Alcohol misuse damages numerous organs, including the liver, heart, brain, and pancreas. The kidney remains a severely understudied target of alcohol-induced injury despite renal injury being commonly observed in end-stage alcohol-associated liver disease (ALD) patients. A 6-week murine ethanol (1-6% v/v) model for early-stage ALD combined with carbon tetrachloride (CCl4) treatment was utilized to reveal mechanisms of renal injury. This paradigm yields elevated kidney damage markers when compared to ethanol consumption alone, including elevated urinary KIM-1 in 3 weeks. Hypothesis-generating tissue spatial analysis was used to explore ethanol-related transcriptomic alterations across kidney morphology. Using a publicly available scRNA-seq dataset, the predominant cell-type specific differences were identified and allowed for the generation of spatially resolved gene clusters. Ethanol + CCl4 increased kidney injury marker gene expression in proximal tubule cells, signifying extensive damage. Overall, a decrease in expression of ethanol metabolizing genes was localized to the renal cortex. Genes associated with the unfolded protein response (UPR) were induced across the kidney and were morphologically associated throughout the nephron. Key mRNAs (Hspa5, Hsp90b1, Ndrg1) and ribosomal transcripts were altered due to ethanol metabolism across proximal tubules. Furthermore, epigenetic alterations in regulatory marks of lysine acetylation or trimethylation are associated with the combination treatment. Collectively, the application of tissue spatial transcriptomics to a well-defined model of alcohol toxicity reveals dynamic morphologic changes in gene expression across renal cell types due to ethanol. Our results indicate ER stress and the UPR are significantly impacted by ethanol metabolism throughout proximal tubules, associating with ethanol-induced renal dysfunction.
Aim We aimed to analyze the associations between markers of monocyte activation (sCD163 and sCD14), of inflammation (Interleukin 6 [IL-6]) and of microbial translocation (lipopolysaccharide [LPS]) and zonulin (a marker of intestinal permeability) in a series of patients with severe Alcohol Use Disorder (AUD) admitted for hospital treatment. Methods Cross sectional study of patients admitted between 2021 and 2024 in two teaching hospitals in Barcelona, Spain. We gathered clinical information and assessed hematological, biochemical parameters and plasma markers on the second day of admission.We performed a multivariable logistic regression analysis adjusted by sex and age to detect associations with zonulin levels in the highest quartile. Results We enrolled 225 patients with AUD (77% male) with a median age was of 51 years Interquartile range [IQR] 43-56). Median alcohol intake was 185 g/day (IQR 100-250) and median duration of AUD was 20 years (IQR 10-30), and 25.9% had advanced liver fibrosis.Median values of plasma markers were: sCD14 2096 ng/ml (IQR: 1714-2615), sCD163 was 618 ng/mL (IQR: 436-945), IL-6 4.43 pg/mL (IQR 2.69-8.76), LPS 24.4 pg/mL (IQR 17.8-37.3) and zonulin 5.0 ng/ml (IQR 3.8-7.5).In the multivariable regression analysis, levels of sCD163 and of LPS in the highest quartile were associated with higher zonulin levels [adjusted Odds Ratio (95% Confidence Interval of 2.66 (1.10-6.44) and 12.2 (5.49-27.12), respectively]. Conclusion Levels of markers of increased intestinal permeability are associated with markers of monocyte activation and of microbial translocation in severe AUD patients admitted for hospital treatment.
Former drinkers are often grouped with lifetime abstainers as the nondrinker reference group in alcohol-related health studies. This classification has the potential to bias estimates when alcohol cessation follows health deterioration. This study examined whether adverse health status and healthcare burden preceded alcohol cessation and whether the inclusion of former drinkers altered estimates for current drinkers. Using two independent Korea Health Panel cohorts from 2010 to 2018 and 2019–2023, adults were classified as lifetime abstainers, former drinkers, or current drinkers. Former drinkers were further classified by self-reported abstinence duration. Unweighted repeated person-period logistic regression with individual-level cluster-robust standard errors was used to assess health status by drinking category, next-year transition from current to former drinking, and differences between conventional and corrected nondrinker reference definitions. In both cohorts, former drinkers, especially recent former drinkers, had higher odds of physical limitation, poor self-rated health, hospitalization, and high out-of-pocket medical spending than lifetime abstainers. Among current drinkers, these indicators of health status and healthcare burden were associated with transition to former drinking in the following year, most consistently among adults aged 40 years or older. Including former drinkers with lifetime abstainers in the nondrinker reference group produced more inverse estimates for current drinking. Former drinkers in the Korea Health Panel appear to include a health-selected subgroup consistent with the sick-quitter mechanism. Separating former drinkers from lifetime abstainers and considering pre-cessation health status may improve the interpretation of alcohol-health associations.
Background One of the risks associated with alcohol use disorder (AUD) is dementia. While the exact pathology is unknown, there is increasing evidence that alcohol consumption may dysregulate iron homeostasis in the brain. Unregulated iron can produce oxidative stress and cellular damage to neurons, including the iron-dependent form of cell death termed ferroptosis. Previous human work has relied on magnetic resonance imaging and quantitative susceptibility mapping, which estimate iron indirectly. We therefore measured iron directly, together with copper and zinc, in three brain regions of donors with and without a diagnosis of AUD. Methods Hippocampus, caudate, and substantia nigra were obtained from the New South Wales Brain Tissue Resource Centre. Tissues came from 40 donors — 20 males and 20 females, half of each with a diagnosis of AUD. Samples were wet-ashed and analysed by total reflection X-ray fluorescence, which quantifies ten elements simultaneously. Data were analysed by two-way analysis of covariance (diagnosis, sex; age as covariate), with simple main effects tested as model contrasts. Because concentrations are expressed per unit wet mass, the seven elements unrelated to the study hypothesis were used as internal reference analytes to screen for common scaling effects. Results In the caudate, iron was elevated in donors with AUD (p = 0.003), an effect confined to women (+47.2 μg g−1, p = 0.0002; men +5.4 μg g−1, p = 0.62). Caudate copper was elevated in both sexes (p = 0.016). In the hippocampus, iron was modestly lower in AUD (p = 0.032). In the substantia nigra, a diagnosis-by-sex interaction was observed for iron and zinc; however, the same interaction was present across the reference elements, and adjustment for tissue composition attenuated the iron interaction (p = 0.091) and abolished that for zinc (p = 0.331). Donor groups were well matched for age, post-mortem interval, brain pH, and RNA integrity, but cirrhosis was present only among donors with AUD, and the caudate copper effect did not persist when these donors were excluded. Conclusions These data provide direct evidence of regional trace-metal differences associated with a diagnosis of AUD, most robustly an elevation of caudate iron in women. The nigral findings should be interpreted with caution, and the copper finding may reflect hepatic disease rather than alcohol exposure per se. Sex differences in metal handling in the striatum warrant replication in a larger, independently characterised cohort.
