Comment Regarding “Gallstones, Cholecystectomy, and Kidney Cancer: Observational and Mendelian Randomization Results Based on Large Cohorts”

In their recent publication, "Gallstones, Cholecystectomy, and Kidney Cancer: Observational and Mendelian Randomization Results Based on Large Cohorts," Kharazmi et al1Kharazmi E. et al.Gastroenterology. 2023; 165: 218-227.e8Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar aim to describe the relationship between gallstones and kidney cancer. We appreciate their work; they describe an association in a nationally representative and large population cohort using Mendelian randomization, which uses genetic variants in nonexperimental designs to decrease confounding.2Lee K. Lim C.Y. J Lipid Atheroscler. 2019; 8: 67-77Crossref PubMed Scopus (46) Google Scholar It remains uncertain what the molecular and mechanistic explanation is for this association. Gallstone disease and kidney cancer share risk factors such as obesity, metabolic syndrome, and diabetes, and alterations in lipid metabolism has been described in both diseases.3Di Ciaula A. et al.Curr Opin Gastroenterol. 2018; 34: 71-80Crossref PubMed Scopus (122) Google Scholar,4Bobulescu I.A. et al.Metabolites. 2021; 11: 608Crossref PubMed Scopus (15) Google Scholar It is plausible that similar alterations in metabolism could lead to both gallstones and kidney cancer and that, despite the thorough analysis, gallstones may just represent a confounding effect. Although the authors' model accounts for diabetes, smoking, and body mass index, additional variables such as serum cholesterol, metabolic syndrome, or altered lipid metabolism are not accounted for in the model and could also be drivers of this association. The authors also show a particularly high relative risk of developing kidney cancer in the first 6 months after surgery, which then opens the question of whether the cholecystectomy itself may induce or accelerate kidney cancer development. An important consideration is that the majority of renal masses are diagnosed incidentally, with the likelihood of finding a renal mass in a patient undergoing cross-sectional imaging reported to be as high as 14.4%.5Vasudev N.S. et al.BMJ Open. 2020; 10e035938Crossref PubMed Scopus (48) Google Scholar,6O'Connor S.D. et al.AJR Am J Roentgenol. 2011; 197: 139-145Crossref PubMed Scopus (116) Google Scholar There may be an unaccounted surveillance bias in patients that underwent a cholecystectomy within 6 months, because they may be imaged more frequently after surgery to rule out potential complications. It is plausible that patients with incidental renal masses are not found upon initial workup of gallstones, which is typically done with right upper quadrant ultrasound examination, but then are discovered after cholecystectomy when cross-sectional imaging is performed. Last, although the use of the International Classification of Diseases codes to detect patients with renal cancer is appropriate, there are no additional data on the kidney cancer diagnosis. It would be interesting to know what portion of the patients had small renal masses that were detected incidentally but did not require intervention, as well as the histologic distribution of these patients. We hypothesize that there may be a higher rate of clear cell renal cell carcinoma in the gallstone population, as they share risk factors. We value the data presented in this article; it is thought-provoking and worthy of further investigation regarding the underlying molecular mechanism. At present, we do not feel these findings are strong enough to justify screening for kidney cancer in patients with gallstones or history of cholecystectomy owing to the absence of a cost–benefit analysis or prospective evidence to support its use. Gallstones, Cholecystectomy, and Kidney Cancer: Observational and Mendelian Randomization Results Based on Large CohortsGastroenterologyVol. 165Issue 1PreviewThe number of gallbladder operations to treat gallstones continues to rise. Patients with gallstone disease have an increased risk of kidney cancer shortly after and even many years after gallbladder surgery. Full-Text PDF Open AccessReplyGastroenterologyVol. 165Issue 5PreviewWe gratefully appreciate the interest of Dr Chinitz at Montefiore Medical Center and Drs Posada Calderon, Strasser, and Brant at Weill Cornell Medicine concerning our article "Gallstones, Cholecystectomy, and Kidney Cancer: Observational and Mendelian Randomization Results Based on Large Cohorts."1 We agree with Posada Calderon et al that further investigation into the subtypes of kidney cancer and the molecular mechanisms underlying the association between gallstones and kidney cancer, as well as future prospective randomized controlled trials and cost–benefit studies, are needed to assess the potential benefits of cancer screening in patients with gallstone disease. Full-Text PDF