Lung cancer is the most common malignant tumor with the highest mortality worldwide, with an estimated 2.20 million new cases and 1.79 million deaths annually (1, 2). It is divided into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) according to different tissue types. Because the early clinical manifestations of lung cancer are not obvious, most patients are already in the advanced stage when diagnosed, and the 5-year survival rate is low. Therefore, improving the early diagnosis rate of lung cancer is the key to improving the 5-year survival rate. A tumor marker is an active substance synthesized and secreted by tumor cells during tumor formation. Detecting serum tumor markers for lung cancer is a non-invasive procedure with important value in diagnosing, monitoring, and evaluating the prognosis of lung cancer.

Lung cancer-related serum markers commonly include carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cytokeratin fragment 19 (CYFRA21-1), Pro-gastrin-releasing peptide (ProGRP), squamous cell carcinoma antigen (SCCA). Studies have reported that carbohydrate antigen 125 (CA125) is important in the diagnosis and metastasis prediction of lung cancer (3, 4). Recently, studies have also explored human epididymis protein 4 (HE4) as a lung cancer biomarker. The results show that serum HE4 levels are elevated in lung cancer patients of various tissue types, which has an auxiliary role in lung cancer screening (5, 6). The value of Lung cancer-related serum tumor markers in the general population has been widely recognized. However, the concentrations of certain tumor markers are elevated even in the absence of malignancy in chronic kidney disease (CKD) (7). It is mainly due to impaired renal metabolism and excretion, which greatly limits the application of some tumor markers in early diagnosis and treatment monitoring. The utility of tumor markers in diagnosing cancer in patients with renal insufficiency remains controversial (8). In recent years, more and more studies have found that reduced kidney function is associated with a higher risk of cancer. The risk for kidney and lung cancers was higher among those with advanced CKD (9–11). For CKD, patients should be integrated into risk stratification of cancer screening and management. Cancer and CKD both affect many people (1, 12). Issues related to tumor markers in patients with CKD are a matter of concern. It is very important to determine their levels in CKD patients to avoid misinterpretation of Lung cancer-related serum tumor markers in arriving at the diagnosis of lung malignant tumor. Based on the above background, this study intends to explore the level changes and clinical diagnostic value of lung cancer-related serum tumor markers in patients with chronic kidney disease, and to preliminarily determine the upper reference limit for patients with different stages, so as not to confuse with early or preneoplastic stages of malignancy. Provide laboratory support for the rational use of Lung cancer-related serum tumor markers in special populations.

Impaired kidney function is not only associated with an increased risk of cancer but is also a feature of many cancer patients. Serum tumor markers are protein substances secreted or shed by tumor cells. Their content is extremely low in healthy people. Elevated serum concentrations often indicate the occurrence of malignant tumors. Each tumor marker has a variable profile of usefulness for screening, determining diagnosis and prognosis, assessing response to therapy, and monitoring for cancer recurrence. We are still unclear about the body’s metabolic process of tumor markers. In clinical applications, it has been found that in addition to related tumors, their concentrations will also be abnormal in the menstrual cycle, pregnancy, metabolism, inflammation, liver function and (or) renal function abnormalities (14). CKD is a disease that seriously endangers human health, with a prevalence of 10.8% in the adult population in China (15). Regardless of the occurrence of malignant tumors, the concentrations of some tumor markers in CKD patients will be higher than those in healthy subjects. However, the impaired renal function does not alter all tumor markers (7). Which indicators will be affected and to what extent is unclear. In this study, the serum tumor markers related to lung cancer levels in CKD patients were analyzed. It was found that the levels of HE4, CYFRA21-1, SCCA and ProGRP were significantly increased in CKD patients. In addition, with the increase in the CKD stage, the false positive rate of the four tumor markers gradually increased significantly. The level of CA125 was not affected in the early stage of CKD and only increased significantly in the late stage. In contrast, the level of NSE was hardly affected by renal function.

Renal insufficiency, dialysis, and kidney transplantation were associated with an increased risk of lung cancer. However, studies have shown that commonly used serum Lung cancer-related tumor markers are elevated in patients with decreased renal function. In a study by Jianzhong Chen et al. (16) in patients with diabetic nephropathy, serum SCCA and CYFRA21-1 levels were significantly increased, while NSE was unaffected. It is worth noting that this study only investigated renal insufficiency due to diabetic nephropathy, while we further analyzed patients with CKD due to various causes and obtained the same results. K. Kamata et al. (17) reported elevated serum proGRP levels in patients with renal insufficiency. Linda Hertlein et al. (18) Among other benign diseases, including lung and ovarian cancer, HE4 concentrations were highest in women and men with renal failure. Our study also found that serum HE4 and ProGRP levels were significantly increased in non-tumor CKD patients. With the aggravation of CKD staging, the average levels of each stage increased, and their levels were significantly different in each stage, which adds new and further evidence to the previous studies. The results of studies on serum CA125 concentrations in CKD patients vary. Some studies have shown that serum CA125 levels in CKD patients are higher than in healthy controls. Still, there is no significant correlation with eGFR (19). Some studies have found significant differences in CAl25 levels in patients with different stages of CKD. In contrast, other studies have shown no exact relationship between CKD stages and CAl25 levels (20). This study did not find significant differences in CA125 levels between CKD patients and healthy controls after adjusting for age confounding variables. But further observed that CA125 levels in different CKD stages were not affected in the early stage of CKD, and only significantly increased in the late stage.

In this study, we found that the changes in HE4, ProGRP, SCC, and CYFRA21-1 in CKD patients had a certain relationship with the CKD stage. The correlation analysis also showed that their levels were significantly positively correlated with creatinine. The false-positive rate of HE4 was also significantly better than that of NSE and CA125. The above results showed that the degree of increase of indexes such as HE4 was closely related to the severity of renal damage. Some indexes showed an increasing trend in the early stage of renal damage.

In addition, to more reasonably interpret the results of Lung cancer-related tumor markers in CKD patients, early detection of tumors can prevent missed diagnosis and missed treatment while simultaneously avoiding the waste of medical resources caused by misdiagnosis and mistreatment. Based on some principles established by the reference interval, this study determined the upper reference limit for CKD patients of different stages so that clinicians can make timely and accurate judgments on the tumor marker results of CKD patients. Unfortunately, due to the insidious nature of the onset of CKD, patients are often not at an early stage when they seek medical attention. Therefore, no CKD stage 1 patients were included in this study. The upper reference limit of the above indicators in patients with CKD1 stage cannot be determined. It is impossible to assess whether indicators such as HE4 are more advantageous in diagnosing earlier renal injury.

Moreover, this study estimates the reference range of CKD patients based on the included research subjects. The results have certain limitations due to the influence of the sample size. Further studies with large samples are needed to determine a more accurate reference range.

Serum levels of HE4, ProGRP, CYFRA21-1, SCC and CA125 were closely related to renal function, while NSE levels were not. This study preliminarily determined the upper reference limits of Lung cancer-related tumor markers in patients with different CKD stages and provided laboratory support for the rational use and interpretation of Lung cancer-related tumor markers in special populations.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by the Ethics Committee of the West China Hospital, Sichuan University. The patients/participants provided their written informed consent to participate in this study.

All authors contributed to the study’s conception and design. QM, BC, and QN performed material preparation, data collection and analysis. JZ and QM wrote the first draft of the manuscript. All authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.