Discordance Between Creatinine-Based and Cystatin C-Based Estimated GFR: Interpretation According to Performance Compared to Measured GFR

Abstract

Rationale & objective: Use of cystatin C in addition to creatinine to estimate glomerular filtration rate (estimated glomerular filtration rate based on cystatin C [eGFRcys] and estimated glomerular filtration rate based on creatinine [eGFRcr], respectively) is increasing. When eGFRcr and eGFRcys are discordant, it is not known which is more accurate, leading to uncertainty in clinical decision making.

Study design: Cross-sectional analysis.

Setting & participants: Four thousand fifty participants with measured glomerular filtration rate (mGFR) from 12 studies in North America and Europe.

Exposures: Serum creatinine and serum cystatin C.

Outcomes: Performance of creatinine-based and cystatin C-based glomerular filtration rate estimating equations compared to mGFR.

Analytical approach: We evaluated the accuracy of eGFRcr, eGFRcys, and the combination (eGFRcr-cys) compared to mGFR according to the magnitude of the difference between eGFRcr and eGFRcys (eGFRdiff). We used CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations to estimate glomerular filtration rate. eGFRdiff was defined as eGFRcys minus eGFRcr and categorized as less than -15, -15 to <15, and ≥15 mL/min/1.73 m² (negative, concordant, and positive groups, respectively). We compared bias (median of mGFR minus eGFR) and the percentage of eGFR within 30% of mGFR.

Results: Thirty percent of participants had discordant eGFRdiff (21.0% and 9.6% negative and positive eGFRdiffs, respectively). In the concordant eGFRdiff group, all equations displayed similar accuracy. In the negative eGFRdiff groups, eGFRcr had a large overestimation of mGFR (-13.4 [-14.5 to -12.2] mL/min/1.73 m²) and eGFRcys had a large underestimation (9.9 [9.1-11.2] mL/min/1.73m²), with opposite results in the positive eGFRdiff group. In both negative and positive eGFRdiff groups, eGFRcr-cys was more accurate than either eGFRcr or eGFRcys. These results were largely consistent across age, sex, race, and body mass index.

Limitations: Few participants with major comorbid conditions.

Conclusions: Discordant eGFRcr and eGFRcys are common. eGFR using the combination of creatinine and cystatin C provides the most accurate estimates among persons with discordant eGFRcr or eGFRcys.

Keywords: Glomerular filtration rate; creatinine; cystatin; estimated GFR.

Graphical abstract

Figure 1

Distribution of difference between eGFRcr and eGFRcys. Top panel shows distribution of eGFR difference (eGFRdiff) on the raw scale, computed as eGFRcys − eGFRcr. Orange dashed lines at −15 and 15 mL/min/1.73 m² indicate the cutoff points for eGFR difference categories. Bottom panels show distribution of eGFRcr, eGFRcys, eGFRcr-cys, and mGFR in the study population. The eGFRcr and eGFRcr-cys correspond to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2021 equations, and eGFRcys to the CKD-EPI 2012 equation. Abbreviations and definitions: eGFRcr, estimated glomerular filtration rate based on creatinine; eGFRcr-cys, estimated glomerular filtration rate based on cystatin C; eGFRcys, estimated glomerular filtration rate based on cystatin C; eGFRdiff, estimated glomerular filtration rate difference; mGFR, measured glomerular filtration rate.

Figure 2

Systematic error in GFR estimating equations by level of estimated GFR according to eGFR difference group. Left panel shows the systematic error (median difference) between measured and estimated GFR for the negative eGFR difference group (eGFRcys − eGFRcr less than −15 mL/min/1.73 m²). Middle panel shows the systematic error (median difference) between measured and estimated GFRs when the eGFR difference is concordant (eGFRcys − eGFRcr −15 to 15 mL/min/1.73 m²). Right panel shows the median difference between measured and estimated GFRs for the positive eGFR difference group eGFRcys − eGFRcr > 15 mL/min/1.73 m². Green, orange, and purples lines are the smoothed regression lines for eGFRcr, eGFRcys, and eGFRcr-cys, respectively. The eGFRcr and eGFRcr-cys correspond to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2021 equations, and eGFRcys to the CKD-EPI 2012 equation. The regression lines are drawn using the lowess smoothing function in R, excluding lowest and highest 2.5% of estimated GFR values. A positive sign indicates underestimation of measured GFR and a negative sign indicates overestimation of measured GFR. The x axis is the eGFR for the specific equation and thus varies across the 3 regression lines. Abbreviations and definitions: eGFR, estimated glomerular filtration rate; eGFRcr, estimated glomerular filtration rate based on creatinine; eGFRcr-cys, estimated glomerular filtration rate based on cystatin C; eGFRcys, estimated glomerular filtration rate based on cystatin C; GFR, glomerular filtration rate; mGFR, measured glomerular filtration rate.

Figure 3

Performance of eGFRcr, eGFRcys, and eGFRcr-cys stratified by estimated glomerular filtration rate (eGFR) difference group and sex, age, and BMI groups. All panels show systematic error (median difference) between measured and estimated glomerular filtration rate stratified by eGFR difference group for subgroups of demographic or clinical characteristics. Green, orange, and purples lines show the data for eGFRcr, eGFRcys and eGFRcr-cys, respectively. The eGFR difference group defined as negative less than −15, concordant −15 to 15, and positive >15 mL/min/1.73 m². The eGFRcr and eGFRcr-cys correspond to the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) 2021 equations, and eGFRcys to the CKD-EPI 2012 equation. Top panel: sex groups. Middle panel: age groups defined as <40, 40 - <65, and ≥65 years. Bottom panel: BMI groups defined as <20, 20 to <25, 25 to <30, and ≥30 kg/m². Abbreviations and definitions: BMI, body mass index; eGFRcr, estimated glomerular filtration rate based on creatinine; eGFRcr-cys, estimated glomerular filtration rate based on cystatin C; eGFRcys, estimated glomerular filtration rate based on cystatin C; eGFRdiff, estimated glomerular filtration rate difference.