Stories of scientific breakthroughs reveal the ways that profound new insights emerge from research efforts over time:
Studies of Underlying Biology of Insulin Secretion Pave the Way to New Treatment for Neonatal Diabetes
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In the 1950s, little did scientists know that new drugs being used to treat type 2 diabetes in adults would be used half a century later to treat a rare form of diabetes in babies.
The drugs are called "sulfonylureas." The initial observation about these drugs came in the early 1940s, when French scientists used them to treat typhoid patients. After treatment, the patients had symptoms of dangerously low blood sugar levels (hypoglycemia). Tests of the same drugs in dogs showed that they stimulate insulin secretion, leading to hypoglycemia. Insulin is a hormone released by the beta cells of the pancreas in response to elevated blood sugar levels. Its release then promotes the uptake of sugar by cells in the body. These novel findings paved the way to clinical trials to test this class of drugs in people with the form of diabetes now known as type 2. People with type 2 diabetes produce insufficient amounts of insulin to compensate for diminished responsiveness of cells to the hormone. In the mid-1950s, sulfonylureas were found to be effective for treating human type 2 diabetes. Sulfonylureas were the first diabetes pills used as an alternative to insulin injections for people with type 2 diabetes.
This result was great news, but it remained unknown exactly how sulfonylureas stimulated insulin secretion. Teasing out this mystery has been the subject of research for several decades. A clue came in 1985, when NIDDK-supported scientists demonstrated that sulfonylureas inhibit a potassium ion channel. This type of channel allows movement of potassium ions between the inside and outside of the beta cell, a common method the cell uses to control its processes. Although this observation shed some light on how the drugs may work, it also led to several new questions: what protein (or proteins) comprised the potassium ion channel? Were sulfonylureas binding directly to the channel or were they binding to an intermediate protein to stimulate insulin release?
A breakthrough came in 1995, when NIDDK-supported scientists cloned a gene encoding the sulfonylurea receptor, or SUR. This protein was the target to which the drugs were binding in beta cells. Interestingly, mutations in the gene encoding SUR were found to be linked to a rare genetic disease, called persistent hyperinsulinemic hypoglycemia of infancy (PHHI). People with this disease have high levels of insulin and correspondingly low blood sugar levels. These findings suggested that SUR was a critical component of cellular pathways regulating insulin secretion. Was SUR the potassium ion channel that was inhibited by sulfonylureas? Research showed that SUR alone could not function as an ion channel. However, a few months later, the same group of NIDDK-supported scientists identified SUR’s partner—a protein called Kir6.2. The combination of SUR and Kir6.2 worked together as a potassium ion channel. This research demonstrated that the previously unidentified potassium ion channel was composed of SUR and Kir6.2; sulfonylureas bound directly to the SUR subunit of the channel to inhibit it.
These pioneering NIDDK-supported discoveries contributed to a model of the regulation of insulin secretion by sugar. The SUR/Kir6.2 ion channel regulates the balance of potassium and calcium ions inside and outside the beta cell, which in turn helps to regulate insulin secretion. In healthy people, when blood sugar levels are low, the channel is “open” and insulin is not secreted. When blood sugar levels are high (e.g., after a meal), sugar metabolism in the beta cell closes the ion channel, and insulin is secreted. Sulfonylureas cause the same biological effect as high sugar levels—they close the channel and stimulate insulin release from the beta cell. Mutations causing PHHI also result in a similar biological effect—they prevent the channel from opening and promote insulin release.
Building on this research foundation, researchers in Europe hypothesized that SUR/Kir6.2 may be involved in monogenic diabetes. These forms of diabetes result from mutations in a single gene; in contrast, type 1 and type 2 diabetes involve variations in multiple genes. The two main forms of monogenic diabetes are neonatal diabetes mellitus and maturity-onset diabetes of the young (MODY). Neonatal diabetes is a rare condition, usually occurring within the first 6 months of life, and may either be permanent, or transient—with the possibility of relapse later in life. While a number of genes had been found that each could cause MODY—the monogenic form of diabetes that is usually diagnosed later in childhood or young adults—the genetic cause of permanent neonatal diabetes was unknown.
In 2004, the European researchers examined the gene encoding Kir6.2 in patients with permanent neonatal diabetes. Several people with the disease had mutations in this gene. Upon examination of the underlying biology of the mutant channels, researchers found that the mutations caused the channels to be "open" all the time, even in the presence of high levels of sugar. Thus, these mutations appeared to prevent insulin release. These findings helped to explain why children with these mutations produce insufficient amounts of insulin and require insulin administration. They also suggested that, if there were another way to close down the channels—such as through treatment with sulfonylureas—perhaps insulin secretion could be restored.
These observations laid the foundation for a recent clinical trial by the same group of scientists to test the effect of switching neonatal diabetes patients from insulin to oral sulfonylurea treatment. People in the trial had mutations in their gene encoding Kir6.2. Strikingly, 90 percent of patients successfully discontinued insulin after receiving the oral drugs. Average blood sugar control improved in all patients who switched treatment strategies. These results are extremely exciting because oral therapy is a much less burdensome treatment strategy than insulin administration, which requires daily injections or use of a pump. It is of particular benefit for babies and young children to be able to take oral medication for their neonatal diabetes, rather than experience an arduous regimen of daily insulin administration.
NIDDK-supported scientists have also recently shown that some people with permanent and transient neonatal diabetes have mutations in their gene encoding SUR. People with these mutations who were switched from insulin to sulfonylurea therapy appeared to respond favorably. Together, these studies demonstrate that mutations in the gene encoding Kir6.2 are the most common cause of permanent neonatal diabetes; mutations in the gene encoding SUR account for fewer cases of permanent and some cases of transient neonatal diabetes.
How do people with PHHI and neonatal diabetes have mutations in the same ion channel, but PHHI patients have too much insulin and patients with neonatal diabetes have insufficient amounts? It turns out that mutations causing PHHI have the opposite effect on the function of the ion channel than mutations causing neonatal diabetes. The mutations causing PHHI prevent the channel from opening, which causes beta cells to secrete insulin continually. The mutations causing neonatal diabetes cause the channels to always remain open, which prevents insulin release. Thus, even though the same ion channel is involved in both diseases, the effects of the different mutations lead to completely opposite biological responses.
These studies identify a novel mechanism for the development of a significant fraction of permanent and transient neonatal diabetes mellitus and identify a less burdensome treatment strategy for some patients. They also pave the way for genetic testing to inform personalized treatments for people with the disease. Importantly, this research elegantly demonstrates how long-term studies of underlying biological mechanisms directly led to an improved treatment option for patients. Incremental studies of how sulfonylureas worked in the beta cell culminated with the NIDDK-supported discovery of the SUR/Kir6.2 potassium ion channel. This discovery not only informed key genetic studies, but also provided a much greater understanding of the basic biology of insulin secretion. Recently, using a whole genome association study, NIH-supported investigators have confirmed that the gene for Kir6.2 can contribute to type 2 diabetes. These studies now serve as the foundation for additional research on the role of this ion channel in diabetes, with the potential to improve and personalize therapies by targeting specific treatments to patients with specific genetic changes underlying their diabetes.
Genetic testing could be helpful in selecting the most appropriate treatment for people with monogenic diabetes. If you think that you or a family member has a monogenic form of diabetes, you should seek help from a healthcare provider. For more information on monogenic forms of diabetes, please see an NIDDK fact sheet available at: http://diabetes.niddk.nih.gov/dm/pubs/mody/mody.pdf
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Advances in Inflammatory Bowel Diseases Research
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NIDDK support for research on genetics and immunology of the inflammatory bowel diseases (IBD) is paving the way to the development of unique and effective therapies for patients who suffer from these diseases.
IBD was described in the medical literature as early as the mid-18th Century, but it was not until the mid-20th Century that the two major subtypes of IBD—Crohn’s disease (CD) and ulcerative colitis (UC)—were identified and distinguished by the area of the intestine they affect. The incidence of these diseases in western, industrialized societies increased dramatically during the 20th century. These are painful and debilitating diseases, characterized by chronic, intermittent intestinal inflammation. In CD, inflammation can occur anywhere in the alimentary tract and sometimes in other sites, but most often occurs in the end of the small bowel and beginning of the large bowel (colon). In UC, the site of inflammation is restricted to the colon, or large intestine. The leading theory for the cause of IBD is that inflammation is triggered by inappropriate immune responses to bacteria that naturally reside in the intestine and that the underlying predisposition to these inappropriate immune responses is caused by multiple interacting genes. Under normal circumstances, most bacteria residing in the gut have a beneficial or benign effect on their host, but an overly active immune system may be provoked by these bacteria in IBD.
Genetic Factors in IBD Uncovered
Studies of human twins and of animals have confirmed that genetic factors contribute to IBD. Some gene variants are specifically associated with either CD or UC, while others are involved in both diseases. The importance of genetic factors is also reflected in family studies showing the incidence of IBD to be higher among family members.
A major research breakthrough on the genetics of IBD came in 2001, with the discovery of the first IBD-associated gene, called NOD2 . The NOD2 gene was found to be associated solely with CD, not with UC. This landmark research, which was supported by the NIDDK, represents one of the earliest, most well-established associations in complex genetic disorders. The product of NOD2 is a cellular protein found in immune cells, called monocytes, and in cells lining the intestinal wall. Although the mechanisms underlying the relationship of the NOD2 gene variant to CD are not yet fully understood, the NOD2 protein is known to activate communication (signaling) pathways in response to components of bacterial cell walls, leading to a variety of immune responses.
Building on this important finding, the NIDDK in 2002 established the Inflammatory Bowel Disease Genetics Consortium (IBDGC). (For more information on the Consortium, see highlights from a Scientific Presentation by Consortium investigator Dr. Judy Cho, which appears later in this chapter).
The Consortium’s efforts were greatly enabled by resources provided by the NIH-sponsored Human Genome Project and the International HapMap Project, which were major drivers in propelling research on human genetics. The Human Genome Project sequenced the 3 billion nucleotide base pairs of the human genome, a monumental effort that concluded in April 2003. Data from this project were made available to scientists around the globe to facilitate the pursuit of medical research. The International HapMap Project, published in 2005, is a catalogue of common small genetic variations called SNPs (single nucleotide polymorphisms) that occur in the nucleotide (or letter) sequences of individuals’ DNA. The Genome and HapMap projects have been accompanied by great strides in the development of new rapid biomedical technologies so that hundreds of thousands of SNPs can now be determined in single DNA samples. The genome-wide association scan based on these advances has become the cutting-edge technology for identifying genes that contribute to human disease, and was used by the Consortium to identify genetic factors in IBD.
Recently, members of the Consortium used this genome-wide association technology in a two-phase study designed to identify additional genes that contribute to CD. In this study, blood samples from CD patients and healthy volunteers were scanned for known genetic variants using over 300,000 SNPs. The first phase of the study was very successful in detecting several significant SNP associations, including a variant of a gene encoding a receptor for the cytokine (an immune system chemical) interleukin-23 (IL-23). Surprisingly, one variant of the gene was shown to protect against CD. Additional studies have shown that the IL-23 receptor is required for CD to develop in animal models.
Because the inflammatory bowel diseases are complex diseases involving the contributions of many genes, it was anticipated that genes also existed that had more subtle associations with IBD, the detection of which would require screening much larger cohorts. Therefore, a second, expanded phase of the study was conducted on a larger population of CD patients and healthy volunteers. In this second phase of the study, scientists discovered another CD associated gene, ATG16L1 , which is involved in autophagy. Autophagy is a process by which cells capture, degrade, and recycle unwanted cellular material into useful molecules. This process has also been associated with the body’s early immune response that is activated by the recognition of bacterial components. The involvement of the autophagy process has been verified by two other scientific research groups. One group identified the autophagy gene, ATG16L1 , using a different protocol in which 72 SNPs, selected through a screening process, were used in a genome-wide association scan of CD patients and healthy controls. The other group identified a second autophagy gene linked to CD, called IRGM , in a major genome-wide association study that scanned 14,000 patients with seven different diseases (2,000 patients for each of the seven diseases) and a shared control set of 3,000 healthy volunteers. The study identified 27 additional disease-related genetic variations, including nine for CD, seven for type 1 diabetes, and three for type 2 diabetes.
Mapping the Molecular Pathways of IBD Development
Discovery of the IBD gene, NOD2 , provided the first evidence linking this disease to the immune response to bacteria. The NOD2 protein is an intracellular sensor of bacterial wall components. Upon sensing the bacteria, NOD2 activates multiple molecular pathways associated with initial responses by the immune system. Extensive research continues to clarify the roles that pathways stimulated by NOD2 play in the errant activation of immune response associated with IBD.
Research on chemicals utilized by the immune system, including cytokines such as interleukins, has demonstrated the important role of pathways activated by these molecules in IBD development. Identification of the interleukin-23 receptor gene as being associated with the risk of developing IBD coincided with other research investigating the roles of IL-23 and its receptor in autoimmunity, the immune system’s inappropriate reaction to the body’s own tissues. Studies exploring the causes of inflammation in autoimmune disease have focused on two cytokines, IL-12 and IL-23, which have related structures, but different functions. These two molecules are dimers that each have one identical subunit, as well as one unique subunit. Antibodies against the common, shared subunit of the two cytokines inhibit inflammation in both animals and in human CD. More recent studies in mice have shown that IL-23, not IL-12, is responsible for inflammation.
In one study examining the roles of IL-12 and IL-23 in IBD, scientists used a mouse model infected with bacteria known to induce inflammation and then analyzed IL-12 and IL-23 subunit expression in the intestine. The mice responded to bacterial infection with increased production of the common subunit of both interleukins and the unique subunit of IL-23, but not the IL-12 unique subunit, demonstrating that inflammation is dependent on IL-23, not IL-12. Furthermore, when antibody was introduced to block the unique IL-23 subunit, inflammation was markedly reduced, confirming that IL-23 is essential for inflammation in the intestine. Confirmation that IL-23, not IL-12, is required for intestinal inflammation was made in another study using two mice strains with double mutations. Both strains contained a mutation that causes them to spontaneously develop inflammation resembling CD. Additionally, the IL-12 unique subunit was inactivated in one strain and the IL-23 unique subunit was inactivated in the second strain. Mice with mutations in the IL-12 unique subunit developed colitis; however the IL-23 unique subunit mutants remained disease free, confirming that active IL-23 is essential for intestinal inflammation. These results point to selective targeting of IL-23 as a potential new therapeutic approach for human IBD.
Recent research has also refined our understanding of the types of immune cells involved in IBD, and how they interact with key molecular pathways. IL-23 has been shown to induce the production of other inflammatory cytokines by immune cells called monocytes and macrophages. IL-23 also activates a recently identified subtype of helper T cells (TH cells), called TH17 cells. Until recently, only two major subsets of TH cells had been identified: TH1 cells, which secrete molecules that destroy intracellular microbes and are associated with CD; and TH2 cells, which secrete molecules that destroy extracellular microbes and are associated with UC. The newly-discovered TH17 cells secrete the inflammatory cytokines TNF-alpha, IL-6, and IL-17, and are thought to be particularly important in causing tissue inflammation in immune diseases, including IBD. Thus, not only has IL-23 been implicated as an important cytokine in IBD, it appears that the cytokine acts through a very specific type of T cell that has only recently been identified. These discoveries suggest important new pathways to be explored to develop treatments for CD.
New Treatments for IBD
The elucidation of new disease genes and the molecular responses they initiate is key to developing drugs that prevent and treat IBD. Two examples from recent years involve molecules known as TNF-alpha and PPAR-gamma. The cytokine TNF-alpha is now recognized as a major factor in the inflammatory immune responses associated with IBD. The drug infliximab was the first recombinant antibody designed to bind to TNF-alpha, thereby preventing it from engaging with receptors that activate inflammatory responses. Infliximab was initially thought to be effective only in treating and maintaining remission of CD, but has now been show to be an effective treatment of UC.
The peroxisome proliferator activated receptor-gamma (PPAR-gamma) regulates gene expression in the nuclei of immune cells and epithelial cells that line the colon and is known for its effects on tumor suppression in the colon and on attenuation of colitis. PPAR-gamma expression was found to be impaired in cells lining the colons of UC patients, indicating a potential role in the treatment UC. Mutant mice with minimal expression of PPAR-gamma in their colon epithelial cells were given a substance that induces colitis, in order to determine if PPAR-gamma plays a protective role against developing UC. Mutant mice exhibited higher levels of molecules that promote inflammation and increased susceptibility to experimental colitis when compared with control mice. Rosiglitazone, a drug used for the treatment of type 2 diabetes, activates the PPAR-gamma receptor. When rosiglitazone was administered to the mice, the severity of the induced colitis was decreased and cytokine production was suppressed in both mutant and control mice, demonstrating that PPAR-gamma plays a role in protecting against colitis. Because administration of rosiglitazone was effective in reducing colitis symptoms in mutant mice expressing minimal levels of PPAR-gamma, as well as control mice, it is possible that rosiglitazone may also act independently of PPAR-gamma in suppressing inflammation.
The efficacy of rosiglitazone in treating UC in humans was recently tested in a multicenter clinical trial supported by the NIDDK. Patients participating in the trial had mild-to-moderate UC and had been previously treated with the drug 5-aminosalicylate, the most common treatment for UC, but had not responded well or were intolerant to the drug. After receiving either rosiglitazone or a placebo, patients were assessed for improvement in their condition. After 12 weeks, 44 percent of patients given rosiglitazone had clinical remission compared to 23 percent of patients given placebo. These data demonstrate that rosiglitazone is effective in the short-term treatment of patients with mild-to-moderate UC who did not benefit from other treatments. Further long-term studies must still be conducted to assess use of this class of drug as a maintenance therapy for UC, and to determine whether they provide an additional new treatment option for patients suffering from UC.
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Polycystic Kidney Disease
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Polycystic kidney disease, or PKD, is the fourth leading cause of kidney failure in the U.S.1 Fluid-filled cysts form in the kidneys and other organs and can, as they grow over time, compromise kidney function. Patients with the disease typically have high blood pressure, urinary tract infections, and chronic pain. There is no primary treatment for PKD, and patients generally receive drugs to control their blood pressure and manage their pain. However, knowledge of the causes of PKD has increased dramatically in the past 20 years due to NIDDK-supported research. Scientists have a better understanding of the genetic causes of PKD, and are studying the use of new technologies to improve disease detection and monitoring. Because of the efforts of many dedicated scientists, there is hope for the future for people with PKD and their families.
What is Polycystic Kidney Disease?
Polycystic kidney disease (PKD) is a genetic disorder characterized by the growth of numerous fluid-filled cysts. These cysts develop primarily in the kidneys, but also can appear in organs such as the liver, pancreas, spleen, and thyroid. In the kidneys, these cysts can slowly replace much of the mass of the kidneys, reducing kidney function and leading to kidney failure. About half of people with the most common form of PKD progress to irreversible kidney failure, also called end-stage renal disease (ESRD). When this occurs, usually in the fifth or sixth decade of life, patients require either a kidney transplant or dialysis to survive. In the United States, an estimated 600,000 people have PKD, and it is the fourth leading cause of kidney failure. While there is no effective treatment for the underlying causes of PKD, patients are usually prescribed pain-relieving drugs, antibiotics to treat infections, as well as medications to control blood pressure that are aimed at preserving or slowing the decline in kidney function.
There are two major inherited forms of PKD, called autosomal dominant and autosomal recessive. Autosomal Dominant PKD, or ADPKD, accounts for about 90 percent of all cases. People with ADPKD usually develop symptoms between the ages of 30 and 40, but symptoms can appear earlier, even in childhood. The genetically recessive form of PKD, Autosomal Recessive PKD, or ARPKD, is a rare inherited form of the disease that displays symptoms in the earliest months of life, even in the womb.
Past Treatment for PKD
About 30 years ago, knowledge about the causes and progression of PKD was limited. The details of the genetics of the dominant form of PKD were unknown. Doctors knew that, on average, half of children born to an affected parent would develop the disease, and that it could be transmitted by either the mother or the father. The mechanism by which the disease caused cysts to form and grow in the kidneys was not known. Diagnosis of well-established disease in adults was relatively straightforward using the imaging techniques that were available at the time, such as ultrasound. However, diagnosis of earlier stages of disease in children and young adults was much more difficult. By the time most people were diagnosed, their kidneys were so damaged that kidney function had begun to decline.
Treatment options for people with chronic kidney disease in general, and ADPKD in particular, were also inadequate. No specific therapy was available. The importance of controlling blood pressure and dietary protein intake in patients with chronic kidney disease was not recognized. Two life-saving kidney function replacement therapies—hemodialysis and kidney transplantation—were developed through fundamental NIH research in the 1960s. Although they were increasingly available, neither was ideal.
Genetic Underpinnings of PKD and Insights from Animal Models
The emergence of molecular biology and modern biotechnology in the late 1970s and early 1980s permitted researchers for the first time to examine in detail the genetic underpinnings of a number of diseases. Scientists have identified two genes associated with ADPKD. The first was found in 1985 on chromosome 16 and was named PKD1 . The second gene, 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. Most cases of the dominant form of PKD can be traced back to mutations in one of these two genes. However, evidence suggests that the disease development also requires other factors. Normally, polycystin-1 and polycystin-2 form an ion channel on the surface of kidney cells. This channel regulates the flow of calcium into and out of the cell. Mutation of either gene inhibits the activity of the channel, thus disrupting calcium-dependent intracellular signaling pathways.
This ion channel is part of a complex of proteins located on the cell surface at the site where tiny, hair-like projections called cilia emerge from the cell into the renal tubule, where waste products are filtered into what will become urine. Under normal conditions, the cilia on the surface of these renal tubule cells detect changes in urine flow, and transmit this information inside the cell through the activation of various molecular signaling pathways. One signaling mechanism is the opening of the ion channel formed by polycystin-1 and -2. The opening allows calcium ions to enter the cell, setting off a cascade of signaling events. However, when one or both are mutated, the channel does not function properly. As a result, calcium does not enter the cell, and the metabolic response to changes in urine flow is disrupted. This abnormality in calcium signaling may result in cells that grow abnormally and retain fluid, ultimately giving rise to multiple, fluid-filled cysts characteristic of PKD.
Disruptions in cilia signaling have been found to underlie a number of diseases of the kidney, as well as other organs. Many genes encode proteins that localize to the cilia, and mutations in these genes often produce similar clinical manifestations. These observations have given rise to the hypothesis that many cystic kidney diseases may arise from defects in primary cilia signaling. Future efforts will be devoted to improved understanding of cilia signaling and identifying potential new therapeutic targets. Because cilia are found on the surface of almost all cells in the body, insights gained from these studies may also benefit people suffering from a number of diseases in which cilia signaling is impaired.
Researchers have also identified the gene associated with ARPKD, called PKHD1 . The protein encoded by this gene, known as fibrocystin or polyductin, is present in fetal and adult kidney cells, and is also present at low levels in the liver and pancreas. Its precise biological function is unknown.
Current Clinical Management and Research Studies of PKD Advances in knowledge about cyst formation and disease progression have been complemented by improvements in the early detection and treatment of the most common form of PKD. The NIDDK supports a number of clinical studies aimed at furthering our knowledge about the origins, progression, and optimal treatment of this disease.
The NIDDK-supported Consortium for Radiologic Imaging Studies of PKD (CRISP) was established to develop innovative imaging techniques and analyses to follow disease progression or to evaluate treatments for the common form of the disease. Importantly, the CRISP study demonstrated that magnetic resonance imaging (MRI) could accurately track structural changes in the kidneys, and that such methods may be able to predict functional changes earlier than standard blood and urine tests in people with the common form of PKD.
The respective roles of PKD1 and PKD2 in disease progression, as indicated by ultrasound analysis, have remained unclear. The CRISP investigators, using a more sensitive MRI method, reported that patients with the PKD1 gene have more cysts and significantly larger kidneys than those with the PKD2 gene. Data from the CRISP study suggest that this difference results from earlier development of cysts, not from a faster growth of cysts, in patients with PKD1 mutations. These clinically important results will inform the development of targeted therapies for patients with this form of the disease.
To expand and follow-up on the important insights gained in the CRISP study, the NIDDK has funded an extension, CRISP II, to continue to monitor this valuable cohort of patients. The extension will enable researchers to determine the extent to which changes in kidney volume do in fact predict changes in kidney function.
The NIDDK, with co-funding from the PKD Foundation, is also conducting two clinical trials of people with the most common form of PKD—one in patients with early kidney disease and another in patients with more advanced disease. These two trials are the largest multi-center studies of PKD conducted to date, and are collectively termed HALT-PKD. These studies are testing whether optimum blood pressure management, in combination with drugs—either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers—will slow the progression of this disease. The NIDDK is also funding an investigator-initiated interventional trial of optimum blood pressure therapy in children and young adults. These interventional studies are the first clinical trials to implement and formally validate the imaging surrogate marker of PKD progression that was developed by the CRISP study.
Hope for the Future
Investigators are continuing to pursue basic biologic studies of the causes of PKD, as well as new avenues for therapies, in the hope that diagnosis and treatment can be improved. As scientists’ understanding of the genetics and progression increases, it is hoped that there will be a decrease in the number of patients with the disease who progress to ESRD. Because PKD can affect patients very differently, even within the same family, the NIH is assembling a large genetic sample collection for future investigations. Studies of these samples may help to identify genetic markers that might predict who will develop more rapidly progressive kidney disease. These genetic studies could also provide new information on identifying key disease pathways and aid in the design of new drug treatment strategies. The studies also could yield clues about how to intervene earlier, more precisely, and more effectively in these patients. Earlier intervention, more intensive management of high blood pressure, and use of drugs that target kidney fibrosis may delay progression to ESRD and give patients additional years of life without the need for dialysis or a kidney transplant. For patients who eventually do need dialysis, the NIH is conducting a trial to determine whether more frequent dialysis improves their quality of life.
Although there have been advances in the knowledge base about dialysis and improvements in technology, a functioning kidney transplant remains a patient’s best hope of living a more normal life. However, normal life expectancy and health-related quality of life are rarely, if ever, restored by organ transplantation. Furthermore, despite the best immunosuppressive therapies, many patients with kidney transplants still lose their transplanted kidneys due to rejection of the transplant by the body’s immune system. Better strategies to maintain the function of transplanted kidneys and prevent chronic scarring are likely to emerge from ongoing basic research and improved imaging methods. The NIDDK and NIH will continue to support research into kidney disease in general, and PKD in particular, working across Institutes and joining with other partners to better understand, monitor, and treat this disease.
1 U.S. Renal Data System, USRDS 2007 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2007.
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