Chronic kidney disease (CKD) and cardiovascular disease (CVD) exhibit a robust bidirectional association, underpinned by shared pathophysiological mechanisms. These conditions represent a global public health challenge, with epidemiological studies consistently demonstrating a substantially higher incidence of cardiovascular events in CKD populations compared to the general cohort [1]. Research indicates that a substantial percentage of CKD patients suffer from cardiovascular illness, and CVD mortality accounts for a significant proportion in advanced CKD patients [2]. Emerging evidence highlights that CKD-specific pathophysiological processes—such as uremia-induced vascular calcification, chronic systemic inflammation, and myocardial fibrosis—substantially amplify cardiovascular morbidity in this population [3]. Therefore, mitigating CVD and its mortality associated with CKD is of paramount importance. CKD exists on a pathological continuum with CVD, a leading cause of death in CKD patients [4]. Progressive renal impairment in CKD drives multisystem dysregulation, including metabolic acidosis, chronic inflammatory states, and oxidative stress, which collectively potentiate cardiovascular pathogenesis [5, 6]. Although the CKD-CVD pathophysiological nexus is well-characterized, investigative efforts have predominantly focused on modulating conventional cardiovascular risk profiles. Contemporary investigations prioritize elucidating CVD risk determinants in CKD cohorts, whereas cardioprotective mechanisms and resilience factors in this population remain underexplored.

Niacin, a water-soluble B-complex vitamin, plays a critical role in maintaining physiological homeostasis and systemic metabolic equilibrium. Its biochemical significance stems from its role as the primary biosynthetic precursor to nicotinamide adenine dinucleotide (NAD⁺) and nicotinamide adenine dinucleotide phosphate (NADP⁺), coenzymes integral to redox reactions and cellular energetics [7]. Energy metabolism, cell signaling, DNA repair, and antioxidant defense are the main functions of NAD and NADP, two vital coenzymes in cells that participate in over 400 metabolic activities [8]. Niacin exists in the body as nicotinamide, contributing to the formation of coenzyme I and coenzyme II, and participating in the synthesis of substances and regulation of energy metabolism reactions in the body. Niacin further contributes to the glucose tolerance factor (GTF), a metalloprotein essential for insulin receptor sensitization and glycemic regulation. Pharmacologically, niacin demonstrates pleiotropic effects, including attenuation of atherogenic dyslipidemia (reduced low-density lipoprotein (LDL)-cholesterol and triglycerides) and endothelial-dependent vasodilation via prostaglandin modulation [9]. Epidemiological studies associate dietary niacin with reduced CVD incidence in the general population [10], however, its cardioprotective efficacy remains inadequately characterized in CKD cohorts [11, 12]. Preclinical evidence suggests niacin ameliorates CKD-associated cardiovascular risks by modulating mineral metabolism (reducing hyperphosphatemia and hypercalcemia), suppressing pro-inflammatory cytokines, and improving endothelial dysfunction [13, 14, 15]. A non-linear, J-shaped association exists between dietary niacin intake and hypertension incidence, with nadir risk observed at a daily intake of 14.3–16.7 mg [16]. Currently, no globally standardized guidelines exist for optimal daily niacin intake thresholds tailored to distinct clinical populations. Furthermore, the pharmacokinetics and dose-response relationship of niacin in CKD patients remain unexplored, limiting evidence-based recommendations. This study establishes a novel tripartite association between CKD, CVD, and niacin bioavailability, interrogating the dose-dependent effects of elevated niacin intake on cardiovascular and its mortality in renal-impaired populations. Elucidating this underexplored nexus, our findings provide mechanistic insights into nutrient-mediated cardiorenal protection, informing precision dietary strategies for high-risk CKD cohorts. Integrating niacin optimization into multimodal CKD management may represent a scalable, cost-effective adjuvant therapy to attenuate cardiovascular burden and mortality in this vulnerable demographic. This therapeutic paradigm could potentially mitigate the incidence and severity of CVD in CKD populations, bridging a critical gap in preventive nephrology.

The multifactorial interplay between niacin bioavailability, CKD, and CVD has emerged as a focal point in translational nephrology and cardiometabolic research. To date, a paucity of evidence exists to delineate the tripartite mechanistic and epidemiological relationships linking niacin status, CKD progression, and CVD pathogenesis. Employing a hybrid cross-sectional and longitudinal design, this study interrogates the temporal and dose-response relationships between dietary niacin exposure and both incident CVD and its mortality within a nationally representative cohort of U.S. adults with CKD. This investigation is poised to provide substantial insights to the current body of medical literature.

This study systematically investigates the dose-dependent relationships between dietary niacin intake and both incident CVD its mortality in CKD populations. This water-soluble vitamin is crucial for health, demonstrating considerable benefits for those with CKD [18, 19]. CKD-driven cardiovascular pathogenesis is mechanistically underpinned by chronic low-grade inflammation, atherogenic dyslipidemia, and redox imbalance, which collectively accelerate vascular remodeling and myocardial injury [20]. Emerging treatment strategies, notably the use of niacin, offer potential cardiovascular protection for CKD patients. Previous investigations have examined binary associations between niacin, CKD, or CVD in isolation. In contrast, our integrative analytical framework elucidates the tri-directional interplay among niacin bioavailability, renal dysfunction, and cardiovascular outcomes, employing systems biology principles. Despite evidence supporting niacin’s cardioprotective properties in general populations, CKD cohorts remain disproportionately burdened by residual cardiovascular risk, underscoring unmet therapeutic needs. Our study innovatively reveals niacin’s protective role against CVD in CKD patients. These results bridge a critical knowledge gap while providing actionable insights for precision nutrition strategies in cardio-renal syndrome management. Specifically, our findings suggest that CKD patients can reduce their CVD risk and related mortality by precisely controlling their dietary niacin intake, thus improving prognosis and informing treatment strategies. In patients with CKD, our study found that there is a significant inverse connection between the amount of dietary niacin consumed and CVD, as well as mortality from CVD. The association persisted as statistically following rigorous adjustment for covariates spanning demographic, biochemical, and comorbidity profiles. The fact that we were able to corroborate these findings led to an increase in our degree of confidence. This was accomplished by doing stratified and sensitivity analyses. Furthermore, a prediction model was constructed in order to evaluate the association between the amount of dietary niacin available and the risk of CVD and mortality. It is interesting that multiple subgroup analyses consistently indicated the benefits of increased dietary niacin intake, highlighting its broad applicability and usefulness across diverse groups.

CKD promotes atherosclerosis via chronic inflammation, heightened reactive oxygen species (ROS), and disruptions in lipid and electrolyte metabolism, resulting in nitric oxide (NO) deficiency, mitochondrial and DNA damage, and uremic toxin accumulation [21]. The CKD milieu is characterized by a pro-inflammatory phenotype marked by elevated circulating levels of CRP, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-$\alpha$), which transcriptionally activate profibrotic pathways driving myocardial hypertrophy and extracellular matrix deposition. IL-6 emerges as a central mediator, potentiating both CKD progression (via tubular epithelial mesenchymal transition) and atherosclerotic plaque vulnerability through matrix metalloproteinase-9 induction [22]. Additional international multicenter studies have demonstrated that elevated IL-6 levels are predictive of risk for all-cause mortality, stroke, and myocardial infarction [23]. A meta-analysis by the CKD Prognosis Consortium (CKD-PC) also confirmed this, after adjusting for potential confounders like diabetes and blood pressure, a lower eGFR and a higher ACR were independently associated with increased CVD mortality [24]. CKD-associated dyslipidemia manifests as a distinct atherogenic profile: elevated triglyceride-rich remnant lipoproteins, small dense LDL particles, and dysfunctional high density lipoprotein (HDL) depleted of apolipoprotein A-I, creating a perfect condition for accelerated atherogenesis [25, 26, 27]. Uremic toxins, such as asymmetric dimethylarginine, impair the vascular protective function of HDL, while hyperphosphatemia facilitates the development of vascular smooth muscle cells into osteoblast-like cells, leading to heart hypertrophy, fibrosis, arterial wall thickening, capillary rarefaction, and microvascular illness [28, 29, 30]. This pathophysiological continuum between renal impairment and cardiovascular disease constitutes a multidimensional network where inflammatory, metabolic, and hemodynamic perturbations reciprocally amplify end-organ damage through positive feedback loops.

A growing body of evidence has delineated the pathophysiological nexus between CKD and CVD, mediated by dysregulated inflammatory cascades, atherogenic dyslipidemia, and systemic oxidative stress [31, 32, 33]. Emerging therapeutic modalities within nephrology research have identified niacin as a promising pharmacological agent for attenuating cardiovascular morbidity in CKD cohorts through pleiotropic mechanisms. In a randomized, double-blind, placebo-controlled experiment conducted by Rakesh Malhotra and associates, patients with CKD were administered niacin (1500 or 2000 mg/day) or a placebo. Participants receiving niacin demonstrated an annual reduction of 0.08 mg/dL in plasma phosphate levels compared to the placebo group, correlating with a lower risk of CVD development [34]. Niacin can decrease plasma triglycerides and LDL cholesterol, increase HDL cholesterol, and improve insulin sensitivity, which helps stabilize blood glucose. This positively affects phosphate metabolism, thereby optimizing lipid metabolism and indirectly influencing phosphate metabolism [35]. Furthermore, Roberto S. Kalil and his team [36] discovered that in a clinical trial, the addition of extended-release niacin to the control group resulted in a significant reduction in triglycerides and an increase in high-density lipoprotein cholesterol over a three-year follow-up among CKD participants, despite the comparable incidence of CVD events between groups. Another foundational study found that in a rat model of CKD with renal ablation, subjects treated with niacin showed significant improvement in hypertension, leading to a reduction in cardiovascular events [37]. A pharmacokinetic study revealed that Nispan® (an extended-release niacin formulation) effectively treated hypertriglyceridemia with low high-density lipoprotein levels, a significant factor in CVD, indirectly reducing the prevalence of CVD [38]. Our investigation revealed that CKD patients with a dietary niacin intake below 14.67 mg/d demonstrated a markedly reduced risk of CVD compared to those with an intake of 14.67 mg/d or more, with results consistent across many models. The ultimate outcome for CKD patients often involves death due to comorbidities, with CVD mortality being a leading cause. A randomized controlled trial analyzing 278 CKD patients revealed that a higher proportion of these patients died from cardiovascular causes, with elevated phosphate levels noted in this group [39]. Notably, another study discovered that niacin may decrease serum phosphate levels in patients with CKD [40]. Chronic inflammation, often present in CKD patients, is a significant contributor to CVD mortality [41]. Recent literature has reported that in 15 randomized controlled trials, niacin significantly reduced inflammation levels, thereby suppressing the body’s inflammatory response [42]. Niacin exerts anti-inflammatory effects in macrophages by activating its receptor HM74A. Specifically, it limits the activation of NF-$\kappa$B p65 and I$\kappa$B$\alpha$, thereby reducing inflammatory cytokine production. Moreover, HM74A activation stimulates PPAR$\gamma$, an anti-inflammatory nuclear protein. When PPAR$\gamma$ is activated in macrophages, it boosts ABCA1/ABCG1 expression, promoting cholesterol efflux and reducing foam cell formation, thus alleviating atherosclerotic lesions [43]. Research indicates that niacin can reduce vascular calcification by activating the GPR109A receptor. This activation inhibits inflammatory cytokine production and release, lessens vascular wall inflammation, and ultimately reduces vascular calcification [44]. Interestingly, some studies have found that niacin can enhance endothelial function, reduce local and systemic inflammation, and promote vascular health. This protective effect helps maintain normal vascular function and prevent vascular disease [45]. According to the combined data, one of the main causes of death for CKD patients is CVD. However, various studies have demonstrated that niacin may decrease CVD mortality through several mechanisms. In our research, we found that during a median survival period of 7 years (ranging from 4.7 to 10.4 years), CKD patients with a dietary niacin intake of $\ge$14.67 mg/d exhibited significantly lower CVD mortality compared to those with an intake of 14.67 mg/d. Discrepancies in findings across studies may result from statistical biases related to sample size. Variables linked to both research characteristics and disease outcomes may not be totally constant among studies, potentially influencing or masking the true relationship. Variability in study results could be due to the sample size leading to statistical variations. It is also possible that characteristics related to both research factors and disease outcomes are not completely aligned in each study, which could affect or obscure the actual relationship.

CVD is a leading cause of death globally, it is essential for patients to be able to estimate its incidence and mortality risk with accuracy [46]. Some past studies have examined niacin intake’s link to CVD risk in the general population. For instance, research has shown an inverse correlation between dietary niacin intake and CVD risk [47]. Another study found that higher niacin intake was associated with lower all-cause mortality in non-alcoholic fatty liver disease patients, but not necessarily with lower CVD mortality [48]. However, these studies didn’t focus on CKD patients, suggesting niacin’s effects may vary across different disease contexts. CKD patients, characterized by complex metabolic disturbances and an inflammatory state, have a different CVD pathogenesis than those already diagnosed with CVD [49]. In CKD patients, maintaining appropriate niacin levels is crucial for lipid metabolism, inflammation reduction, and vascular health. Studies investigating the potential association between niacin intake and CVD risk have only just begun. Using the C-index, NRI, and IDI, in this study, which is the first of its type, the predictive potential of dietary niacin intake on the risk of CVD and death associated to cardiac disease is investigated. Our findings indicate that the inclusion of niacin intake in traditional clinic models can enhance the C-index, reflecting improved discriminatory power of the model. Moreover, the NRI of 0.089 (95% CI: 0.015–0.164) and the IDI of 0.003 (95% CI: 0.001–0.005) suggest that dietary niacin intake significantly improves the reclassification of CVD risk. Additional evidence that dietary niacin intake plays a substantial role in predicting the risk of mortality from CVD is provided by an NRI of 0.131 (95% CI: 0.083–0.168) and an IDI of 0.01 (95% CI: 0.005–0.015) values. Enhancement of the C-index, in the Logistic regression model, the C-index rose from 0.746 (with only traditional clinical variables) to 0.847 (with niacin intake included), indicating a marked improvement in the model’s discriminatory power. In the Cox proportional hazards model, it increased from 0.6592 to 0.6817. Although the rise was modest, it still held some predictive value in survival analysis. Improvement in NRI and IDI, the positive values of NRI and IDI show that the model’s ability to reclassify patient risk became better with the inclusion of niacin intake, allowing for more precise identification of high and low risk patients. From a clinical perspective, these improvements suggest: Better risk stratification, incorporating niacin intake into models helps doctors more accurately identify CVD high risk patients, enabling more targeted prevention and treatment. Personalized prevention, for CKD patients, ensuring adequate niacin intake could be a simple, cost effective way to reduce CVD risk. Complementing existing tools, despite limited enhancement, adding niacin intake to current clinical prediction models can improve CVD risk prediction. This indicates that dietary niacin intake is a significant predictor of CVD risk. After combining these findings, we draw the conclusion that dietary niacin intake is a reliable indicator that improves the precision of estimating mortality and CVD risk. The optimal level of the C-index indicates a high discriminative ability of the model, while the results for NRI and IDI demonstrate that dietary niacin intake can markedly improve the reclassification and predictive accuracy of disease risk. These discoveries emphasize the importance of dietary niacin intake in the assessment of CVD risk and offer new perspectives for future research and clinical practice.

Individuals with CKD often grapple with dyslipidemia, a factor that elevates the risk of CVD [50]. Research indicated that niacin can reduce triglyceride levels in the blood, potentially offering a positive impact on decreasing the risk of cardiovascular events [51]. Additionally, individuals with CKD often endure a persistent state of inflammation, which is strongly linked to the advancement of CVD [52]. Niacin possesses significant anti-inflammatory properties, able to reduce inflammatory markers such C-reactive protein (CRP) levels, thereby contributing to a reduction of cardiovascular risk [53, 54]. As kidney function declines, CKD patients may encounter an accumulation of metabolic waste and oxidative stress markers, exacerbating the damage to the cardiovascular system [55, 56, 57]. The antioxidant effects of niacin help mitigate this damage, further reducing the risk of cardiovascular events [58]. Hyperphosphatemia, prevalent in CKD patients, can be mitigated by niacin’s ability to inhibit intestinal phosphate absorption, aiding in the control of serum phosphorus levels and minimizing the likelihood of cardiovascular incidents [59, 60, 61]. Endothelial dysfunction, a frequent complication in CKD patients, is associated with a heightened risk of CVD [62]. Niacin improves endothelium-dependent vasorelaxation and increases the production of NO, which is essential for maintaining vascular health and preventing CVD. This is achieved by enhancing the activity of endothelial nitric oxide synthase (eNOS) [63]. In summary, niacin positively influences the cardiovascular health of CKD patients through multiple mechanisms, including the improvement of dyslipidemia, anti-inflammatory effects, antioxidant actions, control of serum phosphorus levels, and enhancement of endothelial function. These effects highlight the importance of niacin in the management of CKD patients and offer new perspectives for future research and therapeutic approaches. CKD patients often necessitate dietary restrictions and potentially dialysis, which may lead to insufficient levels of niacin within the body [64]. Our research indicates that niacin intake for CKD patients should exceed 27.7 mg per day, a level that can be achieved through the consumption of niacin-rich foods. Furthermore, if optimal niacin levels are not achieved, niacin supplements can be taken as needed. The present investigation presents both strengths and limitations. The strengths are noteworthy: this is the most comprehensive examination to date of the relationship between dietary niacin intake levels and CVD and its mortality among CKD patients, considering a wide range of potential confounding factors. Significant findings were obtained from predictive studies of the association between dietary niacin intake levels and CVD and related mortality in CKD. The results may be more broadly applied since they are based on a statistically valid sample of persons living in the United States who have CKD. However, several limitations should be considered. There is missing data for some variables, such as BMI, which may impact the results when adjusting the model. The research was conducted in an observational fashion, which means we are unable to establish a causal association between the two variables. The National Death Index has a moderate level of accuracy in classifying CVD mortality, while being a trustworthy indicator of vital condition. We categorized dietary niacin intake by study population quartiles, which may make our results not comparable to other research using different cut points. Furthermore, some potential confounding factors may not have been adequately considered, leading to the existence of residual and unidentified confounders that cannot be completely excluded. Additionally, we recognize the limitations of NHANES dietary recall data, including recall bias and measurement error, as this self-reported data depends on participants’ memory, which can be inaccurate. Therefore, we’ve addressed these issues by rigorously cleaning the data and removing unreliable entries. Meanwhile, the diagnosis of CVD, relying on self-reported physician diagnoses, has certain limitations. Yet, in line with most research, this is currently the best method. Lastly, our observational study of CKD patients reveals a potential inverse association between high dietary niacin intake and CVD risk, yet causality cannot be confirmed. A strength is the use of large-scale population data to identify correlations. However, residual confounding may influence results despite controlling for known variables. This is currently the best method. This limitation stems from database constraints, common in studies based on NHANES. In future research, we will incorporate our own clinical data.

According to the findings of this cohort study of people in the United States who have CKD, a higher intake of dietary niacin may be associated with a lower risk of CVD and subsequent mortality. Furthermore, it is clinically noteworthy that dietary niacin intake levels in CKD patients can be used to predict CVD and related mortality. The dose-response connection between dietary niacin and CVD and death in CKD patients needs further study. This will determine ideal intake. Based on the results of our study, it is currently recommended that CKD patients should have a dietary niacin intake of more than 27.7 mg of per day.

In summary, the strengths of this investigation are noteworthy. This investigation is the most comprehensive examination to date of the relationship between dietary niacin intake levels and CVD and its mortality among CKD, considering a wide range of potential confounding factors. Furthermore, significant findings were obtained from predictive studies of the association between dietary niacin intake levels and CVD and related mortality in CKD. The results may be more broadly applied since they are based on a statistically valid sample of persons living in the United States who have CKD.

All data used in the study were accessible to HW. At the following website: https://wwwn.cdc.gov/nchs/nhanes/Default.aspx, visitors can freely access the information that was gathered from the National Health and Nutrition Examination Survey.

HW was solely responsible for ensuring that the data was accurate and complete. Concept and design by DZ. SYG, GZ, YFL, YL and XTY contributed to the acquisition, analysis, or interpretation of data. Manuscript drafted by DZ. Thorough evaluation of the manuscript for significant intellectual contributions: All authors. Statistical analysis conducted by DZ. Funding acquired: HW. All authors performed a comprehensive assessment of the manuscript’s significant intellectual contributions, approved the final manuscript and have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The NCHS Research Ethics Review Board reviewed and approved the NHANES protocols. Therefore, no ethical approval was required for this study and all participants signed the informed consent.

This research received funding from the National Natural Science Foundation of China (Grant No. 81600234).

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/IJVNR37256.