Polycystic kidney disease and genetics
Polycystic kidney disease (PKD) is a hereditary disorder characterized by the formation of multiple fluid-filled cysts in the kidneys. These cysts can lead to kidney enlargement and impair normal kidney function, potentially causing complications such as high blood pressure, kidney stones, infections, and ultimately kidney failure. The disease primarily arises from genetic mutations in two genes, PKD1 and PKD2, with PKD1 mutations accounting for about 85% of adult cases. PKD is inherited in an autosomal dominant manner, meaning that a child has a 50% chance of inheriting the condition if one parent is affected.
In some cases, PKD can occur due to spontaneous mutations, and a rarer, severe form of the disease caused by mutations in the PKHD1 gene is inherited in an autosomal recessive fashion. Symptoms often emerge in middle age and may include back pain, high blood pressure, and blood in urine, although some individuals remain asymptomatic. Diagnosis typically involves medical history reviews and imaging tests like ultrasound or CT scans. While there is no cure for PKD, various treatments focus on managing symptoms and preventing complications, including medications for high blood pressure and potential surgical interventions. Genetic counseling may be beneficial for individuals with a family history of PKD.
Polycystic kidney disease and genetics
ALSO KNOWN AS: PKD; autosomal dominant polycystic kidney disease; AKPKD; adult polycystic disease; polycystic kidney disease type 2
DEFINITION The word polycystic means many cysts. Polycystic kidney disease (PKD) is an inherited disease that causes many cysts to form in the kidneys.
Cysts, which are sacs filled with fluid, grow in both kidneys causing them to become enlarged. The number of cysts can range from a few to a great number. The size of the cysts can vary from too small to detect to cysts larger than the kidney itself. PKD can be painful and interfere with the normal functioning of the kidney, resulting in infection, kidney stones, high blood pressure, and, eventually, kidney failure. PKD is a potentially serious condition that requires care from a doctor.
Risk Factors
The primary risk factor for PKD is having a parent with the disease. Fifty percent of children born to a parent with the PKD gene develop the disease. In about 10 percent of cases, the gene for the disease was not inherited, but mutated. PKD affects men and women equally.
Etiology and Genetics
The majority of cases of adult-onset polycystic kidney disease result from a genetic disorder, but some cases are known in which the disease has been acquired, usually after years of dialysis for kidney failure of unrelated origin. The genetic forms result from mutations in either of two genes, PKD1 or PKD2. About 85 percent of cases result from mutations in PKD1, found on the short arm of chromosome 16 at position 16p13.3. This gene encodes a large protein called polycystin-1, which normally spans the membrane of kidney cells and receives chemical signals from outside the cell that help the cell respond properly under varying environmental conditions. The protein interacts with polycystin-2 (the product of the PKD2 gene, found on chromosome 4 at position 4q21-q23) to trigger a cascade of cellular reactions. A missing or altered polycystin-1 protein disrupts this signaling, and cells in the renal tissue may grow and divide abnormally, resulting in the cyst development that is symptomatic of the disease. Mutations in PKD2, which account for the remaining 15 percent of adult cases, result in abnormal polycystin-2 proteins that lead to similar physiological malfunctions. Mutations in either gene are inherited in an autosomal dominant fashion, meaning that a single copy of the mutation is sufficient to cause full expression of the disease. An affected individual has a 50 percent chance of transmitting the mutation to each of his or her children. About 10 percent of cases of polycystic kidney disease, however, result from a spontaneous new mutation, so in these instances affected individuals will have unaffected parents.
A rare severe form of polycystic kidney disease that usually is diagnosed at birth or in early infancy results from mutations in the PKHD1 gene (at position 6p12.2). The protein encoded by this gene is fibrocystin, a membrane-spanning protein with functions similar to polycystin-1. This often lethal form of the disease is inherited in an autosomal recessive manner, which means that both copies of the PKHD1 gene must be deficient in order for the individual to be afflicted. Typically, an affected child is born to two unaffected parents, both of whom are carriers of the recessive mutant allele. The probable outcomes for children whose parents are both carriers are 75 percent unaffected and 25 percent affected.
Symptoms
During the early stages of PKD, there are often no symptoms. Some people are never diagnosed because their symptoms are mild. Most symptoms appear in middle age.
Frequently, the first symptom is pain in the back or flank area. Other signs of PKD include high blood pressure, blood in the urine, urinary tract infection, and kidney stones. Additional, less common symptoms may include nail abnormalities, painful menstruation, joint pain, and drowsiness.
Individuals who experience any of these symptoms should not assume it is due to PKD. These symptoms may be caused by other, less serious health conditions. Individuals who experience any one of the symptoms should see their physicians.
Screening and Diagnosis
The doctor will ask about a patient’s symptoms and medical history and will perform a physical exam. When diagnosing PKD, the doctor may begin by looking for signs of the disease, including high blood pressure, enlarged or tender kidneys, enlarged liver, and protein or blood in the urine.
An abdominal ultrasound is usually the test of first choice to detect the presence of cysts on the kidneys. If cysts are too small to be detected by ultrasound and the diagnosis is still in question, an abdominal computed tomography (CT) scan or a magnetic resonance imaging (MRI) scan may be performed.
If the diagnosis still remains unconfirmed, additional tests may be ordered, including a gene linkage study, a blood test that tests the of the patient and family members with and without PKD; and direct DNA sequencing, a blood sample of a patient’s DNA to look for presence of the PKD gene.
Between 10 and 40 percent of patients with PKD also have an aneurysm (a weakness in the wall of a blood vessel) in the brain. If a patient is diagnosed with PKD and there is a family history of a brain aneurysm, the doctor may recommend an arteriogram to detect the presence of an aneurysm.
Treatment and Therapy
Most treatments for PKD treat the disease symptoms or prevent complications. Some of these treatment options may include high blood pressure medication. Since high blood pressure is common with PKD, antihypertensive medications are often prescribed to control blood pressure.
Pain medications must be used cautiously, since some of them can cause further damage to the kidneys. In the event of a urinary tract infection, aggressive treatment with antibiotics is required to avoid further damage to the kidneys.
Cysts may be drained through surgery to relieve pain, blockage, infection, or bleeding. Cyst drainage may also temporarily lower blood pressure. Sometimes, one or both kidneys may be removed, a procedure called a nephrectomy, if pain is severe.
A low-protein diet may reduce stress on the kidney. Avoiding salt can help maintain normal blood pressure, and drinking lots of water can help reduce the risk of kidney stones.
More than half of PKD patients develop kidney failure and require dialysis. Dialysis is used to remove wastes from the blood, since the kidneys cannot. At this stage, dialysis will be a lifelong requirement unless a kidney transplant from a donor can be arranged and performed successfully.
Recent research has led to the development of several drugs that may prevent cysts from developing. An example is somatostatin, which has been studied in humans and may one day be available to prevent polycystic kidneys from developing.
Prevention and Outcomes
PKD is an inherited disease and is not preventable. Individuals who have a family history of PKD may want to talk to their doctors about genetic testing. According to a 2024 study by the online journal StatPearls, about 500,000 people were affected by the condition in the United States.
Bibliography
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Daugirdas, John T. Handbook of Chronic Kidney Disease Management. Philadelphia: Lippincott, 2011. Print.
Kellicker, Patricia Griffin. “Polycystic Kidney Disease.” Health Library. EBSCO Information Services, 11 May 2013. Web. 6 Aug. 2014.
Mahboob, Muddassar, Preeti Rout, Stephen W. Leslie, and Syed Rizwan A. Bokhari. "Autosomal Dominant Polycystic Kidney Disease." StatPearls, 20 Mar. 2024, www.ncbi.nlm.nih.gov/books/NBK532934/. Accessed 6 Sept. 2024.
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