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

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

STUDY DESIGN

Prospective cohort study for outcomes of eGFR and cross-sectional study for determinants of eGFR.

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 β-microglobulin.

EXPOSURE

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

LIMITATIONS

Imprecision in measurements such as 24-hour urine collections.

CONCLUSIONS

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

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