A new equation for calculating a person’s kidney function — their estimated glomerular filtration rate (eGFR) — worked as well with serum cystatin C as it did with serum creatinine as the biomarker. And in both cases, the new equation was more accurate for gauging renal function compared with the method currently endorsed for widespread routine use by two major US kidney groups, the 2021 CKD-EPI equation that’s calculated without a race-based modification.
The new equation, named the EKFC equation after the European Kidney Function Consortium that developed it, depends on adjustments to an individual’s serum creatinine and cystatin C values that derive from median values in healthy populations across the age spectrum (including children and adults), sex, and race. (Sex and race adjustments are not needed for cystatin C but are required when creatinine is the input variable.)
Researchers introduced the EKFC equation with the adjustment factor for serum creatinine in 2021, and in their report describing the equation’s derivation and validation they concluded that the EKFC equation “shows improved accuracy and precision compared with commonly used equations for estimating GFR from serum creatinine levels.”
In January 2023, the same team of researchers reported success in devising and validating an adjustment formula that allows eGFR calculation with the same EKFC equation but using serum levels of cystatin C as the biomarker variable. Once again, the reported performance of the EKFC equation surpassed the accuracy of the 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation without race modification.
“The performance of the EKFC eGFRcys [the cystatin C-based] equation tested in this study was equivalent to that of the EKFC eGFRcr [the creatinine-based] equation, and the EKFC eGFRcys equation had somewhat better accuracy than the 2021 CKD-EPI equations” used without race-based modification, concluded Hans Pottel, PhD, and coauthors in their recent report published online in the New England Journal of Medicine.
“Less Biased, More Accurate”
“The EKFC equations are less biased and more accurate than the 2021 CKD-EPI equations, both the creatinine and cystatin C based equations as well as the combination of both biomarkers,” said Pottel in an interview.
“The difference is most pronounced for young adults, 18-30 years old, where it is known that CKD-EPI largely overestimates GFR, with a bias that’s more than 5 mL/min/1.73m²,” a clinically meaningful bias, explained Pottel, who is professor of public health at KU Leuven, Belgium.
The new cystatin C-based EKFC equation, as well as the EKFC equation when it uses both creatinine and cystatin C, “seem to have less bias and better precision compared with the CKD-EPI” equations, commented Ron T. Gansevoort, MD, a nephrologist and professor at the University of Groningen, the Netherlands, who was not involved with developing or testing the EKFC equation.
“The EKFC eGFRcys equation does not use a sex- or race-specific constant, yet it still works quite well. That is a major step forward,” Gansevoort said in an interview. But he also cautioned that while he sees the EKFC equations using creatinine and cystatin C as “promising,” he also believes they still need external validation, and a lower price for measuring cystatin C, “before widespread implementation can take place.”
Weaker CKD-EPI Performance Outside the United States
European nephrologists are currently seeking an alternative to the race-free 2021 CKD-EPI equation because results in recent studies showed less than optimal accuracy for its GFR estimates in populations outside the United States.
A study of 1.6 million people who underwent serum creatinine testing in Stockholm found that changing from the 2009 to the 2021 CKD-EPI equation decreased the prevalence of CKD at grades 3a-5 from 5.1% to 3.8%, and it reclassified 36.2% of people with grade 3a-5 CKD to a higher (less severe) eGFR category.
A second recent study with a similar design compared the 2009 and 2021 CKD-EPI equations as well as the EKFC equation using serum creatinine in nearly 14,000 people from Europe or Africa and found that the 2021 CKD-EPI equation without race modification had “no added value compared with the previous [2009 CKD-EPI] equation without the race correction.” These results also showed that the EKFC equation using serum creatinine values had “the best performance.”
Based on these performance issues with the 2021 CKD-EPI equation, Gansevoort and several Europe-based co-authors wrote in a recent editorial that the 2009 CKD-EPI equation without race modification would for the time being remain the most widely used European approach to calculating eGFR because the 2021 CKD-EPI equation appears to overestimate eGFR in many European populations.
The EKFC equation looks like a promising new option, the editorialists say, but more validation is needed before widespread routine use. And the EKFC equation using cystatin C looks even better, Gansevoort said subsequently, but again, it requires more validation as well as improved access to cystatin C measurement.