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BACKGROUND The chronic kidney disease (CKD) public health burden is substantial and has not declined as expected with current interventions on disease treatments. A large number of clinical, biological, and behavioural risk factors have been associated with CKD. However, it is unclear which of them are causal. OBJECTIVE To systematically test whether previously reported risk factors for CKD are causally related to the disease in European and East Asian ancestries. DESIGN Two-sample Mendelian randomization (MR) and non-linear MR analyses. PARTICIPANTS 53,703 CKD cases and 960,624 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13,480 CKD cases and 238,118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo. MEASURES Systematic literature mining of PubMed studies identified 45 clinical risk factors and biomarkers with robustly associated genetic variants, including phenotypes related to blood pressure, diabetes, glucose, insulin, lipids, obesity, smoking, sleep disorders, nephrolithiasis, uric acid, coronary artery disease, bone mineral density, homocysteine, C-reactive protein, micro-nutrients and thyroid function, which were selected as exposures. The outcome was CKD (defined by clinical diagnosis or by estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m2). RESULTS Eight risk factors showed evidence of causal effects on CKD in European ancestry, including body mass index (BMI), hypertension, systolic blood pressure, high density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A, type 2 diabetes (T2D) and nephrolithiasis. In East Asian ancestry, BMI, T2D and nephrolithiasis showed evidence of causal effects on CKD. Hypertension showed reliable evidence of a strong causal effect on CKD in Europeans but in contrast appeared to show a null effect in East Asians, suggesting the possibility of different causal risk factors in Europeans and East Asians. Although liability to T2D showed consistent effects on CKD, the effect of glycemic traits on CKD was weak, suggesting T2D may have glucose-independent mechanisms to influence CKD. Non-linear MR indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI above 25 kg/m2. LIMITATION Due to the unbalanced distribution of data between ancestries, we could only test 17 of the 45 risk factors in East Asian participants. CONCLUSIONS Eight CKD-associated risk factors showed evidence of causal effects on the disease in over 1.2 million European and East Asian ancestries. These risk factors were predominantly related to cardio-metabolic health, which supports the shared causal link between cardio-metabolic health and kidney function. This study provides evidence of potential intervention targets for primary prevention of CKD, which could help reduce the global burden of CKD and its cardio-metabolic co-morbidities.

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