Hemodialysis (HD) is a primary renal replacement therapy for end-stage renal disease (ESRD) caused by chronic kidney disease (CKD). Cardiovascular disease (CVD) is the leading cause of mortality in HD patients. These patients face a 50% higher overall risk of developing CVD compared to the general population (1). Moreover, once CVD is present, their CVD-related mortality rate is 20-fold higher (2). Vascular calcification (VC), a key driver of CVD in ESRD, affects 80–90% of CKD patients (3). Early detection and intervention to mitigate VC-associated cardiovascular risks in this population remain critical research priorities.

Sarcopenia is a progressive and generalized skeletal muscle disorder characterized by reduced muscle mass, strength, and physical performance. HD patients frequently develop sarcopenia due to chronic inflammation, metabolic acidosis, protein-energy wasting (PEW), and physical inactivity (4, 5). The prevalence of sarcopenia in HD patients ranges from 4 to 68%, with an overall prevalence of 28.5% (5). Meta-analyses indicate a strong association between sarcopenia and cardiovascular events in dialysis patients (6). Additionally, malnutrition is a major risk factor in CKD patients, contributing to poor clinical outcomes (7). It is commonly defined as “a state resulting from lack of intake or uptake of nutrition that leads to altered body composition (decreased fat free mass) and body cell mass leading to diminished physical and mental function and impaired clinical outcome from disease” (8). There is substantial overlap between sarcopenia and malnutrition, leading Vandewoude et al. (9) to propose the malnutrition-sarcopenia syndrome (MSS), defined as the co-occurrence of malnutrition and sarcopenia. MSS confers a higher mortality risk than either condition alone (10, 11). Despite its clinical significance, research on MSS in HD populations remains limited. Current studies suggest that MSS increases mortality risk in HD patients (12–14), but the underlying mechanisms remain unclear. Crucially, it is unknown whether MSS further exacerbates CVD and VC risk in this high-risk population.

The abdominal aortic calcification (AAC) score has emerged as a widely used quantitative tool for assessing VC severity in HD patients due to its noninvasive nature, operational simplicity, and reproducibility. Building upon these findings, we conducted this study to investigate whether HD patients with MSS exhibit higher AAC prevalence and face increased risks of major adverse cardiovascular events (MACE). Our findings may enhance clinicians’ awareness of these critical associations and underscore the importance of addressing both sarcopenia and malnutrition in routine HD care.

This study provides the first systematic evaluation of the combined effects of sarcopenia and malnutrition on AAC progression and MACE risk in HD patients. Our prospective cohort analysis yielded three principal findings: (1) the coexistence of sarcopenia and malnutrition, termed MSS, was independently associated with significantly elevated risks of both vascular calcification and cardiovascular events; (2) The AAC burden in patients with MSS was significantly more severe than in those with no sarcopenia or malnutrition and those with malnutrition alone. The comparable severity of calcification between the MSS and sarcopenia-alone groups suggests that sarcopenia might be a predominant risk factor for VC; and (3) the malnutrition-sarcopenia interaction accounted for 26.7% of cardiovascular risk through vascular calcification pathways. Although malnutrition and sarcopenia each predict poor outcomes, their combined impact—and the role of AAC as a mediator—has not been previously quantified in hemodialysis patients. These findings offer novel clinical insights for cardiovascular risk stratification in maintenance dialysis populations.

Sarcopenia has emerged as a critical public health concern, particularly among HD patients. Current diagnostic frameworks incorporate three key elements—muscle strength, mass, and physical performance (21, 25). Although both the European Working Group on Sarcopenia in Older People (EWGSOP) (2019) and AWGS 2019 are widely used diagnostic criteria for sarcopenia, the latter was selected for this study due to the Asian origin of our cohort. 46.3% of participants were diagnosed with sarcopenia, with notable gender disparity (female predominance: 54.6% vs. 40.3%, p = 0.002) in our study. Malnutrition prevalence was 32.0% (non-significant gender difference), while sarcopenic patients showed higher malnutrition rates than non-sarcopenic counterparts (39.3% vs. 24.9%, p < 0.001), aligning with previous reports (26).

Malnutrition remains prevalent in CKD populations, The European Society for Clinical Nutrition and Metabolism (ESPEN) guidelines (8, 27) also emphasize that due to the lack of a unified and validated assessment method for malnutrition in CKD, its reported prevalence varies considerably across countries and regions—for example, 37% in UK HD patients (28), 58.8% in Brazil (29), and ranging from 11 to 54% in HD patients depending on assessment methodologies, while meta-analyses estimate an approximate prevalence of 42% in HD cohorts (30). The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline for nutrition in CKD recommend the use of the 7-point Subjective Global Assessment (SGA) as a tool for assessing nutritional status (17). Another validated tool, GNRI, which incorporates serum albumin dynamics and anthropometric parameters, has been validated as a nutritional assessment tool for Japanese CKD patients (24, 31) and demonstrates prognostic utility for mortality prediction in HD populations (14, 32, 33). Although some studies have used lower cutoffs for mortality prediction, the GNRI <92 threshold is widely accepted for identifying malnutrition in HD populations (12, 24, 31). These evidence-based considerations informed our selection of GNRI for malnutrition evaluation.

Both malnutrition (particularly PEW) and sarcopenia are well-established risk factors for multiple complications and mortality in HD patients (34). These conditions frequently coexist and interact through a vicious cycle: malnutrition accelerates muscle loss, while sarcopenia exacerbates nutritional deficits through reduced energy expenditure and decreased dietary intake secondary to physical inactivity (9). This bidirectional relationship creates substantial clinical overlap (13), MSS associated with substantially higher mortality risk compared to either condition alone (35). Our study identified that 18.2% of patients were diagnosed with MSS, a prevalence higher than that in the general population and comparable to the prevalence reported in previous studies of hemodialysis patients (12, 36). We believe that it is necessary to comprehensively evaluate their combined effects rather than consider them as independent entities.

Expanding on the existing body of knowledge, we embarked on the present study to further elucidate the interplay between malnutrition, sarcopenia, and their combined impact on HD patients. Our findings unveiled that individuals with MSS exhibited markedly elevated levels of both CRP and ferritin, which aligns with previous observations (11). These inflammatory biomarkers serve as key indicators of the malnutrition-inflammation-atherosclerosis (MIA) syndrome, a well-documented pathophysiological cascade in HD populations.

Notably, patients who were free from both sarcopenia and malnutrition demonstrated significantly higher serum albumin levels and creatinine levels. These findings reflect a better-preserved nutritional status and muscle mass in this subgroup. Elevated creatinine is a hallmark of ESRD, however, its strong correlation with muscle metabolism (37) and nutritional parameters, independent of dialysis adequacy, highlights the necessity for comprehensive nutritional interventions in HD management protocols.

Additionally, the MSS group had the highest mean age, followed by the sarcopenia alone group, which is consistent with existing studies on HD patients (12, 13). This finding suggests that aging is a significant factor contributing to the development of sarcopenia and the coexistence of sarcopenia and malnutrition. Given the global trend of an aging dialysis population, there is an increasing need to pay attention to this phenomenon.

Survival analyses substantiated these findings, with MSS patients displaying the highest cumulative MACE incidence and poorest overall survival (log-rank p < 0.001). While the Kaplan–Meier curves effectively illustrate the unadjusted association between patient groups and outcomes, this analysis does not account for differences in baseline characteristics. The subsequent multivariate regression models provide a more robust, adjusted estimate of the independent risk associated with MSS. Mediation analysis confirmed that AAC severity partially mediated (26.7%) the MSS-MACE association (β = 0.064, p < 0.001), suggesting malnutrition may potentiate VC in sarcopenic HD patients. The multivariable regression and mediation analyses provide a multi-layered perspective on the pathophysiology linking MSS to adverse outcomes. The differing risk factors for AAC (a structural change) and MACE (a clinical event) are illuminating. AAC was independently associated with traditional factors like age and hypertension, and with factors related to CKD-MBD, such as vitamin D deficiency. Conversely, MACE was more strongly linked to factors indicating functional reserve and acute stress, such as transferrin saturation, and the AAC score itself (underlying vascular burden). The mediation analysis revealed that AAC severity explained only 26.7% of the total effect of MSS on MACE, which suggests that MSS contributes to cardiovascular events through additional pathways beyond vascular calcification. These likely include the profound functional limitation and reduced physiological reserve (making patients more vulnerable to any hemodynamic stress) (12), exacerbated inflammation promoting plaque instability (38, 39), and potential dysregulation of cardiac function directly related to uremic myopathy and metabolic derangements (40).

The combined effects of sarcopenia and malnutrition in HD patients may be explained by several interconnected pathways: (1) Chronic inflammation: Both conditions are associated with a proinflammatory state, creating a vicious cycle that exacerbates the MIA syndrome and accelerates cardiovascular disease progression (5, 40–42). Our findings support this hypothesis, with MSS patients exhibiting significantly elevated CRP and ferritin levels. (2) Vitamin D deficiency: HD patients frequently present with vitamin D deficiency, which contributes to both muscle wasting and vascular calcification. Mechanistically, vitamin D exerts protective effects by (i) upregulating calcification inhibitors (e.g., matrix Gla protein, osteopontin), (ii) suppressing proinflammatory cytokines (43, 44), and (iii) modulating vascular smooth muscle cell calcium sensing via 1,25(OH)₂D₃ (45). (3) Metabolic dysregulation: Additional contributors include insulin resistance, oxidative stress, overactivation of the renin-angiotensin-aldosterone system, and impaired insulin-like growth factor 1 (IGF-1) signaling—all of which may amplify cardiovascular risk in this population (46–48). While these mechanisms require further elucidation, our study underscores the urgent need for clinical interventions targeting MSS in HD patients to mitigate its deleterious cardiovascular consequences.

An intriguing finding worthy of further discussion is the distinct profile of the malnutrition-alone group. These patients, while nutritionally compromised per GNRI, exhibited lower inflammatory markers (CRP, ferritin), less severe vascular calcification, and better survival outcomes compared to the sarcopenia and MSS groups. This suggests that ‘malnutrition’ in isolation may represent a state of primarily caloric and protein deficiency, potentially amenable to nutritional interventions. In contrast, the presence of sarcopenia, either alone or combined with malnutrition (MSS), appears to be a stronger marker of a persistent inflammatory and catabolic state (MIA syndrome) (49), driving more severe vascular pathology and worse clinical outcomes (50). This distinction implies that sarcopenia might be a more critical prognostic indicator than GNRI-defined malnutrition in this population, and that the MSS phenotype identifies those trapped in the most vicious cycle of inflammation, catabolism, and cardiovascular deterioration.

It is important to acknowledge the limitations of our chosen nutritional assessment tool. We used GNRI rather than the Malnutrition-Inflammation Score (MIS) to avoid overlap with sarcopenia diagnostic criteria, which might have omitted some inflammatory aspects. The GNRI incorporates serum albumin, a parameter significantly influenced by systemic inflammation and fluid status, not solely by nutritional intake. This is a deviation from the explicit recommendation by ESPEN against using visceral proteins like albumin for diagnosing malnutrition (8). However, the selection of GNRI was based on its widespread validation and prognostic utility in hemodialysis populations, as evidenced by meta-analyses (22, 32–34). Furthermore, other commonly used tools, such as the MIS and the criteria for PEW, also incorporate albumin, reflecting the challenges in disentangling nutrition from inflammation in this patient group. Consequently, the ‘malnutrition’ identified by GNRI in our cohort, and the associated interventions, likely target a combination of underlying inflammatory drive and true nutritional deficits. However, it is important to note that this study observed standard care rather than a specific nutritional intervention. Future interventional studies are needed to determine whether treating GNRI-defined malnutrition (and by extension, its inflammatory components) can improve cardiovascular outcomes in patients with MSS.

Several limitations should be acknowledged. First, this was a single-center study with a moderate sample size, necessitating external validation. Second, BIA may overestimate lean mass in edema-prone HD patients. Third, malnutrition was not identified according to the KDOQI criteria, but solely through GNRI in this study. GNRI provides a static assessment and may not capture dynamic nutritional changes. Fourth, the 3-year follow-up may be insufficient to fully evaluate long-term VC progression and cardiovascular outcomes. Finally, there is a paucity of RCTs on nutritional or exercise interventions for sarcopenia in dialysis patients, limiting evidence-based recommendations. Furthermore, nutritional support was provided based on clinical need (GNRI <92) rather than random assignment. While our protocol was standardized, the escalation from dietary counseling to ONS and IDPN was contingent upon the severity and persistence of malnutrition, potentially introducing confounding by indication. The observed associations should be interpreted within this context, and future randomized trials are needed to confirm the causal efficacy of targeted nutritional interventions on outcomes in patients with MSS.

In conclusion, the prevalence of MSS in HD population is 18.2%. Compared with patients who have sarcopenia or malnutrition alone, those with MSS are associated with higher AAC scores and a higher incidence of AAC. Moreover, MSS increases the risk of MACE and mortality in HD patients. These findings highlight the importance of conducting comprehensive nutritional assessments in CKD patients undergoing HD to facilitate early identification of sarcopenia and its overlap with malnutrition. It also underscores the necessity of developing relevant management guidelines to optimize the care of hemodialysis patients and improve their prognosis. Future studies should explore the impact of precision nutritional interventions on adverse outcomes, including CVD.