Nephrologists Make the Case for Cystatin C-Based eGFR

Mitchel L. Zoler, PhD

May 18, 2021

A patient's estimated glomerular filtration rate (eGFR) remains a pillar for diagnosing chronic kidney disease (CKD) and tracking its progression. But nephrologists now recognize that eGFR values based entirely on measurement of serum creatinine, the common approach, may be misleading because of nonrenal factors that can skew serum creatinine levels up or down.

The solution, they say, is to complement eGFR calculations based on serum creatinine (eGFRSCr) with a second calculation of eGFR based on serum levels of cystatin C (eGFRCysC), especially for patients in whom a modest change in eGFR could make a significant difference in both their stage of CKD and clinical management.

During a recent webinar organized by the American Kidney Fund, advocates for a more systematic role for eGFRCysC voiced hope that this approach will gain traction in US practice as cystatin C testing becomes more available and more widely recommended.

Cystatin C Can Be Used for a "Second Opinion", to Avoid Factoring in Race

"Cystatin C has fewer nonrenal determinants than creatinine," which means it is less likely to be affected by variables such as muscle mass, activity level, and diet, said Michelle M. Estrella, MD, chief of the Division of Nephrology at the San Francisco VA Healthcare System, California, during the webinar.

She encouraged clinicians to consider ordering a cystatin C test for a "second opinion" eGFR for patients with an eGFRSCr of 30-59 mL/min/1.73m2 to confirm or rule out stage 3 CKD; in those with conditions known to affect eGFRSCr; and in those with conditions that place them at increased risk for CKD progression such as diabetes, hypertension, cardiovascular disease, or heart failure.

Michael G. Shilpak, MD, a nephrologist at the University of California, San Francisco, agreed with these targeted subgroups for routine calculation of eGFRCysC. Measuring eGFRCysC "can have a substantial impact on patient safety," he said during the webinar.

Study results published by Shilpak several years ago documented the role cystatin C measurement can play in refining the diagnosis and prognosis of CKD.

"Use of cystatin C to calculate the eGFR strengthened the associations between eGFR categories and the risks of death and end-stage renal disease across diverse populations," Shilpak and colleagues wrote.

Data in this study showed, for example, that among 6358 patients who had an eGFRSCr of 45-59 mL/min/1.73m2, calculation of their eGFRCysC led to 42% having their renal function reclassified above this range, and 24% placed in a more severe CKD stage with an eGFRCysC < 45 mL/min/1.73m2.

In both cases these reclassifications linked with significant changes in subsequent all-cause mortality. Patients reclassified as having less severe CKD had significantly fewer deaths than those who stayed in the same eGFR stage during an average follow-up of 9 years, while patients reclassified by eGFRCysC as having worse CKD had significantly increased mortality during follow-up compared with patients whose eGFRCysC kept them in the same risk stratum as their eGFRSCr.

Adding to the momentum behind cystatin C testing is the current effort by nephrologists to find an alternative to current formulas for calculating eGFRSCr, which rely on a race coefficient that boosts the calculated number by 16% in Black people. In 2020, the National Kidney Foundation and the American Society of Nephrology formed a joint task force to "reassess the inclusion of race in diagnosing kidney diseases." The task force issued an interim report in April and intends to release final recommendations later in 2021.

Several nephrology opinion leaders noted in a 2020 article that eGFRCysC avoids the need to take race into account.

"Any patient who is Black who wants a cystatin C test should be able to have it," said Shilpak during the webinar.

Cystatin C: Caught in a Catch-22?

In 2012, guidelines for assessing CKD by the Kidney Disease: Improving Global Outcomes (KDIGO) organization endorsed using eGFRCysC to confirm a diagnosis of stage 3 CKD. And in 2019, KDIGO reconfirmed that accurate eGFR assessment should rely on both serum creatinine and cystatin C, noted Estrella.

Shilpak recently coauthored an opinion article that laid out the case for increasing the use of cystatin C testing.

Despite this, cystatin C testing in the US remains underused and caught in a self-perpetuating catch-22, explained Amy B. Karger, MD, PhD, during the webinar.

The US Food and Drug Administration first approved a cystatin C assay in 2001, and in 2010, certified reference material for cystatin C became available that allowed for uniform calibration of tests and nationwide standardization of test results. A further milestone occurred in 2018, when the last of the five major US companies that market clinical chemistry instruments established FDA-approved traceability for their cystatin C test, said Karger, a clinical pathologist at the University of Minnesota in Minneapolis.

But the lack of widespread demand for cystatin C testing means that about 93% of US clinical laboratories do not currently run cystatin C testing in-house, which results in longer turnaround times for results and higher test costs compared with serum creatinine, said Karger.

Longer turnaround and higher cost discourage routine use, but these obstacles would resolve with broader routine use, she noted.

And while a cystatin C test may currently cost more than a serum creatinine assay, the price of the former is not prohibitive. At Karger's institution, the University of Minnesota, a serum creatinine test costs about $2.50, while a cystatin C assay runs about $10.60. At UCSF the incremental cost for adding cystatin C to routine blood work is roughly $5, said Shilpak.

Karger called on nephrologists to work with their local lab directors to bring more cystatin C testing in-house, and for nephrologists and lab specialists to work together to persuade primary care physicians to use cystatin C testing more often.

She reported recently surveying the five major US assay companies and all said they can quickly scale up reagent availability to accommodate a surge in test demand.

The American Kidney Fund webinar was sponsored by Gentian, a company that markets a cystatin C assay. Estrella has reported no relevant financial relationships. Shilpak has reported being an advisor to and holding equity in TAI Diagnostics. Karger has reported receiving grant support from Siemens Healthcare Diagnostics and Kyowa Kirin Pharmaceutical Development.

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