Basics
Description
- Polycystic kidney disease (PKD) is a heritable disorder with diffuse cystic involvement of both kidneys without other dysplastic elements. The term PKD is generally used to describe 2 genetically distinct syndromes:
- Autosomal dominant polycystic kidney disease (ADPKD)
- Saccular, epithelial-lined, fluid-filled cysts of various sizes are derived from all segments of the nephron.
- Cysts progressively enlarge and become disconnected from the tubule of origin.
- Usually not clinically apparent until the 3rd or 4th decade of life
- ’ Ό2 " 5% of patients have early-onset disease.
- Autosomal recessive polycystic kidney disease (ARPKD)
- Fusiform dilations arise from the collecting ducts and maintain contact with the nephron of origin.
- Associated hepatic abnormalities are obligatory such as biliary dysgenesis and periportal fibrosis (congenital hepatic fibrosis), with portal hypertension.
- Affects both the kidneys and the liver in approximately inverse proportions
Epidemiology
- ADPKD
- One of the most common human genetic disorders; the most common renal inherited disease
- A major cause of end-stage renal disease (ESRD) in adults
- Frequency: 1 in 400 " 1,000
- ARPKD
- Incidence of 1 in 20,000 " 40,000 live births
- Exact incidence unknown owing to perinatal deaths in severe cases
Risk Factors
Genetics
- ARPKD
- Mutations in the polycystic kidney hepatic disease 1 gene (PKHD1, chromosome 6)
- ADPKD
- Type I ADPKD accounts for 85 " 90% of cases of ADPKD and is caused by mutations in the PKD1 gene (chromosome 16).
- Large genomic deletions may encompass PKD1 and TSC2 genes, resulting in early-onset ADPKD with tuberous sclerosis.
- Type II ADPKD is caused by mutations in the PKD2 gene (chromosome 4) and accounts for 10 " 15% of the cases.
- Other
- Presymptomatic genetic screening for ADPKD is not recommended.
- Normotensive women with ADPKD usually have uncomplicated pregnancies.
- Higher risk for maternal/fetal complications if there is preexisting hypertension
Pathophysiology
- ADPKD is produced by decreased functional polycystins:
- Polycystin-1 is a membrane mechanoreceptor-like protein that forms multiprotein complexes at focal adhesions, cell " cell junctions, and cilia. It is involved in cell polarity, proliferation, cell " matrix interactions, and secretion.
- Polycystin-2 is a divalent cation channel involved in calcium signaling and intracellular calcium homeostasis and is likely critical for cytoskeletal organization, cell adhesion, migration, and proliferation.
- ARPKD is produced by loss of functional fibrocystin/polyductin:
- Fibrocystin/polyductin is an integral membrane receptor with extracellular protein-interaction sites that transduce intracellular signals to the nucleus.
- Proteins affected in cystic kidney disease localize to cilia on epithelial cells.
- Cilia are critical for cell architecture, proliferation, apoptosis, and polarity.
Etiology
- ADPKD is generally an adult-onset, systemic disorder with cystic and noncystic manifestations. Cysts occur in the kidneys and other epithelial organs (e.g., seminal vesicles, pancreas, and liver):
- Polycystic liver disease is the most common extrarenal manifestation.
- Intracranial aneurysms occur in ’ Ό8%.
- Mitral valve prolapse is the most common valvular abnormality (demonstrated in up to 25% of affected individuals).
- Colonic diverticula in 80% with ESRD
- ARPKD is a renal and hepatic developmental disorder. The hallmark of ARPKD liver disease is congenital hepatic fibrosis and dilation of intrahepatic bile ducts (Caroli disease).
- Severely affected infants may have the oligohydramnios sequence at birth, and associated pulmonary hypoplasia and respiratory complications convey a high mortality risk.
Diagnosis
History
- ADPKD
- Detailed family history is essential.
- Most common presenting complaint in adults is pain.
- Hypertension, gross hematuria, nephrolithiasis, and UTIs are common.
- ARPKD
- Oligohydramnios sequence
- Postnatal respiratory insufficiency
- Renal insufficiency
- Hypertension (may be severe)
- Hepatobiliary manifestations (cholestasis, cholangitis, liver failure, portal hypertension, hypersplenism) evolve in older patients.
- Signs and symptoms
- ADPKD
- Older children are often asymptomatic but may present with hypertension, abdominal pain, abdominal mass, gross hematuria after trauma, proteinuria, UTI/cyst infection, renal calculi, or decreased renal function.
- ARPKD
- Presentation variable
- Severely affected infants have "Potter " oligohydramnios sequence.
- Pulmonary hypoplasia/respiratory insufficiency is a major cause of neonatal mortality.
- Renal insufficiency with neonatal survival
- Hepatobiliary complications later in course (portal hypertension, hematemesis, hepatosplenomegaly hypersplenism with pallor, petechiae)
Physical Exam
- Clinical spectrum variable, particularly in ARPKD
- Hypertension
- Abdominal pain; tenderness at flank or costovertebral angle
- Flank mass or palpable kidneys
- Hepatosplenomegaly, varices, jaundice/icterus, abdominal ascites in ARPKD
Diagnostic Tests & Interpretation
Lab
- Metabolic panel to include BUN, creatinine, electrolytes
- Calcium, phosphorus
- Liver function tests
- CBC
- Urinalysis
- Note: Hyponatremia is often present in the neonatal period in ARPKD.
Imaging
- Ultrasonography is the preferred screening method and should include liver and Doppler to evaluate for portal hypertension in ARPKD.
- ARPKD
- Kidneys enlarged with increased echogenicity and loss of corticomedullary differentiation
- The liver may be normal in infants and young children. Over time, it becomes enlarged and hyperechoic. Dilated intrahepatic biliary ducts may be seen.
- Prenatal ultrasound after 24 " 30 weeks ' gestation may show hyperechoic enlarged kidneys, oligohydramnios, and absence of bladder filling.
- Ultrasound diagnostic criteria for ADPKD
- <40 years should have at least 2 cysts in 1 of the kidneys and 1 cyst in the other kidney or 3 cysts in a single kidney.
- ≥40 and ≤59 years of age should have at least 2 cysts in each kidney.
- >60 years should have at least 4 cysts in each kidney.
- CT scan with contrast
- Has limited use in young children owing to exposure to ionizing radiation.
- It is mostly used in adults with ADPKD because it can distinguish between solid and liquid renal masses.
- MRI with gadolinium
- Heavy-weighted T2 MRI is the most sensitive method currently available.
- Can be used in both conditions
- Particularly useful to evaluate liver involvement in ARPKD
- Avoid gadolinium in patients with advanced chronic kidney disease.
Differential Diagnosis
- Multicystic dysplastic kidney (MCDK)
- Glomerular cystic kidney disease (GCKD)
- Acquired cystic disease may occur in patients with ESRD.
- Genetic syndromes with cystic renal dysplasia, including, but not limited to the following:
- Meckel syndrome
- Jeune syndrome
- Ivemark syndrome
- Zellweger syndrome
- Bardet-Biedl syndrome
- Tuberous sclerosis
Treatment
Medication
- Hypertension is common in PKD. Patients respond well to diuretics, ACE inhibitors, or calcium channel blockers. ACE inhibitors or angiotensin-receptor blockers are 1st line.
- In patients with PKD and nephrolithiasis, thiazide diuretics may be used for hypercalciuria, and potassium citrate supplements if hypocitraturia is found.
- Pyelonephritis in patients with PKD may lead to infected cysts. The treatment should include antibiotics that penetrate into the cysts (quinolones, trimethoprim) if cephalosporins and aminoglycosides fail to eradicate the infection.
Additional Treatment
General Measures
- No currently approved targeted treatments to cure or slow progression
- Medical management is supportive.
- Pain is the most common symptom in ADPKD and can be difficult to treat.
Additional Therapies
Activity: Patients with PKD should not participate in high-contact athletics in which the abdomen may be traumatized repeatedly. Strenuous static exercise should be avoided in hypertensive patients.
Ongoing Care
Follow-up Recommendations
A pediatric nephrologist should be involved in the care of children with PKD.
Diet
In both conditions, dietary changes depend on the degree of renal failure. Sodium restriction is indicated in cases of hypertension and/or edema. Caffeine should be avoided in cases of ADPKD.
Patient Education
- Emotional support and education of patients with PKD and their families can be obtained through the Polycystic Kidney Foundation (http://www.PKDcure.org) and the PKD Alliance (http://www.arpkdchf.org).
- Genetic counseling is indicated in these disorders and genetic testing may help families understand future risks.
Prognosis
- ADPKD
- The probability of being alive and not having ESRD is about 77% at age 50 years, 57% at age 58 years, and 52% at age 73 years. Median onset of ESRD is 53 years (PKD1) versus 69 years (PKD2).
- Cystic expansion occurs at a consistent rate per individual, although it is heterogeneous in the population.
- Larger kidneys are associated with more rapid disease progression.
- PKD1 mutation is more severe because more cysts develop earlier, not because they grow faster.
- ARPKD
- Neonatal onset is fatal in up to 50% of infants because of pulmonary hypoplasia with associated respiratory failure.
- Patients who survive the neonatal period have up to an 80% 10-year survival.
Additional Reading
- Arts HH, Knoers NV. Current insights into renal ciliopathies: what can genetics teach us? Pediatr Neph. 2013;28(6):863 " 874. [View Abstract]
- Dell KM. The spectrum of polycystic kidney disease in children. Adv Chronic Kidney Dis. 2011;18(5):339 " 347. [View Abstract]
- Sweeney WE Jr, Avner ED. Diagnosis and management of childhood polycystic kidney disease. Pediatr Nephrol. 2011;26(5):675 " 692. [View Abstract]
- Torres VE, Harris PC. Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol. 2014;25(1):18 " 32. [View Abstract]
Codes
ICD09
- 753.12 Polycystic kidney, unspecified type
- 753.13 Polycystic kidney, autosomal dominant
- 753.14 Polycystic kidney, autosomal recessive
ICD10
- Q61.3 Polycystic kidney, unspecified
- Q61.19 Other polycystic kidney, infantile type
- Q61.2 Polycystic kidney, adult type
- Q61.11 Cystic dilatation of collecting ducts
SNOMED
- 28728008 Polycystic kidney disease, adult type (disorder)
- 253880009 Autosomal dominant polycystic kidney disease in childhood (disorder)
- 28770003 Polycystic kidney disease, infantile type
- 82525005 Congenital cystic kidney disease (disorder)
FAQ
- Q: What can be done to slow the progression of renal insufficiency in ADPKD?
- A: Well-controlled BP and rapid treatment of UTIs may decrease the progression of renal failure.
- Q: Should asymptomatic older siblings of an infant with ARPKD be evaluated?
- A: Yes. An older child may have congenital hepatic fibrosis with minimal renal involvement.
- Q: Should one screen ADPKD-affected family members for the presence of cerebral vessel aneurysms if other family members have berry aneurysms?
- A: Although routine screening is not recommended, intrafamilial clustering of aneurysms has been reported and it may be advisable to screen children with MRI or cranial CT in a family with aneurysms.