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. ConclusionsThe 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.

Tubular secretion of creatinine and kidney function: an observational study

“…We were able to replicate our prior CRIC crosssectional findings [3] in MDRD and AASK. Specifically, the CrCl/iGFR ratio was progressively larger at lower iGFR level when patients were classified by categories of iGFR in both MDRD and AASK ( Fig.…”

“…In cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between CrCl/ iGFR ratio at different categories of iGFR or different levels of CrCl as in our prior approach [3]. We studied relative secretion of creatinine (CrCl/iGFR) because it is widely reported in the literature.…”

“…First, prior papers have been inconsistent regarding the degree to which CrCl overestimates GFR, with estimates ranging from around 10% [3][4][5][6][7] to over 60% [8,9].…”

“…Second, we recently questioned whether the observed larger ratio of CrCl to measured GFR among those with lower GFR is actually due to proportionally greater tubular creatinine secretion with chronic kidney disease (CKD) progression, as is commonly believed, or whether this can be entirely accounted for by (random) measurement error [3,10]. But our prior study was limited since it was based on only cross-sectional analysis of enrollees from one CKD study (Chronic Renal Insufficiency Cohort [CRIC]), and the CrCl and measured GFR were not obtained simultaneously [3].…”

What Is the Correct Approach for Comparing GFR by Different Methods across Levels of GFR?

“…Zhang et al (1) estimated the measurement error (within-person coefficient of variation) as 10% with mGFR and similarly, 12% with CrCl. Using a Bland-Altman plot, the ratio of CrCl to mGFR did not increase as (mGFR1 CrCl)/2 decreased, and this finding argues against increased tubular secretion of creatinine as GFR declines (1). However, another recent study using a Bland-Altman plot did find CrCl increased relative to mGFR as (mGFR1 CrCl)/2 declined (3).…”