Renal cell carcinoma (RCC) is a common malignant tumor in adults, and its incidence has been increasing over the past two decades (1). In 2020, approximately 73,750 new RCC cases and 14,830 deaths were predicted in the United States (2). Despite an increase in early detection of RCC, nearly 20% of patients already have local progression or metastasis disease at initial diagnosis (3). Moreover, postoperative cancer recurrence occurs in 20%–40% of patients with localized RCC (4). Thus, it is of great value to define the prognostic indicators of survival, metastasis, or recurrence in patients with RCC.

Tumor, node, and metastasis (TNM) staging is an essential traditional prognostic factor for RCC, with limited accuracy when used alone (5, 6). Numerous clinical prognostic or predictive factors have been identified based on clinical trials and retrospective univariate or multivariate analysis, including performance status, appearing symptoms, and paraneoplastic syndromes (7–9). Besides, laboratory values were also used for prognosis, such as serum protein, corrected calcium, erythrocyte sedimentation rate, and neutrophil to lymphocyte ratio (10–12).

Aspartate transaminase (AST) and alanine transaminase (ALT) are the most critical transaminase in the body, reflecting hepatocellular damage (13). The ratio of serum AST to ALT, also known as the De Ritis ratio, is usually used to identify the etiology of various hepatitis (14). Recent studies have confirmed that the De Ritis ratio is a biomarker that can predict the prognosis of several tumors, such as breast cancer, gastric adenocarcinoma, and nasopharyngeal cancer (15–17). However, the prognostic value of this ratio in patients with RCC remains unclear. Bezan et al. (18) found that patients with a high De Ritis ratio had inferior overall survival (OS) and metastasis-free survival (MFS), while another study reported no correlation between high DR Ritis rate and OS (19). Therefore, this study aims to explore the prognostic value of the pretreatment De Ritis ratio in patients with RCC and provide higher-level medical evidence for clinical practice.

RCC is one of the most common solid lesions in the kidney, accounting for about 80%–90% of all renal malignancies (1). The prognosis of RCC is affected by various factors, including patient age, clinical manifestations, laboratory values, and tumor pathologic variables such as pathological stage, nuclear grade, and histological subtype (32, 33). Tumor stage and grade are considered as common prognostic markers for RCC, but the application of these factors in clinical practice remains problematic (34). How to more accurately identify those patients with poor prognosis before treatment and carry out the risk stratification of tumors are of great significance for choosing treatment options and the guidance of postoperative follow-up. Therefore, finding potential prognostic markers for RCC prognosis has become a hot spot in clinical research.

Initially, the serum De Ritis ratio was adopted to evaluate the prognosis of various liver diseases, including viral hepatitis, alcoholic hepatitis, and fatty liver (14). Because laboratory tests are routinely performed before treating cancer patients, the De Ritis ratio can be a simple, convenient, and inexpensive measurement method. Previous studies have reported that the De Ritis ratio was significantly associated with the prognosis of several tumors, including RCC (15–18). However, the actual prognostic value of this ratio in patients with RCC remains controversial. Su et al. (35) conducted a meta-analysis to explore the prognostic value of the De Ritis ratio in urological cancers, and 6 articles focused on RCC were included. They claimed that the patients with a higher De Ritis ratio had inferior OS (4 studies involved). A problem of the study by Su is their interpretation of OS since the data provided by the original research in their studies all indicated that an elevated De Ritis ratio had poor survival. Furthermore, a recent study reported that the De Ritis ratio was not associated with RCC prognosis (31). Thus, it is necessary to reevaluate the role of the De Ritis ratio in the prognosis of RCC based on the existing literature to better guide clinical practice.

Compared with the study by Su, the advantage of the current meta-analysis is that we included five more recent articles and eventually included 6,528 RCC patients for the analysis. The study revealed that patients with a higher pretreatment De Ritis ratio had worse survival outcomes regarding OS and CSS. Subgroup analyses of OS and CSS by ethnicity, disease stage, treatment method, cutoff value, analysis method, or sample size obtained similar results. Previous studies have suggested that histological subtypes are also prognostic factors for RCC (33). However, it was not possible to perform a subgroup analysis to assess the impact of different histological subtypes of the De Ritis ratio on prognosis due to lack of data. Remarkably, Lee et al. (25) found that a higher De Ritis ratio was associated with OS and CSS in localized clear-cell RCC patients, but not in non-clear-cell RCC. Janisch et al. (31) also revealed that an elevated De Ritis ratio was an unfavorable factor for OS in patients with clear-cell histology. Since these favorable results were obtained based on limited studies and insufficient sample sizes, therefore, a prospective large-scale cohort is needed to validate the conclusion.

It should be noted that sensitivity analyses indicated that our results were robust, but moderate heterogeneity among the included studies was found in both survival outcomes, a finding that may be due to different baseline characteristics of individual studies. Therefore, the meta-regression analysis was performed using ethnicity, disease stage, treatment method, cutoff value, analysis method, and sample size to explore the potential sources of heterogeneity. However, none of these factors can explain the heterogeneity of OS. Similar results were obtained for CSS. We also performed a subgroup analysis to investigate the cause of heterogeneity. The results showed that the heterogeneity of most subgroup analyses was slightly reduced, but it was still statistically significant in several subgroups. Thus, the random-effect model was used to calculate the effect size to minimize the impact of heterogeneity on the combined results. In addition, although we have conducted an extensive literature search, we still found a potential publication bias in the study reporting survival outcomes. We used the trim and fill method for further analysis and found that the inclusion of uncollected studies did not influence the results of the pooled effect, which suggests that publication bias may not have a significant effect on the overall findings. Therefore, the results of this study are relatively robust and reliable.

ALT and AST are often used to reflect hepatocellular damage or death. ALT is mainly present in the liver, while AST is widely distributed in various tissues such as the heart, liver, brain, muscle, and kidney tissues (14). Hence, ALT suggests liver disease specifically, while AST may be associated with several diseases that affect other organs. Pathological processes that have been proved to cause tissue damage, high proliferative states, and faster tumor cell turnover tend to enhance the serum AST level rather than ALT level, making the De Ritis (AST/ALT) ratio an attractive potential clinical biomarker (36).

Although the De Ritis ratio is a promising marker, the specific mechanism of this higher ratio and the inferior prognosis of cancer patients remain unclear. Indeed, cancer cells have a higher rate of glycolysis compared with normal cells, even in the presence of oxygen, and abnormal glycolytic metabolism produces sufficient ATP to promote cancer cell proliferation; this phenomenon is known as the “Warburg effect” (37, 38). Increased glycolysis in tumor cells is thought to be related to changes in nicotinamide adenine dinucleotide (NAD)-related enzymes and glucose transporters within mitochondria, according to Dorward et al. (39). A higher lactate dehydrogenase and cytosolic (NADH)/NAD+ ratio plays an essential role in maintaining enhanced glycolysis (40). It must be highlighted that AST is a pivotal component of the malate–aspartate shuttle in the glycolysis pathway that relocates NADH into mitochondria (14). Moreover, the previous study had confirmed that von Hippel-Lindau (VHL) significantly associated with renal clear-cell type RCC was presented in the cytoplasm of mitochondria (41). The loss of VHL and an increase in hypoxia-inducible factor expression influence several metabolic pathways, including glycolysis and oxidative phosphorylation (42). Accordingly, AST may be related to the glycolysis mechanism of clear-cell type RCC with VHL loss (25). However, further investigation is needed to explore the exact mechanism.

Considering that serum ALT and AST are commonly used indicators of clinical hematology, they are simple and easy to measure, and the cost is low. Therefore, the pretreatment De Ritis ratio can be used as an effective prognostic marker in patients with RCC and applied in clinical diagnosis and treatment. Our meta-analysis affirms that patients with an increased pretreatment De Ritis ratio had worse survival outcomes. It could be a potential selection criterion for the hierarchical management of risk factors for RCC (18). Given that a prognostic factor must be verified in well-designed, large-scale with an independent cohort before it can be applied universally, the findings should be interpreted cautiously.

Although the study provides more substantial evidence for the prognostic value of the pretreatment De Ritis ratio in patients with RCC, there are certain limitations. Firstly, the sample size of some of the included studies is relatively small, which may lead to a biased conclusion. Secondly, all included studies were retrospective, which may have an inherent structural bias, and the duration of follow-up was relatively short. Thirdly, similar to the study by Su (35), since this study only includes published literature, it may have potential publication bias. Fourth, patients could not be stratified according to histology due to lack of data. However, we conducted subgroup analysis based on sample size, study population, and disease status to explore potential sources of heterogeneity, which made our results more robust. Fifth, although the included studies attempted to exclude all patients with liver disease, there were still undetected liver pathological conditions that could affect the serum AST or ALT levels and distort the De Ritis ratio.

Available evidence suggests that patients with an increased pretreatment De Ritis ratio have worse OS and CSS, indicating that this ratio may serve as a potential prognostic biomarker in RCC patients. However, prospective, well-designed, and large-scale studies are warranted to validate our findings.

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

Ethical review and approval were not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

YL and QW: conception and design. JL, DC, CM, and LP: acquisition of data and critical revision of the manuscript for important intellectual content. JL, DC, and ZX: analysis and interpretation of data. JL and DC: drafting of the manuscript. QW: supervision. All authors contributed to the article and approved the submitted version.

This work was funded by the National Natural Science Foundation of China (Grant Number 82000721), Post-Doctor Research Project, West China Hospital, Sichuan University (Grant Number 2019HXBH089), Health Commission of Sichuan province (Grant Number 20PJ036), and the Sichuan Province Science and Technology Planning Project (Grant Numbers 2020YJ0054, 2020YFS0320).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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