Data on the relation between renal biomarkers and measured glomerular filtration rate

The data presented in this article are related to the research article entitled “The Diagnostic Value of Rescaled Renal Biomarkers Serum Creatinine and Serum Cystatin C and their Relation with Measured Glomerular Filtration Rate” (Pottel et al. (2017) [1]). Data are presented demonstrating the rationale for the normalization or rescaling of serum cystatin C, equivalent to the rescaling of serum creatinine. Rescaling biomarkers brings them to a notionally common scale with reference interval [0.67–1.33]. This article illustrates the correlation between rescaled biomarkers serum creatinine and serum cystatin C by plotting them in a 2-dimensional graph. The diagnostic value in terms of sensitivity and specificity with measured Glomerular Filtration Rate as the reference method is calculated per age-decade for both rescaled biomarkers. Finally, the interchangeability between detecting impaired kidney function from renal biomarkers and from the Full Age Spectrum FAS-estimating GFR-equation and measured GFR using a fixed and an age-dependent threshold is shown.

of serum cystatin C, equivalent to the rescaling of serum creatinine. Rescaling biomarkers brings them to a notionally common scale with reference interval [0.67- 1.33]. This article illustrates the correlation between rescaled biomarkers serum creatinine and serum cystatin C by plotting them in a 2-dimensional graph. The diagnostic value in terms of sensitivity and specificity with measured Glomerular Filtration Rate as the reference method is calculated per age-decade for both rescaled biomarkers. Finally, the interchangeability between detecting impaired kidney function from renal biomarkers and from the Full Age Spectrum FAS-estimating GFR-equation and measured GFR using a fixed and an age-dependent threshold is shown.

Subject area
Renal Physiology More specific subject area Renal biomarkers serum creatinine (Scr) and serum cystatin C (ScysC) and their relation with directly measured glomerular filtration rate (mGFR) Type of data Assay results for serum creatinine, serum cystatin C and directly measured glomerular filtration rate from various reference methods, demographic data How data was acquired Diagnostic assays, accepted reference methods for GFR

Data format
Data are presented in graphs and tables in analyzed format Experimental factors All biomarker assays are calibrated against the international standard or gold standard method (IDMS for Scr). All methods for GFR are reference methods with accepted sufficient accuracy.

Experimental features
See Table 1 in reference [1].

Data source location
See Table 2 in reference [1]. All data cohorts were presented in previous studies.

Data accessibility
The data used in this article are obtained by pooling different cohorts which are not available in a public repository, and were received by the mentioned institutes for the purpose of this study. The data from the CRIC Study reported here were supplied by the NIDDK Central Repositories. [1]The data are presented in summary tables and graphs within this article.

Value of the data
The data present the rationale for the choice of the rescaling factor for serum cystatin C. Rescaling brings the biomarker to a notionally common scale making its interpretation easy with reference to the reference interval [0.67-1.33].
The upper limit of the reference interval (1.33) is used as a threshold to detect impaired kidney function and this is compared to the definition of impaired kidney function based on a fixed and age-dependent threshold for GFR.
These data give new insights into the relation between renal biomarkers and measured GFR. Analogous to the normalization or rescaling of serum creatinine (Scr), the normalization or rescaling factor(s) for ScysC is defined as the mean (or median) of the ScysC-distribution(s) for healthy subjects. The rescaling factors have previously been defined as Q cysC ¼ 0.82 mg/L for subjects aged o 70 years and Q cysC ¼ 0.95 mg/L for subjects aged Z 70 years [2]. In this article, data and a new analysis are presented to further support these choices for the rescaling of ScysC.
Only 'healthy' subjects were selected, that is, a subgroup is selected from the total collection of 8584 subjects, obtained from the normal population and from nephrology clinics. First, it was required that Scr/Q crea r 1.33, or, only subjects with 'normal' Scr-values were selected. Q crea -values for Scr have been reported for children and adolescents [3,4]. For adults, Q crea ¼ 0.70 mg/dL is used for females and Q crea ¼ 0.90 mg/dL for males. This selection requirement reduces the total dataset from 8584 to 5352 patients. The additional requirement that mGFR Z 60 mL/min/1.73 m² further reduces the dataset from 5352 to 4907. Table 1 shows the numbers, mean, median, standard deviation (SD) and interquartile range (IQR) per age-decade for ScysC in this healthy subjects subgroup.
For each decade, a truncated cumulative Gaussian fit was performed to determine the mean and standard deviation of the sample ( Fig. 1 and Table 1). The dotted line in Fig. 1 represents the linear increase in normalization factor beyond the age of 70 years. In the FAS-cystatin C article [2] it was shown that there was no added value to using this (dotted) straight line fit for the normalization factor beyond 70 years, therefore, to keep it simple, the value of 0.95 mg/L was chosen as the rescaling factor for ScysC for ages 4 70 years.

Rescaled biomarkers
The FAS-equation has been designed for Scr/Q crea but it has recently been shown that it can also be used for ScysC/Q cysC and for the combination of both normalized biomarkers [2,5]. The fact that the same equation can be used to estimate mGFR from renal biomarkers also means that it is expected that Scr/Q crea E ScysC/Q cysC . Fig. 2 is a scatterplot of ScysC/Q cysC against Scr/Q crea , using the corresponding age/sex dependent Q crea -values and Q cysCvalues, for all 8584 subjects. The diagonal line is the identity line, representing equal rescaled biomarkers. The scatter around the identity line indicates the amount to which the rescaled biomarkers deviate from each other. The overall Pearson correlation coefficient (r) between the rescaled biomarkers is 0.87 (p o 0.0001, n ¼ 8584) and Lin's Concordance Correlation Coefficient is 0.857 with 95%CI [0.852-0.863]. Lin's CCC evaluates the degree to which pairs of observations fall on the diagonal or identity line through the origin. For children, r ¼ 0.85, Lin's CCC ¼ 0.828 (n ¼ 767); for adults, r ¼ 0.87 and Lin's CCC ¼ 0.861 (n ¼ 6068) and for older adults r ¼ 0.88, Lin's CCC ¼ 0.852 (n ¼ 1749).

diagnostic value of the single rescaled biomarkers
The diagnostic value of the single renal biomarkers is presented in the Tables 2 and 3. The fixed threshold for mGFR of 60 mL/min/1.73 m² is compared to the age-dependent threshold CO AD ¼ 107.       (Fig. 4).

Interchangeability between biomarkers and mGFR / FAS-eGFR
Comparing (Scr/Q crea þ ScysC/Q cysC )/2 using the threshold of 1.33 with mGFR using the fixed threshold of 60 mL/min/ 1.73 m², for the complete n ¼ 8584 dataset, to detect renal impairment, we have (Table 3a): Exact McNemar's test: p o 0.0001. % agreement ¼ (5067 þ 2488) / 8584 ¼ 88.0%. Comparing (Scr/Q crea þ ScysC/Q cysC )/2 using the threshold of 1.33 with mGFR using an age-dependent threshold, for the complete n ¼ 8584 dataset, to detect renal impairment, we have (Table 3b): Exact McNemar's test: p ¼ 0.1027. % agreement ¼ (5043 þ 2711) / 8584 ¼ 90.3%. Using the FAS combi equation to calculate eGFR from both Scr/Q crea and ScysC/Q cysC , the following table is obtained when comparing FAS-eGFR using the age-dependent threshold with the combined biomarker value (Scr/Q crea þScysC/Q cysC )/2 using the threshold of 1.33 (Table 4): In Fig. 5a-b, the raw mGFR-values are plotted against age, for the subgroups defined by (Scr/Q crea þ ScysC/Q cysC )/2 below and above the threshold of 1.33, together with the fixed threshold for mGFR ¼ 60 mL/min/1.73 m² and the age-dependent threshold obtained from the FAS-equation with (Scr/Q crea þ ScysC/Q cysC )/2 ¼ 1.33. These figures correspond to the Tables 3a and b. Fig. 3. a: Sensitivity and Specificity per age-category. Solid circles correspond to Scr/Q crea as the test result (positive when 4 1.33, negative when r 1.33) and diseases status defined by the fixed mGFR threshold of 60 mL/min/1.73 m². Open circles correspond to the reversed situation, that is, mGFR as the test result (positive when mGFR o 60 and negative when mGFR Z 60) and disease status defined by the Scr/Q crea threshold of 1.33. b: Sensitivity and Specificity per age-category. Solid circles correspond to Scr/Q crea as the test result (positive when 4 1.33, negative when r 1.33) and diseases status defined by the agedependent mGFR threshold CO AD . Open circles correspond to the reversed situation, that is, mGFR as the test result (positive when mGFR o CO AD and negative when mGFR Z CO AD ) and disease status defined by the Scr/Q crea threshold of 1.33.

Experimental design, materials and methods
This is a retrospective study, where the data presented here were collected from 12 previously published cohorts (grand total of 8584 patients) and centralized for pooled data-analysis. Assay data for Scr and ScysC, together with measured GFR, age, sex were centralized for the data-analysis. The total number of patients was subdivided into subgroups corresponding with age-decades with the aim to perform a data-analysis of the diagnostic value (in terms of sensitivity and specificity) of the Fig. 4. a: Sensitivity and Specificity per age-category. Solid circles correspond to ScysC/Q cysC as the test result (positive when 4 1.33, negative when r 1.33) and disease status defined by the fixed mGFR threshold of 60 mL/min/1.73 m². Open circles correspond to the reversed situation, that is, mGFR as the test result (positive when mGFR o 60 and negative when mGFR Z 60) and disease status defined by the ScysC/Q cysC threshold of 1.33. b: Sensitivity and Specificity per age-category. Solid circles correspond to ScysC/Q cysC as the test result (positive when 4 1.33, negative when r 1.33) and diseases status defined by the age-dependent mGFR threshold CO AD . Open circles correspond to the reversed situation, that is, mGFR as the test result (positive when mGFR o CO AD and negative when mGFR Z CO AD ) and disease status defined by the ScysC/Q cysC threshold of 1.33.   biomarkers per age-decade. Sensitivity and specificity were calculated with reference to measured GFR (fixed and age-dependent threshold), and with reference to the rescaled biomarker threshold of 1.33. Scr was traceable to the gold standard Isotope Dilution Mass Spectrometry method, ScysC was obtained from assays calibrated to the international standard or ScysC was recalculated against the calibrator and measured GFR was obtained from accepted reference methods, as described in the main article [1].