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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations 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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys and arterial hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
  • Renal cysts may be seen.
  • Oligohydramnios Oligohydramnios Oligohydramnios refers to amniotic fluid volume less than expected for the current gestational age. Oligohydramnios is diagnosed by ultrasound and defined as an amniotic fluid index (AFI) of ‰¤ 5 cm or a single deep pocket (SDP) of < 2 cm in the 2nd or 3rd trimester. Oligohydramnios and no urine in the fetal bladder
• Potter sequence, which is due to severe oligohydramnios and the compressive effect of enlarged kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys:
  • Positional limb deformities
  • Craniofacial abnormalities
  • Pulmonary hypoplasia Pulmonary hypoplasia Pulmonary hypoplasia is the lack of normal fetal development of the pulmonary parenchyma. The condition is characterized by a decreased number of alveoli and bronchial generations. Oligohydramnios is a notable cause, but conditions that restrict lung development or lead to fetal lung compression can also result in pulmonary hypoplasia. Pulmonary Hypoplasia
  • Growth impairment
  • Feeding difficulties
• Kidney manifestations:
  • Protruding abdomen due to bilaterally enlarged kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
  • Chronic renal failure or even end-stage renal disease (ESRD)
  • Hypertension
  • Hyponatremia Hyponatremia Hyponatremia is defined as a decreased serum sodium (sNa+) concentration less than 135 mmol/L. Serum sodium is the greatest contributor to plasma osmolality, which is very tightly controlled via antidiuretic hormone (ADH) release from the hypothalamus and by the thirst mechanism. Hyponatremia
• Respiratory distress: noted in 50% of patients due to pulmonary insufficiency and hypoplasia 

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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys
  • Polyuria and polydipsia (usually the 1st signs of renal insufficiency)
  • Hypertension
  • Metabolic acidosis Metabolic acidosis The renal system is responsible for eliminating the daily load of non-volatile acids, which is approximately 70 millimoles per day. Metabolic acidosis occurs when there is an increase in the levels of new non-volatile acids (e.g., lactic acid), renal loss of HCO3-, or ingestion of toxic alcohols. Metabolic Acidosis
  • Recurrent urinary tract infections Urinary tract infections Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections (UTIs)
  • Urinary abnormalities such as:
    • Proteinuria
    • Glucosuria
    • Hyperphosphaturia
    • Increased magnesium excretion in urine
  • Progression to CKD CKD Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. Chronic Kidney Disease:
    • Cyst formation and fibrosis
    • Decreased renal function
• Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver manifestations:
  • May be a prominent feature of ARPKD in patients presenting at an older age
  • Can present with hepatomegaly
  • Congenital hepatic fibrosis
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver failure
  • Portal hypertension Portal hypertension Portal hypertension is increased pressure in the portal venous system. This increased pressure can lead to splanchnic vasodilation, collateral blood flow through portosystemic anastomoses, and increased hydrostatic pressure. There are a number of etiologies, including cirrhosis, right-sided congestive heart failure, schistosomiasis, portal vein thrombosis, hepatitis, and Budd-Chiari syndrome. Portal Hypertension
• Other findings: impaired growth and neurologic development, left ventricular hypertrophy

Diagnosis

Physical exam

• Assess for Potter syndrome.
• Assess for palpable kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys. 
• Abdominal tenderness to palpation 
• Assess for pulmonary or liver manifestations of the disease.

Imaging studies

• Ultrasonography of the abdomen:
  • Kidneys: 
    • Enlarged, hyperechogenic kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys bilaterally
    • Poor corticomedullary differentiation
    • Numerous tiny cysts and ductal dilatation
  • Liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. 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

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 Electrolytes Electrolytes are mineral salts that dissolve in water and dissociate into charged particles called ions, which can be either be positively (cations) or negatively (anions) charged. Electrolytes are distributed in the extracellular and intracellular compartments in different concentrations. Electrolytes are essential for various basic life-sustaining functions. Electrolytes
• ACE inhibitor for hypertension Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. Hypertension
• Fluid restriction for hyponatremia
• Supplemental nasogastric feedings for feeding difficulties
• Dialysis Dialysis Renal replacement therapy refers to dialysis and/or kidney transplantation. Dialysis is a procedure by which toxins and excess water are removed from the circulation. Hemodialysis and peritoneal dialysis (PD) are the two types of dialysis, and their primary difference is the location of the filtration process (external to the body in hemodialysis versus inside the body for PD). Overview and Types of 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 Hypertension Hypertension, or high blood pressure, is a common disease that manifests as elevated systemic arterial pressures. Hypertension is most often asymptomatic and is found incidentally as part of a routine physical examination or during triage for an unrelated medical encounter. 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 UTI Urinary tract infections (UTIs) represent a wide spectrum of diseases, from self-limiting simple cystitis to severe pyelonephritis that can result in sepsis and death. Urinary tract infections are most commonly caused by Escherichia coli, but may also be caused by other bacteria and fungi. Urinary Tract Infections)
• 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

Comparison

The 2 main types of PKD are autosomal dominant polycystic kidney disease Autosomal dominant 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 dominant polycystic kidney disease (ADPKD), which is often diagnosed in adulthood, and autosomal recessive polycystic kidney disease (ARPKD), which is often diagnosed antenatally or shortly after birth. Autosomal Dominant Polycystic Kidney Disease ( ADPKD ADPKD 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 dominant polycystic kidney disease (ADPKD), which is often diagnosed in adulthood, and autosomal recessive polycystic kidney disease (ARPKD), which is often diagnosed antenatally or shortly after birth. Autosomal Dominant Polycystic Kidney Disease) and ARPKD.

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 Pain Pain has accompanied humans since they first existed, first lamented as the curse of existence and later understood as an adaptive mechanism that ensures survival. Pain is the most common symptomatic complaint and the main reason why people seek medical care. Physiology of Pain, or renal insufficiency. Conservative management is recommended.
• Acquired renal cystic disease: chronic kidney disease Chronic Kidney Disease Chronic kidney disease (CKD) is kidney impairment that lasts for ≥ 3 months, implying that it is irreversible. Hypertension and diabetes are the most common causes; however, there are a multitude of other etiologies. In the early to moderate stages, CKD is usually asymptomatic and is primarily diagnosed by laboratory abnormalities. 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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations; characterized by maturity-onset diabetes of the young and renal cysts. Other findings include abnormal liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of 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 Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance tuberous sclerosis Tuberous sclerosis Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the TSC genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). 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 Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations).
• Multicystic dysplastic kidney: a severe form of cystic renal disease; the kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. 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 Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys undergo involution, therefore observation and long-term follow-up are recommended.