New Diagnostic Strategy Reveals Many Missed Cases of Kidney Disease, Study Shows

The authors said that the results of the study, which will appear in the April 20, 2011 issue of the Journal of the American Medical Association, have important national implications for the detection and classification of kidney disease. The study is being published early online to coincide with its presentation at the World Congress of Nephrology.

Michael G. Shlipak, MD, MPH

Michael G. Shlipak, MD, MPH

In the study of more than 26,000 adults, the scientists determined that a panel of three tests for kidney disease – creatinine, cystatin C, and urine albumin-to-creatinine ratio (ACR) – was much more accurate in identifying kidney disease and predicting risk of kidney failure and death than the test for creatinine alone, which is the current standard diagnostic test.

Sixteen percent of study participants who were not shown to have chronic kidney disease according to creatinine levels were correctly identified by tests for cystatin C and ACR as having CKD, along with elevated risk of eventual kidney failure and death.

“These were persons with kidney disease who were at high risk of complications and who were simply missed by creatinine,” said 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.

Conversely, among subjects identified as having CKD through elevated creatinine, 24 percent were revealed to not have CKD as shown by measurements of cystatin C and ACR. These participants had the same risk of kidney failure and death as participants with normal creatinine.

Overall, the 3 percent of study participants identified as having CKD according to all three tests had an eight-fold risk of death and a hundred-fold risk of kidney failure compared with participants identified as having CKD according to creatinine alone. More than 70 percent of kidney failures observed during the course of the study occurred among this group.

“Based on creatinine levels, about 14 million people in the United States are currently classified as having CKD,” said Peralta. “We estimate that testing for cystatin C and albumin in the urine would reclassify about 5 million of these people as being without increased risk for kidney disease, and would more accurately predict the risks of kidney failure and death for the other 9 million.”

At the same time, testing for cystatin C and albumin in addition to creatinine would detect persons with occult, or hidden, CKD who are at higher risk for death or kidney failure, according to Peralta. The authors estimate that such testing would identify an additional 20 million Americans with currently undiagnosed kidney disease.

The 26,643 study subjects, whose average age was 65, were participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. REGARDS is a national longitudinal study designed to identify factors that contribute to excess stroke mortality in the so-called “stroke belt” across the mid-southern United States, as well as factors that contribute to excess stroke risk among African Americans. Subjects were followed from January 2003 to June 2010.

Co-author Michael G. Shlipak, MD, MPH, chief of general internal medicine at SFVAMC, said that the paper is one of the first to investigate the utility and accuracy of a “triple-marker” approach to testing for kidney disease.

“An international clinical guideline for kidney disease is currently being written, and our hope is that these results will be taken into consideration by the guideline’s creators,” said Shlipak, who is also a professor in residence of medicine and epidemiology and biostatistics at UCSF. “We are saying to clinicians that if they think a patient has kidney disease based on creatinine, they should measure cystatin C and ACR to find out what the patient’s risks really are.”

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 Shlipak, creatinine is a muscle byproduct and thus affected by the patient’s muscle mass, diet, and age. Cystatin C, a protein made in cells throughout the body, is far less affected by these variables and thus presents a more accurate picture of kidney function, he said.

ACR, said Shlipak, is a marker of kidney injury, “sort of like looking at engine oil to see how worn and rusted the engine is, whereas creatinine and cystatin C tell you how well the engine is still performing – what its horsepower is.”

Co-authors of the study are Suzanne Judd, PhD, of the University of Alabama, Birmingham, AL; Mary Cushman, MD, of the University of Vermont, Burlington, VT; William McClellan, MD, MPH, of Emory University, Atlanta, GA; Neil A. Zakai, MD, of UV; and Monica M. Safford, MD, Xiao Zhang, PhD, Paul Muntner, PhD, and David Warnock, MD, of UA.

The study was supported by funds from the National Institutes of Health, the National Institutes of Diabetes and Digestive and Kidney Diseases, a Robert Wood Johnson Harold Amos award, an American Heart Established Investigator Award, and Amgen Corporation. Some of the funds were administered by the Northern California Institute for Research and Education.

NCIRE – The Veterans Health Research Institute – 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.

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Steve Tokar

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