Elevated blood levels of the protein cystatin C accurately predict higher risk of chronic kidney disease, cardiovascular disease, and death among elderly people with no known kidney problems – risks that the standard kidney function test, which measures the protein creatinine, misses entirely, according to a study led by a researcher at the San Francisco VA Medical Center.
"For the clinician who treats older people or others at risk for kidney disease, this is an important message: A normal creatinine level should not reassure you that your patient has normal kidney function," says lead author Michael Shlipak, MD, chief of general internal medicine at SFVAMC and an associate professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco. "It shows that cystatin is a very promising new tool that complements creatinine in the ongoing effort to detect early kidney disease and prevent its complications."
The study appears in the August 15, 2006 issue of Annals of Internal Medicine.
Shlipak and his colleagues tested blood samples from 4,663 elders living independently in the community who participated in the Cardiovascular Health Study, a national longitudinal study of people aged 65 and older sponsored by the National Institutes of Health.
The researchers measured each participant's creatinine – an end-product of muscle metabolism that is filtered through the kidneys and has been a standard marker of kidney health for "probably 100 years," according to Shlipak – and cystatin C, a blood protein that is also filtered through the kidneys. They then matched test results with health outcomes up to nine years later.
Among participants with no diagnosed chronic kidney disease, those with high levels of cystatin C had significantly greater risk for poor health than those with normal cystatin C levels. Individuals in the high cystatin group were 50 percent more likely to die overall, nearly twice as likely to die of cardiovascular problems, and 30 percent more likely to die of non-cardiovascular problems. They had increased risks of 40 percent for heart failure, 30 percent for heart attack, and 20 percent for stroke. Finally, they were more than three times more likely to develop chronic kidney disease.
"In contrast," the researchers report, "creatinine concentrations had associations with each outcome that were much weaker, and significant only for the outcome of cardiovascular death."
Shlipak says, "This tells us that the creatinine test, while broadly useful as a measure of kidney health, is insensitive. If a creatinine level is high, that's probably an indication of kidney disease. But if it's low, you don't know. You would need to do a cystatin test if there's any other indication of kidney disease or if the patient is in a group that's at risk."
Groups at risk for chronic kidney disease include people over 65, people with diabetes, hypertension, or cardiovascular disease, and African Americans, American Indians, and Hispanic Americans.
"This is also telling us that kidney function declines much more with age than we realized before," adds Shlipak. He terms this syndrome "pre-clinical kidney disease," or pre-CKD.
"We have the tools to slow kidney disease," he notes, including blood pressure control, sugar control for diabetes, and specific medications known as ACE inhibitors. "It's well-established that end-stage kidney disease is rising at a rate of 10 to 20 percent per year. With a heightened awareness of pre-CKD, we can be more aggressive in taking steps to prevent it."
Accurate knowledge of kidney function is also a matter of patient safety, according to Shlipak: "Surgery, some other medical procedures, and certain medications all can have an adverse impact on kidney health."
The cystatin test itself is relatively inexpensive and already widely available, he says. "As demand for it increases, it should become even more commonly available."
The next steps for researchers, says Shlipak, should include longitudinal studies that determine whether a screening test for cystatin C can improve clinical care and health outcomes for large patient populations. "We also want to map out the physiologic consequences of early mild kidney dysfunction, now that we can measure it."
Co-authors of the study are Ronit Katz, PhD, of the University of Washington; Mark J. Sarnak, MD, of Tufts-New England Medical Center; Linda F. Fried, MD, MPH, of the VA Pittsburgh Healthcare System; Anne B. Newman, MD, MPH, of University of Pittsburgh; Catherine Stehman-Breen, MD, MS, of Amgen, Inc.; Stephen L. Seliger, MD, Brian Kestenbaum, MD, and Bruce Psaty, MD, PhD, of the University of Washington; Russell P. Tracy, PhD, of the University of Vermont College of Medicine; and David S. Siscovick, MD, MPH, of the University of Washington.
The study was supported by funds from the National Heart, Lung, and Blood Institute, the American Federation for Aging Research, and the National Institute on Aging that were administered by the Northern California Institute for Research and Education, as well as funds from the Robert Wood Johnson Foundation and the Department of Veterans Affairs.
NCIRE is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.
SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.
UCSF is a leading university that consistently defines health care worldwide by conducting advanced biomedical research, educating graduate students in the life sciences, and providing complex patient care.
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