Alcohol’s Impact on Kidney Function

MURRAY EPSTEIN, M.D.

Both acute and chronic alcohol consumption can compromise kidney function, particularly in conjunction with established liver disease. Investigators have observed alcohol-related changes in the structure and function of the kidneys and impairment in their ability to regulate the volume and composition of fluid and electrolytes in the body. Chronic alcoholic patients may experience low blood concentrations of key electrolytes as well as potentially severe alterations in the body’s acid-base balance. In addition, alcohol can disrupt the hormonal control mechanisms that govern kidney function. By promoting liver disease, chronic drinking has further detrimental effects on the kidneys, including impaired sodium and fluid handling and even acute kidney failure. KEY WORDS: kidney function; kidney disorder; disorder of fluid or electrolyte or acid-base balance; alcoholic liver disorder; hormones; body fluid; blood circulation; blood pressure; sodium; potassium; phosphates; magnesium; calcium; literature review

cell’s function depends not only centrations of these substances in the indirectly, as a consequence of liver on receiving a continuous extracellular fluid. disease. This article first reviews A supply of nutrients and elimi- In addition to their role in regulat- direct effects of alcohol on kidney nating metabolic waste products but ing the body’s fluid composition, the structure, function, and regulation, also on the existence of stable physi- kidneys produce hormones that influ- highlighting relevant effects associated cal and chemical conditions in the ence a host of physiological processes, with liver disease. Following this extracellular fluid1 bathing it. Among including blood pressure regulation, discussion, the article takes a more in- the most important substances con- red blood cell production, and calcium depth look at several important indirect tributing to these conditions are water, metabolism. Besides producing hor- effects of alcohol on the kidneys that sodium, potassium, calcium, and mones, the kidneys respond to the occur once liver disease has become phosphate. Loss or retention of any actions of regulatory hormones pro- established. one of these substances can influence duced in the brain, the parathyroid the body’s handling of the others. In glands in the neck, and the adrenal addition, hydrogen ion concentration GROSS AND MICROSCOPIC glands located atop the kidneys. CHANGES (i.e., acid-base balance) influences Because of the kidneys’ important cell structure and permeability as well and varied role in the body, impair- One way in which alcohol directly as the rate of metabolic reactions. The ment of their function can result in a affects the kidneys is by altering the amounts of these substances must be range of disorders, from mild varia- form and structure of this pair of or- held within very narrow limits, re- tions in fluid balance to acute kidney gans, as demonstrated by various gardless of the large variations possi- animal studies. For example, in an ble in their intake or loss. The kidneys failure and death. Alcohol, one of the numerous factors that can compro- early study on dogs (Chaikoff et al. are the organs primarily responsible 1948), investigators observed several for regulating the amounts and con- mise kidney function, can interfere with kidney function directly, through striking alterations after chronic alco- acute or chronic consumption, or hol administration. The basement MURRAY EPSTEIN, M.D., is professor of membrane of the glomerulus (see sidebar figure) became abnormally medicine in the Nephrology Section 1For a definition of this and other technical at the University of Miami School of terms used in this article, see the glossary, pp. thickened and was characterized by Medicine, Miami, Florida. 93Ð96, and the sidebar, pp. 91Ð92. cell proliferation. Further changes

84 ALCOHOL HEALTH & RESEARCH WORLD Alcohol’s Impact on Kidney Function

included enlarged and altered cells in The few studies focusing on alco- volume (i.e., its diuretic effect) alters the kidney tubules. In another study, hol’s direct effects on perfusion in the body’s fluid level (i.e., hydration Van Thiel and colleagues (1977) human kidneys suggest that regulatory state) and produces disturbances in compared kidney structure and func- mechanisms retain control over this electrolyte concentrations. These tion in alcohol-fed and control rats. component of kidney function despite effects vary depending on factors such The alcohol-fed group experienced alcohol consumption. Even at high as the amount and duration of drink- kidney swelling and significantly blood alcohol levels, only minor fluc- ing, the presence of other diseases, reduced kidney function; in addition, tuations were found in the rates of and the drinker’s nutritional status under microscopic examination, the plasma flow and filtration through the (see table, p. 90). kidneys of alcohol-fed rats were found kidneys (Rubini et al. 1955). to have cells enlarged with increased Additional studies are needed to con- Fluid amounts of protein, fat, and water, firm these observations, however. compared with those of the control Results of subsequent studies in Alcohol can produce urine flow with- animals. animal models seem to vary according in 20 minutes of consumption; as a Similarly, clinicians long have to the species examined, the route and result of urinary fluid losses, the con- noted significant kidney enlargement dose of alcohol administration, and the centration of electrolytes in blood (i.e., nephromegaly) in direct propor- length of time after administration for serum increases. These changes can tion to liver enlargement among which the study groups were observed. be profound in chronic alcoholic pa- chronic alcoholic2 patients afflicted For example, some studies implied tients, who may demonstrate clinical with liver cirrhosis. Laube and col- that acute alcohol consumption does evidence of dehydration. leagues (1967) suggested that both not significantly change kidney hemo- As most investigators now agree, cellular enlargement and cell prolifer- dynamics or sodium excretion in dogs, increased urine flow results from alco- ation contribute to such nephro- but these studies did not extend be- hol’s acute inhibition of the release of megaly. In alcoholic patients with yond 6 hours after alcohol ingestion. antidiuretic hormone (ADH), a hor- cirrhosis, these investigators reported In contrast, earlier studies that exam- mone also known as vasopressin, a 33-percent increase in kidney weight, ined dogs for a longer period reported which normally promotes the forma- whereas they observed no appreciable that a single dose of 3 grams of alco- tion of concentrated urine by inducing kidney enlargement in alcoholic pa- hol per kilogram of body weight (g/kg) the kidneys to conserve fluids. In the tients without cirrhosis compared with elevated plasma volume between 10 absence of ADH, segments of the control subjects (Laube et al. 1967). and 26 hours following alcohol inges- kidney’s tubule system become imper- tion (Nicholson and Taylor 1940).3 meable to water, thus preventing it from being reabsorbed into the body. BLOOD-FLOW CHANGES Another study with dogs (Beard et al. 1965) disclosed that the effects of Under these conditions, the urine Normally the rate of blood flow, or chronic alcohol consumption endured formed is dilute and electrolyte con- perfusion, (i.e., hemodynamics) through even longer. The investigators noted centration in the blood simultaneously the kidneys is tightly controlled, so increased plasma and extracellular fluid rises. Although increased serum elec- that plasma can be filtered and sub- volume 1 week after chronic alcohol trolyte concentration normally acti- stances the body needs can be reab- ingestion, and these volume expansions vates secretion of ADH so that fluid sorbed under optimal circumstances persisted for the remaining 7 weeks of balance can be restored, a rising blood (see sidebar). Established liver disease the study. Similar alterations have been alcohol level disrupts this regulatory impairs this important balancing act, found in body fluid volumes among response by suppressing ADH secre- however, by either greatly augmenting chronic alcoholic patients. tion into the blood. or reducing the rates of plasma flow Interestingly, age makes a difference and filtration through the glomerulus. in how rapidly the body escapes alco- Investigators have not yet fully ex- EFFECTS ON FLUID AND hol’s ADH-suppressive effect. People plained the mechanisms underlying ELECTROLYTE BALANCE older than age 50 overcome suppres- this wide range of abnormalities, One of the main functions of the kid- sion of ADH more quickly than their though, and have devoted little atten- neys is to regulate both the volume and younger counterparts do, despite reach- tion to alcohol’s effects on kidney the composition of body fluid, includ- ing similar serum electrolyte concentra- hemodynamics in people who do not ing electrically charged particles (i.e., tions after alcohol consumption. In have liver disease. ions), such as sodium, potassium, and older people, ADH levels sharply in- chloride ions (i.e., electrolytes). How- crease following alcohol intake, per- 2The terms “alcoholic patient” and “alcoholism” haps in part because sensitivity to as used in this article are summary terms for ever, alcohol’s ability to increase urine the diagnoses of alcohol abuse and alcohol increased electrolyte concentration is dependence as defined variously by the studies 3For a person weighing 150 pounds, this dose enhanced with age. It is not known cited. would be roughly equivalent to 17 drinks. whether chronic alcoholic patients

VOL. 21, NO. 1, 1997 85 experience a similar difference in the complication of advanced liver disease, ADH response as they age, however. as discussed later in this article. CAUSES OF LOW PHOSPHATE LEVELS Sodium Potassium IN ALCOHOLICS The serum sodium level is determined Normally the kidneys are a major The following causes may un- by the balance of fluid in relation to route of potassium ion excretion and derlie low phosphate levels in that of sodium: Not enough fluid in serve as an important site of potassium severe alcoholics: the body results in a sodium concen- regulation. Alcohol consumption tration that is too high (i.e., hyperna- historically has been found to reduce ¥ Phosphorus deficiency in the tremia), whereas excessive amounts of the amount of potassium excreted by diet fluid produce a sodium concentration the kidneys (e.g., Rubini et al. 1955), ¥ Increased blood pH due to that is too low (i.e., hyponatremia). although the body’s hydration state prolonged rapid breathing Hyponatremia does not constitute may help determine whether potassium ¥ Insulin administration merely a biochemical abnormality but excretion will increase or decrease in most likely has clinical consequences response to alcohol. Levels of potassi- ¥ Administration of nutrients as well (e.g., impaired mental activity, um, like those of sodium, also can beyond normal requirements (in hospital settings) neurological symptoms, and, in ex- affect the way the kidneys handle treme instances, seizures). fluid elimination or retention. In addi- ¥ Excessive excretion in urine “Beer drinkers’ hyponatremia” is a tion, potassium depletion has been ¥ Magnesium deficiency. syndrome that appears to result from proposed to exacerbate hyponatremia an intake of excessive fluid in the through any of several mechanisms SOURCE: Adapted from Epstein, M. Alcohol and the kidney. In: Lieber, C.S., ed. Medical and form of beer. Hilden and Svendsen (Epstein 1992): For example, potassi- Nutritional Complications of Alcoholism: (1975) observed hyponatremia in five um losses may stimulate ADH activity, Mechanisms and Management. New York: patients who drank at least 5 liters of thereby increasing the amount of fluid Plenum Medical Book Company, 1992. p. 498. beer per day (L/d) without any other reabsorbed and causing the body’s nourishment. (For comparison, a per- sodium concentration to decrease as a Another potential cause of hypo- son’s normal fluid intake averages a result. Alternatively, potassium losses phosphatemia in alcoholic patients is little more than 2 L/d.) Because beer may increase thirst, also through hor- hyperventilation, which can occur contains few dissolved substances monal mechanisms, thereby promot- during alcohol withdrawal. Prolonged (i.e., solutes), such as sodium, these ing increased fluid intake. rapid, shallow breathing results in patients apparently lacked a sufficient excessive loss of carbon dioxide and quantity of solutes to stimulate the Phosphate decreased blood acidity (i.e., alkalo- kidneys to eliminate excess fluid. sis), which in turn activates an en- Although fluid overload—not alco- Low blood levels of phosphate com- zyme that enhances glucose hol itself—is considered the major con- monly occur acutely in hospitalized breakdown. In glucose breakdown, tributor to beer drinkers’ hyponatremia, alcoholic patients, appearing in more phosphate becomes incorporated into alcohol does appear to directly influ- than one-half of severe alcoholism various metabolic compounds, ulti- ence the kidney’s handling of sodium cases. Indeed, when the condition mately lowering blood levels of phos- and other electrolytes, potentially re- does not appear, clinicians treating phate. As the rate of glucose sulting in hypernatremia. In a study by alcoholic patients should suspect that breakdown increases, profound hy- Rubini and colleagues (1955), subjects another problem is masking the recog- pophosphatemia potentially can result. who consistently drank about 4 ounces nition of low phosphate levels, such as Insulin administration also can lead (oz) of 100-proof bourbon whiskey ongoing muscle dissolution, excess to mild hypophosphatemia, because it experienced decreased sodium, potassi- blood acidity (i.e., acidosis), inade- decreases cellular acidity. Although um, and chloride excretion (i.e., in- quate blood volume, or kidney failure. insulin more likely plays a contributory, creased retention of solutes). Although Several mechanisms may rather than principal, role in produc- some exceptions exist, several historical contribute to abnormally low phos- ing hypophosphatemia in alcoholic studies have reported similar modest phate levels (i.e., hypophosphatemia) patients, there are clinical implications reductions in sodium and potassium (see box). Simply lacking an adequate to consider. Both glucose and amino excretion following alcohol use. amount of phosphate in the diet is one acids are powerful triggers for insulin In general, however, neither acute possible reason for phosphate defi- release, and hospitalized alcoholic nor chronic alcohol consumption direct- ciency. For severely alcoholic patients patients frequently receive intra- ly causes significant changes in serum who eat poorly, such a nutritional venous fluids containing these nutri- sodium concentrations, although im- deficit may be an important contribu- ents. Physicians thus should be prepared paired sodium excretion is a frequent tor to hypophosphatemia. to respond if hypophosphatemia de-

86 ALCOHOL HEALTH & RESEARCH WORLD Alcohol’s Impact on Kidney Function

velops. A similar concern applies to magnesium supplementation treat- condition often seen among chronic another treatment that may lead to ment, however. alcoholic patients. hypophosphatemia: overfeeding pa- Several alcohol-related mechanisms The association between increased tients beyond normal nutrient require- can result in hypomagnesemia. Studies blood pressure and alcohol consump- ments in an attempt to replace dietary historically have shown that alcohol tion has been recognized at least since deficiencies. consumption markedly increases mag- 1915, when Lian reported the preva- Alcoholic patients also may develop nesium excretion in the urine and may lence of high blood pressure (i.e., low blood levels of phosphate by affect magnesium levels in other ways hypertension) in relation to the drink- excreting too much of this ion into as well. For example, when rats are ing habits of French army officers. their urine. Typically, chronic alco- given alcohol, they also require signif- More recent studies have substantiated holic patients are losing up to 1.5 g/d icant magnesium in their diets, sug- this link. For example, in the large- of phosphate through their urine when gesting that alcohol disrupts scale Kaiser-Permanente study, in they have reached the point of being absorption of this nutrient from the which blood pressure measurements sick enough to accept hospitalization. gut. Investigators have speculated that and alcohol histories were obtained (For comparison, a normal healthy alcohol or an intermediate metabolite from more than 80,000 men and women, person excretes 0.7 to 0.8 g/d.) Over directly affects magnesium exchange the association between blood pres- the next several days of hospitaliza- in the kidney tubules (Epstein 1992). sure and drinking was found to be tion, these patients often excrete virtu- independent of age, sex, ethnicity, ally no phosphate in their urine; Calcium weight, smoking habit, and social simultaneously, their blood phosphate class (Klatsky et al. 1977). levels dip to low levels before return- Early studies showed that alcohol con- Clinical studies of hypertensive ing to normal. The combination of sumption markedly increases calcium patients have demonstrated that reduc- low phosphate excretion and low loss in urine. In severely ill alcoholic ing alcohol intake lowers blood pres- blood levels indicates that phosphate patients, low blood levels of calcium sure and resuming consumption raises is simply being shifted from the occur about as often as low blood lev- bloodstream into body cells, implying it. Although the mechanisms responsi- els of phosphate and can cause con- ble for these effects have not been that kidney dysfunction is not a likely vulsions or potentially life-threatening cause of phosphate wasting in this established, an experimental study by muscle spasms when respiratory mus- Chan and Sutter (1983) offers some case. cles are involved. Alcoholic patients Alcohol can induce abnormally high insight. In this study, male rats given with liver disease often have abnor- phosphate levels (i.e., hyperphospha- 20-percent alcohol in their drinking mally low levels of a calcium-binding temia) as well as abnormally low lev- water for 4 weeks experienced de- protein, albumin, and also may have els. In fact, hyperphosphatemia often creased urinary volume and sodium precedes hypophosphatemia. Alcohol impaired vitamin D metabolism; either excretion as well as increased blood consumption apparently leads to exces- of these two factors could result in concentrations of hormones that raise sive phosphate levels by altering mus- reduced blood levels of calcium (i.e., blood pressure by constricting blood cle cell integrity and causing the hypocalcemia). Muscle breakdown vessels. The results of this study sug- muscle cells to release phosphate. This and magnesium deficiency are other gest that alcohol’s influence on blood transfer of phosphate out of muscle potential causes of hypocalcemia in pressure may be attributable, at least cells and into the bloodstream results in alcoholic patients. A direct effect of in part, to its effects on the production an increased amount of phosphate alcohol in reducing calcium levels is of hormones that act on the kidneys to passing through the kidneys’ filtering suggested by at least one experimental regulate fluid balance or that act on system. In response, reabsorption of study: Dogs became hypocalcemic blood vessels to constrict them. phosphate diminishes and excretion in after administration of alcohol above a urine increases in an effort to return critical threshold amount of approxi- ACID-BASE BALANCE EFFECTS blood levels of this ion to normal. mately 1 g/kg (Money et al. 1989). Most of the metabolic reactions essen- Magnesium BODY FLUID VOLUME AND BLOOD tial to life are highly sensitive to the Chronic alcoholism is the leading PRESSURE acidity (i.e., hydrogen ion concentra- cause of low blood levels of magne- tion) of the surrounding fluid. The sium (i.e., hypomagnesemia) in the Chronic alcohol consumption may kidneys play an important role in regu- United States (Epstein 1992). Often it cause both fluid and solutes to accu- lating acidity, thereby helping deter- occurs simultaneously with phosphate mulate, thereby increasing the overall mine the rate at which metabolic deficiencies, also frequently encoun- volume of body fluids. In turn, such reactions proceed. Alcohol can hamper tered among alcoholic patients. Hypo- expansion of body fluid volume can the regulation of acidity, thus affecting magnesemia responds readily to contribute to high blood pressure, a the body’s metabolic balance.

VOL. 21, NO. 1, 1997 87 One example of an alcohol-related administration of paraldehyde, a seda- sition back to normal, which occurred acid-base disturbance already has been tive used for alcohol withdrawal. soon after consumption. mentioned in relation to low levels of Despite the multiple possible causes Alcohol consumption also is phosphate (i.e., respiratory alkalosis of acidosis, disturbances in acid-base known to induce a state of low blood resulting from hyperventilation during balance are more frequently manifested sugar (i.e., hypoglycemia) and acti- alcohol withdrawal). Other acid-base as low acidity (i.e., alkalosis). Alka- vate the portion of the nervous system disturbances are possible as a result of losis was present in 71 percent of pa- that coordinates the body’s response excessive alcohol consumption. These tients with established liver disease in to stress (i.e., the sympathetic nervous disturbances increase the kidneys’ 11 studies, and respiratory alkalosis system). Both of these factors affect workload in restoring acid-base balance was the most common disturbance in 7 hormones that regulate kidney func- through formation of an acidic or basic of the studies (Oster and Perez 1996). tion, just as changes in fluid volume (i.e., alkaline) urine. For instance, the If an acute alcoholic binge induces and electrolyte balance do. opposite of respiratory alkalosis can extensive vomiting, potentially severe occur when a person becomes extreme- alkalosis may result from losses of INDIRECT EFFECTS ly intoxicated. Because alcohol is a fluid, salt, and stomach acid. central nervous system depressant, it Like the kidneys, the liver plays an Physicians have recognized an inter- may slow the rate of breathing as well important role in maintaining acid-base relationship between kidney and liver disorders at least since the time of as reduce the brain’s respiratory cen- balance. Liver diseases—including Hippocrates. Although a disorder in ter’s sensitivity to carbon dioxide lev- alcohol-induced liver problems— one organ can complicate a primary els. As a result, excess carbon dioxide disrupt this function and can contribute accumulates, and the body’s acid level problem in the other (or a pathological directly or indirectly to a wide range of subsequently increases. Respiratory process may involve both organs acid-base disturbances. acidosis is rare but carries an ominous directly), kidney dysfunction compli- prognosis when it occurs. cating a primary disorder of the liver Excess blood acidity in alcoholic REGULATORY EFFECTS (e.g., cirrhosis) is the most clinically patients more often results from severe significant scenario. Frequently, such elevations of a product of glucose To keep the kidneys functioning opti- kidney dysfunction results from liver metabolism (i.e., lactate), which can mally and to maintain functional sta- problems related to alcohol. In fact, be induced by alcohol consumption as bility (i.e., homeostasis) in the body, a most patients in the United States well as other factors. A potentially variety of regulatory mechanisms exert diagnosed with both liver disease and serious condition known as alcoholic their influence. Alcohol can perturb associated kidney dysfunction are ketoacidosis is another disorder associ- these controls, however, to a degree alcohol dependent (Epstein 1992). ated with abnormally high blood acid- that varies with the amount of alcohol (See the article by Maher, pp. 5Ð12.) ity. Characterized by an abnormal consumed and the particular mecha- Three of the most prominent kidney accumulation of ketone bodies, which nism’s sensitivity. function disturbances that arise in the are substances manufactured in the As an example, Puddey and col- presence of established liver disease liver and used as reserve fuels for leagues (1985) evaluated the effects of are impaired sodium handling, im- muscle and brain tissue, ketoacidosis hormones that regulate kidney func- paired fluid handling, and acute kid- also is a complication of uncontrolled tion. Their results show not only how ney failure unexplained by other diabetes and starvation. Typically, alcohol disrupts homeostasis but also causes (i.e., hepatorenal syndrome). alcoholic ketoacidosis occurs in chron- how the body reacts to restore it. ic alcohol abusers following a severe Following moderate alcohol consump- Impaired Sodium Handling binge in which they consume alcoholic tion—about 24 oz—of nonalcoholic Patients with alcohol-induced liver beverages and nothing else over sever- beer with 1 milliliter of alcohol per cirrhosis show a great tendency to al days. Certain people appear to be kilogram of body weight added, the retain salt (i.e., sodium chloride), and particularly prone to alcoholic ketoaci- investigators noted several effects. their urine frequently is virtually free dosis and may develop the condition Alcohol-induced urination reduced the of sodium. A progressive accumula- repeatedly, but the reason for their subjects’ plasma volume, resulting in tion of extracellular fluid results, and susceptibility remains unknown an increased concentration of plasma this excess fluid is sequestered pri- (Epstein 1992). sodium. In addition, the subjects’ marily in the abdominal region, where Additional causes of nonrespiratory blood pressure and plasma potassium it manifests as marked swelling (i.e., acidosis include drinking nonbeverage concentration decreased. These ascites) (see figure). In addition, ex- alcohol (e.g., antifreeze or wood alco- changes in fluid volume, electrolyte cess fluid accumulates in spaces be- hol), which alcoholics sometimes resort balance, and blood pressure may have tween cells, clinically manifested as to consuming when beverage alcohol is stimulated the activity of hormones to swelling (i.e., edema) of the lower unavailable; aspirin overdose; and return body fluid volume and compo- back and legs. As long as cirrhotic

88 ALCOHOL HEALTH & RESEARCH WORLD Alcohol’s Impact on Kidney Function

patients remain unable to excrete al. 1996). The traditional hypothesis of a promising class of new drugs to sodium, they will continue to retain holds that the kidneys of cirrhotic treat this abnormality. Specifically, the sodium they consume in their diet. patients retain sodium in response to drugs known as arginine vasopressin Consequently, they will develop in- ascites that develops when liver dys- antagonists are being developed to creasing ascites and edema and expe- function causes blood vessels to ex- inhibit ADH at the cell receptor level. rience weight gain. In some cases, pand beyond available plasma volume These new drugs should dramatically vast amounts of abdominal fluid may (i.e., the “underfill” theory). In con- facilitate treatment of cirrhotic pa- collect, occasionally more than 7 trast, the “overflow” theory postulates tients with impaired fluid handling. gallons (Epstein 1996). that ascites follows when the kidneys Rigorously limiting sodium intake, retain sodium in response to signals Hepatorenal Syndrome which is the first step in treating as- sent by a dysfunctional liver to ex- cites, will halt fluid retention. Such pand plasma volume. The answer to Hepatorenal syndrome may appear in sodium restriction alone may bring this version of the “chicken-and-egg” patients afflicted with any severe liver about a spontaneous increase in urine question remains to be elucidated. disease, but in the United States, stud- flow and relieve ascites, but how often ies most often have identified alco- this response occurs and in which Impaired Fluid Handling holic cirrhosis as the underlying patients is unknown and unpredictable. disorder. Major clinical features of Other treatment options include vari- In many patients with liver cirrhosis, hepatorenal syndrome include a marked ous diuretic agents and, when ascites the kidneys’ ability to create dilute decrease in urine flow, almost no stubbornly persists, aspiration of the urine is compromised, leading to a state sodium excretion and, usually, hy- excess abdominal fluid. Many sodium- of abnormally low sodium concentra- ponatremia and ascites. Blood urea retaining patients who receive large tion (i.e., hyponatremia). In hypona- nitrogen (BUN) levels and serum quantities of sodium-free water can tremic patients, the amount of fluid concentrations of the waste product excrete copious amounts of dilute retained by the kidneys is dispropor- creatinine are somewhat elevated, but urine, thus demonstrating that the main tionately greater than the amount of rarely to the degree seen in patients kidney dysfunction associated with sodium retained. In other words, the with end-stage kidney failure when their ascites is an impaired ability to kidneys’ ability to excrete excess fluid kidney disease is the primary disorder. excrete sodium, not water. by way of dilute urine is impaired, and Judgments based on such relatively The events leading to abnormal too much fluid is reabsorbed. Hypo- modest BUN and serum creatinine sodium handling in patients with natremia probably is the single most increases often underestimate kidney cirrhosis are complex and controver- common electrolyte disturbance en- dysfunction in patients with hepato- sial, however. Investigators have countered in the management of pa- renal syndrome, however, because advanced several theories suggesting tients with cirrhosis of the liver malnourished cirrhotic patients tend to the involvement of a constellation of (Vaamonde 1996). This abnormality have low levels of urea and creatinine. hormonal, neural, and hemodynamic may reflect the severity of liver disease, Although hepatorenal syndrome mechanisms (Epstein 1996; Laffi et but the available data do not allow often ensues after an event that re- correlation of kidney impairment with duces blood volume (e.g., gastroin- the degree of clinical signs of liver testinal bleeding), it also can occur disease, such as ascites or jaundice. without any apparent precipitating fac- A compromised diluting ability has tor. Some observers have noted that important implications for the manage- patients with cirrhosis frequently de- ment of patients with advanced liver velop hepatorenal syndrome following disease. Restricting the fluid intake of hospital admission, possibly indicating hyponatremic patients eventually should that a hospital-related event can trigger restore a normal fluid balance; unfortu- the syndrome. Regardless of the pre- nately, this restriction may be difficult cipitating factor, patients who develop to implement. Patients frequently fail to kidney failure in the course of alco- comply with their physician’s orders to holic cirrhosis have a grave prognosis. limit their fluid intake. Furthermore, Substantial evidence exists to sup- clinicians sometimes overlook the fact port the concept that kidney failure in that fluids taken with medications also hepatorenal syndrome is not related to must be restricted for these patients and structural damage and is instead func- mistakenly bring pitchers of juice or tional in nature. For example, almost Patient with marked ascites. water to their bedsides. 30 years ago, Koppel and colleagues SOURCE: Reprinted with permission from The difficulties in successfully (1969) demonstrated that kidneys Epstein, M.: The Kidney in Liver Disease, 4th ed. managing dilutional hyponatremia transplanted from patients with hepa- Philadelphia, PA: Hanley & Belfus, 1996. have resulted in the recent emergence torenal syndrome are capable of re-

VOL. 21, NO. 1, 1997 89 CHAIKOFF, I.L.; ENTENMAN, C.; GILLMAN, T.; AND How Alcoholism Contributes to Electrolyte Disturbances CONNOR, C.L. Pathologic reactions in the livers and kidneys of dogs fed alcohol while maintained on a high Disturbance Major Cause(s) protein diet. Archives of Pathology 45(4):435Ð446, 1948.

CHAN, T.C.K., AND SUTTER, M.C. Ethanol consump- Low sodium level Massive intake of solute-free fluid (e.g., beer) tion and blood pressure. Life Sciences 33(20):1965Ð (i.e., hyponatremia) 1973, 1983.

Low potassium level Dietary deficiency or gastrointestinal losses EPSTEIN, M. Alcohol and the kidney. In: Lieber, C.S., (i.e., hypokalemia) Leaky membranes ed. Medical and Nutritional Complications of Extracellular-to-intracellular shifts Alcoholism: Mechanisms and Management. New York: Plenum Medical Book Company, 1992. pp. 495Ð513. Low phosphorus level Dietary deficiency or malabsorption (i.e., hypophosphatemia) Increased cellular uptake EPSTEIN, M. Renal sodium handling in liver disease. In: Epstein, M., ed. The Kidney in Liver Disease. 4th Low magnesium level Dietary deficiency or malabsorption ed. Philadelphia: Hanley & Belfus, 1996. pp. 1Ð31. (i.e., hypomagnesemia) Phosphorus deficiency GONWA, T.A., AND WILKINSON, A.H. Liver transplanta- tion and renal function: Results in patients with and SOURCE: Adapted from Epstein, M. Alcohol and the kidney. In: Lieber, C.S., ed. Medical and Nutritional Compli- without hepatorenal syndrome. In: Epstein, M., ed. The cations of Alcoholism: Mechanisms and Management. New York: Plenum Medical Book Company, 1992. p. 502. Kidney in Liver Disease. 4th ed. Philadelphia: Hanley & Belfus, 1996. pp. 529Ð542. suming normal function in recipients invasive nature of TIPS makes it an HILDEN, T., AND SVENDSEN, T.L. Electrolyte distur- without liver disease. In addition, attractive option for treating hepatore- bances in beer drinkers: A specific “hypo-osmolality Iwatsuki and colleagues (1973) and nal syndrome, and preliminary results syndrome.” Lancet 2(7928):245Ð246, 1975. Gonwa and Wilkinson (1996) docu- show that the procedure is effective mented the return of normal kidney (Somberg 1996). Currently, a clinical IWATSUKI, S.; POPOVTZER, M.M.; CORMAN, J.L.; ISHIKAWA, M.; PUTNAM, C.W.; KATZ, F.H.; AND function in hepatorenal syndrome trial sponsored by the National Institutes STARZL, T.E. Recovery from hepatorenal syndrome patients who receive liver transplants. of Health is investigating the effects of after orthotopic liver transplantation. New England Indeed, liver transplantation is one TIPS on the treatment of ascites and Journal of Medicine 289:1155Ð1159, 1973. of two options available today for improvement of kidney function. KLATSKY, A.L.; FRIEDMAN, G.D.; SIEGELAUB, A.B.; treating hepatorenal syndrome. Gon- AND GERARD, M.J. Alcohol consumption and blood wa and Wilkinson (1996) reported a CONCLUSION pressure Kaiser-Permanente Multiphasic Health 4-year survival rate of 60 percent in Examination data. New England Journal of Medicine 296:1194Ð1200, 1977. hepatorenal syndrome patients who Excessive alcohol consumption can received a liver transplant, which have profound negative effects on the KOPPEL, M.H.; COBURN, J.W.; MIMS, M.M.; GOLDSTEIN, constitutes a major step forward, con- kidneys and their function in maintain- H.; BOYLE, J.D.; AND RUBINI, M.E. Transplantation of sidering the previous uniformly fatal cadaveric kidneys from patients with hepatorenal ing the body’s fluid, electrolyte, and syndrome. Evidence for the functional nature of renal course of the disease. acid-base balance, leaving alcoholic failure in advanced liver disease. New England Journal Another current treatment option is people vulnerable to a host of kidney- of Medicine 280(25):1367Ð1371, 1969. known as transjugular intrahepatic related health problems. Despite the LAFFI, G.; LA VILLA, G.; PINZANI, M.; AND GENTILINI, P. portosystemic shunt (TIPS), in which clinical importance of alcohol’s effects Lipid-derived autacoids and renal function in liver a bypass (i.e., shunt) between two on the kidney, however, relatively few cirrhosis. In: Epstein, M., ed. The Kidney in Liver veins inside the liver (i.e., the hepatic recent studies have been conducted to Disease, 4th ed. Philadelphia: Hanley & Belfus, 1996. vein and the portal vein) is created by characterize them or elucidate their pp. 307Ð337. way of the jugular vein. Obstructions pathophysiology. It is hoped that fu- LAUBE, H.; NORRIS, H.T.; AND ROBBINS, S.L. The in the liver of cirrhotic patients in- ture investigations will focus on this nephromegaly of chronic alcoholics with liver disease. crease pressure in the portal vein, and important subject area. Archives of Pathology 84:290Ð294, 1967. this effect is thought to contribute to LIAN, C. L’alcoolisme, cause d’hypertension artérielle. many kidney complications. The TIPS Bull. Acad. Med. 74:525Ð528, 1915. technique was developed as a means EDITORIAL NOTE to reduce pressure in the portal circuit MONEY, S.R.; PETROIANU, A.; KIMURA, K.; AND JAFFE, The reference list accompanying this B.M. Acute hypocalcemic effect of ethanol in dogs. and offers several advantages: article has been shortened. A complete Alcoholism: Clinical and Experimental Research Because the shunt can be inserted bibliography is available on request. 13(3):453Ð456, 1989. under local anesthesia, TIPS avoids postoperative complications associat- NICHOLSON, W.M., AND TAYLOR, H.M. Blood volume REFERENCES studies in acute alcoholism. Quarterly Journal of ed with surgery. In addition, TIPS Studies on Alcohol 1:472, 1940. does not alter the anatomy of the BEARD, J.D.; BARLOW, G.; AND OVERMAN, R.R. Body blood vessels outside the liver, an fluids and blood electrolytes in dogs subjected to OSTER, J.R., AND PEREZ, G.O. Derangements of acid- important consideration for potential chronic ethanol administration. Journal of base homeostasis in liver disease. In: Epstein, M., ed. Pharmacology and Experimental Therapeutics The Kidney in Liver Disease. 4th ed. Philadelphia: liver-transplant candidates. The less 148(3):348Ð355, 1965. Hanley & Belfus, 1996. pp. 109Ð122.

90 ALCOHOL HEALTH & RESEARCH WORLD Alcohol’s Impact on Kidney Function

PUDDEY, I.B.; VANDONGEN, R.; BEILIN, L.J.; AND ROUSE, metabolism. Journal of Clinical Investigation VAAMONDE, C.A. Renal water handling in liver I.L. Alcohol stimulation of renin release in man: Its 34(3):439Ð447, 1955. disease. In: Epstein, M., ed. The Kidney in Liver relation to the hemodynamic, electrolyte, and sympatho- Disease. 4th ed. Philadelphia: Hanley & Belfus, 1996. adrenal responses to drinking. Journal of Clinical SOMBERG, K.A. Transjugular intrahepatic portosys- pp. 33Ð74. Endocrinology and Metabolism 61(1):37Ð42, 1985. temic shunt in the treatment of refractory ascites and VAN THIEL, D.H.; WILLIAMS, W.D.; GAVALER, J.S.; hepatorenal syndrome. In: Epstein, M., ed. The Kidney RUBINI, M.E.; KLEEMAN, C.R.; AND LAMDIN, E. Studies LITTLE, J.M.; ESTES, L.W.; AND RABIN, B.S. Ethanol— on alcohol diuresis. I. The effect of ethyl alcohol in Liver Disease. 4th ed. Philadelphia: Hanley & its nephrotoxic effect in the rat. American Journal of ingestion on water, electrolyte and acid-base Belfus, 1996. pp. 507Ð516. Pathology 89(1):67Ð84, 1977.

KIDNEY STRUCTURE AND FUNCTION

Cushioned in fatty tissue near the Each of the 2 million functional long, looping conduit called the base of the spinal column, the kid- units (i.e., nephrons) in a pair of nephron tubule. neys are efficiently designed organs normal kidneys forms urine as it As the plasma filtrate passes that perform two primary tasks in filters blood plasma of substances along this channel, the substances the body: excretion of metabolic not needed by the body. Within each the body needs to conserve are reab- end products and precise regulation nephron, blood plasma enters a tiny sorbed into an extensive network of of body fluid constituents. As they ball of unusually permeable capillar- capillaries that wrap the nephron accomplish these tasks, the kidneys ies (i.e., the glomerulus), filters into tubule. Many electrolytes and 99 form and collect urine, which exits a capsule that surrounds the percent of the water in the filtrate are through the ureters to the bladder. glomerulus, then flows through a reabsorbed, while waste products, such as urea (an end product of pro- tein metabolism formed chiefly in Glomerulus Blood 1. Filtration: Blood the liver) and creatinine (an end flow enters the glomerulus product of muscle metabolism), as Efferent through the afferent well as excess electrolytes (particu- arteriole Afferent arteriole and filters into larly sodium, potassium, chloride, arteriole the surrounding cap- and hydrogen ions), continue to sule at the “head” of journey along the tubule. Small the nephron. 2. Reabsorption: amounts of unwanted substances Useful substances also are secreted directly into the are reabsorbed from Capillary Nephron nephron tubules. Together, the fil- the nephron tubule tubule tered and secreted substances form into the adjacent 3. Secretion: Waste urine (see figure) and eventually Collecting peritubular capillary. duct products to be elimi- trickle into a series of progressively nated are taken up larger collecting ducts. Each 4.5- from the peritubular inch-long kidney contains about 250 capillary into the neph- of the largest collecting ducts, each Blood flow ron tubule. duct transmitting urine from approxi- mately 4,000 nephrons. Of the 48 gallons of filtrate pro- cessed through the nephrons of the To urinary bladder kidneys each day, only about 1 to for excretion 1.5 quarts exit as urine. During this Urine formation. Three basic processes—glomerular filtration, tubular reabsorption, filtering process, substances are and tubular secretion—contribute to urine formation, as shown in this schematic. (continued on page 92)

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(continued from page 91) reabsorbed or secreted to varying Key Electrolytes in the Body degrees as the filtrate passes Ion Major Physiological Roles through the distinct segments of the nephron tubule. Sodium Primary positive ion in extracellular fluid. Together with potas- (Na+) sium, maintains electrolyte balance across all cell membranes. Regulating Electrolyte Levels Vital to many basic physiological functions. and Fluid Volume Potassium Primary positive ion in intracellular fluid. Together with sodium, The kidney tubules play an impor- (K+) maintains electrolyte balance across all cell membranes. Vital to tant role in keeping the body’s many basic physiological functions. water and electrolyte levels in Magnesium Required for activity of many enzymes. equilibrium. In many cases, control (Mg2+) mechanisms govern the rate of reabsorption or secretion in re- Calcium Major mineral in body and component of bone. Helps maintain 2+ sponse to the body’s fluctuating (Ca ) normal heartbeat and nerve and muscle function. needs (see table for a summary of Chloride Primary negative ion in extracellular fluid. Plays a role in nerve the body processes influenced by (ClÐ) function and other metabolic processes. key electrolytes). Under the influ- ence of antidiuretic hormone Phosphate Primary negative ion in intracellular fluid. Serves as an important (HPO 2Ð) buffer to maintain proper pH. Phosphorus is a major component (ADH), for example, the tubules 4 can create either a concentrated of bone and is involved in almost all metabolic processes. urine, to discharge excess solutes and conserve water, or a dilute urine, to remove extra water from but this rate can vary widely, depend- BIBLIOGRAPHY body fluids. In the first case, when ing on water intake or dehydration level, for instance. GUYTON, A.C. Human Physiology and body fluids become too concentrated Mechanisms of Disease. 5th ed. Philadelphia: with solutes, the pituitary gland pro- The kidneys continuously per- W.B. Saunders, 1992. pp. 195Ð246. duces abundant ADH, which induces form their tasks of purifying and balancing the constituents of the RHOADES, R., AND PFLANZER, R. Human the kidneys to conserve water and Physiology. 2d ed. Fort Worth: Saunders concentrate urine, an important abili- body’s fluids. Although resilient, the College Publishing, 1992. pp. 823Ð909. ty that enables thriving in an environ- kidneys can deteriorate as a result of ment where water may be scarce. In malnutrition, alcohol abuse or de- the absence of ADH, when body pendence, or liver and other dis- fluids are overly dilute, the kidneys eases. Healthy kidneys are vital to dilute the urine, allowing more water the function of all the body’s organs to leave the body. “Normal” urine and systems. Mary Beth de Ribeaux is a science flow rate is 1 milliliter per minute editor of Alcohol Health & (i.e., approximately 1 to 1.5 L/day), —Mary Beth de Ribeaux Research World

92 ALCOHOL HEALTH & RESEARCH WORLD GLOSSARY

Acetaldehyde: The immediate product of Antioxidants: Chemicals (e.g., gluta- Cerebral cortex: The intricately folded alcohol oxidation, this compound can thione and vitamins A and E) that outer layer of the brain, composed of damage the cellular microstructure of prevent certain destructive chemical nerve-cell bodies and gray matter, that the liver, induce fibrosis, affect energy processes in cells. covers the cerebrum. The cerebral metabolism, and generate free radicals. Apoptosis: A series of chemical reactions cortex contains areas for processing Acid-base balance: Normal body fluid within a cell that are induced by vari- sensory information and for controlling pH (i.e., hydrogen ion concentration), ous events and which result in the motor functions, speech, higher which must be narrowly regulated for cell’s death. cognitive functions, emotions, behavior, and memory. proper body functioning. Atherogenesis: The development of Acidosis: A condition in which body fluids atherosclerosis. Cerebrum: The largest portion of the become too acidic (see alkalosis). brain; includes the cerebral hemi- Atherosclerosis: A disease of the arteries spheres (see cerebral cortex and basal Active transport: The transfer of in which fatty plaques accumulate on ganglia). substances (i.e., molecules or ions) the arteries’ inner walls, usually across a cell membrane from a lower to leading to narrowing and “hardening” Chemokines: Small proteins secreted by a higher concentration, thus requiring of the arteries and eventually immune cells that can attract other energy expenditure. obstructing blood flow. immune cells to the tissue site where the chemokines are produced. Chemo- Alcohol dehydrogenase: An enzyme that Atrial fibrillation: A loss of coordinated kines play a role in chemotaxis. breaks down alcohol. contraction that occurs in one or both Chemotaxis: The directed movement of a Alkalosis: A condition in which body of the upper chambers of the heart, resulting in rapid and irregular heart cell in response to a stimulus, such as a fluids become too alkaline (see acidosis). chemokine. and pulse rates. Allele: One of two or more variants of a Cholesterol: A fatlike substance that is an Atrophy: Wasting away, or shrinkage, of gene. Different alleles for a gene serve important component of cell tissue; caused by cell death rather than the same function (e.g., code for a membranes and is the precursor of shrinkage of individual cells. protein that affects a person’s eye many steroid hormones and bile salts. color) but may result in different B lymphocyte (B cell): A type of white High cholesterol levels are associated phenotypes (e.g., blue eyes or brown blood cell that originates in the bone with coronary artery disease. eyes). marrow and is distributed throughout Cholesteryl ester: The product of a the blood and lymphoid tissues. B cells Amino acids: The building blocks of reaction between cholesterol and an produce antibodies when stimulated by proteins. Some amino acids also func- organic acid. tion as neurotransmitters. the appropriate antigens. Cholesteryl ester transfer protein Basal ganglia: A group of nerve cell Ammonia: A neurotoxic chemical (CETP): A compound that transports structures at the base of the brain that compound that is formed in the body cholesteryl esters from high density are involved in motor control. primarily as a product of protein lipoproteins to low density lipoproteins metabolism. Catalyst: Any substance that facilitates a for eventual removal from the blood. Anemia: A blood condition in which the chemical reaction and which does not Complement: A group of proteins number of functional red blood cells is undergo a permanent chemical change circulating in the blood that are either below normal. itself. bound to antigen and activated by Anterior pituitary: A small gland at the Catecholamines: A group of physiolog- antibodies or are activated by mole- base of the brain that is controlled by ically active substances with various cules found on the surface of some the hypothalamus and which manu- roles in the functioning of the sym- bacteria. Complement activation factures hormones influencing many pathetic and central nervous systems. results in the attraction of phagocytes, organs in the body. Cell-mediated immune response: An the release of chemicals that amplify Antibody: A protein that is produced by B immune response provided by the immune responses, and the destruction cells in response to, and which inter- direct actions of immune system cells of invading bacteria. acts with, an antigen. (primarily T cells), as opposed to an Cortisol: A glucocorticoid produced by Antidiuretic hormone (ADH): A immune response mediated by the adrenal gland that helps regulate hormone produced in the hypotha- antibodies (i.e., humoral immune metabolism. lamus and released from the posterior response). Cytochrome: An enzyme that detoxifies pituitary gland in response to dehydra- Cellular toxin: A toxin that is released foreign compounds. tion; plays an important role in regulat- from a cell; also called endotoxin. Cytokine: A molecule that regulates ing fluid excretion. Cerebellum: The brain structure at the cellular interaction and cellular Antigen: Any substance that is recognized base of the brain that is involved in the functions. Cytokines are produced and by B cells or T cells and stimulates them control of muscle tone, balance, and secreted by a variety of cells, including to initiate an immune response. sensorimotor coordination. immune cells.

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