In this study, we demonstrated that light drinking was associated with a lower risk of CKD, and this association was modified by the BMI status. When the BMI was low, alcohol consumption was associated with a higher risk of CKD. On contrary, when the BMI was high, even heavy alcohol consumption was associated with a lower risk of CKD. These results suggest that a high BMI counteracts the harmful effects of alcohol on kidney function. To the best of our knowledge, our study is the first to evaluate the effect of BMI on the association between alcohol consumption and CKD development.
Our findings on the dose-response association between alcohol consumption and CKD development are partially consistent with those of previous studies. A recent systematic review and two large prospective cohort studies showed that alcohol consumption was associated with a lower risk of CKD regardless of the amount of alcohol consumption.10,21,22 Contrarily, in a large prospective study in Japan, only the light alcohol consumption group (< 20 g/day) was associated with a lower risk of CKD.11 This discrepancy may be due to differences in the background of the target population. Previous epidemiological studies have reported that heavy alcohol consumption was associated with a higher incidence of HT and DM, which are known risk factors for CKD, but the alcohol-induced risk was reduced in those with higher BMI.14–20 However, minimal evidence is available on the association between alcohol consumption and the risk of CKD considering the effect of factors such as body mass on alcohol tolerance.
There are several possible mechanisms by which alcohol consumption may affect renal function, including protective10 and harmful effects.23,24 Regarding protective effects, clinical studies have shown that moderate alcohol intake prevents atherosclerosis via alcohol-induced changes in lipid profile and inflammation.25 Besides, animal studies have reported that low concentrations of alcohol protect podocytes, one of the key structures in the kidney, via acetaldehyde dehydrogenase and 20-hydroxyeicosatetraenoic acid.26 Furthermore, alcohol consumption has been reported to improve insulin sensitivity.27,28 Another animal study reported that podocytes are insulin sensitive and that this insulin sensitivity is important for maintaining the glomerular filtration barrier.29 Regarding harmful effects, excessive alcohol consumption has been reported to have a negative effect on the risk of atherosclerosis.30 Moreover, animal studies have reported that a high ethanol concentration significantly increases superoxide production in podocytes, resulting in increased oxidative stress and damage to podocytes.26 In addition, excessive alcohol consumption can cause liver damage, cirrhosis, and secondary renal damage.31,32 These mechanisms suggest that the harmful effects on renal function are more likely to occur when alcohol concentrations are high or when aldehydes, the metabolic intermediate products of alcohol, accumulate. These harmful effects are enhanced when alcohol is consumed beyond an individual’s capacity; BMI is one of the factors that determine this capacity.33,34 In addition to body mass, genetic variations in the alcohol metabolism capacity should be considered in people with East Asian ancestry, including the Japanese populations. Mutations in the gene encoding the aldehyde dehydrogenase 2 (ALDH2) enzyme reduce acetaldehyde metabolism, predisposing to the flushing response. Individuals with mutations in the ALDH2 gene are likely to have a lower BMI and to consume less alcohol, while those without these mutations tend to have a higher BMI.35 Therefore, we considered that these mutations could partly account for the mechanism regarding the hypothesis that a high BMI would increase alcohol tolerance. A high BMI is still associated with alcohol tolerance, and our study demonstrated robust results regardless of the underlying mechanisms.
Our study has several limitations. First, we could not distinguish between individuals who had never consumed alcohol, those who consumed alcohol previously, and those who consumed alcohol occasionally at baseline, with all the above categorized as infrequent drinkers. The infrequent alcohol consumption category may include people who abstained from drinking due to ill health or pre-existing conditions.36 However, we excluded individuals with a history of CVD, COPD, liver disease, which may have resulted in alcohol cessation for health conditions. Second, this study defined the highest category of alcohol consumption as ≥ 40 g/day and the lowest category as < 20 g/day, which may not be sufficient to show a dose-response relationship between alcohol consumption and CKD. In previous studies examining the association between risk of CKD development and alcohol consumption with the highest consumption category being 60 g/day or more, the association was U-shaped or J-shaped.13,37 Conversely, when the highest consumption category was 30 g or 40 g/day or more, the risk decreased in a negative linear manner.22,38 In our study, overall, alcohol consumption and CKD risk were U-shaped, but there was a dose-dependent increase in risk in the low BMI group, a U-shape in the normal BMI group, and a dose-dependent decrease in risk in the high BMI group. Although it should be validated in a wider range of settings, we believe that stratification by BMI, which partly reflects an individual's alcohol tolerance, will help examine the appropriate alcohol intake associated with CKD in this study. Third, we did not consider metabolizing enzymes such as alcohol dehydrogenase‐1B and ALDH2. Almost all of the study participants were ethnic Japanese, and people with an Asian ancestry may be more sensitive to alcohol than those with a Caucasian ancestry due to genetic differences in alcohol-metabolizing enzymes,39 which may have affected their drinking habits.40 However, genetic tests are not widely available for health examination in the general population, nor is it routinely performed for risk stratification. Further studies are needed to evaluate the association between alcohol consumption and CKD development, considering genetic variations. Fourth, not all participants underwent continuous health checkups, and they may have not been tracked in the process due to moving to another municipality or death. However, we believe that bias is unlikely to occur in our cohort due to continuity in receiving annual checkups by most participants, the similarity in frequency and duration of follow-up across groups divided by drinking status, and the exclusion of individuals with pre-existing conditions. Finally, this was an observational study; therefore, unmeasured confounding factors may exist, although we adjusted for clinically relevant confounders for CKD. However, the strength of the present study is that in our cohort, more than 50% of the people who were eligible for the specified health checkups had been receiving the checks since the program was started in 2008. This percentage is higher than the national average of 30 to 35% for residents in other areas who are covered by the national health insurance scheme.41 Moreover, we have comprehensive lifestyle information, anthropometric measurements, and blood and urine test results for more than 10,000 participants, and these data are comparable to those of the National Database of Health Insurance Claims and the Specific Health Examination Database Open Data Japan, which is considered representative and meaningful.42
In conclusion, light alcohol consumption has beneficial effects on CKD development, and our findings underscore the effect modification of the association between alcohol consumption and CKD development by BMI. The benefits of alcohol consumption cannot be generalized and depend on an individual’s constitution. Further study is needed to investigate the interaction between alcohol consumption and BMI for risk of CKD development in other ethnicities and age groups.