In predicting CKD risk, eGFR better when based on cystatin C

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Anne Paxton

November 2013—Like turning around an ocean-going tanker, changing widely accepted testing practices in kidney disease, one of the nation’s most common disorders, may have to be done gradually. But the latest study comparing the biomarkers cystatin C and creatinine, published in the Sept. 5 New England Journal of Medicine (2013;369:932–943), is the most sweeping study to date and should provide new impetus to wider use of cystatin C.

Filling in one of the last missing pieces, the study, “Cystatin C versus creatinine in determining risk based on kidney function” demonstrates that an estimated glomerular filtration rate (eGFR) using cystatin C offers the best means of predicting not only end-stage renal disease but also death from all causes across diverse populations. The findings, together with the adoption in 2012 of standard cystatin C-based eGFR equations and the increased use of cystatin C in certain patients, “will probably push clinical laboratories to incorporate this kidney biomarker,” says an editorial in the same issue of the journal (974–975).
“By having 90,000 subjects from 16 cohorts across a worldwide distribution, this is the most definitive and well-powered study to really capture the nuance of what cystatin C offers in relation to creatinine,” says Michael Shlipak, MD, MPH, lead author of the article and chief of general internal medicine at the San Francisco VA Medical Center.

Written by the Chronic Kidney Disease Prognosis Consortium, which includes about 200 collaborators and data from 40 countries, the study is a meta-analysis of 11 general-population studies (with 90,750 participants from the United States, Europe, and Australia) and five studies of participants with chronic kidney disease (2,960 participants) for whom standardized measurements of serum creatinine and cystatin C were available.
The authors compared the association of kidney function, as calculated by the measurement of creatinine, cystatin C, or the combination of creatinine and cystatin C, with the rates of death, death from cardiovascular causes, and ESRD. They also compared kidney disease stages that were classified alternatively by creatinine or cystatin C. The kidney function stages categorized by cystatin C were much better at reflecting future risk than were the stages based on creatinine-based estimates of kidney function.

Using a cystatin C-based calculation of eGFR, 42 percent of the study participants were reclassified from a creatinine-based eGFR of 45 to 59 mL per minute per 1.73 m2 to a higher eGFR lower risk stage, while 14 percent of participants with a creatinine-based eGFR of 60 to 89 mL per minute per 1.73 m2 were reclassified to a higher risk stage.

The study found that with an eGFR of 85 mL per minute per 1.73 m2 of body-surface area, when using cystatin C, “that is where your mortality risk begins to elevate, whereas if you use creatinine you don’t see the threshold for detection of CKD until an eGFR of 60,” says Dr. Shlipak. “So you’re completely blind to accumulated risk from 85 to 60. And for a normal person it can be 10 to 15 or even 20 years before you’ll go from 85 to 60.”
“We don’t know yet whether we can slow that decline, to slow the rate of getting to 60. But at least now we can see it, so we can begin testing strategies. That becomes possible when you can actually track kidney function in the normal range.” And those strategies will be the subject of the next set of studies, Dr. Shlipak says.

“Through early detection, we believe we can prevent or delay the onset of chronic kidney disease,” he says. “This has never been done. There is no trial that has ever tested whether CKD screening, even with conventional methods, improves outcomes for non-diabetic persons. In my research group that is our goal. We think with the new testing, it will be that much better because we’ll capture kidney disease more specifically and that much earlier.”

Dr. Coresh

The new study does more than just aggregate existing research because it employs individual level meta-analysis, says study co-author Josef Coresh, MD, PhD, the consortium’s principal investigator and professor in the Johns Hopkins Bloomberg School’s Department of Epidemiology. “That means we reanalyzed the data in every single one of the participating cohorts to answer the research question, using the same methods in every cohort. So the study is not just looking at papers published. We actually go to the original data and say this is our question of interest. We really produced a brand-new thing rather than just a summary of what was there before.”

The evidence now is fairly unequivocal, Dr. Coresh says. “We applied the new equations for eGFR with cystatin C and eGFR with cystatin C and creatinine combined, and those were only published in the NEJM last year by Dr. Inker, et al.” (Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367:20–29). “So this new study takes a big step toward making cystatin C part of the clinical care paradigm rather than the research paradigm.”

The study appears only eight months after clinical guidelines for the treatment of chronic kidney disease, by the working group of the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) foundation, which recommended the use of cystatin C-based eGFR as a supplemental test biomarker in patients with kidney-function ranges in which the creatinine-based eGFR has reduced accuracy. So while the application to each country will depend on resources and the local setting, “The consensus is now broad and global,” says Dr. Coresh.

“We can call this a definitive answer. Now we really need to work this test into clinical practice and help laboratories make the test available,” says Dr. Shlipak, who is also a professor of medicine, epidemiology, and biostatistics at the University of California at San Francisco.

Dr. Inker

Study co-author Lesley A. Inker, MD, MS, associate professor of medicine, Tufts University School of Medicine, stresses that the new study shows once again that a combination of cystatin C and creatinine together is a more accurate estimate of GFR. “For prognosis, cystatin C alone and the combination are similar and perhaps cystatin C better, but for GFR estimation, it is clear, both from our work and now others, that the combination is better.”
One of the new study’s strengths, Dr. Inker adds, is that it includes a broad cross-section of patients. “The study certainly has a lot of data on people from different populations, and it used all the available data on cystatin C for prognosis. It could only include people who were in the cohorts, so it can’t include people too sick to be included in observational studies. So there are always some limitations to the different patient results.” But for showing the value of cystatin C for prognosis, she says, further studies are not likely to be needed.