Ann Lab Med.  2024 Mar;44(2):135-143. 10.3343/alm.2023.0237.

Exploring Renal Function Assessment: Creatinine, Cystatin C, and Estimated Glomerular Filtration Rate Focused on the European Kidney Function Consortium Equation

• Pottel H
• Delanaye P
• Cavalier E

• KMID: 2553379
• DOI: http://doi.org/10.3343/alm.2023.0237

Abstract

Serum creatinine and serum cystatin C are the most widely used renal biomarkers for calculating the estimated glomerular filtration rate (eGFR), which is used to estimate the severity of kidney damage. In this review, we present the basic characteristics of these biomarkers, their advantages and disadvantages, some basic history, and current laboratory measurement practices with state-of-the-art methodology. Their clinical utility is described in terms of normal reference intervals, graphically presented with age-dependent reference intervals, and their use in eGFR equations.

Keyword

Creatinine; Cystatin C; Estimated glomerular filtration rate, Kidney

Figure

• 

  Fig. 1 Median SCr versus age (black curves) and reference limits (red curves) in healthy women and men [12] (left panels) converted to rescaled SCr/Q (right panels). The dots are the actual data from Pottel, et al. [12]. The median SCr concentration in the left panels corresponds to SCr/Q=1 in the right panels. The lower and upper limits in the left panels correspond to SCr/Q=0.67 and SCr/Q=1.33, respectively, in the right panels. Abbreviations: SCr, serum creatinine; SCr/Q, serum creatinine-to-Q value ratio.

• 

  Fig. 2 GFR versus age. The black curve represents the median eGFR based on the EKFC equation, and the red curves define the reference interval. Abbreviations: GFR, glomerular filtration rate; eGFR, estimated GFR; EKFC, European Kidney Function Consortium.

Reference

1. Jaffe M. 1886; Über den Niederschlag, welchen Pikrinsäure in normalen harn erzeugt und über eine neue Reaction des Kreatinins. Z Physiol Chem. 10:391–400. DOI: 10.1515/bchm1.1886.10.5.391.

2. Folin O. 1905; Approximately complete analyses of thirty "normal" urines. Am J Physiol. 13:45–65. DOI: 10.1152/ajplegacy.1905.13.1.45.

3. Delanaye P, Cavalier E, Pottel H. Serum creatinine: not so simple! Nephron. 2017; 136:302–8. DOI: 10.1159/000469669. PMID: 28441651.

4. Hoste L, Deiteren K, Pottel H, Callewaert N, Martens F. 2015; Routine serum creatinine measurements: how well do we perform? BMC Nephrol. 16:21. DOI: 10.1186/s12882-015-0012-x. PMID: 25803560. PMCID: PMC4358903.

5. Dodder NG, Tai SSC, Sniegoski LT, Zhang NF, Welch MJ. 2007; Certification of creatinine in a human serum reference material by GC-MS and LC-MS. Clin Chem. 53:1694–9. DOI: 10.1373/clinchem.2007.090027. PMID: 17660272.

6. Piéroni L, Bargnoux AS, Cristol JP, Cavalier E, Delanaye P. 2017; Did creatinine standardization give benefits to the evaluation of glomerular filtration rate? EJIFCC. 28:251–7.

7. Piéroni L, Delanaye P, Boutten A, Bargnoux AS, Rozet E, Delatour V, et al. 2011; A multicentric evaluation of IDMS-traceable creatinine enzymatic assays. Clin Chim Acta. 412:2070–5. DOI: 10.1016/j.cca.2011.07.012. PMID: 21803031.

8. Boutten A, Bargnoux AS, Carlier MC, Delanaye P, Rozet E, Delatour V, et al. 2013; Enzymatic but not compensated Jaffe methods reach the desirable specifications of NKDEP at normal levels of creatinine. Results of the French multicentric evaluation. Clin Chim Acta. 419:132–5. DOI: 10.1016/j.cca.2013.01.021. PMID: 23415696.

9. Pottel H, Björk J, Courbebaisse M, Couzi L, Ebert N, Eriksen BO, et al. 2021; Development and validation of a modified full age spectrum creatinine-based equation to estimate glomerular filtration rate: a cross-sectional analysis of pooled data. Ann Intern Med. 174:183–91. DOI: 10.7326/M20-4366. PMID: 33166224.

10. Miller WG, Kaufman HW, Levey AS, Straseski JA, Wilhelms KW, Yu HE, et al. 2022; National Kidney Foundation Laboratory Engagement Working Group recommendations for implementing the CKD-EPI 2021 race-free equations for estimated glomerular filtration rate: practical guidance for clinical laboratories. Clin Chem. 68:511–20. DOI: 10.1093/clinchem/hvab278. PMID: 34918062.

11. Delanaye P, Pottel H, Glassock RJ. 2022; Americentrism in estimation of glomerular filtration rate equations. Kidney Int. 101:856–8. DOI: 10.1016/j.kint.2022.02.022. PMID: 35283173.

12. Pottel H, Vrydags N, Mahieu B, Vandewynckele E, Croes K, Martens F. 2008; Establishing age/sex related serum creatinine reference intervals from hospital laboratory data based on different statistical methods. Clin Chim Acta. 396:49–55. DOI: 10.1016/j.cca.2008.06.017. PMID: 18621041.

13. Ceriotti F, Boyd JC, Klein G, Henny J, Queraltó J, Kairisto V, et al. 2008; Reference intervals for serum creatinine concentrations: assessment of available data for global application. Clin Chem. 54:559–66. DOI: 10.1373/clinchem.2007.099648. PMID: 18202155.

14. Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A. 1976; A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics. 58:259–63. DOI: 10.1542/peds.58.2.259. PMID: 951142.

15. Schwartz GJ, Muñoz A, Schneider MF, Mak RH, Kaskel F, Warady BA, et al. 2009; New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 20:629–37. DOI: 10.1681/ASN.2008030287. PMID: 19158356. PMCID: PMC2653687.

16. Cockcroft DW, Gault MH. 1976; Prediction of creatinine clearance from serum creatinine. Nephron. 16:31–41. DOI: 10.1159/000180580. PMID: 1244564.

17. Pottel H, Hoste L, Dubourg L, Ebert N, Schaeffner E, Eriksen BO, et al. 2016; An estimated glomerular filtration rate equation for the full age spectrum. Nephrol Dial Transplant. 31:798–806. DOI: 10.1093/ndt/gfv454. PMID: 26932693. PMCID: PMC4848755.

18. Pottel H, Hoste L, Yayo E, Delanaye P. 2017; Glomerular filtration rate in healthy living potential kidney donors: a meta-analysis supporting the construction of the full age spectrum equation. Nephron. 135:105–19. DOI: 10.1159/000450893. PMID: 27764827.

19. Pottel H, Björk J, Bökenkamp A, Berg U, Åsling-Monemi K, Selistre L, et al. 2019; Estimating glomerular filtration rate at the transition from pediatric to adult care. Kidney Int. 95:1234–43. DOI: 10.1016/j.kint.2018.12.020. PMID: 30922665.

20. Inker LA, Eneanya ND, Coresh J, Tighiouart H, Wang D, Sang Y, et al. 2021; New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med. 385:1737–49. DOI: 10.1056/NEJMoa2102953. PMID: 34554658. PMCID: PMC8822996.

21. Pottel H, Cavalier E, Björk J, Nyman U, Grubb A, Ebert N, et al. 2022; Standardization of serum creatinine is essential for accurate use of unbiased estimated GFR equations: evidence from three cohorts matched on renal function. Clin Kidney J. 15:2258–65. DOI: 10.1093/ckj/sfac182. PMID: 36381377. PMCID: PMC9664577.

22. Delanaye P, Vidal-Petiot E, Björk J, Ebert N, Eriksen BO, Dubourg L, et al. 2023; Performance of creatinine-based equations to estimate glomerular filtration rate in White and Black populations in Europe, Brazil and Africa. Nephrol Dial Transplant. 38:106–18. DOI: 10.1093/ndt/gfac241. PMID: 36002032.

23. Kim H, Hur M, Lee S, Lee GH, Moon HW, Yun YM. 2022; European Kidney Function Consortium Equation vs. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) refit equations for estimating glomerular filtration rate: comparison with CKD-EPI equations in the Korean population. J Clin Med. 11:4323. DOI: 10.3390/jcm11154323. PMID: 35893414. PMCID: PMC9331398.

24. Jeong TD, Hong J, Lee W, Chun S, Min WK. 2023; Accuracy of the new creatinine-based equations for estimating glomerular filtration rate in Koreans. Ann Lab Med. 43:244–52. DOI: 10.3343/alm.2023.43.3.244. PMID: 36544336. PMCID: PMC9791020.

25. Zhao L, Li HL, Liu HJ, Ma J, Liu W, Huang JM, et al. 2023; Validation of the EKFC equation for glomerular filtration rate estimation and comparison with the Asian-modified CKD-EPI equation in Chinese chronic kidney disease patients in an external study. Ren Fail. 45:2150217. DOI: 10.1080/0886022X.2022.2150217. PMID: 36632770. PMCID: PMC9848359.

26. Soveri I, Berg UB, Björk J, Elinder CG, Grubb A, Mejare I, et al. 2014; Measuring GFR: a systematic review. Am J Kidney Dis. 64:411–24. DOI: 10.1053/j.ajkd.2014.04.010. PMID: 24840668.

27. Grubb A, Simonsen O, Sturfelt G, Truedsson L, Thysell H. 1985; Serum concentration of cystatin C, factor D and beta 2-microglobulin as a measure of glomerular filtration rate. Acta Med Scand. 218:499–503. DOI: 10.1111/j.0954-6820.1985.tb08880.x. PMID: 3911736.

28. Pottel H, Björk J, Rule AD, Ebert N, Eriksen BO, Dubourg L, et al. 2023; Cystatin C-based equation to estimate GFR without the inclusion of race and sex. N Engl J Med. 388:333–43. DOI: 10.1056/NEJMoa2203769. PMID: 36720134.

29. Risch L, Huber AR. 2002; Glucocorticoids and increased serum cystatin C concentrations. Clin Chim Acta. 320:133–4. DOI: 10.1016/S0009-8981(02)00044-X. PMID: 11983211.

30. Filler G, Bökenkamp A, Hofmann W, Le Bricon T, Martínez-Brú C, Grubb A. 2005; Cystatin C as a marker of GFR-history, indications, and future research. Clin Biochem. 38:1–8. DOI: 10.1016/j.clinbiochem.2004.09.025. PMID: 15607309.

31. Grubb A, Blirup-Jensen S, Lindström V, Schmidt C, Althaus H, Zegers I, et al. 2010; First certified reference material for cystatin C in human serum ERM-DA471/IFCC. Clin Chem Lab Med. 48:1619–21. DOI: 10.1515/CCLM.2010.318. PMID: 21034257.

32. Eckfeldt JH, Karger AB, Miller WG, Rynders GP, Inker LA. 2015; Performance in measurement of serum cystatin C by laboratories participating in the College of American Pathologists 2014 CYS Survey. Arch Pathol Lab Med. 139:888–93. DOI: 10.5858/arpa.2014-0427-CP. PMID: 25884370.

33. Bargnoux AS, Piéroni L, Cristol JP, Kuster N, Delanaye P, Carlier MC, et al. 2017; Multicenter evaluation of cystatin C measurement after assay standardization. Clin Chem. 63:833–41. DOI: 10.1373/clinchem.2016.264325. PMID: 28188233.

34. Ebert N, Delanaye P, Shlipak M, Jakob O, Martus P, Bartel J, et al. 2016; Cystatin C standardization decreases assay variation and improves assessment of glomerular filtration rate. Clin Chim Acta. 456:115–21. DOI: 10.1016/j.cca.2016.03.002. PMID: 26947968.

35. Karger AB, Long T, Inker LA, Eckfeldt JH. College of American Pathologists Accuracy Based Committee and Chemistry Resource Committee. 2022; Improved performance in measurement of serum cystatin C by laboratories participating in the College of American Pathologists 2019 CYS survey. Arch Pathol Lab Med. 146:1218–23. DOI: 10.5858/arpa.2021-0306-CP. PMID: 35192685.

36. Ebert N, Shlipak MG. 2020; Cystatin C is ready for clinical use. Curr Opin Nephrol Hypertens. 29:591–8. DOI: 10.1097/MNH.0000000000000638. PMID: 32868529.

37. Chen DC, Potok OA, Rifkin D, Estrella MM. 2022; Advantages, limitations, and clinical considerations in using cystatin C to estimate GFR. Kidney360. 3:1807–14. DOI: 10.34067/KID.0003202022. PMID: 36514729. PMCID: PMC9717651.

38. Shardlow A, McIntyre NJ, Fraser SDS, Roderick P, Raftery J, Fluck RJ, et al. 2017; The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: a primary care cohort study. PLoS Med. 14:e1002400. DOI: 10.1371/journal.pmed.1002400. PMID: 29016597. PMCID: PMC5634538.

39. Pottel H, Delanaye P, Schaeffner E, Dubourg L, Eriksen BO, Melsom T, et al. 2017; Estimating glomerular filtration rate for the full age spectrum from serum creatinine and cystatin C. Nephrol Dial Transplant. 32:497–507. DOI: 10.1093/ndt/gfw425. PMID: 28089986. PMCID: PMC5837496.

40. Delgado C, Baweja M, Burrows NR, Crews DC, Eneanya ND, Gadegbeku CA, et al. 2021; Reassessing the inclusion of race in diagnosing kidney diseases: an interim report from the NKF-ASN task force. Am J Kidney Dis. 78:103–15. DOI: 10.1053/j.ajkd.2021.03.008. PMID: 33845065. PMCID: PMC8238889.

41. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, et al. 2012; Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 367:20–9. DOI: 10.1056/NEJMoa1114248. PMID: 22762315. PMCID: PMC4398023.

42. Ottosson Frost C, Gille-Johnson P, Blomstrand E, St-Aubin V, Leion F, Grubb A. 2022; Cystatin C-based equations for estimating glomerular filtration rate do not require race or sex coefficients. Scand J Clin Lab Invest. 82:162–6. DOI: 10.1080/00365513.2022.2031279. PMID: 35107398.

43. Malmgren L, Öberg C, den Bakker E, Leion F, Siódmiak J, Åkesson A, et al. 2023; The complexity of kidney disease and diagnosing it - cystatin C, selective glomerular hypofiltration syndromes and proteome regulation. J Intern Med. 293:293–308. DOI: 10.1111/joim.13589. PMID: 36385445. PMCID: PMC10107454.

44. Benoit SW, Ciccia EA, Devarajan P. 2020; Cystatin C as a biomarker of chronic kidney disease: latest developments. Expert Rev Mol Diagn. 20:1019–26. DOI: 10.1080/14737159.2020.1768849. PMID: 32450046. PMCID: PMC7657956.

45. Grubb A, Horio M, Hansson LO, Björk J, Nyman U, Flodin M, et al. 2014; Generation of a new cystatin C-based estimating equation for glomerular filtration rate by use of 7 assays standardized to the international calibrator. Clin Chem. 60:974–86. DOI: 10.1373/clinchem.2013.220707. PMID: 24829272.

46. Erlandsen EJ, Randers E. 2018; Reference intervals for plasma cystatin C and plasma creatinine in adults using methods traceable to international calibrators and reference methods. J Clin Lab Anal. 32:e22433. DOI: 10.1002/jcla.22433. PMID: 29573343. PMCID: PMC6817201.

47. Edinga-Melenge BE, Yakam AT, Nansseu JR, Bilong C, Belinga S, Minkala E, et al. 2019; Reference intervals for serum cystatin C and serum creatinine in an adult sub-Saharan African population. BMC Clin Pathol. 19:4. DOI: 10.1186/s12907-019-0086-7. PMID: 30923459. PMCID: PMC6423796.

48. Adeli K, Higgins V, Trajcevski K, White-Al Habeeb N. 2017; The Canadian laboratory initiative on pediatric reference intervals: a CALIPER white paper. Crit Rev Clin Lab Sci. 54:358–413. DOI: 10.1080/10408363.2017.1379945. PMID: 29017389.

49. Ziegelasch N, Vogel M, Müller E, Tremel N, Jurkutat A, Löffler M, et al. 2019; Cystatin C serum levels in healthy children are related to age, gender, and pubertal stage. Pediatr Nephrol. 34:449–57. DOI: 10.1007/s00467-018-4087-z. PMID: 30460495. PMCID: PMC6349798.

50. Grubb A, Nyman U, Björk J. 2012; Improved estimation of glomerular filtration rate (GFR) by comparison of eGFRcystatin C and eGFRcreatinine. Scand J Clin Lab Invest. 72:73–7. DOI: 10.3109/00365513.2011.634023. PMID: 22121923. PMCID: PMC3279136.

51. Shlipak MG, Matsushita K, Ärnlöv J, Inker LA, Katz R, Polkinghorne KR, et al. 2013; Cystatin C versus creatinine in determining risk based on kidney function. N Engl J Med. 369:932–43. DOI: 10.1056/NEJMoa1214234. PMID: 24004120. PMCID: PMC3993094.

52. Grubb A, Lindström V, Jonsson M, Bäck SE, Åhlund T, Rippe B, et al. Reduction in glomerular pore size is not restricted to pregnant women. Evidence for a new syndrome: "shrunken pore syndrome.". Scand J Clin Lab Invest. 2015; 75:333–40. DOI: 10.3109/00365513.2015.1025427. PMID: 25919022. PMCID: PMC4487590.

53. Teaford HR, Barreto JN, Vollmer KJ, Rule AD, Barreto EF. 2020; Cystatin C: a primer for pharmacists. Pharmacy (Basel). 8:35. DOI: 10.3390/pharmacy8010035. PMID: 32182861. PMCID: PMC7151673.

54. Agarwal R, Delanaye P. 2019; Glomerular filtration rate: when to measure and in which patients? Nephrol Dial Transplant. 34:2001–7. DOI: 10.1093/ndt/gfy363. PMID: 30520986.