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Background An inverse observational association between alcohol use and the risk of chronic kidney disease (CKD) or end-stage kidney disease (ESKD) has been reported. The causal effect of alcohol use on the risk of ESKD warrants additional investigation. Methods The study was an observational cohort study investigating the UK Biobank and performed Mendelian randomization (MR) analysis. Amounts of alcohol use were collected using a touchscreen questionnaire. In the observational analysis, 212,133 participants without prevalent ESKD were studied, and the association between alcohol use and the risk of prevalent CKD or incident ESKD was investigated. The genetic analysis included 337,138 participants of white British ancestry. For one-sample MR, an analysis based on a polygenic risk score (PRS) was conducted with genetically predicted alcohol intake. The MR analysis investigated ESKD outcome and related comorbidities. Results Lower alcohol use was observationally associated with a higher risk of prevalent CKD or incident ESKD. However, the genetic risk of CKD was significantly associated with lower alcohol use, suggesting reverse causation. A higher PRS for alcohol use was significantly associated with a higher risk of ESKD (per units of one phenotypical alcohol drink; adjusted odds ratio of 1.16 [95% confidence interval, 1.02-1.31]) and related comorbidities, including hypertension, diabetes mellitus, obesity, and central obesity. Conclusion The inverse observational association between alcohol use and the risk of CKD or ESKD may have been affected by reverse causation. Our study supports a causal effect of alcohol use on a higher risk of ESKD and related predisposing comorbidities.

Additional file 1: Table 5. TEAEs with no corresponding category.

Additional file 1: Supplemental Methods. Detailed methods for the Mendelian randomization analysis. Supplemental Figure 1. Distribution of the phenotypical eGFR values and allele scores for log-transformed eGFR. Supplemental Table 1. Genetic instruments for log-transformed eGFR based on creatinine levels. Supplemental Table 2. Genetic instruments for log-transformed eGFR based on cystatin C levels. Supplemental Table 3. Localized averaged causal estimates calculated from 100 percentile ranges of strata according to the instrument-free exposure.

Additional file 1: Figure S1. Location map of the study participants. Table S1. Risk of BPR in PM 10 concentration by exposure durations from events day. Table S2. Risk of DCGF in PM 10 concentration by exposure durations from events day. Table S3.. Risk of all-cause mortality in PM 10 concentration by exposure durations from events day. Table S4. Association between average annual PM10 and SO2, CO, NO2 and O3 exposure in outcomes after kidney transplant.

Additional File 1: Supplemental Methods and Supplemental Table 1-Supplemental Table 5. Supplemental Methods ��� The reasons that another, more recent GWAS for atrial fibrillation was not selected for the dataset implemented to develop genetic instruments. Supplemental Table 1. Results of the MR analysis including overlapping samples using the 84 SNPs from the most recent GWAS meta-analysis as the genetic instruments for atrial fibrillation. Supplemental Table 2. Genetic instrument for atrial fibrillation developed from the GWAS within the individuals of European ancestry. Supplemental Table 3 ��� Causal estimates from atrial filtration on chronic kidney disease as positive outcome in the CKDGen GWAS data. Supplemental Table 4. Causal estimates from atrial fibrillation on brain grey or white matter volume of the UK Biobank participants by summary-level Mendelian randomization including palindromic SNPs. Supplemental Table 5. Causal estimates from atrial fibrillation on brain grey or white matter volume of the UK Biobank participants by summary-level Mendelian randomization inferring strand information