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Polycystic kidney disease (PKD) is one of the most common life threatening genetic disorder and affects many people worldwide. It can vary in certain parts of the world from 1 to 400 people to 1 in 1000 people affected worldwide depending on the part of the world.
PKD is a genetic disorder characterized by the growth of numerous fluid – filled cysts on the kidneys which dramatically enlarge kidneys which severely compromises kidneys function. PKD is prevalent, inherited condition for which there is currently no effective specific clinical therapy. The cysts are derived from renal tubular epithelial cells which gradually compress the parenchyma and compromise renal function.
Current interests in the research field focus on understanding and exploiting signalling mechanisms underlying disease pathogenesis as well as the role of the primary cilium in cystogenesis. The primary purpose is to highlight pathogenetic pathways underlying renal cyst formation as well as possible therapeutic targets for the treatment of PKD. (Ross and Wilson 2002)
The disease is characterized by the slow development, over decades, of large fluid filled cysts in the kidneys. Significant impairments of renal function will usually occur by late middle age and at this stage approximately 50% of the patients will progress to end stage renal disease, requiring transplant or dialysis.
In order to understand the disease and its mechanisms it is required to understand the functions and structure of normal healthy kidneys.
Kidneys are bean shaped organs about 11cm long, 6 cm wide, 3 cm thick and each weighs approximately 150g. The kidneys are the part of the urinary system and play major role in the excretory systems of the body. The kidneys lie on the posterior abdominal wall, one on each side of the vertebral column behind the peritoneum and below the diaphragm. They extend from the level of the 12th thoratic vertebra to the 3rd lumbar vertebra, receiving some protection from the lower rib cage. The right kidney is usually slightly lower than the left because of the considerable space occupied by the liver. The kidneys are embedded in, and held in position by, a mass of fat. There are 3 areas of tissue which can be distinguished along the longitudinal section of the kidney:
- fibrous capsule surrounding the kidney
- the cortex, a reddish brown layer of tissue below the capsule
- the medulla, the innermost layer, consisting of pale conical shape striations, the renal pyramids (J.C.E. Underwood 2004)
The basic unit of kidney is nephron, each comprises a glomerulus connected to a tubule. Each kidney contains approximately 1 million nephrons and a smaller number of collecting tubules. The collecting tubules transport urine through the pyramids to the renal pelvis giving them their striped appearance. The tubules are supported by a small amount of connecting tissue containing blood vessels, nerves and lymph vessels. The nephron consists of a tubule closed at one end, the other end opening into a collecting tubule. The closed or blind end forms the cup – shaped glomerular capsule also known as Bowmans capsule which almost completely encloses a network of arterial capillaries, the glomerulus.
The nerve supply to blood vessels of the kidney consists of sympathetic and parasympathetic nerves. The presence of both branches of autonomic nervous system permits control of renal blood vessel diameter and renal blood flow independently of autoregulation. (Ross and Wilson 2002)
The main functions of kidneys include:
- Eliminating metabolic waste products
- Regulating fluid and electrolyte balance
- Influencing acid – base balance
The kidneys also produce the following hormones:
- prostaglandins, which affect salt and water regulation and influence vascular tone
- erythropoietin which stimulates red blood cells production
- 1,25 – dihydroxycholecalciferol, which enhances calcium absorption from the gut and phosphate reabsorption by renal tubules
- renin, which acts on the angiotensin pathway to increase vascular tone and aldosterone production (J.C.E. Underwood 2004)
Healthy Kidney Picture
The kidneys have large functional reserve, and the loss of one kidney produces little to no ill effects. However, in renal disease like PKD waste products can accumulate, causing condition known as uraemia. If the glomerular filters become excessively leaky, large protein molecules are lost in the urine causing proteinuria. If the glomeruli are severely damaged, erythrocytes (red blood cells) pass through causing haematuria.
There are 2 types of inherited polycystic disease: autosomal recessive and autosomal dominant.
When cysts form in the kidneys, they are filled with fluid. PKD cysts can profoundly enlarge the kidneys while replacing much of the normal structure, resulting in reduced kidney function and leading to kidney failure. Polycystic kidney disease is one of the most common cause of kidney failure. PKD causes kidneys to fail and this process can happen after many years. At this stage patient will require dialysis or kidney transplantation. About one-half of people with the most common type of PKD progress to kidney failure, also called end-stage renal disease (ESRD). Two major inherited forms of PKD exist:
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. ( C. M. Porth 2004)
Autosomal recessive PKD is a rare inherited form. Symptoms of autosomal recessive PKD begin in the earliest months of life, even in the womb. The disorder inherited as a recessive trait, meaning that both parents are carriers of the gene and that there is a one in four chance to of the parents having another child with the disorder. Because the condition is present at birth, it formely was called infantile or childhood polycystic disease. The condition is bilateral and significant renal dysfunction usually is present, accompanied by variable degrees of liver fibrosis and portal hypertension. The disorder is usually diagnosed by ultrasanography. (PKD foundation 2011)
There is no known treatment for the disease. Approximately 30% of infants die in the perinatal period, often because larger kidneys compromise expansion of the lungs. The majority of surviving infants develop hypertension. Autosomal recessive polycystic kidney disease (ARPKD) is a severe form of inherited childhood nephropathy. The disease is quite rare 1 in 20,000 live births. The disease is characterized by fusiform dilatation of collecting ducts and congenital hepatic fibrosis. Up to 30% die as neonates due to respiratory insufficiency and Progression to end stage renal disease occurs in 20-45% of cases within 15 years but a proportion maintain renal function into adulthood where complications of liver disease predominate. The ARPKD disease gene, PKHD1, has recently been identified through analysis of an orthologous animal model, the PCK rat. PKHD1 is a large gene (470 kb) with 67 exons from which multiple transcripts may be generated by alternative splicing. It is highly expressed in kidney, with lower levels in liver and pancreas. The ARPKD protein, fibrocystin (4074 aa and 447 kDa), is predicted to be an integral membrane, receptor-like protein containing multiple copies of an Ig-like domain (TIG). Fibrocystin is localized to the branching ureteric bud, collecting and biliary ducts, consistent with the disease phenotype, and often absent from ARPKD tissue. In common with other PKD-related proteins, fibrocystin is localized to the primary cilia of renal epithelial cells, reinforcing the link between ciliary dysfunction and cyst development. Screens of PKHD1 have revealed 119 different mutations of various types spread throughout the gene. Several ancestral changes have been described, some localized to specific geographic populations. The preliminary studies associate two truncating mutations with severe disease. The complexities of PKHD1, marked allelic heterogeneity and high level of missense changes complicate gene-based diagnostics. Average life expectancy for patients with ARPKD is 18 years.
Some children may present with less severe kidney problems and more severe liver disease. (Peter C. Harris and Sandro Rossetti 2003)
Since Autosomal Dominant Polycystic Kidney Disease (ADPKD) is present in 90% of all PKD cases it will be important to outline the structure and causes of this disease.
Two mutant genes have been implicated in most cases of the disorder. A PKD gene called PKD1 located on chromosome 16, is responsible for approximately 85% of cases. It encodes a large membrane protein called polycystin 1 that has domains similar to proteins involved in cell to cell and cell to extracellular matrix interactions. A second gene called PKD2 is located on chromosome 4. It encodes for a product called polycystin 2 which is an integral membrane protein that is similar to certain calcium channel proteins as well as a portion of polycystin1. Although the two mutations produce almost identical disease phenotypes, disease progression is typically more rapid in people with ADPKD type 1 disease than those with ADPKD type 2 disease.
The link between the genetic defect in the polycystin proteins and the formation of the fluid filled cysts in the kidney have not been fully established. It is presumed that the membrane proteins may play role in cell to cell matrix interactions that are important in tubular epithelial cell growth and differentiation. As a result the hypothesis has been developed that cysts develop as a result of abnormality in cell differentiation, increased transepithelial fluid secretion and formation of an abnormal extracellular matrix that allows the cyst to grow and separate from adjacent tubules. In addition cyst fluids have been shown to harbour mediators that enhance fluid secretion and induce inflammation, resulting further enlargement of the cysts and the interstitial fibrosis that is characteristic of progressive polycystic kidney disease. ( C. M. Porth 2004)
The mutant ADPKD gene is present in all tubular cells of affected persons, but cysts develop only in some tubules. Progression of the disease is characterized by tubular dilatation with cyst formation interspersed among normally functioning nephrons. Fluid collects in the cyst while it is still part of the tubular lumen, or it is secreted into the cyst after it has separated from the tubule. As the fluid accumulates, the cyst gradually increase in size, with some becoming as large as 5 cm in diameter. The kidneys of persons with PKD eventually become enlarged because of the presence of the multiple cysts. Cysts may also be found in the liver and less commonly in the pancreas and spleen.
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, scientists had isolated the proteins these two genes produce-polycystin-1 and polycystin-2.
When both the PKD1 and PKD2 genes are normal, the proteins they produce work together to foster normal kidney development and inhibit cyst formation. A mutation in either of the genes can lead to cyst formation, but evidence suggests that disease development also requires other factors, in addition to the mutation in one of the PKD genes. Patients with ADPKD present mutation within PKD1 gene, while remaining 10-15 % of cases occur from mutations in PKD2 gene. Patients with PKD 1 mutation have more severe symptoms than patients with PKD2 mutation. Average life span of patients with PKD1 is approximately 54 years, where as patients with PKD2 mutation have average life span of approximately 74 years.
At the moment over 300 truncating mutations of PKD1 and 91 mutations of PKD2 have been identified in patients with ADPKD. There are approximately another 100 disease-causing mutations which are resulted by change in the codons.
PKD1 gene (polycystic kidney disease 1, ch16p13.3, 46 exons) encodes polycystin-1 (PC-1), a 462 kD, 4303 amino acid integral membrane protein with 11 transmembrane domains, a long extracellular Nterminus with multiple binding domains and a short cytoplasmic Cterminus that interacts with multiple proteins. PKD2 gene (polycystic kidney disease 2, ch4q21, 15 exons), encodes polycystin-2. Polycystin-2 (PC-2) is a significantly smaller 110 kD protein with six transmembrane domains. Both PC1 and PC2 interact with each other.
Polycystin-1 is found in the basolateral plasma membrane domain of polarized epithelial cells, where it participates both in intercellular adherence junctions and in focal adhesion complexes with the underlying basement membrane. A cleavage product of PC-1 that includes the C-terminal tail can translocates to the nucleus to regulate gene transcription.
Most of the polycystin-2 protein is concentrated in intracellular compartments, where it appears to play a role in regulating the release of calcium from intracellular stores. Its role as a cation channel is consistent with the fact that it is a member of the TRP family of ion channels. Both PC1 and PC2 are critically involved in renal cystic disease. It is clear that renal cystogenesis occurs when both copies of one or the other polycystin gene are either mutated or knocked out. (Vinita Takiar, Michael J. Caplan 2011)
During the research in mice, homozygous mutations of PKD1 and PKD2 result in embryonic lethality. Heterozygous mice appear essentially phenotypically normal, occasionally developing a few hepatic and renal cysts later in life. In addition, decreasing PKD1 expression is sufficient to cause cystic disease in mice while overexpression of polycystin-1 in transgenic mice also results in renal cyst formation. A study by Piontek revealed that inactivation of PKD1 prior to postnatal day 13 in conditional knockout mice results in an extremely rapid disease course of cyst development, while inactivation after this developmental time point results in much milder disease progression. These findings suggest that the polycystin proteins may function as important “brakes” on cell growth and division during renal development and that rapid proliferation of renal epithelial cells, such as occurs during renal development, may create an environment that facilitates the cellular consequences of polycystin mutation to manifest.
It has been suggested that polycystin-1 and polycystin-2 may mediate fluid flow resulting in an increase in intracellular calcium. This evidence supports the fact that patients with PKD are more prone to kidney stones.
When polycystins are mutated, then one or more of the cellular signaling functions are compromised, and cystogenesis ensues.
Cysts originate as dilatations in the walls of intact tubules, initially filling from fluid filtered in the glomerulus. However, as the cysts enlarge, they lose their connections to the parent nephron. It is unclear what event(s) initiate cyst formation in ADPKD or what factors determine cyst localization along the nephron, although there is clearly an association with genetic predispositions that result in either abnormal cellular differentiation or maturation. These abnormal cellular responses are hypothesized to arise, at least in part, from abnormal cilium formation, abnormal protein targeting, cyclic AMP activation, and unregulated cell proliferation and growth. The epithelial cells that line the nephron normally function to drive the net absorption of fluid and electrolytes. It is estimated that cyst fluid production by PKD cells range from 26 to 475 ml per year. (Roser Torra, Alejandro Darnell 1999)
Genetic analyses of most families with PKD confirm mutations in either the PKD1 or PKD2 gene. In about 10 to 15 percent of cases, however, families with autosomal dominant PKD do not show obvious abnormalities or mutations in the PKD1 and PKD2 genes, using current testing methods.
Researchers have also recently identified the autosomal recessive PKD gene, called PKHD1, on chromosome 6. Genetic testing for autosomal recessive PKD to detect mutations in PKHD1 is now offered by a limited number of molecular genetic diagnostics laboratories in the United States.
Researchers have bred rodents 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 recent years, researchers have discovered several compounds that appear to inhibit cyst formation in mice with the PKD gene. Some of these compounds are in clinical testing in humans. Scientists hope further testing will lead to safe and effective treatments for humans with the disease.
Recent clinical studies of autosomal dominant PKD are exploring new imaging methods for tracking progression of cystic kidney disease. These methods, using MRI, are helping scientists design better clinical trials for new treatments of autosomal dominant PKD. (Vinita Takiar, Michael J. Caplan 2011)
Autosomal dominant PKD is usually diagnosed by kidney imaging studies. One of the most common form of diagnosis is ultrasound, but more precise studies, such as computerized tomography (CT) scans can be used for detection of smaller cysts. Magnetic resonance imaging (MRI) are also widely used. Once cysts have grown to about one-half inch, 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 is usually the preferred method for diagnosis of patients with symptoms and for screening of asymptomatic family members. The ability to detect cysts increases with age; 80% to 90% of affected persons older than age of 20 have detectable cysts.
Diagnosis can also be made with a genetic test that detects mutations in the autosomal dominant PKD genes, called PKD1 and PKD2. Although this test can detect the presence of the autosomal dominant PKD mutations before large cysts develop, its usefulness is limited by two factors: detection of a disease gene cannot predict the onset of symptoms or ultimate severity of the disease, and if a disease gene is detected, no specific prevention or cure for the disease exists.
ADPKD which is inherited as an autosomal trait, results in the fluid filled cysts in both kidneys which leads eventually to progression of chronic renal failure. But disease can also cause hypertension, cardiovascular abnormalities, cerebral aneurysm, and cyst formation in other organs such as liver and pancreas. ( C. M. Porth 2004)
End-stage renal disease.
Recent advances in the understanding of pathways governing renal cystogenesis have led to a number of promising possibilities for therapeutic intervention. Some pathways target fluid secretion, while others target cellular growth and proliferation. Cyclic AMP was one of the first molecules implicated in the hyper-secretory phenotype of cyst formation that has been targeted by specific therapeutic interventions. Increased cAMP levels are a common feature of most models of PKD. Cyclic AMP is also involved in the stimulation of the MAPK/ ERK signalling pathway. Although the precise mechanism underlying the increase in cAMP is not known, it has been noted that vasopressin levels are increased in human ADPKD.
Upregulation of the vasopressin V2 (V2) receptor is also found in the PKD2 mouse models. The V2 receptor stimulates cAMP accumulation. Blockers of the V2 receptor have produced impressive therapeutic effects in animal models of PKD. In
addition, activating the somatostatin receptor reduces cellular cAMP levels, and somatostatin analogues have also produced promising results in human trials. Ongoing clinical trials are currently evaluating the efficacy of the V2 receptor antagonist, tolvaptan, and long-acting somatostatins. Other potential therapies that are directed at addressing fluid secretion include CFTR inhibitors and KCa3.1 inhibitors, which inhibit the basolateral potassium channel necessary for cAMP-dependent chloride secretion. (Vinita Takiar, Michael J. Caplan 2011)
After many years, PKD can cause the kidneys to fail. 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 filter, where it is cleaned before re-entering the body; in peritoneal dialysis, a fluid is introduced into the abdomen, where it absorbs wastes and 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.
The treatment for ADPKD is largely supportive and aimed at delaying the progression of the disease. Control of hypertension and prevention of ascending urinary tract infections are important. Although a cure for autosomal dominant PKD is not available, treatment can ease symptoms and prolong life.
The recent research on animals suggest future potential treatments for patients with PKD.
At present, there are no FDA-approved therapies for the treatment of PKD, and patients who progress to end-stage renal disease require renal replacement therapy. Recent research has suggested a number of promising target molecules and pathways, and extensive efforts are underway to explore and exploit these new avenues. (PKD foundation, 2011)
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