In this hospital-based case–control study, we observed a significant positive relationship between corrected serum calcium after dialysis and the risk of PDF. Subgroup analyses indicated that the level of corrected serum calcium was associated with an increased risk of PDF among older patients (aged ≥ 65 years).

Previous studies found inconsistent results regarding the association between serum calcium levels and the risk of PDF. A cross-sectional survey in China by Zuo et al. indicated that serum calcium was negatively associated with fatigue in patients undergoing HD [18]. This apparent discrepancy with the current results might be due to differences in the methods of fatigue assessment, sample sizes, incorporated calcium form, and the covariates assessed. The previous study included 511 patients receiving HD and only explored the correlation between calcium and fatigue, without adjusting for any covariates. In addition, fatigue symptoms were evaluated using the Revised Piper Fatigue Scale in their study. A prospective multicenter study in Italy conducted by Bossola et al. found no association between serum calcium and PDF risk in ESRD patients receiving chronic HD [17]. This inconsistency with our findings might be attributable to differences in geographical locations and/or ethnicity, and their small sample size (only 271 HD patients). Nevertheless, another cross-sectional study by Karakan et al. in Turkey found a positive association between serum calcium and overall fatigue scores in patients undergoing chronic HD [19], consistent with the current results.

Although the present study found an association between corrected serum calcium levels after dialysis and the risk of PDF, the underlying biological mechanism remains unclear. Disturbances of calcium and phosphorus metabolism are common complications in HD patients, which could in turn activate the oxidative stress response and present a micro-inflammatory state. As we all know, the cause of fatigue is to promote inflammatory cytokines and reduce ATP libraries (energy loss). At the same time, chronic fatigue syndrome was thought to be associated with persistent activation of nuclear factor-kappa B (NF-κB), which result in augmented nitrosative–oxidative stress, lowered ATP pools, and chronic inflammation [20,21,22]. On one hand, NF-κB activation induces the production of high levels of reactive oxygen species (ROS), such as superoxide, on the other hand, it induces the production of nitric oxide, leading to the production of peroxynitrite, therefore, leading to changes in cell structure and function [23]. In particular, metabolic consequences will follow, such as derangement of citric acid cycle and oxidative phosphorylation, which result in lowered ATP [23,24,25] and NADH/NAD redox pool [23]. In addition, ROS damage ion channels, especially calcium pumps. In this way, the intracellular free calcium level increases [26,27,28], like ROS, which can induce a new round of NF-κB activation [26]. Bossola et al. suggested that inflammatory factors could cause fatigue in patients receiving chronic HD [29]. Cytokines and activated immune-inflammatory pathways might cause fatigue via direct effects on the central nervous system (hypothalamus, pituitary gland) and adrenal glands, or indirectly by inducing sleep disorders, depression, or anxiety [30]. Furthermore, MHD patients suffered from long term anemia, hypertension and drug therapy, which further reduce the quality of sleep and increase the fatigue of patients [31, 32]. In addition, drug therapy including calcium-containing phosphorus binders and active vitamin D, which can lead to increased serum calcium levels, which further lead to chronic kidney disease-mineral bone disorder [33], resulting in patient discomfort and restricted activities, thus affecting the patient’s quality of life and potentially leading to fatigue.

In the current subgroup analysis, we also observed a significant positive association between serum calcium and PDF in patients aged 65 and older. To the best of our knowledge, age has previously been identified as a risk factor for PDF in MHD patients [34]. Compared with younger, older people have significantly lower metabolic capacity and less physical activity, potentially leading to calcium and phosphorus metabolism disorders and resulting in fatigue after dialysis.

This study had several strengths. First, this was the first study to provide evidence that between corrected serum calcium levels after dialysis and PDF risk. Second, the study included a relatively large sample size (610 MHD patients) compared with other studies. Third, we explored corrected serum calcium levels after dialysis and the risk of PDF, which could more precisely clarify the relationship between these factors. However, the study also had some limitations. First, it was a retrospective study conducted at a single dialysis unit, which might have led to selection bias. However, our analyses were adjusted for a large number of potential confounders to overcome the differences between the two groups. Second, this was a case–control study, with reduced ability to identify a causal association compared with cohort studies; however, it could provide clues for future follow-up studies. Third, we did not use traditional questionnaires to assess patients’ fatigue status after dialysis, but a previous study using the same approach showed that patients’ subjective feelings were an important factor affecting their clinical treatment [17]. Fourth, due to the limited availability of data, although we tried to control for some potential confounding factors, we were unable to control for other conventional risk factors, such as family genetic history, smoking, drinking, occupational exposure, 25-OH-VD status, hydration status, body fluid composition and diet. However, given that adjusting for a large number of factors had little effect on the magnitude of the associations, we considered that it was unlikely that any unmeasured or imperfectly measured factors would materially change the results. Finally, corresponding parameters in the model were not optimized before the study commencement and it will be the subject of future work.

In conclusion, the present case–control study indicated that there was a positive association between corrected serum calcium levels after dialysis and the risk of PDF. These results suggest that prevention strategies aimed at reducing corrected serum calcium levels should be implemented to decrease the risk of PDF in the future. Given the limitations of the current study design, future large prospective studies are needed to confirm our findings and to determine the mechanism responsible for the observed relationship.