Sensitivity analysis for the association with eGFR excluding potentially pleiotropic genetic predictors. UK Biobank in Mendelian randomization using different analysis methods. Table S10. Sensitivity analysis on the associations of genetic proxies for antihypertensive drugs with albuminuria and PIK-93 UACR using genetic variants derived from UK Biobank in Mendelian randomization using different analysis methods. Physique S1. Comparison using different units of genetic proxies for ACE inhibitors, CCBs and BBs. (a) for eGFR, (b) for UACR, (c) for albuminuria. Black square refers to using genetic variants based on the study of Walker et al. [11] in UK Biobank, grey circle refers to using genetic variants based on the study of Gill et al. [12] and Georgakis and Gill et al. [16] in meta-analysis of UK Biobank and ICBP. Figure S2. Associations of genetic proxies for antihypertensive drugs with eGFR by drug target in each drug class, overall antihypertensives and systolic blood pressure. SBP, systolic blood pressure. ACE, Angiotensin-converting enzyme; ARB, Angiotensin II Receptor Blocker; BBs, beta-adrenoceptor blockers; CCBs, calcium channel blockers; PSDs, potassium-sparing diuretics; SBP, systolic blood pressure. Figure S3. Associations of genetic proxies for antihypertensive PIK-93 drugs with UACR by drug target in each drug class, overall antihypertensives and systolic blood pressure. ACE, Angiotensin-converting enzyme; ARB, Angiotensin II Receptor Blocker; BBs, beta-adrenoceptor blockers; CCBs, calcium channel blockers; PSDs, potassium-sparing diuretics; SBP, systolic blood pressure. Figure S4. Associations of genetic proxies for antihypertensive drugs with albuminuria by drug target in each drug class, overall antihypertensives and systolic blood pressure. BBs, beta-adrenoceptor blockers; CCBs, calcium channel blockers; PSDs, potassium-sparing diuretics; SBP, systolic blood pressure. 12916_2021_1951_MOESM1_ESM.pdf (846K) GUID:?E1944A56-B064-42E5-9ED1-1E6EE42DC025 Data Availability StatementThe access of data from the UK Biobank can be obtained by application to the UK Biobank (http://biobank.ctsu.ox.ac.uk/crystal/). The summary statistics can be downloaded from the website https://pan.ukbb.broadinstitute.org/downloads/index.html;https://ckdgen.imbi.uni-freiburg.de/. Abstract Background Angiotensin-converting enzyme (ACE) inhibitors and/or in combination with calcium channel blockers (CCBs) are generally recommended as the first-line antihypertensive therapy for people with hypertension and kidney dysfunction. Evidence from large randomized controlled trials comprehensively comparing renal effects of different classes of antihypertensive drugs is lacking. Methods We used a Mendelian randomization study to obtain unconfounded associations of genetic proxies for antihypertensives with kidney function. Specifically, we used published genetic variants in genes regulating target proteins of these drugs and then applied to a meta-analysis of the largest available genome-wide association studies of kidney function (estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (UACR), and albuminuria). Inverse variance weighting was used as the main analysis and to combine estimates from different sources. Results Genetically predicted ACE inhibition was associated with higher eGFR (effect size 0.06, 95% confidence interval (CI) 0.008, 0.11), while genetic proxies for beta-blockers were associated with lower eGFR (??0.02, 95% CI ??0.04, ??0.004) when meta-analyzing the UK Biobank and CKDGen. Genetic proxies for CCBs were associated with lower UACR (??0.15, 95% CI ??0.28, ??0.02) and lower risk of albuminuria (odds ratio 0.58, 95% CI 0.37, 0.90) in CKDGen. The associations were strong to using different analysis methods and different genetic instruments. Conclusions Our findings suggest the reno-protective associations of genetically proxied ACE inhibitors and CCBs, while genetic proxies for beta-blockers may be related to lower eGFR. Understanding the underlying PIK-93 mechanisms would be valuable, with implications for drug development and repositioning of treatments for kidney disease. Supplementary Information The online version contains supplementary material available at 10.1186/s12916-021-01951-4. Keywords: Antihypertensives, Kidney function, Mendelian randomization Background Hypertension is usually a leading contributor to global years of life lost because of its role in cardiovascular disease [1]. Hypertension is also a key risk factor for impaired kidney function, which might also be affected by kidney function Adipor2 [2]. Different classes of antihypertensive drugs, acting via different targets, may have different renal effects. Most PIK-93 guidelines recommend the use of angiotensin-converting enzyme (ACE) inhibitors as the first-line antihypertensive therapy for the treatment of hypertension in patients with chronic kidney disease (CKD) [3]. The European Society of Cardiology (ESC)/European Society of Hypertension (ESH) guidelines also.