eGFR: Readjusting its rating.

G FR is the accepted metric for evaluating renal function but measuring it directly (mGFR) can be cumbersome, time-consuming, and costly. The constant infusion method using inulin as the filtration marker, introduced in 1934 by Richards and Smith (1), has undergone many revisions that have now made mGFR easier to perform, although not widely available (2,3). A simple, reliable, unbiased, precise, and accurate estimation of mGFR, without reliance on constant infusions or timed urinary collections, would be welcome; however, as illustrated by the extensive compendium of comparisons of mGFR (using classical inulin clearance methods) to eGFR by Botev et al. (4) in this issue of CJASN, this objective is far from being realized. Although formulaic methods to approximate the values of mGFR from serum creatinine (Scr) levels have been used for many decades, the seminal description of the Modification of Diet in Renal Disease (MDRD) equation (eGFR-MDRD) in 1999 galvanized interest in this common and important clinical issue (5). The often used Cockcroft-Gault equation (6) was never intended to be an approximation of GFR but rather was designed to estimate endogenous creatinine clearance, which is not equivalent to GFR because of the effects of tubular secretion of creatinine (TScr). In normal individuals, this can be compensated for by a correction factor, because TScr is relatively constant (at approximately 22 to 24% of GFR) (7); however, TScr can vary markedly in disease states, particularly those associated with heavy proteinuria (8). Compared with mGFR, the current widely used eGFR-MDRD formulas (original and reexpressed [5,9]) have limitations because of variable degrees of bias, imprecision, and inaccuracy (10). The studies of Botev et al. (4) in this issue of CJASN provide additional quantitative data on the ranges of bias, precision, and accuracy of eGFR-MDRD according to the levels of mGFR, as measured by inulin clearance. The bias of eGFR declines markedly from 17 ml/min per 1.73 m when the mGFR is 60 ml/min per 1.73 m to much lower values when the mGFR is 60 ml/min per 1.73 m. Precision of eGFR is poor at levels of mGFR 60 ml/min per 1.73 m (1 SD 21 ml/min per 1.73 m) but gradually improves (in absolute but not in relative terms) as the mGFR declines. For an mGFR between 30 and 59 ml/min per 1.73 m, the precision of eGFR-MDRD is still poor at 13 ml/min per 1.73 m (1 SD). Of greater importance is the finding that the accuracy of the eGFRMDRD actually deteriorates with declining mGFR (p30 72% with mGFR 60 ml/min per 1.73 m; p30 63% with mGFR 60 ml/min per 1.73 m). Thus, eGFR-MDRD has very significant limitations as a method for approximating mGFR, especially when renal function is normal or near normal. It comes as no surprise, therefore, that use of the eGFR-MDRD equation gives rise to many “misclassifications” of chronic kidney disease (CKD) when it is applied to the Kidney Disease Outcomes Quality Initiative (KDOQI)-CKD classification/staging system, which is heavily influenced by eGFR values (11). One might ask what the use of an estimated, or approximate, GFR value is in clinical practice and whether its inherent imprecision and inaccuracy really matter. The reciprocal relationship of the Scr concentration to mGFR and all of the variables that influence its concentration in serum make it difficult for clinicians to convert a single value in an individual patient to a rough value for GFR by simple mental calculation. Renal function is usually overestimated in this process. Estimating equations remove some of the “guesswork,” and because reductions in GFR are linearly related to loss of renal function on an almost 0 to 100 scale, a low eGFR is more likely to be noticed than a Scr level modestly above the “normal” range for a given laboratory. Sequential changes in the individual patient with unequivocal renal impairment can be very useful in plotting the rate of change and predicting outcomes. The overriding question is how does the eGFR-MDRD perform in clinical practice? In this respect, the record of eGFRMDRD is a mixed one (12,13). For the diagnosis of CKD, as advocated by KDOQI, the eGFR-MDRD is clearly a failure. It frequently leads to errors in assigning individuals to the various categories of CKD. This is due to two complementary characteristics: (1) The intrinsic imprecision and inaccuracy of eGFR compared with mGFR and (2) the use of an absolute threshold for defining stages 3, 4, and 5 CKD rather than a percentile based on age and gender (12). Very clearly, eGFR-MDRD is unsuitable for diagnosing CKD and for the same reason is not suited for screening a general population for CKD (14). Methods for eGFR are also not accurate enough for use in qualifying living donors for renal transplantation (15). An actual mGFR (using I-iothalamate, cold iothalamate, iohexol or Cr-EDTA, or alternative methods) provides a better assessment of renal function in such individuals. Conversely, eGFR may be quite useful in determining the Published online ahead of print. Publication date available at www.cjasn.org.