The MDRD (Modification of Diet in Renal Disease) Study equation is widely used to estimate glomerular filtration rate (GFR) and many laboratories report this every time a serum creatinine is requested. However, it has been widely reported that such calculated values underestimate GFR when creatinine is “normal” or “near-normal”. A recent study in the American Journal of Kidney Diseases  compared the performance of the newer CKD Epidemiology Collaboration (CKD-EPI) and the MDRD Study equations for GFR and concluded that CKD-EPI equation  is more accurate than the MDRD Study equation overall, and across most subgroups.
How many more equations will be proposed over time to estimate GFR - what’s wrong with using serum creatinine alone?
There are many equations for estimation of GFR in the literature. The rationale for the adoption of these has always been that serum creatinine is of limited value for the detection of early deterioration in GFR. This is said to be because creatinine concentrations rise over the upper reference limit only when GFR has already decreased by at least 50%.
However, it has been known for many years that this negative view of serum creatinine is actually dogma rather than fact. The alleged difficulties are simply due to the marked biological individuality of serum creatinine. Creatinine has very low within-subject biological variation and large between-subject biological variation . In consequence, the span of creatinine concentrations found in any healthy individual occupies only a small part of the dispersion of the conventional population-based reference interval. As a result, individuals can have values for serum creatinine concentration that are highly unusual for them (showing deteriorating GFR) but these values will still lie well within the population-based reference interval. Such values will not be flagged by laboratories nor considered worthy of note by clinicians or other health care workers.
How can that situation be improved? Recently, on behalf of the IFCC Committee on Reference Intervals and Decision Limits, a group published a detailed paper on reference intervals for serum creatinine concentrations and gave population-based data for both males and females, aged 18–74 years, each as a single interval . The authors considered that that these might be adopted by any laboratory serving a similar population and using a method of comparable specificity that is traceable to the creatinine reference system (an important issue, per se). But, the problems of interpretation would remain using such a simple set of reference values. What is required to make traditional reference intervals of higher clinical utility is to ensure that the between-subject biological variation is as small as possible compared to the within-subject variation. This is what stratification of reference values achieves. A study which shows the requirement for age and gender stratified reference intervals for creatinine has been published by Kallner et al . If such well-stratified reference intervals were available, they would be of value in aiding in diagnosis, screening, and case-finding and there might then be less need for estimates of GFR based on equations, although these, as a tool for addressing the major public health issue of CKD, have undoubtedly proven effective in enabling direction of patients into care pathways and in raising the profile of this problem. However, such estimates, because they are based on creatinine and other factors such as age, gender, and ethnicity, intrinsically have a larger uncertainty of measurement.
The ultimate reference interval is a person-specific one and this is particularly germane for monitoring individuals over time. Changes in results in an individual are not satisfactorily monitored using population-based reference intervals, even when stratified. What is required is the recognition that changes in results are due to analytical and within-subject biological variation as well as improvement or deterioration. It is easy to calculate the Reference Change Value (RCV) required to assess the significance of change in any individual using a simple formula based on analytical imprecision and the well-documented biological variation for creatinine . Such RCV should be developed by laboratories and used in their reporting systems instead of, or as well as, stratified reference intervals. Then, the conclusion in a recent superb Editorial  which should be made compulsory reading for all laboratory staff, nephrologists and the many others involved in CKD - the reality is that serum creatinine is still a very good measure of GFR and is by far the most sensitive serum biomarker for detecting small GFR changes in an individual - could be translated into everyday practice
- Stevens LA, Schmidt CH, Greene T, et al. Comparative performance of the CKD Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) Study equations for estimating GFR levels above 60 mL/min/1.73 m2. Am J Kid Dis 2010;56:486-95
- Levey AS, Stevens LA, Schmidt CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-12
- Fraser CG. Biological Variation: From Principles to Practice. Washington, AACC Press, 2001.
- Ceriotti F, Boyd JC, Klein G, et al. Reference intervals for serum creatinine concentrations: assessment of available data for global application. Clin Chem 2008;54:559–66
- Kallner A, Ayling PA, Khatami Z. Does eGFR improve the diagnostic capability of S-creatinine concentration results? A retrospective population based study. Int. J Med Sci 2008;5:7-19
- Dalton RN. Serum creatinine and glomerular filtration rate: perception and reality. Clin Chem 2010;56:687–9