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Fifty-seven cirrhotic patients with intractable ascites had a portosystemic shunt. In 35 patients, a peritoneovenous shunt had previously failed. Forty-six patients were in Pugh's class B and 11 were in class C. There were three operative deaths (5.3%). Fifty-three (98.2%) of the 54 survivors were cleared of ascites. In one patient, ascites persisted because of postshunt heart failure that resulted in a marked increase of caval pressure. Twenty-seven patients (50%) had late encephalopathy, which was severe and disabling in 12 (22%). One-and three-year survival rates were 72% and 36%, respectively. These results suggest that although portosystemic shunts are remarkably effective in dealing with ascites, the high rate of postoperative encephalopathy is a strong argument against their routine use in the management of intractable ascites in cirrhosis.

Renal nerves were stimulated either directly (loop electrodes) or indirectly (bilateral carotid occlusion with maintenance of control blood pressure) in anesthetized dogs to determine the effects on r

Effect of dialysate volume on peritoneal dialysis kinetics. The effect of peritoneal dialysate volume on the rates of transperitoneal urea and creatinine equilibration was determined over a 120-min sampling period. Equilibration half-time (t 1/2 ) was prolonged when volume was increased from 1 to 2 to 3 liters. Some data suggest this delay was not attributable to a decrease in peritoneal permeability or blood flow. If that is true, our data indicate that slower urea equilibration with larger dialysate volumes is due to changes in volume/surface area relationships. Because solutes equilibrated more rapidly into 1 liter than into 2 liters, peritoneal clearances using an exchange schedule of 1 liter every 30 min were comparable to those obtained with 2 liters exchanged every 60 min. Therefore, patients susceptible to cardiopulmonary complications may be dialyzed without loss of efficiency by infusing 1 liter every 30 min instead of the usual 2 liters every 60 min. Effet du volume de dialyse sur la cinetique de la dialyse peritoneale. L'effet du volume du dialysat peritoneal sur les vitesses d'equilibration transperitoneale de l'uree et de la creatinine a ete etudie pendant une periode de prelevements de 120 min. Le temps de demi-equilibration (t 1/2 ) est allonge quand le volume est augmente de 1 a 2 et de 2 a 3 litres. Certains faits suggerent que ce retard n'est pas attribuable a une diminution de la permeabilite ou du debit sanguin peritoneaux. Dans ce cas nos resultats indiqueraient que l'equilibration plus lente de l'uree, quand le volume de dialysat est plus grand, serait liee aux modifications du rapport volume/surface. Du fait que les substances dissoutes s'equilibrent plus rapidement dans 1 l que dans 2 l les clearances peritoneales sont comparables dans un programme d'echange d'un litre toutes les 30 minutes a celles obtennes dans un programme d'exchange de 2 litres toutes les 60 minutes. Par consequent il est possible de dialyser les malades exposes a des complications cardiopulmonaires sans perte d'efficacite, en injectant 1 litre toutes les 30 minutes au lieu des 2 litres habituels toutes les 60 minutes.

Two patients are presented who were uremic requiring dialysis despite steady state serum creatinine levels (Cr) of 4.0 and 4.4 mg percent. Their blood urea nitrogen/creatinine (BUN/Cr) ratios of 54 and 44 were shown to be due to excessive creatinine secretion and urea reabsorption. Evaluation of serum creatinine alone may occasionally give misleading information regarding the level of renal function. If clinical evidence of uremia is present while serum creatinine value is relatively low, measurement of glomerular filtration rate (GFR) by Na-iothalamate 125I (OIT) or inulin is essential.

Acute uremia induced both soluble and mitochondrial tyrosine aminotransferase activity, EC 2.6.1.5, in rat liver. Such induction was demonstrated to be independent of glucocorticoid action. Mitochondrial aspartate aminotransferase, EC 2.6.1.1, although identical with mitochondrial tyrosine aminotransferase, was not elevated during acute uremia. Purified antibody specific against cytosol tyrosine aminotransferase cross-reacted significantly with the mitochondrial enzyme from uremic rats, suggesting that the elevation of activity was due to translocation of the induced cytosol enzyme form to the mitochondria. Considerable translocation was also caused by a combination of fasting together with some factor known to increase urea synthesis in the liver, such as high nitrogen loads or intraperitoneal injection of hydrocortisone. Intravenous injection of rats with Triton WR-1339 resulted in the separation of lysosomes from mitochondria during sucrose density gradient centrifugation. All of the tyrosine aminotransferase activity was associated with the mitochondria and not with the lysosomes. Treatment of intact mitochondria with the antisoluble tyrosine aminotransferase antibody resulted in inhibition of about 50% of the total inhibitable mitochondrial activity, suggesting that some of the translocated cytosol enzyme may not be exposed and thus may be unavailable for antibody cross-reaction. In vitro crossover experiments using induced cytosol tyrosine aminotransferase with normal mitochondria resulted in an elevation of the mitochondrial activity, whereas incubation of noninduced cytosol enzyme with mitochondria from induced rats did not. Consequently, the translocation phenomenon is a function of altered cytosol tyrosine aminotransferase rather than altered mitochondria.

Sodium metabolism, aldosterone excretion, and response to salt and salt-retaining steroid hormones were studied in six patients with orthostatic hypotension. One patient demonstrated definite, and three others minimal, renal salt wasting; two conserved sodium normally. Aldosterone excretion was normal in two patients and reduced in one. Treatment response did not correlate with renal salt wasting or aldosterone excretion. Improvement with treatment correlated with positive sodium balance and weight gain. Dietary sodium restriction blocked the steroid effect, indicating salt and steroids acted mainly through sodium and water retention. Other data in two subjects suggested the salt-retaining hormones may have had an additional effect. Blood pressure diminished in each patient during dietary sodium deprivation and increased with salt administration. Fludrocortisone (Florinef) acetate, given with salt, consistently increased blood pressure further. Thus, full benefit from steroid therapy in these patients required attention to dietary sodium intake.

These in vivo studies demonstrate that the removal of glutethimide during dialysis is significantly increased when lipid is substituted for the usual aqueous dialysis solution. The very low water solubility of many lipid soluble compounds probably limits their removal by routine dialysis methods. Their high lipid solubility not only permits relatively small volumes of lipid dialysate to contain large amounts of these drugs, but also prevents back diffusion after they have crossed a semipermeable membrane from an aqueous into a lipid phase. This maintains a maximum effective diffusion gradient, resulting in an increased rate of net transfer across the membrane. Concentration ratios during peritoneal dialysis with lipid increased more rapidly than during hemodialysis. This suggests that glutethimide diffuses through the lipid-containing cells of the peritoneum more readily than it does through the cellulose dialyzer membrane. Peritoneal dialysis with lipid emulsion regularly produced visible lipemia which was associated with a slight increase in blood glutethimide concentration. This suggests that glutethimide was extracted from tissue depots into the lipemic plasma. The long-term effects of intraperitoneal lipid emulsion infusion have not been adequately studied, and clinical use of peritoneal dialysis with lipid must await further animal tolerance studies. (Author)

PATIENTS undergoing peritoneal dialysis frequently require antibiotic therapy for intraperitoneal and systemic infections. Since information concerning transperitoneal movement of antibiotics is limited, drug dosage and route of administration in such patients are usually chosen empirically. Insufficient data are available to determine if antibiotic dosage should be supplemented by intraperitoneal therapy or increased because of removal of antibiotic in dialysate. The present study was undertaken to measure intraperitoneal concentrations of methicillin and tetracycline after systemic administration and conversely to determine serum concentrations of methicillin after intraperitoneal administration. Materials and Methods Patients with chronic renal disease and azotemia requiring peritoneal dialysis were . . .

A study was undertaken to determine the clinical course, complications and pathogenesis of renal failure in patients with cirrhosis of the liver. Azotemia was present in a high percentage of the patients who died of cirrhosis, particularly in those with hepatic coma. In patients who had cirrhosis without azotemia, impaired ability to excrete water strongly indicated that the development of renal failure was imminent and that the prognosis was grave. In some cases, elevations of blood creatinine and/or uric acid levels were apparent before elevations of blood urea nitrogen concentrations, and provided early indications that renal insufficiency existed. Serum sodium concentration was less than 125 mEq. per L. in 19 per cent of the patients who died of cirrhosis. Hyponatremia usually was due to overhydration. Despite oliguria and azotemia, serum potassium concentrations usually were normal or low rather than high. Renal function studies and fluid balances were followed serially in fifteen patients who eventually died of renal failure. Eight demonstrated clinical evidence of acute tubular necrosis and two had "prerenal" azotemia. In the remaining five patients azotemia developed following acute and apparently spontaneous reductions in glomerular filtration rate. Initially tubular functions were intact, but prior to death these also deteriorated. Decreases in the glomerular filtration rate often followed episodes of "spontaneous" hepatic precoma or coma. Hepatic coma or an associated metabolic abnormality may cause alterations in renal function, or aggravate pre-existing abnormalities in renal function associated with severe liver disease. In some patients with cirrhosis, impaired renal function is characterized by limited ability to excrete water, reductions in renal plasma flow and glomerular filtration rate, and intact tubular function. Although their exact cause and relation to hepatic disease are not established, these abnormalities are often demonstrable before renal insufficiency is overt. They may make patients with cirrhosis more susceptible to the development of progressive renal failure when intercurrent incidents known to affect renal function adversely are superimposed. In other cases the abnormalities may progress and cause renal failure that uniformly follows a clinical course ending with death.

Renal functional abnormalities associated with advanced liver disease were evaluated in twenty-two patients by determining the effects of angiotensin infusions and of increasing tubular loads of para-aminohippurate (PAH) upon the extraction of PAH. Angiotensin infused intravenously produced variable changes in renal blood flow, glomerular filtration rate and urinary excretion of sodium and water, but did not alter extraction of PAH. This agent did not change the distribution of blood flow within the kidney as estimated from PAH extraction. To the extent that in some patients renal ischemia and hypoxia may have been induced, these changes also had no effect upon the extraction ratio of PAH (E PAH ). The E PAH was below normal during control periods in eight of the twenty-two patients. Reduced E PAH was associated with, but was not a consequence of, decreased renal plasma flow and glomerular filtration rate and a poor urine flow response to water administration. Chronic renal disease, tubular necrosis, renal hypoxia, excessive tubular load of PAH or low urine flow rate could not be incriminated as causes of the decreased E PAH . The decreased E PAH and associated renal functional changes noted in some patients with cirrhosis are explained best by a hemodynamic alteration involving renal cortical vasoconstriction with relative increase in medullary blood flow. Ten patients were given a PAH load. Five responded normally. In the other five changes in E PAH were consistent with the presence of a defect in ability to transport PAH.

SummaryIncorporation of L-(U-14C)-leu-cine into protein was examined in vitro using cell-free preparations of liver from fasting acutely uremic, fasting normal, and non-fasting normal rats. The amount of incorporation was similar in the fasting and non-fasting normals. Incorporation by the acutely uremic liver preparations was significantly greater than by either control group. The measured hepatic leucine levels indicated that these findings cannot be ascribed to less dilution of label by endogenous free leucine. These results indicate that hepatic protein synthesis in rats is altered in uremia.

Stop-flow studies using infusions of aldosterone-3H or its 3H acid-labile conjugate were done on five rhesus monkeys. The aldosterone-3H urine-to-plasma (U/P) ratio decreased in the same distal urine samples as sodium. The 3H acid-labile conjugate U/P-to-inulin U/P ratio increased in the more proximal samples either with conjugate formed endogenously during aldosterone-3H infusions or with labeled conjugate infused alone. Aldosterone reabsorption occurred at a distal site in the renal tubule, and secretion of its acid-labile conjugate occurred at a proximal site.

A B S T R A C T Tissue composition and in vivo tissue protein synthesis were altered by acute uremia, induced in rats by bilateral nephrectomy. Net protein synthesis (anabolism minus catabolism) was increased in liver and heart and decreased in skeletal muscle, as judged from changes in total organ weight, ratios of protein: DNA and RNA: DNA, and leucine-"C incorporation into trichloroacetic acid (TCA) -insoluble, nucleic acid-free material. Concentration of free lysine, a major constituent of histones and ribonucleoproteins, also was increased in liver and decreased in skeletal muscle, a finding suggesting lysine shifted from muscle to liver in association with the changes in protein synthesis. Acute uremia also altered tissue levels of other amino acids. Hepatic concentrations and liver: blood concentration ratios tended to be increased for the essential, but not for the nonessential amino acids. Moreover, the phenylalanine: tyrosine concentration ratio, which reflects activity of the enzyme phenylalanine hydroxylase, was increased in blood, muscle, and liver. These findings indicate uremia selectively alters tissue composition and protein synthesis in different organs and may modify intermediary metabolism of some individual amino acids.

Compartmentalization of ascites and nonascitic fluid was demonstrated in cirrhotic patients treated with dietary sodium restriction, diuretic therapy or paracentesis. Disparity between ascitic and nonascitic fluid absorption rates, evident during spontaneous diuresis, was exaggerated by diuretic administration. Despite rapid diuresis maximum ascites absorption rate was 930 ml per 24 hours — close to the rate of intraperitoneal saline absorption by noncirrhotic human subjects. After paracentesis ascitic fluid re-formed at as much as three and a half times the maximum absorption rate. It began to form during the paracentesis procedure and continued at a gradually decreasing rate for three to four days. The ascites formed largely by a shift of nonascitic fluid to the peritoneal cavity. However, some patients also formed ascites from retained exogenous fluid; they gained weight, and mild dilutional hyponatremia developed. Compartmentalization of ascites and edema probably causes some complications th...

Of 15 patients with hepatic cirrhosis in whom renal acid excretion and potassium conservation were studied, urinary pH fell normally after acid loading in four, and the response was borderline in two and clearly abnormal in nine. Blood pH before acid loading and total hydrogen ion excretion after acidification were normal in most patients. However, titratable acidity of urine was reduced, and ammonium excretion increased. Two patients had a more severe defect with low rates of total hydrogen ion excretion and "spontaneous" metabolic acidosis. Impaired renal potassium conservation accompanied the acidification abnormality in six patients. Hypercalciuria was present in two, and renal glycosuria in one. The coexistence of renal tubular acidosis and cirrhosis may explain why some cirrhotic patients readily become hypokalemic and remain so despite treatment with potassium salts. Renal tubular acidosis, through its effects on ammonium metabolism, may also make some patients susceptible to recurrent epi...

Stop-flow studies were done in 2 dogs during the infusion of cortisol-3H. The cortisol-3H U/P to creatinine U/P ratio decreases maximally at the site where minimal sodium concentration is reached and indicates reabsorption of cortisol in the distal tubule. Lesser decreases in the ratio were observed in more proximal segments of the tubule and reabsorption may occur there also. Cortisol reabsorption occurs over a segment of the renal tubule similar to its site of action. (Endocrinology 84: 681,1969)

PATIENTS with idiopathic orthostatic hypotension demonstrate various hemodynamic abnormalities in response to standing. Reflex peripheral vasoconstriction fails to occur normally,1 venous return to the heart and cardiac output are low,1 2 3 and the flow of blood to brain, liver and kidneys is decreased.4 The decrease in renal blood flow results in a diminished glomerular filtration rate5 , 6 and occasionally in urea retention.4 This decrease in glomerular filtration rate may account for the diminished urinary sodium excretions noted in these patients when they stand5 , 7; however, the possibility that changes in sodium excretion are due to alterations in the tubular reabsorption of sodium . . .

Cirrhotic ascites results when local transperitoneal Starling forces, chiefly hydrostatic and protein oncotic pressures, are disturbed. In addition, fluid retention occurs invariably; total body sodium and water content is increased. Treatment is directed at removing abnormal fluid accumulation by dietary and pharmacologic means. The specific approach should be individualized; care must be taken to prevent diuretic-induced complications such as electrolyte imbalance and hypovolemia.

THE peritoneal membrane is used extensively as a dialyzing surface for the treatment of uremia, hyperkalemia, overhydration and poisoning with a variety of drugs.1 , 2 It has also been utilized therapeutically by pediatricians for administration of blood,3 , 4 fluid and electrolytes,4 5 6 particularly in areas of the world where nursing personnel are not available to monitor intravenous infusions. Rate of movement of water and solutes from blood to peritoneal fluid has been studied in detail.1 By contrast, little is known about kinetics of fluid absorption. In the present study absorption of isotonic saline solution from the peritoneal cavity was studied in adult human . . .

Metolazone, a new diuretic agent, was administered to patients with ascites and edema. After injection of a single dose, natriuresis, diuresis, and kaliuresis began promptly and persisted for two to three days. This uniquely prolonged duration of action is attributable to avid protein-binding and enterohepatic recycling of the drug, which result in slow disappearance from the body. In three of four responsive patients potassium excretions increased only slightly, despite moderately large increases in sodium excretion. Three other patients who were resistant to metolazone demonstrated kaliuresis even though the daily rate of sodium excretion increased by only a few milliequivalents. Metolazone appears to be a clinically useful diuretic agent which continues to act for an unusually long time after administration of a single dose. During metolazone therapy, natriuresis and kaliuresis may occur independently of each other.

Excerpt Rates of ascitic fluid absorption and edema mobilization were measured in patients with hepatic cirrhosis who were undergoing spontaneous or drug-induced diuresis. Ascites absorption rate w...