Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Aug;86(2):192-201.
doi: 10.1053/j.ajkd.2025.03.018. Epub 2025 May 13.

Complex Etiologies of the Discordance Between Cystatin C- and Creatinine-Based Estimated GFR and Its Adverse Associations: Findings From the CRIC Study

Ian E McCoy  1 , Jingrong Yang  2 , Alan S Go  2 , Hernan Rincon-Choles  3 , Jonathan Taliercio  3 , Sylvia E Rosas  4 , Mark Unruh  5 , Vallabh Shah  5 , Debbie L Cohen  6 , Jiang He  7 , Jing Chen  8 , James Sondheimer  9 , Afshin Parsa  10 , Wei Yang  11 , Panduranga S Rao  12 , Chi-Yuan Hsu  13 ; Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
Collaborators, Affiliations

Complex Etiologies of the Discordance Between Cystatin C- and Creatinine-Based Estimated GFR and Its Adverse Associations: Findings From the CRIC Study

Ian E McCoy et al. Am J Kidney Dis. 2025 Aug.

Abstract

Rationale & objective: The difference between glomerular filtration rate (GFR) estimated by cystatin C and creatinine (eGFRdiff, defined as eGFRcys-eGFRcr) has been repeatedly associated with adverse outcomes, often ascribed to low muscle mass. However, it is unclear to what extent putative determinants of eGFRdiff, such as low muscle mass, explain associations between eGFRdiff and the outcomes of death and heart failure. Determinants of eGFRdiff have not been investigated to assess their impacts on eGFRcys, eGFRcr, and ultimately eGFRdiff in a dataset with measured GFR.

Study design: Prospective cohort study for outcomes of eGFRdiff and cross-sectional study for determinants of eGFRdiff.

Setting & participants: 1,290 adult participants in the Chronic Renal Insufficiency Cohort (CRIC) Study with directly measured iothalamate GFR, 24-hour urine creatinine collections, and plasma measurements of larger molecules such as β2-microglobulin.

Exposure: Baseline eGFRdiff (eGFRcys-eGFRcr) for prospective analysis; putative eGFRdiff determinants for cross-sectional analyses.

Outcome: Time to all-cause death, heart failure hospitalization for prospective analyses, and eGFR for cross-sectional analyses.

Analytical approach: Cox proportional hazards regression for prospective analysis and linear regression for cross-sectional analyses.

Results: Among adults with CKD, a more positive eGFRdiff was associated with decreased risk of death (adjusted HR, 0.80 [95% CI, 0.74-0.88]) and heart failure hospitalization (adjusted HR 0.83 [95% CI, 0.73-94]). Neither association was substantially changed by adjustment for putative determinants of eGFRdiff. Estimated GFRdiff was weakly correlated with markers of muscle mass, middle molecule clearance, and other putative determinants of eGFRdiff (eg, obesity, inflammation). Only 36% of the variance in eGFRdiff was explained by these factors.

Limitations: Imprecision in measurements such as 24-hour urine collections.

Conclusions: The associations of eGFRdiff with adverse outcomes were unchanged by adjustment for markers of putative determinants such as muscle mass. Examined putative determinants of eGFRdiff accounted for a minority of the variance in eGFRdiff.

Plain-language summary: The difference between estimated glomerular filtration rates (eGFRdiff) using serum creatinine and cystatin C (eGFRcys-eGFRcr) has been repeatedly associated with adverse outcomes, including death and heart failure. The biological mechanisms underlying eGFRdiff are unclear. In this study of adult patients with CKD, we found that adjustment for these proposed causes of eGFRdiff, including measures of muscle mass and protein intake (daily urine creatinine excretion) and kidney clearance of larger molecules (β2-microglobulin and β-trace protein levels relative to measured GFR), did not change the associations between eGFRdiff and subsequent adverse outcomes. Only 36% of the variance in eGFRdiff was accounted for by the proposed causes. Further research is needed to uncover the pathophysiology behind these associations.

Keywords: Chronic kidney disease; cystatin C; estimated glomerular filtration rate; serum creatinine.

PubMed Disclaimer

References

    1. Chen DC, Shlipak MG, Scherzer R, et al. Association of Intra-individual Differences in Estimated GFR by Creatinine Versus Cystatin C With Incident Heart Failure. American Journal of Kidney Diseases. 2022;80(6):762–772.e1. doi: 10.1053/j.ajkd.2022.05.011 - DOI - PMC - PubMed
    1. Kim H, Park JT, Lee J, et al. The difference between cystatin C– and creatinine-based eGFR is associated with adverse cardiovascular outcome in patients with chronic kidney disease. Atherosclerosis. 2021;335(July):53–61. doi: 10.1016/j.atherosclerosis.2021.08.036 - DOI - PubMed
    1. Potok OA, Ix JH, Shlipak MG, et al. The Difference Between Cystatin C– and Creatinine-Based Estimated GFR and Associations With Frailty and Adverse Outcomes: A Cohort Analysis of the Systolic Blood Pressure Intervention Trial (SPRINT). American Journal of Kidney Diseases. 2020;76(6):765–774. doi: 10.1053/j.ajkd.2020.05.017 - DOI - PMC - PubMed
    1. Carrero JJ, Fu EL, Sang Y, et al. Discordances Between Creatinine- and Cystatin C–Based Estimated GFR and Adverse Clinical Outcomes in Routine Clinical Practice. American Journal of Kidney Diseases. 2023;82(5):534–542. doi: 10.1053/j.ajkd.2023.04.002 - DOI - PubMed
    1. Yuan JH, Rifkin DE, Ginsberg C, et al. Difference between kidney function by cystatin C versus creatinine and association with muscle mass and frailty. Journal of the American Geriatrics Society. 2024;(April):1–8. doi: 10.1111/jgs.19014 - DOI - PMC - PubMed