Autosomal dominant polycystic kidney
|Polycystic Kidney Disease|
|Classification and external resources|
Autosomal dominant polycystic kidney disease ("ADPKD", "autosomal dominant PKD" or "Adult-onset PKD") is an inherited systemic disorder that predominantly affects the kidneys, but may affect other organs including the liver, pancreas, brain, and arterial blood vessels. Approximately 50% of people with this disease will develop end stage kidney disease and require dialysis or kidney transplantation. Progression to end stage kidney disease usually happens in the 4th to 6th decades of life. Autosomal dominant polycystic kidney disease occurs worldwide and affects about 1 in 400 to 1 in 1000 people.
Defects in two genes are thought to be responsible for ADPKD. In 85% of patients, ADPKD is caused by mutations in the gene PKD1 on chromosome 16 (TRPP1); in 15% of patients mutations in PKD2 (TRPP2) are causative.
Autosomal recessive polycystic kidney disease is a distinct disease that also leads to cysts in the kidneys and liver, typically presents in childhood, only affects about 1 in 20,000 people and has different causes and prognosis.
Recent studies in fundamental cell biology of cilia and flagella using experimental model organisms such as the round worm Caenorhabditis elegans and the mouse Mus musculus have shed light on how PKD develops in human patients.
All cilia and flagella are constructed and maintained by the process of intraflagellar transport, a cellular function that is also essential for the insertion of proteins at specific sites along cilia and flagella membranes. These inserted membrane proteins can initiate environmental sensing and intracellular signaling pathways. They play a special role in the cilia of renal epithelial cells, and are thought to be critical for normal renal cell development and function and are sorted out and localized to the cilia of renal epithelial cells by the aforementioned intraflagellar transport mechanism. Ciliated epithelial cells line the lumen of the urinary collecting ducts and sense the flow of urine. Failure in flow-sensing signaling results in proliferation of these renal epithelial cells, producing the characteristic multiple cysts of PKD. PKD may result from mutations of signaling and environmental sensing proteins, or failure in intraflagellar transport.
Two PKD genes, PKD1 and PKD2, encode membrane proteins that localize to a non-motile cilium on the renal tube cell. Polycystin-2 encoded by PKD2 gene is a calcium channel that allows extracellular calcium ions to enter the cell. Polycystin-1, encoded by PKD1 gene, is thought to be associated with polycystin-2 protein and regulates polycystin-2's channel activity. The calcium ions are important cellular messengers, which trigger complicated biochemical pathways that lead to quiescence and differentiation. Malfunctions of polycystin-1 or polycystin-2 proteins, defects in the assembly of the cilium on the renal tube cell, failures in targeting these two proteins to the cilium, and deregulations of calcium signaling all likely cause the occurrence of PKD.
As stated above, defects in two genes are thought to be responsible for ADPKD. In 85% of patients, ADPKD is caused by mutations in the gene PKD1 on chromosome 16 (TRPP1); in 15% of patients mutations in PKD2 (TRPP2) are causative.
PKD and the "two hit" hypothesis
The two hit hypothesis (aka Knudson hypothesis ) is often used to explain the manifestation of polycystic kidney disease later in life even though the mutation is present at birth. This term is borrowed from cancer research stating that both copies of the gene present in the genome have to be "silenced" before cancer manifests itself (in Knudson's case the silenced gene was Rb1). In ADPKD the original "hit" is congenital (in either the PKD1 or PKD2 genes) and the subsequent "hit" occurs later in life as the cells grow and divide. The two hit hypothesis as it relates to PKD was originally proposed by Reeders in 1992. Support for this hypothesis comes from the fact that ARPKD patients develop disease at birth, and somatic mutations in the "normal" copy of PKD1 or PKD2 have been found in cyst-lining epithelia
Relation to other rare genetic disorders
Recent findings in genetic research have suggested that a large number of genetic disorders, both genetic syndromes and genetic diseases, that were not previously identified in the medical literature as related, may be, in fact, highly related in the genetypical root cause of the widely varying, phenotypically-observed disorders. Thus, PKD is a ciliopathy. Other known ciliopathies include primary ciliary dyskinesia, Bardet-Biedl syndrome, polycystic liver disease, nephronophthisis, Alstrom syndrome, Meckel-Gruber syndrome, and some forms of retinal degeneration.
A definite diagnosis of ADPKD relies on imaging or molecular genetic testing. The sensitivity of testing is nearly 100% for all patients with ADPKD who are age 30 years or older and for younger patients with PKD1 mutations; these criteria are only 67% sensitive for patients with PKD2 mutations who are younger than age 30 years. Large echogenic kidneys without distinct macroscopic cysts in an infant/child at 50% risk for ADPKD are diagnostic. In the absence of a family history of ADPKD, the presence of bilateral renal enlargement and cysts, with or without the presence of hepatic cysts, and the absence of other manifestations suggestive of a different renal cystic disease provide presumptive, but not definite, evidence for the diagnosis.
Molecular genetic testing by linkage analysis or direct mutation screening is available clinically; however, genetic heterogeneity is a significant complication to molecular genetic testing. Sometimes a relatively large number of affected family members need to be tested in order to establish which one of the two possible genes is responsible within each family. The large size and complexity of PKD1 and PKD2 genes, as well as marked allelic heterogeneity, present obstacles to molecular testing by direct DNA analysis. In the research setting, mutation detection rates of 50-75% have been obtained for PKD1 and ~75% for PKD2. Clinical testing of the PKD1 and PKD2 genes by direct sequence analysis is now available, with a detection rate for disease-causing mutations of 50-70%.
Genetic counseling may be helpful for families at risk for polycystic kidney disease.
Although a cure for PKD is not available, treatment can ease the symptoms and prolong life.
- Pain: Over-the-counter pain medications, such as paracetamol (acetaminophen) can relieve pain. For most but not all cases of severe pain, surgery to shrink cysts can relieve pain in the back and flanks. However, surgery provides only temporary relief and usually does not slow the disease's progression toward kidney failure.
- Urinary tract infections: Patients with PKD tend to have frequent urinary tract infections, which can be treated with antibiotics. Early treatment is important, because infection can spread from the urinary tract to the cysts in the kidneys. Cyst infections are difficult to treat because many antibiotics do not penetrate into the cysts. However, some antibiotics are effective.
- High blood pressure: Keeping blood pressure under control can slow the effects of PKD. Lifestyle changes including low salt diet and various medications especially ACE inhibitors and angiotensin receptor blockers can lower high blood pressure. Recommended target BP in these patients is 130/80 mm Hg or lower.
- End-stage renal disease: There are two options for replacing kidney functions: dialysis or transplantation. Healthy (non-PKD) kidneys transplanted into PKD patients do not develop cysts.
Despite significant research, prognosis of this disease has changed little over time. It is suggested that avoidance of caffeine may prevent cyst formation. Although not well-proven, treatment of hypertension and a low protein diet may slow progression of the disease.
Between PKD1 and PKD2, the former has the worse prognosis.
- Grantham, Jared (Oct 2, 2008). "Autosomal Dominant Polycystic Kidney Disease". New England Journal of Medicine 359 (14): 1477–1485. doi:10.1056/NEJMcp0804458. PMID 18832246.
- Torres, Vicente; Harris, Peter C (20 May 2009). "Autosomal dominant polycystic kidney disease: the last 3 years". Kidney International 76 (2): 149–168. doi:10.1038/ki.2009.128. PMC 2812475. PMID 19455193.
- DALGAARD OZ (1957). "Bilateral polycystic disease of the kidneys; a follow-up of two hundred and eighty-four patients and their families". Acta Med. Scand. Suppl. 328: 1–255. PMID 13469269.
- Zerres K, Mücher G, Becker J, et al. (1998). "Prenatal diagnosis of autosomal recessive polycystic kidney disease (ARPKD): molecular genetics, clinical experience, and fetal morphology". Am. J. Med. Genet. 76 (2): 137–44. doi:10.1002/(SICI)1096-8628(19980305)76:2<137::AID-AJMG6>3.0.CO;2-Q. PMID 9511976.
- Calvet, James P. (Oct 2002). "Cilia in PKD—Letting It All Hang Out". Journal of the American Society of Nephrology 13 (10): 2614–16. PMID 12239253.
- Yoder BK, Hou X, Guay-Woodford LM (Oct 2002). "The Polycystic Kidney Disease Proteins, Polycystin-1, Polycystin-2, Polaris, and Cystin, Are Co-Localized in Renal Cilia". Journal of the American Society of Nephrology 13 (10): 2508–2516. doi:10.1097/01.ASN.0000029587.47950.25. PMID 12239239.
- First Aid for the USMLE. 2011, pg. 472
- Reeders ST (1992). "Multilocus polycystic disease". Nat. Genet. 1 (4): 235–7. doi:10.1038/ng0792-235. PMID 1338768.
- Badano, Jose L.; Norimasa Mitsuma, Phil L. Beales, Nicholas Katsanis (September 2006). "The Ciliopathies : An Emerging Class of Human Genetic Disorders". Annual Review of Genomics and Human Genetics 7: 125–148. doi:10.1146/annurev.genom.7.080505.115610. PMID 16722803. Retrieved 2008-06-15.
|Wikimedia Commons has media related to Autosomal dominant polycystic kidney.|
- Photo demonstrating size of polycystic kidneys
- The Polycystic Kidney Disease Foundation website - more details on trials, treatments, nutrition, and support.