Chronic kidney disease (CKD) has been world-recognized as a serious public issue, while the current number of CKD patients around the world has exceeded 700 million and is continually growing (GBD Chronic Kidney Disease Collaboration, 2020). As the renal function further deteriorates, by the time the condition progresses to end-stage renal disease (ESRD), patients have no choice but to choose renal replacement therapy such as hemodialysis, peritoneal dialysis, and renal transplantation, of which most ESRD patients receive hemodialysis (Zhang et al., 2020). Although its methods have been increasingly improved recently, there has been no significant reduction in patient mortality (Johansen et al., 2021). It has been demonstrated that the primary cause of death in maintenance hemodialysis (MHD) patients is cardiovascular events (Ahmadmehrabi and Tang, 2018). And inflammation is a key element in disease progression, all-cause and cardiovascular mortality in MHD patients (Liakopoulos et al., 2017; Cobo et al., 2018). Therefore, it is indispensable to recognize and intervene in the inflammatory status of MHD patients timely to promote better survival. However, traditional inflammatory markers, such as tumor necrosis factor-α and interleukin-6, are hardly tested routinely for the inconvenience and high cost of testing.

Ferritin is a primary intracellular iron storing protein and a vital inflammatory response protein in the body, closely related to iron metabolism and inflammatory response of the organism (Moreira et al., 2020). The latest view argues that ferritin is also an aggravating factor of inflammation (Ruscitti and Giacomelli, 2020). In ESRD patients receiving MHD, serum ferritin levels may often be elevated in varying amounts due to underlying systemic inflammation, regardless of the iron stores of the body (Kim et al., 2017). Previous studies have demonstrated that a high serum ferritin level is a significant predictor of death in MHD patients (Jenq et al., 2009; Kuragano et al., 2014; Kuragano et al., 2020). Neutrophil-to-lymphocyte ratio (NLR) is a novel inflammatory index proposed recently, reflecting the balance between anti-inflammatory and pro-inflammatory mechanisms of the body (Buonacera et al., 2022). It is also a prognostic indicator for morbidity and mortality of many diseases, including tumors, cardiovascular disease (CVD), liver disease, and surgical disease (Pineault et al., 2017). Studies have indicated that NLR can be used to predict survival rates in MHD patients (Zhang et al., 2021; Mayne et al., 2022). Serum ferritin and NLR are both easily accessible and inexpensive indicators in clinical practice. However, there is a lack of studies that consider both together. Accordingly, our study intended to assess the relations between serum ferritin and NLR with all-cause mortality in MHD patients and explore the combined predictive value of the two for patient prognosis.

The main findings presented in this study suggest that increased serum ferritin and NLR may be independent risk factors contributing to all-cause mortality for ESRD patients undergoing MHD and may be valuable predictors of outcomes for MHD patients. In addition, the combination of the two is more valuable in predicting the prognosis of patients receiving MHD than either index (p < 0.05).

Initially, ferritin was considered a reflection of iron storage status in the body and later a vital biomarker of inflammatory events in the body (Mahroum et al., 2022). Many inflammatory events of the organism, such as acute or chronic infections, liver disorders, hematological illnesses, and other malignant conditions, are always accompanied by an increase in serum ferritin level (Kernan and Carcillo, 2017). The latest ideas suggest that ferritin may have pathogenic effects and is not an innocent byproduct of inflammation (Sharif et al., 2018; Mahroum et al., 2022). High ferritin level is strongly associated with iron overload (Gattermann et al., 2021). In MHD patients, iron overload could promote the progression of kidney injury by increasing oxidative stress, stimulating inflammation, increasing tissue-iron deposition, and increasing the risk of infection in the organism (Batchelor et al., 2020). Meanwhile, iron overload has been demonstrated to contribute to an elevation in plasma heparin levels, which are strongly associated with the progress of CVD, such as atherosclerotic plaque formation, increased plaque instability and vascular sclerosis (Ueda and Takasawa, 2018). Unfortunately, CVD is widely known as the first death cause for MHD patients (Cozzolino et al., 2018). Our study found that the higher the serum ferritin levels in patients receiving MHD, the higher the risk of poor outcomes, which is consistent with previous findings (Karaboyas et al., 2018; Maeda et al., 2020). In addition, our study obtained the cut-off value of serum ferritin in predicting outcomes of MHD patients, namely, 346.05 μg/L. In an observational cohort study by Shoji et al., they discovered that serum ferritin was U-shaped correlated with overall mortality in MHD (Shoji et al., 2017). That appears a little different from the results of our study, which may be due to varying statistical methods and different patient baseline data. We analyzed it through ROC curves and Kaplan-Meier survival curves. However, Shoji et al. used a traditional baseline model and handled ferritin as a stratification factor (Gafter-Gvili et al., 2019). Furthermore, low serum ferritin levels imply iron deficiency anemia in the organism, which could increase the mortality risk of MHD patients (Afari and Bhat, 2016). Our study did not focus on the effect of low serum ferritin levels, which was a deficiency of this study.

Apart from serum ferritin, we also focused on the NLR--a novel proposed indicator of systemic inflammation in recent years. NLR was proved to have significant prognostic value among various diseases with inflammatory risk, such as CVD, COVID-19, renal cell carcinoma and sepsis (Afari and Bhat, 2016; Çalışkan et al., 2018; Huang et al., 2020; Pirsalehi et al., 2020). In addition, the research by Yilmaz et al. indicated that high NLR was associated markedly with the existence of uric acid and proteinuria in CKD patients (Yilmaz et al., 2017). Wongmahisorn et al.’s research revealed that high NLR was also remarkably correlated with early failure of hemodialysis arteriovenous fistulas in patients receiving MHD (Wongmahisorn, 2019). All those factors are detrimental to the prognosis of MHD patients. In our study, Survival rates were lower in those with higher NLR. Previous studies have reported similar results but did not get a clear threshold to suggest its optimal range (Ouellet et al., 2016; Zhang et al., 2021). Instead, we got the cut-off value for NLR in predicting the prognosis of MHD patients, which is 3.225.

Besides, we plotted the ROC curve for predicting patient outcomes by the combination of serum ferritin with NLR, which shows a more excellent predicting value, with an AUC of 0.849. That appears to be a novel finding, but there is still a need for more multi-center, large-sample clinical trials to further validate it. Therefore, clinicians should be more attentive to serum ferritin and NLR since they are both readily available and low-cost as vital predictors of overall mortality in MHD patients.

In addition, serum ferritin and NLR can serve as targets for therapeutic interventions, not just as biomarkers for disease prognosis. One intervention measure is to restrict the generation of inflammation molecules by avoiding various infections, congestive heart failure, dialyzer incompatibility, and poor water quality (Cobo et al., 2018). Furthermore, establishing a positive living style with appropriate physical exercise, a healthy diet and non-smoking should be significantly encouraged to decrease inflammation (Jankowska et al., 2017). Finally, MHD patients with anemia should take iron supplements appropriately to keep the serum ferritin within a reasonable range, improving their prognosis (Fishbane et al., 2014). However, there remains a lack of consensus regarding the maximum standard serum ferritin levels limit in MHD patients (Malaki, 2018). KDIGO recommends iron supplements if ferritin ≤500 μg/L for CKD patients with anemia (Kidney Disease Improving Global Outcomes, 2012). Practice guidelines from the Renal Association (2017) raise the upper limit of serum ferritin to 800 μg/L when taking iron supplements (Mikhail et al., 2017). The threshold value of serum ferritin derived in our study slightly differs from the above values, probably owing to the Chinese population studied and the small number of samples. Therefore, our findings are more applicable to the Chinese probably. Nevertheless, there is still a need for more high-quality clinical studies to explore this issue.

Meanwhile, the results of the Cox proportional hazard regression analysis showed that combined diabetes, combined heart failure and lower serum albumin levels were independent risk factors of all-cause death among MHD patients. A systematic evaluation noted that diabetes and cardiovascular disease can significantly increase the risk of cardiac death in MHD patients (Ma and Zhao, 2017). Serum albumin may reflect the nutritional status of the body. Previous research has demonstrated that hypoalbuminemia is a significant risk factor for all-cause mortality in MHD patients (Tang et al., 2021). So, it is essential to attend to the management of clinical comorbidities such as diabetes, heart failure and malnutrition to assess patient prognosis comprehensively.

There are still deficiencies in this study. Since patients’ treatment protocols were constantly adjusted according to the actual condition of the organism, some potentially confounding factors, such as medication status and hemodialysis mode, were not incorporated in this study, and their effects on the outcome cannot be excluded. Furthermore, as mentioned previously, the small number of samples may result in biased results. Therefore, there remains a need for clinical trials from multicenter with large samples to validate further the relevance of serum ferritin and NLR to the outcomes of MHD patients.

Serum ferritin and NLR can be predictive factors in the prognosis of MHD patients. Moreover, the combination of the two has a higher predictive value.