Clinical Laboratory Strategies: March 13, 2008

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Expanding Cystatin C’s Use in the Elderly
Marker of Kidney Disease May Predict Other Disorders

By Deborah Levenson


A growing body of evidence shows that certain chronic diseases in their early stages lead to decline in kidney function, giving rise to the idea that kidney function might be a good predictor of morbidity and mortality, especially in older patients. However, the creatinine and creatinine clearance tests that are most often used to determine how well the kidneys work are often inaccurate in patients with mild impairment. Cystatin has potential as an alternative for these patients. Now new research suggests that cystatin C may also help predict risk of developing five debilitating conditions that are common among the elderly. This issue of Strategies examines its findings.

Recent papers have pointed to the benefits of using cystatin C as an alternative to creatinine and creatinine clearance tests for measuring renal function in patients with diabetes, and for prognosis for cardiovascular events and mortality. A serum protein that is filtered out of the blood by the kidneys, cystatin C is produced steadily by all types of nucleated cells in the body and is freely filtered by the kidney’s glomerular membrane because of its low molecular mass. Many studies have shown that cystatin C is a better marker of the glomerular filtration rate and hence of kidney function than creatinine, the most commonly used measure of kidney function. Now new research shows an association between cystatin C—even at relatively normal levels—and a group of conditions associated with aging. (Archives of Internal Medicine 2008; 168: 147–153)

A research team from five major universities concluded that cystatin C levels in the highest quartile were associated with greater risk for a composite outcome of five conditions. The team considered survival without any of these conditions—cancer, CVD, chronic obstructive pulmonary disease, physical disability, and cognitive impairment—to be “successful aging.” The team came to this conclusion after following 2,140 community-based participants age 65 and older over 6 years of participation in the Cardiovascular Health Study. Researchers adjusted their analysis using an accelerated failure time model to evaluate the percentage reduction in “successful years” of life expectancy by level of cystatin C. They used a separate Cox proportional hazards model to determine whether cystatin C was related to incident physical and cognitive disability.

The cohort’s median cystatin C, creatinine, and estimated GFR were 1.06 mg/L, 0.93 mg/dL, and 78 mL/min/1.73 m2, respectively. Participants with higher cystatin C levels were more likely to be older and white and to have higher body mass index, fibrinogen, CRP, and insulin levels, a higher prevalence of electrocardiographic left ventricular hypertrophy, an AAI or 0.9 or less, and lower levels of high-density lipoprotein cholesterol and albumin. The adjusted percentage reduction in successful life years in the highest, versus the lowest, quartile of cystatin C was 27% (95% CI, 11%–39%). The highest versus the lowest quartile of cystatin C was also independently associated with incident cognitive or physical disability. (HR 1.39; 95% CI, 1.00–1.98)

Kidney Function as a Quality of Life Indicator

In this report, the research team refers to the development of any of the debilitating diseases as “unsuccessful aging.” The term embraces the idea that quality of life trumps longevity, and that kidney function is key in both maintaining and predicting quality of life in the elderly, noted senior author Michael G. Shlipak, MD, MPH, General Internist at San Francisco Veterans Affairs Medical Center and Associate Professor of Medicine and Epidemiology at University of California, San Francisco. “We think that kidney function is a remarkable indicator of cumulative life stress because the kidney acts as a filter for substances that the body produces in response to that stress,” he said. “Clinicians are always measuring creatinine, and they could be creating a false sense of security for many patients,” Shlipak added, noting that creatinine is notoriously inaccurate in patients with normal or near-normal kidney function. “Cystatin C could be a tool for tracking changes in kidney function over time, and for catching decline before it gets worse.”

In an effort to better understand what specifically makes kidney function decline, Shlipak and colleagues are now tracking cystatin C levels in the same cohort over 7 years to better understand biologic risk factors and why decline may be gentle or more severe. He has not yet published any results from this research.

Cystatin C as a Predictor: Not Ready Yet

Shlipak cautioned against using his current data as a basis for offering cystatin C to predict for risk of the five health problems, even though commercial tests are available. “This isn’t the paper that tips the scales on a decision to offer cystatin C for these five conditions. Rather, it shows that cystatin C is a promising prognostic marker.” 

Future studies on using cystatin C in screening should involve subjects with no known kidney disease and link cystatin C to GFR, Shlipak advised. The ultimate goal is to show that intervention can prevent a person with high cystatin C from developing chronic kidney disease. “That would provide the proper evidence for using cystatin C as a screening tool,” Shlipak explained, suggesting that cystatin C might have a different purpose as a tool for tracking kidney function in persons with established kidney disease. “If someone already has some kidney function decline, can cystatin C help us determine how to dose medications or when to put someone on dialysis? These are hypotheses worth investigating.” 

Shlipak cautioned against any future implementation of cystatin C screening without a well-formed idea of how it can spur useful intervention. “If you implement screening with cystatin C and tell half the population they have abnormal kidney function without offering them an intervention, you’re not doing anybody any favors,” he said.

In an editorial that accompanied one of Shlipak’s earlier papers on cystatin C, Josef Coresh, MD, PhD, and Brad Astor, PhD, of Johns Hopkins University in Baltimore, Md.,  said that if other researchers confirm the the paper’s finding that cystatin C is a prognostic marker of death, CVD, and incident chronic kidney disease, cystatin C “will uniquely predict” risk of these conditions in patients with apparently normal estimated GFRs based on serum creatinine. But they criticized that prior study for its lack of data on albuminuria, a widespread and strong risk factor for CVD, and death that is also correlated to decreased GFR. Any redefinition of chronic or preclinical kidney disease should incorporate such information, they emphasized. 

Just One Marker

When it comes to teasing out biological age from chronological age, “no one marker is probably going to do it all,” maintained Robert Christenson, PhD, Director of Clinical Chemistry Laboratories at University of Maryland Medical Center and Professor of Pathology and Medical Research Technology at University of Maryland, Baltimore. He hopes for a test to predict successful aging that would incorporate several markers that could be plugged into an algorithm to produce a score that reflects biological age. Such a group of markers would optimally include variables included in the Framingham risk score, Christenson remarked, because they are now widely used by clinicians. But no marker would be useful without trials showing that it adds not only information about risk, but also data showing that specific interventions—like aggressive blood pressure control, ACE inhibitors, or angiotensin receptor blockers in the case of cystatin C—bring specific improved outcomes.

Siemens currently offers a cystatin C test originally marketed by Dade Behring (Deerfield, Ill.). Now a second cystatin C test has received FDA clearance. The Diazyme Cystatin C Assay, marketed by Diazyme (Poway, Calif.), can run on all open clinical chemistry analyzers, according to the company.   


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