The association between statin administration and renal cell carcinoma; a systematic review and meta-analysis

practice/research/medical education: Our meta-analysis showed that statin administration was not associated with the risk of renal cell carcinoma (RCC) development. Moreover, the patient gender and study type did not affect the relationship between statin administration and the incidence risk of RCC. However, the overall survival in administration was 35% higher in statin users compared to non-users. Please cite this paper as: Ramezannezhad P, Khosravifarsani M. The association between statin administration and renal cell carcinoma; a systematic review and meta-analysis. J Renal Inj Prev. 2023; 12(2): e32192


Introduction
Almost 403 000 new cases of renal cancer and 175 000 related deaths occur annually worldwide (1). Renal cell carcinoma (RCC) is the most frequently occurring form of renal cancer, representing approximately 90% of cases (2). It is the sixth most prevalent tumor in men and the tenth most common tumor in women globally, accounting for 5% and 3% of all oncological diagnoses, respectively (3). The incidence of RCC is rising around the globe, with nearly 76 000 new cases estimated in 2021 in the US (4,5).
Smoking, obesity, and family history are three potential risk factors identified for RCC (6).
Statins or 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors are the most common class of drugs prescribed for lowering plasma cholesterol levels that considerably decrease the risk of cardiovascular events and mortality (7,8). Experimental studies have consistently suggested the antineoplastic effects of statins against several tumor types (9)(10)(11). In human observational studies, statin usage has been shown to reduce cancer-specific mortality risk in prostate, colorectal, and breast cancers (12)(13)(14).
At the cellular level, statins have been related to the halting of cell-cycle progression, apoptosis induction, and inhibition of cell signaling pathways implicated in tumor invasion and metastasis (15). Given the scarcity and inconsistency of the existing epidemiological studies regarding statin administration and RCC risk in humans (16,17), this study aims to address the possible relationship between statin usage and RCC incidence using a systematic review and meta-analysis approach.

Study design
This study designed based on PRISMA reporting guidelines for systematic reviews and meta-analyses, and its protocol was registered on the PROSPERO (International Prospective Register of Systematic Reviews) website (CRD42023393647, https://www.crd.york.ac.uk/ prospero/#recordDetails).

Search strategy
International databases, including Scopus, PubMed, Cochrane, Web of Science, as well as the Google scholar search engine, were searched without time restriction in this meta-analysis. The search process was performed using the following keywords: "Renal cell carcinoma, " "Renal cell cancer, " "Renal cell adenocarcinoma, " "Statin, " and "Hydroxymethyl glutaryl coenzyme A reductase inhibitors". The literature search was updated until January 2023. For an advanced query, the mentioned databases were searched using a combination of keywords with Boolean operators "AND" and "OR". The search strategy for the PubMed database is provided as follows; (

PICO components
Population: Studies related to patients with hypercholesterolemia. Intervention: statin usage. Comparison: those not on statin therapy. Outcome: the incidence risk of RCC. Studies evaluating the effect of statin usage on overall survival (OS), disease progression (DP), and progression-free survival (PFS) in RCC patients were examined as the secondary outcome.

Inclusion criteria
This meta-analysis included all case-control and cohort studies investigating the impact of statin usage on RCC incidence.

Exclusion criteria
The studies that met the following criteria were excluded from the study; lacking the required information for data analysis; duplicate studies; case-report studies; studies that examined the effect of statin in combination with another medication on RCC incidence; studies with poor quality according to Newcastle Ottawa Scale (NOS) checklist; studies that explored the effect of stain on tumors other than RCC.

Qualitative assessment
Two researchers performed the quality assessment separately using the NOS (18). Each study was scored ranging from zero to nine, with higher scores indicating higher study quality. The cut-off point of the checklist was set at five in this study. Articles with scores below five were excluded from the study. However, all articles in this meta-analysis were of acceptable quality. A third researcher resolved any potential discrepancies between the two researchers regarding the quality assessment.

Data extraction
To minimize data collection errors, the same two researchers independently extracted the data from the eligible articles and entered them into a checklist containing the author's name, the number of patients, average age, country, publication year, study type, and the odds ratio (hazard ratio) between statin usage and the incidence risk of RCC.

Statistical analysis
The odds ratio (OR) or hazard ratio (HR) was utilized to establish the relationship between statin usage and RCC occurrence. Logarithmic OR (HR) was considered in all studies to pool their results. The heterogeneity of the studies was assessed using the I 2 index. Random effects model was adopted, given the high heterogeneity of the studies (I 2 =92.4%). With the help of STATA 14 software, the data were statistically analyzed. The significance level of the tests was considered P < 0.05.

Results
Initially, 521 studies were retrieved by searching in databases and the Google Scholar search engine. After checking the titles, 189 duplicates were removed, and the abstracts of 332 studies were screened. At this stage, 85 articles were excluded due to irrelevancy, incomplete abstracts, and unavailable full text. The remaining 247 were assessed for potential inclusion. After applying the other exclusion criteria, ultimately, 15 articles with high quality entered the systematic review and meta-analysis process (Figure 1). A part of the information of the reviewed articles is given in Table 1.

Evaluation of secondary outcomes
The impact of statin usage on OS in RCC was 0.65 (HR: 0.65; 95% CI: 0.53, 0.80, P = 0.114, I 2 = 43.6%). This relationship was statistically significant, with statin usage improving the overall cancer survival in RCC patients ( Figure 3).

Discussion
By screening 15 articles in this meta-analysis, we found that the OS rate for RCC patients was 35% higher in statin users than in non-users. Nevertheless, no relationship between statin usage and the risk of RCC incidence, RCC progression, and PFS was observed. However, the obtained results might have been drastically different if it was possible to stratify the identified studies by statin dose and duration.
The Similar results were also achieved from nine case-control studies (OR = 1.03, 95% CI: 0.99 to 1.07) (34). Our results corroborate those of the above meta-analysis, suggesting   (36), which was in line with the results of our study. One reason for the consistency between our results and those of the Nayan et al study may be that RCC is the most common subtype of renal cancer.

Conclusion
Our results suggested that statin usage was not associated with the risk of RCC development. Moreover, the patient gender and study type did not affect the relationship between statin usage and the incidence risk of RCC. However, the OS in RCC was 35% higher in statin users compared to non-users. Nonetheless, statin usage did not influence DP and PFS in RCC patients. Given the limitations of this study, further clinical trials in this area are essential.

Limitations of the study
This study faced limitations, including the limited number of studies and not stratifying the outcomes by statin dose, type, and duration.    a lack of a statistically significant relationship between statin usage and cancer development, including prostate, bladder, and renal cancers.
A previous meta-analysis by Wu et al (2020), comprising five studies and 5299 patients, assessed the relationship between statin usage and OS in RCC patients. Based on