Autosomal Recessive Polycystic Kidney Disease

Polycystic kidney disease (PKD) is an inherited genetic disorder leading to the development of numerous fluid-filled cysts in the kidneys. The 2 main types of PKD are autosomal recessive polycystic kidney disease (ARPKD), which is often diagnosed antenatally or shortly after birth, and autosomal dominant polycystic kidney disease (ADPKD), which is often diagnosed in adulthood. Autosomal recessive polycystic kidney disease is primarily characterized by cystic dilatations of the renal collecting ducts and intrahepatic bile duct dilatation with hepatic fibrosis. Diagnosis is through physical exam and ultrasonography. Management requires a multidisciplinary approach to slow the progression of renal disease by controlling hypertension, proteinuria, and symptoms. The prognosis of ARPKD depends on the age at presentation, along with the degree of hepatic and renal involvement. Patients progressing to end-stage renal disease (ESRD) will need renal replacement therapy.

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Epidemiology and Etiology

Epidemiology

Polycystic kidney disease (PKD) affects about 500,000 people in the United States. Autosomal recessive polycystic kidney disease (ARPKD) (formerly known as infantile PKD), is 1 of the 2 main types of PKD.

  • Prevalence: 1 per 20,000 live births
  • ⅓ present before 1 year old
  • ⅓ present between 1–20 years old
  • ⅓ present after 20 years old

Etiology

  • ARPKD: autosomal recessive
  • Either a mutation of: 
    • PKHD1 on chromosome 6p21 OR:
      • Encodes fibrocystin (large integral membrane protein) found in the cortical and medullary collecting ducts of the kidney and hepatic bile duct cells
      • Defect in fibrocystin → dysfunction of renal cilia
    • DZIP1L (less common):
      • Located on the 2nd locus for ARPKD
      • Presentation includes enlarged hyperechogenic kidneys and arterial hypertension

Clinical Presentation

General manifestations

Manifestations vary by age and affect the following:

  • Kidneys:
    • Cystic dilations of the collecting ducts
    • Microcysts < 2 mm in size
    • Impaired renal function
  • Hepatobiliary tract: intrahepatic bile duct dilatation and hepatic fibrosis

Antenatal and neonatal

  • Can be detected antenatally (by 24-weeks gestational age):
    • Enlarged kidneys
    • Renal cysts may be seen.
    • Oligohydramnios and no urine in the fetal bladder
  • Potter sequence, which is due to severe oligohydramnios and the compressive effect of enlarged kidneys:
    • Positional limb deformities
    • Craniofacial abnormalities
    • Pulmonary hypoplasia
    • Growth impairment
    • Feeding difficulties
  • Kidney manifestations:
    • Protruding abdomen due to bilaterally enlarged kidneys
    • Chronic renal failure or even end-stage renal disease (ESRD)
    • Hypertension
    • Hyponatremia
  • Respiratory distress: noted in 50% of patients due to pulmonary insufficiency and hypoplasia 
ARPKD

Autosomal recessive polycystic kidney disease (ARPKD):
a) Baby with a distended abdomen due to voluminous kidneys, leading to respiratory problems and early demise
b) Abdominal situs of a perinatally demised ARPKD patient with symmetrically enlarged kidneys in their reniform configuration

Image: “Fig. 2” by Carsten Bergmann. License: CC BY 2.0

Infancy and childhood

In the 1st 3 years, survivors of the neonatal period experience a temporary improvement of renal function, followed by a decline.

  • Kidney manifestations:
    • Protruding abdomen due to bilaterally enlarged kidneys
    • Polyuria and polydipsia (usually the 1st signs of renal insufficiency)
    • Hypertension
    • Metabolic acidosis
    • Recurrent urinary tract infections (UTIs)
    • Urinary abnormalities such as:
      • Proteinuria
      • Glucosuria
      • Hyperphosphaturia
      • Increased magnesium excretion in urine
    • Progression to CKD:
      • Cyst formation and fibrosis
      • Decreased renal function
  • Liver manifestations:
    • May be a prominent feature of ARPKD in patients presenting at an older age
    • Can present with hepatomegaly
    • Congenital hepatic fibrosis
    • Liver failure
    • Portal hypertension
  • Other findings: impaired growth and neurologic development, left ventricular hypertrophy

Diagnosis

Physical exam

  • Assess for Potter syndrome.
  • Assess for palpable kidneys. 
  • Abdominal tenderness to palpation 
  • Assess for pulmonary or liver manifestations of the disease.

Imaging studies

  • Ultrasonography of the abdomen:
    • Kidneys: 
      • Enlarged, hyperechogenic kidneys bilaterally
      • Poor corticomedullary differentiation
      • Numerous tiny cysts and ductal dilatation
    • Liver: 
      • Hepatomegaly 
      • Hyperechogenic cysts
      • Dilatation of the main bile ducts and the peripheral intrahepatic ducts
  • MRI or CT for further characterization of the disease, or if inconclusive ultrasound findings:
    • MRI: renal enlargement with microcysts in a hyperintense radial pattern in the cortex and medulla
    • CT: not the initial choice due to radiation
Ultrasonography of the right kidney demonstrating autosomal recessive polycystic kidney disease

Ultrasonography of the right kidney demonstrating autosomal recessive polycystic kidney disease (ARPKD):
diffusely increased echogenicity, loss of corticomedullary differentiation, and multiple microcysts within the renal parenchyma

Image: “Autosomal Recessive Polycystic Kidney Disease” by Shogan PJS. License: CC BY 4.0

Genetic testing

  • Diagnosis is inconclusive after imaging.
  • Prenatal diagnosis
  • Genetic counseling (determine familial carriers of the mutated PKHD1 gene)

Management and Prognosis

Management approach

Antenatal management (if detected early):

  • Ultrasound monitoring every 2–3 weeks (check renal size and amniotic fluid volume)
  • Neonatal intensive care planning

Neonatal management:

  • Supportive respiratory care (if respiratory distress due to pulmonary hypoplasia)
  • Mechanical ventilation
  • Monitor/manage renal function and serum electrolytes
  • ACE inhibitor for hypertension
  • Fluid restriction for hyponatremia
  • Supplemental nasogastric feedings for feeding difficulties
  • Dialysis if ESRD
  • Nephrectomy if absolutely needed for survival

Infancy and childhood management:

  • Monitor kidney function.
  • Monitor liver status:
    • Check for signs of portal hypertension.
    • Yearly abdominal ultrasound
  • May require supplemental feedings for feeding intolerance and growth
  • ACE inhibitor or ARB for blood pressure control
  • Manage complications (e.g., UTI)
  • Kidney transplantation for ESRD
  • May need a liver transplant

Prognosis

  • Affected largely by the degree of renal and hepatic involvement (usually dependent on the age of presentation)
  • Worst prognosis (mortality rate of 30%): presentation as a neonate with severe renal disease and pulmonary insufficiency
  • Survival past the 1st month: > 80% chance of survival past 15 years old
Autosomal recessive polycystic kidney disease

Autosomal recessive polycystic kidney disease (ARPKD) in a fetus:
On the left, a gross specimen is shown of a right kidney measuring 10 × 7 × 4 cm. The cut surface is spongy with poor corticomedullary differentiation. There are multiple, tiny cysts with some at right angles to the cortical surface.
On the right, a photomicrograph is showing numerous cysts lined by a single layer of low cuboidal epithelial cells with thick, peritubular mesenchyme. The glomeruli are normal (H&E, 40x).

Image: “Autosomal recessive polycystic kidney” by Department of Urology, Kasturba Medical College, Manipal, India. License: CC BY 2.0

Comparison

The 2 main types of PKD are autosomal dominant polycystic kidney disease (ADPKD) and ARPKD.

Table: ADPKD vs. ARPKD
ADPKDARPKD
Inheritance Autosomal dominant Autosomal recessive
Genes involved PKD1, PKD2 PKHD1
Associated proteins Polycystin-1, polycystin-2 Fibrocystin
Age of presentation Adulthood Antenatal, neonatal, infant
Clinical features
  • Impaired renal function
  • Enlarged kidneys
  • Cerebral aneurysm
  • Hepatic and pancreatic cysts
  • Colon diverticulosis
  • Abdominal hernias
  • Impaired renal function
  • Enlarged kidneys
  • Intrahepatic bile duct dilatation and hepatic fibrosis
  • Pulmonary hypoplasia
Gross and pathologic morphology
  • Large kidneys, surface full of cysts, distorted renal architecture
  • Round cysts of varying size (microcysts and macrocysts)
  • Functioning nephrons between cysts
  • Large kidneys, smooth surface, preserved general shape of kidneys
  • Microcysts (usually < 2 mm), which are tubular (affecting the collecting ducts and tubules), radiating from the medulla to the cortex
  • Dilation of collecting ducts
Ultrasound findings Multiple cysts (based on age):
  • < 40 years of age: ≥ 3
  • 40–59 years of age: ≥ 2 each kidney
  • 60 years and above: ≥ 4 each kidney
  • Enlarged, echogenic kidneys
  • Poor corticomedullary differentiation
  • Multiple tiny cysts
ADPKD: autosomal dominant polycystic kidney disease
ARPKD: autosomal recessive polycystic kidney disease

Differential Diagnosis

  • Multiple benign simple cysts: asymptomatic renal cysts found in children. The cysts increase in number with age. Patients without PKD generally do not have gross hematuria, flank pain, or renal insufficiency. Conservative management is recommended.
  • Acquired renal cystic disease: chronic kidney disease is frequently associated with the development of multiple small cysts bilaterally. The cysts are often small (< 0.5 cm) and patients have no family history. The kidneys have a smooth contour and are small to normal in size. Associated extrarenal manifestations are not noted.
  • Renal cysts and diabetes syndrome: associated with TCF2 gene mutation; characterized by maturity-onset diabetes of the young and renal cysts. Other findings include abnormal liver enzymes, elevated uric acid, and pancreatic malformations. Renal function varies from mild reduction to ESRD.
  • Nephronophthisis: autosomal-recessive disorder associated with dysfunction of the primary cilia, basal bodies, and centrosomes. The kidney appears echogenic with loss of corticomedullary differentiation on ultrasound. Renal size, however, is usually normal or slightly small. Hepatic fibrosis is also found.
  • Autosomal dominant tuberous sclerosis complex: multiple, bilateral kidney cysts. Other findings include renal angiomyolipomas, facial angiofibromas, hypomelanotic macules, and retinal nodular hamartomas. Diagnosis is based on clinical findings and genetic testing (TSC1 or TSC2 pathogenic mutation).
  • Multicystic dysplastic kidney: a severe form of cystic renal disease; the kidneys fill with cysts without renal tissue. Most cases are unilateral (boys more affected). Diagnosis is made with antenatal ultrasound. The majority of affected kidneys undergo involution, therefore observation and long-term follow-up are recommended.

References

  1. Guler, S., Cimen, S., Hurton, S., et al. (2015). Diagnosis and Treatment Modalities of Symptomatic Polycystic Kidney Disease. In Li X (Ed.), Polycystic Kidney Disease [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK373387/
  2. Halvorson, C.R., Bremmer, M.S., Jacobs, S.C. (2010). Polycystic kidney disease: inheritance, pathophysiology, prognosis, and treatment. Int. J. Nephrol. Renovasc. Dis. 3:69–83.
  3. Kruskal, J.B., Richie, J.P. (2021). Simple and complex renal cysts in adults. UpToDate. Retrieved Feb 25, 2021, from https://www.uptodate.com/contents/simple-and-complex-renal-cysts-in-adults
  4. National Institute of Diabetes and Digestive and Kidney Diseases. (2017). Autosomal Recessive Polycystic Kidney Disease. Retrieved February 25, 2021, from https://www.niddk.nih.gov/health-information/kidney-disease/polycystic-kidney-disease/autosomal-recessive-pkd#treat 
  5. National Institute of Diabetes and Digestive and Kidney Diseases. (2017). What is Polycystic Kidney Disease? Retrieved February 25, 2021, from https://www.niddk.nih.gov/health-information/kidney-disease/polycystic-kidney-disease/what-is-pkd#symptoms
  6. National Organization for Rare Disorders. (2020). Autosomal Recessive Polycystic Kidney Disease. Retrieved February 25, 2021, from https://rarediseases.org/rare-diseases/autosomal-recessive-polycystic-kidney-disease/#symptoms 
  7. Niaudet P. (2020). Autosomal recessive polycystic kidney disease in children. UpToDate. Retrieved Feb 25, 2021, from https://www.uptodate.com/contents/autosomal-recessive-polycystic-kidney-disease-in-children
  8. Niaudet, P. (2020). Renal cystic diseases in children. UpToDate. Retrieved 16 Apr 2021 from https://www.uptodate.com/contents/renal-cystic-diseases-in-children
  9. Patil A., Sweeney W.E. Jr., Avner E.D., et al. (2015). Childhood Polycystic Kidney Disease. Polycystic Kidney Disease. https://www.ncbi.nlm.nih.gov/books/NBK373381/
  10. Srinath A., Shneider B.L. (2012). Congenital hepatic fibrosis and autosomal recessive polycystic kidney disease. J Pediatr Gastroenterol Nutr. 54, 580–7.
  11. Zhou J, & Pollak M.R. (2018). Polycystic kidney disease and other inherited disorders of tubule growth and development. Jameson JL, et al. (Ed.), Harrison’s Principles of Internal Medicine (20th ed.) https://accessmedicine-mhmedical-com.aucmed.idm.oclc.org/content.aspx?bookid=2129&sectionid=192281464

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