Clinical Laboratory Strategies: May 26, 2011
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Improving Detection of Chronic Kidney Disease
Study Finds Triple Marker Approach Superior
By Bill Malone

An estimated 26 million Americans have chronic kidney disease (CKD), and early detection using creatinine-based estimated glomerular filtration rate (eGFR) has made the lab a key player in getting effective treatment to patients with CKD as early in the disease as possible. This issue of Strategies looks at new research that found including cystatin C and urine albumin-to-creatinine ratio could improve the predictive accuracy of eGFR by creatinine.

Chronic kidney disease (CKD) is usually detected by creatinine-based estimated glomerular filtration rate (eGFR), sometimes along with urine albumin-to-creatinine ratio (ACR), and clinical labs now routinely report eGFR in common comprehensive metabolic panels. However, creatinine-based eGFR has well known limitations and is affected by muscle mass, race, age, and other factors. The rising prevalence of CKD and lack of awareness about the disease has sent researchers looking for new approaches to finding and treating CKD early. One recent study reported that combining a relatively new assay, cystatin C, with the established creatinine and albumin markers, greatly improved detection of occult CKD as well as assessment of risk for end-stage CKD and death (JAMA 2011;305:1545-1552).

Carmen A. Peralta, MD, MAS of the San Francisco VA Medical Center and the University of California San Francisco and colleagues conducted the study over 7 years, and included 26,643 adults. They classified subjects into eight groups defined by creatinine, ACR, and cystatin C. The primary outcomes measured were all-cause mortality and incident end-stage renal disease. Over a median follow-up of 4.6 years, 1,940 participants died and 177 developed end-stage renal disease. Of the 11% classified as having CKD based on creatinine, 24% had CKD defined by creatinine alone and 5% had CKD defined by creatinine and ACR. CKD was defined by creatinine and cystatin C for 40%, and by all three markers for 30%. Among the participants without CKD as defined by creatinine, 16% had CKD detected by cystatin C, ACR, or both.

The quest for a better testing strategy for CKD came from a dilemma in everyday clinical practice, Peralta said. “The problem that we face in clinical practice is that essentially the only tool clinicians have to detect kidney disease early is a chemistry panel that includes creatinine, and for patients with diabetes, checking urine for albumin,” she said. “But this strategy likely misclassifies many people, and in fact that’s what we found in this study.” Peralta is assistant professor of nephrology at the University of California, San Francisco.

The researchers found that their triple-marker approach significantly improved risk prediction. Cystatin C and albuminuria were both strongly and independently associated with all-cause death among subjects with or without CKD defined by creatinine. Adding eGFR based on cystatin C reclassified 5.2% of the cohort to a higher-risk group and 3.2% to a lower-risk group. Patients reclassified to the higher risk group by cystatin C had a three-fold higher mortality risk than those reclassified as lower-risk and their risk of end-stage renal disease was four-fold higher.

Peralta stressed that the increased sensitivity of the triple-marker approach underscores the burden of occult CKD. “We found that 16% of persons had CKD that was not detected by creatinine,” she noted. “That’s a huge number if you extrapolate it out to the entire U.S. population. What this means for the future of clinical practice is yet to be determined because we need to study this a lot more. But clearly we’re missing a significant number of people.”

On the other side, the triple-marker approach also found a significant number of subjects classified with CKD by creatinine who had very low risk. “Another important message is that among the people who were detected as having kidney disease with creatinine, almost 25 percent had no CKD by cystatin C or urine albumin, and their risk for death or end-stage renal disease looks exactly as if all three markers were normal,” Peralta said. “So you might imagine that the conventional strategy is identifying people who perhaps don’t need to use as many resources from the medical system. We can’t say that they don’t have kidney disease, but we can say that they would be at low-risk. That is something that with more research could really affect clinical practice.”

The benefit of adding urine albumin, and especially cystatin C, comes from these markers representing different elements of pathology of the kidney, Peralta explained. “Creatinine is measuring the ability of the kidney to filter, while albumin detects damage. Those two are very complimentary because the biology differs,” she said. “With cystatin C, the interesting thing is that it is made by all nucleated cells in the body, and is not affected by age or muscle mas. Cystatin C may have other associations not related to kidney function, so there is still much work to be done, but I think what we’re understanding now is that there is something about cystatin C where it’s able to pick up risk that creatinine can’t.”

This study adds to growing evidence about the utility of cystatin C for nephrology, according to Stephen Fadem, MD. “When you combine cystatin C with ACR and creatinine, this really gives us an amazing ability not only to assess the GFR but also to get a closer relationship to mortality,” he said. “This is really significant, because if you can put patients into a more accurate classification of their disease, then it drives home the importance of trying to take better care of them. This is a very important study.” Fadem is clinical professor of medicine at Baylor College of Medicine, chief medical officer of Kidney Associates, PLLC, and medical director of Houston Kidney Center/DaVita Integrated Service Network in Houston, Texas. Fadem was not associated with the study.

Peralta and Fadem agreed that cystatin C and other markers could contribute to a CKD panel, similar to the way panels of tests reveal a more complete picture for other diseases. “If you look at other fields like cardiovascular disease or liver disease, they don’t have just one test, they have many,” said Peralta. “There is a lot of precedent from other diseases that we use more than just one marker because each marker is affected by different things and brings something unique.”

“My hope is that labs come up with a CKD panel that will include cystatin C, ACR, creatinine, and also serum phosphorus, uric acid, and maybe electrolytes and fibroblast growth factor 23,” said Fadem. “I think this paper opens up the opportunity to recognize that we cannot just rely on one test at a time, we need a whole arsenal of tests that can put things into perspective.”

Before such a panel could become a part of routine clinical practice, more research needs to be done to replicate results in other populations, such as the elderly and children, or in higher-risk minority populations. In the meantime, clinicians and labs should get to know cystatin C better, Peralta said. She noted that there are FDA-approved assays for cystatin C, that it’s been standardized internationally, and that the cost of the test continues to fall. “Cystatin C is a fully automated test, and I think it will become easier and easier to utilize,” she said. “There is a misconception that cystatin C is expensive and hard to do, which it isn’t. It’s down in price dramatically from even a year ago and international standardization is key, something that took years to accomplish for creatinine.”

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