Association of Intra-individual Differences in Estimated GFR by Creatinine Versus Cystatin C With Incident Heart Failure

Abstract

Rationale & objective: Lower estimated glomerular filtration rate (eGFR) is associated with heart failure (HF) risk. However, eGFR based on cystatin C (eGFR_cys) and creatinine (eGFR_cr) may differ substantially within an individual. The clinical implications of these differences for risk of HF among persons with chronic kidney disease (CKD) are unknown.

Study design: Prospective cohort study.

Setting & participants: 4,512 adults with CKD and without prevalent HF who enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Exposure: Difference in GFR estimates (eGFR_diff; ie, eGFR_cys minus eGFR_cr).

Outcome: Incident HF hospitalization.

Analytical approach: Fine-Gray proportional subhazards regression was used to investigate the associations of baseline, time-updated, and slope of eGFR_diff with incident HF.

Results: Of 4,512 participants, one-third had eGFR_cys and eGFR_cr values that differed by over 15 mL/min/1.73 m². In multivariable-adjusted models, each 15 mL/min/1.73 m² lower baseline eGFR_diff was associated with higher risk of incident HF hospitalization (hazard ratio [HR], 1.20 [95% CI, 1.07-1.34]). In time-updated analyses, those with eGFR_diff less than -15 mL/min/1.73 m² had higher risk of incident HF hospitalization (HR, 1.99 [95% CI, 1.39-2.86]), and those with eGFR_diff ≥15 mL/min/1.73 m² had lower risk of incident HF hospitalization (HR, 0.67 [95% CI, 0.49-0.91]) compared with participants with similar eGFR_cys and eGFR_cr. Participants with faster declines in eGFR_cys relative to eGFR_cr had higher risk of incident HF (HR, 1.49 [95% CI, 1.19-1.85]) compared with those in whom eGFR_cys and eGFR_cr declined in parallel.

Limitations: Entry into the CRIC Study was determined by eGFR_cr, which constrained the range of baseline eGFR_cr-but not eGFR_cys-values.

Conclusions: Among persons with CKD who have large differences between eGFR_cys and eGFR_cr, risk for incident HF is more strongly associated with eGFR_cys. Diverging slopes between eGFR_cys and eGFR_cr over time are also independently associated with risk of incident HF.

Keywords: Biomarker; HF hospitalization; cardiovascular risk stratification; chronic kidney disease (CKD); creatinine; cystatin C; eGFR slope; estimated glomerular filtration rate (eGFR); filtration marker; heart failure (HF); kidney function; measurement accuracy.

Figure 1.

Scatterplot of the relation between eGFRcys, eGFRcr, and eGFRdiff_{cys – cr} at baseline Colors indicate estimated glomerular filtration rate difference (eGFRdiff_{cys – cr}) category: red = eGFRdiff_{cys – cr} < −15, dark blue = eGFRdiff_{cys – cr} −15 to 15, grey = eGFRdiff_{cys – cr} ≥ 15. Diagonal line represents eGFRdiff_{cys – cr} of zero. Abbreviations: eGFRcys, cystatin C-based estimated glomerular filtration rate; eGFRcr, creatinine-based estimated glomerular filtration rate

Figure 2.

Crude incidence rates of incident heart failure (HF) by baseline and slope of eGFRdiff_{cys – cr} category among participants without prevalent HF at baseline (n=4512)