FRAMINGHAM, Mass., Nov. 27 (UPI) -- U.S. medical scientists say a drug that alters renal cell proliferation may prove a useful treatment for polycystic kidney disease
Oxana Ibraghimov-Beskrovnaya and colleagues at the Genzyme Corp. in Framingham, Mass., found (r)-roscovitine -- a drug that interferes with cell proliferation -- slows disease progression in two mouse models of autosomal dominant polycystic kidney disease, or ADPKD.The researchers found a single pulse treatment produced robust, long-lasting effects in mice, and was effective against cysts found in different parts of the kidney.Human ADPKD is a late-onset genetic disorder without effective treatment, the scientists noted, with fluid-filled cysts forming in the kidney tubules, leading to renal failure.The researchers suspect the cells making up the hair-like cilia that line the kidney tubules have abnormal cell cycles and (r)-roscovitine alters that by inhibiting enzymes called cyclin-dependent kinases.The study appears online in the journal Nature and will be published in the print edition at a later date.
http://www.dailyindia.com/show/86448.php/Drug-shows-promise-for-renal-disease
Wednesday, November 29, 2006
Yale Cell Biologist, Joel Rosenbaum, To Receive American Society For Cell Biology's Highest Honor For Scientific Research In Cell Biology
Joel Rosenbaum, professor in the Department of Molecular, Cellular and Developmental Biology (MCDB) and faculty member at Yale since 1967, has been named the recipient of the 2006 E. B. Wilson Medal, the American Society for Cell Biology's highest honor for scientific research in cell biology. The medal will be presented to Rosenbaum for significant advances, over a lifetime, on the assembly, maintenance and function of fine, hair-like cell organelles, called cilia and flagella (interchangeable terms), which extend from the cell surface. Recently, Rosenbaum and his students and colleagues have shown that the cilia are fundamental to the pathogenesis of one of the most prevalent of human diseases, PKD, polycystic kidney disease, forms of which can affect as many as 1 in 500 people. Rosenbaum has produced much of his groundbreaking research by studying cilia/flagella in single celled protistans, principally the bi-flagellate alga, Chlamydomonas. Cilia are best studied in organisms like Chlamydomonas because their structure has been conserved even to humans, and they can be grown in quantity to isolate flagella in large amounts. Further, their cell division is easily synchronized and the genome sequence of Chlamydomonas and the flagellar "proteome," or complete catalogue of proteins, has been published. Using this organism, Rosenbaum designed systems to study flagellar growth and regeneration. In some of his initial studies, as a post doctoral fellow at the University of Chicago, Rosenbaum showed that flagella grew and elongated by adding on new subunits to their tips, distant from the cell body where the flagellar proteins are synthesized. When listening to Rosenbaum present this "flagellar tip growth" story in the mid-1970s, former Yale Professor and Nobel laureate George Palade suggested that there "must be elevators in the flagella" carrying subunits from their site of synthesis in the cell body to the tip of the flagella where assembly takes place. Finally, in 1992, using new high-resolution microscopes in the laboratory of Paul Forscher, who had recently joined the department, Rosenbaum's graduate student, Keith Kozminski, was first able to observe these elevators. He saw particles moving up and down the length of the flagella, between the membrane and the microtubule-based core of the flagella. They named the process intraflagellar transport (IFT). These initial observations led to biochemical and genetic studies showing that molecular motors controlled movement of the IFT particles. When the motors were stopped, flagella would not form, and already-formed flagella became shorter. They also showed that the IFT particles served as transports, carrying prefabricated parts of the flagellar core to the tip for assembly, and recycling turnover products from the tip back to the cell body. Over the next several years, IFT particles were isolated, their polypeptides identified, and many of the genes for IFT cloned. When the IFT genes were compared with the various available "on line" gene libraries, they were surprised to find that a sequence matching one Chlamydomonas IFT gene, called "IFT88" was in the mouse genome and was the gene which was defective in the then-current mouse model of polycystic kidney disease (PKD). The relationship between an IFT particle gene that would block flagella assembly in Chlamydomonas when mutated and produce PKD in the mouse model seemed remote. Few had paid attention to the fact that the cells forming the kidney tubules each had a single non-motile "primary" cilium pointing toward the center of the tubule. When Rosenbaum and his colleagues Gregory Pazour and George Witman at University of Massachusetts Medical School examined kidney tubules of the PKD mutant mouse with the scanning electron microscope, they found that the cilia were either short or missing. They also provided conclusive evidence for the importance of cilia in the PKD pathology by demonstrating that the polycystins, gene products of the PKD genes, were located on these cilia. Because cilia were related directly to the disease, this became known as the "ciliary hypothesis of PKD." "Researchers at the NIH and Yale Medical School have now shown that these cilia bend when urine flows down the tubules, admitting calcium through the polycystins, which are mechano-receptors in the ciliary membrane. Through a signaling pathway, the calcium represses cell division," said Rosenbaum. "If calcium does not flow in, because the cilia are missing, or the polycystins on the membrane are missing or ineffective, a signal is sent to the nucleus and the tubule cells divide-and continue to divide. PKD is, therefore, a cancer of the kidney, where cells that should not be dividing start to divide because of a defect in a signaling pathway starting at the cilium" This sensory role of primary non-motile cilia has now become the model for many other diseases and syndromes, all of which trace back in many different tissues to defects in receptors or channels on the ciliary membrane, or to the complete lack of the cilium due to a defect in the IFT process. Rosenbaum's laboratory is now working on the connection between cilia and the cell cycle. "These primary non-motile cilia must resorb prior to cell division or the cell will not divide," he said. Their latest work shows that when the amount of one of the IFT polypeptides, a small G protein, is decreased, the cell cycle is severely inhibited. This IFT small G-protein is a direct link between cilia and the cell cycle. In a normal cell cycle, the protein decreases, taking all the other IFT polypeptides with it, causing the cilia to shorten, and permitting the ciliary basal bodies/centrioles to migrate to the center of the cell to form the mitotic apparatus. Following chromosome separation, the amount of this IFT protein again increases, and the cell divides. If the amount of the IFT protein is kept low experimentally, the cells will not divide, and will die. Understanding the IFT process has also led to discoveries on causes of conditions like situs inversus, a condition in which the heart or other organs grow on the wrong side of the body's midline during embryonic development. Rosenbaum's colleague in pediatric cardiology, Associate Professor Martina Brueckner, has shown that the presence of cilia in the embryonic nodal region is directly related to this condition; if the cilia are missing or not functioning, situs inversus results. In the mutant mouse with defective or missing cilia, situs inversus occurs as well as PKD in many cases. Many of these mice are also blind, because the rod outer segments of the retina form from cilia during embryogenesis, and are maintained in adults by IFT in a piece of the cilium in the adult rod cell. Finally, a complex of diseases called Bardet-Biedl Syndrome (BBS), which can manifest itself in diabetes, polydactyly, and obesity, all stem from defects in the cilia or the ciliary basal body/centriole. "It seems as though, each month a new disease is shown to have its origin in these oft-neglected cell organelles," said Rosenbaum." The exciting thing, Rosenbaum feels, is that all of this work relating to human diseases began with studies initiated on flagellar assembly in a green alga. It is an example of the continuity of life, or as Rosenbaum says, "If you've seen one cilium, you have [almost] seen them all." Rosenbaum is the seventh member of the Yale faculty to receive the Wilson Award, In 2005, Joan A. Steitz, Sterling Professor of Molecular Biophysics & Biochemistry and Investigator of the Howard Hugnes Medical Institute, received the award for her work on small nuclear ribonucleoproteins, known now as SnRNPs. In 2004, Thomas D. Pollard, Sterling Professor and Chair of the Department of Molecular Cellular & Developmental Biology, received the award for his pioneering work on the molecular basis of cell movement. Other past Yale faculty who have received the award are George Palade and Marilyn Farquhar (University of California, San Diego), Joseph Gall (Carnegie Institute of Embryology), and Bruce Nicklas (Duke University). ### Yale News Releases are available via the World Wide Web at http://www.yale.edu/opa
Tuesday, November 28, 2006
What is a Brain Aneurysm?
A brain aneurysm, also called a cerebral or intracranial aneurysm, is an abnormal bulging outward of one of the arteries in the brain. It is estimated that up to one in 15 people in the United States will develop a brain aneurysm during their lifetime.
Brain aneurysms are often discovered when they rupture, causing bleeding into the brain or the space closely surrounding the brain called the subarachnoid space, causing a subarachnoid hemorrhage. Subarachnoid hemorrhage from a ruptured brain aneurysm can lead to a hemorrhagic stroke, brain damage and death.
The main goals of treatment once an aneurysm has ruptured are to stop the bleeding and potential permanent damage to the brain and to reduce the risk of recurrence. Unruptured brain aneurysms are sometimes treated to prevent rupture. Learn more about treatment options for a brain aneurysm.
Incidence Rates of Brain Aneurysms
Approximately 0.2 to 3 percent of people with a brain aneurysm may suffer from bleeding per year
The annual incidence of aneurysmal subarachnoid hemorrhage in the U.S. exceeds 30,000 people. Ten to 15 percent of these patients will die before reaching the hospital and over 50 percent will die within the first thirty days after rupture. Of those who survive, about half suffer some permanent neurological deficit
Brain aneurysms can occur in people of all ages, but are most commonly detected in those ages 35 to 60
Women are actually more likely to get a brain aneurysm than men, with a ratio of 3:2
Symptoms of Brain Aneurysms
Ruptured Cerebral Aneurysm Symptoms
Sometimes patients describing "the worst headache in my life" are actually experiencing one of the symptoms of brain aneurysms related to having a rupture. Other ruptured cerebral aneurysm symptoms include:
Nausea and vomiting
Stiff neck or neck pain
Blurred vision or double vision
Pain above and behind the eye
Dilated pupils
Sensitivity to light
Loss of sensation
Unruptured Cerebral Aneurysm Symptoms
Before an aneurysm ruptures, patients often experience no symptoms of brain aneurysms. In about 40 percent of cases, people with unruptured aneurysms will experience some or all of the following cerebral aneurysm symptoms:
Peripheral vision deficits
Thinking or processing problems
Speech complications
Perceptual problems
Sudden changes in behavior
Loss of balance and coordination
Decreased concentration
Short-term memory difficulty
Fatigue
Because the symptoms of brain aneurysms can also be associated with other medical conditions, diagnostic neuroradiology is regularly used to identify both ruptured and unruptured brain aneurysms.
Diagnosis of Brain Aneurysms
Diagnosis of a ruptured cerebral aneurysm is commonly made by finding signs of subarachnoid hemorrhage on a CT scan (Computerized Tomography, sometimes called a CAT scan). The CT scan is a computerized test that rapidly X-rays the body in cross-sections, or slices, as the body is moved through a large, circular machine. If the CT scan is negative but a ruptured aneurysm is still suspected, a lumbar puncture is performed to detect blood in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord.
To determine the exact location, size and shape of an aneurysm (ruptured or unruptured), neuroradiologists will use either cerebral angiography or tomographic angiography.
Cerebral angiography, the traditional method, involves introducing a catheter (small plastic tube) into an artery (usually in the leg) and steering it through the blood vessels of the body to the artery involved by the aneurysm. A special dye, called a contract agent, is injected into the patient's artery and its distribution is shown on X-ray projections. This method may not detect some aneurysms due to overlapping structures or spasm.
Computed Tomographic Angiography (CTA) is an alternative to the traditional method and can be performed without the need for arterial catheterization. This test combines a regular CT scan with a contrast dye injected into a vein. Once the dye is injected into a vein, it travels to the brain arteries, and images are created using a CT scan. These images show exactly how blood flows into the brain arteries.
http://www.brainaneurysm.com/
Brain aneurysms are often discovered when they rupture, causing bleeding into the brain or the space closely surrounding the brain called the subarachnoid space, causing a subarachnoid hemorrhage. Subarachnoid hemorrhage from a ruptured brain aneurysm can lead to a hemorrhagic stroke, brain damage and death.
The main goals of treatment once an aneurysm has ruptured are to stop the bleeding and potential permanent damage to the brain and to reduce the risk of recurrence. Unruptured brain aneurysms are sometimes treated to prevent rupture. Learn more about treatment options for a brain aneurysm.
Incidence Rates of Brain Aneurysms
Approximately 0.2 to 3 percent of people with a brain aneurysm may suffer from bleeding per year
The annual incidence of aneurysmal subarachnoid hemorrhage in the U.S. exceeds 30,000 people. Ten to 15 percent of these patients will die before reaching the hospital and over 50 percent will die within the first thirty days after rupture. Of those who survive, about half suffer some permanent neurological deficit
Brain aneurysms can occur in people of all ages, but are most commonly detected in those ages 35 to 60
Women are actually more likely to get a brain aneurysm than men, with a ratio of 3:2
Symptoms of Brain Aneurysms
Ruptured Cerebral Aneurysm Symptoms
Sometimes patients describing "the worst headache in my life" are actually experiencing one of the symptoms of brain aneurysms related to having a rupture. Other ruptured cerebral aneurysm symptoms include:
Nausea and vomiting
Stiff neck or neck pain
Blurred vision or double vision
Pain above and behind the eye
Dilated pupils
Sensitivity to light
Loss of sensation
Unruptured Cerebral Aneurysm Symptoms
Before an aneurysm ruptures, patients often experience no symptoms of brain aneurysms. In about 40 percent of cases, people with unruptured aneurysms will experience some or all of the following cerebral aneurysm symptoms:
Peripheral vision deficits
Thinking or processing problems
Speech complications
Perceptual problems
Sudden changes in behavior
Loss of balance and coordination
Decreased concentration
Short-term memory difficulty
Fatigue
Because the symptoms of brain aneurysms can also be associated with other medical conditions, diagnostic neuroradiology is regularly used to identify both ruptured and unruptured brain aneurysms.
Diagnosis of Brain Aneurysms
Diagnosis of a ruptured cerebral aneurysm is commonly made by finding signs of subarachnoid hemorrhage on a CT scan (Computerized Tomography, sometimes called a CAT scan). The CT scan is a computerized test that rapidly X-rays the body in cross-sections, or slices, as the body is moved through a large, circular machine. If the CT scan is negative but a ruptured aneurysm is still suspected, a lumbar puncture is performed to detect blood in the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord.
To determine the exact location, size and shape of an aneurysm (ruptured or unruptured), neuroradiologists will use either cerebral angiography or tomographic angiography.
Cerebral angiography, the traditional method, involves introducing a catheter (small plastic tube) into an artery (usually in the leg) and steering it through the blood vessels of the body to the artery involved by the aneurysm. A special dye, called a contract agent, is injected into the patient's artery and its distribution is shown on X-ray projections. This method may not detect some aneurysms due to overlapping structures or spasm.
Computed Tomographic Angiography (CTA) is an alternative to the traditional method and can be performed without the need for arterial catheterization. This test combines a regular CT scan with a contrast dye injected into a vein. Once the dye is injected into a vein, it travels to the brain arteries, and images are created using a CT scan. These images show exactly how blood flows into the brain arteries.
http://www.brainaneurysm.com/
Monday, November 27, 2006
Polycystic Kidney Disease
Autosomal Dominant PKD
Autosomal Recessive PKD
Acquired Cystic Kidney Disease
Hope Through Research
Points to Remember
For More Information
Polycystic kidney disease (PKD) is a genetic disorder characterized by the growth of numerous cysts in the kidneys. The cysts are filled with fluid. PKD cysts can slowly replace much of the mass of the kidneys, reducing kidney function and leading to kidney failure.
The kidneys are two organs, each about the size of a fist, located in the upper part of a person's abdomen, toward the back. The kidneys filter wastes from the blood to form urine. They also regulate amounts of certain vital substances in the body.
When PKD causes kidneys to fail—which usually happens after many years—the patient requires dialysis or kidney transplantation. About one-half of people with the major type of PKD progress to kidney failure, also called end-stage renal disease (ESRD).
PKD can cause cysts in the liver and problems in other organs, such as the heart and blood vessels in the brain. These complications help doctors distinguish PKD from the usually harmless "simple" cysts that often form in the kidneys in later years of life.
In the United States, about 500,000 people have PKD, and it is the fourth leading cause of kidney failure. Medical professionals describe two major inherited forms of PKD and a noninherited form:
Autosomal dominant PKD is the most common inherited form. Symptoms usually develop between the ages of 30 and 40, but they can begin earlier, even in childhood. About 90 percent of all PKD cases are autosomal dominant PKD.
Autosomal recessive PKD is a rare inherited form. Symptoms of autosomal recessive PKD begin in the earliest months of life, even in the womb.
Acquired cystic kidney disease (ACKD) develops in association with long-term kidney problems, especially in patients who have kidney failure and who have been on dialysis for a long time. Therefore it tends to occur in later years of life. It is not an inherited form of PKD.
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Autosomal Dominant PKD
What is autosomal dominant PKD?
Autosomal dominant PKD is one of the most common inherited disorders. The phrase "autosomal dominant" means that if one parent has the disease, there is a 50-percent chance that the disease will pass to a child (see Genetic Diseases). At least one parent must have the disease for a child to inherit it. Either the mother or father can pass it along, but new mutations may account for one-fourth of new cases. In some rare cases, the cause of autosomal dominant PKD occurs spontaneously in the child soon after conception—in these cases the parents are not the source of this disease.
Many people with autosomal dominant PKD live for decades without developing symptoms. For this reason, autosomal dominant PKD is often called "adult polycystic kidney disease." Yet, in some cases, cysts may form earlier, even in the first years of life.
The disease is thought to occur equally in men and women and equally in people of all races. However, some studies suggest that it occurs more often in whites than in blacks and more often in females than in males.
The cysts grow out of nephrons, the tiny filtering units inside the kidneys. The cysts eventually separate from the nephrons and continue to enlarge. The kidneys enlarge along with the cysts (which can number in the thousands), while retaining roughly their kidney shape. In fully developed PKD, a cyst-filled kidney can weigh as much as 22 pounds. High blood pressure occurs early in the disease, often before cysts appear.
What are the symptoms of autosomal dominant PKD?
The most common symptoms are pain in the back and the sides (between the ribs and hips), and headaches. The dull pain can be temporary or persistent, mild or severe.
People with autosomal dominant PKD also can experience the following:
urinary tract infections
hematuria (blood in the urine)
liver and pancreatic cysts
abnormal heart valves
high blood pressure
kidney stones
aneurysms (bulges in the walls of blood vessels) in the brain
diverticulosis (small sacs on the colon)
How is autosomal dominant PKD diagnosed?
To diagnose autosomal dominant PKD, a doctor typically observes three or more kidney cysts using ultrasound imaging. The diagnosis is strengthened by a family history of autosomal dominant PKD and the presence of cysts in other organs.
In most cases of autosomal dominant PKD, the person's physical condition appears normal for many years, even decades, so the disease can go unnoticed. Physical checkups and blood and urine tests may not lead to diagnosis. The slow, undetected progression is why some people live for many years without knowing they have autosomal dominant PKD.
Once cysts have formed, however, diagnosis is possible with imaging technology. Ultrasound, which passes sound waves through the body to create a picture of the kidneys, is used most often. Ultrasound imaging employs no injected dyes or radiation and is safe for all patients, including pregnant women. It can also detect cysts in the kidneys of a fetus.
More powerful and expensive imaging procedures such as computed tomography (CT scan) and magnetic resonance imaging (MRI) also can detect cysts, but they usually are not required for diagnosis because ultrasound provides adequate information. CT scans require x rays and sometimes injected dyes.
A genetic test can detect mutations in the PKD1 and PKD2 genes. Although this test can detect the presence of the autosomal dominant PKD mutations before cysts develop, its usefulness is limited by two factors; it cannot predict the onset or ultimate severity of the disease, and no absolute cure is available to prevent the onset of the disease. On the other hand, a young person who knows of a PKD gene mutation may be able to forestall the disease through diet and blood pressure control. The test may also be used to determine whether a young member of a PKD family can safely donate a kidney to a parent. Anyone considering genetic testing should receive counseling to understand all the implications of the test.
How is autosomal dominant PKD treated?
Although a cure for autosomal dominant PKD is not available, treatment can ease the symptoms and prolong life.
Pain. A doctor will first suggest over-the-counter pain medications, such as aspirin or Tylenol. 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.
Headaches that are severe or that seem to feel different from other headaches might be caused by aneurysms, or swollen blood vessels, in the brain. Headaches also can be caused by high blood pressure. People with autosomal dominant PKD should see a doctor if they have severe or recurring headaches—even before considering over-the-counter pain medications.
Urinary tract infections. Patients with autosomal dominant PKD tend to have frequent urinary tract infections, which can be treated with antibiotics. People with the disease should seek treatment for urinary tract infections immediately, 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 autosomal dominant PKD. Lifestyle changes and various medications can lower high blood pressure. Patients should ask their doctors about such treatments. Sometimes proper diet and exercise are enough to keep blood pressure low.
End-stage renal disease. Because kidneys are essential for life, people with ESRD must seek one of two options for replacing kidney functions: dialysis or transplantation. In hemodialysis, blood is circulated into an external machine, where it is cleaned before reentering the body; in peritoneal dialysis, a fluid is introduced into the abdomen, where it absorbs wastes, and it is then removed. Transplantation of healthy kidneys into ESRD patients has become a common and successful procedure. Healthy (non-PKD) kidneys transplanted into PKD patients do not develop cysts
Autosomal Recessive PKD
What is autosomal recessive PKD?
Autosomal recessive PKD is caused by a particular genetic flaw that is different from the genetic flaw that causes autosomal dominant PKD. Parents who do not have PKD can have a child with the disease if both parents carry the abnormal gene and both pass the gene to their baby. The chance of this happening (when both parents carry the abnormal gene) is one in four. If only one parent carries the abnormal gene, the baby cannot get the disease.
The symptoms of autosomal recessive PKD can begin before birth, so it is often called "infantile PKD." Children born with autosomal recessive PKD usually develop kidney failure within a few years. Severity of the disease varies. Babies with the worst cases die hours or days after birth. Children with an infantile version may have sufficient renal function for normal activities for a few years. People with the juvenile version may live into their teens and twenties and usually will have liver problems as well.
What are the symptoms of autosomal recessive PKD?
Children with autosomal recessive PKD experience high blood pressure, urinary tract infections, and frequent urination. The disease usually affects the liver, spleen, and pancreas, resulting in low blood-cell counts, varicose veins, and hemorrhoids. Because kidney function is crucial for early physical development, children with autosomal recessive PKD are usually smaller than average size.
How is autosomal recessive PKD diagnosed?
Ultrasound imaging of the fetus or newborn baby reveals cysts in the kidneys but does not distinguish between the cysts of autosomal recessive and autosomal dominant PKD. Ultrasound examination of kidneys of relatives can be helpful; for example, a parent or grandparent with autosomal dominant PKD cysts could help confirm diagnosis of autosomal dominant PKD in a fetus or child. (It is extremely rare, although not impossible, for a person with autosomal recessive PKD to become a parent.) Because autosomal recessive PKD tends to scar the liver, ultrasound imaging of the liver also aids in diagnosis.
How is autosomal recessive PKD treated?
Medicines can control high blood pressure in autosomal recessive PKD, and antibiotics can control urinary tract infections. Eating increased amounts of nutritious food improves growth in children with autosomal recessive PKD. In some cases, growth hormones are used. In response to kidney failure, autosomal recessive PKD patients must receive dialysis or transplantation (see End-stage renal disease).
Acquired Cystic Kidney Disease
What is ACKD?
ACKD develops in kidneys with long-term damage and bad scarring, so it often is associated with dialysis and end-stage renal disease. About 90 percent of people on dialysis for 5 years develop ACKD. People with ACKD can have any underlying kidney disease, such as glomerulonephritis or kidney disease of diabetes.
The cysts of ACKD may bleed. Kidney tumors, including kidney (renal) cancer, can develop in people with ACKD. Renal cancer is rare yet occurs at least twice as often in ACKD patients as in the general population.
How is ACKD diagnosed?
Patients with ACKD usually seek help because they notice blood in their urine (hematuria). The cysts bleed into the urinary system, which discolors urine. Diagnosis is confirmed using ultrasound, CT scan, or MRI of the kidneys.
How is ACKD treated?
Most ACKD patients are already receiving treatment for kidney problems. In rare cases, surgery is used to stop bleeding of cysts and to remove tumors or suspected tumors.
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Hope Through Research
Scientists have begun to identify the processes that trigger formation of PKD cysts. Advances in the field of genetics have increased our understanding of the abnormal genes responsible for autosomal dominant and autosomal recessive PKD. Scientists have located two genes associated with autosomal dominant PKD. The first was located in 1985 on chromosome 16 and labeled PKD1. PKD2 was localized to chromosome 4 in 1993. Within 3 years, the scientists had isolated the proteins these two genes produce—polycystin-1 and polycystin-2.
When both of these genes are normal, the proteins they produce work together to foster normal kidney development and inhibit cyst formation. A mutation in either PKD1 or PKD2 can lead to cyst formation, but evidence suggests that the disease development also requires other factors, in addition to the mutation in one of the PKD genes.
Genetic analyses of most families with PKD confirm mutations in either the PKD1 or PKD2 gene. In rare cases, however, families with PKD have been found to have normal PKD1 and PKD2 genes. As a result, researchers theorize that a PKD3 gene exists, but that gene has not been mapped or identified.
Researchers recently identified the autosomal recessive PKD gene (called PKHD1) on chromosome 6. No genetic test kit is yet available to detect mutations in PKHD1.
Researchers have bred mice with a genetic disease that parallels both inherited forms of human PKD. Studying these mice will lead to greater understanding of the genetic and nongenetic mechanisms involved in cyst formation. In 2000, scientists reported that a cancer drug was successful in inhibiting cyst formation in mice with the PKD gene. In 2003, scientists also demonstrated that another compound, one that blocks function of a kidney receptor, inhibits cyst formation in mice with the ADPKD or ARPKD gene. The scientists hope that further testing will lead to safe and effective treatments for humans.
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Points to Remember
The three types of PKD are
two inherited forms:
a common form that usually causes symptoms in midlife
a rare form that usually causes symptoms in early childhood
a noninherited form associated with long-term kidney problems, dialysis, and old age
The signs of PKD include
pain in the back and lower sides
headaches
urinary tract infections
blood in the urine
cysts in the kidneys and other organs
Diagnosis of PKD is obtained by
ultrasound imaging of kidney cysts
ultrasound imaging of cysts in other organs
family medical history (genetic testing)
PKD has no cure. Treatments include
medicine and surgery to reduce pain
antibiotics to resolve infections
dialysis to replace functions of failed kidneys
kidney transplantation
For More Information
Polycystic Kidney Disease Foundation9221 Ward Parkway, Suite 400Kansas City, MO 64114–3367Phone: 1–800–PKD–CURE (753–2873) or 816–931–2600Email: pkdcure@pkdcure.orgInternet: www.pkdcure.org
American Association of Kidney Patients3505 East Frontage Road, Suite 315Tampa, FL 33607Phone: 1–800–749–2257 or 813–636–8100Email: info@aakp.orgInternet: www.aakp.org
National Kidney Foundation30 East 33rd StreetNew York, NY 10016Phone: 1–800–622–9010 or 212–889–2210Email: info@kidney.orgInternet: www.kidney.org
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The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this document are used only because they are considered necessary in the context of the information provided. If a product is not mentioned, the omission does not mean or imply that the product is unsatisfactory.
National Kidney and Urologic Diseases Information Clearinghouse
3 Information WayBethesda, MD 20892–3580Email: nkudic@info.niddk.nih.gov
The National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC) is a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health of the U.S. Department of Health and Human Services. Established in 1987, the Clearinghouse provides information about diseases of the kidneys and urologic system to people with kidney and urologic disorders and to their families, health care professionals, and the public. The NKUDIC answers inquiries, develops and distributes publications, and works closely with professional and patient organizations and Government agencies to coordinate resources about kidney and urologic diseases.
Publications produced by the Clearinghouse are carefully reviewed by both NIDDK scientists and outside experts.
This publication is not copyrighted. The Clearinghouse encourages users of this publication to duplicate and distribute as many copies as desired.
NIH Publication No. 05–4008December 2004
http://kidney.niddk.nih.gov/kudiseases/pubs/polycystic/
Autosomal Recessive PKD
Acquired Cystic Kidney Disease
Hope Through Research
Points to Remember
For More Information
Polycystic kidney disease (PKD) is a genetic disorder characterized by the growth of numerous cysts in the kidneys. The cysts are filled with fluid. PKD cysts can slowly replace much of the mass of the kidneys, reducing kidney function and leading to kidney failure.
The kidneys are two organs, each about the size of a fist, located in the upper part of a person's abdomen, toward the back. The kidneys filter wastes from the blood to form urine. They also regulate amounts of certain vital substances in the body.
When PKD causes kidneys to fail—which usually happens after many years—the patient requires dialysis or kidney transplantation. About one-half of people with the major type of PKD progress to kidney failure, also called end-stage renal disease (ESRD).
PKD can cause cysts in the liver and problems in other organs, such as the heart and blood vessels in the brain. These complications help doctors distinguish PKD from the usually harmless "simple" cysts that often form in the kidneys in later years of life.
In the United States, about 500,000 people have PKD, and it is the fourth leading cause of kidney failure. Medical professionals describe two major inherited forms of PKD and a noninherited form:
Autosomal dominant PKD is the most common inherited form. Symptoms usually develop between the ages of 30 and 40, but they can begin earlier, even in childhood. About 90 percent of all PKD cases are autosomal dominant PKD.
Autosomal recessive PKD is a rare inherited form. Symptoms of autosomal recessive PKD begin in the earliest months of life, even in the womb.
Acquired cystic kidney disease (ACKD) develops in association with long-term kidney problems, especially in patients who have kidney failure and who have been on dialysis for a long time. Therefore it tends to occur in later years of life. It is not an inherited form of PKD.
[Top]
Autosomal Dominant PKD
What is autosomal dominant PKD?
Autosomal dominant PKD is one of the most common inherited disorders. The phrase "autosomal dominant" means that if one parent has the disease, there is a 50-percent chance that the disease will pass to a child (see Genetic Diseases). At least one parent must have the disease for a child to inherit it. Either the mother or father can pass it along, but new mutations may account for one-fourth of new cases. In some rare cases, the cause of autosomal dominant PKD occurs spontaneously in the child soon after conception—in these cases the parents are not the source of this disease.
Many people with autosomal dominant PKD live for decades without developing symptoms. For this reason, autosomal dominant PKD is often called "adult polycystic kidney disease." Yet, in some cases, cysts may form earlier, even in the first years of life.
The disease is thought to occur equally in men and women and equally in people of all races. However, some studies suggest that it occurs more often in whites than in blacks and more often in females than in males.
The cysts grow out of nephrons, the tiny filtering units inside the kidneys. The cysts eventually separate from the nephrons and continue to enlarge. The kidneys enlarge along with the cysts (which can number in the thousands), while retaining roughly their kidney shape. In fully developed PKD, a cyst-filled kidney can weigh as much as 22 pounds. High blood pressure occurs early in the disease, often before cysts appear.
What are the symptoms of autosomal dominant PKD?
The most common symptoms are pain in the back and the sides (between the ribs and hips), and headaches. The dull pain can be temporary or persistent, mild or severe.
People with autosomal dominant PKD also can experience the following:
urinary tract infections
hematuria (blood in the urine)
liver and pancreatic cysts
abnormal heart valves
high blood pressure
kidney stones
aneurysms (bulges in the walls of blood vessels) in the brain
diverticulosis (small sacs on the colon)
How is autosomal dominant PKD diagnosed?
To diagnose autosomal dominant PKD, a doctor typically observes three or more kidney cysts using ultrasound imaging. The diagnosis is strengthened by a family history of autosomal dominant PKD and the presence of cysts in other organs.
In most cases of autosomal dominant PKD, the person's physical condition appears normal for many years, even decades, so the disease can go unnoticed. Physical checkups and blood and urine tests may not lead to diagnosis. The slow, undetected progression is why some people live for many years without knowing they have autosomal dominant PKD.
Once cysts have formed, however, diagnosis is possible with imaging technology. Ultrasound, which passes sound waves through the body to create a picture of the kidneys, is used most often. Ultrasound imaging employs no injected dyes or radiation and is safe for all patients, including pregnant women. It can also detect cysts in the kidneys of a fetus.
More powerful and expensive imaging procedures such as computed tomography (CT scan) and magnetic resonance imaging (MRI) also can detect cysts, but they usually are not required for diagnosis because ultrasound provides adequate information. CT scans require x rays and sometimes injected dyes.
A genetic test can detect mutations in the PKD1 and PKD2 genes. Although this test can detect the presence of the autosomal dominant PKD mutations before cysts develop, its usefulness is limited by two factors; it cannot predict the onset or ultimate severity of the disease, and no absolute cure is available to prevent the onset of the disease. On the other hand, a young person who knows of a PKD gene mutation may be able to forestall the disease through diet and blood pressure control. The test may also be used to determine whether a young member of a PKD family can safely donate a kidney to a parent. Anyone considering genetic testing should receive counseling to understand all the implications of the test.
How is autosomal dominant PKD treated?
Although a cure for autosomal dominant PKD is not available, treatment can ease the symptoms and prolong life.
Pain. A doctor will first suggest over-the-counter pain medications, such as aspirin or Tylenol. 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.
Headaches that are severe or that seem to feel different from other headaches might be caused by aneurysms, or swollen blood vessels, in the brain. Headaches also can be caused by high blood pressure. People with autosomal dominant PKD should see a doctor if they have severe or recurring headaches—even before considering over-the-counter pain medications.
Urinary tract infections. Patients with autosomal dominant PKD tend to have frequent urinary tract infections, which can be treated with antibiotics. People with the disease should seek treatment for urinary tract infections immediately, 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 autosomal dominant PKD. Lifestyle changes and various medications can lower high blood pressure. Patients should ask their doctors about such treatments. Sometimes proper diet and exercise are enough to keep blood pressure low.
End-stage renal disease. Because kidneys are essential for life, people with ESRD must seek one of two options for replacing kidney functions: dialysis or transplantation. In hemodialysis, blood is circulated into an external machine, where it is cleaned before reentering the body; in peritoneal dialysis, a fluid is introduced into the abdomen, where it absorbs wastes, and it is then removed. Transplantation of healthy kidneys into ESRD patients has become a common and successful procedure. Healthy (non-PKD) kidneys transplanted into PKD patients do not develop cysts
Autosomal Recessive PKD
What is autosomal recessive PKD?
Autosomal recessive PKD is caused by a particular genetic flaw that is different from the genetic flaw that causes autosomal dominant PKD. Parents who do not have PKD can have a child with the disease if both parents carry the abnormal gene and both pass the gene to their baby. The chance of this happening (when both parents carry the abnormal gene) is one in four. If only one parent carries the abnormal gene, the baby cannot get the disease.
The symptoms of autosomal recessive PKD can begin before birth, so it is often called "infantile PKD." Children born with autosomal recessive PKD usually develop kidney failure within a few years. Severity of the disease varies. Babies with the worst cases die hours or days after birth. Children with an infantile version may have sufficient renal function for normal activities for a few years. People with the juvenile version may live into their teens and twenties and usually will have liver problems as well.
What are the symptoms of autosomal recessive PKD?
Children with autosomal recessive PKD experience high blood pressure, urinary tract infections, and frequent urination. The disease usually affects the liver, spleen, and pancreas, resulting in low blood-cell counts, varicose veins, and hemorrhoids. Because kidney function is crucial for early physical development, children with autosomal recessive PKD are usually smaller than average size.
How is autosomal recessive PKD diagnosed?
Ultrasound imaging of the fetus or newborn baby reveals cysts in the kidneys but does not distinguish between the cysts of autosomal recessive and autosomal dominant PKD. Ultrasound examination of kidneys of relatives can be helpful; for example, a parent or grandparent with autosomal dominant PKD cysts could help confirm diagnosis of autosomal dominant PKD in a fetus or child. (It is extremely rare, although not impossible, for a person with autosomal recessive PKD to become a parent.) Because autosomal recessive PKD tends to scar the liver, ultrasound imaging of the liver also aids in diagnosis.
How is autosomal recessive PKD treated?
Medicines can control high blood pressure in autosomal recessive PKD, and antibiotics can control urinary tract infections. Eating increased amounts of nutritious food improves growth in children with autosomal recessive PKD. In some cases, growth hormones are used. In response to kidney failure, autosomal recessive PKD patients must receive dialysis or transplantation (see End-stage renal disease).
Acquired Cystic Kidney Disease
What is ACKD?
ACKD develops in kidneys with long-term damage and bad scarring, so it often is associated with dialysis and end-stage renal disease. About 90 percent of people on dialysis for 5 years develop ACKD. People with ACKD can have any underlying kidney disease, such as glomerulonephritis or kidney disease of diabetes.
The cysts of ACKD may bleed. Kidney tumors, including kidney (renal) cancer, can develop in people with ACKD. Renal cancer is rare yet occurs at least twice as often in ACKD patients as in the general population.
How is ACKD diagnosed?
Patients with ACKD usually seek help because they notice blood in their urine (hematuria). The cysts bleed into the urinary system, which discolors urine. Diagnosis is confirmed using ultrasound, CT scan, or MRI of the kidneys.
How is ACKD treated?
Most ACKD patients are already receiving treatment for kidney problems. In rare cases, surgery is used to stop bleeding of cysts and to remove tumors or suspected tumors.
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Hope Through Research
Scientists have begun to identify the processes that trigger formation of PKD cysts. Advances in the field of genetics have increased our understanding of the abnormal genes responsible for autosomal dominant and autosomal recessive PKD. Scientists have located two genes associated with autosomal dominant PKD. The first was located in 1985 on chromosome 16 and labeled PKD1. PKD2 was localized to chromosome 4 in 1993. Within 3 years, the scientists had isolated the proteins these two genes produce—polycystin-1 and polycystin-2.
When both of these genes are normal, the proteins they produce work together to foster normal kidney development and inhibit cyst formation. A mutation in either PKD1 or PKD2 can lead to cyst formation, but evidence suggests that the disease development also requires other factors, in addition to the mutation in one of the PKD genes.
Genetic analyses of most families with PKD confirm mutations in either the PKD1 or PKD2 gene. In rare cases, however, families with PKD have been found to have normal PKD1 and PKD2 genes. As a result, researchers theorize that a PKD3 gene exists, but that gene has not been mapped or identified.
Researchers recently identified the autosomal recessive PKD gene (called PKHD1) on chromosome 6. No genetic test kit is yet available to detect mutations in PKHD1.
Researchers have bred mice with a genetic disease that parallels both inherited forms of human PKD. Studying these mice will lead to greater understanding of the genetic and nongenetic mechanisms involved in cyst formation. In 2000, scientists reported that a cancer drug was successful in inhibiting cyst formation in mice with the PKD gene. In 2003, scientists also demonstrated that another compound, one that blocks function of a kidney receptor, inhibits cyst formation in mice with the ADPKD or ARPKD gene. The scientists hope that further testing will lead to safe and effective treatments for humans.
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Points to Remember
The three types of PKD are
two inherited forms:
a common form that usually causes symptoms in midlife
a rare form that usually causes symptoms in early childhood
a noninherited form associated with long-term kidney problems, dialysis, and old age
The signs of PKD include
pain in the back and lower sides
headaches
urinary tract infections
blood in the urine
cysts in the kidneys and other organs
Diagnosis of PKD is obtained by
ultrasound imaging of kidney cysts
ultrasound imaging of cysts in other organs
family medical history (genetic testing)
PKD has no cure. Treatments include
medicine and surgery to reduce pain
antibiotics to resolve infections
dialysis to replace functions of failed kidneys
kidney transplantation
For More Information
Polycystic Kidney Disease Foundation9221 Ward Parkway, Suite 400Kansas City, MO 64114–3367Phone: 1–800–PKD–CURE (753–2873) or 816–931–2600Email: pkdcure@pkdcure.orgInternet: www.pkdcure.org
American Association of Kidney Patients3505 East Frontage Road, Suite 315Tampa, FL 33607Phone: 1–800–749–2257 or 813–636–8100Email: info@aakp.orgInternet: www.aakp.org
National Kidney Foundation30 East 33rd StreetNew York, NY 10016Phone: 1–800–622–9010 or 212–889–2210Email: info@kidney.orgInternet: www.kidney.org
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The U.S. Government does not endorse or favor any specific commercial product or company. Trade, proprietary, or company names appearing in this document are used only because they are considered necessary in the context of the information provided. If a product is not mentioned, the omission does not mean or imply that the product is unsatisfactory.
National Kidney and Urologic Diseases Information Clearinghouse
3 Information WayBethesda, MD 20892–3580Email: nkudic@info.niddk.nih.gov
The National Kidney and Urologic Diseases Information Clearinghouse (NKUDIC) is a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The NIDDK is part of the National Institutes of Health of the U.S. Department of Health and Human Services. Established in 1987, the Clearinghouse provides information about diseases of the kidneys and urologic system to people with kidney and urologic disorders and to their families, health care professionals, and the public. The NKUDIC answers inquiries, develops and distributes publications, and works closely with professional and patient organizations and Government agencies to coordinate resources about kidney and urologic diseases.
Publications produced by the Clearinghouse are carefully reviewed by both NIDDK scientists and outside experts.
This publication is not copyrighted. The Clearinghouse encourages users of this publication to duplicate and distribute as many copies as desired.
NIH Publication No. 05–4008December 2004
http://kidney.niddk.nih.gov/kudiseases/pubs/polycystic/
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Sunday, November 26, 2006
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