We developed a new equation, the CKD-EPI equation, to estimate GFR in adults from serum creatinine using a large database pooled from 10 studies. Using data pooled from 16 additional studies, we validated the CKD-EPI equation and showed that it is more accurate than the widely-used MDRD Study equation. The CKD-EPI equation has lower bias, especially at estimated GFR greater than 60 mL/min/1.73 m2; however, precision remains limited. The improved accuracy of the CKD-EPI equation overcomes some of the limitations of the MDRD Study equation and has important implications for public health and clinical practice.
Lower bias at higher estimated GFR reflects use of a spline term for serum creatinine. The spline accounts for a weaker relationship between creatinine and GFR at lower vs. higher creatinine levels, consistent with reports from studies comprised primarily of subjects with higher measured GFR, such as kidney donors and young people with Type 1 diabetes without microalbuminuria (10
). Like the MDRD Study equation, the CKD-EPI equation includes age, race and sex as surrogates for non-GFR determinants of serum creatinine. These variables are associated with muscle mass, the main determinant of creatinine generation (39
). Imprecision of GFR estimates suggests that age, race and sex do not account for all variation in non-GFR determinants of serum creatinine.
The CKD-EPI equation should lead to more accurate estimates of the distribution of estimated GFR and the burden of CKD in the US population. Median estimated GFR was 9.5 ml/min/1.73 m2
higher, leading to a 1.6% lower prevalence estimate for CKD (11.5% compared to 13.1% using the MDRD Study equation). Concerns have been raised about the use of the MDRD Study equation because of the high prevalence estimates in the elderly, women and Whites, compared to the low incidence rates of treated kidney failure in these groups (7
). Using the CKD-EPI equation, the prevalence is reduced in women and Whites, but remains high in the elderly. Possible explanations for the remaining disparities between prevalence and incidence include competing risk from fatal cardiovascular disease in the elderly and faster progression of kidney disease in men and Blacks (42
Greater accuracy of the CKD-EPI equation should improve clinical decision making in patients with decreased kidney function. In particular, lower bias should reduce the rate of false-positive diagnoses of CKD stage 3 (estimated GFR <60 ml/min/1.73 m2
) in patients without CKD (measured GFR above 60 ml/min/1.73 m2
and absence of markers of kidney damage). Patients with CKD are at higher risk for a variety of complications (44
), and guidelines and recommendations call for reduction in dosage of drugs excreted by the kidney, avoidance of contrast media for imaging procedures, avoidance of phosphate-based enemas in preparation for colonoscopy, and lower targets for cardiovascular risk factors in patients with decreased GFR. Importantly, falsely low levels of estimated GFR could lead to insufficient drug dosing, withholding important diagnostic tests, and over-aggressive cardiovascular risk factor reduction in patients without CKD. The impact of more accurate estimates at higher levels of GFR on clinical decision making should be evaluated.
Strengths of this study include its design, with separate large databases for development and validation of the new equation, and a pre-specified rigorous statistical analytical plan for introduction and testing of all variables in the development dataset. The pooled development and validation databases include participants with diverse clinical characteristics, with and without kidney disease, and across a wide range of measured GFR, allowing more general applicability than the MDRD Study equation. Comparison of equations in a separate validation dataset overcomes limitations of differences among studies in patient characteristics and methods for measurement of GFR and serum creatinine.
There are weaknesses of this study. First, it is unlikely that a single equation will work equally well in all populations. Second, we have pooled studies of different populations to develop and validate the CKD-EPI equation. We performed extensive analyses to examine possible study-effects, but cannot rule out that some of the findings may reflect the specific studies included in our database. Third, the study population with higher levels of GFR is not representative of the general population, and there were relatively few participants older than 70 years of age or racial minorities other than Black who are at increased risk for CKD. Fourth, we had incomplete data on diabetes type, immunosuppressive agents for transplantation, measures of muscle mass, and other clinical conditions and medications that might affect serum creatinine independently from GFR; however, the variables that we evaluated are the most readily available and easy to ascertain for widespread clinical application. Fifth, the CKD-EPI equation is more complex than the MDRD Study equation, but can readily be implemented into clinical laboratory information systems using the same input variables as required for use of the MDRD Study equation. Finally, the new equation does not overcome limitations of serum creatinine as an endogenous filtration marker. All creatinine-based equations should be used with caution in people with abnormally high or low levels of muscle mass. Nevertheless, serum creatinine is central for clinical assessment of kidney function at the present time, and GFR estimates based on serum creatinine will continue to be used in clinical practice for the foreseeable future.
Further research is necessary to improve GFR estimation. Imprecision in GFR estimates may be secondary to non-GFR determinants of creatinine. Measures of imprecision may also be inflated by measurement error in GFR. Research should be directed towards improving GFR measurement and evaluation of cystatin C and novel filtration markers for GFR estimation, either alone or in combination with serum creatinine (51
). Studies in representative populations are necessary, especially in the elderly and racial and ethnic minorities.
In summary, the CKD-EPI creatinine equation is more accurate than the MDRD Study equation across a wide variety of populations and clinical conditions. Bias is improved, especially at higher levels of estimated GFR, although precision remains suboptimal. Improved accuracy of the CKD-EPI equation could have important implications for public health and clinical practice. We suggest that the CKD-EPI equation could replace the MDRD Study equation for estimated GFR reporting for general clinical use.