Also sent was a synthetically prepared elevated cystatin C pool to see if it performed similarly to the CKD pool sample, “as a way to prove that the synthetically spiked sample would be commutable as well, and the synthetically spiked sample did mirror what the CKD pool showed,” she said.
The question was: “Is there an improvement in the harmonization of cystatin C methods? That is in fact what we saw,” Dr. Karger said. The coefficients of variation for the all-method mean declined for all three samples. “They were much higher in 2014, and all of those CVs decreased in the 2019 Survey.”
Cystatin C assay accuracy was assessed by using reference material and a calibration line. “We assigned a value to the healthy pool and the CKD pool. There was an accuracy-based target, and then we could assess the bias,” she said. In the two pools, there was a decrease in the bias of the all-method mean from the target between 2014 and 2019, so accuracy, too, had improved.
CAP cystatin C Survey data for 2025 for the six most commonly used methods for cystatin C testing reveal “pretty good” agreement between the methods, she said. “The CVs continue to drop. In 2025 they’re even lower than they were in 2019. So we’re moving in the right direction in terms of the assays being in better and better agreement as time goes on.”
Heterogeneous assay systems (reagents and instrument produced by different manufacturers) are common with cystatin C, Dr. Karger said, because some prominent reagent manufacturers do not market their own instrumentation. Studies have shown that homogeneous assay systems (a single manufacturer of both) have better precision and performance than heterogeneous systems, she noted. However, the 2025 CAP CYS-A Survey data were mixed: “It was dependent on the manufacturer.”
The lack of greater assay availability is a barrier to widespread implementation of cystatin C. Historically, cystatin C was run on specialized immunoassay instruments, but more instrument manufacturers have made it available in recent years on traditional clinical chemistry instrumentation.
“So it is becoming more available for use in big and small labs,” Dr. Karger said. “However, there remains a reliance on open channel reagents and heterogeneous system use, and some laboratories may be reluctant to venture into using heterogeneous reagents for their system.” For this and other reasons, most laboratories still do not have cystatin C as an in-house test option, she said.
Low test use is a financial disincentive to bringing cystatin C testing in-house. The M Health Fairview health system in Minnesota does not have a high volume of cystatin C testing; there, a creatinine test costs $2.50 and a cystatin C test is $10.60, Dr. Karger said. “Higher volumes could drive that cost down.”
The Medicare reimbursement rates are now favorable, she noted, at $5.12 for creatinine and $18.52 for cystatin C. But the Medicare coverage determination rules have not been updated to reflect much of the new data related to cystatin C, she said, and thus the reimbursement requirements for cystatin C testing remain fairly restrictive: adults with eGFR-creatinine 45–59 mL/min/1.73 m2 (CKD stage 3A), and if confirmation is warranted owing to concerns about creatinine inaccuracy, and if confirmation is warranted to make decisions that depend on more accurate knowledge of GFR.
It is unclear how nongovernment third-party payers would reimburse if cystatin C were used more routinely, Dr. Karger said, particularly if performed concurrently with creatinine. She spoke with a cystatin C assay manufacturer that had plans to include cystatin C on every renal panel, but the concept was rejected based on feedback it would not be reimbursed.
Another barrier: lack of education on how to use cystatin C. Non-nephrologists may be unaware of the updated KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease that describes the indications for cystatin C use, she said, “and clinicians may not understand how cystatin C eGFR should be used in combination with, or instead of, creatinine eGFR.” There also may be a lack of understanding about how to handle discrepant creatinine and cystatin C eGFR results. “So we need to educate our providers.”