Chronic kidney disease (CKD), characterized by persistent structural or functional renal impairment with reduced glomerular filtration rate (GFR) (1), has emerged as a global health crisis affecting approximately 850 million individuals worldwide (2). CKD currently ranks among the fastest-growing causes of mortality globally, with projections indicating it will become the fifth leading contributor to years of life lost by 2040 (3). Of particular clinical significance, CKD has been firmly established as an independent risk factor for cardiovascular disease (CVD) - the predominant driver of both morbidity and mortality in this vulnerable patient population (4).

The pathophysiology of CVD in CKD patients involves a complex interplay of inflammation, nutritional deficiencies, and immune dysregulation (5, 6). Emerging evidence suggests that anti-inflammatory and immunomodulatory strategies may offer cardiovascular benefits (7), while dietary modifications and lifestyle interventions have demonstrated efficacy in CVD prevention (8). Consequently, integrated evaluation of nutritional, inflammatory, and immunological parameters may provide valuable insights for reducing CVD risk in CKD patients. Clinical studies have identified serum albumin as an independent predictor of all-cause and cardiovascular mortality (9), while C-reactive protein (CRP) has been widely validated as a robust biomarker for cardiovascular risk assessment. Furthermore, growing evidence implicates immune mechanisms in CVD pathogenesis, with lymphocyte counts emerging as significant prognostic indicators (10). Therefore, an indicator capable of integrating and reflecting these interconnected pathological processes may provide a more precise assessment of cardiovascular risk in CKD patients than any single parameter. The recently developed C-reactive protein-to-albumin-to-lymphocyte (CALLY) index represents a novel composite biomarker that simultaneously reflects inflammatory status (CRP), immune competence (lymphocytes), and nutritional adequacy (albumin) (11). Its design is grounded in robust pathophysiological rationale. CRP is a key acute-phase protein and a classic marker of systemic inflammation. As a central mediator of systemic inflammation, CRP directly drives endothelial dysfunction and atherosclerosis (12). Elevated serum CRP levels are associated with an increased risk of CKD (13). Serum albumin is not only a marker of nutritional reserves but also a negative acute-phase reactant; its synthesis decreases while its catabolism increases under inflammatory conditions, and decreased levels are closely associated with protein-energy wasting and poor prognosis (14, 15). Lymphocyte count reflects the state of adaptive immunity; in the context of CKD-associated chronic inflammation and uremia, it is prone to exhaustion and is closely linked to poor prognosis (16). The integration of these three components into the CALLY index theoretically provides a more comprehensive reflection of CVD risk in CKD patients. In recent years, emerging empirical evidence also supports the application value of the CALLY index in this context.

Recent studies shows that a higher CALLY index is an independent protective factor associated with reduced all-cause mortality in patients undergoing maintenance hemodialysis (17). Studies in patients with cardiorenal syndrome (CRS) also indicate that the CALLY index is inversely associated with CRS risk, and its predictive capability is superior to that of traditional inflammatory markers (18). Furthermore, derived from routinely available clinical parameters, this index offers practical advantages of accessibility and ease of calculation (19). Retrospective studies have demonstrated the clinical utility of the CALLY index across various conditions, showing inverse associations with peripheral artery disease (PAD) (20), depression (21), and stroke risk in hypertensive patients (22). Moreover, prior studies have shown superior prognostic performance compared to conventional biomarkers such as systemic immune-inflammation index (SII), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lymphocyte-to-monocyte ratio (LMR) in CRS (18), hepatocellular carcinoma (19), colorectal cancer (23), and post - percutaneous coronary intervention (PCI) coronary artery disease (CAD) (24), suggesting its potential as a more comprehensive risk assessment tool. However, to date, there are limited evidence on whether CALLY index affects the incidence of CVD and mortality among patients with CKD.

To address this knowledge gap, we utilized data from the UK Biobank to investigate the associations between the CALLY index and CVD incidence, all-cause and CVD-specific mortality in patients with CKD. In addition, we conducted comparative analyses against established inflammatory markers, including the SII, NLR, PLR, and LMR, aiming to establish its relative prediction superiority.

Utilizing data from the UK Biobank, our study provides novel evidence supporting the CALLY index as an independent predictor of adverse cardiovascular outcomes in CKD patients. We observed significant inverse associations between the CALLY index and CVD incidence, all-cause mortality, and CVD-specific mortality, with higher index values consistently correlating with lower risks of these endpoints. Importantly, these associations remained robust even after extensive adjustment for key confounders, including lifestyle factors (diet, physical activity, smoking, and alcohol consumption) and renal function (eGFR). These findings suggest that the CALLY index, integrating inflammatory, nutritional, and immunological markers, may serve as a valuable tool for risk stratification and mortality prediction in CKD patients, potentially enhancing early intervention strategies for this high-risk population.

To our knowledge, epidemiological evidence regarding the associations of CALLY index with incidence of CVD and all-cause and CVD-specific mortality remain unclear in patients with CKD. Based on a prospective cohort design, our findings provide the first evidence that CALLY index as an independent predictor of CVD incidence and prognosis in CKD patients, underscoring its potential for integration into clinical prediction models to enable personalized risk management. Notably, a prior cross-sectional analyses included 8,146 participants from the National Health and Nutrition Examination Survey (NHANES) database showed that the CALLY index may be a potential indicator for early identification of individuals at higher risk of stroke in hypertensive patients (22). Another study found the inverse relationship between the CALLY index and angina in United States adults (33). Interestingly, emerging evidence has demonstrated the significant negative associations between the CALLY index and risk of PAD (20), osteoarthritis (34), depression (21), and retinopathy (33). However, the aforementioned studies were primarily limited to cross-sectional designs with relatively small sample sizes. In addition, studies in the field of disease prognosis assessment have shown that CALLY index can be used as an independent prognostic factor for patients with COPD (35), acute ischemic stroke (36), CVD (37), sepsis (38), and multiple types of cancers (11, 23, 39, 40). By contrast, its potential utility in CKD populations remains to be fully elucidated, with no dedicated studies currently available in this specific patient cohort.

CVD risk emerges early in CKD and escalates progressively with disease severity (4, 41). CKD predisposes patients to diverse CVD subtypes, including IHD (42), MI (43), and stroke (44), driven by a pathophysiological triad of chronic inflammation, malnutrition, and immune dysfunction that synergistically accelerates CVD progression (45). Central to this process is low-grade microinflammation, characterized by elevated CRP-a hepatic acute-phase reactant upregulated by pro-inflammatory cytokines such as IL-6 (46). In CKD, uremic toxin accumulation, oxidative stress, and gut dysbiosis perpetuate inflammatory pathway activation (47), increasing circulating CRP and IL-6. These mediators exacerbate endothelial dysfunction, atherosclerotic plaque instability (48, 49), and ultimately, thrombotic events such as MI and stroke (50, 51). Concurrently, lymphopenia, a marker of immunosuppression, reflects immunosenescence and malnutrition (52). Emerging therapies like finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), mitigate inflammation and renal injury while preserving potassium homeostasis, yet may inadvertently modulate T-cell function via the IL-17/IL-23 axis (53). Similarly, systemic immune-inflammation (e.g., elevated SII) exacerbates renal fibrosis by suppressing the anti-aging protein α-Klotho (54), further compounding CVD risk. Hypoalbuminemia, prevalent in CKD, reflecting both protein-energy wasting and inflammatory catabolism. Depleted albumin impairs antioxidant, anticoagulant, and endothelial protective functions, promoting coronary stenosis and thrombosis (55). Given the complex pathophysiology of CVD, reliance on a single biomarker is likely insufficient to comprehensively capture multidimensional health risk of patients. Instead, integrated indices like the CALLY index, combining CRP (inflammation), albumin (nutrition), and lymphocytes (immunity) (36, 56), offer a holistic assessment of this pathogenic triad (37, 49), thereby overcoming the limitations of conventional single-parameter biomarkers. Higher CALLY values signify optimal inflammatory control and immune-nutritional homeostasis, supporting its utility in risk stratification and personalized CVD prevention.

In the present study, the RCS analyses revealed significant nonlinear, L-shaped associations between the CALLY index and all examined clinical endpoints (CVD incidence, all-cause mortality, and CVD-specific mortality). This nonlinear pattern indicates a saturation effect, where excessively low CALLY index values are associated with increased risk of CVD events, while intermediate and high levels confer optimal protection. Previous studies have also reported similar L-shaped associations between the CALLY index and various health outcomes, including all-cause mortality in rheumatoid arthritis patients (57), stroke (58), and angina pectoris risk (59). The observed L-shaped relationships may be attributed to the role of CALLY index as an integrative biomarker of inflammation, nutrition, and immune homeostasis. At low CALLY levels, the concomitant presence of chronic inflammation, malnutrition, and immune dysregulation likely synergistically promotes the CVD pathogenesis. As the CALLY index increases, the mitigation of these pathological processes may explain the plateau in risk reduction at intermediate-to-high levels, where further increments no longer confer additional benefits (59). This saturation effect may align with biological thresholds beyond which inflammation is adequately controlled, nutritional reserves are sufficient, and immune responses reach equilibrium. Notably, the consistency of L-shaped associations across diverse endpoints and populations underscores the broad utility of CALLY index in risk stratification, while its non-linearity highlights the need for targeted interventions in individuals with critically low values. The inflection point of this curve provides a practical threshold for risk stratification. The primary clinical utility of this index lies in risk stratification. Moreover, compared with traditional risk scores based on demographic and metabolic parameters, the CALLY index offers a direct and complementary measure that reflects the pathological interplay of inflammation, nutrition, and immunity relevant to CKD. Future research should focus on prospectively validating this specific threshold in independent cohorts and exploring whether integrating the CALLY index with established risk models enhances prognostic accuracy for CKD patients.

Our study has several strengths. Firstly, the inclusion of participants from the UK Biobank based on a nationally-representative population provided a relatively large sample size and extended follow-up period, ensuring robust statistical power for detecting clinically meaningful associations and mitigating risks of selection bias. Secondly, we comprehensively adjusted for key confounders including sociodemographic characteristics, detailed lifestyle factors, dietary, anthropometric measures, and complete medical history, which substantially reduces potential confounding effects. Thirdly, to examine the robustness of our findings, we comprehensively conducted sensitivity and subgroup analyses and found that the results were largely unchanged. Moreover, our study employed RCS analysis to comprehensively characterize the complex dose-response relationships between the CALLY index and incidence of CVD and all-cause and CVD-specific mortality, and identified precise inflection points where CALLY index values demonstrated maximum protective effects against outcomes through further application of two-segmented Cox proportional hazard models. This methodological innovation may contribute to determining clinically meaningful threshold values that may inform future risk stratification protocols.

However, several limitations warrant consideration when interpreting our results. Firstly, the single measurement of CRP, albumin, and lymphocyte may not adequately capture their dynamic biological variations. Future longitudinal studies incorporating repeated assessments would be valuable to better characterize the temporal trajectory of the CALLY index and its association with cardiovascular events and mortality in patients with CKD, thereby improving causal inference. Secondly, as an observational study, our findings demonstrate associations but cannot establish causality. Despite extensive covariate adjustment, potential confounding by unmeasured factors such as environmental exposures, genetic predispositions, or medication use (e.g., statins, anti-inflammatory agents, dialysis therapy) remain possible. Thirdly, and importantly, the predominantly White European ancestry of UK Biobank participants significantly limits the generalizability of our findings. Differences in genetic background, lifestyle, comorbidities, and the prevalence and etiology of CKD across ethnic groups may influence the association between the CALLY index and cardiovascular outcomes. Therefore, our results require explicit validation in more ethnically and geographically diverse populations, before they can be considered broadly applicable. Future studies should elucidate associations between the CALLY index and underlying pathophysiological pathways of CVD in CKD models, while designing and implementing CALLY-directed precision intervention trials (nutritional/anti-inflammatory regimens) to develop prognostic risk reduction strategies for CVD in CKD populations.

In this large prospective cohort study of patients with CKD, we demonstrated that a moderate-to-high CALLY index was significantly associated with a reduced risk of CVD events-including IHD, MI, and stroke, as well as lower all-cause and CVD-specific mortality. In addition, our findings suggest that the CALLY index shows a stronger association with cardiovascular risk than conventional inflammatory biomarkers, independent of traditional risk factors. Importantly, our results highlight the clinical utility of the CALLY index as an objective and integrative tool for early CVD risk stratification in CKD patients.