Highlights of research being conducted by NIDDK-supported scientists
Kidney Stones as a Systemic Disease
Dr. Gary Curhan
(Download PDF version - 236KB)
Dr. Gary Curhan is an Associate Professor of Medicine at Harvard Medical School and an Associate Professor of Epidemiology at the Harvard School of Public Health. He is a leading researcher in the field of kidney disease, as well as a number of other chronic diseases, including interstitial cystitis and high blood pressure. The following represents highlights of a scientific presentation by Dr. Curhan at the September 2007 meeting of the NIDDK National Advisory Council. Dr. Curhan shared with the Council his view of kidney stone disease as an organ-specific manifestation of a more generalized systemic disorder, rather than simply a disease of the kidneys.
Kidney stone disease is a common and painful health problem in the U.S. It is also a growing problem: the number of people in the U.S. with kidney stones has increased significantly over the past 30 years. White Americans are more prone to develop kidney stones than African Americans, and men are more likely to develop stones than women. For unknown reasons, some individuals are prone to repeatedly developing stones. Each year, people make almost three million visits to health care providers and more than half a million people go to emergency rooms for kidney stone problems.1
The first symptom of a kidney stone typically appears when the stone moves from the kidney into the ureter, causing irritation or blockage and resulting in extreme pain. Most kidney stones can pass harmlessly—though not painlessly—through the urinary system. In such cases, medication to alleviate the pain may be the only medical intervention needed. Stones that cause lasting symptoms or other complications may be treated by various techniques, most of which do not involve major surgery. In severe cases, however, surgery may be required to remove the stone.
In addition to being extremely painful, kidney stones also are costly to treat. According to the 2007 edition of Urologic Diseases in America, kidney stones are the second-costliest urologic disease, accounting for over $2 billion spent on medical care,2 with another $4 million to $14 million spent on prescription drugs.3 These numbers do not include costs not associated with direct medical expenditures, such as time lost from work.
Composition of Kidney Stones
Kidney stones can consist of a number of different components. The most common type of stone, accounting for two-thirds of all stones, is a combination of calcium and oxalate. Less common types of stones include stones caused by urinary tract infections, and stones made of uric acid or the amino acid cystine. “Nephrolithiasis” is the medical term used to describe stones occurring in the kidney, while stones in the urinary tract are formally designated as “urolithiasis.” For the sake of simplicity, “kidney stone” is often used to designate stones regardless of their location in the kidney or urinary tract.
Urine is a liquid with various substances dissolved in it, and there is a finite amount of material that can be dissolved in a given quantity of water. If this limit is exceeded, material will fall out of solution and crystallize. Once this process starts, the nascent crystals attract other dissolved elements in the water, and the crystal grows in size. Although the precise steps that lead to kidney stone formation are not known, one way to think about crystal formation is as a problem of too much material trying to remain dissolved in too little water.
Risk factors for kidney stones encompass gastrointestinal, skeletal, and metabolic factors, as well as obesity. At first glance, the connection of most of these factors to the kidney may not be obvious. However, closer examination reveals clues that implicate kidney stone disease as an organ-specific manifestation of more general systemic disturbances.
Risk Factors: Gastrointestinal
Because the most common type of kidney stone, the calcium oxalate stone, consists of two components found in a normal diet, it might stand to reason that increasing consumption of these factors would increase the risk of stone formation. Indeed, patients prone to developing stones are often counseled to limit their dietary intake of calcium and oxalate. However, studies reveal that increased dietary intake of calcium does not increase the risk of stone formation and may in fact reduce the risk. Increased dietary intake of oxalate has, at best, a modest impact on stone risk. Surprisingly, however, increased dietary intake of fructose correlates with a dramatic increase in risk of developing a kidney stone. Fructose is one of the two sugar molecules that comprise ordinary table sugar and is a major component of high fructose corn syrup, which is used in a large number of food products. It seems that, in some individuals, fructose can be metabolized into oxalate. This observation underscores the complexity in using diet modification in people prone to developing kidney stones, because traditional advice to limit intake of oxalate-containing foods may not be sufficient to reduce risk of stone development (for more details regarding the assessment of dietary oxalate and its role in stone formation, see the accompanying research advance, “Dietary Oxalate Is Not a Major Contributor to Kidney Stone Formation”).
Risk Factors: Bone
In addition to providing structural support and protecting internal organs, the skeleton represents a large repository for calcium. The skeleton is an active site of tissue breakdown and regeneration throughout life. In diseases such as osteoporosis, more calcium is lost from bone than is deposited, resulting in a net negative calcium balance. Researchers have known for years that patients with elevated calcium levels in their urine are likely to have lower bone mineral density, emphasizing that there are metabolic sources for urinary calcium, as well as dietary sources.
Of course, skeletal remodeling is not the only source of circulating calcium, as this mineral is an important component of the diet. Does increased calcium in the diet increase one’s risk of developing kidney stones? Quite the opposite: several large epidemiologic studies and one randomized trial suggest that high dietary calcium intake is associated with a decreased risk of kidney stones, and that people with the lowest dietary calcium intake had an increased risk of kidney stones. The reason for this is unclear, but it is possible that higher levels of dietary calcium bind to oxalate in the digestive tract and prevent it from being absorbed and eventually moving to the kidneys where it might form stones.
Risk Factors: Obesity
It has been know for years that increasing body weight puts individuals at risk for high blood pressure, diabetes, and a host of other health problems. Recent research has also uncovered a role for obesity in the formation of kidney stones. Studies have shown that the risk of stone formation can be almost twice as great in women who weigh more than 220 pounds compared to those who weigh less than 150 pounds; overweight men are also at higher risk. The increase in relative risk is also seen if one looks at body mass index, which takes both height and weight into account. The reason for this correlation is unclear, but it is the subject of ongoing research.
As rates of obesity in the U.S. continue to rise, more people are turning to bariatric surgery as a way to address the problem. In this surgery, doctors alter the digestive tract in order to restrict food intake and, in some cases, interrupt the digestive process. When researchers examined urine oxalate levels in patients who had undergone this procedure, they found levels were two to three times higher than normal, and elevation in oxalate seems to result in a higher risk of stone formation. This finding underscores the complex metabolic pathways that regulate oxalate absorption and excretion and how changes to the digestive tract may have unexpected results on overall metabolism.
Risk Factors: Endocrine and Metabolic Pathways
Diabetes significantly increases an individual’s risk of kidney disease, blindness, amputation, and cardiovascular disease. Scientists have recently shown that diabetes also increases the risk of developing kidney stones between 20 and 50 percent, and that this increase is especially apparent in younger women. There is also evidence that people with diabetes have a lower than normal urine pH—meaning that their urine is more acidic. This change in urine composition, sometimes accompanied by a decrease in urine volume, may also contribute to stone formation in these individuals. This observation further emphasizes that kidney stones may arise as much from generalized metabolic derangement as from kidney-specific factors.
Risk Factors: Genetics
As is the case with many diseases, it is likely that kidney stones arise from both environmental and genetic causes. Much of what is known about stone formation concerns dietary and metabolic factors, but it is likely that genetics plays an important role in determining an individual’s likelihood of developing kidney stones. Currently, a number of potential candidate genes have been identified, including the calcium sensing receptor, the vitamin D receptor, and the oxalate transporter protein in the intestine. Large genome-wide association scans that might identify other candidates have only recently begun, but hold great promise for the future (for more information about genome-wide association scans, see the chapter on Cross-Cutting Science.)
Conclusion
Kidney stone disease should be thought of as a systemic disorder and not just a disease of the kidneys. In the past several years, significant progress has been made in understanding the causes of the disease, but much work remains to be done. Moving forward, new paradigms regarding the underlying causes of the disease will shape the research agenda, especially regarding the origins of stones and the risk factors that contribute to their formation. Future large studies of genetics and gene-environment interactions will further our understanding of this complex disorder.
1 Kidney Stones in Adults, National Kidney and Urologic Diseases Information Clearinghouse, National Institute of Diabetes and Digestive and Kidney Diseases. http://kidney.niddk.nih.gov/kudiseases/pubs/stonesadults/index.htm
2 Litwin MS and Saigal CS: Introduction in Urologic Diseases in America (pp. 1-7). NIDDK, NIH Publication Number 07–5512, 2007.
3 Pearle MS, Calhoun E, and Curhan GC: Urolithiasis in Urologic Diseases in America (pp. 281-319). NIDDK, NIH Publication Number 07-5512, 2007.
Back To Top
The Intersection of Drug Metabolism and Diabetes
Dr. David Moore
(Download PDF version - 204KB)
Dr. David D. Moore is a professor in the departments of Molecular and Cellular Biology and Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas. He received his Ph.D. in Molecular Biology from the University of Wisconsin, Madison. He trained as a post-doctoral fellow in the laboratory of Dr. Howard Goodman at the University of California, San Francisco. He has received numerous awards for his teaching and research, including the Edmund B. Astwood Award from the Endocrine Society. The following are highlights from the scientific presentation that Dr. Moore gave to the NIDDK’s National Advisory Council in May 2007.
Dr. Moore’s presentation focused on nuclear hormone receptors, which are proteins that help certain chemicals, such as vitamin D or the sex hormones estrogen and testosterone, exert some of their effects. Typically, when one of these chemicals enters a cell it binds to its receptor, and the hormone-receptor complex then interacts with both specific DNA sites and other proteins to turn some genes in the nucleus “on” and others “off.” Most of the 48 nuclear hormone receptors encoded by the human genome actually bind—not to true hormones—but to other chemicals coming from outside the body. Through support from NIDDK, the National Heart, Lung, and Blood Institute and the National Institute of Environmental Health Sciences, the Nuclear Receptor Signaling Atlas project is cataloging the diverse and extremely important physiological effects of these proteins. An important subset of these receptors plays a vital role in triggering the process by which the body eliminates certain drugs or toxins, a process called drug metabolism.
Dr. Moore first discussed recent research from his laboratory that has shed light on the way that type 1diabetes influences drug metabolism via CAR, a member of the nuclear hormone receptor family originally cloned in his laboratory. Dr. Moore then presented work showing that drug metabolism mediated by CAR may be helpful in achieving healthier blood glucose levels in patients with type 2 diabetes. Thus, not only can diabetes influence drug metabolism, but also drug metabolism can affect diabetes.
Diabetes Impacts Drug Metabolism
The experiments Dr. Moore highlighted were inspired by observations from other researchers that type 1 diabetes accelerates metabolism of certain drugs, both in humans and in rodent models. Dr. Moore’s lab looked at drug metabolism genes that are turned on by CAR. The researchers found that these genes were turned on in a mouse model of type 1 diabetes. Controlling the diabetes reversed the effect: when insulin was given to the mice, the CAR-induced genes turned off.
In fact, type 1 diabetes not only leads to activation of drug metabolic genes, but also has a profound effect on the metabolism of certain drugs. Mice with induced type 1 diabetes rapidly clear their systems of a compound that induces temporary paralysis, while normal mice cannot. These experiments also underline the central importance of the CAR nuclear receptor in affecting drug metabolism: mice without CAR take much longer to clear the drug, whether or not they have diabetes.
How does CAR promote speedier drug metabolism in animals or people with diabetes? The answer may have to do with an unusual property of CAR compared to other nuclear hormone receptors. In addition to its response to binding to a hormone or other activating molecule from outside the cell, CAR can move into the nucleus and turn on its target genes when it is activated by an enzyme within the cell called AMP kinase. Not surprisingly, AMP kinase is activated by certain drugs. In addition, the Moore lab found it to be modestly activated in the livers of mice with uncontrolled type 1 diabetes. Further research will be required to extend these suggestive results and determine the actual mechanism underlying the impact of type 1 diabetes on drug metabolism.
Drug Metabolism Impacts Diabetes
Early in the course of type 2 diabetes, the pancreas reacts to elevated blood glucose by producing more insulin to try to compensate. However, because the disease is characterized by insulin resistance, the result is that both blood sugar and insulin are elevated in these patients if they do not have proper treatment. Gradually, during the course of the disease, years of elevated blood glucose take their toll on insulin-producing cells, diminishing their ability to produce the vital hormone. Thus, without proper treatment, glucose control often goes from bad to worse.
Surprisingly, researchers have found that phenobarbital, a medication formerly used to treat epilepsy, also has the effect of reducing blood glucose levels in people with type 2 diabetes. The effect is only observed in patients whose disease is in its early stages and whose ability to produce insulin is not yet seriously diminished or lost. Phenobarbital has no impact on blood glucose or insulin levels either in those whose type 2 diabetes has progressed to the point where insulin production falls, or in people who do not have the disease.
Phenobarbital is an effective treatment for epilepsy, but it is no longer widely used because it has two serious side effects: it is a potent sedative, and it is such a powerful activator of drug metabolism (via CAR) that it can adversely affect the way a patient’s other medications are handled by the body. The effect on blood glucose can also be thought of as a side effect, albeit a potentially beneficial one in some patients due to its theoretical benefit for some people with type 2 diabetes. However, because of its serious side effects and the availability of safer medications that improve insulin sensitivity, phenobarbital is not a recommended treatment for the disease.
Nevertheless, understanding the way phenobarbital exerts its effects might point the way to other avenues of diabetes treatment. The lower blood glucose levels observed in type 2 diabetes patients taking phenobarbital might result from an overall improvement in insulin sensitivity among the body’s cells that allows them to absorb more glucose, or they might come from a more subtle metabolic effect.
To distinguish between these possibilities, the Moore lab examined a strain of mice that are obese because they lack a key hormonal mediator of appetite control. Invariably, the uncontrolled appetite of these mice leads them to become obese and to develop type 2 diabetes at a very young age. As in humans, a drug treatment that stimulates CAR helped normalize the otherwise sharply elevated blood glucose levels typically observed in these animals. When the obese mouse strain was modified by deleting the gene for CAR, the drug treatment had no effect on blood glucose, indicating that CAR is necessary for the effect.
If CAR has a general effect on insulin sensitivity, CAR stimulation would be expected to improve the ability of all tissues in the animal to absorb glucose. However, when the Moore group looked more carefully at how specific tissues in these mice respond to a sudden surge of injected glucose, they discovered this was not the case. CAR stimulation did not improve glucose clearance in peripheral tissues. Rather, the effect was confined to the liver.
One possible explanation for the importance of the liver in mediating CAR’s glucose-modulating effects relates to the liver’s vital metabolic role in keeping blood glucose sufficiently high to facilitate brain function during periods of fasting. The liver does this by liberating glucose from energy stores. One of the important messages insulin sends to the body is to tell the liver that it should stop producing glucose when blood levels of the molecule begin to rise after a meal, and to signal to the body that it should instead switch to replenishing energy stores. Because of the insulin resistance observed in type 2 diabetes, however, the liver continues to produce glucose even when its concentration in the blood is already too high. Interestingly, CAR seems to reduce the activities of several proteins with a key function in liver glucose production, while stimulating proteins that direct blood glucose into energy stores.
Conclusion
Dr. Moore’s presentation made the surprising case for two distinct intersections between the physiology of drug metabolism and that of diabetes. First, he recounted research that has shown the profound effect that type 1 diabetes can have on the metabolism of certain drugs by stimulating the CAR nuclear receptor. These data may ultimately bear not only on the way type 1 diabetes is treated, but also on the way people with the disease are treated for other conditions. Second, he showed that drug treatments that trigger CAR signaling can impact blood glucose levels in a mouse model of type 2 diabetes, probably by modulating glucose metabolism in the liver. These observations suggest that inhibiting glucose production and/or stimulating glucose storage by the liver is a potentially valuable approach to treating type 2 diabetes, perhaps in conjunction with other therapies.
Back To Top
Genetics of Inflammatory Bowel Diseases (IBD): IL23R as an IBD Susceptibility Gene
Dr. Judy Cho
(Download PDF version - 196KB)
Dr. Judy Cho is an Associate Professor in the Department of Medicine and Genetics at the Yale School of Medicine and the Director of Yale’s Inflammatory Bowel Disease Center. A leader in the field of inflammatory bowel disease (IBD) research, Dr. Cho and her colleagues are widely recognized for their 2001 discovery of the first known gene to increase susceptibility to Crohn’s disease—the NOD2/CARD15 gene. Dr. Cho is the Chair of NIDDK’s Inflammatory Bowel Disease Genetics Consortium Steering Committee and Principal Investigator of the Consortium’s Data Coordinating Center. Recently, the NIDDK IBD Genetics Consortium identified IL-23R as another IBD susceptibility gene. Dr. Cho presented this clinical research study to the NIDDK Advisory Council at their February 2007 meeting. The following are highlights from her presentation. (Additional information on IBD-related research conducted by Dr. Cho and other NIDDK-sponsored researchers is presented in this chapter’s “Story of Discovery.”)
The inflammatory bowel diseases are chronic, intermittent intestinal inflammations which are thought to result from inappropriate responses by the immune system to bacteria normally found in the intestine. Symptoms include diarrhea, abdominal pain, intestinal bleeding, and, in cases of childhood onset, growth retardation. IBD occurs frequently in young people—with a peak age of onset between 15 and 30 years of age. Because IBD is largely seen in industrialized societies, some researchers have suggested that it may be associated with changes in intestinal microbial populations during the industrialization process.
The two major subtypes of IBD are ulcerative colitis (UC) and Crohn’s disease (CD), which are distinguished by the area of the intestines affected. The site of inflammation with UC is restricted to the colon, or large intestine. In CD, inflammation is found in the small intestine and often affects both the small and large intestines. Ileal CD, which targets a part of the small intestine known as the ileum, is the most common form of Crohn’s disease.
Although little is understood regarding its etiology, IBD is known to involve complex interactions between multiple genes, as well as the microbial environment of the intestine. Two genetic associations with IBD had been well-established, the NOD2 gene, identified by Dr. Cho and her colleagues, and a variant in another area of the genome called IBD5. The discoveries of these genetic variations provided two pieces of the complex IBD puzzle, but did not fully explain the incidence of IBD. Thus, the search continued for other genes associated with this disease.
Searching for Additional IBD Genes
The prevalence of Crohn’s disease is several times higher in the Ashkenazi Jewish population of European ancestry than in the non-Jewish population of European ancestry. In this genome-wide association study, over 300,000 naturally occurring genetic variations were screened in Ashkenazi Jewish and non-Jewish patients and healthy controls. These variations, known as SNPs (single nucleotide polymorphisms) are small differences in an individual’s DNA sequence that can have varying disease consequences ranging from causing major genetic diseases such as cystic fibrosis or sickle cell anemia to more subtle effects that alter disease risk. SNPs are valuable disease biomarkers used in both research and clinical diagnoses.
The study began with a genome-wide screen of non-Jewish ileal CD patient and control cohorts. Ileal CD patients were selected exclusively to minimize genetic differences within the patient cohort. The screen identified three SNPs having highly significant associations with CD. Two of the three SNPs were located in the previously identified CD susceptibility gene, NOD2. However, the third was located in the IL23 receptor gene (IL23R). Surprisingly, this uncommon gene variant was found to confer protection against CD.
Ileal CD patients of Ashkenazi Jewish ancestry and their controls were then screened for IL23R markers. Highly significant differences were observed in the frequency of the protective marker in the two study groups. For example, this marker was identified in only two percent of CD patients in contrast to seven percent of the controls, supporting its protective role in preventing CD.
Following the two screens, the research team conducted a study to determine the frequency of the transmission of IL23R markers in nuclear IBD families consisting of children who were affected by IBD (CD, UC, and indeterminate IBD) and both of their parents. The study revealed that the protective variant of IL23R was much less likely to be passed down from parents to their IBD-affected children. Both Jewish and non-Jewish families with this marker were protected against developing CD; however, only the non-Jewish population showed a similar protective effect against UC.
The unexpected identification of a gene variant that protects against the risk of IBD has given new insights into the molecular underpinnings of this disease. These findings substantiate a hypothesis, supported by recent immunological studies, that the IL23R gene is required for the manifestation of clinical IBD. Importantly, these research results also provide potential therapeutic targets for its prevention and treatment.
The Inflammatory Bowel Disease Genetics Consortium (IBDGC)
In 2002, the NIDDK established the Consortium to provide the research resources necessary to take advantage of the wealth of genetic information provided by the NIH-sponsored Human Genome Project in elucidating the disease mechanisms of IBD. The infrastructure established to accomplish the Consortium’s mission includes a Data Coordinating Center, which oversees genetic analysis, database analysis, and coordination between six Genetic Research Centers. The Centers recruit patients and healthy volunteers for IBD study cohorts, submit patient blood samples and phenotype data to a repository, and conduct genetic research studies. Governance of the Consortium is provided by a Steering Committee consisting of Consortium scientists and a NIDDK health science administrator.
As Chair of the Steering Committee and head of the Data Coordinating Center and of one of the research centers, Dr. Cho has played a significant role in the development of the Consortium. In describing the Consortium’s major advantages, Dr. Cho identified:
- Synergy of expertise provided by gastroenterologists who are primarily interested in IBD and geneticists whose interests include IBD and complex disorders;
- Stringent quality control attained through sample and data uniformity;
- Ability to recruit the large numbers of patients required to identify the genes responsible for IBD;
- Availability of resources necessary for high risk, high priority projects—including genetic studies of disease differences in minority populations; and
- Knowledge of priorities and opportunities provided by NIH oversight.
The Consortium has developed collaborations with outside investigators, providing valuable data, genotyping services, and research resources. For example, immortalized cell lines are being derived from patients’ blood samples. These cell lines and the DNA extracted from them will be linked to the patients’ phenotypic data and stored for use in Consortium research projects. They will also be made available to the broader scientific community. Additionally, control datasets representing different populations are being analyzed and made available on the web. This approach provides major research effectiveness and cost-saving advantages for future IBD studies.
A Vision for Future IBD Research
Dr. Cho described her vision for the future of IBD research and her major priorities. These include developing models of disease risk, developing biomarkers, predicting disease course, and finding ways to prevent disease. These endeavors all have as their underpinnings the identification of the multiple genes that contribute to IBD and the elucidation of their interactions with each other and their environment. Even genes with limited direct associations with IBD may have significant biological consequences that must be considered in designing important risk models. Biomarkers that reflect genetic variation and the molecular consequences of gene expression are important research indicators of disease risk, disease prognosis, and patient response to therapies. Thus, biomarkers will serve as major drivers in the development of new approaches to the prevention and cure of IBD.
The IBD genome-wide association study presented by Dr. Cho has continued to yield important genetic discoveries. An expansion of this study identified three new IBD susceptibility genes which are described in the IBD Story of Discovery, also in this chapter.
Back To Top
