Bakker, SJL

Erler, NS

Gans, ROB

Groothof, D

Post, A

Shehab, NBN

English

EUR Research Repository

RESEARCH LETTER Nephrol Dial Transplant , 2023, 0 , 1–3 https://doi.org/10.1093/ndt/gfad224 Advance access publication date: 18 October 2023 Rounding creatinine, cystatin C or both: impact on discordance group assignment and GFR-estimating equation performance Dion Groothof 1 , Naser B.N. Shehab 1 , Adrian Post 1 , Reinold O.B. Gans 1 , Stephan J.L. Bakker 1 and Nicole S. Erler 2 ,3 1 Department of Internal Medicine, Division of Nephrology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands 2 Department of Biostatistics, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands 3 Department of Epidemiology, Erasmus Medical Center, Erasmus University Rotterdam, Rotterdam, The Netherlands Correspondence to: Dion Groothof; E-mail: d.groothof@umcg.nl                                      We used the cystatin C–based CKD-EPI equation from 2012 to compute eGFRcys, as it was not updated because it does not in- clude race [ 3 ]. We assessed the performance of GFR-estimating equations under the various rounding scenarios by computing the bias (systematic error) as the median difference between mea- sured GFR and eGFR, the interquartile range of the difference be- tween measured GFR and eGFR as a measure of imprecision, and the percentage of estimates less than 30% different from the mea- sured GFR (referred to as the P30). Confidence intervals around these performance measures were obtained via bootstrapping, stratified by discordance groups to maintain the proportion of subjects within discordance groups. Statistical analyses were per- formed with R version 4.3.1 (Vienna, Austria). The mean (standard deviation) age, measured GFR, eGFRcr, eGFRcys and eGFRcr-cys of the total sample (49.8% male) were 56.1 (11.2) years and 87.3 (29.7), 74.3 (22.0), 73.1 (26.0) and 75.8 (24.6) mL/min/1.73 m 2 , respectively. Median (25th; 75th percentile) serum creatinine and cystatin C were 1.03 (0.85; 1.30) mg/dL and 1.05 (0.85; 1.28) mg/L, respectively. Using two decimals for both markers, 229 (19.3%) subjects were assigned to the eGFR- cys < eGFRcr discordance group. Rounding creatinine, cystatin C or both markers to one decimal resulted in respective assignment of 235 (19.8%), 229 (19.3%) and 232 (19.6%) subjects to this discor- dance group, while rounding to zero decimals resulted in respec- tive assignment of 306 (25.8%), 377 (31.8%) and 87 (7.3%) subjects to this discordance group, consistent with the larger information loss in this rounding scenario. While 799 (67.5%) subjects were assigned to the eGFRcys ≈ eGFRcr concordance group when using two decimals for both markers, rounding of creatinine, cystatin C or both markers to one decimal resulted in respective assignment of 782 (66.0%), 797 (67.3%) and 783 (66.1%) subjects, and rounding to zero decimals resulted in respective assignment of 509 (43.0%), 550 (46.5%) and 1048 (88.5%) subjects to this group. For the eGFR- cys > eGFRcr discordance group, 156 (13.2%) subjects were as- signed using two decimals for both markers. Rounding creatinine, cystatin C or both markers to one decimal resulted in respective assignment of 167 (14.1%), 158 (13.3%) and 169 (14.3%) subjects and rounding to zero decimals resulted in respective assignment of 369 (31.2%), 257 (21.7%) and 49 (4.1%) subjects, respectively, to this group. Downloaded from https://academic.oup.com/ndt/advance-article/doi/10.1093/ndt/gfad224/7321591 by guest on 06 December 2023To the Editor, Accurate estimation of glomerular filtration rate (GFR) is in-tegral to routine medical care and clinical decision-making. Cur-rent guidelines endorse using serum creatinine as the initial testand an estimating equation to derive GFR [ 1 ]. If this estimatedGFR (eGFR) is considered less accurate (e.g. due to lower-than-average muscle mass [ 2 ]), confirmatory testing with muscle mass–independent cystatin C is recommended [ 1 ]. However, evidencerelating to the performance of cystatin C as GFR marker in real-world settings is lacking and is confined to research settings [ 3 ].A recent study addressing this knowledge gap found that eGFRbased on both creatinine and cystatin C (eGFRcr-cys) outperformsGFR derived from creatinine (eGFRcr) or cystatin C (eGFRcys) ina real-world setting, particularly when eGFRcr and eGFRcys arediscordant [ 4 ]. Importantly, this and another recent study [ 5 ] pre-sented cystatin C values as integers, a less informative formatthan the typically used real numbers [ 3 , 6 –8 ], especially whenrounding from one to zero decimals. However, the impact ofrounding levels of kidney function markers on the performanceof GFR-estimating equations has never been quantified. This isa crucial area to explore, as rounding may influence the per-formance of GFR-estimating equations, potentially compromis-ing clinical decision-making and invalidating conclusions fromstudies. To explore this area, we followed previous methodology fordeveloping GFR-estimating equations [ 3 , 4 ] and quantified theimpact of rounding creatinine, cystatin C or both on subjectassignment to discordance groups [ 4 ] and the performance ofGFR-estimating equations [ 3 , 4 ] using data from 1184 adults re-ferred for iothalamate clearance at the University Medical Cen-ter Groningen, Groningen, The Netherlands. GFR was measuredby continuous low-dose infusion of the radiolabelled tracer 125 I-iothalamate, as described elsewhere [ 9 ]. After a 2-h stabilizationperiod, urinary clearances of 125 I-iothalamate were calculated andcorrected for possible voiding errors (e.g. incomplete bladder emp-tying and dead space) by multiplying by the ratio of the plasmaand urinary clearance of 131 I-hippuran. The day-to-day GFR vari-ability is 2.5% [ 9 ]. We used the new creatinine-based ChronicKidney Disease Epidemiology Collaboration (CKD-EPI) equationsfrom 2021, which omit race, to compute eGFRcr and eGFRcr-cys.Received: August 30, 2023; Editorial decision: October 16, 2023 © The Author(s) 2023. Published by Oxford University Press on behalf of the ERA. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 2 | Nephrol Dial Transplant , 2023, Vol. 0, No. 0 A B CFigure 1: Comparison of the performance of GFR-estimating equations stratified by discordance groups under various rounding conditions for levels of serum creatinine and/or cystatin C. A subject was assigned to the eGFRcys < eGFRcr discordance group when eGFRcys was more than 20% lower than eGFRcr (Panel A); the eGFRcys ≈ eGFRcr concordance group when eGFRcys was within 20% of eGFRcr (Panel B); and the eGFRcys > eGFRcr discordance group when eGFRcys was more than 20% higher than eGFRcr (Panel C). Each row of plots shows a different performance measure, whereas the columns contain the different scenarios of rounding serum creatinine (in mg/dL), serum cystatin C (in mg/L) or both markers simultaneously. The median bias was defined as the mid-point of the distribution of the difference between mGFR and eGFR (i.e. mGFR – eGFR). Therefore, a positive (negative) bias implies underestimation (overestimation) of the mGFR. The IQR was defined as the 75th percentile of the bias subtracted from the 25th percentile of the bias and is considered as a measure of imprecision. The P30 was defined as the percentage of subjects with an eGFR within 30% of the mGFR. Shown are the performance measures and corresponding 95% bootstrap confidence intervals. Differences in performance measures when rounding to one versus zero decimal places with non-overlapping 95% confidence intervals are indicated with an asterisk. cr, creatinine; cys, cystatin C; IQR, interquartile range; mGFR, measured glomerular filtration rate.  o  m  w  p  r  c  z  e  –  r  d  c  a  a  r  m  1  d  m  w  c  m  a  –  m  b  m t  m  m  p  i  h  e  f  t  c v  c  D  1  G  n  t  u  v p  [  p  c  t  p  t  l  a  s  f  i  t  fl  s t  a  Downloaded from https://academic.oup.com/ndt/advance-article/doi/10.1093/ndt/gfad224/7321591 by guest on 06 December 2023Rounding either marker or both simultaneously from two tone decimal appeared to have negligible effect on the perfor-ance of all estimating equations across discordance groups,hile rounding from one to zero decimals substantially affectederformance (Fig. 1 A–C). Therefore, we focused on the latterounding scenario for further result description. In the eGFR-ys < eGFRcr discordance group, rounding creatinine from one toero decimals significantly shifted the median biases (95% CI) ofGFRcr and eGFRcr-cys from-1.25 (4.25; 1.40) and –11.34 (–13.39;8.66) to 8.13 (6.69; 9.11) and –5.54 (–6.72; –4.42) mL/min/1.73 m 2 ,espectively. Moreover, rounding of cystatin C from one to zeroecimals significantly shifted the median biases of eGFRcr, eGFR-ys and eGFRcr-cys from –0.73 (–3.63; 1.48), –20.08 (23.00; 16.65)nd 11.25 (13.66; –8.63) to 10.22 (12.28; 8.10), 33.47 (35.76; –31.43)nd –22.60 (24.20; 19.79) mL/min/1.73 m 2 , respectively. Finally,ounding both from one to zero decimals significantly shifted theedian biases of eGFRcr from –0.95 (–3.72; 1.50) to 12.45 (8.48;6.01) mL/min/1.73 m 2 (Fig. 1 A). In the eGFRcys ≈ eGFRcr concor-ance group, rounding affected performance measures only mini-ally (Fig. 1 B). In the eGFRcys > eGFRcr discordance group, eGFRcras the estimating equation affected most by rounding. Roundingreatinine from one to zero decimals significantly increased theedian bias of eGFRcr and eGFRcr-cys from –20.00 (21.49; –17.66)nd –6.30 (–9.09; –3.54) to 32.80 (35.54; –31.74) and –15.13 (–18.02;13.44) mL/min/1.73 m 2 , respectively. Furthermore, rounding botharkers from one to zero decimals likewise increased the medianias of eGFRcr from –19.91 (21.24; –16.60) to 32.99 (37.18; 29.43)L/min/1.73 m 2 (Fig. 1 C). Rounding the first decimal of creatinine and cystatin C valueso zero decimals appears to substantially affect both the assign-ent of subjects to discordance groups and the resulting perfor-ance of estimating equations to levels that may severely com-romise decision-making and invalidate study conclusions. Thisssue is also of importance in the study of selective glomerularypofiltration syndromes, which uses the ratio of eGFRcys toGFRcr as criterion [ 10 ]. Using integers instead of real numbersor creatinine or cystatin C may inadvertently introduce bias intohese metrics, potentially misdirecting clinical and research out-omes. With two US national kidney disease organizations recently ad-ocating for more routine use of cystatin C [ 11 ], clinicians will in-reasingly face discordant values between eGFRcr and eGFRcys.iscordant values, currently an active area of research [ 4 , 5 , 8 ,0 , 12 ], imply that eGFRcr, eGFRcys or both differ from measuredFR. Our work sheds light on how using integers instead of realumbers for creatinine and cystatin C levels affects GFR estima-ion, highlighting one contributing factor to discordant eGFR val-es. However, several other factors can also produce discordantalues. Measurement errors, which can arise during three distincthases in the laboratory testing process, as detailed elsewhere 13 ], can contribute to the production of discordant values. There-analytical phase of the laboratory testing process entailshallenges related to patient assessment, specimen collection,ransport and laboratory receipt. The analytical phase encom-asses all steps from specimen preparation to test result verifica-ion and, despite a decline in errors recently, still faces challengesike improper specimen processing, instrument-related errorsnd assay-related errors. Assay-related errors include sensitivity,pecificity, within-run and between-run variability, and inter-ering substances—typically being well-documented quantitiesn assay manuals. The post-analytical phase focusses on effec-ive communication and interpretation of results. Altogether,aws in each of these phases can accumulate errors, which canubstantially affect eGFR accuracy. The assumptions underlying different GFR-estimating equa-ions can also influence eGFR accuracy, depending on the us-ge context. Inclusion of age and sex as variables in currentlyD. Groothof et al . | 3                                                  RA. This is an Open Access article distributed under the terms of the Creative Downloaded from https://academic.oup.com/ndt/advance-article/doi/10.1093/ndt/gfad224/7321591 by guest on 06 December 2023recommended GFR-estimating equations [ 11 ] partially accountsfor variability in creatinine and cystatin C levels unrelated to GFR,known as ‘non-GFR determinants’ [ 3 ]. However, this inherentlyholds the assumption that non-GFR determinants are consistentamong individuals of identical age and sex, which leaves eGFRsubject to residual confounding if this assumption is not met [ 2 ].Moreover, there may be (unidentified) non-GFR determinants un-related to age and sex that affect eGFR [ 1 ]. In summary, our findings underscore the necessity of adheringto a logical set of rules for appropriate rounding of biological mea-surements, a process that involves gathering the expanded uncer-tainty of a particular assay and identifying the number of signifi-cant decimals [ 14 ]. For serum creatinine (in mg/dL) and cystatin C(in mg/L), this means using real numbers with two decimal placesas per typical measurement imprecision of assays. Adherence tothese rules will maximize accuracy in both clinical practice andresearch. ACKNOWLEDGEMENTS The authors greatly appreciate all of the hospital staff for theirefforts in facilitating this study and thank all subjects involved inthis study. We also acknowledge the work the doctors and nurseswho collected and entered the data. FUNDING None. DATA AVAILABILITY STATEMENT The data underlying this article and R code to implement the anal-yses will be shared on reasonable request to the correspondingauthor. AUTHORS’ CONTRIBUTIONS All authors have substantially contributed to the manuscriptdesign and/or revision and have approved this final version of thework. The authors have agreed to take accountability for all as-pects of this study. The corresponding author had full access toall of the data in the study and takes responsibility for the in-tegrity of the data and the accuracy of the data analysis, andD.G., S.J.L.B. and N.S.E. had final responsibility for the decision tosubmit for publication. The authors’ responsibilities were as fol-lows: D.G. conducted literature search, analyzed the data, cre-ated the figure and drafted the paper; D.G. and N.S.E. conceivedand designed the study; S.J.L.B. acquired data; D.G. and S.J.L.B. in-terpreted the data; all authors critically revised the manuscriptfor important intellectual content; and N.S.E. supervised thestudy. CONFLICT OF INTEREST STATEMENT All authors declare no conflicts of interest for the research,authorship and/or publication of this article. Received: August 30, 2023; Editorial decision: October 16, 2023 © The Author(s) 2023. Published by Oxford University Press on behalf of the ECommons Attribution License ( https://creativecommons.org/licenses/by/4.0/ ), whimedium, provided the original work is properly cited. REFERENCES 1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evalua- tion and Management of Chronic Kidney Disease. Kidney Int Suppl 2013; 3 :1–150. https://doi.org/10.1038/kisup.2012.73 2. Groothof D, Post A, Polinder-Bos HA. et al. Muscle mass and esti-mates of renal function: a longitudinal cohort study. J Cachexia Sarcopenia Muscle 2022; 13 :2031–43. https://doi.org/10.1002/jcsm. 12969 3. Inker LA, Eneanya ND, Coresh J. et al. New creatinine- and cys-tatin C–based equations to estimate GFR without race. N Engl JMed 2021; 385 :1737–49. https://doi.org/10.1056/NEJMoa2102953 4. Fu EL, Levey AS, Coresh J. et al. Accuracy of GFR estimatingequations in patients with discordances between creatinine and cystatin C-based estimations. J Am Soc Nephrol 2023; 34 :1241–51.https://doi.org/10.1681/ASN.0000000000000128 5. Fu EL, Levey AS, Coresh J. et al. Accuracy of GFR-estimating equations based on creatinine, cystatin C or both in routine care. Nephrol Dial Transplant 2023;gfad219. Online ahead of print.https://doi.org/10.1093/ndt/gfad219 6. Grubb A, Horio M, Hansson L-O. et al. Generation of a new cys-tatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibra- tor. Clin Chem 2014; 60 :974–86. https://doi.org/10.1373/clinchem. 2013.220707 7. Pottel H, Björk J, Rule AD. et al. Cystatin C–based equation to es-timate GFR without the inclusion of race and sex. N Engl J Med2023; 388 :333–43. https://doi.org/10.1056/NEJMoa2203769 8. 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Rounding creatinine, cystatin C or both:impact on discordance group assignment and GFR-estimating equation performance

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Rounding creatinine, cystatin C or both:impact on discordance group assignment and GFR-estimating equation performance

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