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A bidirectional Mendelian randomization study supports causal effects of kidney function on blood pressure
Open accessAbstract
Blood pressure and kidney function have a bidirectional relation. Hypertension has long been considered as a risk factor for kidney function decline. However, whether intensive blood pressure control could promote kidney health has been uncertain. The kidney is known to have a major role in affecting blood pressure through sodium extraction and regulating electrolyte balance. This bidirectional relation makes causal inference between these two traits difficult. Therefore, to examine the causal relations between these two traits, we performed two-sample Mendelian randomization analyses using summary statistics of large-scale genome-wide association studies. We selected genetic instruments more likely to be specific for kidney function using meta-analyses of complementary kidney function biomarkers (glomerular filtration rate estimated from serum creatinine [eGFRcr], and blood urea nitrogen from the CKDGen Consortium). Systolic and diastolic blood pressure summary statistics were from the International Consortium for Blood Pressure and UK Biobank. Significant evidence supported the causal effects of higher kidney function on lower blood pressure. Based on the mode-based Mendelian randomization method, the effect estimates for one standard deviation (SD) higher in log-transformed eGFRcr was -0.17 SD unit (95 % confidence interval: -0.09 to -0.24) in systolic blood pressure and -0.15 SD unit (95% confidence interval: -0.07 to -0.22) in diastolic blood pressure. In contrast, the causal effects of blood pressure on kidney function were not statistically significant. Thus, our results support causal effects of higher kidney function on lower blood pressure and suggest preventing kidney function decline can reduce the public health burden of hypertension.
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“An important distinction is that unlike other BP lowering agents, 24 there appears to be no association between baseline values and the magnitude of BP reduction, an observation which we have extended to people with CKD.”
From Blood Pressure Effects of Canagliflozin and Clinical Outcomes in Type 2 Diabetes and Chronic Kidney Disease: Insights From the CREDENCE Trial (2021) · cites this paper as [24]
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Self-citationHerrett, E. L., Strongman, H., Gadd, S., Tomlinson, L. A., Nitsch, D., Bhaskaran, K., Williamson, E., van Staa, T. P., Sofat, R., Timmis, A., et al. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00281-6 · Cited by 21
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Plasma metabolites and risk of myocardial infarction: a bidirectional Mendelian randomization study
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“…MR (16, 17), bidirectional MR (18), gene-environment interaction MR (19), drug-target MR (20), and network MR (21), which expand the application domains of MR. MR research methods include inverse variance weighting, MR-Egger regression, weighted median, and pattern-based estimation (22–28).”
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“It can reduce the impact of reverse causality to ensure maximum validity (25, 26).”
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“Tomake sure the effects of SNPs on the exposure correspond to the same allele as their effects on outcome, the matching of effect alleles of each SNP between the summary statistics of the exposure and the outcomewas examined using the harmonise_data function (25).”
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Blood pressure and kidney disease: chicken or egg (or both)?
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Mendelian randomization analysis using multiple biomarkers of an underlying common exposure
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Kidney function may partially mediated the protective effect of urinary uromodulin on kidney stone
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“The advantage of this method is that genetic variations are not influenced by acquired environmental factors and lifestyle habits, thus minimizing the possibility of reverse causality [12, 13].”
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“Mendelian-randomization study by Yu and colleagues (32), where no association between a BP GRS and kidney function was found.”
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Inflammatory factors and the risk of urolithiasis: a bidirectional Mendelian randomization study
Huang, K., Peng, Z., Zha, C., Li, W., Deng, G., Chen, X., Luo, Y., Ji, Z., Wang, Q., & Jiang, K. (2024) · Frontiers in Medicine · doi:10.3389/fmed.2024.1432275 · Cited by 5
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“Accordingly, impaired kidney function has long been linked to hypertension [34].”
Eicosanoids and Related Metabolites Associated with ESKD in a Community-Based Cohort
Surapaneni, A., Schlosser, P., Rhee, E. P., Cheng, S. C., Jain, M., Alotaiabi, M., Coresh, J., & Grams, M. E. (2023) · Kidney360 · doi:10.34067/kid.0000000000000334 · Cited by 5
“18 For the eicosanoid to eGFR direction, we used P , 5 3 10 2 7 as a fi lter for selection of signi fi cant SNPs. Correlated SNPs were removed using linkage disequilibrium clumping (ld_clump function) with the reference European population in a window of 500 kb and an R 2 threshold of 0.01.”
MethodInfluentialSelf-citationDietary patterns, polygenic risk, and kidney cancer incidence: a UK Biobank cohort study
Zou, M., Deng, R., Qiu, J., Mao, K., Shang, J., Zhu, S., Cai, L., Wang, Y., Gong, K., & Zhou, J. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07373-7 · Cited by 4
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“The specific process has been described in the study of Yu et al.(22) The 17 SNP are not found in the outcome summary data (ADPN).”
MethodKidney Function Measures and Mortality: A Mendelian Randomization Study
Shan, Y., Zhang, J., Lu, Y., Liao, J., Liu, Y., Dai, L., Li, J., Song, C., Su, G., Hägg, S., et al. (2023) · American Journal of Kidney Diseases · doi:10.1053/j.ajkd.2023.10.014 · Cited by 4
Liang, N., Ma, X., Cao, Y., Liu, T., Fang, J., & Zhang, X. (2024) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/0118715303288685240808073238 · Cited by 5
Ma, J., Gao, Y., Hou, S., Cui, S., & Zhu, J. (2025) · Current Medicinal Chemistry · doi:10.2174/0109298673348645241226091059 · Cited by 4
Wang, D., Ren, K., Zhu, Z., Lv, Y., Jin, H., Zhang, L., & Wang, Y. (2025) · Medicine · doi:10.1097/md.0000000000045166 · Cited by 3
“[18] While a recent cohort study proposed a biological age score predictive of diabetes complications, its restricted bio-marker scope (e.g., omitting renal/inflammatory markers) limits generalizability to DKD. [19] Therefore, this study aims to comprehensively investigate the relationship between…”
Li, Y., Sun, T., Chen, J., & Zhang, L. (2024) · Global Medical Genetics · doi:10.1055/s-0044-1779665 · Cited by 3
“19 In the main analysis, estimates were derived using inverse variance weighting (IVW) meta-analysis with multiplicative random effects, assuming balanced pleiotropy.”
Chen, X., Jiang, G., Zhao, T., Sun, N., Liu, S., Guo, H., Zeng, C., & Liu, Y. (2024) · Cell & Bioscience · doi:10.1186/s13578-024-01323-4 · Cited by 3
Qi, N., Lyu, Z., Huang, L., Zhao, Y., Zhang, W., Zhou, X., Zhang, Y., & Cui, J. (2025) · Thrombosis Journal · doi:10.1186/s12959-025-00692-1 · Cited by 3
“This approach minimizes the influence of common confounding factors, such as environmental influences and lifestyle habits, and reduces the risk of reverse causation compared to other statistical methods [17, 18].”
Suleman, R., Janjua, R. R., Shaukat, A., Raza, A., Arshad, A., & Malik, A. N. (2024) · Journal of Health and Rehabilitation Research · doi:10.61919/jhrr.v4i1.384 · Cited by 2
Ma, J., Hou, S., Gu, X., Guo, P., & Zhu, J. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1533959 · Cited by 2
Qi, N., Zhou, X., Zhao, Y., Huang, L., & Cui, J. (2025) · Technology and Health Care · doi:10.1177/09287329251339074 · Cited by 2
Blood Pressure and Mortality in Mexico City: A Mendelian Randomization Study
Turner, M., Kuri-Morales, P. A., Alegre-Díaz, J., Baca, P., Garcilazo‐Ávila, A., González-Carballo, C., Ramírez-Reyes, R., Rivas, F., Aguilar-Ramirez, D. J., Bragg, F., et al. (2025) · Hypertension · doi:10.1161/hypertensionaha.125.25348 · Cited by 2
Sun, Q., Chen, H., & Liu, S. (2026) · Clinical Rheumatology · doi:10.1007/s10067-026-07937-y · Cited by 3
Research progress on targeted molecular fluorescent probes for the visualization of renal diseases
Lin, T., & Ye, Y. (2026) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2026.218183 · Cited by 2
Zhao, Z., He, K., Liu, B., Nie, W., Luo, X., & Liu, J. (2024) · Angewandte Chemie · doi:10.1002/ange.202406016 · Cited by 2
Zhan, S., Chen, J., Wei, L., Gan, S., Zhang, Q., & Fu, H. (2024) · Journal of Asthma · doi:10.1080/02770903.2024.2430368 · Cited by 2
Intake of coffee and blood pressure: A Mendelian randomized study
Zhong, J., Huang, S., Dong, S., Zheng, W., & Tong, S. (2025) · Nutrition Metabolism and Cardiovascular Diseases · doi:10.1016/j.numecd.2025.104273 · Cited by 2
Hypertension and Kidney Disease
Fadem, S. Z. (2022) · Springer eBooks · doi:10.1007/978-3-030-93528-3_5 · Cited by 2
Gill, D., Pan, Y., Lash, J. P., & Kelly, T. N. (2022) · Hypertension · doi:10.1161/hypertensionaha.122.19445 · Cited by 2
Chen, H., Zhou, X., & Yang, Q. (2021) · Toxicology · doi:10.1016/j.tox.2021.152895 · Cited by 1
Zhao, M., Xiao, M., Zhang, H., Tan, Q., Ji, J., Cheng, Y., & Lü, F. (2025) · Frontiers in Endocrinology · doi:10.3389/fendo.2025.1442918 · Cited by 1
“This was veri fi ed by the latest Mendelian randomization study, which found that improved renal function only had a causal effect on lowering blood pressure, while the reverse causality between the two was not signi fi cant (16).”
Zhang, L., Feng, B., Liu, Z., & Liu, Y. (2025) · Renal Failure · doi:10.1080/0886022x.2025.2476051 · Cited by 1
Song, Y., & Yang, C. (2025) · European journal of medical research · doi:10.1186/s40001-025-02988-4 · Cited by 1
“Previous studies have confirmed that eGFR can serve as an important predictor for the onset of hypertension in normotensive individuals [15, 16].”
Liu, B., Zhang, T., Han, J., Bi, W., Nie, C., & Zhang, J. (2025) · Discover Oncology · doi:10.1007/s12672-025-03533-9 · Cited by 1
Guo, W., Dong, L., Lu, Q., Xie, M., Yang, Y., Zhang, Y., Lu, X., & Yu, Q. (2025) · ALPHA PSYCHIATRY · doi:10.31083/ap46108 · Cited by 1
“…of the MR methodology that can utilize existing genome-wide large-sample public datasets to examine the “exposure” (as risk factor) and “outcome” (as disease) without the need to directly analyze individual-level data, which compensates for the typical shortcomings of observational studies [31,47].”
Kakar, A., LITKOWSKI, E. M., Scadden, A. W., Anwar, M. Y., Konigsberg, I. R., Stanislawski, M. A., DuPre, N. C., Mitra, R., Baumgartner, R., Raffield, L. M., et al. (2025) · BMC Nephrology · doi:10.1186/s12882-025-04425-4 · Cited by 1
“Additionally, results from recent Mendelian randomization studies also support the causal effects of higher kidney function on lower BP, but the causal effects of BP on kidney function have not been supported [19, 39].”
Ding, M., Li, Y., Yao, S., & Wang, K. (2026) · Annals of Vascular Surgery · doi:10.1016/j.avsg.2026.03.008 · Cited by 1
Liu, J., Liang, P., Wang, Y., Huang, H. M., Zhang, S., Li, G., & Wu, H. (2026) · Medicine · doi:10.1097/md.0000000000048110 · Cited by 1
“[35,36] 39] In this study, we conducted a two-sample MR analysis based on GWAS data and systematically screened immune phenotypes that may have causal relationships with the risk of anxiety disorders.”
Resistant Hypertension Variants Link to Hyperaldosteronism and Potassium Levels
Tragante, V., Sulem, P., Þorleifsson, G., Frigge, M. L., Arthur, J. G., Asselbergs, F. W., Banasik, K., Brunak, S., Christensen, A. H., Crawford, D. C., et al. (2026) · Hypertension · doi:10.1161/hypertensionaha.123.22301 · Cited by 3
Metadata
- Authors
- Yu, Z., Coresh, J., Qi, G., Grams, M., Boerwinkle, E., Snieder, H., Teumer, A., Pattaro, C., Köttgen, A., Chatterjee, N., & Tin, A.
- Affiliations
- Johns Hopkins University (US)
- Baylor College of Medicine (US)
- University Medical Center Groningen (NL)
- Universitätsmedizin Greifswald (DE)
- Eurac Research (IT)
- Corresponding author
- Tin, Adrienne
- ORCID
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2020-09
- Volume
- 98
- Issue
- 3
- Pages
- 708-716
- ISSN
- 0085-2538 (ISSN-L)
- PMC
- PMC7784392
- OpenAlex
- W3028085141
- Cited by
- 135
- References
- 61
- Citations by year
- 2026: 8 · 2025: 25 · 2024: 29 · 2023: 17 · 2022: 24 · 2021: 26 · 2020: 6
- FWCI
- 10.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion, other-oa)
- PubMed (publishedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- Open Research (University of Surrey) (submittedVersion, cc-by)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
- Funders
- National Human Genome Research Institute (R01 HG010480-01)
- Deutsche Forschungsgemeinschaft
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01 AR073178-01A1, HHSN268201100009C)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- renal function, blood pressure, bidirectional causality, estimated glomerular filtration rate, blood urea nitrogen, hypertension, renal function decline, intensive blood pressure control, systolic blood pressure, diastolic blood pressure, genetic instruments
- MeSH terms
- Blood Pressure, Humans, Hypertension, Kidney, Genome-Wide Association Study, Mendelian Randomization Analysis
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