Risk factors for renal cell carcinoma: An umbrella review of systematic reviews and meta-analyses

Renal cell carcinoma (RCC) is the most common type of kidney malignancy. However, evidence regarding its risk factors has not been systematically synthesized. This umbrella review aimed to summarize the existing evidence and establish an evidence-based framework for interpreting these associations. Up to January 2026, a systematic search was conducted in PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews. Methodological quality of systematic reviews or meta-analyses (SRs/MAs) was assessed using AMSTAR 2, while the certainty of evidence was evaluated with GRADE and further categorized according to the evidence classification criteria. Through a systematic search and selection process, 44 SRs/MAs were identified, of which 32 were included for data extraction. A total of 84 unique summary effect estimates were extracted and classified into three domains: lifestyle factors, circulating biomarkers, and disease and treatment-related factors. Methodological quality of 32 SRs/MAs by AMSTAR 2 ranged from critically low to moderate. GRADE assessment indicated that most associations were supported by very low quality evidence, with only 7 rated as low (moderate alcohol drinking, HCV infection, obesity, ever smoking, kidney transplantation, heart transplantation and each additional serving/day of vegetable intake). Among the statistically significant exposures, 4 were supported by Class I evidence, whereas 10, 10, and 18 were categorized as Class II, Class III, and Class IV evidence, respectively. Low quality evidence suggests that obesity, HCV infection, ever smoking, and solid organ transplantations (kidney, heart) are associated with an increased risk of RCC, whereas an increased daily intake of vegetables is associated with reduced risk. Notably, low quality evidence indicates that moderate alcohol drinking is linked to a lower risk of RCC, but this finding requires further validation from more large-scale, long-term follow-up studies, even though it has been assigned to Class I evidence. Overall, given the low to very low certainty of the evidence in this umbrella review, these findings should be interpreted cautiously, and further high quality prospective studies are warranted to validate these associations.