Estimated Glomerular Filtration Rate From a Panel of Filtration Markers—Hope for Increased Accuracy Beyond Measured Glomerular Filtration Rate?  Lesley A. Inker, Andrew S. Levey, Josef Coresh  Advances in Chronic Kidney Disease  Volume 25, Issue 1, Pages 67-75 (January 2018) DOI: 10.1053/j.ackd.2017.10.004 Copyright © 2017 National Kidney Foundation, Inc. Terms and Conditions

Figure 1 Variability in measured GFR and its effect on performance of GFR estimating equations. Left hand: Bland–Altman plot of the difference of the two prerandomization glomerular filtration rate measurements (mGFRs) by the average of prerandomization mGFRs. Symbols indicate consistent African American Study of Kidney Disease (AASK) mGFRs (black plus signs), discrepant AASK mGFRs (gray plus signs), consistent Modification of Diet in Renal Disease (MDRD) Study mGFRs (black circles), and discrepant MDRD Study mGFRs (gray circles). Right hand: Estimated accuracy of CKD-EPI creatinine-cystatin C equation and the MDRD Study equation in estimating six different gold standard measured glomerular filtration rates (mGFRs): reference mGFR, average of two mGFRs, and the average of three mGFRs without and with limiting the analysis to consistent (within 25% of each other) mGFRs. Boxes indicate the CKD-EPI creatinine-cystatin C equation, and circles indicate the MDRD Study equation. Dotted lines include all participants. Solid lines include only participants with consistent (<25%) mGFRs. P30 is calculated as the percentage of estimated GFR within 30% of the gold standard (the average of three mGFRs). Reprinted with Permission from Kwong YT, Stevens LA, Selvin E, et al. Imprecision of urinary iothalamate clearance as a gold standard measure of GFR decreases the diagnostic accuracy of kidney function estimating equations. American Journal of Kidney Diseases. 2010; 56(1):39-49.17 Abbreviations: CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; GFR, glomerular filtration rate. Advances in Chronic Kidney Disease 2018 25, 67-75DOI: (10.1053/j.ackd.2017.10.004) Copyright © 2017 National Kidney Foundation, Inc. Terms and Conditions

Figure 2 Determinants of serum levels of endogenous filtration markers. The serum concentration (S) of an endogenous filtration marker is determined by its generation (G), extra-renal elimination (E), and urinary excretion (UV). Urinary excretion is the sum of filtered load (GFR × S) plus secretion (TS) minus tubular reabsorption (TR). In the steady state, urinary excretion is equals generation minus extra-renal elimination. By substitution and rearrangement, GFR can be expressed as the reciprocal of the serum concentration multiplied by the non-GFR determinants. Modified with Permission from Stevens LA and Levey AS. Measured GFR as a confirmatory test for estimated GFR. J Am Soc Nephrol. 2009; 20(11):2305-2313.8 Abbreviation: GFR, glomerular filtration rate. Advances in Chronic Kidney Disease 2018 25, 67-75DOI: (10.1053/j.ackd.2017.10.004) Copyright © 2017 National Kidney Foundation, Inc. Terms and Conditions

Figure 3 Non-GFR determinants of LMW serum proteins in CKD studies. Percent difference in levels of filtration markers, adjusted for measured glomerular filtration rate (mGFR), mGFR measurement error, study, and full multivariable adjustment in MDRD Study, AASK, and CRIC (N = 3156). All predictors listed in the first column are included as part of the multivariable-adjusted model. In addition, log-mGFR, urine urea nitrogen, and log urine protein were included in the model. Percent difference in levels of filtration markers for an interquartile range (IQR) increase in continuous variables, defined as the difference between the 25th and 75th percentiles. Strength of association for statistically significant results is indicated by color: red, strong (absolute change >10%); orange, intermediate (absolute change 5%–10% inclusive); and yellow, weak (absolute change <5%). Modified with permission from Non-GFR Determinants of Low-Molecular-Weight Serum Protein Filtration Markers in CKD.26 Abbreviations: AASK, African American Study of Kidney Disease; CRIC, chronic renal insufficiency cohort; GFR, glomerular filtration rate; LMW, low molecular weight; MDRD, Modification of Diet in Renal Disease. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.) Advances in Chronic Kidney Disease 2018 25, 67-75DOI: (10.1053/j.ackd.2017.10.004) Copyright © 2017 National Kidney Foundation, Inc. Terms and Conditions

Figure 4 Theoretical effects of the addition of filtration markers on precision (RMSE) of regressions relating filtration markers to mGFR or true GFR. Simulations show the effect of additional markers on model performance. Lines connect simulations based on data from MDRD Study and AASK. Two assumptions were used in the simulations: first, after accounting for correlation of the markers with mGFR, the markers have a mild-to-moderate correlation with each other (r = 0.42); and second, after accounting for correlation of the markers with mGFR, the markers are not correlated with each other (r = 0). Diamonds indicate RMSE for single markers on the left and another mGFR (mean [SD] 62 [19] days apart) on the right. Bottom 2 lines show RMSE is lower in models for true GFR (tGFR). Creatinine and cystatin C are correlated even conditional on true GFR, which diminishes the effect of their combination. The 2nd and 4th lines demonstrate the additional improvement if uncorrelated markers are added into a panel. Abbreviations: AASK, African American Study of Kidney Disease; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; mGFR, measured glomerular filtration rate; SD, standard deviation. Advances in Chronic Kidney Disease 2018 25, 67-75DOI: (10.1053/j.ackd.2017.10.004) Copyright © 2017 National Kidney Foundation, Inc. Terms and Conditions