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Cystatin C as a GFR Estimation Marker in Acute and Chronic Illness: A

Systematic Review

Article in Kidney Medicine · September 2023

DOI: 10.1016/j.xkme.2023.100727

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 Original Research

1 Cystatin C as a GFR Estimation Marker in Acute and 57

2 58
3 Q1 Chronic Illness: A Systematic Review 59
4 60
Q7 Ogechi M. Adingwupu, Ernesto Rodolpho Barbosa, Paul M. Palevsky, Joseph A. Vassalotti,
5 61
Andrew S. Levey, and Lesley A. Inker
6 62
7 63
8 Rationale and Objective: Creatinine-based GFR Analytical Approach: Bias and percentages of Complete author and article 64
9 estimating (eGFRcr) equations may be inaccurate estimates within 30% of mGFR (P30) of eGFR information provided before 65
references.
10 in populations with acute or chronic illness. The compared with mGFR were evaluated. 66
11 accuracy of GFR equations that use cystatin C Correspondence to
67
(eGFRcys) or creatinine-cystatin C (eGFRcr-cys) Results: Of the 179 citations, 26 studies met the L.A. Inker (Lesley.Inker@
12 is not well studied in these populations. inclusion criteria: 24 in adults and 2 in children in tuftsmedicine.org) 68
13 clinical populations with cancer (n=5), HIV (n=5), Kidney Med. 69
14 Study Design: A systematic review of original ar- cirrhosis (n=3), liver transplant (n=3), heart failure XX(XX):100727. Published 70
ticles identified from PubMed and expert sources. (n=2), neuromuscular diseases (n=1) critical illness
15 Two reviewers screened articles independently and
online month xx, xxxx. 71
(n=5), and obesity (n=2). In general, eGFRcr-cys
16 identified those meeting inclusion criteria.
doi: 10.1016/ 72
had greater accuracy than eGFRcr or eGFRcys j.xkme.2023.100727
17 equations among study populations with cancer, 73
18 Setting and Study Populations: Adults and chil- © 2023 The Authors. 74
dren with acute or chronic illness. HIV, and obesity, but did not perform consistently Published by Elsevier Inc.
19 better in cirrhosis, liver transplant, heart failure, on behalf of the National 75
20 Selection Criteria for Studies: Studies published neuromuscular disease, and critical illness. Kidney Foundation, Inc. This 76
since 2011 that compared performance of eGFRcr,
21 Limitations: Participants were selected because
is an open access article 77
eGFRcys, and eGFRcr-cys relative to measured under the CC BY-NC-ND
22 GFR (mGFR), used standardized assays for of concern for inaccurate eGFRcr, which may bias license (http:// 78
23 creatinine or cystatin C, and used eGFR equations results. Most studies had small sample sizes, creativecommons.org/ 79
24 developed using such assays. Studies of limiting generalizability. licenses/by-nc-nd/4.0/). 80
25 ambulatory clinical populations or research studies
Conclusions: eGFRcr-cys improves GFR estima- 81
26 in populations with only CKD, kidney transplant
tion in populations with a variety of acute and chronic 82
27 recipients, only diabetes, kidney donor candidates, 83
illnesses, providing indications for cystatin C mea-
and community-based cohorts were excluded.
28 surement. Performance was poor in many studies, 84
29 Data Extraction: Data extracted from full text. suggesting the need for more frequent mGFR. 85
30 86
31 87
32 88
33
34 C hronic kidney disease (CKD) is common, especially in
people with acute and chronic illness. Estimating GFR
using serum creatinine (eGFRcr) is the initial test for
nephrology societies encourage increased use of cystatin C to
improve the accuracy of race-free GFR estimates.6 Estimated
GFR from cystatin C (eGFRcys) is generally not more accurate
89
90
35 91
36 glomerular filtration rate (GFR) evaluation, but eGFRcr is than eGFRcr in populations without comorbid illness, indi- 92
37 less accurate relative to measured GFR (mGFR) in such cating the presence of the non-GFR determinants of cystatin C. 93
38 populations.1 Systematic differences in the non-GFR de- Higher levels of cystatin C have been associated with greater 94
39 terminants of creatinine between these populations and adiposity, smoking, hyperthyroidism, glucocorticoid excess, 95
40 those used to develop the equations are likely the critical and chronic inflammation, as indicated by insulin resistance, 96
41 cause of error in eGFRcr. Non-GFR determinants of higher levels of C-reactive protein and tumor necrosis factor, or 97
42 creatinine include generation by diet and muscle mass, lower levels of serum albumin.3,5,7-15 98
43 tubular secretion, and extra-renal elimination.2,3 Common Studies in ambulatory clinical populations with CKD or 99
44 examples of error in eGFRcr because of presence of non- diabetes, kidney donor candidates, and community-based 100
45 GFR determinants of serum creatinine include over- populations in adults and children have demonstrated that 101
46 estimation of mGFR owing to decreased creatinine gen- estimated GFR using both creatinine and cystatin C (eGFRcr-cys) 102
47 eration (muscle wasting), underestimation of mGFR provides more accurate estimates of mGFR than either 103
48 owing to drug-induced inhibition of tubular creatinine eGFRcr or eGFRcys.6,16-19 We have previously hypothe- 104
49 secretion (trimethoprim and dolutegravir) or decreased sized that the greater accuracy of eGFRcr-cys is because of 105
50 extra-renal creatinine elimination (antibiotics in patients the fact that the non-GFR determinants of creatinine and 106
51 with gastrointestinal bacterial overgrowth). cystatin C are partially independent of each other and 107
52 Cystatin C is an alternative filtration marker that is receiving therefore the use of both markers reduces the error owing 108
53 increased attention. After adjustment for mGFR, compared to non-GFR determinants.16,20 In populations with acute 109
54 with creatinine, cystatin C is less affected by age, sex, and race or chronic illness, in which eGFRcr may be inaccurate, it is 110
55 and alterations in diet, muscle mass, tubular handling, and not known whether eGFRcr-cys continues to provide more 111
56 extra-renal elimination.2-5 Recent recommendations by US accurate estimates than both eGFRcr and eGFRcys. 112

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and eGFRcr-cys using equations developed by multiple

113 PLAIN-LANGUAGE SUMMARY research groups. A broad preliminary database search of 169
114 Kidney function, specifically glomerular filtration rate key words was performed, followed by a refined search 170
115 (GFR), estimated using creatinine (eGFRcr) is often using the MesH Advanced Search Builder (Table S1). We 171
116 inaccurate in people with acute and chronic illness. The included additional studies received from experts. 172
117 accuracy of estimates using cystatin C alone (eGFRcys) 173
118 or together with creatinine (eGFRcr-cys) is not well Study Selection 174
119 studied in these populations. We conducted a system- The target population included both adults and children 175
120 atic review to address the knowledge gap. Of the 179 with acute or chronic illness other than CKD. Studies were 176
121 papers reviewed, we identified 26 studies in clinical eligible if they (1) included mGFR using plasma or urinary 177
122 populations with cancer (n=5); HIV (n=5); cirrhosis
clearance of an exogenous filtration marker (iothalamate, 178
123 iohexol, dextran, 51Cr-ethylenediaminetetraacetic acid 179
(n=3); liver transplant (n=3); heart failure (n=2);
124 [EDTA], 99mTc-diethylenetriamine pentaacetate [DTPA]) 180
125 neuromuscular disease (n=1); critical illness (n=5); and as the reference standard; (2) used estimating equations 181
126 obesity (n=2). In general, eGFRcr-cys improved the that were developed using assays for serum creatinine and 182
127 GFR estimation in HIV, cancer, and obesity, providing cystatin C that were standardized to international reference 183
128 indications for cystatin C measurement. Performance materials; (3) used assays for standardized serum creati- 184
129 was poor in many studies, suggesting the need for more nine and cystatin C assays in the study population; (4) 185
130 frequent measured GFR. reported at least 1 performance metric relative to mGFR 186
131 (ie, bias or P30); and (5) were original research articles 187
132 A decade ago, we performed a systematic review to
published in English. Of eligible studies, we excluded 188
133 summarize available data to compare the performance of
those in populations outside the scope of this review. 189
134 eGFRcys, eGFRcr, and eGFRcr-cys relative to mGFR in
Because our goal was to focus on populations with acute 190
135 general and clinical populations. At the time, we reviewed
and chronic illness, we excluded studies of ambulatory 191
136 8 studies in all; 2 were in healthy volunteers and 6 were in
clinical populations or research studies in populations with 192
137 patients with CKD (n=1), diabetes (n=1), cystic fibrosis
CKD (including kidney transplant recipients) or diabetes, 193
138 (n=1), Fabry disease (n=1), HIV (n=1), and liver trans-
kidney donor candidates, and community-based cohorts 194
139 plant patients (n=1). We found mixed results as to
(Fig S1). For papers that reported on key subgroups, we 195
140 whether eGFRcys performed better than eGFRcr in general
report each subgroup as a separate study (here on in 196
141 and CKD populations, and in populations with chronic
referred to as studies). Within some studies, results for 1 197
142 illness. Of importance, comparisons were limited by use of
or more equations are reported; thus performance of each 198
143 assays for creatinine and cystatin C that were not traceable
equation is a unit of analysis (here on in referred to as 199
144 to reference materials, small sample sizes, and variation in
reports). 200
145 metrics to evaluate equation performance. We thought it 201
146 timely to reassess this question given that growing interest
Data Extraction and Quality Assessment 202
147 in the use of cystatin C has sparked national efforts to Two authors (OMA and ERB) reviewed the titles and 203
148 facilitate its increased, routine, and timely use in clinical abstracts for initial study selection. The final list of selected 204
149 practice.6 The goal of our study was to update our studies was discussed with the corresponding author (LAI) 205
150 assessment of the comparative performance of eGFRcr, to rule out discrepancies and for additional validation. Full- 206
151 eGFRcys, and eGFRcr-cys equations relative to mGFR in text papers were reviewed to assess risk of bias using the 207
152 populations with acute or chronic illness in which eGFRcr national institute of health quality assessment tool for 208
153 may be inaccurate. We then use these results to make some observational cohort and cross-sectional studies (Item 209
154 suggestions for the use of cystatin C and measured GFR in S1).21 Data was extracted from eligible studies and 210
155 clinical practice. inputted into a spreadsheet created to capture pertinent 211
156 information. For each study, we collected data on the study 212
157 details (eg, study design, sample size, population, and 213
158 METHODS location), patient characteristics (eg, age, sex, and 214
159 The methods and reporting in this review follow Preferred ethnicity), laboratory methods (eg, creatinine, cystatin C, 215
160 Reporting Items for Systematic Reviews and Meta-Analyses and GFR measurement methods), eGFR equations, and the 216
161 (PRISMA) guidelines. The study was registered on PROS- measured outcomes. 217
162 PERO (ID CRD42023414735). 218
163 Metrics for Performance Relative to Measured GFR 219
164 Data Sources and Searches Many metrics are used to assess performance of eGFR 220
165 We used the PubMed or MEDLINE database to conduct a equations relative to mGFR. We used bias and P30 because 221
166 comprehensive search of literature published from 2011 to they were reported most consistently. Bias was defined as 222
167 date that evaluated the performance of eGFRcr, eGFRcys, the median or mean difference of eGFR − mGFR. Where 223
168 224

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bias was defined otherwise (ie, mGFR − eGFR), we con- Performance of GFR Estimating Equations
225 verted to former for consistency. Thus, a positive bias The bias and P30 of eGFRcr, eGFRcys, and eGFRcr-cys 281
226 denotes an overestimate of mGFR and negative bias an varied across the 26 studies in acute and chronic illness 282
227 underestimate. To facilitate comparisons, bias was further populations (Figs 1 and 2). Overall, there were 30 reports Q3283
228 categorized by its magnitude into small (less than +/− of bias for eGFRcr, 27 for eGFRcys, and 22 for eGFRcr-cys. 284
229 5 mL/min/1.73 m2), medium (+/− 5 to +/− 10 mL/ 21 (69%) of the 30 eGFRcr reports showed moderate or 285
230 min/1.73 m2), and large (greater than +/− 10 mL/min/ large bias, with the majority (81%) showing an over- 286
231 1.73 m2). For comparison among the equations, we use estimate of mGFR. Fifteen of the 27 (54%) eGFRcys re- 287
232 small bias (regardless of over or underestimate), medium ports demonstrated moderate or large bias with majority 288
233 overestimate, medium underestimate, large overestimate, (73%) showing an underestimate of mGFR. Fourteen of 289
234 or large underestimate. P30 was defined as the proportion the 22 (61%) eGFRcr-cys reports showed moderate-to- 290
235 of eGFR within 30% of mGFR. P30 was further categorized large bias, with the majority (64%) showing an underes- 291
236 by magnitude into high (90%), moderate (80%-89%), timate of mGFR. There was a similar number of reports of 292
237 and low (< 80%). P30 from 75%-80% to 90% has been P30 overall, as with bias for eGFRcr and eGFRcys. eGFRcr- 293
238 considered to be adequate for decision-making in many cys had one additional report of P30.23 None of the eGFRcr Q4294
239 clinical circumstances; P30 >90% is considered optimal.22 reports had high P30, but 2 of the 26 (7%) reports for 295
240 eGFRcys and 5 of the 23 (21%) reports for eGFRcr-cys 296
241 reported a high P30. 297
RESULTS
242 298
243 We reviewed 179 titles and abstracts, 44 of which qualified
Cancer 299
244 for full-text review (Fig S1). After full-text review, 24 papers
There were 5 publications of cancer populations.24-27 Two 300
245 matched the eligibility criteria. Table S2 shows the reasons for
studies were in hematopoietic stem cell transplant recipients, 301
246 exclusion. Of the 14 studies excluded for use of unstandard-
and 4 were in blood and solid organ cancer patients. Four 302
247 ized cystatin C measures, 4 were performed after the avail-
were conducted in Japan and 1 in Brazil, and 4 were in adults 303
248 ability of cystatin C assays traceable to reference materials.23 304
and 1 in children. Of the 5 reports in Japan, only 2 used
249 Two of the 24 papers evaluated 2 subgroups, respectively;
modifications of equations recommended for Japan. 305
250 hence, we reported these 2 papers as 4 studies. Thus, we
Among the 4 reports in adults, the direction and 306
251 Q2 included 26 studies in our final evaluation (Table 1).24-47 The 307
magnitude of bias varied. For eGFRcr, 1 report showed
252 bias of included papers is shown in Table S3.
small bias and the others showed moderate to large over 308
253 The 26 studies were conducted between 1988 and
or- underestimate of mGFR. For eGFRcys, 3 reports 309
254 2020 and include the following comorbid illnesses: cancer
showed small bias and 1 report showed moderate under- 310
255 (n=5); HIV (n=5); cirrhosis (n=3); liver transplant (n=3);
estimate. For eGFRcr-cys, there were 3 reports, with 1 311
256 heart failure (n=2); critical illness (n=5); neuromuscular
showing small bias and the other 2 showing moderate 312
257 disease (n=1); and obesity (n=2). Most were adult only
underestimates. The P30 for eGFRcr-cys was moderate to 313
258 studies; however, some were in children or both children
high (81%-92%). 314
259 and adults. Of note, only 13 studies had a sample size of 315
260 more than 100. 316
HIV
261 317
262 GFR Estimating Equations Evaluated Five publications of adults with HIV were included. Three 318
263 A total of 17 eGFR equations developed by 8 research were conducted in North America, one in Europe, and one 319
264 groups were evaluated across the 26 studies (Fig S1; in Japan.28-32 Among the 4 reports from North America 320
265 Table 2).48-58 This included 5 adult, 3 pediatric, and 1 full and Europe, the direction and magnitude of bias for 321
266 age spectrum eGFRcr equation; 2 adult, 2 pediatric, and 1 eGFRcr, eGFRcys, and eGFRcr-cys varied. The P30 was 322
267 full age spectrum eGFRcys equation, and 2 adult and 1 moderate to high in all reports for eGFRcr-cys (81%-91%) 323
268 pediatric eGFRcr-cys equation. Furthermore, 9 of the and 4 of 5 reports for eGFRcys (80%-93%).28-32 324
269 equations evaluated were developed in North American 325
270 populations, 4 in Japanese populations, and 4 in European Cirrhosis and Liver Transplant Recipients 326
271 populations. Of note, a few studies used equations that Six publications of populations with liver disease were 327
272 were not developed specifically for their geographic pop- included (3 with cirrhosis and 3 with liver transplants). 328
273 ulation, even though geographic-specific equations exis- For adults with cirrhosis and liver transplant,33-37 the di- 329
274 ted. For instance, a study of Japanese cancer patients used rection and magnitude of bias of eGFRcr, eGFRcys, and 330
275 the CKD-EPI equations, when known Japanese modifica- eGFRcr-cys varied. The range for P30 was low for eGFRcr 331
276 tions of these equations exist. Because the MDRD study (41%-76%), and low to moderate for eGFRcr-cys, and 332
277 equation was not reported by itself and was not recom- eGFRcys (60%-86%, and 42%-83%, respectively). For 333
278 mended over the era in which these studies were con- children with transplants, eGFRcr had a small bias or large 334
279 ducted, we report on its performance only in overestimation, whereas all eGFRcys showed small bias. 335
280 supplementary information (Figs S2 and S3). P30 for eGFRcys was moderate (86%-88%), whereas P30 336

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Table 1.
4

nnn Q6

GFR Measurement Measured

Method Filtration Marker GFR, mL/min/
Author, year Study Period N Age, y Male, n (%) (Clearance Method) 1.73m2
Cancer
Shibata et al24 (2015) 2007-2010 41 66 (7.3) 26 (63) Inulin (U) 76.3 (26.4)
Hingorani et al25 (2015) 2009-2013 50 55 (23-72)a 38 (76) Iohexol (P) 99.9 (24.6)
Hingorani et al25 (2015)b 2009-2013 35 55 (23-69)a 28 (80) Iohexol (P) 86.1 (28.9)
Matsuoka et al26 (2020)b 2016-2019 17 11 (5-17)a 9 (53) Inulin (U) 105.8 (22.8)
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Costa et al27 (2021) 2015-2017 1200 59 (13) 611 (51) 51

Cr-EDTA (P) 78.5 (21.7)
HIV
Inker et al28 (2012) 2009-2011 200 48 (8) 145 (73) Iohexol (P) 87 (26)
Bhasin et al29 (2013) Nr 187 49 (45-53)a 121 (65) Iohexol (P) 101 (85-116)a
Gagneux-Brunon et al30 (2013) 2011-2012 203 49 (10) 166 (82) Iohexol (P) 95 (24)
Yukawa et al31 (2018) 2014 15 46 (42-46.5)a 15 (100) Inulin (U) 84.6 (77.3-97.6)a
Lucas et al32 (2020) 2010-2019 222 50 (45-54)a 145 (65) Iohexol (P) 88 (74-100)8
Cirrhosis
De Souza et al33 (2014) 2010-2012 202 56 (19-72)a 145 (72) Inulin, U 83 (6-167)a
Torre et al34 (2016) 2013-2014 91 51 (12) 43 (47) 99m
Tc-DTPA (U) 71.7 (28.1)
St€ammler et al35 (2023) 2012-2019 203 59 (13) 90 (63) Iothal (U)/ Inulin (U) 62.5 (26.5)
Liver Transplant
Wagner et al36 (2012) 2008-2010 49 men: 54 (30-64); 33(67) Inulin (P) 60.1 (10.9-97.8)a
women: 54 (41-69)a
Allen et al37 (2015) 1988-2010 401 56 (11) 229 (57) Iothal (U) 49 (34-65)
Bluhme et al38 (2021) 2007-2015 91 13.9 (8.3) 48 (53) Iohexol (P) 96 (40.5)
Heart Failure
Kervella et al39 (2017) 2012-2016 66 67 (14) 48 (73) Inulin (U) 26 (11)
Swolinsky et al40 (2021) 2019 38 72 (14) 29 (76) Dextran (P) 35 (12)
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Neuromuscular Disease
Aldenbratt et al41 (2021) 2010-2014 145 46 (14) 68 (47) Iohexol (P) 81 (19)
Critical Illness
Delanaye et al42 (2014) Nr 47 62 (17) 25 (53) Iohexol (U) 96 (54)
Carlier et al43 (2015) 2005; 2008-2009 68 58 (39-68)a 46 (68) Inulin (U) 80 (31-114)a
Ravn et al44 (2019) 2013-2014 30 67 (54-72)a 14 (47) Iohexol (P) 84.5 (64-104)a
Sangla et al45 (2020) 2018-2019 63 66 (54-75)a 43 (68) Iohexol (P) 51.5 (19.3-85.6)a
Haines et al46 (2023) 2019-2020 27 51 (38-63)a 25 (66)a Iohexol (P) 58 (39-70)a
Obesity
Chang et al47 (2020) (prebariatric) Nr 27 46.2 (10.8) 9 (33) Iohexol (P) 84.1 (22.0)

Adingwupu et al
Chang et al47 (2020) (postbariatric) Nr 27 47.1 (10.8) 9 (33.3) Iohexol (P) 89.2 (19.9)
Note: Age and measured GFR are expressed as mean (SD) or median (IQR or range). Male is expressed as N (percent). Creatinine and cystatin C assays used in all studies were calibrated to certified reference materials such as
IDMS for creatinine and ERM4-DA471/IFCC for cystatin C.
Abbreviations: NR, not reported; P, plasma clearance; U, urine clearance; GFR, glomerular filtration rate; DTPA, diethylenetriamine penta-acetate; EDTA, ethylenediamine tetra-acetic acid; Iothal, iothalamate.
a
Presented as median values.
b
Presented as hematopoietic stem cell transplant studies.
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Table 2. Characteristics of Estimating GFR Equations Evaluated
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Adingwupu et al
Development Dataset
GFR
Measurement
Method Filtration
Marker
mGFR mL/ (Clearance Validation
Equation, Y Population n Age, y min/1.7m2 Method) Dataset n Variables
Creatinine
MDRD,48,49 2006 CKD (adults) 1,070 50.6 ± 12.7 39.8 ± 21.2 Iothal (U) 558 (I) Cr, age, sex, and race
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CKD-EPI,49 2009 CKD and non-CKD (adults) 8,254 47 ± 15 68 ± 40 Iothal (U) 3771 (E) Cr, age, sex, and race
Matsuo,50,c 2009 CKD or healthy kidney 413 51.4 ± 16.5 59.1 ± 35.4 Inulin (U) 350 Cr, age, and sex
donors (adults)
CkiD,51 2009 CKD (children) 349 10.8 (7.7- 41.3 (32.0-51.7)a Iohexol (P) 168(I) Cr and height
14.3)a
Lund-Malmo Referred for GFR evaluation 850 60 (26-85) 55 (9-121)b Iohexol (P) 850 (I) Cr, age, and sex
Revised,52 2011 (adults)
Lyon,53 2012 CKD or referred for GFR 360 12.7 (9.5- 86 (65-109)a Inulin (U) 109 (E) Cr, sex, age, and
evaluation (children) 15.3)a height
Uemura,54,c 2014 CKD (children) 131 10.8 (7.5- 66.6 (46.5-93.5)a Inulin (U) 131(I) Cr
13.9)a
FAS,55 2016 CKD or general population NA 1- ≥70 53-95b Inulin (U), Iothal 6,870 Cr and Q
(adults and children) (P/U), and
Iohexol (P)
CKD-EPI,17 2021 CKD and non-CKD (adults) 8,254 47 ± 15 68 ± 40 Iothal (U) 4,050 (E) Cr, age, and sex
Cystatin C
CKiD,18 2012 CKD (children) 643 1-16b 43.3 (32.6-55.6)a Iohexol (P) 322 (I) Cys
CKD-EPI,16 2012 CKD (adults) 5,352 47 ± 15 68 ± 39 Iothal (U) 1,119 (E) Cys, age, and sex
Horio,56,c 2013 CKD (adults) 413 51 ± 17 59 ± 35 Inulin (U) 350 (E) Cys, age, and sex
Uemura,57,c 2014 CKD (children) 135 10.6 (7.0- 66.3 (46.1-93.3)a Inulin (U) 135 (I) Cys
13.7)a
CAPA,58 2014 CKD or referred for GFR 3,164 2-86b 9-200b Iohexol (P) 1,796 (E) Cys and age
evaluation (adults and Inulin (P/U)
children)
Creatinine-
Cystatin C
CKiD,18 2012 CKD (children) 643 1-16b 43.3 (32.6-55.6)a Iohexol (P) 322 (I) Cr, Cys, BUN, height,
and sex
CKD-EPI,16 2012 CKD (adults) 5,352 47 ± 15 68 ± 39 Iothal (U) 1,119 (E) Cr, Cys, age, sex, and
race
CKD-EPI,17 2021 CKD and non-CKD (adults) 5,352 47 ± 15 68 ± 39 Iothal (U) 4,050 (E) Cr, Cys, age, and sex
Note: Data are presented as mean (standard deviation or range), median (IQR), and N (percent).
Abbreviations: Cys, Cystatin C; Cr, creatinine; E, external validation; I, internal validation; P, plasma clearance; U, urine clearance; Iothal, iothalamate; NA, not applicable; CKD, chronic kidney disease; GFR, glomerular filtration rate;
mGFR, measured GFR.
a
Indicates median (IQR).
b
Indicates range.
c
Indicates Japanese equations.
5

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 Adingwupu et al

Study, year Country GFR N Age Creatinine Cystatin C Creatinine-Cystatin C

561 measurement
method
Equations Bias Equations Bias Equations Bias 617
562 Cancer 618
563 Shibata, 201524 Japan Inulin (U) 41 A Japanese eGFR
(Matsuo)
0.01
Japanese eGFR
(Horio)
0.1
_
_ 619
hematological cancer
564 Hingorani, 2015 25 Japan Iohexol (P) 50 A CKD-EPI 2009 -15.6 CKD-EPI 2012 -1.1 CKD-EPI 2012 -7.9
620
565 hematological cancer (-21.4, -9.8) (-7.9, 5.8) (-13.1,-2.7) 621
Japan Iohexol (P) 35 A CKD-EPI 2009 CKD-EPI 2012 CKD-EPI 2012
566 622
25
Hingorani, 2015 -8 -7.1 -8.2
HSC (-15.1, -0.9) (-15.4, 1.2) (-15.1, -1.3)
567 Matsuoka, 202026 Japan Inulin (U) 17 C Bedside CKiD 50.4 CKiD −16.7 CKiD 9.1 623
568 HSC (38.6, 62.1) (−24.1, −9.2) (1.9, 16.3) 624
Uemura 27.7 Uemura 20.2 _
569 (16.1, 39.2) (10.8, 29.5)
_ 625
570 Costa e Silva, 2021 27 Brazil EDTA (P) 1200 A CKD-EPI 2009 8.1 CKD-EPI 2012 -4.6 CKD-EPI 2012 2 626
571 solid organ cancer
HIV
(7.1, 8.9) (-5.5, -3.7) (1.1, 2.6)
627
572 Inker, 201228 USA Iohexol (P) 200 A CKD-EPI 2009 -5.4 CKD-EPI 2012 -4.3 CKD-EPI 2012 -6.4 628
573 (-7.9, -2.9) (-7.7, -1.2) (-9.3, -3.1) 629
Bhasin, 201332 USA Iohexol (P) 187 A CKD-EPI 2009 -1.1 CKD-EPI 2012 -16.3 CKD-EPI 2012 -7.2
574 (-12.4, - 10.4) (-27.8, -1.8) (-19.8, - 2.2)
630
575 Gagneuax-Brunon, 201329 France Iohexol (P) 203 A CKD-EPI 2009 2.6 CKD-EPI 2012 1.2 CKD-EPI 2012 2.5 631
576 Yukawa, 201830 Japan Inulin (U) 15 A Japanese eGFR
(Matsuo)
-23.6
((-34.1, -16.1))
Japanese eGFRcys
(Horio)
-0.6
(-8.3, 1.3)
_
_ 632
577 USA Iohexol (P) 222 A CKD-EPI 2009 8.7 CKD-EPI 2012 -3.8 CKD-EPI 2012 2.2 633
578 Lucas, 202031 (6.8, 10.6) (-5.8, -1.7) (0.6,3.8) 634
Cirrhosis
579 De Souza, 201433 France Inulin (U) 202 A CKD-EPI 2009 - CKD-EPI 2012 - CKD-EPI 2012 - 635
580 Torre, 201634 Mexico DTPA (U) 91 A CKD-EPI 2009 29.6 CKD-EPI 2012 -1.4 CKD-EPI2012 11.7 636
581 USA & Iothal (U) 203 A CKD-EPI2009
((24.6, 34.6))
_
(-6.4, 3.5)
CKD-EPI2012
((7.4, 16.1))
637
Stammler, 202337 1 -6
582 France (-1, 3)
_
(-8, -5) 638
583 CKD-EPI2021 4 _
_
CKD-EPI2021 -4 639
584 Liver Transplant
(2, 7) (-6, -3)
640
585 Wagner, 201236 Austria Inulin (U) 49 A CKD-EPI 2009 13.9 CKD-EPI 2012 -12.2 _ _ 641
586 Allen, 201535* USA Iothalamate (U) 401 A CKD-EPI 2009 8.2 CKD-EPI 2012 -27.9 CKD-EPI 2012 -12.3
642
(6.2, 10.2) (-25.9, -29.8) (-10.6, -14.0)
587 Bluhme, 202138 Sweden Iohexol (P) 91 C CKiD/MDRD 18.5 CKD-EPI2012 0.2 _ 643
_
588 (14.6, 22.3) (-3.0, 3.3) 644
Lyon 4 CAPA 3.1 _
589 (0.5, 7.6) (-0.4, 6.6)
_ 645
590 FAS 13.5 _
_
_
_
646
591 (9.1, 18.0)
647
Heart Failure
592 Kervella, 201739 France Inulin (U) 66 A CKD-EPI 2009 15.2 CKD-EPI 2012 4.1 CKD-EPI 2012 7.8 648
593 (11.5, 19.0) (1.6, 6.5) (5.6, 10.1) 649
Swolinsky, 202140 Germany Dextran (P) 38 A CKD-EPI2009 CKD-EPI 2012 -4 CKD-EPI 2012 -0.4
594 Neuromuscular Disease
5.4
650
595 Aldenbratt, 202241 Sweden Iohexol (P) 145 A CKD-EPI2009 27 CAPA 22.2 CAPA+CKD- 26.1 651
EPI2009
596 (24, 35) (19.1, 25.2) (23.6, 29.1) 652
Critical Illness
597 Delanaye, 201442 Belgium & Iohexol (U) 47 A CKD-EPI 2009 1 CKD-EPI 2012 -26 CKD-EPI 2012 -12 653
598 43
France
Belgium Inulin (U) 68 A CKD-EPI 2009 CKD-EPI 2012 CKD-EPI 2012
654
Carlier, 2015 23.4 -9.3 3.9
599 ((10.5, 29.7)) ((-17.2, -3.7)) (-1.3, 9.5) 655
600 Ravn, 201945 Sweden Iohexol (P) 30 A LM-REV 8 CAPA -26 CKD-EPI2012 -10 656
601 CKD-EPI2009
(-4.2, 16.2)
14 CKD-EPI2012
(-30.4, -19.7)
-25 CAPA+LM-REV
(-17.1, -0.6)
-11.5
657
602 (2.2, 24.1) (-32.3, -20.3) (-19.6, -0.1) 658
603 Sangla, 2020 44 Switzerland Iohexol (P) 63 A CKD-EPI 2009 24 CKD-EPI 2012 11 CKD-EPI 2012 17 659
( -37, 84) (-40, 63) (-30, 64)
604 Haines, 202346 United Iohexol (P) 27 A CKD-EPI 2021 59 CKD-EPI 2012 22
660
605 Kingdom (49, 69) (13, 31) 661
web 4C=FPO

606 Obesity
USA Iohexol (P) 27 A CKD-EPI 2009 CKD-EPI 2012 CKD-EPI 2012
662
Chang, 202047 3.6 −8.1 -4
607 Pre-bariatric (−3.2, 8.9) ((−16.1, −0.9)) (-8.0, 0.7) 663
608 Chang, 2020 47 USA Iohexol (P) 27 A CKD-EPI 2009 8.4 CKD-EPI 2012 -10.7 CKD-EPI 2012 -1.9 664
(-7.6, 3.8)
609 Post-bariatric (1.5, 12.3) (-16.2, -5.5)
665
610 Figure 1. Bias creatinine and cystatin c estimating GFR equations by clinical population. Bias was defined as the median or mean 666
611 difference between eGFR and mGFR (ie, eGFR − mGFR medium underestimate). Positive bias denotes overestimate and negative 667
612 bias underestimate. * Bias in study given as %Bias (ln). Units are mL/min/1.73m2 for bias. (Green box) indicates small bias with 668
613 magnitude of median difference of between −5 and +5 mL/min/1.73 m2; (yellow box) indicates medium underestimate as me- 669
614 dian difference of −5 to −10 mL/min/1.732m2. (spotted yellow box) indicates medium overestimate as median difference of 670
615 671
616 672

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Study, year Country N Age Creatinine Cystatin C Creatinine-Cystatin C

673 Equations Accuracy, P 30 Equations Accuracy, P 30 Equations Accuracy, P 30 729
674 Cancer
730
Shibata, 201524 Japan 41 A Matsuo _ Horio _ _ _
675 hematological cancer
731
676 Hingorani, 201525 Japan 50 A CKD-EPI 2009 79 CKD-EPI 2012 76 CKD-EPI 2012 89 732
677 hematological cancer 733
Hingorani, 201525 Japan 50 A CKD-EPI 2009 82 CKD-EPI 2012 CKD-EPI 2012 84
678 HSC
72
734
679 Matsuoka, 202026 Japan 17 P Bedside CKiD 23 CKiD 81 CKiD 81 735
680 HSC Uemura 55 Uemura 61 _ _ 736
681 Costa e Silva, 202127 Brazil 1200 A CKD-EPI 2009 81 (79, 83) CKD-EPI 2012 88 (86, 90) CKD-EPI 2012 92 (91, 94)
737
solid organ cancer
682 HIV
738
683 Inker, 201228 USA 200 A CKD-EPI 2009 85 (80, 90) CKD-EPI 2012 83 (77, 88) CKD-EPI 2012 90 (86, 94) 739
684 Bhasin, 201332 USA 187 A CKD-EPI 2009 89 (83, 93) CKD-EPI 2012 79 (72, 85) CKD-EPI 2012 91 (85, 94) 740
Gagneuax-Brunon, 201329 France 203 A CKD-EPI 2009 82 CKD-EPI 2012 80 CKD-EPI 2012 81
685 Yukawa, 201830 Japan 15 A Matsuo Horio 93 (79, 100) _ _
741
40 (12, 68)
686 Lucas, 202031 USA 222 A CKD-EPI 2009 79 (76, 82) CKD-EPI 2012 83 (80, 85) CKD-EPI 2012 88 (86, 91) 742
687 Cirrhosis 743
688 De Souza, 201433 France 202 A CKD-EPI 2009 56 CKD-EPI 2012 83 CKD-EPI 2012 78 744
Torre, 201634 Mexico 91 A CKD-EPI 2009 41 (30, 51) CKD-EPI 2012 63 (52, 73) CKD-EPI 2012 60 (50, 71)
689 Stammler, 202337 USA & 203 A CKD-EPI 2009 (
75 (69, 81)) _ _ CKD-EPI 2012 86 (81, 91) 745
690 France CKD-EPI 2021 74 (68, 80) _ _ CKD-EPI 2021 86 (81, 90) 746
691 Liver Transplant 747
Wagner, 201236 CKD-EPI 2009 CKD-EPI 2012 _
692 Austria 49 A 52 42 _
748
Allen, 201535 USA 401 A CKD-EPI 2009 76 (72, 79) CKD-EPI 2012 60 (56, 64) CKD-EPI 2012 84 (82, 87)
693 Bluhme, 202138 Sweden 91 P CKiD/MDRD 68 (61, 75) CKD-EPI 2012 86 (82, 91) _ _ 749
694 Lyon 84 (79, 89) CAPA 88 (83, 92) _ _ 750
695 FAS 68 (60, 77) _ _ _ _
751
Heart Failure
696 Kervella, 201739 France 66 A CKD-EPI 2009 33 (23,
( 45)) CKD-EPI 2012 65 (53,
( 76)) CKD-EPI 2012 52 (40,
( 63))
752
697 Swolinsky, 202140 Germany 38 A CKD-EPI 2009 66 CKD-EPI 2012 56 CKD-EPI 2012 74 753
698 Neuromuscular Disease 754
CKD-EPI2009 37 (30, 46) CAPA 49 (41, 57) CAPA+ CKD- 44 (35, 51)
699 Aldenbratt, 202241 Sweden 145 A
EPI2009
755
700 Critical Illness 756
701 Delanaye, 201442 Belgium&
France
47 A CKD-EPI 2009 60 CKD-EPI 2012 53 CKD-EPI 2012 62
757
702 Carlier, 2015 43
Belgium 68 A CKD-EPI 2009 40 (29, 52) CKD-EPI 2012 45 (33, 57) CKD-EPI 2012 54 (11, 65) 758
703 Ravn, 201945 Sweden 30 A LM-REV 67 (49, 81) CAPA 47 (30, 64) CKD-EPI2012 80 (63, 91) 759
CKD-EPI2009 CKD-EPI2012 87 (70, 95)
704 63 (46, 78) 43 (27, 61) CAPA+LM-REV
760
Sangla, 202044 Switzerland 63 A CKD-EPI 2009 44 CKD-EPI 2012 46 CKD-EPI 2012 56
705 Haines, 202346 United 27 A CKD-EPI 2021 CKD-EPI 2012 _ 761
_ _ _
706 Kingdom 762
web 4C=FPO

707 Obesity
763
Chang, 202047 USA 27 A CKD-EPI 2009 85 (70, 96) CKD-EPI 2012 78 (59, 93) CKD-EPI 2012 93 (81, 100)
708 Pre-bariatric 764
709 Chang, 202047 USA 27 A CKD-EPI 2009 85 (70, 96) CKD-EPI 2012 93 (81, 100) CKD-EPI 2012 93 (81, 100) 765
710 Post-bariatric 766
711 767
Figure 2. Accuracy of creatinine and cystatin C estimating GFR equations by clinical population. Accuracy was defined as the pro-
712 768
portion of eGFR within 30% of mGFR (P30). Where defined as 1-P30, we converted it to P30 for consistency. Units are percent for P30.
713 Green box indicates high accuracy with P30 of magnitude > 90%. Yellow box indicates moderate accuracy with P30 of
769
714 magnitude 80%-90 %; (red box) indicates low accuracy with P30 of magnitude less than 80%. GFR, glomerular filtration rate; 770
715 mGFR, measured GFR; eGFR, estimated GFR. 771
716 772
717 was low to moderate for eGFRcr (68%-84%). The eGFRcr- all 3 equations (33%-66%, 52%-74%, and 56%-65%, 773
718 cys was not reported.38 respectively).39,40 774
719 775
720 Heart Failure Neuromuscular Disease 776
721 Two studies of adults with heart failure in Europe were One publication of adults with primary neuromuscular 777
722 included. For eGFRcr and eGFRcr-cys, the 2 reports disease in Europe was included. A large overestimation 778
723 showed small bias or moderate-to-large overestimates. The with low P30 (all < 50%) was observed for eGFRcr, 779
724 bias was small for both reports of eGFRcys. P30 was low for eGFRcys, and eGFRcr-cys.41 780
725 781
726 5-10 mL/min/1.732m2. Red box indicates large underestimate as median difference of less than −10 mL/min/1.732m2 (ie, 782
727 greater magnitude than less than −10). Spotted red box indicates large overestimate as median difference of greater 783
728 than 10 mL/min/1.73 m2. HSC, hematopoietic stem cell transplant; A, adult; C, children. 784

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Table 3. Indications for Measurement of Cystatin C

785 Specific Clinical Cause of Decreased Comments on GFR Evaluation for 841
786 Domain Condition Accuracy Individual Patients 842
787 Body habitus and Anorexia nervosa68 non-GFR determinants eGFRcys may be appropriate if no comorbid 843
788 changes in muscle of Scr illness other than reduction in muscle mass 844
789 mass Extreme sport/exercise/ non-GFR determinants eGFRcys may be appropriate if increase in 845
790 body builder of Scr muscle mass is the only abnormality 846
791 Above knee amputation67 non-GFR determinants eGFRcys may be appropriate in those 847
of Scr without other comorbid conditions
792 Suggest eGFRcr-cys in those with comorbid 848
793 illness 849
794 Spinal cord injury with non-GFR determinants eGFRcys may be appropriate in those 850
795 paraplegia/paraparesis of Scr without other comorbid illness 851
or quadriplegia/ Suggest eGFRcr-cys in those with comorbid
796 quadriparesis illness
852
797 Class III obesity47 non-GFR determinants eGFRcr-cys demonstrated to be most 853
798 of Scr and Scys accurate 854
799 Lifestyle Smoking3,8,69 non-GFR determinants Minimal data but suggest eGFRcr if no 855
800 of Scys changes to non-GFR determinants of Scr or 856
801 comorbid illness 857
802 Diet Low protein diet70,71 non-GFR determinants eGFRcys may be appropriate if no changes 858
of Scr to non-GFR determinants of Scr or
803 Keto-diets non-GFR determinants comorbid illness 859
804 of Scr 860
805 Vegetarian non-GFR determinants 861
806 of Scr 862
807 High protein diets and non-GFR determinants 863
808 creatine supplements of Scr 864
809 Illness other than Malnutrition Chronic illness, eGFRcr-cys because of coexistence of 865
CKD presumed effect on non- malnutrition and inflammation
810 GFR determinants of Scr Suggest using mGFR for treatment 866
811 and Scys decisions based on level of GFR 867
812 Cancer24-27 Chronic illness, eGFRcr-cys demonstrated to be most 868
813 presumed effect on non- accurate in populations studied but 869
GFR determinants of Scr likelihood of lesser accuracy in more frail
814 and Scys patients.
870
815 Suggest using mGFR for critical treatment 871
816 decisions based on level of GFR 872
817 Heart failure39,40 Chronic illness, Minimal data but eGFRcys less biased but 873
818 presumed impact on all have low inaccuracy. Suggest using 874
non-GFR determinants eGFRcr-cys or eGFRcys for routine GFR
819 of Scr and Scys evaluation. 875
820 Suggest using mGFR for critical treatment 876
821 decisions based on level of GFR 877
822 Cirrhosis or liver Chronic illness, Minimal data but eGFRcys less biased but 878
823 transplant33-38 presumed effect on non- all have low inaccuracy. Suggest using 879
GFR determinants of Scr eGFRcr-cys or eGFRcys for routine GFR
824 and Scys evaluation. 880
825 Critical illness42-46 Chronic illness, Minimal data but suggests eGFRcr and 881
826 presumed effect on non- eGFRcys have bias and low accuracy. 882
827 GFR determinants of Scr Suggest using mGFR for treatment 883
and Scys decisions based on level of GFR
828 884
HIV28,29,30-32 Chronic illness, eGFRcr-cys demonstrated to be most
829 presumed effect on non- accurate in populations studied but 885
830 GFR determinants of Scr likelihood of lesser accuracy in more frail 886
831 and Scys patients. 887
832 Suggest using mGFR for critical treatment 888
decisions based on level of GFR
833 889
Catabolic consuming Chronic illness, Minimal data but concern that eGFRcr and
834 diseases (eg, TB, presumed impact on eGFRcys have bias. Suggest using eGFRcr- 890
835 hematologic, non-GFR determinants cys for routine GFR evaluation. 891
836 malignancies, and severe of Scr and Scys Suggest using mGFR for treatment 892
837 skin diseases)25,26 decisions based on level of GFR 893
838 (Continued) 894
839 895
840 896

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Table 3 (Cont'd). Indications for Measurement of Cystatin C

897 Specific Clinical Cause of Decreased Comments on GFR Evaluation for 953
898 Domain Condition Accuracy Individual Patients 954
899 Muscle wasting Chronic illness, Minimal data. A study shows large bias for 955
900 diseases41 presumed impact on both eGFRcr and eGFRcys Suggest using 956
901 non-GFR determinants eGFRcr-cys for routine GFR evaluation. 957
of Scr and Scys Suggest using mGFR for treatment
902 decisions based on level of GFR 958
903 Drug effects Steroids (anabolic and non-GFR determinants No data and physiological effect on Scys
959
904 hormone) of Scr. Effect on Scys not unknown, suggest eGFRcr-cys 960
905 known 961
906 Decreases in tubular non-GFR determinants eGFRcys may be appropriate if drug affects 962
907 secretion72 of Scr only creatinine and no comorbid illness 963
908 Broad spectrum non-GFR determinants eGFRcys may be appropriate if drug affects 964
antibiotics that decrease of Scr only creatinine and no comorbid illness
909 extra-renal elimination 965
910 Abbreviations: GFR, glomerular filtration rate; mGFR, measured GFR obtained from plasma or urinary clearance of exogamous filtration markers; eGFR, estimated 966
911 GFR; Scr or cr, creatinine; Scys or cys, cystatin C; TB, tuberculous; BMI, body mass index; CKD, chronic kidney disease. 967
912 968
913 969
914 Critical Illness evaluating the performance of eGFR equations using cys- 970
915 Five publications of adults admitted to intensive care units tatin C, creatinine, or both in 26 studies in populations 971
916 in Europe were included (Fig 1). For both eGFRcr and with acute and chronic illness, including cancer, HIV, 972
917 eGFRcr-cys, 1 reported small bias and the rest showed cirrhosis, liver transplant, heart failure, neuromuscular 973
918 moderate-to-large overestimate. All reports for eGFRcys disease, critical illness, and obesity. The key observations 974
919 showed moderate-to-large underestimate or overestimate. were the following: First, common use of non- 975
920 P30 was low for all reports of eGFRcr (40%-67%) and standardized assays for cystatin C and use of equations 976
921 eGFRcys (43%-53%), and moderate for 2 of the 5 reports developed with nonstandardized assays more than a 977
922 of eGFRcr-cys (80%-87%).42-46 decade following standardization of the cystatin C assay. 978
923 Second, insufficient data for all populations studies, both 979
924 Obesity in terms of the number of studies for any 1 population as 980
925 One publication reported on adults with baseline body well as large inconsistencies in the relative performance of 981
926 mass index ≥ 35 kg/m2 from a single center in North eGFRcr versus eGFRcys even among populations with the 982
927 America before and 6 months after bariatric surgery. same comorbid illness. Third, more reports of moderate- 983
928 Before surgery, there was small bias for eGFRcr and to-large bias for eGFRcr than for eGFRcys and eGFRcr- 984
929 eGFRcr-cys and moderate underestimate for eGFRcys. P30 cys, consistent with selection of study populations for 985
930 was low to high, and higher for eGFRcr-cys than eGFRcr or known variation in non-GFR determinants of serum 986
931 eGFRcys (93% vs 85% and 78%, respectively). After sur- creatinine, and more reports of eGFRcr overestimating 987
932 gery, the magnitude of bias increased for both eGFRcr and mGFR than underestimating mGFR, consistent with 988
933 eGFRcys but decreased for eGFRcr-cys. P30 for eGFRcr-cys decreased creatinine generation. Fourth, possible support 989
934 remained consistent and high (93%).47 for better performance of eGFRcr-cys than eGFRcr or 990
935 eGFRcys among study populations with cancer, HIV, and 991
936 obesity is consistent with findings in the general and 992
937 DISCUSSION populations with CKD, but not for populations with 993
938 The greater accuracy of eGFRcr-cys compared with either cirrhosis, liver transplant, heart failure, neuromuscular 994
939 eGFRcr or eGFRcys was recognized over a decade ago, but disease, and critical illness populations. Fifth, no apparent 995
940 uptake of cystatin C measurement has been slow.59,60 variation in findings across estimating equations devel- 996
941 With the more widespread use of standardized assays,61 oped by different research groups, indicating the main 997
942 the confirmation of greater accuracy of eGFRcr-cys than explanation for our findings relates to the endogenous 998
943 eGFRcr or eGFRcys from independent research filtration markers rather than the specific equations used. 999
944 groups,16,62,63 and the greater importance of use of Our study adds to the previous literature by summarizing 1000
945 eGFRcr-cys compared with race-free eGFRcr in the United available data to support indications for use of cystatin C 1001
946 States, and the recommendation for its use in the most in clinical practice; performance was poor in many 1002
947 recent KDIGO 2023 guidelines, we anticipate substantial studies, suggesting the need for more frequent mGFR in 1003
948 future growth in utilization of cystatin C. However, there these settings. 1004
949 are not explicit indications for when cystatin C should be Compared with our previous systematic review pub- 1005
950 measured, preventing widespread implementation of these lished in 2011, we found improved consistency in 1006
951 recommendations. To provide evidence to support such reporting of performance metrics, with most studies 1007
952 indications, we performed a systematic review of papers reporting measures of bias and P30, and most, but not all, 1008

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1009 1065
1010 1066
1011 1067
1012 1068
1013 1069
1014 1070
1015 1071
1016 1072
1017 1073
1018 1074
1019 1075
1020 1076
1021 1077
1022 1078
1023 1079
1024 1080
1025 1081
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1027 1083
1028 1084
1029 1085
1030 1086
1031 1087
1032 1088
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1035 1091
1036 1092
1037 1093
1038 1094
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1041 1097
1042 1098
1043 1099
1044 1100
1045 1101
1046 1102
1047 1103
1048 1104
1049 1105
1050 1106
1051 1107
web 4C=FPO

1052 1108
1053 1109
1054 1110
1055 1111
1056 Figure 3. GFR evaluation using initial and supportive tests. The algorithm describes the approach to the evaluation of GFR. Our
1112
1057 approach is to use initial and supportive testing to develop a final assessment of true glomerular filtration rate (GFR) and to apply 1113
1058 it in individual decision-making at a single point in time.1 The initial test for evaluation of GFR is often eGFRcr, which will be available 1114
1059 in most patients because creatinine is measured routinely as part of the basic metabolic panel. If the eGFRcr is expected to be inac- 1115
1060 curate, or if a more accurate assessment of GFR is needed for clinical decision-making, such as diagnosis or staging of CKD or drug 1116
1061 dosing, then cystatin C should be measured and the discordance between eGFRcr and eGFRcys should be assessed.69,73 If eGFRcr 1117
1062 and eGFRcys are not discordant (not within 15 mL/min/1.73 m2 or 20%-30% of each other), then accuracy of eGFRcr, eGFRcys, 1118
1063 and eGFRcr-cys is similar. If eGFRcr and eGFRcys are discordant, then eGFRcr-cys is generally more accurate than either eGFRcr 1119
1064 or eGFRcys, with some exceptions, such as otherwise healthy populations with decreased creatinine generation owing to reduced 1120

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reporting 95% confidence intervals around the estimated HIV, and obesity supports possible use of eGFRcr-cys in
1121 value. Use of uniform metrics facilitates comparisons these clinical setting. However, the very ill or frail were 1177
1122 across the studies. We noted greater use of standardized not represented in these cohorts, and it is possible that 1178
1123 assays, although 14 studies were excluded for not using eGFRcr-cys may not be as accurate as observed in the 1179
1124 standardized cystatin C. However, several limitations in the included studies. We suggest more investigations. In the 1180
1125 available data persisted. For many of the included studies, meantime, we suggest increased use of mGFR for GFR- 1181
1126 the cystatin C and GFR measurements were performed based decisions, as for example, in the decisions to use 1182
1127 because of concern that eGFRcr is not accurate, likely of carboplatin versus cis-platinum to avoid kidney toxicity 1183
1128 biasing the results against the eGFRcr. Furthermore, few at low GFR. The lack of studies and low accuracy of eGFR 1184
1129 studies had a large sample size, with only a few studies per in populations with liver disease, heart failure, neuro- 1185
1130 comorbid illness, which limits the generalizability of the muscular disease, or critical illness suggests consideration 1186
1131 reported findings. A further limitation is that only 2 studies of mGFR in these settings, too, as for example in clinical 1187
1132 evaluated the newest of GFR estimating equations, such as decisions surrounding combined heart and kidney or liver 1188
1133 EKFC or 2021 CKD-EPI equations.17,64 Few studies in and kidney transplantation versus heart or liver trans- 1189
1134 children with comorbid illnesses were found during our plantation alone. By contrast, in otherwise healthy pop- 1190
1135 literature search indicating a gap in knowledge for this age ulations with decreased creatinine generation owing to 1191
1136 group. reduced muscle mass, or decreased creatinine secretion 1192
1137 Observed differences between eGFR and mGFR are because of use of specific medications, we would hy- 1193
1138 related to biological or analytical variation in either mGFR pothesize that eGFRcys may be more accurate than 1194
1139 or eGFR (Table S4). Error in eGFR because of biological eGFRcr.67,68 1195
1140 variation in non-GFR determinants of the endogenous With more frequent cystatin C measurement, an algo- 1196
1141 filtration marker is the most likely explanation for our rithmic approach will be helpful to encourage appropriate 1197
1142 findings. We had expected to see poor performance of measurement of cystatin C or mGFR based on accuracy of 1198
1143 eGFRcr as the effect of comorbid illness on muscle mass eGFR, as suggested in Table 3, and the clinical need (Fig 3). 1199
1144 leading to decreased creatinine generation is well-known. The algorithm also provides guidance to physicians if large 1200
1145 The poor performance of eGFRcys and eGFRcr-cys in discordance between eGFRcr and eGFRcys is observed.69,73 1201
1146 many studies suggests that these illnesses are also associ- In such settings, eGFRcr-cys is generally more accurate than 1202
1147 ated with variation in non-GFR determinants of cystatin C, either eGFRcr or eGFRcys, with some exceptions. For 1203
1148 which if present could reduce the accuracy of eGFRcys and example, in otherwise healthy populations with decreased 1204
1149 of eGFRcr-cys. Possibility of analytical variability for both creatinine generation owing to reduced muscle mass, or 1205
1150 exogenous and endogenous filtration markers should also decreased creatinine secretion or extra-renal elimination 1206
1151 be considered. Although we restricted the studies to those because of use of specific medications, eGFRcys may be the 1207
1152 which used standardized assays for both creatinine and most accurate. In addition, a study suggests that in the 1208
1153 cystatin C, there are not traceability programs for exoge- elderly, the lower eGFR, regardless of the marker, may be 1209
1154 nous filtration markers, and thus we could not impose a more likely be to be correct because of higher prevalence of 1210
1155 similar restriction for mGFR. In addition, we included all CKD.69,73-75 If an even more accurate assessment of GFR is 1211
1156 methods for mGFR, despite recognition of variability to needed for clinical decision-making, then GFR should be 1212
1157 each other and the importance of tailoring the protocol for measured using plasma or urinary clearance of exogenous 1213
1158 the population.65 One study in a critical illness population filtration markers, if available. This approach would need to 1214
1159 used plasma clearance of iohexol, known to lead to higher be taken for each time GFR is being used to make important 1215
1160 values in mGFR relative to the true GFR. In this study, large clinical decisions. 1216
1161 differences between eGFR and mGFR were observed, Our data support current recommendations for incor- 1217
1162 which may be potentially due in part to error in poration of cystatin C measurements into routine clinical 1218
1163 mGFR.44,66 testing. In the United States, the National Kidney Foun- 1219
1164 In Table 3,67-72 we list indications for measurement of dation Laboratory Engagement Group has several initiatives 1220
1165 cystatin C. The greater accuracy of eGFRcr-cys in cancer, for widespread education and policy changes.76 Our data 1221
1166 1222
1167 1223
muscle mass, or decreased creatinine secretion or extra-renal elimination because of use of specific medications, when eGFRcys
1168 1224
may be more accurate. If an even more accurate assessment of GFR is needed for a clinical decision, then GFR should be measured
1169 1225
using plasma or urinary clearance of exogenous filtration markers, if available. This consideration should be applied to anytime GFR is
1170 required for a clinical decision. It is important to determine how accurate an assessment of GFR needs to be for a clinical decision. 1226
1171 P30 for eGFR does not generally exceed 90% (90% of eGFR within 30% of mGFR). P15 for mGFR does not generally exceed 90% 1227
1172 (90% of mGFR within 15% of true mGFR). At a GFR of 60 mL/min/1.73 m2, 30% accuracy for eGFR corresponds to 42-78 mL/min/ 1228
1173 1.73 m2 and 15% accuracy for mGFR corresponds to 51-69 mL/min/1.73 m2. At a GFR of 30 mL/min/1.73 m2, 30% accuracy for 1229
1174 eGFR corresponds to 21-39 mL/min/1.73 m2 and 15% accuracy for mGFR corresponds to 26-35 mL/min/1.73 m2. *Use eGFRcr 1230
1175 or eGFRcr-cys depending on discordance between eGFRcr and eGFRcys. 1231
1176 1232

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also reinforce the message that measuring GFR using advisory council for Alport Foundation and the scientific advisory
1233 clearance of exogenous filtration markers is an important board for National Kidney Foundation. Dr Levey serves as Co- 1289
Director of CKD-EPI and reports receiving payment to institution
1234 part of GFR evaluation and would also require increased from the National Institute of Health and the National Kidney 1290
1235 efforts for widespread implementation. The sparsity of data Foundation; honoraria from academic medical centers as a visiting 1291
1236 and well-conducted studies in these clinical populations Professor or Lecturer; payment from AstraZeneca for participation 1292
1237 highlights the need for more high-quality research on on data safety/advisory board for clinical trials of Dapagliflozin. Dr 1293
1238 estimated and measured GFR in populations with acute or Palevsky is the immediate past president of the National Kidney 1294
Foundation and presently serves as a member of the board of
1239 chronic comorbid illness. directors. Dr Vassalotti reports serving as co-investigator for the 1295
1240 CDC Kidney Disease Surveillance Project and principal 1296
1241 SUPPLEMENTARY MATERIAL investigator of Kidney Score Platform for the Veterans Affairs 1297
1242 Supplementary File (PDF) Center for Innovation; receiving consulting fees from Renalytix, Plc 1298
1243 Figure S1. Flow chart of systematic review.
and participation on its clinical advisory board; and serving as 1299
Chief Medical Officer of National Kidney Foundation, Inc. The
1244 Figure S2. Bias creatinine and cystatin c estimating GFR equations remaining authors declare that they have no relevant financial 1300
1245 (including MDRD) by clinical population. interests. 1301
1246 Figure S3. Accuracy of creatinine and cystatin c estimating GFR Peer Review: Received April 21, 2023. Evaluated by 3 external peer 1302
1247 equations (including MDRD) by clinical population. reviewers and an external statistics/methods peer reviewer, with 1303
1248 Item S1. Risk of bias assessment tool. direct editorial input from an Associate Editor, who served as 1304
1249 Table S1. Search Strategy.
Acting Editor-in-Chief. Accepted in revised form September 11, 1305
2023. The involvement of an Acting Editor-in-Chief was to comply
1250 Table S2. Studies Excluded at Full-Text Review. with Kidney Medicine’s procedures for potential conflicts of
1306
1251 interest for editors, described in the Information for Authors and 1307
Table S3. Quality Assessment of Included Papers.
1252 Journal Policies. 1308
Table S4. Factors Affecting Errors in GFR Estimates.
1253 1309
1254 1310
1255 ARTICLE INFORMATION 1311
1256 Authors’ Full Names and Academic Degrees: Ogechi M.
REFERENCES 1312
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Lesley A. Inker, MD MS
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Authors’ Affiliations: Department of Medicine, Division of
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1287 consulting fees from Diamtrix; and participation on the medical Clin J Am Soc Nephrol. 2016;11(2):280-286. 1343
1288 1344

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