From Pages to Practice
Ms. Appleton is a 66-year-old Black woman who has come to you for primary care for the last 5 years, during which time her creatinine level has remained stable at 1.0. Previously, the electronic medical record (EMR) indicated that her estimated glomerular filtration rate (eGFR) was 67mL/min. However, your institution recently removed the different GFR estimates for Black and non-Black patients, and now the EMR states that her creatinine of 1.0 correlates with a GFR range from 55 to 67 mL/min. Why did your institution change GFR reporting? Does your patient suddenly now have stage 3 chronic kidney disease (CKD)?
Use of serum creatinine to calculate GFR is standard practice. Because adults who identify as Black have higher average serum creatinine levels, historically GFR calculations based on creatinine have incorporated race as a factor. However, with acknowledgement that race is a social and not a biologic construct, the accuracy of these formulas has been called into question. The concern is that this systematic overestimation of GFR in Blacks results in underdiagnosis of CKD and delayed care, including nephrology referral and transplant workup. As a result, many institutions have removed race from standard GFR formulas, calling into question the accuracy of these legacy equations. Serum cystatin C has emerged as a potential alternative to creatinine to measure GFR, prompting investigators to study new formulas that more accurately measure renal function in diverse populations.
Two recent studies examined the effect of removing race from existing formulas and explored formulas based on serum cystatin C. In one study conducted by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI), investigators developed a new eGFR equation based on two development data sets (8254 participants and 5352 participants, respectively) and tested it in a validation data set (4050 participants). In the validation data set, the standard creatinine equation that included race overestimated GFR in Blacks more than in non-Blacks, but when adjustment for Black race was omitted, GFR was underestimated. A new equation using creatinine, age, sex, and omitting race underestimated GFR in Blacks and overestimated GFR in non-Blacks. Equations that used both creatinine and cystatin C without race were more accurate than the equations based on creatinine only.
The CRIC Study was a cross-sectional analysis of data from 1248 patients that included patient-reported race, genetic ancestry markers, serum creatinine, and serum cystatin C. The investigators similarly found that omitting race from a creatinine-based model led to underestimation and lower accuracy of the GFR. The misclassification of GFR could not be eliminated by incorporating body-composition metrics or other non-GFR determinants of serum creatinine. However, the investigators were able to develop a more unbiased and accurate estimate of GFR with a formula based on cystatin C rather than creatinine.
Taken together, these two studies suggest that more accurate measures of GFR may be possible by replacing existing formulas based on serum creatinine with formulas that include serum cystatin C, with or without serum creatinine. Further study is necessary to understand the logistical implications of changing GFR measurement strategies on existing laboratory, medical education, and training systems.
Regarding Ms. Appleton, the creatinine-based formula used at your institution may have overestimated her GFR, but now with removal of race, could underestimate it. It is important to discuss with her the limitations and inaccuracy of existing formulas, suggest that a diagnosis of CKD3 is possible, and use a shared-decision-making framework to discuss options for management, including medication optimization and potential referral to a nephrologist.
The following NEJM Journal Watch summary provides further details of the studies.
Allan S. Brett, MD, reviewing Hsu C et al. N Engl J Med 2021 Sep 23 Inker LA et al. N Engl J Med 2021 Sep 23
Estimation of the glomerular filtration rate (GFR) generally is based on serum creatinine, age, and sex — and incorporates an adjustment for race (Black or non-Black). Recently, however, race-based adjustment has been questioned, and in two new studies, researchers have addressed this issue.
In one study, researchers compared directly measured GFR (using urinary 125I-iothalomate clearance) and estimated GFR (eGFR) in 1248 adults with chronic kidney disease of varying severity; 37% of participants self-identified as Black and 63% as non-Black. When race was omitted from the calculation of creatinine-based eGFR, the eGFR was less accurate than when race was included; the same pattern was found when genetic ancestry was substituted for race. However, when serum cystatin C was used to calculate eGFR (instead of serum creatinine), adjustment for race was not necessary to achieve acceptable accuracy.
In another study, researchers used data from several preexisting datasets to examine the accuracy of equations for estimating GFR — with or without race, and with incorporation of creatinine, cystatin C, or both. They found that equations based on age, sex, and both serum creatinine and cystatin C — with race omitted — were reasonably accurate for both Black and non-Black populations.
Comment: The growing acknowledgement of race as a socially constructed category has led to controversy about inclusion of race in predictive algorithms for GFR, pulmonary function, and other entities. Ideally, new calculators and algorithms would replace racial categories with biological variables that improve predictive accuracy. For eGFR, these two studies point to use of cystatin C (a small protein that is filtered in the glomerulus) as one such variable. However, it remains unclear whether widespread use of cystatin C would improve clinical outcomes — and reduce racial disparities in those outcomes — in patients with chronic kidney disease.