Coronary artery disease (CAD) stands as a predominant contributor to global morbidity and mortality, representing a critical public health challenge [1, 2]. Acute coronary syndrome (ACS) is a serious type of CAD with a poor prognosis, especially in the elderly [3]. Despite the promotion of healthy lifestyles, controlling cardiovascular risk factors and appropriate antithrombotic treatments, ischemic events still occur [4]. This fact suggests that targeting traditional risk factors may not be sufficient to improve clinical outcomes, and new targets and therapies need to be identified.

Chronic kidney disease (CKD) imposes a growing burden on public health and is closely linked to cardiovascular disease (CVD) [5, 6]. Estimated glomerular filtration rate (eGFR) serves as a common clinical indicator for renal function. Several studies have shown that lower eGFR was associated with an increased cardiovascular risk [7, 8, 9, 10, 11]. However, emerging evidence points to a U-shaped relationship between eGFR and mortality, suggesting that renal hyperfiltration might be a powerful predictor for poor cardiovascular prognosis [12, 13].

The World Health Organization (WHO) defines the population aged 80 and above as “oldest-old”, who are rapidly increasing worldwide and have different physiological status from younger populations due to aging, frailty, malnutrition and comorbidities [14]. Advanced age is associated with a rising prevalence of chronic conditions such as hypertension and diabetes. The cumulative effect of these diseases and their complications significantly diminishes the quality of life and increases the susceptibility to adverse clinical outcomes in older individuals. Frailty is a common geriatric syndrome reflecting decreased physiological reserve and increased vulnerability to stressors [15] and poses a higher risk of readmission and mortality [16]. A community-based study in China reported an overall frailty prevalence of 9.9% in the elderly, which rose sharply to 26% among those aged 80 and above [17]. Despite growing research interest in the elderly, advanced-age patients are still systematically excluded from large clinical trials. Less than 10% of ACS trials include patients over 75 [18], leading to limited generalizability of findings in this population. To address this gap, the present study aimed to determine the prognostic role of baseline eGFR in ACS patients aged 80 years and older.

Advancing age is an important predictor of adverse outcomes following ACS [20]. However, large-scale randomized controlled trials mostly excluded the elderly population $\ge$80 years of age, which has dramatically increased in the past decades. To address this gap, we conducted what is, to our knowledge, the first study systematically designed to explore the prognostic value of eGFR and potential role of renal hyperfiltration in ACS patients aged 80 and above. The baseline data showed that the majority of participants had experienced hypertension, diabetes mellitus, dyslipidemia, and other cardiovascular risk factors. Survival analysis revealed that reduced eGFR was an independent predictor of the long-term risk for MACE. Notably, while L-eGFR was associated with an increased risk for MACE, patients in the H-eGFR group exhibited better clinical outcomes compared to those in the M-eGFR group.

In recent years, eGFR has emerged as a predictor of cardiovascular risk in different populations. Based on the data of the UK Biobank, Lees et al. [21] reported that the incidence of cardiovascular events gradually increased with the decline of eGFR. A Chinese cohort study of 28,187 individuals yielded similar conclusions [22]. In patients with ACS, reduced eGFR predicts not only the risk of in-hospital death [23], but also adverse long-term outcomes [24, 25]. Nevertheless, there is limited data supporting eGFR as a predictor of cardiovascular outcome in older populations, especially those over 80 years. Our study, including more than 550 ACS patients aged $\ge$80 years, demonstrated that the decrease in eGFR was an independent risk factor for long-term MACE. Patients with reduced eGFR often present with comorbidities such as hypertension, diabetes, and dyslipidemia, which promote the development of atherosclerosis through inflammatory and oxidative pathways. In addition, CKD patients usually exhibit chronic inflammation and dysregulation of calcium-phosphorus metabolism. Uremic toxin-related endothelial damage also accelerates the process of atherosclerosis and myocardial remodeling [26]. In summary, this study reached similar conclusions to previous studies regarding the impact of reduced eGFR on prognosis in elderly ACS patients.

Recently, renal hyperfiltration has also shown predictive value for adverse clinical outcomes in several studies, which might be related to the activation of the renin-angiotensin-aldosterone system and the increased activity of the sympathetic nervous system [27]. Patients with type 2 diabetes and an eGFR 45 or $\ge$120 have an elevated risk of all-cause mortality [28]. In a study involving 8794 participants, in which low eGFR, normal eGFR, and high eGFR were defined by the 5th and 95th percentile, researchers reported that the low eGFR and the high eGFR group had a 2-times and 1.5-times increased risk of cardiovascular events compared with the normal eGFR group. These findings support a U-shaped relationship between eGFR and poor clinical outcomes [29]. Renal hyperfiltration has usually been considered a characteristic in the early stage of diabetes [27]. However, a study based on KIHD research data that was conducted to investigate the role of renal hyperfiltration in populations without diabetes, suggested that the correlation between renal hyperfiltration and mortality was not mediated by diabetes [30].

In our study, the L-eGFR and H-eGFR groups were defined by the 20th and 80th percentiles of the eGFR levels. Contrary to prior reports, the H-eGFR group which represented patients with renal hyperfiltration, did not show the same effect. Instead, our data revealed an association between H-eGFR and a reduced risk of MACE in the very elderly ACS patients. This seemingly paradoxical finding could be explained by several factors specific to our study population. First, the eGFR calculated by MDRD equation depended on serum creatinine concentration, which might be lower due to the decrease in muscle mass in the elderly [31]. Considering that the muscle mass of males is generally higher than that of females, there is reason to doubt that patients in the M-eGFR and H-eGFR groups, whose proportion of males was higher than that of the L-eGFR group, had better overall condition and lower risk of frailty. Additionally, given the physiological decline in renal function associated with aging, the cut-off for ‘high’ eGFR in our study may merely represent the upper end of the normal range for younger populations, rather than a truly pathological hyperfiltration state. Furthermore, our study specifically focused on a very elderly ACS population, in which survival bias is likely to be a significant factor. The higher eGFR may not represent a pathological state but rather indicate greater renal functional reserve. Lastly, the follow-up time of this study was considerably longer. For example, the hypertension in the very elderly (HYVET) trial reported a U-shaped relationship between eGFR and later cardiovascular events and mortality, which followed participants for a mean of only 2.1 years [32]. Our longer follow-up may have been necessary to uncover the distinct long-term prognostic role of high eGFR in this population. Therefore, the relationship between renal hyperfiltration and prognosis of advanced-age ACS patients remains unclear and further investigations into the underlying mechanisms are needed.

Our study has several limitations. First, as a single-center, retrospective observational study conducted in China with a relatively small sample size, our findings may lack generalizability to broader elderly ACS populations, and causality between eGFR and MACE cannot be inferred. Second, the lack of dynamic eGFR monitoring during follow-up is a constraint. Relying solely on baseline eGFR measurements to predict long-term prognosis is inherently limited. Third, commonly used cardiovascular medications, such as antiplatelet agents, statins, and renin-angiotensin-aldosterone system inhibitors, can influence both renal function and cardiovascular outcomes. However, accurate data on the use of medications were unavailable, as patients or family members could not provide specific details concerning their treatment. Fourth, while malnutrition is highly prevalent in the very oldest, our assessment was restricted to BMI and albumin levels, lacking more comprehensive nutritional indicators. Finally, the MDRD formula calculated eGFR based on serum creatinine, which is influenced by muscle mass and dietary protein intake in the elderly. Moreover, since the MDRD formula was primarily derived from populations with a mean age under 70 years, its application in our study cohort may have systematically underestimated the true glomerular filtration rate.

Reduced eGFR levels were independently associated with an increased risk for long-term MACE in advanced-age patients with ACS, implying that measurement of eGFR at admission may serve as a prognostic tool. Moreover, the H-eGFR group showed a better prognosis. Therefore, further investigations are warranted to investigate the underlying mechanism between renal hyperfiltration and prognosis in elderly ACS patients to help guide us to improve clinical outcomes through treatments targeting renal function.

The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request.

YFL, TTS and AMD designed the research study. YFL and TTS performed the research and analyzed the data. YFL wrote the manuscript. YZG, XRH and WZ provided help and advice on data collection. ZZL, NQL and JXL made substantial contributions to analysis and interpretation of data, and reviewed it critically for important intellectual content. AMD reviewed and edited the final manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was conducted in accordance with the Declaration of Helsinki and approved by the Medical Ethics Committee of Fuwai Hospital [Approval Number: 2021-1461]. Given that the research involved only analysis of existing medical records without additional patient risk, and all data were anonymized, the requirement for written informed consent was formally waived by the Institutional Review Board.

We gratefully acknowledge all the participants and colleagues who took part in the study for their valuable contributions.

This research was funded by grants from the National Key Research and Development Program of China [grant number 2022YFC3602400, 2022YFC3602405], the Key Projects of the National Health Commission of China [grant number 2020-ZD13], and the Projects of the National Health Commission [grant number 2020-ZYB03].

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/RCM45446.