How unmeasured muscle mass affects estimated GFR and diagnostic inaccuracy

Background: Estimated glomerular filtration (eGFR) results based on serum creatinine are frequently inaccurate with differences against measured GFR (mGFR) often attributed to unmeasured non-functional factors, such as muscle mass. Methods: The influence of muscle mass (measured by dual-energy x-ray absorptiometry, DEXA) on eGFR error (eGFR-mGFR) was evaluated using isotopic mGFR (Tc99m DTPA plasma clearance) in 137 kidney transplant recipients. Serum creatinine was measured by isotopic-calibrated enzymatic analysis, converted to eGFR using Chronic Kidney Disease EPIdemiology (CKD-EPI) formula, then unindexed from body surface area. Findings: Unindexed CKD-EPI eGFR error displayed absent fixed bias but modest proportional bias against reference mGFR. eGFR error correlated with total lean mass by DEXA (r=-0.350, P<0.001) and appendicular skeletal muscle index (ASMI), a proxy for muscularity (r=-0.420, P<0.001). eGFR was falsely reduced by -5.9 +/- 1.4 mls/min per 10 kg lean mass. Adipose mass and percentage fat had no effect on error. Muscle-associated error varied with each eGFR formula and influenced all CKD stages. Systemic eGFR error was predicted by ASMI, mGFR, recipient age, and trimethoprim use using multivariable regression. Residual plots demonstrated heteroscedasticity and greater imprecision at higher mGFR levels (P<0.001), from increased variance corresponding to higher absolute values and unreliable prediction by serum creatinine of high mGFR. Serum creatinine correlated with ASMI independent of mGFR level (r = 0.416, P<0.001). The diagnostic test performance of CKD-EPI eGFR to predict CKD stage 3 (by mGFR) was weakest in cachexia (sensitivity 68.4%) and muscularity (specificity 47.4%, positive predictive value 54.5% for the highest ASMI quartile). Interpretation: Serum creatinine and eGFR are imperfect estimates of true renal function, with systemic errors from muscle mass, tubular secretion, and intrinsic proportional bias; and additional inaccuracy at the extremes of renal function and patient muscularity. Cautious interpretation of eGFR results in the context of body habitus and clinical condition is recommended. (c) 2020 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)