This cross-sectional study used data that were extracted from the Korea National Health and Nutrition Examination Survey (KNHANES) 2024, which is a nationally representative annual survey with a multistage sampling design. The present study included data from 5,520 individuals aged ≥ 19 years with normal kidney function (excluding those with chronic renal failure and elevated serum creatinine levels), and available data on serum phosphate levels were analyzed. Individuals with hypophosphatemia (n=30, 0.5%) were excluded owing to the small number of patients involved and their distinct pathophysiology. The survey protocol was approved by the Korea Disease Control and Prevention Agency, all participants provided written informed consent prior to data collection, and researchers followed the Declaration of Helsinki guidelines. The Institutional Review Board (IRB) of the Korea Centers for Disease Control and Prevention approved KNHANES, and the Gachon University Gil Medical Center approved the study protocol (IRB No. GCIRB2026-050).

Serum phosphate levels were measured using an enzymatic colorimetric method (ammonium molybdate/ultraviolet method) using a Hitachi 7600 Automated Analyzer (Hitachi Ltd., Tokyo, Japan) at the Neodin Medical Institute, Seoul, Korea. The intra- and inter-assay coefficients of variation were both <2.5%. Participants were classified as normophosphatemic or hyperphosphatemic based on a serum phosphate cutoff level of 4.5 mg/dL. Perceived stress was assessed using a single self-reported question: how much stress do you experience in your daily life? Participants were determined to have a high level of perceived chronic stress if they selected “moderate” or “severe” from the following response options: none, mild, moderate, and severe. This single-item question regarding habitual and persistent stress levels in daily life, rather than acute or episodic stress, has been used as a proxy measure of perceived chronic stress in prior epidemiological studies utilizing KNHANES data, including investigations of associations between stress and cardiovascular disease, obesity, and metabolic syndrome [5,6]. Herein, “perceived chronic stress” refers to this self-reported habitual stress level.

The analysis included the following covariates: age, sex, economic status (based on average household monthly income), low educational attainment (middle school or lower), residence (rural or urban), current smoking, frequent drinking (≥once per week), aerobic exercise (≥2.5 h/week of moderate-intensity activity, ≥1.25 h/week of high-intensity activity, or a combination of activities), obesity (body mass index ≥25 kg/m²), hypertension or type 2 diabetes (based on physician-diagnosed disease history), depressive mood (Patient Health Questionnaire-9 score ≥5), and anxiety (Generalized Anxiety Disorder scale-7 score ≥5).

Means and standard deviations or percentages were used to describe the participant characteristics, and multivariate logistic regression, after adjustment for potential confounders, was used to estimate the odds of hyperphosphatemia according to the perceived chronic stress level. All statistical tests were two-sided, and P<0.05 was considered statistically significant. Analyses were performed using STATA software (version 17.0; StataCorp LLC, College Station, TX, USA).

The participants’ characteristics according to their perceived chronic stress levels are presented in Table 1. Compared with the low-stress group, participants in the high-stress group were more likely to be younger, female, urban residents, current smokers, highly educated, of higher economic status, or to have hypertension. Furthermore, they had significantly higher depression and anxiety scores, and elevated serum phosphate levels. Multivariate logistic regression revealed that the association between high perceived chronic stress and hyperphosphatemia was only significant in the middle-aged group (40- to 64-year-olds; adjusted odds ratio, 1.47; 95% confidence interval, 1.12-1.93), but not in younger or older adults (Fig. 1).

Hyperphosphatemia is a well-established driver of vascular calcification and mortality in chronic kidney disease; however, emerging evidence underscores its adverse effects on individuals with normal renal function in the general population [7]. This study is the first to examine the association between perceived chronic stress and hyperphosphatemia in a general population cohort. However, previous studies reported an association between acute anxiety and reduced serum phosphate levels. Maddock et al. [8] observed lower serum phosphate in patients with major depression who had higher anxiety levels, a finding that was attributed to the intracellular phosphate shift that was promoted hyperventilation-induced acute respiratory alkalosis. Similarly, a preliminary study by Pérez-Costillas et al. [9] showed that, by reflecting acute metabolic changes during panic attacks, serum phosphate may serve as a state marker in panic disorder. These prior findings, however, are mechanistically distinct from the present results: although the prior studies described transient hypophosphatemia driven by acute hyperventilation or panic episodes in clinical psychiatric populations, the present study examined persistent hyperphosphatemia in association with habitual chronic stress in a general population. In the context of chronic stress, sustained HPA-axis activation and cortisol elevation promoted the intake of phosphate-rich processed foods, and thereby elevate dietary phosphate load and potentially increased the serum phosphate level over time [10]. Thus, the direction of phosphate change may diverge depending on whether the stressor is acute (favoring hypophosphatemia via respiratory alkalosis) or chronic (favoring hyperphosphatemia via dietary and neuroendocrine mechanisms).

Chronic stress-induced cortisol elevation increases the intake of phosphate-rich processed foods, and thereby elevated the dietary phosphate level [10]. These findings suggest that routine screening for perceived stress in middle-aged adults with elevated serum phosphate could facilitate early intervention strategies, such as stress management programs or dietary phosphate counseling, to mitigate cardiometabolic risk in otherwise healthy individuals. Dietary phosphate intake may represent an important mediating pathway between chronic stress and hyperphosphatemia because stress-driven overeating or binge-eating behaviors can substantially increase phosphate consumption through processed and convenience foods.

The significant association between perceived chronic stress and hyperphosphatemia in middle-aged individuals may stem from age-dependent differences in phosphate homeostasis and the stress response. One possible explanation is that, in younger adult cohorts, wherein stress exposure and baseline phosphate levels tend to be inherently elevated, a ceiling effect may attenuate the stress-phosphate link as serum phosphate approaches its physiological maximum; however, this hypothesis was not directly tested in the present study. Conversely, in older adults, the absence of a significant association could potentially reflect a floor effect, whereby low baseline serum phosphate levels that are attributable to age-related renal dysfunction, reduced muscle mass, and vitamin D dysregulation may limit further stress-induced elevations. However, this interpretation is speculative and requires prospective validation. Moreover, blunted HPA-axis responsiveness and frailty further attenuate stress-mediated metabolic perturbations [11].

The strengths of this study include the use of a large nationally representative sample with rigorous laboratory measurements and comprehensive adjustment for potential confounders, including mental health indicators. However, the present study has some limitations. First, the cross-sectional design prevents the inference of causality. Second, perceived chronic stress was assessed using a single self-report question, which may have introduced recall bias and failed to capture objective stress biomarkers. Specifically, a single-item measure that encompasses psychological, physiological, and behavioral dimensions cannot adequately capture the multidimensional nature of chronic stress. Future studies should incorporate validated multidimensional stress-assessment instruments, such as the perceived stress scale or Cohen’s stress scale, alongside objective biological stress markers, such as salivary or serum cortisol and dehydroepiandrosterone sulfate (DHEA-S), to provide a more comprehensive characterization of the stress-phosphate relationship. Third, serum phosphate levels were measured at a single time point; thus, diurnal or intraindividual fluctuations were not captured. Fourth, dietary phosphate intake, which could be an important mediating variable between chronic stress and serum phosphate levels, was not included in this analysis. Although the KNHANES includes 24-hour dietary recall data from which phosphate intake can be estimated, the high proportion of missing dietary data in the 2024 survey cycle would have substantially reduced the analytical sample size, and thereby precluded its inclusion as a covariate in the primary analysis. Future studies with complete dietary data should examine whether dietary phosphate intake mediates or confounds the stress-phosphate association. Fifth, data on serum 25-hydroxyvitamin D, which regulates intestinal and renal phosphate reabsorption and in which Korean adults are frequently deficient, were unavailable in the KNHANES 2024 dataset that was used in the present analysis. Considering the known role of vitamin D in phosphate homeostasis, its absence as a covariate represents a potential source of residual confounding. Future studies should consider vitamin D status when examining the stress-phosphate relationship. Longitudinal studies with objective stress measures, detailed dietary assessments, and repeated phosphate homeostasis profiling are warranted to confirm these findings and to elucidate the underlying mechanisms.