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. ADPKD patients commonly present with hypertension, hematuria, and flank pain. Extrarenal manifestations include intracerebral aneurysm, hepatic and pancreatic cysts, and cardiac valvular abnormalities. Diagnosis is by history, physical exam, and ultrasonography. Management requires a multidisciplinary approach and many patients require renal replacement therapy. The end goal is to slow the progression of renal disease by controlling hypertension, proteinuria, and symptoms. ADPKD prognosis is dependent on a variety of factors. A cerebral aneurysm is a complication associated with a particularly poor prognosis.

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Epidemiology and Etiology

Epidemiology

Polycystic kidney disease (PKD) affects about 500,000 people in the United States. One of the 2 main types of PKD is autosomal dominant polycystic kidney disease (ADPKD).

  • Most commonly inherited kidney disease
  • Prevalence: 1 in 1,000 live births
  • Cause of CKD in 5% of annual dialysis initiation
  • Decline in renal function often noted by the 4th decade of life

Etiology

  • Autosomal dominant (positive family history)
  • Either a mutation of: 
    • PKD1 (encodes polycystin-1) on chromosome 16 OR
    • PKD2 (encodes polycystin-2) on chromosome 4

Clinical Presentation

The age of symptom onset is variable, but typically in adulthood. Patients with PKD1 mutation present with symptoms earlier than patients with PKD2.

Renal manifestations

  • Hypertension
  • Hematuria
  • Proteinuria
  • Kidney function impairment
  • Flank or abdominal pain
  • Enlarged, palpable kidneys on physical exam (patients with PKD1 mutation have larger kidneys and more cysts than patients with PKD2)
  • Recurrent urinary tract infections (UTIs)
  • Nephrolithiasis 

Extrarenal manifestations

  • Cerebral aneurysm:
    • 4 times higher risk than the general population
    • Can rupture with subarachnoid hemorrhage or intracerebral hemorrhage (ICH)
    • The most serious risk factor associated with ADPKD
  • Benign, asymptomatic hepatic cysts:
    • Higher prevalence as age increases
    • Can be complicated by cyst infection or hemorrhage
  • Benign, asymptomatic pancreatic cysts
  • Seminal vesicle cysts
  • Cardiac valvular abnormalities:
    • Most commonly mild mitral valve prolapse or aortic regurgitation
    • Often asymptomatic with a mild murmur
  • Colonic diverticula
  • Abdominal wall and inguinal hernias

Diagnosis

Diagnosis is made with the combination of positive family history and the presence of multiple, bilateral renal cysts.

Physical exam

  • Assess for palpable kidneys.
  • Assess for syndromic features and extrarenal manifestations.

Imaging studies

  • Ultrasonography of abdomen to detect renal cysts (1st line)
  • CT or MRI:
    • If ultrasound findings inconclusive
    • Can detect cysts of smaller size
    • Determines total kidney volume (helps assess the risk of kidney disease progression)
Ultrasound of autosomal dominant polycystic kidney disease

Ultrasound of autosomal dominant polycystic kidney disease (ADPKD):
sagittal gray-scale ultrasound scan of both kidneys shows numerous cystic, space-occupying lesions with marked internal echogenic debris and thick septa, representing the numerous infected cysts

Image: “Value of ultrasound-guided irrigation and drainage of refractory pyocysts in ADPKD” by Saedi D, Varedi P, Varedi P, Mahmoodi S, Gashti HN, Darabi M. License: CC BY 2.0

Genetic testing

  • If imaging tests uncertain
  • If atypical features:
    • Early, severe ADPKD
    • Renal failure without significantly enlarged kidneys
    • The disease is significantly discordant with family members.
    • Significant asymmetry of disease between each kidney
    • ADPKD without a family history
  • If information is needed for reproductive counseling

Management and Prognosis

Management approach

Goals:

  • To slow renal disease progression
  • To control blood pressure and lower cardiovascular risk

Treatment measures:

  • ACE inhibitors and ARBs for blood pressure control
  • Restrict dietary sodium.
  • Increase fluid intake.
  • Manage complications (e.g., UTIs, nephrolithiasis).
  • Tolvaptan for high-risk patients:
    • Blocks the positive effect of vasopressin on cyst production
    • Can decrease cyst growth 

For end-stage renal disease (ESRD):

  • Hemodialysis or peritoneal dialysis
  • Kidney transplantation

Screening

  • Benefits of genetic counseling and screening for patients and family: 
    • Information on diagnosis and prevention/treatment of complications
    • Family planning (risks of passing condition to offspring)
    • Possible kidney transplant donor among relatives
  • Screening for intracerebral aneurysms with presymptomatic imaging (MRA or CT angiography):
    • Family history of intracranial aneurysm
    • Plans to have major surgery
    • High-risk occupations (ruptured aneurysm could put other lives at risk, e.g., pilot)
    • Requires anticoagulation (increased risk of bleeding)

Prognosis

  • Varies from person to person
  • Generally a slow rate of disease progression
  • About ½ of patients ≥ 75 years of age require dialysis and/or kidney transplantation.
  • Most patients die from cardiac causes.
  • Particularly poor prognosis with a ruptured cerebral aneurysm
Gross pathology from nephrectomy in a patient with autosomal dominant polycystic kidney disease

Gross pathology from nephrectomy in a patient with autosomal dominant polycystic kidney disease (ADPKD)

Image: “Incidental renal cell carcinoma presenting in a renal transplant recipient with autosomal dominant polycystic kidney disease” by Misumi T, Ide K, Onoe T, Banshodani M, Tazawa H, Teraoka Y, Hotta R, Yamashita M, Tashiro H, Ohdan H. License: CC BY 2.0, cropped by Lecturio.

Comparison

The 2 main types of polycystic kidney disease are ADPKD and autosomal recessive polycystic kidney disease (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), radiate 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 of age: ≥ 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: Renal cysts are a common, asymptomatic, incidental finding in adults. The cysts increase in number with age. Differentiation from mild ADPKD may be difficult. Patients without ADPKD generally do not have a family history, gross hematuria, flank pain, or renal insufficiency.
  • Localized renal cystic disease: a localized, benign condition confused with PKD. Unlike PKD, the condition is a localized cystic disease and neither bilateral nor progressive. Patients have no family history of ADPKD. 
  • 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.
  • Medullary sponge kidney: malformation of the collecting ducts (tubular dilatation) limited to the medullary pyramids. The condition may mimic PKD on urographic studies. Patients can present with kidney stones, hematuria, and UTIs. Unlike PKD, the renal cortex is spared, which can be seen on CT or MRI.
  • 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).
  • Autosomal dominant tubulointerstitial kidney disease: a rare genetic disorder characterized by a gradual decline in kidney function from the teenage years. The onset of ESRD is variable. Presentation includes early-onset gout, hyperuricemia, and, in some, renal cysts. Unlike PKD, cysts are at the corticomedullary junction and the kidneys are small to normal in size.

References

  1. Bennett W.M., Torres V.E. (2020). Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations. UpToDate. Retrieved Feb 25, 2021, from https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-extrarenal-manifestations
  2. Chapman AB, Rahbari-Oskoui FF, Bennett WM. (2020). Autosomal dominant polycystic kidney disease (ADPKD): Renal manifestations. UpToDate. Retrieved Feb 25, 2021, from https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-renal-manifestations
  3. Chapman A.B., Rahbari-Oskoui, F.F., Bennett, W.M. (2020). Autosomal dominant polycystic kidney disease (ADPKD): Treatment. UpToDate. Retrieved Feb 25, 2021, from https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-treatment
  4. Genetic and Rare Disease Information Center. (2020). Autosomal dominant polycystic kidney disease. Retrieved February 25, 2021, from https://rarediseases.info.nih.gov/diseases/10413/autosomal-dominant-polycystic-kidney-disease 
  5. 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]. Brisbane (AU): Codon Publications. https://www.ncbi.nlm.nih.gov/books/NBK373387/
  6. 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.
  7. 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
  8. Merck Manual. (2019). Autosomal Dominant Polycystic Kidney Disease (ADPKD). https://rarediseases.info.nih.gov/diseases/10413/autosomal-dominant-polycystic-kidney-disease
  9. National Institute of Diabetes and Digestive and Kidney Diseases. (2017). What is Polycystic Kidney Disease? https://www.niddk.nih.gov/health-information/kidney-disease/polycystic-kidney-disease/what-is-pkd#symptoms
  10. 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/
  11. Torres V.E., Bennett W.M. (2021). Autosomal dominant polycystic kidney disease (ADPKD) in adults: Epidemiology, clinical presentation, and diagnosis. UpToDate. Retrieved Feb 25, 2021, from https://www.uptodate.com/contents/autosomal-dominant-polycystic-kidney-disease-adpkd-in-adults-epidemiology-clinical-presentation-and-diagnosis
  12. Zhou J, & Pollak M.R. (2018). Polycystic kidney disease and other inherited disorders of tubule growth and development. In Jameson LJ, 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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