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

Abstract

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

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

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 eGFR_diff (eGFR_cys-eGFR_cr) for prospective analysis; putative eGFR_diff 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 eGFR_diff 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 eGFR_diff. Estimated GFR_diff was weakly correlated with markers of muscle mass, middle molecule clearance, and other putative determinants of eGFR_diff (eg, obesity, inflammation). Only 36% of the variance in eGFR_diff was explained by these factors.

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

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

Plain-language summary: The difference between estimated glomerular filtration rates (eGFR_diff) using serum creatinine and cystatin C (eGFR_cys-eGFR_cr) has been repeatedly associated with adverse outcomes, including death and heart failure. The biological mechanisms underlying eGFR_diff are unclear. In this study of adult patients with CKD, we found that adjustment for these proposed causes of eGFR_diff, 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 eGFR_diff and subsequent adverse outcomes. Only 36% of the variance in eGFR_diff 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.