Measurement Error as Alternative Explanation for the Observation that CrCl/GFR Ratio is Higher at Lower GFR

Abstract

Background and objectives: Overestimation of GFR by urinary creatinine clearance (CrCl) at lower levels of GFR has long been attributed to enhanced creatinine secretion. However, this does not take into consideration the contribution of errors in measured GFR (and CrCl) due to short-term biologic variability or test imprecision.

Design, setting, participants, & measurements: We analyzed cross-sectional data among 1342 participants from the Chronic Renal Insufficiency Cohort study with baseline measurement of GFR by iothalamate clearance (iGFR) and CrCl by 24-hour urine collection. We examined the CrCl/iGFR ratio classified by categories of iGFR and also by categories of CrCl.

Results: Overall, mean CrCl/iGFR ratio was 1.13. CrCl/iGFR ratio was higher at lower iGFR categories. In contrast, this ratio was lower at lower CrCl levels. We hypothesize these relationships could be due to measurement error, which is bolstered by replicating these trends in a simulation and modeling exercise in which there was no variation in the ratio of CrCl/iGFR with true kidney function but taking into account the effect of measurement error in both CrCl and iGFR (of magnitudes previously described in the literature). In our simulated data, the observed CrCl/iGFR ratio was higher at lower observed iGFR levels when patients were classified by categories of observed iGFR. When the same patients were classified by categories of observed CrCl, the observed CrCl/iGFR ratio was lower at lower observed CrCl levels.

Conclusions: The combined empirical and modeling results suggest that measurement errors (in both CrCl and iGFR) should be considered as an alternative explanation for the longstanding observation that the ratio of CrCl to iGFR gets larger as iGFR decreases.

Figure 1.

Relationship between true kidney function, observed CrCl, and observed iGFR in simulation data and in CRIC data.

Figure 2.

Distribution of iGFR, CrCl, as well as CrCl/iGFR ratio stratified by categories of iGFR and by categories of CrCl in 1342 CRIC participants (box plots show median, interquartile range, and outliers; whiskers represent the highest and lowest values that are not outliers >1.5 box lengths from one hinge of the box). The much wider spread in the values of the unconstrained kidney function metric versus the constrained values and how this varies by strata of kidney function metric are graphically displayed. For example, in (A), by definition, those in the lowest iGFR category all have iGFR<30 ml/min per 1.73 m² but the CrCl values among them may be as high as >75 ml/min per 1.73 m². So the average CrCl/iGFR ratio is >1. By comparison, in (B), those in the lowest CrCl category, by definition, all have CrCl<30 ml/min per 1.73 m² but the iGFR values among them may be as high as >75 ml/min per 1.73 m²; so, the average CrCl/iGFR ratio is <1. CrCl, urinary creatinine clearance; iGFR, measurement of GFR by iothalamate clearance.