Differences Between Cystatin C and Creatinine-based eGFR—Early Evidence of a Clinical Marker for Frailty

Frailty is defined as a medical syndrome of multisystem dysregulation and is manifested as a compromised resistance to stressors that increases vulnerability to dependence and mortality.¹ While frailty was originally identified and validated in community-dwelling older adults, there is increasing evidence that frailty is a marker of health status for adult nephrology patients of all ages.^2–4 Frailty is common among patients with kidney disease likely due to elevated levels of inflammation, lack of physical activity, and sarcopenia.^{5, 6} However, there are challenges to measuring frailty. First, there are over 60 available tools to measure the construct of frailty.^{1, 7} Second, the most commonly researched, validated measures of frailty, the Physical Frailty Phenotype (PFP) and the Frailty Index (FI), respectively,⁷ can be challenging to measure in clinical practice. Specifically, the FI is based on deficit accumulation, involving a complex algorithm of 35-items with measures of health, activities, pain, depression, energy, in addition to direct measures of medical history, cognitive assessments and laboratory data. The PFP incorporates five components: shrinking (self-report of unintentional weight loss of 10 pounds in the past year, on the basis of dry weight), weakness (grip strength below an established cut-off on the basis of sex and BMI), exhaustion (self-report), low activity (kilocalories per week below an established cut-off), and slowed walking speed (walking time of 15 feet below an established cut-off by sex and height).⁸ Both of these instruments lack the simplicity and ease of use ideal for implementation in clinical practice,⁹ and are prone to potential misclassification given that they are best at capturing only patients with more severe forms of frailty.¹⁰ Therefore, identifying clinical markers of frailty earlier in the process that can predict adverse outcomes may be useful for risk stratification in the care of nephrology patients.

In this issue of American Journal of Kidney Diseases, Dr. Potok and colleagues evaluate the utility of measuring the differences between cystatin C and creatinine-based eGFRs as a proxy for frailty using the FI from the Systolic Blood Pressure Intervention Trial (SPRINT) (citation to be added) and the PFP using the Cardiovascular Health Study (CHS) (citation to be added). The authors hypothesize that a high-creatinine-based eGFR relative to a cystatin C measure of eGFR may reflect the influence of muscle mass and diet and as such capture important clinical information. Importantly, differences in estimates of GFR from cystatin C and creatinine-based models are easy to measure and use information that would otherwise be ignored by clinical practice. In this editorial, we summarize the key findings from these studies, highlight the importance of measuring the difference between cystatin C and creatinine-based eGFR, and address the clinical and public health implications of these studies.

In the SPRINT study (n=9,092), the difference in GFR estimated by cystatin C and creatinine was associated with the validated 35-item FI. Participants who had a difference in eGFR measures (eGFR based on cystatin C - eGFR based on creatinine) less than −15mL/min/1.73m² had a 1.41-fold increased odds of being frail on the FI; those with differences of 15mL/min/1.73m² or higher had a lower odds of being frail (OR=0.61). The association between differences in eGFR and prevalent frailty were significant regardless of the patients eGFR category (based on creatinine). This study then tested the predictive validity of the differences in eGFR and found that greater differences were associated with subsequent injurious falls, hospitalizations, CVD events, and mortality.

Importantly, Dr. Potok and colleagues followed up this assessment in the SPRINT cohort with a parallel analysis using the PFP among community-dwelling older adults enrolled in CHS (n=4,635). Interestingly, in CHS 16% were “frail” based on their differences in GFR (estimated by cystatin C and creatinine that were less than −15mL/min/1.73m²), which is higher than the prevalence frailty identified using the PFP. This may suggest that difference in GFR represents an earlier marker of frailty compared to the PFP. The authors note that differences in GFR estimated by cystatin C and creatinine identified patients who were frail (differences less than −15mL/min/1.73m² OR=2.38) based on the PFP; this exposure was also associated with pre-frailty (differences less than −15mL/min/1.73m² OR=1.59). Furthermore, among those who were not frail at baseline, a greater difference in GFR estimated by cystatin C and creatinine was associated with a greater incidence of the development of frailty (differences less than −15mL/min/1.73m² OR=6.97).

Given the authors use of both a clinical trial cohort and a community-dwelling cohort to test their hypothesis about the differences in eGFR based on cystatin C and creatinine and the robustness of these results to the definition of frailty with the use of two common, validated frailty instruments, it is highly likely that these results are generalizable to the larger population of nephrology patients aged 50 years and older. Further research is needed to determine whether these findings, like the findings on frailty,¹¹ are applicable across all age groups, including younger adult nephrology patients (aged 18–49 years). Furthermore, there is the potential for misclassification of risk using equations to estimate GFR,¹² particularly among patients with normal kidney function,¹² and as such, any new classification based on two of these equations should account for the compound misclassification. This is particularly important as the clinical community considers moving away from race-based models to estimate GFR.¹³

Using differences in GFR rather than frailty as a screener would overcome some of the known challenges to implementing frailty in clinical practice; however, the development of this novel measure of vulnerability should still be grounded in validation theory to ensure that it accurately and precisely measures what it intends to¹⁴ in light of the potential misclassification issues of these equations. When physicians observe a higher eGFR based on cystatin C than one based on creatinine they should consider conducting a comprehensive geriatric assessment.¹⁵ This simple clinical marker that is often ignored could be an important step in targeting geriatric nephrology care to the most vulnerable patient population and improving long-term health outcomes.