Background Obesity and type 2 diabetes (T2D) are correlated risk factors for chronic kidney disease (CKD). Methods Using summary data from GIANT (Genetic Investigation of Anthropometric Traits), DIAGRAM (DIAbetes Genetics Replication And Meta-analysis), and CKDGen (CKD Genetics), we examined causality and directionality of the association between obesity and kidney function. Bidirectional 2-sample Mendelian randomization (MR) estimated the total causal effects of body mass index (BMI) and waist-to-hip ratio (WHR) on kidney function, and vice versa. Effects of adverse obesity and T2D were examined by stratifying BMI variants by their association with WHR and T2D. Multivariable MR estimated the direct causal effects of BMI and WHR on kidney function. The inverse variance weighted random-effects MR for Europeans was the main analysis, accompanied by several sensitivity MR analyses. Results One standard deviation (SD ≈ 4.8 kg/m2) genetically higher BMI was associated with decreased estimated glomerular filtration rate (eGFR) [β=−0.032 (95% confidence intervals: −0.036, −0.027) log[eGFR], P = 1 × 10−43], increased blood urea nitrogen (BUN) [β = 0.010 (0.005, 0.015) log[BUN], P = 3 × 10−6], increased urinary albumin-to-creatinine ratio [β = 0.199 (0.067, 0.332) log[urinary albumin-to-creatinine ratio (UACR)], P = 0.003] in individuals with diabetes, and increased risk of microalbuminuria [odds ratios (OR) = 1.15 [1.04–1.28], P = 0.009] and CKD [1.13 (1.07–1.19), P = 3 × 10−6]. Corresponding estimates for WHR and for trans-ethnic populations were overall similar. The associations were driven by adverse obesity, and for microalbuminuria additionally by T2D. While genetically high BMI, unlike WHR, was directly associated with eGFR, BUN, and CKD, the pathway to albuminuria was likely through T2D. Genetically predicted kidney function was not associated with BMI or WHR. Conclusions Genetically high BMI is associated with impaired kidney function, driven by adverse obesity, and for albuminuria additionally by T2D.

中文翻译：

---

肥胖与肾功能：双样本孟德尔随机研究

背景 肥胖和 2 型糖尿病 (T2D) 是慢性肾脏病 (CKD) 的相关危险因素。方法 使用来自 GIANT（人体测量特征的遗传调查）、DIAGRAM（糖尿病遗传学复制和荟萃分析）和 CKDGen（CKD 遗传学）的汇总数据，我们检查了肥胖与肾功能之间关联的因果关系和方向性。双向 2 样本孟德尔随机化 (MR) 估计了体重指数 (BMI) 和腰臀比 (WHR) 对肾功能的总因果影响，反之亦然。通过根据 BMI 变量与 WHR 和 T2D 的关联对它们进行分层来检查不良肥胖和 T2D 的影响。多变量 MR 估计了 BMI 和 WHR 对肾功能的直接因果影响。欧洲人的逆方差加权随机效应 MR 是主要分析，伴随着几个敏感性 MR 分析。结果 一个标准差 (SD ≈ 4.8 kg/m2) 遗传上较高的 BMI 与估计肾小球滤过率 (eGFR) 降低相关 [β=−0.032（95% 置信区间：−0.036，−0.027）log[eGFR]，P = 1 × 10−43]，血尿素氮 (BUN) 增加 [β = 0.010 (0.005, 0.015) log[BUN]，P = 3 × 10−6]，尿白蛋白肌酐比增加 [β = 0.199 ( 0.067, 0.332) log[尿白蛋白与肌酐比值 (UACR)]，P = 0.003] 在糖尿病患者中，微量白蛋白尿的风险增加 [比值比 (OR) = 1.15 [1.04–1.28]，P = 0.009]和 CKD [1.13 (1.07–1.19)，P = 3 × 10−6]。WHR 和跨种族人群的相应估计总体上相似。这些关联是由不良肥胖驱动的，微量白蛋白尿是由 T2D 驱动的。虽然与 WHR 不同，遗传性高 BMI 与 eGFR、BUN 和 CKD 直接相关，但白蛋白尿的途径可能是通过 T2D。遗传预测的肾功能与 BMI 或 WHR 无关。结论 遗传性高 BMI 与由不良肥胖驱动的肾功能受损相关，另外与 T2D 相关的白蛋白尿相关。