Skip to main content

Volume 38 Issue 2

Alcohol Misuse and Kidney Injury: Epidemiological Evidence and Potential Mechanisms

Zoltan V. Varga, M.D., Ph.D.; Csaba Matyas, M.D.; Janos Paloczi, Ph.D.; and Pal Pacher, M.D., Ph.D.

Zoltan V. Varga, M.D., Ph.D., is a visiting research fellow; Csaba Matyas, M.D., is a visiting research fellow; Janos Paloczi, Ph.D., is a visiting research fellow; and Pal Pacher, M.D., Ph.D., is a senior investigator and lab chief, all in the Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland.

    Abstract

    Chronic alcohol consumption is a well-known risk factor for tissue injury. The link between alcohol use disorder (AUD) and kidney injury is intriguing but controversial, and the molecular mechanisms by which alcohol may damage the kidneys are poorly understood. Epidemiological studies attempting to link AUD and kidney disease are, to date, inconclusive, and there is little experimental evidence directly linking alcohol consumption to kidney injury. However, studies conducted primarily in other organs and tissues suggest several possible mechanisms by which alcohol may promote kidney dysfunction. One possible mechanism is oxidative stress resulting from increased production of reactive oxygen species, which leads to an excessive amount of free radicals, which in turn trigger tissue injury and increase inflammation. In addition, AUD’s effect on other major organs (liver, heart, intestines, and skeletal muscle) appears to promote unfavorable pathological processes that are harmful to the kidneys. Notably, these mechanisms have not yet been validated experimentally in the kidney. Additional research is needed to clarify if alcohol does indeed promote kidney injury and the mechanisms by which alcohol-induced kidney injury may occur.

    Alcohol use disorder (AUD) is a substantial public health problem, affecting 15.7 million people age 12 and older in the United States (Center for Behavioral Health Statistics and Quality 2016). In 2012, 5.9 percent of all global deaths were attributable to alcohol—7.6 percent for men and 4.0 percent for women. Moreover, alcohol-attributable deaths have increased worldwide, making alcohol the fifth leading risk factor for premature death and disability in 2010 and the first among people ages 15 to 49 (World Health Organization 2014).

    Among the major consequences of chronic AUD that contribute to alcohol-related morbidity and mortality are liver cirrhosis, liver cancer, pancreatitis, and cardiovascular complications. To date, the epidemiological evidence connecting AUD and an increased incidence of chronic kidney disease is controversial. However, several preclinical studies suggest that alcohol consumption has a profound effect on the kidney and imply that there may be an independent pathologic entity, which we refer to here as “alcoholic kidney injury.”

    Studies conducted primarily in other organs and tissues suggest several possible mechanisms by which alcohol may promote kidney dysfunction. In particular, alcoholic kidney injury may be associated with a complex interaction of ethanol-induced oxidative stress and pro-inflammatory alterations. This may be complicated by the interplay between the kidneys and other organs, including the liver, intestines, skeletal muscle, and cardiovascular system. This brief synopsis reviews the evidence in support of these hypotheses.

    Kidney Diseases and AUD: Lessons From Epidemiology

    It is well established that cardiovascular diseases (including hypertension and ischemic heart disease) and diabetic microvascular complications are major risk factors for the development of chronic kidney diseases (Briasoulis et al. 2012; Carlsson et al. 2005; Reynolds et al. 2003; Ronksley et al. 2011). In turn, heavy alcohol consumption is implicated in the development of these cardiac diseases, with chronic, heavy drinkers at higher risk than those who consume small to moderate amounts of alcohol.

    That said, epidemiological data have yet to confirm a relationship between alcohol consumption and chronic kidney disease. A recent meta-analysis (Cheungpasitporn et al. 2015) found little support for such a relationship. The researchers performed an extensive literature search using online databases (MEDLINE, EMBASE and Cochrane Databases) to identify studies investigating the association between high alcohol consumption and chronic kidney disease, end-stage renal disease, or proteinuria (i.e., excess protein in the urine that indicates kidney damage). Their analysis included 20 studies representing a total of 292,431 patients. The researchers reported that the pooled risk ratios of chronic kidney disease, proteinuria, and end-stage renal disease in patients with high alcohol consumption were 0.83, 0.85, and 1.00, respectively, indicating decreased risk or no risk of kidney disease in heavy alcohol consumers (Cheungpasitporn et al. 2015).

    Other studies report similar findings, showing that the incidence of kidney disease is comparable or even lower in heavier drinkers (more than 210 g/week alcohol consumption) than in those who drink moderately (70–210 g/week alcohol consumption) (Buja et al. 2011; Knight et al. 2003; Koning et al. 2015; Reynolds et al. 2008; Sato et al. 2014; Yamagata et al. 2007). In contrast, some studies find that heavy alcohol consumption may predict poorer outcome in patients with chronic kidney diseases (Kronborg et al. 2008; Shankar et al. 2006; White et al. 2009). For example, White and colleagues (2009) reported that heavier drinkers (those consuming more than 30 g of alcohol/week) were at higher risk of incident albuminuria, which is typically a symptom of kidney disease. Japanese (Yamagata et al. 2007) and Italian (Buja et al. 2011) cohort studies revealed a U-shaped association between alcohol consumption and incidence of proteinuria. It is possible that the contradictory findings are the result of varying effects of different types of alcoholic beverages on the kidney, or the result of different alcohol consumption patterns in different countries. In addition, the self-reporting nature of drinking behaviors and the amount of alcohol consumed may bias some of the conclusions as shown, for example, by Parekh and Klag (2001), who found that people who drink heavily underreport their alcohol consumption.

    Potential Mechanisms of Alcoholic Kidney Injury: Lessons From Experimental Studies

    If alcohol consumption does in fact influence kidney disease, the question remains: How? There is direct and indirect evidence for several possible mechanisms. These changes are caused either by alcohol itself or by excessive amounts of the products formed when cells break down (or metabolize) alcohol, including acetaldehyde, NADH, and free radicals. These alcohol-related pathophysiologic changes in cells have been linked to damage in many organs and may play a role in kidney damage. In addition, complex interactions between organs may further complicate and accentuate the development of kidney pathology in people with AUD (see figure).

    Image
    Graphic showing possible mechanism for alcohol-induced kidney injury. Chronic alcohol consumption induces profound injury in several organs that may affect and aggravate the deleterious effect of ethanol on the kidney. Ethanol itself markedly induces the expression of the microsomal ethanol oxidation system (CYP2E1), producing reactive oxygen species as a byproduct. Increased gastrointestinal permeability and endotoxin load may lead to alcoholic steatohepatitis resulting in excessive immunoglobulin A (IgA)
    Figure Possible mechanism for alcohol-induced kidney injury. Chronic alcohol consumption induces profound injury in several organs that may affect and aggravate the deleterious effect of ethanol on the kidney. Ethanol itself markedly induces the expression of the microsomal ethanol oxidation system (CYP2E1), producing reactive oxygen species as a byproduct. Increased gastrointestinal permeability and endotoxin load may lead to alcoholic steatohepatitis resulting in excessive immunoglobulin A (IgA) load (due to increased intestinal production and decreased hepatic IgA clearance). IgA deposits may accumulate in the kidney, leading to glomerulopathy. Renal microcirculatory alterations in advanced liver cirrhosis leads to hepatorenal syndrome. Alcohol-induced skeletal muscle damage leads to excessive amounts of circulating myoglobin, causing renal tubular injury as a result of increased oxidative stress. Due to the development of alcoholic cardiomyopathy, chronic renal hypoxia develops, activating the renin–angiotensin–aldosterone system (RAAS), which in turn leads to further free radical production and to the propagation of fibrotic pathways.

    Oxidative Stress

    Free radicals (also called reactive oxygen species [ROS]) are one of the by-products of alcohol metabolism and are known to cause cellular damage, unless the body can use antioxidants to clean them up. Oxidative stress occurs when the body cannot detoxify free radicals as fast as they are being produced, and it is pivotal in triggering alcohol-related tissue injury. Studies suggest that several mechanisms produce ROS in alcohol-damaged organs, including the liver (Cederbaum et al. 2009), heart (Tan et al. 2012; Varga et al. 2015), and kidney (Latchoumycandane et al. 2015). The mechanisms producing ROS in organs include nonenzymatic mechanisms such as mitochondrial electron transport chain malfunction (Gyamfi et al. 2012; Mantena et al. 2008) and enzymatic mechanisms that involve enzymes such as NADPH oxidases (Kono et al. 2000) and the enzyme CYP2E1 (Lu and Cederbaum 2008). CYP2E1 is of particular interest when thinking about potential mechanisms for alcohol-related kidney damage. The body mainly metabolizes alcohol using the enzyme alcohol dehydrogenase, which is expressed primarily in the liver. However, during chronic ethanol consumption, the body also uses CYP2E1 in the liver as well as the kidneys. Interestingly, studies find that CYP2E1 induction is much more robust in the kidneys compared with the liver (Roberts et al. 1994; Zerilli et al. 1995). This massive induction of CYP2E1 in the kidneys results in oxidative stress that modifies phospholipids in cell membranes. Such modified phospholipids may in turn activate immune cells called neutrophil granulocytes, which further aggravates oxidative stress, promoting a vicious cycle (Latchoumycandane et al. 2015).

    Studies suggest that ethanol consumption may increase renal expression of other potential sources of free radicals involving a family of enzymes called nitric oxide synthases (Tirapelli et al. 2012). Nitric oxide synthase stimulates the production of nitric oxide, which, if produced excessively, can react with other molecules and create free radicals that trigger tissue damage in the kidneys (Pacher et al. 2007; Szalay et al. 2015). Tirapelli and colleagues (2012) showed that ethanol consumption increased the expression of two nitric oxide synthases. However, it is still unclear exactly how ethanol upregulates nitric oxide synthases, or whether it does so directly or indirectly. It may be that toxins released from the intestines into blood circulation because of ethanol’s effects on the digestive system activate the expression of nitric oxide synthase. Another theory suggests that both enzymes may undergo the process of uncoupling due to oxidation or lack of critical coenzymes (e.g., tetrahydrobiopterin). Uncoupling eventually leads to generation of damaging ROS like superoxide anion, instead of the vasorelaxant nitric oxide that maintains normal blood flow in the kidney.

    Alcohol-Metabolism Derived Intermediaries

    Along with oxidative stress, increasing evidence suggests that some nonoxidative mechanisms also factor into alcohol-related organ damage. Specifically, ethanol metabolism produces fatty acid ethyl esters in various organs (Laposata and Lange 1986), which can cause ethanol-induced organ damage. Calabrese and Rizza (1999) found that ethanol induced a significant increase in the levels of fatty acid ethyl esters. They measured the highest levels in the heart, followed by kidney, brain, and liver.

    Due to the metabolism of ethanol, significant amounts of acetate are produced and subsequently incorporated into acetyl-coenzyme-A, a molecule that participates in metabolism of proteins, lipids, and carbohydrates. This leads to the reprogramming of systemic metabolism. Protein acetylation—adding an acetyl group to a protein—is integral to regulating processes controlled by mitochondria, including fatty acid metabolism and antioxidant defense (Choudhary et al. 2014). Our current understanding is that the balance of lysine acetylation and deacetylation (the removal of an acetyl group) of key proteins (e.g., of the master regulator of mitochondrial biogenesis, PGC-1 alpha) serves, at least in part, to trigger a switch in metabolic status in conditions of overnutrition or undernutrition (Bai et al. 2015; Ghanta et al. 2013; Jeninga et al. 2010). A recent study demonstrated that ethanol induces mitochondrial protein hyperacetylation (excessive modification by acetylation of the lysine residues of a protein) in the kidney, which might interfere with the function of some mitochondrial proteins involved in alcohol metabolism or defense against oxidative stress (e.g., superoxide dismutase 2, aldehyde dehydrogenase 2, gluthatione peroxidase). This could also be a significant factor contributing to ethanol-induced mitochondrial dysfunction in the kidneys (Harris et al. 2015).

    Alcohol-Induced Intestinal Damage

    Alcohol-induced intestinal damage and increased mucosal translocation of bacterial endotoxin are crucial in the initiation and progression of alcoholic liver injury and in the pathogenesis of other alcohol-related diseases (Bala et al. 2014; Purohit et al. 2008). (For an in-depth discussion of alcohol and the digestive tract, see the article by Keshavarzian in this issue.) The direct role of alcohol-related endotoxin release in alcoholic kidney injury has not yet been studied. However, it is possible that activation of the innate immune system due to endotoxins released by a leaky gut plays a central role in the development of renal damage, as it does for liver damage (Zhang et al. 2008).

    Substantial experimental and clinical evidence suggests that increased intestinal permeability and endotoxin release caused by excessive alcohol consumption leads to higher levels of circulating immunoglobulin A (IgA), an antibody critical to the immune response of mucous membranes. The kidney is particularly sensitive to an increased IgA load. In fact, IgA glomerulonephritis—acute inflammation of the kidney caused by an IgA immune response—is one of the most common types of primary glomerulonephritis worldwide (D’Amico 1987). This IgA-related kidney disease leads to clinical symptoms of renal injury and eventually progresses into renal failure (Amore et al. 1994; Bene et al. 1988; Pouria and Feehally 1999). Experimental studies suggest that heavy alcohol consumption induces IgA kidney disease (Smith et al. 1990). In addition, rats given intragastric infusions of a commercial whiskey (1.5 ml/100 gm body weight) 3 times a week along with a nutrient-deficient diet develop a more severe form of IgA nephropathy (Amore et al. 1994).

    Evidence also exists that alcohol-related damage to the liver, in particular advanced liver cirrhosis, leads to hepatorenal syndrome (HRS)—a deterioration in renal function related to impaired circulation. The underlying mechanisms involved in the development and progression of HRS are incompletely understood, although it is plausible that the altered balance between vasoconstrictor and vasodilator factors plays a significant role (Lenz 2005).

    Alcoholic Skeletal Myopathy: A Potential Indirect Mechanism

    Severe AUD is frequently associated with various acute or chronic muscle symptoms, including difficulties with gait, muscle cramps, pain, and overall reduced muscle mass. In fact, biochemical lesions in the muscles and the resulting myopathy develop independently of any peripheral neuropathy, macro- and micronutrient malnutrition, and overt liver disease in people with AUD. In chronic alcoholic myopathy, a person’s entire muscle mass may be reduced by up to one-third. It is the most common skeletal muscle disorder in the industrialized world, present at varying severity in approximately half of alcohol misusers (Preedy et al. 2001). To date, studies have not examined whether there is a direct link between acute alcoholic myopathy and kidney injury. However, several lines of research suggest there might be a connection.

    Although the mechanism of alcoholic myopathy is not fully understood, it is likely that disruption of mitochondria-related energy homeostasis is important in promoting muscle cell (myocyte) injury (Eisner et al. 2014). In rare cases in malnourished chronic alcoholics, acute alcoholic myopathy, also termed acute alcoholic necrotizing myopathy or alcoholic rhabdomyolysis, also may occur, which may lead to reversible or irreversible acute kidney injury (Haller and Knochel 1984; Hewitt and Winter 1995; Muthukumar et al. 1999; Sofat et al. 1999).

    A few studies have linked rhabdomyolysis and myoglobin toxicity with acute kidney injury, supporting a possible association among alcohol use, alcohol-related acute myopathy, and kidney damage. For example, Belliere and colleagues (2015) showed a link between rhabdomyolysis and excessive macrophage infiltration in the kidney, which in turn led to pro-inflammatory marker expression and consequent tissue injury (Belliere et al. 2015). Another study by Plotnikov and colleagues (2009) showed that mitochondria isolated from rat kidneys were damaged by oxidative stress when incubated with myoglobin. This finding suggests that rhabdomyolysis and myoglobin toxicity may trigger oxidative stress in the kidney via mitochondrial injury.

    Alcoholic Cardiomyopathy: Another Potential Confounder

    Several epidemiological studies have shown that mild alcohol consumption benefits cardiovascular health (Coate 1993; Kannel and Ellison 1996) by reducing the risk of coronary heart disease (Mukamal et al. 2006). In contrast, heavy drinking leads to the development of nonischemic dilated cardiomyopathy (Klatsky 2007) and significantly increases the risk of sudden cardiac death (Hookana et al. 2011).

    Chronic or acute heart failure can lead to chronic or acute dysfunction in the kidneys, known as cardiorenal syndrome (Cleland et al. 2012). The complex renal pathophysiological response leads to fluid buildup in tissues, ischemic injury, peripheral vasoconstriction, and activation of the hormone system that helps regulate blood flow (called the renin−angiotensin−aldosterone system, or RAAS) (Palazzuoli and Ronco 2011). The overactivation of RAAS further aggravates oxidative stress in chronic alcoholism (Ungvari et al. 2004). As a consequence, oxidative stress not only propagates kidney failure, but it also contributes to the progression of chronic heart failure (Pacher et al. 2005) and leads to a vicious cycle in alcohol-induced cardiovascular complications.

    Conclusions

    As noted above, there is much to learn about alcoholic kidney disease and the complex interplay among multiple organs affected by alcohol consumption. Although research suggests several potential mechanisms by which alcohol may directly or indirectly affect the kidneys, they have not yet been validated experimentally. Future research will hopefully explore these hypotheses to provide a better understanding of alcoholic kidney injury. This article highlights the effects of other organs on kidney and renal function; however, it should be noted that alcoholic kidney injury itself may have negative metabolic consequences. One such complication is impaired vitamin D metabolism (Shankar et al. 2008), which may influence the function of several other organs, creating a vicious cycle.

    The treatment of alcoholic kidney injury is still largely symptomatic, despite accumulating knowledge about underlying mechanisms. Both preclinical and human studies highlight the central role of oxidative stress and inflammation in triggering and driving the pathological processes associated with alcoholic kidney injury. Early diagnosis of this condition and rigorous abstinence from alcohol are very important for slowing down the progression of the disease and allowing the kidneys to regenerate.

    From the Publisher

    Acknowledgments

    The authors are indebted to Dr. George Kunos, NIAAA Scientific Director, for his ongoing support and critical reading of the manuscript. Dr. Varga was supported by a grant from the Rosztoczy Foundation. Dr. Matyas was supported by a scholarship from the Hungarian-American Enterprise Scholarship Fund/Council on International Educational Exchange.

    Financial disclosure

    The authors declare that they have no competing financial interests.

    References

    Amore, A.; Coppo, R.; Roccatello, D.; et al. Experimental IgA nephropathy secondary to hepatocellular injury induced by dietary deficiencies and heavy alcohol intake. Laboratory Investigations 70:68–77, 1994. PMID: 8302021

    Bai, P.; Nagy, L.; Fodor, T.; et al. Poly(ADP-ribose) polymerases as modulators of mitochondrial activity. Trends in Endocrinology and Metabolism: TEM 26:75–83, 2015. PMID: 25497347

    Bala, S.; Marcos, M.; Gattu, A.; et al. Acute binge drinking increases serum endotoxin and bacterial DNA levels in healthy individuals. PLoS One 9:e96864, 2014. PMID: 24828436

    Belliere, J.; Casemayou, A.; Ducasse, L.; et al. Specific macrophage subtypes influence the progression of rhabdomyolysis-induced kidney injury. Journal of the American Society of Nephrology 26:1363–1377. 2015. PMID: 25270069

    Bene, M.C.; De Korwin, J.D.; Hurault de Ligny, B.; et al. IgA nephropathy and alcoholic liver cirrhosis. A prospective necropsy study. American Journal of Clinical Pathology 89:769–773, 1988. PMID: 3369369

    Briasoulis, A.; Agarwal, V.; and Messerli, F.H. Alcohol consumption and the risk of hypertension in men and women: A systematic review and meta-analysis. Journal of Clinical Hypertension (Greenwich) 14:792–798. 2012. PMID: 23126352

    Buja, A.; Scafato, E.; Baggio, B.; et al. Renal impairment and moderate alcohol consumption in the elderly. Results from the Italian Longitudinal Study on Aging (ILSA). Public Health Nutrition 14:1907–1918, 2011. PMID: 21729477

    Calabrese, V., and Rizza, V. Effects of L-carnitine on the formation of fatty acid ethyl esters in brain and peripheral organs after short-term ethanol administration in rat. Neurochemical Research 24(1):79–84, 1999. PMID: 9973240

    Carlsson, S.; Hammar, N.; and Grill, V. Alcohol consumption and type 2 diabetes: Meta-analysis of epidemiological studies indicates a U-shaped relationship. Diabetologia 48(6):1051–1054, 2005. PMID: 15864527

    Cederbaum, A.I.; Lu, Y.; and Wu, D. Role of oxidative stress in alcohol-induced liver injury. Archives of Toxicology 83:519–548, 2009. PMID: 19448996

    Center for Behavioral Health Statistics and Quality. Key Substance Use and Mental Health Indicators in the United States: Results from the 2015 National Survey on Drug Use and Health (HHS Publication No. SMA 16-4984, NSDUH Series H-51). Rockville, MD: Substance Abuse and Mental Health Services Administration, 2016. Available at: https://www.samhsa.gov/data/sites/default/files/NSDUH-FFR1-2015/NSDUH-FFR1-2015/NSDUH-FFR1-2015.pdf. Accessed December 28, 2016.

    Cheungpasitporn, W.; Thongprayoon, C.; Kittanamongkolchai, W.; et al. High alcohol consumption and the risk of renal damage: A systematic review and meta-analysis. QJM: Monthly Journal of the Association of Physicians 108:539–548, 2015. PMID: 25519235

    Choudhary, C.; Weinert, B.T.; Nishida, Y.; et al. The growing landscape of lysine acetylation links metabolism and cell signalling. Nature Reviews. Molecular Cell Biology 15:536–550, 2014. PMID: 25053359

    Cleland, J.G.; Carubelli, V.; Castiello, T.; et al. Renal dysfunction in acute and chronic heart failure: Prevalence, incidence and prognosis. Heart Failure Reviews 17:133–149, 2012. PMID: 22426973

    Coate, D. Moderate drinking and coronary heart disease mortality: Evidence from NHANES I and the NHANES I Follow-up. American Journal of Public Health 83:888–890, 1993. PMID: 8498629

    D’Amico, G. The commonest glomerulonephritis in the world: IgA nephropathy. Quarterly Journal of Medicine 64:709–727, 1987. PMID: 3329736

    Eisner, V.; Lenaers, G.; and Hajnóczky, G. Mitochondrial fusion is frequent in skeletal muscle and supports excitation-contraction coupling. Journal of Cell Biology 205(2):179–195, 2014. PMID: 24751540

    Ghanta, S.; Grossmann, R.E.; and Brenner, C. Mitochondrial protein acetylation as a cell-intrinsic, evolutionary driver of fat storage: Chemical and metabolic logic of acetyl-lysine modifications. Critical Reviews in Biochemistry and Molecular Biology 48(6):561–574, 2013. PMID: 24050258

    Gyamfi, D.; Everitt, H.E.; Tewfik, I.; et al. Hepatic mitochondrial dysfunction induced by fatty acids and ethanol. Free Radical Biology & Medicine 53(11):2131–2145, 2012. PMID: 23010494

    Haller, R.G., and Knochel, J.P. Skeletal muscle disease in alcoholism. Medical Clinics of North America 68(1):91–103, 1984. PMID: 6361420

    Harris, P.S.; Roy, S.R.; Coughlan, C.; et al. Chronic ethanol consumption induces mitochondrial protein acetylation and oxidative stress in the kidney. Redox Biology 6:33–40, 2015. PMID: 26177469

    Hewitt, S.M., and Winter, R.J. Rhabdomyolysis following acute alcohol intoxication. Journal of Accident and Emergency Medicine 12(2):143–144, 1995. PMID: 7582413

    Hookana, E.; Junttila, M.J.; Puurunen, V.P.; et al. Causes of nonischemic sudden cardiac death in the current era. Heart Rhythm 8:1570–1575, 2011. PMID: 21740887

    Jeninga, E.H.; Schoonjans, K.; and Auwerx, J. Reversible acetylation of PGC-1: Connecting energy sensors and effectors to guarantee metabolic flexibility. Oncogene 29(33):4617–4624, 2010. PMID: 20531298

    Kannel, W.B., and Ellison, R.C. Alcohol and coronary heart disease: The evidence for a protective effect. Clinica Chimica Acta; International Journal of Clinical Chemistry 246(1–2):59–76, 1996. PMID: 8814971

    Klatsky, A.L. Alcohol, cardiovascular diseases and diabetes mellitus. Pharmacological Research 55(3):237–247, 2007. PMID: 17363263

    Knight, E.L.; Stampfer, M.J.; Rimm, E.B.; et al. Moderate alcohol intake and renal function decline in women: A prospective study. Nephrology, Dialysis, Transplantation 18(8):1549–1554, 2003. PMID: 12897093

    Koning, S.H.; Gansevoort, R.T.; Mukamal, K.J.; et al. Alcohol consumption is inversely associated with the risk of developing chronic kidney disease. Kidney International 87(5):1009–1016, 2015. PMID: 25587707

    Kono, H.; Rusyn, I.; Yin, M.; et al. NADPH oxidase-derived free radicals are key oxidants in alcohol-induced liver disease. Journal of Clinical Investigation 106(7):867–872, 2000. PMID: 11018074

    Kronborg, J.; Solbu, M.; Njølstad, I.; et al. Predictors of change in estimated GFR: A population-based 7-year follow-up from the Tromsø study. Nephrology, Dialysis, Transplantation 23:2818–2826, 2008. PMID: 18400822

    Laposata, E.A., and Lange, L.G. Presence of nonoxidative ethanol metabolism in human organs commonly damaged by ethanol abuse. Science 231(4737):497–499, 1986. PMID: 3941913

    Latchoumycandane, C.; Nagy, L.E.; and McIntyre, T.M. Myeloperoxidase formation of PAF receptor ligands induces PAF receptor-dependent kidney injury during ethanol consumption. Free Radical Biology and Medicine 86:179–190, 2015. PMID: 26003521

    Lenz, K. Hepatorenal syndrome—is it central hypovolemia, a cardiac disease, or part of gradually developing multiorgan dysfunction? Hepatology 42(2):263–265, 2005. PMID: 16025501

    Lu, Y., and Cederbaum, A.I. CYP2E1 and oxidative liver injury by alcohol. Free Radical Biology & Medicine 44(5):723–738, 2008. PMID: 18078827

    Mantena, S.K.; King, A.L.; Andringa, K.K.; et al. Mitochondrial dysfunction and oxidative stress in the pathogenesis of alcohol- and obesity-induced fatty liver diseases. Free Radical Biology & Medicine 44(7):1259–1272, 2008. PMID: 18242193

    Mukamal, K.J.; Chiuve, S.E.; and Rimm, E.B. Alcohol consumption and risk for coronary heart disease in men with healthy lifestyles. Archives of Internal Medicine 166(19):2145–2150, 2006. PMID: 17060546

    Muthukumar, T.; Jha, V.; Sud, A.; et al. Acute renal failure due to nontraumatic rhabdomyolysis following binge drinking. Renal Failure 21(5):545–549, 1999. PMID: 10517000

    Pacher, P.; Beckman, J.S.; and Liaudet, L. Nitric oxide and peroxynitrite in health and disease. Physiological Reviews 87(1):315–424, 2007. PMID: 17237348

    Pacher, P.; Schulz, R.; Liaudet, L.; Szabo, C. Nitrosative stress and pharmacological modulation of heart failure. Trends in Pharmacological Sciences 26(6):302–310, 2005. PMID: 15925705

    Palazzuoli, A., and Ronco, C. Cardio-renal syndrome: An entity cardiologists and nephrologists should be dealing with collegially. Heart Failure Reviews 16(6):503–508, 2011. PMID: 21822604

    Parekh, R.S., and Klag, M.J. Alcohol: Role in the development of hypertension and end-stage renal disease. Current Opinion in Nephrology and Hypertension 10(3):385–390, 2001. PMID: 11342802

    Plotnikov, E.Y.; Chupyrkina, A.A.; Pevzner, I.B.; et al. Myoglobin causes oxidative stress, increase of NO production and dysfunction of kidney’s mitochondria. Biochimica et Biophysica Acta 1792(8):796–803, 2009. PMID: 19545623

    Pouria, S., and Feehally, J. Glomerular IgA deposition in liver disease. Nephrology, Dialysis, Transplantation 14(10):2279–2282, 1999. PMID: 10528642

    Preedy, V.R.; Adachi, J.; Ueno, Y.; et al. Alcoholic skeletal muscle myopathy: Definitions, features, contribution of neuropathy, impact and diagnosis. European Journal of Neurology: The Official Journal of the European Federation of Neurological Societies 8(6):677–687, 2001. PMID: 11784353

    Purohit, V.; Bode, J.C.; Bode, C.; et al. Alcohol, intestinal bacterial growth, intestinal permeability to endotoxin, and medical consequences: Summary of a symposium. Alcohol 42(5):349–361, 2008. PMID: 18504085

    Reynolds, K.; Lewis, B.; Nolen, J.D.; et al. Alcohol consumption and risk of stroke: A meta-analysis. JAMA 289(5):579–588, 2003. PMID: 12578491

    Reynolds, K.; Gu, D.; Chen, J.; et al. Alcohol consumption and the risk of end-stage renal disease among Chinese men. Kidney International 73(7):870–876, 2008. PMID: 18185503

    Roberts, B.J., Shoaf, S.E., Jeong, K.S.; Song, B. J. Induction of CYP2E1 in liver, kidney, brain and intestine during chronic ethanol administration and withdrawal: Evidence that CYP2E1 possesses a rapid phase half-life of 6 hours or less. Biochemical and Biophysical Research Communications 205(2):1064–1071, 1994. PMID: 7802633

    Ronksley, P.E.; Brien, S.E.; Turner, B.J.; et al. Association of alcohol consumption with selected cardiovascular disease outcomes: A systematic review and meta-analysis. BMJ 342:d671, 2011. PMID: 21343207

    Sato, K.K.; Hayashi, T.; Uehara, S.; et al. Drinking pattern and risk of chronic kidney disease: The Kansai Healthcare Study. American Journal of Nephrology 40(6):516–522, 2014. PMID: 25531762

    Shankar, A.; Klein, R.; and Klein, B.E. The association among smoking, heavy drinking, and chronic kidney disease. American Journal of Epidemiology 164(3):263–271, 2006. PMID: 16775042

    Shankar, K.; Liu, X.; Singhal, R.; et al. Chronic ethanol consumption leads to disruption of vitamin D3 homeostasis associated with induction of renal 1,25 dihydroxyvitamin D3-24-hydroxylase (CYP24A1). Endocrinology 149(4):1748–1756, 2008. PMID: 18162528

    Smith, S.M.; Yu, G.S.; and Tsukamoto, H. IgA nephropathy in alcohol abuse: An animal model. Laboratory Investigation: A Journal of Technical Methods and Pathology 62(2):179–184, 1990. PMID: 2304330

    Sofat, N.; Bell, S.; Turner, J.; Warrens, A.N. A case of acute renal failure and compartment syndrome after an alcoholic binge. Journal of Accident & Emergency Medicine 16(4):296–298, 1999. PMID: 10417945

    Szalay, C.I.; Erdélyi, K.; Kökény, G.; et al. Oxidative/nitrative stress and inflammation drive progression of doxorubicin-induced renal fibrosis in rats as revealed by comparing a normal and a fibrosis-resistant rat strain. PLoS One 10(6):e0127090, 2015. PMID: 26086199

    Tan, Y.; Li, X.; Prabhu, S.D.; et al. Angiotensin II plays a critical role in alcohol-induced cardiac nitrative damage, cell death, remodeling, and cardiomyopathy in a protein kinase C/nicotinamide adenine dinucleotide phosphate oxidase-dependent manner. Journal of the American College of Cardiology 59(16):1477–1486, 2012. PMID: 22497828

    Tirapelli, L.F.; Martins-Oliveira, A.; Batalhao, M.E.; et al. Ethanol consumption increases the expression of endothelial nitric oxide synthase, inducible nitric oxide synthase and metalloproteinases in the rat kidney. Journal of Pharmacy and Pharmacology 64(1):68–76, 2012. PMID: 22150674

    Ungvari, Z.; Csiszar, A.; Kaminski, P.M.; et al. Chronic high pressure-induced arterial oxidative stress: Involvement of protein kinase C-dependent NAD(P)H oxidase and local renin-angiotensin system. American Journal of Pathology 165(1):219–226, 2004. PMID: 15215177

    Varga, Z.V.; Ferdinandy, P.; Liaudet, L.; Pacher, P. Drug-induced mitochondrial dysfunction and cardiotoxicity. American Journal of Physiology. Heart and Circulatory Physiology 309(9):H1453–H1467, 2015. PMID: 26386112

    White, S.L.; Polkinghorne, K.R.; Cass, A.; et al. Alcohol consumption and 5-year onset of chronic kidney disease: The AusDiab Study. Nephrology, Dialysis, Transplantation 24(8):2464–2472, 2009. PMID: 19307230

    World Health Organization (WHO). Global Status Report on Alcohol and Health 2014. Geneva: WHO, 2014. Available at: http://www.who.int/substance_abuse/publications/global_alcohol_report/msb_gsr_2014_1.pdf. Accessed December 28, 2016.

    Yamagata, K.; Ishida, K.; Sairenchi, T.; et al. Risk factors for chronic kidney disease in a community-based population: A 10-year follow-up study. Kidney International 71(2):159–166, 2007. PMID: 17136030

    Zerilli, A.; Lucas, D.; Amet, Y.; et al. Cytochrome P-450 2E1 in rat liver, kidney and lung microsomes after chronic administration of ethanol either orally or by inhalation. Alcohol and Alcoholism 30(3):357–365, 1995. PMID: 7545990

    Zhang, B.; Ramesh, G.; Uematsu, S.; et al. TLR4 signaling mediates inflammation and tissue injury in nephrotoxicity. Journal of the American Society of Nephrology: JASN 19(5):923–932, 2008. PMID: 18256356