Estimated GFR by Creatinine Versus Cystatin C and Heart Failure Risk

Patients with chronic kidney disease (CKD) face increased risk of developing heart failure. There is a strong and independent association between lower estimated glomerular filtration rate (eGFR) and risk of heart failure events. There are variations in eGFR among individual patients depending on whether creatinine or cystatin C is used for estimation of GFR. Cystatin C had been shown to have stronger and more linear associations with incident heart failure compared with creatinine; however, creatinine-based eGFR (eGFR_cr) is more widely used in clinical practice than cystatin C-based eGFR (eGFR_cys).

Previous studies with population-based cohorts or clinical trials have found associations of the difference in GFR estimates (eGFR_diff, defined as eGFR_cys minus eGFR_cr). According to Debbie C. Chen, MD, and colleagues, the associations of eGFR_diff with hospitalizations for heart failure have not been examined in a cohort of participants with established CKD. There are also only few available data on the clinical interpretation of changes in eGFR_diff over time.

Dr. Chen et al conducted a prospective cohort study to answer three questions: (1) Among individuals without prevalent heart failure at baseline, is baseline eGFR_diff independently associated with incident heart failure hospitalization? (2) Does the inclusion of time-updated measures yield stronger associations between eGFR_diff and incident heart failure? (3) Is widening or narrowing of eGFR_diff over time independently associated with incident heart failure? Results were reported in the American Journal of Kidney Diseases [2022;80(6):762-771].

The study cohort included adults with CKD and without prevalent heart failure who enrolled in the CRIC (Chronic Renal Insufficiency Cohort) study. The study exposure was the difference in GFR estimates (eGFR_diff [eGFR_cys minus eGFR_cr]). The outcome of interest was incident heart failure hospitalization. The associations of baseline, time-updated, and slope of eGFR_diff with incident heart failure were investigated using Fine-Gray proportional subhazards regression.

A total of 4512 CRIC study participants were included in the analysis. Of those, 44% (n=1981) were female, 42% (n=1906) were non-Hispanic Black, and 11% (n=447) were Hispanic. Mean age was 59.4 years, eGFR_cys was 55 mL/min/1.73 m² , and mean eGFR_cr was 49 mL/min/1.73 m². Baseline eGFR_diff ranged from –52 to 65 mL/min/1.73 m².

A total of 2977 patients had a midrange baseline eGFR_diff (eGFR_cys similar to eGFR_cr); 340 had a negative baseline eGFR_diff (eGFR_cys lower than eGFR_cr); and 1195 had a positive baseline eGFR_diff (eGFR_cys higher than eGFR_cr). Those in the negative eGFR_diff group were generally older and had the highest prevalence of diabetes and cardiovascular disease compared with the other two groups. Those in the eGFR_diff positive group were younger and had lower prevalence of baseline comorbidities and medication use.

Twelve percent (n=532) of the study participants developed incident heart failure, with median time to incident heart failure hospitalization of 3.5 years. Following adjustment for demographics and eGFR, there was an association between each 15-mL/min/1.73 m² lower baseline eGFR_diff and a 56% higher risk of incident heart failure. After additional multivariable adjustment, the association was attenuated to 20%. Participants with negative eGFR_diff had the highest crude rate of incident heart failure, and those with positive eGFR_diff had the lowest incidence of heart failure. Compared with the midrange eGFR_diff group, the positive and negative eGFR_diff groups were not statistically significantly associated with multivariable-adjusted risk of incident heart failure.

Following multivariable adjustments accounting for time-updated eGFR_diff and covariates, there was an association between each 15 mL/min/1.73 m² lower baseline eGFR_diff and 36% higher risk of incident heart failure. Compared with the group with midrange eGFR_diff, the adjusted risk of incident heart failure was higher among participants in the group with negative eGFR_diff (subdistribution hazard ratio [HR], 1.99; 95% CI, 1.39-2.86), and those in the positive eGFR_diff group had a lower adjusted risk of incident heart failure (subdistribution HR, 0.67; 95% CI, 0.49-0.91). There was modest attenuation with further adjustment for markers of nutritional status and inflammation.

Slopes of eGFR_diff were derived using a median of four annual eGFR_diff values. The mean annual change in eGFRdiff was –0.4 mL/min/1.73 m². Following adjustment for baseline eGFR_diff, in multivariable models including adjustment for baseline eGFR_diff, each 1-SD lower eGFR_diff slope was associated with 37% higher risk of incident heart failure. Participants with faster declines in eGFR_cys relative to eGFR_cr had higher risk of incident heart failure (HR, 1.49; 95% CI, 1.19-1.85) compared with those in whom eGFR_cys and eGFR_cr declined in parallel.

The researchers cited some limitations to the study findings, including entry into the CRIC study being determined by eGFR_cr, the use of the absolute rather than relative difference between eGFR_cys and eGFR_cr, not calibrating cystatin C measures to a traceable international standard, lack of sufficient data on ejection fraction at the time of hospitalization for heart failure, and using a joint model to obtain within-participant estimates of eGFR_diff slope.

In summary, the authors said, “Our study showed that large differences between eGFR_cys and eGFR_cr convey important prognostic information regarding risk of incident heart failure hospitalization. During longitudinal follow-up, steeper declines in eGFR_cys than eGFR_cr portend higher risk of heart failure events. Thus, in patients with CKD, annual measures of serum creatinine and cystatin C and separate reporting of both eGFR_cys and eGFR_cr could optimize the assessment of heart failure risk.”

Takeaway Points

1. Researchers reported results of a prospective cohort study designed to assess the clinical implications of differences in estimated glomerular filtration rate based on cystatin C (eGFR_cys) and eGFR based on creatinine (eGFR_cr) on the risk of heart failure in individuals with chronic kidney disease.
2. The study cohort included participants in the CRIC (Chronic Renal Insufficiency Cohort) study, a multicenter observational cohort study that enrolled 5499 adults from seven clinical centers in the United States.
3. Among participants with large differences between eGFR_cys and eGFR_cr, there was an increased risk of incident heart failure; diverging slopes between eGFR_cys and eGFR_cr over time were also independently associated with the risk of incident heart failure.

Source: American Journal of Kidney Diseases