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Polycystic Kidney Disease
Maricarmen Malagon-Rogers, MD
image BASICS
DESCRIPTION
  • A group of monogenic disorders that results in renal cyst development
  • The most frequent are two genetically distinct conditions: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD).
  • ADPKD is one of the most common human genetic disorders.
EPIDEMIOLOGY
  • ADPKD is generally late onset.
    • Mean age of end-stage kidney disease (ESKD) 57 to 69 years
    • More progressive disease in men than in women
    • Up to 90% of adults have cysts in the liver.
  • ARPKD usually present in infants.
    • A minority in older children and young adults may manifest as liver disease.
    • Nonobstructive intrahepatic bile dilatation is sometimes seen.
    • Found on all continents and in all races
Incidence
  • Mean age of ESKD: PKD1 mutation, 54.3 years versus PKD2 mutation, 74 years
  • ARPKD affects 1/20,000 live births; carrier level is 1/70.
  • ADPKD affects 1/400 to 1,000 live births.
Prevalence
As ESKD, ADPKD: 8.7/1 million in the United States; 7/1 million in Europe
ETIOLOGY AND PATHOPHYSIOLOGY
  • ADPKD
    • PKD1 and PKD2 mutations disrupt the function of polycystins on the primary cilium, forming fluid-filled cysts that progressively increase in size, leading to gross enlargement of the kidney, and distortion of the renal architecture.
    • Glomerular hyperfiltration compensates for the progressive loss of healthy glomeruli, and therefore, by the time GFR decline becomes detectable, as much as ½ of the original functional glomeruli are irreversibly lost.
    • The majority of patients with ADPKD ultimately progress to ESKD (1).
  • ARPKD
    • PKHD1 product fibrocystin is also located in cilia.
  • ADPKD: Cysts arise from only 5% of nephrons:
    • Autosomal dominant pattern of inheritance but a molecularly recessive disease with the 2-hit hypothesis
    • Requires genetic and environmental factors
  • ARPKD: Mutations are scattered throughout the gene with genotype-phenotype correlation.
Genetics
  • ADPKD
    • Autosomal dominant inheritance
    • 50% of children of an affected adult are affected.
    • 100% penetrance; genetic imprinting and genetic anticipation are seen as well.
    • Two genes isolated
      • PKD1 on chromosome 16p13.3 (85% of patients) encodes polycystin 1
      • PKD2 on chromosome 4q21 (15% of patients) encodes polycystin 2
  • ARPKD
    • Autosomal recessive inheritance
    • Siblings have a 1:4 chance of being affected; gene PKHD1 on chromosome 6p21.1-p12 encodes fibrocystin.
RISK FACTORS
  • Large inter- and intrafamilial variability
  • A more rapidly progressive clinical course is predicted by onset of ESKD at <55 years, development of stage 3 CKD at <40 years old, onset of HTN at <18 years, total kidney volume greater than the expected for a given age, or presence of multiple complications (gross hematuria, microalbuminuria) (1).
GENERAL PREVENTION
Genetic counseling
COMMONLY ASSOCIATED CONDITIONS
  • ADPKD
    • Cysts in other organs
      • Polycystic liver disease in 58% of young age group to 94% of 45-year-olds
      • Pancreatic cysts: 5%
      • Seminal cysts: 40%
      • Arachnoid cysts: 8%
    • Vascular manifestations
      • Intracerebral aneurysms in 6% of patients without family history and in 16% with family history
      • Aortic dissections
    • Cardiac manifestations: mitral valve prolapse: 25%
    • Diverticular disease
  • ARPKD: liver involvement: affected in inverse proportion to renal disease; congenital hepatic fibrosis with portal HTN
image DIAGNOSIS
PHYSICAL EXAM
  • HTN
  • Flank masses
DIFFERENTIAL DIAGNOSIS
  • ADPKD and ARPKD
  • Tuberous sclerosis: prevalence 1/6,000
  • Von Hippel-Lindau syndrome: prevalence 1/36,000
  • Nephronophthisis: accounts for 10-20% of cases of renal failure in children; medullary cystic kidney disease
  • Renal cystic dysplasias: multicystic dysplastic kidneys: grossly deformed kidneys; most common type of bilateral cystic diseases in newborns (prevalence: 1/4,000)
  • Simple cysts: most common cystic abnormality
    • Localized or unilateral renal cystic disease
    • Medullary sponge kidney
    • Acquired renal cystic disease
  • Renal cystic neoplasms: benign multilocular cyst (cystic nephroma)
DIAGNOSTIC TESTS & INTERPRETATION
Electrolytes, BUN/creatinine, urine analysis plus urinary citrate
Initial Tests (lab, imaging)
  • ADPKD
    • Renal dysfunction
      • Impaired renal concentration (3), hypocitraturia aciduria
      • Hyperfiltration
      • Elevated creatinine
    • Urinalysis: hematuria and mild proteinuria
  • ARPKD
    • Electrolyte abnormalities and renal insufficiency
    • Anemia, thrombocytopenia, leukopenia
  • ADPKD
    • US: It is the easiest diagnostic method. However, it is suboptimal for disease exclusion at age <40 years (2)
      • Renal enlargement is universal.
      • In at-risk patients: By age 30 years, two renal cysts (bilateral or unilateral) are 100% diagnostic. In children, it sometimes appears similar to ARPKD; may be diagnosed in utero.
      • Presence of hepatic cysts in young adults is pathognomonic for ADPKD.
      • In the absence of family history, bilateral renal enlargement and cysts make the diagnosis.
    • CT scan/MRI ideally should be part of the initial evaluation (2).
      • Kidney volume assessed by CT or MRI is a main predictor of progression.
      • Helpful in identifying cysts in other organs
      • In subjects <40 years, fewer than five cysts by MRI excludes the diagnosis (2).
  • ARPKD
    • US: Kidneys are enlarged, homogeneously hyperechogenic (cortex and medulla).
    • CT scan is more sensitive if diagnosis is in doubt.
    • Presence of hepatic fibrosis helps the diagnosis.
Follow-Up Tests & Special Considerations
  • Diagnosis and prevention of secondary problems because of renal and liver abnormalities
  • Follow-up of combined renal volume to assess disease severity
  • Beyond age 2 years, renal size decreases in ARPKD but continues to grow in ADPKD at an average rate of 5.27% per year. Total kidney volume identifies patients with progressive disease (2).
P.821

Diagnostic Procedures/Other
  • Genetic testing is available for PKD1 and PKD2 in ADPKD when imaging results are equivocal and for potential living related donors (4).
  • For PKHD1 in ARPKD, a prenatal diagnosis is feasible in about 72% of patients.
Test Interpretation
  • ADPKD
    • Kidneys are diffusely cystic and, although enlarged, retain their general shape.
    • Cysts range from a few millimeters to several centimeters and are distributed evenly throughout the cortex and medulla.
    • They arise in all segments of the nephron, although they arise initially from the collecting ducts.
    • One kidney may be larger than the other.
  • ARPKD
    • Disease is a spectrum, ranging from severe renal disease with mild liver damage to mild renal disease with severe liver damage.
    • Renal enlargement is due to fusiform dilatation of the collecting ducts in the cortex and medulla in the newborn period.
    • Liver lesion is diffuse but limited to fibrotic portal areas.
image TREATMENT
GENERAL MEASURES
  • HTN: moderate sodium restriction, weight control, and regular exercise
  • Medications: ACE inhibitors; angiotensin receptor blockers (ARBs)
  • Pain: narcotics and other analgesics; bed rest; limit NSAIDs (they worsen renal function)
  • Urolithiasis: treated with alkalinization of urine and hydration therapy; surgery as needed
  • UTIs/Infections of cysts: lipid-soluble antibiotics more effective (e.g., trimethoprim-sulfamethoxazole and chloramphenicol); fluoroquinolones also useful
  • Dialysis for ESKD patients
  • Hematuria: Reduce physical activity.
MEDICATION
  • No specific drug therapy is yet available for PKD, although several studies are being conducted for specific treatments (2,5).
  • HTN: should be very well controlled to prevent complications. ACE inhibitors are preferred if no contraindications are present.
  • The use of antihypertensive medications has been found to decrease mortality (6).
  • Hyperlipidemia: statins preferred
ISSUES FOR REFERRAL
  • Nephrologist primary management
  • Urologic consultation for management of symptomatic/infected cysts
  • Genetic counseling is critical.
SURGERY/OTHER PROCEDURES
  • Indications for surgical intervention
    • Uncontrollable HTN
    • Severe back and loin pain, abdominal fullness
    • Renal deterioration due to enlarging cysts
    • Hematuria/hemorrhage or recurrent UTI
  • Open and laparoscopic cyst unroofing: may decrease pain and narcotics requirements; has not been proven to prevent renal failure or to prolong current renal function
  • Percutaneous cyst aspiration ± injection of sclerosing agent; not usually performed secondary to recurrent fluid accumulation
  • Renal transplant for ESKD
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
Severe pain, gross hematuria with clots
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
None in early stages of the disease; avoid vigorous activity if disease advances. Recurrent gross hematuria is secondary to trauma, associated with faster decline of renal function.
Patient Monitoring
  • Monitor BP and renal function. Encourage hydration. Treat UTI and stone disease aggressively.
  • Avoid nephrotoxic drugs.
  • Creatinine and BP monitoring at least twice a year; more often as needed
  • Screening for intracranial aneurysms (7)
DIET
  • Low-protein diet may retard renal insufficiency.
  • Limit caffeine because this might increase cyst growth.
  • High water intake to decrease ADH >3 liters a day (5)
PROGNOSIS
  • Renal failure in 2% by age 40 years; 23% by age 50 years; 48% by age 73 years
  • ADPKD accounts for 10-15% of dialysis patients.
  • No increased incidence of renal cell cancer
REFERENCES
1. Schrier RW, Brosnahan G, Cadnapaphornchai MA, et al. Predictors of autosomal dominant polycystic disease progression. J Am Soc Nephrol. 2014;25(11):2399-2418.
2. Chapman AB, Devuyst O, Eckardt KU, et al. Autosomal-dominant polycystic kidney disease (ADPKD): executive summary from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int. 2015;88(1):17-27. doi:10.1038/ki.2015.59.
3. Zittema D, Boertien WE, van Beek AP, et al. Vasopressin, copeptin, and renal concentrating capacity in patients with autosomal dominant polycystic kidney disease without renal impairment. Clin J Am Soc Nephrol. 2012;7(6):906-913.
4. Harris PC, Rossetti S. Molecular diagnostics for autosomal dominant polycystic kidney disease. Nat Rev Nephrol. 2010;6(4):197-206.
5. Mahnensmith RL. Novel treatments of autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2014;9(5):831-836.
6. Patch C, Charlton J, Roderick PJ, et al. Use of antihypertensive medications and mortality of patients with autosomal dominant polycystic kidney disease: a population-based study. Am J Kidney Dis. 2011;57(6):856-862.
7. Rozenfeld MN, Ansari SA, Shaibani A, et al. Should patients with autosomal dominant polycystic kidney disease be screened for cerebral aneurysms? AJNR Am J Neuroradiol. 2014;35(1):3-9.
Additional Reading
&NA;
  • Chapman AB, Bost JE, Torres VE, et al. Kidney volume and functional outcomes in autosomal dominant polycystic kidney disease. Clin J Am Soc Nephrol. 2012;7(3):479-486.
  • Harris PC, Torres VE. Polycystic kidney disease. Annu Rev Med. 2009;60:321-337.
  • Torres VE, Chapman AB, Devuyst O, et al. Tolvaptan in patients with autosomal dominant polycystic kidney disease. N Engl J Med. 2012;367(25):2407-2418.
  • Torres VE, Harris PC. Polycystic kidney disease in 2011: connecting the dots toward a polycystic kidney disease therapy. Nat Rev Nephrol. 2011;8(2):66-68.
  • Torres VE, Harris PC, Pirson Y. Autosomal dominant polycystic kidney disease. Lancet. 2007;369(9569):1287-1301.
  • Wilson PD. Polycystic kidney disease. N Engl J Med. 2004;350(2):151-164.
See Also
&NA;
Chronic Kidney Disease
Codes
&NA;
ICD10
  • Q61.3 Polycystic kidney, unspecified
  • Q61.19 Other polycystic kidney, infantile type
  • Q61.2 Polycystic kidney, adult type
Clinical Pearls
&NA;
  • Most PKD patients eventually develop ESKD. No specific treatment has been proven to prevent EKRD, but hydration and control of BP are reasonable goals and should be started soon.
  • Patients may benefit from a nephrology consultation after the initial diagnosis to counsel regarding disease progression prevention. Then, they can be followed by primary care if the disease was an incidental finding or no significant kidney dysfunction is present.