The Difference Between Cystatin C- and Creatinine-Based Estimated GFR in Heart Failure With Reduced Ejection Fraction: Insights From PARADIGM-HF

Abstract

Rationale & objective: The clinical implications of the discrepancy between cystatin C (cysC)- and serum creatinine (Scr)-estimated glomerular filtration rate (eGFR) in patients with heart failure (HF) and reduced ejection fraction (HFrEF) are unknown.

Study design: Post-hoc analysis of randomized trial data.

Setting & participants: 1,970 patients with HFrEF enrolled in PARADIGM-HF with available baseline cysC and Scr measurements.

Exposure: Intraindividual differences between eGFR based on cysC (eGFR_cysC) and Scr (eGFR_Scr; eGFRdiff_cysC-Scr).

Outcomes: Clinical outcomes included the PARADIGM-HF primary end point (composite of cardiovascular [CV] mortality or HF hospitalization), CV mortality, all-cause mortality, and worsening kidney function. We also examined poor health-related quality of life (HRQoL), frailty, and worsening HF (WHF), defined as HF hospitalization, emergency department visit, or outpatient intensification of therapy between baseline and 8-month follow-up.

Analytical approach: Fine-Gray subdistribution hazard models and Cox proportional hazards models were used to regress clinical outcomes on baseline eGFRdiff_cysC-Scr. Logistic regression was used to investigate the association of baseline eGFRdiff_cysC-Scr with poor HRQoL and frailty. Linear regression models were used to assess the association of WHF with eGFR_cysC, eGFR_Scr, and eGFRdiff_cysC-Scr at 8-month follow-up.

Results: Baseline eGFRdiff_cysC-Scr was higher than +10 and lower than-10mL/min/1.73m² in 13.0% and 35.7% of patients, respectively. More negative values of eGFRdiff_cysC-Scr were associated with worse outcomes ([sub]hazard ratio per standard deviation: PARADIGM-HF primary end point, 1.18; P=0.008; CV mortality, 1.34; P=0.001; all-cause mortality, 1.39; P<0.001; worsening kidney function, 1.31; P=0.05). For a 1-standard-deviation decrease in eGFRdiff_cysC-Scr, the prevalences of poor HRQoL and frailty increased by 29% and 17%, respectively (P≤0.008). WHF was associated with a more pronounced decrease in eGFR_cysC than in eGFR_Scr, resulting in a change in 8-month eGFRdiff_cysC-Scr of-4.67mL/min/1.73m² (P<0.001).

Limitations: Lack of gold-standard assessment of kidney function.

Conclusions: In patients with HFrEF, discrepancies between eGFR_cysC and eGFR_Scr are common and are associated with clinical outcomes, HRQoL, and frailty. The decline in kidney function associated with WHF is more marked when assessed with eGFR_cysC than with eGFR_Scr.

Plain-language summary: Kidney function assessment traditionally relies on serum creatinine (Scr) to establish an estimated glomerular filtration rate (eGFR). However, this has been challenged with the introduction of an alternative marker, cystatin C (cysC). Muscle mass and nutritional status have differential effects on eGFR based on cysC (eGFR_cysC) and Scr (eGFR_Scr). Among ambulatory patients with heart failure enrolled in PARADIGM-HF, we investigated the clinical significance of the difference between eGFR_cysC and eGFR_Scr. More negative values (ie, eGFR_Scr>eGFR_cysC) were associated with worse clinical outcomes (including mortality), poor quality of life, and frailty. In patients with progressive heart failure, which is characterized by muscle loss and poor nutritional status, the decline in kidney function was more pronounced when eGFR was estimated using cysC rather than Scr.

Keywords: Cystatin C; estimated glomerular filtration rate; heart failure; kidney function; reduced ejection fraction.