In recent years, researchers have noted the benefits of using cystatin C for prognosis of chronic kidney disease (CKD), as well as cardiovascular events and mortality. Now researchers have demonstrated the potential of cystatin C as an alternative for calculating estimated glomerular filtration rate (eGFR)—both alone and in combination with creatinine. This issue of Strategies explores their findings.

The previous issue of Strategies explored research from the Chronic Kidney Disease Prognosis Consortium, covering recent research that showed the power of the new Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) creatinine-based eGFR equation to predict risk of end-stage renal disease and death (JAMA 2012;307:1941-1951). Meanwhile, a related group of CKD-EPI researchers have been examining the utility of cystatin C, a marker known to be less sensitive to muscle mass and diet than creatinine. In their recent report, Lesley Inker, MD, of Tufts Medical Center in Boston, Mass., and colleagues found that a combined creatinine-cystatin C equation performed better than equations based on either marker alone (N Engl J Med 2012;367:20-29).

Inker and her colleagues used data from CKD-EPI collaborators in 13 studies with 5,352 participants and developed both a cystatin C eGFR equation and a combination creatinine-cystatin C equation. The CKD-EPI equation using creatinine alone was used for comparison. They validated their new equations using data from five additional studies with 1,119 participants. They found that in people with creatinine-based eGFR 45-74 mL /min /1.73 m2, the combined cystatin C-creatinine equation improved classification for measured GFR <60 mL/min/1.73 m2, correctly reclassifying 16.9% of those with an eGFR of 45–59 mL/min/1.73 m2 as having a GFR >60 mL/min/1.73 m2.

Although bias was similar among the three equations, precision improved with the combination equation. The interquartile range for the difference was 13.4 mL/min/1.73 m2 for the combined equation versus 15.4 mL/min/1.73 m2 and 16.4 mL/min/1.73 m2 for the creatinine and cystatin C equations, respectively. The combined creatinine-cystatin C equation demonstrated improved accuracy as well. Only 8.5% of the estimates produced by the combination equation were >30% of measured GFR, compared to 12.8% and 14.1% for the creatinine and cystatin C equations. Using an eGFR threshold of <60 mL/min/1.73m2, the combined equation reclassified 5.5% of participants compared to the creatinine equation.

“In our study, it is significant that across the range of GFR, the combined equation provided a better estimate of GFR than equations using either marker alone,” Inker said. “The combined equation represents a 34% improvement in accuracy over the creatinine-based equation.” Inker is an associate professor of medicine at Tufts University School of Medicine and the director for quality improvement and the Kidney and Blood Pressure Center at Tufts Medical Center.

The improvements found in the combined equation are likely due to the two markers having different non-GFR determinants, according to Inker. “While creatinine and cystatin C based GFR estimates have similar performance when used alone, together they show improved precision because of non-overlapping, non-GFR determinants,” she said.

Should a creatinine-cystatin C equation replace creatinine-only equations? Not yet, according to the researchers. However, the study demonstrates that cystatin C could be valuable as a confirmatory test for CKD in patients with lower eGFR, or in patients with muscle wasting or chronic illness. The authors suggest that for patients with a creatinine-based eGFR of 45-59 mL/min/1.73m2, their findings support measuring cystatin C and then re-estimating eGFR on the basis of both markers. “This more accurate classification would result in more selective use of resources, such as test for complications of chronic kidney disease, adjustment of medication doses, and referrals to nephrologists,” the authors wrote.

Michael Shlipak, MD, MPH, chief of the division of general internal medicine at the San Francisco VA Medical Center, laid out two scenarios in which physicians might use cystatin C routinely. First, confirmation of borderline CKD, or stage 3a, for those with an eGFR of 45-60 mL/min/1.73m2 by creatinine. “In this population, about one third have normal cystatin C, and they are at low risk,” he said. For those with eGFR > 60 mL/min/1.73m2, Shlipak recommended screening with cystatin C those at high risk, such as patients with diabetes, HIV, cirrhosis, cardiovascular disease, heart failure, and the elderly. Shlipak, who was not associated with the study, is also professor-in-residence in the departments of medicine and epidemiology and biostatistics at the University of California, San Francisco.

Inker would like to build more data around whether cystatin C is truly a better marker for patients who are frail or have low muscle mass. “The big theory out there is that cystatin C is better for these patients, but we need more data on this,” she said. “These are people who get a lot of medical care and take a lot of medications, and it would be very informative to see if cystatin C truly is better in those populations instead of just assuming that is the case.” Another area for further research is looking at racial and ethnic groups, Inker added, noting that there were few blacks in the study’s validation data set.

Standardization of assays for cystatin C is an ongoing issue. The International Federation for Clinical Chemistry and Laboratory Medicine (IFCC) Working Group on Standardization of Cystatin C developed a serum-based reference material with the aim of enabling different manufacturers to develop assays that produce comparable results. However, IFCC is still in the process of establishing the commutability of the reference material, leaving unanswered questions about how different assays can be compared when looking at real patient samples. While CKD-EPI researchers used an assay traceable to the IFCC reference material, Inker noted that more work remains on the standardization front.

Despite these caveats, Shlipak urged more labs to offer cystatin C. “There is no longer any excuse for not offering cystatin C in a lab,” he said. “This study is the final piece that needs to push us forward to routine availability. Currently, clinicians say that the test is not available in the lab—and labs say no one is asking for it. Labs need to take the lead on this now.” He noted that many of the obstacles to routinely offering cystatin C in labs have now been dealt with, including the lack of a generalized equation or reference standard. In addition, the test is available on automated analyzers and can be run for less than $5, he said.

Shlipak also emphasized that he and others have advocated a triple-marker approach to CKD that included cystatin C, in combination with creatinine and the albumin-to-creatinine ratio (JAMA 2011;305:1545-52). “Kidney disease is important enough to have three tests,” he said. “Clearly our current clinical practice relying only on creatinine is woefully inadequate.”