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BACKGROUND: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation. METHODS AND FINDINGS: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose. CONCLUSIONS: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.

Purpose: To compare renal function and survival outcomes in patients with baseline chronic kidney disease (CKD) stage 2 undergoing partial (PN) or radical nephrectomy (RN), as nephron-sparing surgery is considered to be elective in this group. Methods: Retrospective analysis of patients with CKD stage 2 and T1/T2 renal mass undergoing PN or RN from 2001 to 2015. Patients were stratified into substage CKD 2a or CKD 2b and analyzed between types of surgery. Primary outcome was overall survival (OS), eGFR < 45 at last follow-up was the secondary outcome. Multivariable analysis (MVA) was conducted for predictors of eGFR < 45 and OS. Kaplan–Meier analyses were conducted for freedom from eGFR < 45 and OS. Results: 1213 patients analyzed (CKD 2a 609/CKD 2b 604) on MVA, RN (OR 3.68, p = 0.001) and CKD 2b (OR 3.3, p = 0.002) were independently associated with development of eGFR < 45 at last follow-up and RN (OR 3.76, p = 0.005) and eGFR < 45 (OR 2.51, p = 0.029) were associated with decreased OS. Kaplan–Meier analyses revealed that patients with CKD 2a/PN had the highest 5-year freedom from eGFR < 45 (94.3%) compared to CKD 2a/RN patients (91.5%), CKD2b/PN patients (87.6%) and CKD 2b/RN patients 82.0% (p < 0.001). Kaplan–Meier analyses for OS demonstrated that patients with CKD 2a/PN had significantly greater 5-year OS (97.6%) compared to CKD 2a/RN patients (95.2%), CKD 2b/PN patients (93.2%), and CKD 2b/RN patients (92.4%, p = 0.043). Conclusions: Patients with baseline CKD stage 2, particularly CKD 2b and undergoing RN, are at increased risk of GFR < 45, which was associated with decreased OS. In patients with CKD 2b, a nephron-sparing strategy is indicated and should be prioritized when feasible.