We thank the Siemens representatives (Siemens Healthcare Diagnostics Inc, Tarrytown, New York) for clarifying the status of their cystatin C measurement procedures' traceability to the ERM-DA471/IFCC international reference material in the United States and in other countries. What they say is consistent with the US lab to non-US lab bias we reported in the College of American Pathologists (CAP) Survey data. Note that the Siemens recommended correction of +17.4% across the entire measurement range does not agree with the +12% correction that we recommended in 2011 based on the observed calibration bias of a series of serum samples when we used ERM DA471/IFCC to make their results traceable to ERM-DA471/IFCC.1 We suspect at least a partial explanation for the discrepancy in percentage bias is that the magnitude of the Siemens measurement procedures' bias seems to be slightly concentration dependent, both based on the CAP CYS Survey data we reported in our paper and based on our 2011 report describing a “re-expressed” CKD-EPI cystatin C–based estimated glomerular filtration rate (eGFR) equation. There was an intercept when comparing the original Siemens results to the recalibrated ERM-DA471/IFCC-traceable results for a series of frozen serum pools from healthy individuals and patients who had mild to moderate chronic renal disease (see equation 4 in Box 1 of Inker et al1 ). For simplicity, we opted to recommend a uniform percentage correction across the measurement range because the intercept of the Deming regression was not statistically different from zero, although the lack of statistical significance may well have been due to lack of statistical power rather than the fact that the intercept was truly zero.
We are delighted that Siemens is undertaking recalibration to make their measurement procedures distributed in the US traceable to ERM-DA471/IFCC reference material, because the company produces several of the most commonly used cystatin C measurement procedures in the world. However, we have been disappointed that both ERM-DA471/IFCC-traceable and nontraceable methods have been offered for so long. Most clinicians simply use the cystatin C measurements that their laboratory provides in various eGFR equations—such as the Kidney Disease Improving Global Outcomes–recommended CKD-EPI cystatin C eGFR equations2,3 —without regard for or knowledge of the standardization status of the laboratory method used. It is very difficult for a clinician to know what calibration or calibration corrections a clinical laboratory has or has not employed for reporting cystatin C concentration.
Consequently, it is important that clinical laboratories ensure they only provide cystatin C results using methods with calibration traceable to the ERM-DA471/IFCC international reference material. Even for clinical laboratory personnel, the information on calibration traceability is often buried in instructions for use of the reagents or calibrator material, and at times it is solely in special technical bulletins which a laboratory director may or may not have seen. We believe this lack of uniform calibration traceability of many routine cystatin C measurement procedures has seriously impeded cystatin C's acceptance as a biomarker used for estimating GFR. All manufacturers should carefully check their calibration systems to be sure they are traceable to ERM-DA471/IFCC international reference material in order to prevent erroneous eGFR values being reported to clinicians.
Dr Eckfeldt is a paid consultant for Gentian, which is a Norwegian manufacturer of cystatin C reagents, and his laboratory has received free or steeply discounted reagents from Siemens Healthcare and Roche Diagnostics in support of several National Institutes of Health–funded studies. Dr Inker has a patent pending (PCT/US2015/044567): precise estimation of glomerular filtration rate from multiple biomarkers. The authors have no other relevant financial interest in the products or companies described in this article.