Hepatic Failure and the Kidney

Vol. 51 , Xo.l Printed in U.S.A.

GASTROEXTEROLOGY

Copyright© 1966 by The Williams & Wilkins Co.

PROGRESS IN GASTROENTEROLOGY

HEPATIC FAILURE

A~D

W. H. J.

THE

KID~EY

SrmiER SKILL ,

D .J.\1. , l'vi.R.C.P.

Gastrointestinal Research Uni t, Mayo Clinic and Mayo Fo undation, Rochester, .llinnesota

During the first half of the last decade, prevailing concepts applied to abnormal renal function or disorders of water and electrolyte metabolism in patients with hepatic disease were effectively challenged.1·6 Subsequently, the clinical and pathophysiological characteristics of renal failure associated with severe impairment of hepat ic function have been reappraised, and attempts to define or correlate the components involved in these processes will be reviewed here. The necessary omission of the greater part of an extensive and simultaneous literature pertaining to experimental preparations, contemporary theories of renal transport mechanisms, and effects of diuretic agents implies no irrelevance of these contributions to the subject. The causes, specificity, and interrelationships of renal and hepatic failure are not beyond dispute, despite remarkable efforts by hepatologists and their colleagues to apply and interpret the sophisticated techniques often appropriate to investigation of renal function. Indeed, occasionally one senses mutual frustration in comprehending each other's criteria, methods, classifications, and conclusions. Nevertheless, it has been conceded that progressive clinical deterioration accompanied by hyponatremia, azotemia, and oliguria in the absence of specific morphological evidence of Address requests for reprints to: Dr. W. H. J. Summerskill, Mayo Clinic, 200 First Avenue, S.W., Rochester, Minnesota 55901. This investigation was supported in part by Research Grant AM-06908 from the National Institutes of Health, United States Public Health Service. 94

renal disease comprises an important syndrome in patients with hepatic failure.'- 15 Interrelationships between the Liver and the Kidney

The numerous associations known or postulated between diseases or disordered function of the liver and kidney (table 1) have been summarized recently, and rejection of the term "hepatorenal syndrome" is generally urged, at least until specific interrelationships between the two organs are confirmed by experimental and clini cal data. 7 • 1o, 12 Patients with primary diseases of both the liver and the kidney, which may occur with more than coincidental frequency,8 or with systemic disorders involving both organs are most readily classified. An association is recognized also between hypernephroma and abnormal tests of hepatic function, which are corrected by surgical removal of the tumor.l6· 17 By contrast, azotemia developing during hepatic failure is seldom attributable to any of these factors, although certain circumstances incidental to, and often inseparable from, hepatic disease command close consideration.l 5 • 18 -21 Thus, therapeutic measures or complications of hepatic disease may lead to renal circulatory failure, tubular necrosis, or nephropathy and these often appear to be sequelae to decreases in plasma volume or arterial blood pressure. Depletion of potassium or sodium secondary to dietetic or diuretic therapy, the nephrotoxicity of neomycin and other drugs, paracentesis abdominis or other surgical procedures, and, especially, hemorrhage from gastroesophageal varices have

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been

incriminated in these regards. 7 • 1 4 The specificity of the effect on the kidney of jaundice, due either to parenchymal disease of the liver or to obstruction of the extrahepatic biliary system, can be defined less confidently. Azotemia appears to occur ·with undue frequency following operations on the biliary tract, and it has been postulated that bilirubinemia predisposes the kidney to tubular necrosis in the presence of arterial hypotension. 24 - 26 Although arterial blood pressure is not consistently decreased in azotemic pa19 • 2 2 , 23

TABLE

1. Live1·-kidney inlen·elationships

1. Sepa rate diseases of liver a nd kidney (increased incidence?) 2. Systemic di so rders involving b oth liver and kidney (infectio us, tox ic, infl a mmatory, infiltrative) 3. Prima ry renal disease (tumor) affecting hepatic function 4. Prima ry disease of liver or bilia ry system affecting renal fun ction a . Renal circulatory failure with azotemia assoc iate d with severe p are nchymal disease of the liver b. R enal tubular necrosis or dysfunction due to extrarenal factors (circul atory, toxic, metabolic)

TABLE

95

tients, 10 and despite high or normal plasma volumes in cirrhosis, 27 azotemia has often been accepted as occurring invariably on a prerenal basis, as a sequel to reduction of the theoretical effective extracellular fluid volume. However, applications of newer techniques, together with more careful assessment of the role of possible precipitating mechanisms, have indicated that renal failure may also arise spontaneously as an intrinsic part of hepatic failure. 9 • 2 0, 2 8 Such a relationship is now accepted,to. 12 • 13 29 3 • • 0 although in individual cases it is often difficult to appraise the contribution of exogenous factors; and differentiation between tubular necrosis and the spontaneous development of renal failure is less precise 10 • 12 • 13 than ideally depicted (table 2) . For example, scrutiny of 76 examples of cirrhosis and azotemia revealed no cause for renal failure other than its association with advanced hepatic disease in one-third of the patients ;10 in the remainder, exogenous factors, of which gastrointestinal hemorrhage was the most frequent, could not be exonerated. Others 12 • 13 have found no plausible explanation for azotemia other than its association with hepatic failure in comparable proportions of cases. Indeed, the extrarenal factors once ac-

2 . Differentiation between spontaneous renal fai luTe and Tenal tubular necrosis in hepatic disease Spontaneous renal failure

Jaundice ... .... . ... . . ...... . . . .. . . . .. .. . .. .. . . ..... . Ascites ... Hepatic function .. Precipitating factors .... Course. . .. . ..... . . . . Arterial h ypotension. . . . ...... . .. . Oliguria . . ... . . .. .. . Specific gravity of urine . . . . . ... ... . . .. . . Protein, casts , and blood cells in urine . . ..... . . . . . . . Tubular reabsorption of N a . .. . . . . . . ...... . . ... . Tubular rea bsorption of K. . . . . .. .... . Osmolality of urine . . . . . .. ... ... .. . ... .. .. . . . . GFR and ERPF• . . . . . . . . . . . . . .... .. .. . ... . ... . Filtration fr a ction. . . . . . .. .. . .. .. . .. .. . . . . ... . Extraction r atio for P AH•. . . . . ....... . . . . . .. .. . Specific r enal histological cha nge ... . .. .. . . .. .... .. . . .

M aybe Usually Poor M aybe Variable Late Late >1.010 No Increased plasma) Low Often high Normal No

Renal tubular necrosis

Often Maybe Variable Yes Rapid Early Early ±1.010 Yes Decreased >sodium Low ( < plasma) Low Often low Low Sometimes

• GFR, glomerular filtration rate; ERPF, estimated renal plasma flow; P AH, p-aminohippuric acid-

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corded prime importance in etiology may often be agonal or may serve only to reveal a previously prejudiced state of renal function.10· 11 Hence, reductions of glomerular filtration rate (GFR) and estimated renal plasma flow (ERPF) may be present in cirrhosis prior to clinically evident deterioration,11· 12· 31 and are sometimes of such a degree that the term "preazotemia" has been applied.l 0 Frequency and Characteristics of Azotemia with Hepatic Failure

The incidence of azotemia in hepatic failure is debatable, but Chalmers32 believed that almost every patient with progressive cirrhosis had terminal oliguria and uremia, and more than 50% of patients dying from cirrhosis reviewed by Shear and his associates 12 had evidence of renal failure. Some assert that the syndrome was once rare and is becoming more frequent because patients survive other complications of hepatic diseases as a result of better treatment. 15· 33 Vesin and his associates/ 9 also impressed by an increasing incidence of azotemia in hepatic disease, preferred to conclude that advances in therapy were responsible, because newer diuretics caused a fall in plasma volume and hence renal circulatory failure. Conversely, no increase in renal failure was discerned between 1958 and 1962 in 102 patients who died from cirrhosis at the Cleveland Metropolitan General Hospital. 12 The likelihood that previously the syndrome was often overlooked is supported by a review of appended data relating to hepatic coma and antedating modern diuretic treatment ;34 this review disclosed hyponatremia and azotemia, which had then been considered peripheral to the main theme, in the majority of patients. Reports of azotemia and hepatic failure usually concern patients with cirrhosis of various types. 10 · 12 · 14 The specificity of the hepatic disease and the frequency of its associated features have been investigated inadequately, but comparable findings have been recorded in patients with acute hepatitis18 or cancer of the liver. 35 It is also un-

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certain whether the abnormalities of renal function differ greatly from those sometimes arising in other conditions, including cardiac failure. 8 Pertinent information concerning the incidence, the specificities of the hepatic and renal components, and the frequency of significant precipitating factors in the syndrome can therefore still be gained, both by retrospective and by prospective studies. The salient features of spontaneous azotemia in patients vvith cirrhosis are better definecJ.7· 10· 12· 14 Ascites is almost invariable and is usually refractory to treatment. Other complications of cirrhosis, including hepatic coma and portal hypertension, are frequently recorded. Jaundice may or may not be present, but hepatic function is severely impaired by most clinical and biochemical criteria. Initially, fatigue and anorexia are associated with hyponatremia, hypokalemia, hypochloremia, and elevated concentrations of blood urea and serum creatinine. Patients may later experience nausea, vomiting, and thirst; simultaneously the biochemical abnormalities become more pronounced. Less often, hyperkalemia 7 • 9 • 14 20 • or, rarely, hypernatremia 36 may be found; the pH of whole blood is variable but often abnormal, 9 • 10 and occasionally unexplained anemia has been reported. 10 · 20 \iVith further deterioration, the neuropsychiatric disorder, electroencephalographic changes, and elevated blood ammonia concentrations consistent with and indistinguishable from hepatic coma appear. Hyperammonemia is presumably sustained by hydrolysis of the increased amounts of urea excreted into the gut, 37 although the contrasting possibility that a metabolic abnormality associated with hepatic coma adversely affects renal function has been proposed. 12 During this late phase, oliguria and arterial hypotension become evident and deepening coma with an unfavorable outcome is the rule. 7· 10· 12· 14 Features of hepatic failure still predominate and death not infrequently results from massive gastrointestinal hemorrhage. 10 · 12 It has been rightly emphasized 10 that oliguria and arterial hypotension often appear only in the final stage of the spontaneous syndrome, thus

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contrasting with earlier concepts that azotemia invariably had a prerenal basis.

The Kidney Urinalysis, tests of renal function, and examination of the kidney, when mterpreted in relation to the clinical findings , can assist in establishing a diagnosis (table 2) ; equivocal results are not uncommon 8 • 10· 12 and may reflect the operation of more than one factor in the development of azotemia. The wide variety of gross or histological changes described in the kidneys of patients with hepatic disease includes several of dubious rele,·ance, such as hydropic changes in the tubular epithelium, tubular dilation, areas of interstitial nephritis, and so-called biliary nephrosis ;7 • 8· 10 even the presence of tubular necro sis is seldom obvious on histological examination. 7 Jones and his associates38 found significantly greater numbers of renal glomerular lesions in patients with hepatic disease at autopsy; splitting, fraying, or thickening of the basement membran e was observed in 28% of their series. :More recently, Salomon and his colleagues30 identified glomerular changes in renal biopsy tissue from all of 24 patients with hepatic disease. Studies by electron microscopy revealed deposits in the capillary wall and mesangium, thickening of the baEement membranes, and an increased mesangial matrix. These glomerular changes, like other morphological findings, have not been correlated with abnormalities of renal function or with the type, duration, or severity of the hepatic disease.ss. 39 Renal circulatory function. Conventional tests of renal function show reduced clearances of inulin, p-aminohippuric acid (PAR), creatinine, and urea; 11 • 29, 40-43 additional features may be expected when azotemia is on an extrarenal basis and attributable to tubular necrosis (table 2). Progressive deterioration in clearance values has been correlated with the severity of the clinical condition (fig. 1) as indicated by the presence of ascites, its resistance to treatment, and the presence of azotemia.U A disorder of renal hemodynamic function 11 • 29 · 40 - 43 has been inferred histol~gic al

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from the absence of diagnostic features on urinalysis, the apparent adequacy of the functioning renal mass when examined histologically, and the frequently high filtration fraction. 11 Total renal plasma flow 41 and the renal fraction of cardiac output are reduced, 41· 44 although cardiac output and indices, 40 · 41 · 44 mean arterial blood pressure,41 and systemic vascular resistance 41 are usually within the normal range; however, an increased blood flow to another region cannot be excluded as leading to the low renal component of cardiac output. Theoretically, the reduced plasma colloid osmotic pressure and serum osmolality common to such patients may influence renal circulatory and tubular function ;45 - 49 these factors require fuller study in cirrhosis 12 but no maj or contribution by them to renal failure has been substantiated.12· 50 Ren al hemodynamic function is also unlikely to be impaired greatly as a result of compression of the renal venous outflow by the hydrostatic effects of ascites, as renal vein pressures are neither consistently nor sufficiently above the normal range. 41 Moreover, GFR and ERPF are little influenced by disappearance of the ascites, 11 although some aspects of renal function may improve.51 Finding that extraction r atios of P AH and arterial-renal vein oxygen differences were usually normal , Baldus and his colleagues41 considered that arterial-venous shunting of blood within the kidneys, comparable to that occurring in other organs in cirrhosis, was an unlikely cause of the decreased PAR clearance. However, Shear and his associates 40 found low extraction ratios in three patients and frequently subnormal filtr ation fractions; these observations, together with evidence adduced by others from the impairment of renal concentrating ability in cirrhosis, 52 have prompted the suggestion that increased medullary blood flow and shunting of blood around the glomerular capillaries account for renal circulatory failure. It has been stressed that applications of CPAH to renal blood flow are unreliable at low rates of urine excretion 53 and that extraction ratios are technically difficult to determine in

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PROGRESS I N GJJS'l'ROEiV'l'EROLCGY 1000 ~----------------------------------------~-.

Group 900

x I

A. B. • IT A. B.

®

800

Never asc it es Responsive ascit es Resistant ascites Azotemia a nd ascites

700

600

500

.

®

400

300

200

100

20

40

60

80

100

120

140

160

c1N (mi./min.) FIG. 1. Comparison of inulin and p-aminohippuric acid (PAH) clearances in 45 patients with cirrhosis. Diagonal lines represent mean and range for normal filtration fraction. (Reproduced with permission from: Baldus, W. P ., R.N. Feichter, W. H. J. Summerskill, J. C. Hunt, and K. G. Wakim. 1964. The kidney in cirrhosis. II. Disorders of renal function. Ann. Intern. M ed. 60 : 366-377.

patients with hepatic and renal failure; consequently, the development of newer methods, including use of the local thermo dilution catheter, 53 the nitrous oxide technique,54 and renal artery perfusion with indocyanine green 55 may yield more instructive results. Since total renal vascular resistance is significantly elevated in patients with more severe impairment of renal hemodynamic function,4 1 an increase in t he resistance offered by the renal vasculature could account for t he various functional abnormalities observed. The site of increased resistance cannot be stated, nor can such an abnormality be designated as compensatory or causal. If t he latter, a substance

liberated or inadequately inactivated by the failing liver demands consideration. An alternative theory might implicate an interrelationship between the renal and hepatic circulations mediated t hrough t he autonomic nervous system. Thus, occlusion of the portal vein or ligation of the hepatic artery causes a striking reduction of renal blood flow in t he dog and the effect is abolished by sympathectomy and splanchnicectomy.50· 57 Subsequently, hepatic periarterial nerve crush alone has been shown to be as effective as hepatic anoxia in evoking renal vasoconstriction. 58 The possible re lationships between hepatic and renal blood flows in cirrhosis await investigation, and the fun ction of the autonomic nervous

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PROGRESS IN GASTROENTEROLOGY

system in such patients is unknown. How may biliary operations affect the periarterial nerve plexus and influence postoperative renal function in man? And might the indirect evidence of depletion of tissue norepinephrine stores in those with terminal oliguria and hyponatremia 59 imply that deranged autonomic vascular control of the renal circulation is crucial to the initiation of azotemia in cirrhosis? Renal tubular junction. Abnormalities of renal tubular function are accepted as contributing to the formation of ascites and also to other characteristics associated with azotemia in patients with cirrhosis, but are uncertainly related to the impairment of the renal circulation. Tubular reabsorption of sodium often exceeds 99.5% of the filtered load 11 · 40 and, although occurring proximally, is associated with increased production of aldosterone as well as with impaired metabolism of the compound by the diseased liver. 60 Overly tenacious retention of sodium, with relatively greater amounts of potassium in the urine, persists despite progressive reduction in GFR.U Osmolar clearance is low 11 • 40 and tubular reabsorption of urea may be increased in oliguric patients.U Martini 7 has expressed the view that excessive tubular reabsorption of sodium and water by the kidneys is "basic" to the development of azotemia, but it is also relevant that diuretic therapy or adrenalectomy influences water and electrolyte excretion without consistently affecting other aspects of renal function. Excessive reabsorption of sodium occurs particularly in the proximal tubule in patients with cirrhosis and has not been directly related to alterations in GFR and ERPF.l 1 • 4 ° Current concepts implicate diminished renal perfusion as a stimulus to secondary hyperaldosteronism, 61 and the juxtaglomerular indices, as well as the width of the zona glomerulosa of the adrenal cortices, may be increased in patients with cirrhosis and ascites. 62 By perfusing isolated rat kidneys, Tobian and his colleagues63 have correlated transport of sodium in the distal convoluted tubule and collecting ducts with perfusion pressures. The curious natriuresis and lack of pressor response which follow administration of

99

angiotensin to patients with cirrhosis and ascites coincide with renal vasoconstriction, a fall in ERPF, but no change in GFR ;64 · 65 whatever clue to the pathogenesis of renal circulatory failure these phenomena may sequester is not immediately apparent. The defective renal tubular excretion of water in patients with cirrhosis, characterized by reductions in maximal urine flow and free water clearance, bears a highly significant relationship to the reduction in GFR 11 · 40 and decreased osmolar clearance,40 but not to the rate of sodium excretion.11· 40 Additional factors believed to influence water transport by the kidney in cirrhosis include an increased medullary blood flow, defective delivery of sodium to the ascending loop of Henle and distal tubule, and increased vasopressin activity. 8 • 11 • 40 · 66, 67 It has been proposed that urinary flow rates depend on solute excretion and that the GFR limits urine flow by determining the quantity of solute available. 40 The discrepancies between sodium excretion and either water excretion or GFR may therefore in part be explained by variations in dietary sodium intake and also by the greater proximal tubular reabsorption of sodium in cirrhosis. 40 Patients with cirrhosis also cannot excrete a highly concentrated urine, an abnormality not evidently attributable to changes in GFR, sodium excretion, or free water clearance. 52 The overhydration and hyponatremia characteristic of azotemia in cirrhosis are consistent with excess vasopressin activity, since the site of action of vasopressin on the renal tubule accords with the pattern of water excretion in cirrhosis. 8 • 67 Valid definition of the participation of vasopressin in these changes has hitherto been hindered by lack of reliable assay techniques, but enlightenment can be anticipated if newer methods68· 69 prove generally applicable to human plasma. Water and Electrolyte Metabo1ism

The predisposition to azotemia of patients with ascites is not readily explained by incidental factors such as diet, diuretic therapy, and paracentesis, or by the common association of both fluid retention and renal failure with severe impairment of

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PROGRESS IN GASTROENTEROLOGY NoE

TB'1

1 BW

BW

(% )

KE

i3w

(mEq ./kg.) (mEq./kg )

Nos

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(mEq!L.)

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•g 20~----~----~------L-~--------~--~------~

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----- Mean no rma l value

FIG. 2. Values for total body water (TBW), exchangeable sodium (NaE), and exchangeable potassium (KE) in relation to body weight (BW) and serum concentration of sodium (Nas) and potassium (Ks). (Reproduced with permission from Summerskill, W . H. J., W. P. Baldus, and R.N. Feichter. 1962. Renal function in cirrhosis with ascites : Clinical, biochemical and physiologic changes, p . 90-98. In G. A. Martini, and S. Sherlock. Aktuelle Probleme der H epatologie: Ultrastruktur Steroidstoffwechsel Durchblutung Leber und Niere. Georg Thieme Verlag, Stuttgart.)

hepatic function. Only scant and tentative direct control of water and electrolyte metabolism or renal function has been assigned to the liver ;70 -72 and no convincing relationship can be extrapolated from the derangements of hydrostatic and osmotic equilibrium proposed by Starling as causal in ascites formation . Impaired inactivation and increased secretion of adrenal hormones influence renal tubular function in hepatic disease, 60 but the possible additional participation of abnormal transport mechanisms in the gut mucosa 73 · 74 or peritoneum has received relatively scant attention. The concept that osmoreceptors, sensitive to reductions in the theoretical effective extracellular fluid volume due to loss of water and electrolytes into the peritoneum, initiate the reduction in renal blood flow is attractive; but currently it is susceptible neither to proof nor to refutation. Hy-

ponatremia and hypoalbuminemia undoubtedly may affect circulatory and tubular function of the normal kidney, 4 5 - 49 but raising serum osmolality or plasma colloid osmotic pressure has produced neither impressive nor sustained effect on renal hemodynamics, nor sodium and water reabsorption in patients with cirrhosis.5o, 75 • 76 The gross abnormalities of water and electrolyte metabolism in cirrhosis and ascites (fig. 2) are inseparable from other aspects of azotemia/· 9 • 10 · 76 and awareness of their characteristics is essential to considerations of etiology and management. Total body water (TBW) and total body exchangeable sodium (NaE) are increased20· 28 · 77 and hyponatremia is the rule in azotemic patients, with serum sodium concentrations (Nas) usually falling below 130 mEq per liter.7· 10, 12 , 20, 28, 77 Hyponatremia is of the dilutional variety and

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PROGRESS IN GASTROENTEROLOGY

has therefore been termed "paradoxical"; overhydration may be aggravated by thirst, and the osmolality of plasma sometimes is less than that of the urine. 11 Overhydration and hyponatremia cause inconstant and nonspecific complaints. 67 In animals, hyponatremia may augment t issue catabolism,78 thereby increasing blood urea concentrations, and a discrepancy between concentrations of blood urea and plasma creatinine has been commented upon in cirrhosis ;10 this could also reflect excessive tubular reabsorption of urea 11 independently of an alteration in GFR, and such a mechanism .ha~ been promoted by vasopressin in experimental preparations.' 9 Total body exchangeable potassium (Kd is difficult to refer to conventional parameters in the presence of ascites, 80 but values appear low 80 -82 and the deficit often approximates 500 mEq. 80 Dietary inadequacies, diuretic therapy, or secondary hyperaldosteronism may lead to potassium depletion, but a correlation with the degree of impairment of hepatic function has also been claimed 80 and repletion of body stores by supplemental potassium may not be achieved in such patients. 80 · 81 Potassium deficiency must be evaluated as a causal factor for several abnormalities presented by azotemic patients, including extracellular · alkalosis, 82 hyperammonemia,83 hepatic coma,84 and renal tubular dysfunction, but its contribution to symptomatology and the frequency of therapeutic response to potassium therapy in hepatic failure may have been overstated.77· 82 As with Na 8 , serum concentrations of potassium (Ks) are unreliable as indicators of body stores in cirrhosis. 8° Ks values are usually low and are abnormal in approximately half the patients ;80 · 82 hyperkalemia may develop in azotemia and lead to cardiac conduction defects or even death.9· 1o. 19 · 20 · 77 Hypochloremia is usual in azotemia/ 0 but chloride deficiency has seldom been demonstrated convincingly; the likelihood must be considered in those receiving diuretics, especially ethacrynic acid, 85 and when extracellular alkalosis is present. 86 A respiratory alkalosis of uncertain cause is frequent, but variable disorders of acid-base equilibrium occur in

101

hepatic failure and none is characteristic of azotemia. 10 · 82 · 87 Despite greater hyponatremia and hyperkalemia, N aE is usually increased and KE is often decreased in azotemic patients. Values for NaE and KE do not necessarily differ from those associated with ascites in patients without azotemia, but relatively less water and more sodium may be excreted during diuretic therapy when renal circulatory function is impaired. 9· 20 · 28, 77 There is also some indication that changes in Ks and N as during azotemia partially reflect transpositions of sodium and potassium between the intracellular and extracellular fluid compartments. 28 The abnormalities of fluid and electrolyte metabolism and their relationships to hepatic and renal function may be delineated by more intricate experimental models, 88 -91 since alterations in water and solute control reflect changes in membrane transport which may be common to all cells. 92 Prognosis and Treatment

The spontaneous development of azotemia during hepatic failure has been described variously as "an almost certain portent of death," 59 "lethal," 12 and "terminal." 21 Improvement has occasioned case reports,93 - 95 since the syndrome has been irreversible without exception in some series. 12· 33 However, azotemia has not been uniformly fatal in the experiences of others, 9 • 10· 77 and the outlook is considered rather less bleak if a well defined precipitating factor can be identified and treated. Shaldon and W alker 13 suggested that tubular necrosis carries a better prognosis than spontaneous azotemia and salvaged 4 of 11 patients with evidence of the former lesion as a complication of assorted hepatobiliary disorders. The duration of azotemia prior to death or recovery varies from a few days to more than 6 weeks. 10 • 40 Death is attributable primarily to hepatic failure, and prognosis is related most clearly to the degree of reversibility of the hepatic disease and the prospect of comparable improvement in renal function ;10 · 11 blood pressure, urine output, duration of azotemia, or height of blood urea concentrations apparently discriminates less ef-

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fectively between survivors and the remainder.10 The development of dilutional hyponatremia is "ominous" in patients with ascites, 67 and the prospect is particularly poor when values drop below 125 mEq per liter. 7 • 1o, 77 Although 9 of 15 patients with hyponatremia of t his degree recovered in one series, mortality was greatly increased in the presence of azotemia. 18 Under such circumstances, the serum sodium concentration is one of the less unreliable tests of "liver function" when used as an index of the severity and prognosis of t he hepatic disease. Since hyponatremia is due to overhydration and since the latter is related to impairment of GFR, it is not surprising that the defective excretion of a water lo ad also implies a poor prognosis. The grave outlook may reflect also the inadequacy of current treatment. Standard conservative measures 10 · 12 · 77 are designed to permit maximal time for the recovery of hepatic function upon which the outcome appears to depend. As a precaution, paracentesis or other procedures likely to precipitate the syndrome are avoided in vulnerable patients, and complications such as gastrointestinal hemorrhage, which may also lead to azotemia, are treated vigorously. Other developments incident to hepatic failure, including hepatic coma, call for prompt management by standard procedures; recently, new approaches to the control of hyperammonemia by reducing urease activity with diets, 96 using enzyme inhibitors, 97 or inducing immunity to urease 98 have been proposed. The effect of diuretics on renal function is uncertain and variable, but as they may provoke decreases in GFR and plasma volume, albeit usually reversible, 23 such therapy is prudently withheld from azotemic individuals. Continued restriction of dietary sodium is usually advisable for patients with ascites. Restriction of fluid intake is mandatory for over hydration and oliguria; and it should be considered for any patient whose serum sodium concentration falls below 130 mEq per liter, or when the urine output is less than 500 ml in 24 hr, regardless of blood urea concentration. Administration of saline to patients with ascites is hazardous; favorable results are few 93 and such

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treatment is permissible only if a well defined sodium deficit can be demonstrated 12 and when accompanied by restriction of fluid intake. Supplements of potassium are appropriate if there is evidence of deficiency, but should be given cautiously lest hyperkalem.lli develop. 10· 28 This complication may require the administration of ion exchange resins, glucose, and insulin. Attempts to increase plasma colloid osmotic pressure and serum osmolality by infusions of albumin, albumin-saline, or ascitic fluid have variable effects on urine volume, GFR, and sodium excretion, 23 · 50 · 75 • 76 • 94 but the duration and magnitude of these changes are seldom of practical significance in patients with the greatest impairment of renal function. 5 ° Further data based on larger series of patients, and the effects of greater amounts of albumin given over longer periods, are desirable,1 2 together with more comprehensive studies of the effects on renal function and their relationships to alterations in plasma volume and colloid osmotic pressure. The results of standard procedures should not deter an empirical attitude toward therapy. Norepinephrine, aminophylline, mannitol, metaraminol, and prednisone influence various aspects of renal circulatory or tubular function in health and in some disease states, but their effects have appeared inconsistent in cirrhosis and discouraging in patients with impaired renal function ;10· 12· 20 · 23 · 43 · 59 · 99 trials of other and newer compounds are justifiable. Hemodialysis, when not precluded by blood coagulation problems, or peritoneal dialysis should control several of the metabolic disorders, including those pertaining to water, electrolytes, ammonia, and urea. Although information is limited and disappointing,l2· 13· 100 greater experience should be gained in selected cases. The more experimental approaches, including use of the porcine liver 101 · 102 and cross-circulation procedures 103 in hepatic and renal failure, should be limited to specialized centers, but represent important potential sources of original contributions which may be translated in the future to the better management of the azotemia in hepatic failure.

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Concluding Comment

An association between impairment of hepatic function and renal circulatory failure is established but remains undefined: Is it mediated by osmotic, neurogenic, or toxic factors? The reduction in renal perfusion ultimately leads to azotemia, but may earlier affect tubular function and thereby increase or initiate retention of water and sodium by the kidneys. What causes abnormal proximal tubular function and how is the latter related to changes in renal blood flow, which may involve either the prerenal 01; intrarenal circulation? With progressive deterioration of hepatic function, azotemia develops spontaneously; alternatively, the precarious state of renal circulatory function predisposes patients to renal failure as an acute complication of several circumstances incident to the course or management of progressive hepatic disease and ascites. To what extent do the features of these . conditions differ from, rather than resemble, each other? From this narrative survey of recent information and veiwpoints pertaining to the kidney in hepatic failure, it is concluded that conjectures directed toward further investigations are currently more appropriate than deductions regarding etiology and treatment. REFERENCES 1. Talso, P. J., N. Spafford, G. Ferenzi, and H. 0. Jackson. 1956. Paradoxical hypo-

natremia associated with congestive heart failure and with cirrhosis of the liver. Metabolism 5: 58-69. 2. Hecker, R., and S. Sherlock. 1956. Electrolyte and circulatory changes in terminal liver failure. Lancet 2: 1121-1125. 3. Birkenfeld, L. W., J. Leibman, M. P. O'Meara, and I. S. Edelman. 1958. Total exchangeable sodium, total exchangeable potassium and total body water in edematous patients with cirrhosis of the liver and congestive heart failure. J. Clin. Invest. 37: 687-698.

4. Edelman, I. S., J. Leibman, M. P. O'Meara, and L. W. Birkenfeld. 1958. Interrelations between serum sodium concentration, serum osmolarity and total exchangeable sodium, total exchangeable potassium and total body water. J . Clin. Invest. 37: 12361254.

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5. Papper, S. 1958. The role of the kidney in

Laennec 's cirrhosis of the liver. Medicine 37 : 299-316.

6. Papper, S., J. L. Belsky, and K. H. Bleifer. 1959. Renal failure in Laennec's cirrhosis of the liver. I. Description of clinical and laboratory features. Ann. Intern. Med. 51 : 759-773. 7. Martini, G. A. 1962. Gibt es ein hepato-

renales Syndrom? Deutsch. Med. Wschr. 87: 2408-2419.

8. Eisner, G. M., and M. F. Levitt. 1961. The cirrhotic nephropathy, p. 119-133. In H.

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43. Lancestremere, R. G., E. L. Klingler, Jr., E. Frisch, and S. Papper. 1963. Simultane-

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