Reassessing obesity and smoking as renal cell carcinoma risk factors: TriNetX 2016-2025 analysis.

Abstract

e16527 Background: Obesity and smoking are established risk factors for renal cell carcinoma (RCC). Most prior studies predate widespread adoption of ICD-10, which reliably differentiates between renal parenchymal and urothelial malignancies of the renal pelvis and ureter. Earlier studies grouped tumor types and used non-specific obesity definitions, potentially producing inaccurate risk estimates. A contemporary reassessment, employing precise tumor classification and detailed obesity definitions, is warranted. Methods: We conducted a retrospective cohort study using TriNetX. Patients (≥18 years) who received care using a general medical evaluation code (ICD-10 Z00) were included. Three exposure cohorts were defined: class I–II obesity (BMI 30.0–39.9 kg/m²), class III obesity (BMI ≥40.0 kg/m²), and smoking exposure. Patients with urothelial malignancies of the renal pelvis or ureter (C65–C66) were excluded. The primary outcome was incident RCC through 5 years. Propensity score matching (1:1) was performed. Obesity analyses were matched on clinical covariates, with smoking status included, while smoking analyses included BMI. Covariates included age, sex, race, ethnicity, hypertension, chronic kidney disease, type 2 diabetes mellitus, and chronic obstructive pulmonary disease. Analyses were conducted within the TriNetX platform. Patients were censored at the last follow-up. Results: The study included 2,487,294 patients with class I–II obesity, 1,779,240 with class III obesity, and 2,396,453 smokers. RCC incidence was 0.44% in class I–II obesity, 0.52% in class III, and 0.43% among smokers, compared with 0.20–0.23% in controls. Obesity and smoking were independently associated with RCC risk. Class III obesity demonstrated the strongest association (relative risk [RR], 2.26; 95% CI, 2.21–2.31; P < 0.001), followed by class I–II obesity (RR, 1.94; 95% CI, 1.90–1.98; P = 0.001). Smoking demonstrated elevated RCC risk (RR, 1.57; 95% CI, 1.54–1.61; P < 0.001). Conclusions: In a large, contemporary U.S. study, obesity demonstrated a stronger and graded association with RCC risk than smoking. These findings suggest that earlier studies may have overestimated smoking-associated risk and underestimated obesity-associated risk due to the inclusion of urothelial malignancies and non-specific obesity coding. Smoking and obesity remain independent and modifiable risk factors for RCC. To our knowledge, this is the first large-scale study to reassess these risk factors specifically in renal parenchymal tumors, excluding renal pelvis tumors. Exposure Group Patients (n) RCC Events (n) Relative Risk Ratio for RCC (95% CI) P Value Obesity Class I–II (BMI 30-39.9) 2487294 10879 1.94 (1.90–1.98) 0.001 Class III Obesity (BMI 40) 1779240 9310 2.26 (2.21–2.31) <0.001 Non-obese Controls 15382621 30355 Reference Smokers 2396453 10318 1.57 (1.54–1.61) <0.001 Never Smokers 17811442 40804 Reference