The specific symptoms and their severity can vary greatly from one person to another, even among members of the same family. Most affected individuals develop symptoms between the third and fifth decades of life. However, symptoms may occur during childhood or even in infancy. Some affected individuals never develop obvious symptoms (asymptomatic) and may be diagnosed with ADPKD incidentally in the eighth or ninth decade of life. ADPKD is a highly variable, multisystem disorder; it is important to note that affected individuals will not have all of the symptoms discussed below.
KIDNEY (RENAL) DISEASE
The characteristic finding of ADPKD is the development of fluid-filled sacs (cysts) in the kidneys. All individuals with ADPKD develop cysts in the kidneys, but the number, size, progression and severity of cyst development varies greatly from one person to another. In most cases, renal cysts continue to grow and multiply, potentially causing a variety of symptoms including abnormal enlargement of the kidneys, high blood pressure (hypertension), flank pain, hematuria, poor function of the kidneys (renal insufficiency) and, potentially, kidney failure.
Hypertension affects approximately 50 percent of individuals aged 20-34 most of whom have normal kidney function. In some cases, hypertension may be the first symptom noted. Hypertension usually occurs long before the development of renal failure. Nearly all individuals who develop renal failure have hypertension.
Pain is the most commonly reported symptom of ADPKD. Pain may be described as a sense or feeling of fullness or chronic pain affecting the “flank,” the area of the body between the last rib and the hip (i.e., where the kidneys are located). In some cases, pain may be severe (acute) due to bleeding (hemorrhaging) complications, the passage of kidney stones or chronic urinary tract infection.
Eventually, affected individuals may develop renal insufficiency, which refers to the impaired ability of the kidneys to perform their basic functions. The kidneys are two bean-shaped organs located under the ribcage. The kidneys have several functions including filtering and excreting waste products from the blood and body, creating certain hormones, and helping maintain the balance of certain chemicals in the body such as potassium, sodium, chloride calcium and other electrolytes. Damage to the kidneys in ADPKD may be slowly progressive and can cause a variety of symptoms including weakness and fatigue, changes in appetite, puffiness or swelling, back pain, poor digestion, nausea and vomiting and nocturia (night-time urination) (due to decreased urinary concentration).
The progression to end stage renal disease is slowly progressive in most cases. End stage renal disease is when the kidneys can no longer function properly; they will not be able to filter waste products, regulate hormones or electrolytes, or concentrate urine sufficiently to maintain life. Approximately 50 percent of individuals with the ADPKD1 type develop end stage renal disease by 53 years of age. Those with the ADPKD2 type develop kidney failure about 20 years later.. A wide variety of symptoms may be associated with end stage renal disease including fatigue, weakness, weight loss, difficulty breathing, nausea, vomiting, and cognitive problems such as difficulties concentrating or thinking clearly.
Additional symptoms that can occur in individuals with ADPKD include blood in the urine (hematuria), abdominal or lower back pain, the development of kidney stones (nephrolithiasis), chronic urinary traction infections, and cyst infections. Hematuria affects approximately 40 percent of individuals. Significant (gross) hematuria before the age of 30 is associated with an increased risk of progression of kidney disease. Kidney stones affect approximately 20 percent of individuals with ADPKD. Cyst infections are associated with fever and back or abdominal pain.
Individuals with ADPKD may have symptoms caused by problems outside the kidneys (extrarenal disease). For example, affected individuals may develop cysts in other organs of the body especially the liver (polycystic liver disease). The frequency of polycystic liver disease increases with age affecting more than 90 % of patients with ADPKD1 or ADPKD2. Liver cysts usually develop much later in life and progress much slower than kidney cysts. Women tend to have more liver cysts and larger livers than men. In most cases polycystic liver disease does not cause symptoms. Symptoms that can occur include enlargement of the liver (hepatomegaly), pain in the lower portion of the back, an abnormal early feeling of fullness (early satiety), shortness of breath especially upon exertion (dyspnea), and backflow of the contents of the stomach into the esophagus (gastroesophageal reflux). Yellowing of the eyes and the skin (jaundice) occur rarely if cysts block the bile ducts.
Other organs that may be affected by the formation of cysts include the pancreas, arachnoid membrane (a layer of tissue in the brain), and the glands of the male reproductive tract that produce fluid that is part of semen (seminal vesicles). Cysts affecting the pancreas usually do not cause symptoms except in rare cases in which inflammation of the pancreas (pancreatitis) occurs. Cysts affecting the arachnoid membrane usually do not cause symptoms, but may increase the risk of developing a collection of blood between the outer and middle layers of the covering (meninges) of the brain (subdural hematoma). Cysts affecting the seminal vesicles can potentially cause infertility.
ADPKD can also potentially affect the heart and blood vessels (cardiovascular system). Involvement of the valves of the heart can cause mitral valve prolapse. The mitral valve is located between the left upper and left lower chambers (left atrium and left ventricle) of the heart. Mitral valve prolapse occurs when one or both of the flaps (cusps) of the mitral valve bulge or collapse backward (prolapse) into the left upper chamber (atrium) of the heart. In some cases, this may allow leakage or the backward flow of blood from the left lower chamber of the heart (ventricle) back into the left atrium (mitral regurgitation). In some cases, no associated symptoms are apparent (asymptomatic). However, in other cases, mitral valve prolapse can result in chest pain, abnormal heart rhythms (arrhythmias), fatigue, dizziness, and/or other symptoms and signs.
Some individuals with ADPKD may develop a thickening of the walls the heart, especially within the left ventricle (ventricular hypertrophy). The left ventricle is the lower left chamber of the heart through which oxygenated blood passes into the main artery of the body (aorta). Left ventricular hypertrophy can obstruct the flow of blood from the heart and can be associated with a variety of symptoms.
Some affected individuals may develop widening (dilatation) of the part of the aorta (the main artery of the body) that is attached to the heart (aortic root). Aortic root dilatation can cause aortic insufficiency, in which the valves of the aorta weaken or balloon allowing blood to flow backward into the left ventricle. This can cause a rising pulse rate, chest pain, fatigue, palpitations, shortness of breath and fainting. In rare cases, some individuals with ADPKD have developed an aortic dissection, a life-threatening condition in which there is a tear within the middle layer of the wall of the aorta. This tear causes the middle layer to separate (dissect) from the inner layer.
Another potentially serious complication of ADPKD is the development of weak areas in the walls of the blood vessels of the brain (intracranial aneurysm). Intracranial aneurysms can cause paralysis (palsy) of certain cranial nerves and seizures due to compression of nearby brain structures. If aneurysms rupture they can cause life-threatening bleeding complications. Intracranial aneurysms tend to cluster within families; they occur in approximately 16 percent of individuals with ADPKD with a positive family history of aneurysms. Intracranial aneurysms occur in approximately 6 percent of individuals with ADPKD with a negative family history of aneurysms.
Patients frequently have weaknesses in the abdominal wall near the midline (ventral hernia), in the wall of the abdomen near the bellybutton (umbilical hernia) or protrusion of part of the intestines through a tear in the wall of the lower abdomen (inguinal hernia).
Some individuals with ADPKD may develop out-pouches diverticula on the walls of the large intestines (colon). Inflammation within these may cause abdominal pain, changes in bowel movements (e.g., diarrhea or constipation) and bleeding from part of the large intestines via the rectum.
ADPKD is caused by mutations of one of two genes, the ADPKD1 gene or the ADPKD2 gene. Mutations of the ADPKD1 gene account for approximately 85 percent of cases; the ADPKD2 gene accounts for approximately 15 percent of cases. These mutations are inherited as an autosomal dominant trait. In approximately 10 percent of cases, the mutation occurs randomly for no apparent reason (sporadically). Mutations of the ADPKD1 gene are generally associated with more severe disease, earlier age of onset and early age of onset of end stage renal disease.
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
Researchers believe that additional factors influence the severity of ADPKD including modifier genes and environmental factors. Modifier genes, unlike the genes that cause ADPKD, affect the clinical severity of the disorder. Modifier genes and environmental factors contribute to the wide variability in the severity of ADPKD in affected individuals.
Investigators have determined that the ADPKD1 gene is located on the short arm (p) on chromosome 16 (16p13.3) and that the ADPKD2 gene is located on the long arm (q) of chromosome 4 (4q21). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 16p13.3” refers to band 13.3 on the short arm of chromosome 16. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The ADPKD1 gene contains instructions for creating (encoding) a protein known as polycystin-1; the ADPKD2 gene encodes a protein known as polycystin-2. The exact roles that these proteins play in the proper function and health of the body are not fully understood. These proteins most likely have multiple functions. Researchers speculate that these proteins are involved in regulating the development of tubes and blood vessels in the kidneys and other organs and also help to increase the flow of calcium through cell membranes.
The symptoms of ADPKD result from the development and continued enlargement of cysts in the kidneys and other organ systems of the body. Cysts within the kidneys form in the walls of hair-sized structures called nephrons, which are small tubules that serve as the basic filtering units of the kidneys and help remove waste from the blood. Cysts form on the walls of nephrons and resemble blisters. Most cysts eventually separate from the nephron and continue to grow as isolated sacs of fluid. Cysts grow like tumors to cause the kidneys to become abnormally large. Kidney cysts in ADPKD can potentially number in the thousands and range in size from pin-head to larger than a grapefruit.
ADPKD affects males and females in equal numbers. Although a head-count has never been done, autopsy records show that between 1 in 400-1,000 people in the general population had ADPKD. There are approximately 6,000 new cases diagnosed each year in the United States. Approximately 6-10 percent of individuals receiving dialysis and renal transplant treatments in the United States have ADPKD. ADPKD is estimated to affect approximately 200,000 to 600,000 in the United States and another 12,000,000 people million worldwide, but only about one-fourth may know they have the disease.
ADPKD is diagnosed by a thorough clinical evaluation, a complete patient and family history, and imaging techniques, such as ultrasonography, computed tomography and magnetic resonance imaging. Such imaging studies are typically conducted for individuals with symptoms suggestive of ADPKD; in addition, they may be recommended as screening procedures for relatives of those diagnosed with ADPKD. Ultrasonography is a diagnostic study in which reflected echoes of high-frequency sound waves create an image of certain internal organs such as the kidneys. In some affected individuals, additional imaging studies, such as computerized tomography (CT) and magnetic resonance (MR) imaging, may also be recommended to help detect small cysts and determine the full extent of the disorder. During CT scanning, a computer and x-rays are used to create cross-sectional images of certain tissue structures.
As discussed, ADPKD usually causes symptoms beginning during adulthood. However, in some cases, it may be detected in childhood or infancy or even before birth (prenatally) with ultrasonography. During fetal ultrasonography, reflected sound waves are used to create an image of the developing fetus within the uterus.
Molecular genetic testing for mutations in the ADPKD1 and ADPKD2 genes is available to confirm the diagnosis.
As noted earlier, in individuals with ADPKD, there is a potential risk of bleeding (intracranial hemorrhaging) within the brain. It is advisable that people with a family history of intracranial hemorrhaging or with headaches undergo appropriate screening tests (e.g., magnetic resonance angiography [MRA], CT scanning).
The treatment of individuals with ADPKD involves detailed attention to diet, fluid intake, blood pressure control and the avoidance of harmful drug and life-style choices. Implementation of these measures early in the course of the disease should slow the progression of kidney (renal) disease and preserve kidney function to some extent. . Effective treatment requires the coordinated efforts of a team of specialists working together to systematically and comprehensively plan an affected individual’s personal prescription. Such specialists may include primary care family physicians, pediatricians or internists who collaborate with physicians specializing in disorders of the kidneys (nephrologists), surgical disorders of the urinary tract (urologists), dietitians, and/or other health care professionals. Genetic counseling may be of benefit for affected individuals and their families.
In individuals with ADPKD, therapy typically includes aggressive treatment of high blood pressure (hypertension). Angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARB) are preferred by most specialists who treat hypertension in ADPKD patients. These drugs block substances known to cause the hypertension by narrowing blood vessels (constrict) within the cystic kidneys. In individuals with ADPKD, these drugs may be more effective in preserving kidney function and preventing left ventricular hypertrophy than other therapies for hypertension.
Pain associated with ADPKD can be treated in several ways. Acute pain associated with the rupture of a cyst into adjacent kidney tissue or into the urine collecting system can usually be treated with additional fluid intake, bed rest, and analgesics. Acute pain caused by infections, kidney stones, or a tumor will require an intervention study to be ruled out. Individuals with chronic, mild pain may be able to control it with over-the-counter medications containing acetaminophen. Long-term use of drugs that are toxic to the kidneys such as combination analgesic and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided. For more disabling pain, tricyclic antidepressant drugs or narcotics may be necessary. Splanchic nerve blockade, a procedure in which the injection of local anesthesia or steroids into certain nerves provides temporary relief of pain and ablation of nerves to the kidneys may give some relief. In rare cases a catastrophic decline in the quality of life may necessitate percutaneous cyst decompression, surgical incision and drainage of cysts, or even nephrectomy.
Research has indicated that certain lifestyle modifications may be beneficial for some individuals with ADPKD. Although no specific diet is proven to ameliorate disease progression, some physicians recommend that individuals with ADPKD avoid foods and drinks containing caffeine, limit the amount of protein they eat, and reduce the amount of salt in their diets. Diets should be enriched in fruits and vegetables to provide sufficient potassium and reduce the intake of acid-forming foods. Affected individuals are also encouraged to exercise as much as they are able, to not smoke and to drink extra water throughout the day. Adults are advised to drink 3 liters (quarts) per day and children proportionately less.
In some cases, as cysts grow larger they cause obstruction or compression of nearby structures such as organs or blood vessels. In these cases, surgery may be necessary to drain cysts. Cysts can also rupture causing bleeding (hemorrhaging) or become infected. Cyst hemorrhaging usually responds to bed rest, certain painkillers (analgesics), and fluid intake (hydration) to prevent the formation of obstructing blood clots.
Cyst infections may be difficult to treat and require aggressive antibiotic therapy. However, because antibiotics have difficulty penetrating cysts, this therapy is not always effective. Lipophilic antibiotics (floxacin derivatives) are most effective in troublesome infections. When infected cysts do not respond to antibiotic therapy, surgery to drain the cysts may be necessary.
Kidney Stones (Nephrolithiasis)
Individuals with ADPKD should drink plenty of water as a preventive (prophylactic) measure against the formation of kidney stones. Individuals with chronic stone formation should take in 3-4 liters of water and potassium citrate. In some cases, extracorporeal shock-wave lithotripsy (in which shock waves are used to break apart kidney stones) or percutaneous nephrostolithotomy (in which a needle is passed through the skin into the kidney to remove small stones) may be used to treat affected individuals.
Urinary Tract Infections
Chronic urinary tract infections or kidney infections should be promptly treated with antibiotics to prevent the spread of infection to cysts within the kidneys, which is much more difficult to treat. Women with ADPKD are more susceptible to developing urinary tract infections than men.
Polycystic Liver Disease
In most cases, polycystic liver disease does not require treatment. When polycystic liver disease causes symptoms, affected individuals may be advised to avoid caffeine and estrogens (e.g., hormone replacement therapy). In women who require hormone replacement therapy, transdermal preparations avoid sending high concentrations of drug to the liver as occurs when they are taken by mouth. Certain medications such as proton pump inhibitors, which reduce acids level in the stomach, or H2 blockers may be used to provide relief from gastro-esophageal reflux disease (GERD).
In severe cases, certain procedures may be required to reduce the number of cysts and the size of the liver. Such procedures include percutaneous cyst aspiration, in which a needle is passed through the skin to drain fluid from a cyst; laparoscopic cyst fenestration, in which a small incision is made in the abdominal wall allowing a surgeon to cut a hole into the cyst through which the fluid to drains into the abdominal cavity; and surgical removal (resection) of part of the liver along with cyst fenestration. In rare cases, a liver transplant may be required. The specific procedure used depends on several factors including the progression of the disease, the size, number and location of the cysts, an individual’s age and general health, and other elements.
In some cases, liver cysts may become infected. Treatment with lipophilic antibiotics is recommended and percutaneous cyst drainage may be required.
Affected individuals with a family history of intracranial aneurysms or who have had a previously ruptured aneurysm should be periodically screened for the development of aneurysms. If an aneurysm is large enough, physicians may recommend surgical clipping of the aneurysm, in which a metal clip (usually titanium) is placed at the base or neck of the aneurysms where it bulges out from the blood vessel. This clip prevents blood from flowing into the aneurysm.
End Stage Renal Disease (ERSD)
Individuals with end stage renal disease, in which the kidneys no longer function, require dialysis. Hemodialysis is a procedure in which a machine is used to rinse the blood and remove waste products from the bloodstream, helping to control blood pressure and helping to maintain proper levels of essential chemicals such as potassium. With peritoneal dialysis, the rinsing fluid is placed in the abdominal cavity for several hours and then withdrawn Individuals with ADPKD generally tend to do better on dialysis than individuals undergoing dialysis for other reasons.
End stage renal disease is not reversible so individuals will require lifelong dialysis treatment or a kidney transplant.
Advances in understanding the cause, development and progression of ADPKD have led researchers to explore new therapeutic options for affected individuals. New therapies under study include drugs that block the activity of vasopressin (vasopressin antagonists), a drug that inhibits the activity of certain hormones (somatostatin), and drugs that block the activity of a protein called mTOR (mTOR antagonists).
Vasopressin is an antidiuretic hormone used by the kidneys to manage water balance in the body. Vasopressin antagonists such as tolvaptan are being studied as a potential treatment for individuals with ADPKD. These drugs have dramatically reduced cyst development in four different animal models of renal cystic disease, including adpkd2. A controlled clinical trial determined that tolvaptan slowed the rate of increase in kidney size and reduced the rate of decline in renal function in patients with moderately advanced disease. The drug is approved for use in Japan, but is awaiting approval in the United States and Europe.
Drinking extra amounts of water throughout the day suppresses plasma vasopressin levels and increases urination. Thus, drinking extra plain water has the potential to ameliorate disease progression similar to the blockade of vasopressin V2 receptors in collecting ducts. It is recommended that children and adults with ADPKD drink water frequently when playing or exercising in hot weather.
Octreotide, a long-acting form of somatostatin, has slowed the growth of polycystic kidneys in some individuals with ADPKD. Octreotide has also slowed the growth of the liver in individuals with associated polycystic liver disease. More research is necessary to determine the long-term safety and effectiveness of this potential therapy for ADPKD.
Researchers are also investigating drugs that block the activity of mTOR (mTOR antagonists). mTOR is a protein that is involved in various chemical processes of the body including cell growth and proliferation. mTOR stands for mammalian target of rapamycin. mTOR antagonists such as sirolimus are being studying in individuals with ADPKD. Two controlled clinical trials explored the effect of mTOR inhibitors in patients with advanced disease and found no benefit. More research is necessary to determine the long-term safety and effectiveness of mTOR antagonists as a therapy for individuals with ADPKD.
Pravastatin, which lowers blood cholesterol, reduced the rate of increase in kidney size in children with ADPKD. More work is required before recommending that this agent be prescribed to patients.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
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