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cells function depends not onlyon receiving a continuoussupply of nutrients and elimi-

nating metabolic waste products butalso on the existence of stable physi-cal and chemical conditions in theextracellular fluid1 bathing it. Amongthe most important substances con-tributing to these conditions are water,sodium, potassium, calcium, andphosphate. Loss or retention of anyone of these substances can influencethe bodys handling of the others. Inaddition, hydrogen ion concentration(i.e., acid-base balance) influencescell structure and permeability as well

as the rate of metabolic reactions. Theamounts of these substances must beheld within very narrow limits, re-gardless of the large variations possi-ble in their intake or loss. The kidneysare the organs primarily responsiblefor regulating the amounts and con-

centrations of these substances in theextracellular fluid.

In addition to their role in regulat-

ing the bodys fluid composition, thekidneys produce hormones that influ-ence a host of physiological processes,including blood pressure regulation,red blood cell production, and calciummetabolism. Besides producing hor-mones, the kidneys respond to theactions of regulatory hormones pro-duced in the brain, the parathyroidglands in the neck, and the adrenalglands located atop the kidneys.

Because of the kidneys importantand varied role in the body, impair-ment of their function can result in arange of disorders, from mild varia-tions in fluid balance to acute kidneyfailure and death. Alcohol, one of thenumerous factors that can compro-mise kidney function, can interferewith kidney function directly, throughacute or chronic consumption, or

indirectly, as a consequence of liverdisease. This article first reviewsdirect effects of alcohol on kidney

structure, function, and regulation,highlighting relevant effects associatedwith liver disease. Following thisdiscussion, the article takes a more in-depth look at several important indirecteffects of alcohol on the kidneys thatoccur once liver disease has becomeestablished.

GROSS AND MICROSCOPICCHANGES

One way in which alcohol directlyaffects the kidneys is by altering theform and structure of this pair of or-gans, as demonstrated by variousanimal studies. For example, in anearly study on dogs (Chaikoff et al.1948), investigators observed severalstriking alterations after chronic alco-hol administration. The basementmembrane of the glomerulus (seesidebar figure) became abnormallythickened and was characterized bycell proliferation. Further changes

84 ALCOHOL HEALTH & RESEARCH WORLD

A

1For a definition of this and other technicalterms used in this article, see the glossary, pp.9396, and the sidebar, pp. 9192.

MURRAYEPSTEIN, M.D., is professor ofmedicine in the Nephrology Sectionat the University of Miami School of

Medicine, Miami, Florida.

Alcohols Impact on

Kidney FunctionMURRAY EPSTEIN, M.D.

Both acute and chronic alcohol consumption can compromise kidney function,particularly in conjunction with established liver disease. Investigators have observedalcohol-related changes in the structure and function of the kidneys and impairment intheir ability to regulate the volume and composition of fluid and electrolytes in thebody. Chronic alcoholic patients may experience low blood concentrations of key

electrolytes as well as potentially severe alterations in the bodys 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 effectson the kidneys, including impaired sodium and fluid handling and even acute kidneyfailure. KEY WORDS: kidney function; kidney disorder; disorder of fluid or electrolyte oracid-base balance; alcoholic liver disorder; hormones; body fluid; blood circulation; bloodpressure; sodium; potassium; phosphates; magnesium; calcium; literature review


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included enlarged and altered cells inthe kidney tubules. In another study,Van Thiel and colleagues (1977)compared kidney structure and func-tion in alcohol-fed and control rats.The alcohol-fed group experienced

kidney swelling and significantlyreduced kidney function; in addition,under microscopic examination, thekidneys of alcohol-fed rats were foundto have cells enlarged with increasedamounts of protein, fat, and water,compared with those of the controlanimals.

Similarly, clinicians long havenoted significant kidney enlargement(i.e., nephromegaly) in direct propor-tion to liver enlargement amongchronic alcoholic2 patients afflictedwith liver cirrhosis. Laube and col-leagues (1967) suggested that bothcellular enlargement and cell prolifer-ation contribute to such nephro-megaly. In alcoholic patients withcirrhosis, these investigators reporteda 33-percent increase in kidney weight,whereas they observed no appreciablekidney enlargement in alcoholic pa-tients without cirrhosis compared withcontrol subjects (Laube et al. 1967).

BLOOD-FLOW CHANGES

Normally the rate of blood flow, orperfusion, (i.e., hemodynamics) throughthe kidneys is tightly controlled, sothat plasma can be filtered and sub-stances the body needs can be reab-sorbed under optimal circumstances(see sidebar). Established liver diseaseimpairs this important balancing act,however, by either greatly augmentingor reducing the rates of plasma flowand filtration through the glomerulus.

Investigators have not yet fully ex-plained the mechanisms underlyingthis wide range of abnormalities,though, and have devoted little atten-tion to alcohols effects on kidneyhemodynamics in people who do nothave liver disease.

The few studies focusing on alco-hols direct effects on perfusion inhuman kidneys suggest that regulatorymechanisms retain control over thiscomponent of kidney function despitealcohol consumption. Even at high

blood alcohol levels, only minor fluc-tuations were found in the rates ofplasma flow and filtration through thekidneys (Rubini et al. 1955).Additional studies are needed to con-firm these observations, however.

Results of subsequent studies inanimal models seem to vary accordingto the species examined, the route anddose of alcohol administration, and thelength of time after administration forwhich the study groups were observed.For example, some studies impliedthat acute alcohol consumption doesnot significantly change kidney hemo-dynamics or sodium excretion in dogs,but these studies did not extend be-yond 6 hours after alcohol ingestion.In contrast, earlier studies that exam-ined dogs for a longer period reportedthat a single dose of 3 grams of alco-hol per kilogram of body weight (g/kg)elevated plasma volume between 10and 26 hours following alcohol inges-tion (Nicholson and Taylor 1940).3

Another study with dogs (Beard etal. 1965) disclosed that the effects ofchronic alcohol consumption enduredeven longer. The investigators notedincreased plasma and extracellular fluidvolume 1 week after chronic alcoholingestion, and these volume expansionspersisted for the remaining 7 weeks ofthe study. Similar alterations have beenfound in body fluid volumes amongchronic alcoholic patients.

EFFECTS ON FLUID ANDELECTROLYTE BALANCE

One of the main functions of the kid-neys is to regulate both the volume andthe composition of body fluid, includ-ing electrically charged particles (i.e.,ions), such as sodium, potassium, andchloride ions (i.e., electrolytes). How-ever, alcohols ability to increase urine

volume (i.e., its diuretic effect) altersthe bodys fluid level (i.e., hydrationstate) and produces disturbances inelectrolyte concentrations. Theseeffects vary depending on factors suchas the amount and duration of drink-

ing, the presence of other diseases,and the drinkers nutritional status(see table, p. 90).

Fluid

Alcohol can produce urine flow with-in 20 minutes of consumption; as aresult of urinary fluid losses, the con-centration of electrolytes in bloodserum increases. These changes canbe profound in chronic alcoholic pa-tients, who may demonstrate clinical

evidence of dehydration.As most investigators now agree,

increased urine flow results from alco-hols acute inhibition of the release ofantidiuretic hormone (ADH), a hor-mone also known as vasopressin,which normally promotes the forma-tion of concentrated urine by inducingthe kidneys to conserve fluids. In theabsence of ADH, segments of thekidneys tubule system become imper-meable to water, thus preventing it

from being reabsorbed into the body.Under these conditions, the urineformed is dilute and electrolyte con-centration in the blood simultaneouslyrises. Although increased serum elec-trolyte concentration normally acti-vates secretion of ADH so that fluidbalance can be restored, a rising bloodalcohol level disrupts this regulatoryresponse by suppressing ADH secre-tion into the blood.

Interestingly, age makes a differencein how rapidly the body escapes alco-

hols ADH-suppressive effect. Peopleolder than age 50 overcome suppres-sion of ADH more quickly than theiryounger counterparts do, despite reach-ing similar serum electrolyte concentra-tions after alcohol consumption. Inolder people, ADH levels sharply in-crease following alcohol intake, per-haps in part because sensitivity toincreased electrolyte concentration isenhanced with age. It is not knownwhether chronic alcoholic patients

VOL. 21, NO. 1, 1997 85

2The terms alcoholic patient and alcoholismas used in this article are summary terms forthe diagnoses of alcohol abuse and alcoholdependence as defined variously by the studiescited.

3For a person weighing 150 pounds, this dosewould be roughly equivalent to 17 drinks.

Alcohols Impact on Kidney Function


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experience a similar difference in theADH response as they age, however.

Sodium

The serum sodium level is determined

by the balance of fluid in relation tothat of sodium: Not enough fluid inthe body results in a sodium concen-tration that is too high (i.e., hyperna-tremia), whereas excessive amounts offluid produce a sodium concentrationthat is too low (i.e., hyponatremia).Hyponatremia does not constitutemerely a biochemical abnormality butmost likely has clinical consequencesas well (e.g., impaired mental activity,neurological symptoms, and, in ex-treme instances, seizures).

Beer drinkers hyponatremia is asyndrome that appears to result froman intake of excessive fluid in theform of beer. Hilden and Svendsen(1975) observed hyponatremia in fivepatients who drank at least 5 liters ofbeer per day (L/d) without any othernourishment. (For comparison, a per-sons normal fluid intake averages alittle more than 2 L/d.) Because beercontains few dissolved substances(i.e., solutes), such as sodium, these

patients apparently lacked a sufficientquantity of solutes to stimulate thekidneys to eliminate excess fluid.

Although fluid overloadnot alco-hol itselfis considered the major con-tributor to beer drinkers hyponatremia,alcohol does appear to directly influ-ence the kidneys handling of sodiumand other electrolytes, potentially re-sulting in hypernatremia. In a study byRubini and colleagues (1955), subjectswho consistently drank about 4 ounces(oz) of 100-proof bourbon whiskey

experienced decreased sodium, potassi-um, and chloride excretion (i.e., in-creased retention of solutes). Althoughsome exceptions exist, several historicalstudies have reported similar modestreductions in sodium and potassiumexcretion following alcohol use.

In general, however, neither acutenor chronic alcohol consumption direct-ly causes significant changes in serumsodium concentrations, although im-paired sodium excretion is a frequent

complication of advanced liver disease,as discussed later in this article.

Potassium

Normally the kidneys are a major

route of potassium ion excretion andserve as an important site of potassiumregulation. Alcohol consumptionhistorically has been found to reducethe amount of potassium excreted bythe kidneys (e.g., Rubini et al. 1955),although the bodys hydration statemay help determine whether potassiumexcretion will increase or decrease inresponse to alcohol. Levels of potassi-um, like those of sodium, also canaffect the way the kidneys handlefluid elimination or retention. In addi-

tion, potassium depletion has beenproposed to exacerbate hyponatremiathrough any of several mechanisms(Epstein 1992): For example, potassi-um losses may stimulate ADH activity,thereby increasing the amount of fluidreabsorbed and causing the bodyssodium concentration to decrease as aresult. Alternatively, potassium lossesmay increase thirst, also through hor-monal mechanisms, thereby promot-ing increased fluid intake.

Phosphate

Low blood levels of phosphate com-monly occur acutely in hospitalizedalcoholic patients, appearing in morethan one-half of severe alcoholismcases. Indeed, when the conditiondoes not appear, clinicians treatingalcoholic patients should suspect thatanother problem is masking the recog-nition of low phosphate levels, such asongoing muscle dissolution, excess

blood acidity (i.e., acidosis), inade-quate blood volume, or kidney failure.

Several mechanisms maycontribute to abnormally low phos-phate levels (i.e., hypophosphatemia)(see box). Simply lacking an adequateamount of phosphate in the diet is onepossible reason for phosphate defi-ciency. For severely alcoholic patientswho eat poorly, such a nutritionaldeficit may be an important contribu-tor to hypophosphatemia.

Another potential cause of hypo-phosphatemia in alcoholic patients ishyperventilation, which can occurduring alcohol withdrawal. Prolongedrapid, shallow breathing results in

excessive loss of carbon dioxide anddecreased blood acidity (i.e., alkalo-sis), which in turn activates an en-zyme that enhances glucosebreakdown. In glucose breakdown,phosphate becomes incorporated intovarious metabolic compounds, ulti-mately lowering blood levels of phos-phate. As the rate of glucosebreakdown increases, profound hy-pophosphatemia potentially can result

Insulin administration also can leadto mild hypophosphatemia, because it

decreases cellular acidity. Althoughinsulin more likely plays a contributoryrather than principal, role in produc-ing hypophosphatemia in alcoholicpatients, there are clinical implicationsto consider. Both glucose and aminoacids are powerful triggers for insulinrelease, and hospitalized alcoholicpatients frequently receive intra-venous fluids containing these nutri-ents. Physicians thus should be preparedto respond if hypophosphatemia de-


CAUSES OF LOWPHOSPHATE LEVELS

IN ALCOHOLICS

The following causes may un-

derlie low phosphate levels insevere alcoholics:

Phosphorus deficiency in thediet

Increased blood pH due toprolonged rapid breathing

Insulin administration

Administration of nutrientsbeyond normal requirements(in hospital settings)

Excessive excretion in urine

Magnesium deficiency.

SOURCE: Adapted from Epstein, M. Alcohol

and the kidney. In: Lieber, C.S., ed. Medical and

Nutritional Complications of Alcoholism:

Mechanisms and Management. New York:

Plenum Medical Book Company, 1992. p. 498.


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velops. A similar concern applies toanother treatment that may lead tohypophosphatemia: overfeeding pa-tients beyond normal nutrient require-ments in an attempt to replace dietarydeficiencies.

Alcoholic patients also may developlow blood levels of phosphate byexcreting too much of this ion intotheir urine. Typically, chronic alco-holic patients are losing up to 1.5 g/dof phosphate through their urine whenthey have reached the point of beingsick enough to accept hospitalization.(For comparison, a normal healthyperson excretes 0.7 to 0.8 g/d.) Overthe next several days of hospitaliza-tion, these patients often excrete virtu-ally no phosphate in their urine;simultaneously, their blood phosphatelevels dip to low levels before return-ing to normal. The combination oflow phosphate excretion and lowblood levels indicates that phosphateis simply being shifted from thebloodstream into body cells, implyingthat kidney dysfunction is not a likelycause of phosphate wasting in thiscase.

Alcohol can induce abnormally highphosphate levels (i.e., hyperphospha-

temia) as well as abnormally low lev-els. In fact, hyperphosphatemia oftenprecedes hypophosphatemia. Alcoholconsumption apparently leads to exces-sive phosphate levels by altering mus-cle cell integrity and causing themuscle cells to release phosphate. Thistransfer of phosphate out of musclecells and into the bloodstream results inan increased amount of phosphatepassing through the kidneys filteringsystem. In response, reabsorption ofphosphate diminishes and excretion in

urine increases in an effort to returnblood levels of this ion to normal.

Magnesium

Chronic alcoholism is the leadingcause of low blood levels of magne-sium (i.e., hypomagnesemia) in theUnited States (Epstein 1992). Often itoccurs simultaneously with phosphatedeficiencies, also frequently encoun-tered among alcoholic patients. Hypo-magnesemia responds readily to

magnesium supplementation treat-ment, however.

Several alcohol-related mechanismscan result in hypomagnesemia. Studieshistorically have shown that alcoholconsumption markedly increases mag-

nesium excretion in the urine and mayaffect magnesium levels in other waysas well. For example, when rats aregiven alcohol, they also require signif-icant magnesium in their diets, sug-gesting that alcohol disruptsabsorption of this nutrient from thegut. Investigators have speculated thatalcohol or an intermediate metabolitedirectly affects magnesium exchangein the kidney tubules (Epstein 1992).

CalciumEarly studies showed that alcohol con-sumption markedly increases calciumloss in urine. In severely ill alcoholicpatients, low blood levels of calciumoccur about as often as low blood lev-els of phosphate and can cause con-vulsions or potentially life-threateningmuscle spasms when respiratory mus-cles are involved. Alcoholic patientswith liver disease often have abnor-mally low levels of a calcium-binding

protein, albumin, and also may haveimpaired vitamin D metabolism; eitherof these two factors could result inreduced blood levels of calcium (i.e.,hypocalcemia). Muscle breakdownand magnesium deficiency are otherpotential causes of hypocalcemia inalcoholic patients. A direct effect ofalcohol in reducing calcium levels issuggested by at least one experimentalstudy: Dogs became hypocalcemicafter administration of alcohol above a

critical threshold amount of approxi-mately 1 g/kg (Money et al. 1989).

BODY FLUID VOLUME AND BLOODPRESSURE

Chronic alcohol consumption maycause both fluid and solutes to accu-

mulate, thereby increasing the overall

volume of body fluids. In turn, such

expansion of body fluid volume can

contribute to high blood pressure, a

condition often seen among chronicalcoholic patients.

The association between increasedblood pressure and alcohol consump-tion has been recognized at least since1915, when Lian reported the preva-

lence of high blood pressure (i.e.,hypertension) in relation to the drink-ing habits of French army officers.More recent studies have substantiatedthis link. For example, in the large-scale Kaiser-Permanente study, inwhich blood pressure measurementsand alcohol histories were obtainedfrom more than 80,000 men and women,the association between blood pres-sure and drinking was found to beindependent of age, sex, ethnicity,

weight, smoking habit, and socialclass (Klatsky et al. 1977).Clinical studies of hypertensive

patients have demonstrated that reduc-ing alcohol intake lowers blood pres-sure and resuming consumption raisesit. Although the mechanisms responsi-ble for these effects have not beenestablished, an experimental study byChan and Sutter (1983) offers someinsight. In this study, male rats given20-percent alcohol in their drinkingwater for 4 weeks experienced de-

creased urinary volume and sodiumexcretion as well as increased bloodconcentrations of hormones that raiseblood pressure by constricting bloodvessels. The results of this study sug-gest that alcohols influence on bloodpressure may be attributable, at leastin part, to its effects on the productionof hormones that act on the kidneys toregulate fluid balance or that act onblood vessels to constrict them.

ACID-BASE BALANCE EFFECTS

Most of the metabolic reactions essen-tial to life are highly sensitive to theacidity (i.e., hydrogen ion concentra-tion) of the surrounding fluid. Thekidneys play an important role in regu-lating acidity, thereby helping deter-mine the rate at which metabolicreactions proceed. Alcohol can hamperthe regulation of acidity, thus affectingthe bodys metabolic balance.

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One example of an alcohol-relatedacid-base disturbance already has beenmentioned in relation to low levels ofphosphate (i.e., respiratory alkalosisresulting from hyperventilation duringalcohol withdrawal). Other acid-base

disturbances are possible as a result ofexcessive alcohol consumption. Thesedisturbances increase the kidneysworkload in restoring acid-base balancethrough formation of an acidic or basic(i.e., alkaline) urine. For instance, theopposite of respiratory alkalosis canoccur when a person becomes extreme-ly intoxicated. Because alcohol is acentral nervous system depressant, itmay slow the rate of breathing as wellas reduce the brains respiratory cen-ters sensitivity to carbon dioxide lev-els. As a result, excess carbon dioxideaccumulates, and the bodys acid levelsubsequently increases. Respiratoryacidosis is rare but carries an ominousprognosis when it occurs.

Excess blood acidity in alcoholicpatients more often results from severeelevations of a product of glucosemetabolism (i.e., lactate), which canbe induced by alcohol consumption aswell as other factors. A potentiallyserious condition known as alcoholic

ketoacidosis is another disorder associ-ated with abnormally high blood acid-ity. Characterized by an abnormalaccumulation of ketone bodies, whichare substances manufactured in theliver and used as reserve fuels formuscle and brain tissue, ketoacidosisalso is a complication of uncontrolleddiabetes and starvation. Typically,alcoholic ketoacidosis occurs in chron-ic alcohol abusers following a severebinge in which they consume alcoholicbeverages and nothing else over sever-

al days. Certain people appear to beparticularly prone to alcoholic ketoaci-dosis and may develop the conditionrepeatedly, but the reason for theirsusceptibility remains unknown(Epstein 1992).

Additional causes of nonrespiratoryacidosis include drinking nonbeveragealcohol (e.g., antifreeze or wood alco-hol), which alcoholics sometimes resortto consuming when beverage alcohol isunavailable; aspirin overdose; and

administration of paraldehyde, a seda-tive used for alcohol withdrawal.

Despite the multiple possible causesof acidosis, disturbances in acid-basebalance are more frequently manifestedas low acidity (i.e., alkalosis). Alka-

losis was present in 71 percent of pa-tients with established liver disease in11 studies, and respiratory alkalosiswas the most common disturbance in 7of the studies (Oster and Perez 1996).If an acute alcoholic binge inducesextensive vomiting, potentially severealkalosis may result from losses offluid, salt, and stomach acid.

Like the kidneys, the liver plays animportant role in maintaining acid-basebalance. Liver diseasesincluding

alcohol-induced liver problemsdisrupt this function and can contributedirectly or indirectly to a wide range ofacid-base disturbances.

REGULATORY EFFECTS

To keep the kidneys functioning opti-mally and to maintain functional sta-bility (i.e., homeostasis) in the body, avariety of regulatory mechanisms exerttheir influence. Alcohol can perturbthese controls, however, to a degreethat varies with the amount of alcoholconsumed and the particular mecha-nisms sensitivity.

As an example, Puddey and col-leagues (1985) evaluated the effects ofhormones that regulate kidney func-tion. Their results show not only howalcohol disrupts homeostasis but alsohow the body reacts to restore it.Following moderate alcohol consump-tionabout 24 ozof nonalcoholicbeer with 1 milliliter of alcohol per

kilogram of body weight added, theinvestigators noted several effects.Alcohol-induced urination reduced thesubjects plasma volume, resulting inan increased concentration of plasmasodium. In addition, the subjectsblood pressure and plasma potassiumconcentration decreased. Thesechanges in fluid volume, electrolytebalance, and blood pressure may havestimulated the activity of hormones toreturn body fluid volume and compo-

sition back to normal, which occurredsoon after consumption.

Alcohol consumption also isknown to induce a state of low bloodsugar (i.e., hypoglycemia) and acti-vate the portion of the nervous system

that coordinates the bodys responseto stress (i.e., the sympathetic nervoussystem). Both of these factors affecthormones that regulate kidney func-tion, just as changes in fluid volumeand electrolyte balance do.

INDIRECT EFFECTS

Physicians have recognized an inter-relationship between kidney and liverdisorders at least since the time ofHippocrates. Although a disorder inone organ can complicate a primaryproblem in the other (or a pathologicaprocess may involve both organsdirectly), kidney dysfunction compli-cating a primary disorder of the liver(e.g., cirrhosis) is the most clinicallysignificant scenario. Frequently, suchkidney dysfunction results from liverproblems related to alcohol. In fact,most patients in the United Statesdiagnosed with both liver disease andassociated kidney dysfunction arealcohol dependent (Epstein 1992).(See the article by Maher, pp. 512.)Three of the most prominent kidneyfunction disturbances that arise in thepresence of established liver diseaseare impaired sodium handling, im-paired fluid handling, and acute kid-ney failure unexplained by othercauses (i.e., hepatorenal syndrome).

Impaired Sodium Handling

Patients with alcohol-induced livercirrhosis show a great tendency toretain salt (i.e., sodium chloride), andtheir urine frequently is virtually freeof sodium. A progressive accumula-tion of extracellular fluid results, andthis excess fluid is sequestered pri-marily in the abdominal region, whereit manifests as marked swelling (i.e.,ascites) (see figure). In addition, ex-cess fluid accumulates in spaces be-tween cells, clinically manifested asswelling (i.e., edema) of the lowerback and legs. As long as cirrhotic



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patients remain unable to excretesodium, they will continue to retainthe sodium they consume in their diet.Consequently, they will develop in-creasing ascites and edema and expe-rience weight gain. In some cases,

vast amounts of abdominal fluid maycollect, occasionally more than 7gallons (Epstein 1996).

Rigorously limiting sodium intake,which is the first step in treating as-cites, will halt fluid retention. Suchsodium restriction alone may bringabout a spontaneous increase in urineflow and relieve ascites, but how oftenthis response occurs and in whichpatients is unknown and unpredictable.Other treatment options include vari-ous diuretic agents and, when ascites

stubbornly persists, aspiration of theexcess abdominal fluid. Many sodium-retaining patients who receive largequantities of sodium-free water canexcrete copious amounts of diluteurine, thus demonstrating that the mainkidney dysfunction associated withtheir ascites is an impaired ability toexcrete sodium, not water.

The events leading to abnormalsodium handling in patients withcirrhosis are complex and controver-sial, however. Investigators have

advanced several theories suggestingthe involvement of a constellation ofhormonal, neural, and hemodynamicmechanisms (Epstein 1996; Laffi et

al. 1996). The traditional hypothesisholds that the kidneys of cirrhoticpatients retain sodium in response toascites that develops when liver dys-function causes blood vessels to ex-pand beyond available plasma volume

(i.e., the underfill theory). In con-trast, the overflow theory postulatesthat ascites follows when the kidneysretain sodium in response to signalssent by a dysfunctional liver to ex-pand plasma volume. The answer tothis version of the chicken-and-eggquestion remains to be elucidated.

Impaired Fluid Handling

In many patients with liver cirrhosis,the kidneys ability to create dilute

urine is compromised, leading to a stateof abnormally low sodium concentra-tion (i.e., hyponatremia). In hypona-tremic patients, the amount of fluidretained by the kidneys is dispropor-tionately greater than the amount ofsodium retained. In other words, thekidneys ability to excrete excess fluidby way of dilute urine is impaired, andtoo much fluid is reabsorbed. Hypo-natremia probably is the single mostcommon electrolyte disturbance en-countered in the management of pa-

tients with cirrhosis of the liver(Vaamonde 1996). This abnormalitymay reflect the severity of liver disease,but the available data do not allowcorrelation of kidney impairment withthe degree of clinical signs of liverdisease, such as ascites or jaundice.

A compromised diluting ability hasimportant implications for the manage-ment of patients with advanced liverdisease. Restricting the fluid intake ofhyponatremic patients eventually shouldrestore a normal fluid balance; unfortu-nately, this restriction may be difficultto implement. Patients frequently fail tocomply with their physicians orders tolimit their fluid intake. Furthermore,clinicians sometimes overlook the factthat fluids taken with medications alsomust be restricted for these patients andmistakenly bring pitchers of juice orwater to their bedsides.

The difficulties in successfullymanaging dilutional hyponatremiahave resulted in the recent emergence

of a promising class of new drugs totreat this abnormality. Specifically,drugs known as arginine vasopressinantagonists are being developed toinhibit ADH at the cell receptor level.These new drugs should dramatically

facilitate treatment of cirrhotic pa-tients with impaired fluid handling.

Hepatorenal Syndrome

Hepatorenal syndrome may appear inpatients afflicted with any severe liverdisease, but in the United States, stud-ies most often have identified alco-holic cirrhosis as the underlyingdisorder. Major clinical features ofhepatorenal syndrome include a markeddecrease in urine flow, almost no

sodium excretion and, usually, hy-ponatremia and ascites. Blood ureanitrogen (BUN) levels and serumconcentrations of the waste productcreatinine are somewhat elevated, butrarely to the degree seen in patientswith end-stage kidney failure whenkidney disease is the primary disorder.Judgments based on such relativelymodest BUN and serum creatinineincreases often underestimate kidneydysfunction in patients with hepato-renal syndrome, however, because

malnourished cirrhotic patients tend tohave low levels of urea and creatinine.

Although hepatorenal syndromeoften ensues after an event that re-duces blood volume (e.g., gastroin-testinal bleeding), it also can occurwithout any apparent precipitating fac-tor. Some observers have noted thatpatients with cirrhosis frequently de-velop hepatorenal syndrome followinghospital admission, possibly indicatingthat a hospital-related event can triggerthe syndrome. Regardless of the pre-cipitating factor, patients who developkidney failure in the course of alco-holic cirrhosis have a grave prognosis.

Substantial evidence exists to sup-port the concept that kidney failure inhepatorenal syndrome is not related tostructural damage and is instead func-tional in nature. For example, almost30 years ago, Koppel and colleagues(1969) demonstrated that kidneystransplanted from patients with hepa-torenal syndrome are capable of re-

Patient with marked ascites.

SOURCE:Reprinted with permission from

Epstein, M.: The Kidney in Liver Disease, 4th ed.

Philadelphia, PA: Hanley & Belfus, 1996.


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suming normal function in recipients

without liver disease. In addition,Iwatsuki and colleagues (1973) andGonwa and Wilkinson (1996) docu-mented the return of normal kidneyfunction in hepatorenal syndromepatients who receive liver transplants.

Indeed, liver transplantation is oneof two options available today fortreating hepatorenal syndrome. Gon-wa and Wilkinson (1996) reported a4-year survival rate of 60 percent inhepatorenal syndrome patients whoreceived a liver transplant, which

constitutes a major step forward, con-sidering the previous uniformly fatalcourse of the disease.

Another current treatment option isknown as transjugular intrahepaticportosystemic shunt (TIPS), in whicha bypass (i.e., shunt) between twoveins inside the liver (i.e., the hepaticvein and the portal vein) is created byway of the jugular vein. Obstructionsin the liver of cirrhotic patients in-crease pressure in the portal vein, andthis effect is thought to contribute to

many kidney complications. The TIPStechnique was developed as a meansto reduce pressure in the portal circuitand offers several advantages:Because the shunt can be insertedunder local anesthesia, TIPS avoidspostoperative complications associat-ed with surgery. In addition, TIPSdoes not alter the anatomy of theblood vessels outside the liver, animportant consideration for potentialliver-transplant candidates. The less

invasive nature of TIPS makes it an

attractive option for treating hepatore-nal syndrome, and preliminary resultsshow that the procedure is effective(Somberg 1996). Currently, a clinicaltrial sponsored by the National Institutesof Health is investigating the effects ofTIPS on the treatment of ascites andimprovement of kidney function.

CONCLUSION

Excessive alcohol consumption canhave profound negative effects on the

kidneys and their function in maintain-ing the bodys fluid, electrolyte, andacid-base balance, leaving alcoholicpeople vulnerable to a host of kidney-related health problems. Despite theclinical importance of alcohols effectson the kidney, however, relatively fewrecent studies have been conducted tocharacterize them or elucidate theirpathophysiology. It is hoped that fu-ture investigations will focus on thisimportant subject area. s

EDITORIAL NOTE

The reference list accompanying thisarticle has been shortened. A completebibliography is available on request.

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syndrome.Lancet2(7928):245246, 1975.

IWATSUKI, S.; POPOVTZER, M.M.; CORMAN, J.L.;

ISHIKAWA, M.; PUTNAM, C.W.; KATZ, F.H.; AND

STARZL, T.E. Recovery from hepatorenal syndrome

after orthotopic liver transplantation.New England

Journal of Medicine 289:11551159, 1973.

KLATSKY, A.L.; FRIEDMAN, G.D.; SIEGELAUB, A.B.;

AND GERARD, M.J. Alcohol consumption and blood

pressure Kaiser-Permanente Multiphasic Health

Examination data.New England Journal of Medicine

296:11941200, 1977.

KOPPEL, M.H.; COBURN, J.W.; MIMS, M.M.; GOLDSTEIN

H.; BOYLE, J.D.; AND RUBINI, M.E. Transplantation ofcadaveric kidneys from patients with hepatorenal

syndrome. Evidence for the functional nature of renal

failure in advanced liver disease.New England Journal

of Medicine 280(25):13671371, 1969.

LAFFI, G.; LA VILLA, G.; PINZANI, M.; AND GENTILINI, P

Lipid-derived autacoids and renal function in liver

cirrhosis. In: Epstein, M., ed. The Kidney in Liver

Disease, 4th ed. Philadelphia: Hanley & Belfus, 1996

pp. 307337.

LAUBE, H.; NORRIS, H.T.; AND ROBBINS, S.L. The

nephromegaly of chronic alcoholics with liver disease

Archives of Pathology 84:290294, 1967.

LIAN, C. Lalcoolisme, cause dhypertension artrielle

Bull. Acad. Med. 74:525528, 1915.

MONEY, S.R.; PETROIANU, A.; KIMURA, K.; AND JAFFE

B.M. Acute hypocalcemic effect of ethanol in dogs.

Alcoholism: Clinical and Experimental Research

13(3):453456, 1989.

NICHOLSON, W.M., AND TAYLOR, H.M. Blood volume

studies in acute alcoholism. Quarterly Journal of

Studies on Alcohol 1:472, 1940.

OSTER, J.R., AND PEREZ, G.O. Derangements of acid-

base homeostasis in liver disease. In: Epstein, M., ed.

The Kidney in Liver Disease. 4th ed. Philadelphia:

Hanley & Belfus, 1996. pp. 109122.


How Alcoholism Contributes to Electrolyte Disturbances

Disturbance Major Cause(s)

Low sodium level Massive intake of solute-free fluid (e.g., beer)

(i.e., hyponatremia)

Low potassium level Dietary deficiency or gastrointestinal losses

(i.e., hypokalemia) Leaky membranes

Extracellular-to-intracellular shifts

Low phosphorus level Dietary deficiency or malabsorption

(i.e., hypophosphatemia) Increased cellular uptake

Low magnesium level Dietary deficiency or malabsorption

(i.e., hypomagnesemia) Phosphorus deficiency

SOURCE: Adapted from Epstein, M. Alcohol and the kidney. In: Lieber, C.S., ed. Medical and Nutritional Compli-

cations of Alcoholism: Mechanisms and Management. New York: Plenum Medical Book Company, 1992. p. 502.


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PUDDEY, I.B.; VANDONGEN, R.; BEILIN, L.J.; AND ROUSE,

I.L. Alcohol stimulation of renin release in man: Its

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adrenal responses to drinking.Journal of Clinical

Endocrinology and Metabolism 61(1):3742, 1985.

RUBINI, M.E.; KLEEMAN, C.R.; AND LAMDIN, E. Studies

on alcohol diuresis. I. The effect of ethyl alcohol

ingestion on water, electrolyte and acid-base

metabolism.Journal of Clinical Investigation

34(3):439447, 1955.

SOMBERG, K.A. Transjugular intrahepatic portosys-

temic shunt in the treatment of refractory ascites and

hepatorenal syndrome. In: Epstein, M., ed. The Kidney

in Liver Disease. 4th ed. Philadelphia: Hanley &

Belfus, 1996. pp. 507516.

VAAMONDE, C.A. Renal water handling in liver

disease. In: Epstein, M., ed. The Kidney in Liver

Disease. 4th ed. Philadelphia: Hanley & Belfus, 1996.

pp. 3374.

VAN THIEL, D.H.; WILLIAMS, W.D.; GAVALER, J.S.;

LITTLE, J.M.; ESTES, L.W.; AND RABIN, B.S. Ethanol

its nephrotoxic effect in the rat.American Journal of

Pathology 89(1):6784, 1977.

Cushioned in fatty tissue near thebase of the spinal column, the kid-

neys are efficiently designed organsthat perform two primary tasks inthe body: excretion of metabolicend products and precise regulationof body fluid constituents. As theyaccomplish these tasks, the kidneysform and collect urine, which exitsthrough the ureters to the bladder.

Each of the 2 million functionalunits (i.e., nephrons) in a pair of

normal kidneys forms urine as itfilters blood plasma of substancesnot needed by the body. Within eachnephron, blood plasma enters a tinyball of unusually permeable capillar-ies (i.e., the glomerulus), filters intoa capsule that surrounds theglomerulus, then flows through a

long, looping conduit called thenephron tubule.

As the plasma filtrate passesalong this channel, the substancesthe body needs to conserve are reab-sorbed into an extensive network ofcapillaries that wrap the nephrontubule. Many electrolytes and 99percent of the water in the filtrate arereabsorbed, while waste products,such as urea (an end product of pro-tein metabolism formed chiefly inthe liver) and creatinine (an endproduct of muscle metabolism), aswell as excess electrolytes (particu-

larly sodium, potassium, chloride,and hydrogen ions), continue tojourney along the tubule. Smallamounts of unwanted substancesalso are secreted directly into thenephron tubules. Together, the fil-tered and secreted substances formurine (see figure) and eventuallytrickle into a series of progressivelylarger collecting ducts. Each 4.5-inch-long kidney contains about 250of the largest collecting ducts, eachduct transmitting urine from approxi-

mately 4,000 nephrons.Of the 48 gallons of filtrate pro-

cessed through the nephrons of thekidneys each day, only about 1 to1.5 quarts exit as urine. During thisfiltering process, substances are

Urine formation. Three basic processesglomerular filtration, tubular reabsorption,

and tubular secretioncontribute to urine formation, as shown in this schematic.

Efferent

arteriole Afferentarteriole

Bloodflow

Blood flow

Nephrontubule

Capillary

Collectingduct

To urinary bladderfor excretion

Glomerulus 1. Filtration: Blood

enters the glomerulus

through the afferent

arteriole and filters intothe surrounding cap-

sule at the head of

the nephron.2. Reabsorption:

Useful substances

are reabsorbed from

the nephron tubule

into the adjacent

peritubular capillary.3. Secretion: Waste

products to be elimi-

nated are taken up

from the peritubular

capillary into the neph-

ron tubule.

KIDNEY STRUCTURE AND FUNCTION

(continued on page 92)


9/1092 ALCOHOL HEALTH & RESEARCH WORLD

reabsorbed or secreted to varyingdegrees as the filtrate passesthrough the distinct segments ofthe nephron tubule.

Regulating Electrolyte Levelsand Fluid Volume

The kidney tubules play an impor-tant role in keeping the bodyswater and electrolyte levels inequilibrium. In many cases, controlmechanisms govern the rate of

reabsorption or secretion in re-sponse to the bodys fluctuatingneeds (see table for a summary ofthe body processes influenced bykey electrolytes). Under the influ-ence of antidiuretic hormone(ADH), for example, the tubulescan create either a concentratedurine, to discharge excess solutesand conserve water, or a diluteurine, to remove extra water frombody fluids. In the first case, whenbody fluids become too concentratedwith solutes, the pituitary gland pro-duces abundant ADH, which inducesthe kidneys to conserve water andconcentrate urine, an important abili-ty that enables thriving in an environ-ment where water may be scarce. Inthe absence of ADH, when bodyfluids are overly dilute, the kidneysdilute the urine, allowing more waterto leave the body. Normal urineflow rate is 1 milliliter per minute(i.e., approximately 1 to 1.5 L/day),

but this rate can vary widely, depend-ing on water intake or dehydrationlevel, for instance.

The kidneys continuously per-form their tasks of purifying andbalancing the constituents of thebodys fluids. Although resilient, thekidneys can deteriorate as a result ofmalnutrition, alcohol abuse or de-pendence, or liver and other dis-eases. Healthy kidneys are vital tothe function of all the bodys organsand systems.

Mary Beth de Ribeaux

BIBLIOGRAPHY

GUYTON, A.C.Human Physiology andMechanisms of Disease. 5th ed. Philadelphia:

W.B. Saunders, 1992. pp. 195246.

RHOADES, R., AND PFLANZER, R.HumanPhysiology. 2d ed. Fort Worth: SaundersCollege Publishing, 1992. pp. 823909.

Mary Beth de Ribeaux is a scienceeditor ofAlcohol Health &Research World

Key Electrolytes in the Body

Ion Major Physiological Roles

Sodium Primary positive ion in extracellular fluid. Together with potas-

(Na+) sium, maintains electrolyte balance across all cell membranes.

Vital to many basic physiological functions.

Potassium Primary positive ion in intracellular fluid. Together with sodium,

(K+) maintains electrolyte balance across all cell membranes. Vital to

many basic physiological functions.

Magnesium Required for activity of many enzymes.

(Mg2+)

Calcium Major mineral in body and component of bone. Helps maintain(Ca2+) normal heartbeat and nerve and muscle function.

Chloride Primary negative ion in extracellular fluid. Plays a role in nerve

(Cl) function and other metabolic processes.

Phosphate Primary negative ion in intracellular fluid. Serves as an important

(HPO42) buffer to maintain proper pH. Phosphorus is a major component

of bone and is involved in almost all metabolic processes.

KIDNEY STRUCTURE AND FUNCTION

(continued from page 91)


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Acetaldehyde: The immediate product ofalcohol oxidation, this compound can

damage the cellular microstructure ofthe liver, inducefibrosis, affect energymetabolism, and generatefree radicals.

Acid-base balance: Normal body fluidpH (i.e., hydrogen ion concentration),which must be narrowly regulated forproper body functioning.

Acidosis: A condition in which body fluidsbecome too acidic (see alkalosis).

Active transport: The transfer ofsubstances (i.e., molecules or ions)across a cell membrane from a lower toa higher concentration, thus requiring

energy expenditure.Alcohol dehydrogenase: An enzyme that

breaks down alcohol.

Alkalosis: A condition in which bodyfluids become too alkaline (see acidosis).

Allele: One of two or more variants of agene. Different alleles for a gene servethe same function (e.g., code for a

protein that affects a persons eyecolor) but may result in different

phenotypes (e.g., blue eyes or browneyes).

Amino acids: The building blocks of

proteins. Some amino acids also func-tion as neurotransmitters.

Ammonia: A neurotoxic chemicalcompound that is formed in the bodyprimarily as a product ofproteinmetabolism.

Anemia: A blood condition in which thenumber of functional red blood cells isbelow normal.

Anterior pituitary: A small gland at thebase of the brain that is controlled bythe hypothalamus and which manu-factures hormones influencing many

organs in the body.Antibody: Aprotein that is produced byB

cells in response to, and which inter-acts with, an antigen.

Antidiuretic hormone (ADH): Ahormone produced in the hypotha-lamus and released from the posteriorpituitary gland in response to dehydra-tion; plays an important role in regulat-ing fluid excretion.

Antigen: Any substance that is recognizedbyB cells or T cells and stimulates themto initiate an immune response.

Antioxidants: Chemicals (e.g., gluta-thione and vitamins A and E) that

prevent certain destructive chemicalprocesses in cells.

Apoptosis: A series of chemical reactionswithin a cell that are induced by vari-ous events and which result in thecells death.

Atherogenesis: The development ofatherosclerosis.

Atherosclerosis: A disease of the arteriesin which fatty plaques accumulate onthe arteries inner walls, usuallyleading to narrowing and hardeningof the arteries and eventually

obstructing blood flow.Atrial fibrillation: A loss of coordinated

contraction that occurs in one or bothof the upper chambers of the heart,resulting in rapid and irregular heartand pulse rates.

Atrophy: Wasting away, or shrinkage, oftissue; caused by cell death rather thanshrinkage of individual cells.

B lymphocyte (B cell): A type ofwhiteblood cell that originates in the bonemarrow and is distributed throughoutthe blood and lymphoid tissues. B cells

produce antibodies when stimulated bythe appropriate antigens.

Basal ganglia: A group of nerve cellstructures at the base of the brain thatare involved in motor control.

Catalyst: Any substance that facilitates achemical reaction and which does notundergo a permanent chemical changeitself.

Catecholamines: A group of physiolog-ically active substances with variousroles in the functioning of the sym-pathetic and central nervous systems.

Cell-mediated immune response: Animmune response provided by thedirect actions of immune system cells(primarily T cells), as opposed to animmune response mediated byantibodies (i.e., humoral immuneresponse).

Cellular toxin: A toxin that is releasedfrom a cell; also called endotoxin.

Cerebellum: The brain structure at thebase of the brain that is involved in thecontrol of muscle tone, balance, andsensorimotor coordination.

Cerebral cortex: The intricately foldedouter layer of the brain, composed of

nerve-cell bodies and gray matter, thatcovers the cerebrum. The cerebralcortex contains areas for processingsensory information and for controllingmotor functions, speech, highercognitive functions, emotions,behavior, and memory.

Cerebrum: The largest portion of thebrain; includes the cerebral hemi-spheres (see cerebral cortex and basalganglia).

Chemokines: Smallproteins secreted byimmune cells that can attract otherimmune cells to the tissue site where

the chemokines are produced. Chemo-kines play a role in chemotaxis.

Chemotaxis: The directed movement of acell in response to a stimulus, such as achemokine.

Cholesterol: A fatlike substance that is animportant component of cellmembranes and is the precursor ofmany steroid hormones and bile salts.High cholesterol levels are associatedwith coronary artery disease.

Cholesteryl ester: The product of areaction between cholesterol and an

organic acid.

Cholesteryl ester transfer protein(CETP): A compound that transportscholesteryl esters from high densitylipoproteins to low density lipoproteinsfor eventual removal from the blood.

Complement: A group ofproteinscirculating in the blood that are eitherbound to antigen and activated byantibodies or are activated by mole-cules found on the surface of somebacteria. Complement activationresults in the attraction ofphagocytes,

the release of chemicals that amplifyimmune responses, and the destructionof invading bacteria.

Cortisol: A glucocorticoidproduced bythe adrenal gland that helps regulatemetabolism.

Cytochrome: An enzyme that detoxifiesforeign compounds.

Cytokine: A molecule that regulatescellular interaction and cellularfunctions. Cytokines are produced andsecreted by a variety of cells, includingimmune cells.

G L O S S A R Y

alcohol+kidney

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