Cystatin C, a blood marker of kidney function, proved significantly more accurate than the standard blood marker, creatinine, in predicting serious complications of kidney disease, in a study by researchers at the San Francisco VA Medical Center and the University of California, San Francisco. Among adults who were identified as having chronic kidney disease by high creatinine levels, the researchers found that only patients who also had abnormally high levels of cystatin C were at high risk for death, cardiovascular disease, heart failure, or kidney failure. People with high creatinine but normal cystatin C levels had risks similar to those with normal creatinine levels.
The researchers also found that a small but important segment of the study population was missed by creatinine but identified by cystatin C as being at significant risk of serious complications, according to lead author Carmen A. Peralta, MD, MAS, an SFVAMC researcher and an assistant professor of medicine in residence in the division of nephrology at UCSF.
The study of 11,909 participants appears online on December 16, 2010, in the JASN Express section of the Journal of the American Society of Nephrology. The authors analyzed patient data from two prospective studies: the Multi-Ethnic Study of Atherosclerosis and the Cardiovascular Health Study, both sponsored by the National Heart, Lung, and Blood Institute.
Principal investigator Michael G. Shlipak, MD, MPH, chief of general internal medicine at SFVAMC, said that the current study highlights a potential clinical use for cystatin C as a method for confirming a diagnosis of chronic kidney disease. Shlipak has been a leader among physicians in identifying cystatin C as an alternative, accurate, and reliable marker of kidney function.
Both cystatin C and creatinine are substances made in the body and filtered by the kidneys. High levels of the substances in the blood indicate that the kidneys are losing the ability to filter them, and thus are losing function. However, explained Peralta, creatinine is a byproduct made in muscles, so it is affected by what you eat and especially by how much muscle you have. Thus, a bodybuilder with healthy kidneys might have an elevated creatinine level because of high muscle mass, whereas a frail elderly person might have normal or even low levels of creatinine, but in fact this persons kidneys are not working well – its just that theres not much creatinine because theres not much muscle.
In contrast, cystatin C is a protein made in cells throughout the body. In studies so far, it does not seem to be that affected by age or muscle mass or diet, said Shlipak, who is also a professor in residence of medicine and epidemiology and biostatistics at UCSF.
Shlipak proposes that cystatin C, which can cost as little as $17 per test, be added as a method for confirming or staging chronic kidney disease in guidelines that are currently being formulated by nephrologists. Its vital that we have an accurate diagnostic test, because kidney disease does not show symptoms until its too late, when your kidneys have almost failed completely, he said. Being missed by creatinine is an important limitation in our current method of diagnosing kidney disease, said Peralta. Yet, she adds, being falsely identified with kidney disease through inaccurate test results can be disastrous as well. There is fear and psychological stress, particularly in communities of color, where people have a lot of friends and family members who are on dialysis, she noted. You can also be subjected to unnecessary and expensive tests and medications.
Cystic fibrosis is a genetic disease that causes a thick, sticky mucus to build up in the lungs and digestive tract. A clinical trial of a new drug called denufosol found that those given the medication for six months prevented some of the accumulation and improved performance on lung tests.
The Cystic Fibrosis Foundation estimates that about 30,000 children and adults in the United States have the condition that clogs the lungs and leads to life-threatening lung infections. The mucus also obstructs the pancreas and stops natural enzymes from helping the body break down and absorb food.
Cystic fibrosis is caused by a genetic mutation that disrupts the cystic fibrosis transmembrane regulator (CFTR) protein, an ion channel. Denufosol tetrasodium inhalation solution works by correcting ion transport in patients to enhance airway hydration and mucus clearance by increasing chloride secretion, inhibiting sodium absorption and increasing ciliary beat frequency.
Frank J. Accurso MD of the University of Colorado and colleagues included about 350 children with cystic fibrosis aged five and older in the study called TIGER-1, The Transport of Ions to Generate Epithelial Rehydration. All had a forced expiratory volume (FEV1) at least 75% of normal, indicating normal to mildly impaired lung function characteristic of early cystic fibrosis.
The patients were randomized to receive either 60 milligrams of inhaled denufosol three times daily or a matching placebo for 24 weeks. This was followed by another 24-week open-label safety extension phase.
The patients on the new medication had increase in FEV1 of 0.048 L, approximately 2% over baseline. In addition, the researchers found further lung improvement by 0.115L by the end of the open-label phase. The placebo group, when switched over to denofusol in the open-label phase, also improved by a mean 0.078 L in FEV1.
Big improvements weren't expected, says Accurso, because the drug is primarily designed to prevent or delay loss of lung function rather than act as a rescue therapy.
Denufosol appeared to be safe without serious adverse events or impaired growth of the young patients, suggesting it could be suitable as an early intervention. Intervention for cystic fibrosis early in its course has the potential to delay or prevent progressive changes that lead to irreversible airflow obstructions, the researchers say in their study published in the American Journal of Respiratory and Critical Care Medicine.
A second phase III trial, which is called TIGER-2, is ongoing which will incorporate a longer placebo-controlled treatment phase. Inspire Pharmaceuticals is targeting a potential US commercial launch of the drug for 2012, pending FDA approval.
Accurso FJ, et al “Denufosol Tetrasodium in Patients with Cystic Fibrosis and Normal to Mildly Impaired Lung Function” Am J Respir Crit Care Med 2011.
Nutrition experts at Oregon State University have essentially “cured” laboratory mice of mild, diet-induced diabetes by stimulating the production of a particular enzyme. The findings could offer a new approach to diabetes therapy, experts say, especially if a drug could be identified that would do the same thing, which in this case was accomplished with genetic manipulation.
Increased levels of this enzyme, called fatty acid elongase-5, restored normal function to diseased livers in mice, restored normal levels of blood glucose and insulin, and effectively corrected the risk factors incurred with diet-induced diabetes. “This effect was fairly remarkable and not anticipated,” said Donald Jump, a professor of nutrition and exercise sciences at Oregon State, where he is an expert on lipid metabolism and principal investigator with OSU’s Linus Pauling Institute. “It doesn’t provide a therapy yet, but could be fairly important if we can find a drug to raise levels of this enzyme,” Jump said. “There are already some drugs on the market that do this to a point, and further research in the field would be merited.”
The studies were done on a family of enzymes called “fatty acid elongases,” which have been known of for decades. Humans get essential fatty acids that they cannot naturally make from certain foods in their diet. These essential fatty acids are converted to longer and more unsaturated fatty acids. The fatty acid end products of these reactions are important for managing metabolism, inflammation, cognitive function, cardiovascular health, reproduction, vision and other metabolic roles.
The enzymes that do this are called fatty acid elongases, and much has been learned in recent years about them. In research on diet-induced obesity and diabetes, OSU studied enzyme conversion pathways, and found that elongase-5 was often impaired in mice with elevated insulin levels and diet-induced obesity.
The scientists used an established system, based on a recombinant adenovirus, to import the gene responsible for production of elongase-5 into the livers of obese, diabetic mice. When this “delivery system” began to function and the mice produced higher levels of the enzyme, their diet-induced liver defects and elevated blood sugar disappeared.
“The use of a genetic delivery system such as this was functional, but it may not be a permanent solution,” Jump said. “For human therapy, it would be better to find a drug that could accomplish the same thing, and that may be possible. There are already drugs on the market, such as some fibrate drugs, that induce higher levels of elongase-5 to some extent.”
There are also drugs used with diabetic patients that can lower blood sugar levels, Jump said, but some have side effects and undesired complications. The potential for raising levels of elongase-5 would be a new, specific and targeted approach to diabetes therapy, he said. While lowering blood sugar, the elevated levels of elongase-5 also reduced triglycerides in the liver, another desirable goal. Elevated triglycerides are associated with “fatty liver,” also known as non-alcoholic fatty liver disease. This can progress to more severe liver diseases such as fibrosis, cirrhosis and cancer.
Further research is needed to define the exact biological mechanisms at work in this process, and determine what the fatty acids do that affects carbohydrate and triglyceride metabolism, he said. It appears that high fat diets suppress elongase-5 activity.
“These studies establish a link between fatty acid elongation and hepatic glucose and triglyceride metabolism,” the researchers wrote in their report, “and suggest a role for regulators of elongase-5 activity in the treatment of diet-induced hyperglycemia and fatty liver.”
The study was published in the Journal of Lipid Research. The research was supported by the National Institutes of Health and the National Institute for Food and Agriculture of the U.S. Department of Agriculture.
Steering clear of full-fat, fried, and processed foods is not just good for overall health, it could help prevent chronic lung conditions, a large UK study has revealed.
Led by Seif Shaheen, Professor of Respiratory Epidemiology at Barts and The London School of Medicine, the study – involving 1,551 men and 1,391 women with an average age of 66 – showed that those whose diet favoured fresh fruit and vegetables, oily fish and wholegrain products had far better lung function than those who chose a diet high in fat, sugar and processed food.
The diets of those involved were investigated to assess what kinds of food they consumed on a regular basis. Their lung function was also tested using a spirometer, a device which measures the amount of air that a person can blow out of their lungs in one second. This simple test illustrates how healthy the lungs are, and determines whether any blockage or obstruction exists in the airways. If the airways are obstructed, the person is diagnosed with Chronic Obstructive Pulmonary Disease (COPD).
The study also revealed that the beneficial effects of the sensible diet were particularly strong in men who smoked.
Lung health in particular may be positively affected by a sensible diet because of the antioxidants contained in fruit and wholegrains, and the omega-3 fatty acids found in oily fish – that protect the lungs against the adverse effects of smoking.
Professor Shaheen said: “Whilst cessation of smoking is still the number one way to improve lung health, this study is important because it suggests that cases of COPD might be prevented if people, especially male smokers, ate more fruit and vegetables, oily fish and wholegrain cereals, and less white bread, sugar, full fat dairy products, fried food and processed meat. However, the only way to confirm this would be to carry out a randomised controlled trial.”
Dr. Nick and his colleagues analyzed epidemiological and health data on 156 CF patients over 40 year of age who receive care at National Jewish Health, the largest adult cystic fibrosis clinic in the nation. In addition, data were analyzed on nearly 3,000 patients from around the nation who were included in the Cystic Fibrosis Foundation Patient Registry from 1992-2007.
The researchers found that the fate of females changes considerably in the older CF population. It has long been recognized that a “gender gap” is present in CF, favoring males. Historically, females have been diagnosed later, had a poorer prognosis, and survived fewer years than males.
Accordingly, Dr. Nick's analysis showed that fewer females diagnosed as children survived to age 40. However, among those diagnosed as adults, females represented a significant majority, accounting for 72 percent of patients in Colorado and 54 percent nationally. Among the adult diagnosed patients, females survived on average 9 to 14 years longer than males.
The complex factors that account for the differential fate of female CF patients is not understood, although Dr. Nick believes it could be a mixture of behavioral and biological factors.
Dr. Nick's findings also indicate that patients diagnosed as adults do not really have milder diseases — as is commonly believed — just a delayed onset of an equally severe form of the disease. Although patients diagnosed as adults live longer than those diagnosed as children, the adult-diagnosed patients lose lung function as rapidly those diagnosed in childhood, and approximately 85% die of respiratory failure or post-transplant complications.
Dr. Nick believes there is a significant number of adults whose CF remains undiagnosed. His analysis indicates that once those patients are accurately diagnosed, proper care can significantly improve their health. Patients diagnosed as adults and subsequently followed at a CF center reversed progressive lung function decline and improved their lung function for at least four years. Older patients commonly do not get specialized CF care. It is generally recognized that the team approach to treatment provided by the 112 CF Foundation-accredited Care Centers results in better clinical outcomes. However, less than half of long-term CF survivors continued to be seen at CF Centers as they pass 40 years, with the fewest among the adult-diagnosed patients.
“In the coming years, more and more cystic fibrosis patients will be living into their 40s, 50s and beyond,” said Dr. Nick. “Our findings concerning the role of gender, in survival, progression of disease, and type of care in current long-term survivors provides important insights that will help us prepare for better treatment of the steadily aging CF population.”
In previous research, scientists using information collected from the National Health and Nutrition Examination Survey (NHANES), a long-term collection of studies designed to assess the health and nutritional status of adults and children in the US, had found a link between sugar containing sodas and urinary protein. However, they did not collect data on any kidney function changes related to drinking sweetened sodas. So, in their second study, Dr. Lin and Dr. Curhan, decided to specifically check for any kidney function decline in women who drink sodas regularly. Once again, they used data from the Nurses' Health Study.
In a statement for the media, Dr. Lin reported they found “a significant two-fold increased odds, between two or more servings per day of artificially sweetened soda and faster kidney function decline; no relation between sugar-sweetened beverages and kidney function decline was noted.” Moreover, this association persisted even when the researchers accounted for age, obesity, high blood pressure, cardiovascular disease, physical activity, calorie intake, diabetes and cigarette smoking. Clearly, artificially sweetened sodas are detrimental to kidney health.
“There are currently limited data on the role of diet in kidney disease,” said Dr. Lin in a statement to the press. “While more study is needed, our research suggests that higher sodium and artificially sweetened soda intake are associated with greater rate of decline in kidney function.”