The present cohort study, including 26,788 members of the general population with non-CKD, revealed that a daily higher alcohol consumption (≥40 g/day) was significantly associated with a higher incidence of proteinuria and CKD among women. These findings suggest that women might be vulnerable to excess alcohol consumption, which might lead to kidney dysfunction. An advantage of the present study confirmed the robustness of the influence of alcohol consumption on two clinically important outcome measures of kidney dysfunction (incidence of proteinuria and eGFR <60 mL/min/1.73 m2 with 25% decline).
Although multiple observational cohort studies have evaluated the relationship between alcohol consumption and incidence of CKD , incidence of proteinuria [9, 15, 21, 25], incidence of low eGFR [8, 9, 12, 16], and GFR annual decline , these results were not entirely consistent, possibly due to different sample sizes, different definitions of alcohol intake levels and CKD outcome measures, or different lifestyles of participants.
Among several large cohort studies that evaluated the relationship between alcohol consumption and incidence of proteinuria, Yamagata et al. reported that an average daily alcohol consumption of ≤20 g of ethanol was associated with a decreased risk of future proteinuria in Japanese men and women compared with non-drinkers, while consumption of >20 g of ethanol was not associated with the risk of future proteinuria . However, this study did not evaluate the clinical impact of heavy alcohol consumption on the incidence of proteinuria. Uehara et al. showed a significant influence of high alcohol consumption (>69 g/day) , which showed a J-shaped association in 9154 non-diabetic Japanese men. However, this study did not include women, and thus, its influence on women was unknown. Recently, Kimura et al. showed that women were more vulnerable to high doses of alcohol consumption (≥60 g/day) than men for the incidence of proteinuria in a general population-based large retrospective cohort study, including 11,286 Japanese male and female participants . Although it was compatible with the present study, this study only focused on the incidence of proteinuria as a surrogate marker of end-stage renal disease (ESRD); it should be evaluated by other clinically important surrogate renal outcomes, such as eGFR.
Meanwhile, among the other few studies that evaluated not only the incidence of proteinuria but also eGFR decline as a CKD surrogate marker, one prospective cohort study including 6259 Australian male and female participants showed that the risk of developing new-onset albuminuria began to rise for an average daily alcohol consumption (≥30 g/day), compared with consumption of <10 g/day . However, inversely, the risk of developing a low eGFR was significantly reduced at the same threshold. This discrepancy should be cautiously interpreted. In addition, another recent large, nationwide, retrospective cohort study in Korea, including 118,492 participants, assessed the relationship between alcohol consumption and the incidence of CKD, defined as the incidence of proteinuria, low eGFR (eGFR <60 mL/min/1.73 m2), and eGFR annual decline . It showed that a J-shaped association of alcohol consumption with incident proteinuria was observed in men; a lower risk in men drinking <10 g of alcohol/day and a higher risk in men drinking higher levels of alcohol (≥40 g/day) were observed compared to those in non-drinkers, and a positive association was seen in women who consumed alcohol with any range of consumption compared with non-drinkers. However, when evaluating the low eGFR incidence and eGFR annual decline as outcomes, a negative association between alcohol intake and outcomes was observed in both sexes. These results were conflicting in each CKD outcome definition; therefore, these results should be interpreted cautiously. Meanwhile, in another large, prospective, population-based cohort, including 5476 male and female participants in the Netherlands, alcohol consumption was inversely associated with the risk of developing CKD, defined as either an eGFR <60 mL/min/1.73 m2 or proteinuria (24-hour urinary albumin excretion >30 mg) .
In the present study, we clarified that a larger amount of alcohol consumption was a risk factor for the incidence of proteinuria and CKD in women. The findings of the present study, as well as a previous study , suggest that avoiding excess alcohol consumption might be an important lifestyle modification to prevent kidney dysfunction, especially in women.
Although the precise mechanism of the nephrotoxic effect of alcohol is unsolved , one of the plausible mechanisms by which excess alcohol consumption induces kidney dysfunction is considered to be by inducing the depression of nephrin and podocin in podocytes, which causes proteinuria, leading to kidney dysfunction, and which is mediated by oxidative stress . Furthermore, previous studies have shown that higher alcohol consumption is associated with an increased risk of future hypertension , leading to the incidence of proteinuria . In the present study, the difference in blood pressure between each alcohol consumption group was not clinically significant, suggesting that the difference in blood pressure between each alcohol consumption group did not influence the occurrence of kidney dysfunction. Conversely, another study suggested that alcohol consumption might improve kidney antioxidant activities and capacity; namely, a small amount of ethanol pretreatment can increase the activities of inducible nitric oxide synthase and antioxidant capacities in the kidneys, which ameliorated oxidative stress in a bilateral renal ischemia reperfusion simulation model as a compensatory mechanism . However, the optimal range of alcohol consumption to induce a positive effect on kidney function is unknown. Thus, further studies should evaluate this issue.
Regarding the mechanism for the sex difference in the impact of alcohol on kidney function, one possibility may be the different pharmacokinetics of alcohol between males and females. Compared with males, females are more likely to have higher concentrations of alcohol, partly because females, with a lower proportion of body water, have a smaller distribution volume of alcohol [15, 30]. Furthermore, it might be due to the differences in metabolism of alcohol because of lower activity of alcohol dehydrogenase in females than in males, leading to a higher concentration of alcohol in women than in men, even within a similar level of alcohol consumption . Further studies should be conducted to explain these mechanisms.
This study has several limitations. First, self-reported alcohol consumption may be biased. Second, in the present study, proteinuria was measured using a dipstick, but dipstick tests are more likely to yield false-positive and false-negative results than specific laboratory methods. Third, because of the retrospective nature of the present study, confounding factors such as excess alcohol consumption, unhealthy behaviors, and calorie-dense and hypersaline foods could not be evaluated . This should be evaluated in future studies.