Early identification of individuals at high risk of mortality remains a critical challenge in public health and clinical practice. Accurate risk stratification enables the implementation of targeted interventions, optimizes the allocation of healthcare resources, and ultimately improves patient outcomes. Although numerous prognostic factors have been identified, there remains an urgent need for simple, reliable, and cost-effective biomarkers that can be readily integrated into routine clinical practice. In recent years, hematological and biochemical parameters obtained from routine laboratory tests, such as the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI), have garnered increasing attention as potential prognostic biomarkers in the general population due to their wide availability and low cost [1]-[3].

Red blood cell distribution width (RDW) is an indicator in routine laboratory testing that reflects the heterogeneity of red blood cell volume. Traditionally used for the differential diagnosis of anemias, RDW is now recognized as a biomarker of systemic inflammation, oxidative stress, and impaired erythropoiesis. Numerous studies have demonstrated that elevated RDW levels are independently associated with an increased risk of mortality in patients with cardiovascular diseases, cancers, sepsis, and chronic kidney disease (CKD) [4]. Serum albumin is the most abundant circulating protein in blood, which plays a pivotal role in maintaining colloid osmotic pressure, transporting various substances, and regulating immune responses. Low serum albumin levels are an important biomarker of nutritional status, inflammatory response, and hepatic synthetic function [5] [6]. Multiple studies have reported that serum albumin concentration is negatively correlated with the incidence of functional impairment, diseases, and mortality [7]-[9].

Given the complementary biological significance of red blood cell distribution width (RDW) and albumin, a novel integrated biomarker―the red blood cell distribution width to albumin ratio (RAR)―has been proposed, which integrates information on inflammation, oxidative stress, and nutritional status. Compared with individual indicators, RAR may provide a more comprehensive assessment of health status and exhibit superior prognostic performance. Recently, RAR has been demonstrated to be a potential risk biomarker for adverse outcomes in various diseases, including acute myocardial infarction (AMI), atrial fibrillation (AF), diabetes mellitus (DM), heart failure (HF), chronic kidney disease (CKD), and stroke [10]-[15]. However, the association between RAR and mortality in the general population remains unclear to date.

Therefore, we hypothesized that elevated RAR is related to increased risk of all-cause mortality in the general population. This study aimed to investigate the potential association between RAR and all-cause mortality risk using data from the National Health and Nutrition Examination Survey (NHANES).

In this study, we identified a significant, independent, and nonlinear positive association between RAR and all-cause mortality. After adjustment for potential confounders, participants in the highest RAR quartile exhibited a more than 5-fold increased risk of all-cause mortality compared with those in the lowest quartile. RCS analysis further confirmed this nonlinear dose-response relationship, with mortality risk accelerating progressively as RAR levels rose. These associations remained consistent across multiple subgroups, demonstrating the robustness of our findings. The findings of this study could provide important evidence on the utility of RAR as a simple and cost-effective prognostic marker for population-level risk stratification.

Our findings align with and extend the growing body of evidence supporting the prognostic significance of RAR in specific disease populations. Elevated RAR has been consistently shown to predict adverse outcomes in patients with cardiovascular disease, including coronary artery disease, acute myocardial infarction, heart failure, and ischemic stroke [16]-[19]. A recent systematic review and dose-response meta-analysis of 16 studies involving 30,933 patients with cardiovascular disease found that each 1 unit increase in RAR corresponded to a 27% higher risk of all-cause mortality [20]. Beyond cardiovascular disease, RAR has emerged as a strong independent predictor of mortality in patients with diabetes mellitus [21], chronic kidney disease [22], various malignancies [23], and critical illness [24]. However, the vast majority of prior research has focused on individuals with established diseases, and data on the association between RAR and mortality in unselected community-dwelling populations remain scarce. Our study, with a large sample size, longer follow-up period, and nationally representative design, provides far more robust evidence and is the first to fully characterize the nonlinear dose-response relationship between RAR and mortality in the general population.

At present, the precise biological mechanisms underlying the association between the red blood cell distribution width to albumin ratio (RAR) and mortality have not been fully elucidated. Existing studies hypothesize that this association may be mediated primarily through multiple pathways, including chronic inflammation, oxidative stress, and nutritional status. Elevation of the RAR index typically results from increased red blood cell distribution width (RDW) and/or decreased serum albumin levels. Among these, RDW serves as an indicator reflecting the heterogeneity of red blood cell volume. Its elevation can be mediated by pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β [4] [25], which lead to impaired erythropoiesis and abnormal red blood cell survival. Meanwhile, hyperglycemia can further impair red blood cell function by affecting hemodynamic parameters such as blood viscosity and promoting inflammatory responses. Serum albumin is an important biomarker for assessing nutritional status and inflammatory responses in the body [26] [27]. Previous studies have confirmed that both elevated RDW alone and decreased albumin alone are significantly associated with an increased risk of developing various chronic diseases (including cardiovascular diseases, diabetes, and chronic kidney disease) and elevated all-cause mortality in the general population [28]-[33]. Specifically, RDW has been identified as a novel prognostic marker for chronic inflammation. Therefore, RAR, as the combined index of RDW and albumin, can more comprehensively integrate and reflect an individual’s long-term inflammatory status, nutritional imbalance, and other underlying metabolic abnormalities, which provides a theoretical basis for its application as a derived biomarker in routine laboratory tests for clinical prognostic assessment.

Strengths and Limitations:

Our study has several strengths. First, the large sample size and nationally representative design ensure that our findings are generalizable to the entire civilian noninstitutionalized adult population of the United States. Second, mortality data were obtained from the National Death Index (NDI), the gold standard for mortality ascertainment in the US, which minimizes misclassification of outcomes. Finally, RAR is a simple, inexpensive, and widely available biomarker that can be easily calculated from routine complete blood count and basic chemistry panels, making it highly feasible for implementation in both primary care and population health settings.

Several limitations of the study should be acknowledged. First, this is an observational study, and we cannot establish a causal relationship between RAR and all-cause mortality. Second, RAR was measured only once at baseline, and we did not have information on changes in RAR levels during follow-up. Third, some covariates, including clinical information, were based on self-report, which may be subject to recall bias. Fourth, although we adjusted for a wide range of confounders, residual confounding from unmeasured factors such as physical activity level, dietary patterns, and medication use cannot be completely excluded. Finally, our study was conducted exclusively in the US population, and the results may not be directly generalizable to other countries or ethnic groups.

This cohort study demonstrated that RAR is independently associated with all-cause mortality in the US general population, with a nonlinear positive dose-response relationship. Additionally, since RAR is assessed via routine laboratory tests, it serves as a promising indicator that is simple, reliable, and inexpensively accessible for identifying individuals in clinical practice at high risk of mortality. Future prospective studies are needed to validate these findings and investigate the potential mechanisms between RAR and all-cause mortality risk.

The authors sincerely thank the NHANES staff team for their dedicated efforts and all participants involved for their valuable contributions to the data.

This work was supported by the Tianjin Key Medical Discipline Construction Project (No. TJYXZDXK-3-010B), Tianjin Health Research Project (No. TJWJ2023QN044), and Natural Science Foundation of Tianjin Science and Technology Bureau (No. 21JCQNJC01460).

The authors declare no conflicts of interest regarding the publication of this paper.