medwireNews: Combining cystatin C with conventional creatinine measurements offers a better estimate of the glomerular filtration rate (GFR) and the risk of adverse outcomes in older adults, suggests a study published in the Annals of Internal Medicine.
The researchers explain that the accuracy of creatinine to estimate GFR may be limited in older individuals because “low muscle mass, which is frequently found with chronic disease or inactivity, may lead to low creatinine levels and consequently high eGFRcr that does not accurately represent true GFR.”
To investigate, they studied the associations between eGFRcr and eGFRcr-cys and eight adverse outcomes: all-cause mortality, cardiovascular mortality, kidney failure with replacement therapy (KFRT), all-cause hospitalization; and hospitalization with infection, myocardial infarction or stroke, heart failure, or acute kidney injury (AKI).
Shoshana Ballew (New York University Grossman School of Medicine, USA) and colleagues found that the association between eGFRcr and the risk for adverse outcomes tended to be U-shaped, with higher risks at values above 90 mL/min per1.73 m2 for all outcomes except KFRT and AKI.
By contrast, the associations of eGFRcr-cys with adverse outcomes were more linear, which the team suggests is “more plausible” because “[t]hese differences are due to non-GFR determinants that influence creatinine and cystatin C levels. Besides GFR, creatinine is also influenced by muscle mass, diet, and physical activity, whereas cystatin C is influenced by inflammation, obesity, smoking, thyroid diseases, and glucocorticoid use.”
They add: “Combining both markers in eGFRcr-cys improves precision by reducing errors that are due to variation in the non-GFR determinants of each marker.”
The current study evaluated healthcare data from Stockholm, Sweden, on 82,154 participants aged 65 years or older who underwent same-day outpatient creatinine and cystatin C testing between 2010 and 2019. They had a mean age of 77 years and 50% were women.
In all, 41% of the participants had a history of cardiovascular disease and 25% had diabetes. The mean eGFRs at baseline were 67 mL/min per 1.73 m2 for eGFRcr and 61 mL/min per 1.73 m2 for eGFRcr-cys.
Over 3.9 years of follow-up, 31,219 of the participants died and 841 progressed to KFRT, and there were 51,096 hospitalizations.
After adjusting for covariates, including age, sex, hypertension, diabetes, cardiovascular disease, antihypertensive use, total and high-density lipoprotein cholesterol, and urinary albumin-to-creatinine ratio, the team found that lower eGFRcr and eGFRcr-cys were both associated with a higher risk for all adverse events.
And eGFRcr-cys was more strongly associated with these events than eGFRcr, the researchers note. For example, the hazard ratio (HR) for all-cause mortality with a level of 60 versus 80 mL/min per 1.73 m2 was significantly different for eGFRcr-cys but not for eGFRcr, at a respective 1.2 versus 1.0, as was the HR for KFRT using the two eGFR definitions, at 2.6 versus 1.4.
The lack of association with eGFRcr “is likely explained by the use of creatinine as a filtration marker rather than the GFR threshold per se,” say Ballew et al.
In addition, absolute incidence rates for all events, except for KFRT and AKI, were highest in the oldest individuals who had levels of 60 mL/min per 1.73 m2 and below, particularly when measured by eGFRcr-cys.
For example, the incidence rates for all-cause mortality per 100 person–years among 80- versus 70-year-olds with eGFRcr levels of 60 mL/min per 1.73 m2 were 6.4 versus 2.6 and the corresponding rates using an eGFRcr-cys of 60 mL/min per 1.73 m2 were 7.4 and 3.3. For hospitalization, the corresponding incidence rates with eGFRcr were 51 versus 39 and with eGFRcr-cys were 52 versus 44.
“The broad range of risks associated with CKD at older age is better appreciated when cystatin C is included in GFR estimation,” the team remarks.
The researchers also highlight that when eGFRcr measurement was replaced with eGFRcr-cys, 31.2% of older adults were recategorized, predominantly to a more severe GFR category.
“Given that many treatment recommendations are based on GFR thresholds, implementation of cystatin C testing would have a significant effect on clinical practice,” the investigators conclude.
In a related editorial, Georges Nakhoul and Crystal Gadegbeku, both from Cleveland Clinic Health System in Ohio, USA, comment: “The significance of this study is that it sheds light on the possibility that we are measuring more than kidney function with CKD staging.”
Before using these estimating equations, they point out the need to “focus research on linking clinical outcomes to measured GFR values to better guide us on what to measure, what the measurements mean, and how we should intervene.”
They conclude: “As we have more tools in the toolbox to consider management within the framework of cardiovascular-kidney-metabolic syndrome, it is timely to gain insight on the appropriate use of kidney biomarkers in what is likely multisystemic disease, particularly in the aging population.”
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Ann Intern Med 2024; doi:10.7326/M23-1138
Ann Intern Med 2024; doi:10.7326/M24-0111