrotoxic mediations
• Social support and respite care
MEDICATION
First Line
• Thiazides to help urine-concentrating defect
• Treatment of renal osteodystrophy with vitamin D and phosphate binders
• Recombinant human erythropoietin
• Growth hormone treatment
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Preemptive bilateral nephrectomy and peritoneal dialysis catheter (significant pulmonary distress)
• Unilateral nephrectomy (improve feedings, help with breathing)
• Gastrostomy tube placement (improve feedings)
• Splenorenal shunt or portocaval shunt procedures (portal HTN)
• Renal transplantation (ESRD)
• Liver transplantation (hepatic failure)
• Progressive liver fibrosis with portal hypertension may require combined liver and kidney transplantation
ADDITIONAL TREATMENT
Radiation Therapy
N/A
Additional Therapies
• Adequate hydration
• Correct acid–base and electrolyte abnormalities
• Aggressive HTN control
• Peritoneal dialysis
• Enteral feedings
• Advanced pulmonary support as required
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Prenatal: Abnormal prenatal US (oligohydramnios, enlarged reniform kidneys, absent urine in bladder, seen after 30-wk gestation) (5)
• Neonates: If present at birth, the usual clinical course is death. Patients have feeding intolerance, respiratory distress
• Infants: Palpable flank masses, abdominal mass, respiratory distress, HTN, polydipsia, polyuria, edema, feeding intolerance, Potter phenotype, nonspecific GI complaints, failure to thrive, growth retardation, infection
• Older children: Palpable flank mass, abdominal mass, Potter phenotype, GI bleed, hematuria, pyuria, polydipsia, polyuria, HTN, nonspecific GI complaints, edema, growth retardation, fatigue, infection. Will eventually develop renal failure and HTN
• All patients with ARPKD have liver involvement. Those with severe ARPKD have mild congenital hepatic fibrosis and those with severe congenital hepatic fibrosis have milder ARPKD
COMPLICATIONS
• Renal: Renal failure (concentrating defect with polydipsia and polyuria), HTN, anemia, occasional metabolic acidosis, hyponatremia, osteodystrophy, growth failure, UTI
• Hepatobiliary: Hepatosplenomegaly, bleeding esophageal varices, portal thrombosis, hypersplenism, choledochal cysts, bacterial cholangitis
• Pulmonary: Respiratory failure, pulmonary hypoplasia, pneumothorax, atelectasis, poor diaphragmatic excursion
• GI: Feeding intolerance, failure to thrive
FOLLOW-UP
Patient Monitoring
• Progressive renal failure in most patients requiring ongoing renal assessments
• Blood pressure
• Liver functions and ultrasound at least annually
• Overall assessment of growth and nutritional status
• Parental counselling is critical as there is a 1 in 4 chance of another child having the disease
Patient Resources
PKD Foundation http://www.pkdcure.org/learn/arpkd
REFERENCES
1. Ward CJ, Hogan MC, Rossetti S, et al. The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet. 2002;30:259–269.
2. Adeva M, El-Youssef M, Rossetti S, et al. Clinical and molecular characterization defines a broadened spectrum of autosomal recessive polycystic kidney disease (ARPKD). Medicine (Baltimore).2006:85:1–21. (Level II evidence)
3. Bergmann C, Senderek J, Küpper F, et al. PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD). Hum Mutat. 2004:5:453–463.
4. Levine E, Hartman DS, Mellstrup JW, et al. Current concepts and controversies in imaging of renal cystic disease. Urol Clin North Am. 1997;24:523–543. (Level III evidence)
5. Roy S, lon MJ, Trompeter RS, et al. Autosomal recessive polycystic kidney disease: Long-term outcome of neonatal survivors. Pediatr Nephrol. 1997;11:302–306. (Level II-3 evidence)
ADDITIONAL READING
Brinkert F, Lehnhardt A, Montoya C, et al. Combined liver-kidney transplantation for children with autosomal recessive polycystic kidney disease (ARPKD): Indication and outcome. Transpl Int. 2013;26(6):640–650.
See Also (Topic, Algorithm, Media)
• Acquired Renal Cystic Disease
• Meckel–Gruber Syndrome (Meckel Syndrome)
• Multicystic Dysplastic Kidney
• Nephronophthisis (Juvenile, Infantile, and Adolescent)
• Polycystic Kidney Disease, Autosomal Dominant
• Polycystic Kidney Disease, Autosomal Recessive Image 
• Renal Cysts (Intrarenal, Peripelvic, and Parapelvic)
• Renal Dysplasia, Hypodysplasia, and Hypoplasia
• Renal Mass
CODES
ICD9
• 751.69 Other anomalies of gallbladder, bile ducts, and liver
• 753.14 Polycystic kidney, autosomal recessive
• 777.8 Other specified perinatal disorders of digestive system
ICD10
• P78.89 Other specified perinatal digestive system disorders
• Q44.5 Other congenital malformations of bile ducts
• Q61.19 Other polycystic kidney, infantile type
CLINICAL/SURGICAL PEARLS
• Renal and liver involvement is typical.
• Often fatal if present at birth.
• Treatments are supportive; no specific therapy.