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Trans-ethnic Mendelian-randomization study reveals causal relationships between cardiometabolic factors and chronic
Jie Zheng1, Yuemiao Zhang2, Humaira Rasheed1,3
1MRC Integrative Epidemiology Unit (IEU), Bristol Medical School, University of Bristol, Oakfield House, Oakfield Grove, Bristol, UK.
Insights
This study used Mendelian randomization to identify causal risk factors for chronic kidney disease (CKD). Eight factors, including BMI and hypertension, were causally linked to CKD in Europeans, while three were identified in East Asians.
Area of Science:
- Genetics
- Epidemiology
- Nephrology
Background:
- Chronic kidney disease (CKD) is a significant global health concern.
- Identifying causal risk factors is crucial for effective prevention and treatment strategies.
- Previous studies suggested several risk factors, but causal relationships require robust validation.
Purpose of the Study:
- To systematically investigate the causal relationships between reported risk factors and CKD.
- To differentiate causal links across European and East Asian ancestries.
- To inform the development of targeted interventions for CKD prevention.
Main Methods:
- Mendelian randomization analysis was employed to assess causality.
- Genetic data from large cohorts of European (n=51,672 cases, 958,102 controls) and East Asian (n=13,093 cases, 238,118 controls) ancestries were utilized.
- CKD was defined by clinical diagnosis or estimated glomerular filtration rate <60 ml/min/1.73 m².
Main Results:
- Eight risk factors demonstrated causal effects on CKD in Europeans: 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 Asians, genetically predicted BMI, T2D, and nephrolithiasis showed causal links to CKD.
- Hypertension showed a causal effect in Europeans but not in East Asians. A threshold effect of BMI on CKD risk was observed at BMI >25 kg/m².
Conclusions:
- Several cardiometabolic risk factors, including BMI, hypertension, and T2D, have a causal impact on CKD development.
- Ancestry-specific differences in causal risk factors for CKD were observed.
- Findings provide evidence for prioritizing interventions targeting these causal factors to reduce CKD burden.
Background:
This study was to systematically test whether previously reported risk factors for chronic kidney disease (CKD) are causally related to CKD in European and East Asian ancestries using Mendelian randomization.
Methods:
A total of 45 risk factors with genetic data in European ancestry and 17 risk factors in East Asian participants were identified as exposures from PubMed. We defined the CKD by clinical diagnosis or by estimated glomerular filtration rate of <60 ml/min/1.73 m2. Ultimately, 51 672 CKD cases and 958 102 controls of European ancestry from CKDGen, UK Biobank and HUNT, and 13 093 CKD cases and 238 118 controls of East Asian ancestry from Biobank Japan, China Kadoorie Biobank and Japan-Kidney-Biobank/ToMMo were included.
Results:
Eight risk factors showed reliable evidence of causal effects on CKD in Europeans, including genetically predicted 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 Asians, BMI, T2D and nephrolithiasis showed evidence of causality on CKD. In two independent replication analyses, we observed that increased hypertension risk showed reliable evidence of a causal effect on increasing CKD risk in Europeans but in contrast showed a null effect in East Asians. Although liability to T2D showed consistent effects on CKD, the effects of glycaemic phenotypes on CKD were weak. Non-linear Mendelian randomization indicated a threshold relationship between genetically predicted BMI and CKD, with increased risk at BMI of >25 kg/m2.
Conclusions:
Eight cardiometabolic risk factors showed causal effects on CKD in Europeans and three of them showed causality in East Asians, providing insights into the design of future interventions to reduce the burden of CKD.
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