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)

Abstract

Rationale & objective: In prior research and in practice, the difference between estimated glomerular filtration rate (eGFR) calculated from cystatin C level and eGFR calculated from creatinine level has not been assessed for clinical significance and relevance. We evaluated whether these differences contain important information about frailty.

Study design: A cohort analysis of the Systolic Blood Pressure Intervention Trial (SPRINT).

Setting & participants: 9,092 hypertensive SPRINT participants who had baseline measurements of serum creatinine, cystatin C, and frailty.

Exposure: eGFRs calculated using CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations (eGFR_cys and eGFR_cr), and eGFR_Diff, calculated as eGFR_cys-eGFR_cr.

Outcomes: A validated 35-item frailty index that included questionnaire data for general and physical health, limitations of activities, pain, depression, sleep, energy level, self-care, and smoking status, as well as medical history, cognitive assessment, and laboratory data. We defined frailty as frailty index score>0.21 (range, 0-1). The incidence of injurious falls, hospitalizations, cardiovascular events, and mortality was also recorded.

Analytical approach: We used logistic regression to model the cross-sectional association of baseline eGFR_Diff with frailty among all SPRINT participants. Adjusted proportional hazards regression was used to evaluate the association of eGFR_Diff with adverse outcomes and mortality.

Results: Mean age was 68±9 (SD) years, mean eGFR_cys and eGFR_cr were 73±23 and 72±20mL/min/1.73m², and mean eGFR_Diff was 0.5±15mL/min/1.73m². In adjusted models, each 1-SD higher eGFR_Diff was associated with 24% lower odds of prevalent frailty (OR, 0.76; 95% CI, 0.71-0.81), as well as with lower incidence rate of injurious falls (HR, 0.84; 95% CI, 0.77-0.92), hospitalization (HR, 0.91; 95% CI, 0.88-0.95), cardiovascular events (HR, 0.89; 95% CI, 0.81-0.97), and all-cause mortality (HR, 0.71; 95% CI, 0.63-0.82); P<0.01.

Limitations: Gold-standard measure of kidney function and assessment of muscle mass were not available.

Conclusions: The difference between eGFR_cys and eGFR_cr is associated with frailty and health status. Positive eGFR_Diff is strongly associated with lower risks for longitudinal adverse outcomes and mortality, even after adjusting for chronic kidney disease stage and baseline frailty.

Keywords: Estimated glomerular filtration rate (eGFR); aging; cardiovascular disease; cystatin C; death; falls; filtration marker; frailty; kidney function; muscle mass; older adults; renal disease; risk stratification; sarcopenia; serum creatinine.

Figure 1.

Distributions of glomerular filtration rate (GFR) estimated using serum cystatin C level (eGFR_cys), GFR estimated using creatinine level (eGFR_cr), and eGFR_Diff (eGFR_cys – eGFR_cr).

Figure 2.

Adjusted spline curves of the association of the difference in estimated glomerular filtration rate (eGFR_Diff; GFR estimated using cystatin C level [eGFR_cys] – GFR estimated using creatinine level [eGFR_cr]) with injurious falls, hospitalizations, cardiovascular events, and mortality. Abbreviations: CI, confidence interval; REF, reference.