Edward E. Owen

THE KIDNEY AS A SOURCE OF BLOOD AMMONIA IN PATIENTS WITH LIVER DISEASE: THE EFFECT OF ACETAZOLAMIDE *†

The role of the gastrointestinal tract as a major source of blood ammonia has been extensively studied in animals and in patients with liver disease. Less information is available concerning the relative contribution to the blood ammonia by other organs, such as muscle, liver, brain and kidney, which are known to be concerned with ammonia metabolism (1). The renal release of ammonia into the systemic circulation was first demonstrated by the observations of Nash and Benedict in 1921 (2). Although the magnitude of this ammonia release and its effect on the arterial ammonia concentration have not been determined, factors affecting the quantity of ammonia excreted into urine have engendered considerable investigation. Current evidence indicates that changes in urine pH are important determinants of urinary ammonia excretion, lesser amounts of ammonia appearing in alkaline than in acid urines (3-8). Studies in unilaterally nephrectomized dogs suggest that total renal ammonia production may remain unchanged following acute alterations in urine pH (9). Of particular interest in this regard have been the observations of significant increases in arterial ammonia concentrations of cirrhotic patients given Diamox (acetazolamide) (10-12), an agent which is known to increase urine pH. The present investigation is concerned with the release of ammonia into the renal vein of patients with liver disease, with particular emphasis on the effect of intravenous acetazolamide.

THE EFFECT OF INDUCED HYPERAMMONEMIA ON RENAL AMMONIA METABOLISM

Although the excretion of ammonia into urine has been extensively studied, there is little information in animals or man concerning the quantitative and regulatory aspects of the ammonia released into the renal veins. Previous observations in this laboratory and in others have demonstrated that the kidney consistently releases ammonia into the systemic circulation of normal subjects and patients with liver disease whose arterial ammonia concentrations are normal (1-5). Patients with liver disease and moderate to marked hyperammonemia, however, usually release minimal quantities of ammonia into their renal veins and occasionally exhibit renal uptake of ammonia from the circulation (2). In order to further define the possible role of the blood ammonia concentration on renal ammonia release, acute hyperammonemia has been induced in normal subjects and the subsequent changes in renal vein ammonia release and urine ammonia excretion determined.

Amino Acid Uptake and Fatty Acid Esterification by Intestinal Mucosa from Patients with Whipple's Disease and Nontropical Sprue

Summary 1)The uptake of C 14 -L-arginine, C 14 -Llysine, C 14 -DL-ornithine, and C 14 -L-phenylalanine by duodenal mucosa from 3 patients with Whipples disease, 2 patients with nontropical sprue, and 10 control patients with normal intestinal mucosal morphology has been determined. In most experiments the ability of similar mucosal tissue to incorporate C 14 -labeled palmitic acid into triglyceride was obtained concomitantly. 2)The uptake of C 14 -L-arginine, C 14 -lysine, and C 14 -DL-ornithine by duodenal mucosa from patients with Whipples disease and nontropical sprue was consistently lower than corresponding values obtained in control patients and healthy volunteers.1o The mucosal uptake of C 14 -L-phenylalanine was more variable, and a definite reduction in the uptake of this amino acid was apparent only in two patients with untreated Whipples disease, and one patient with severe nontropical sprue. With the exception of one determination in a patient with Whipples disease, the rate of incorporaton of C 14 -labeled palmitic acid into triglyceride was uniformly lower in Whipples disease and nontropical sprue than values obtained from similar measurements in control patients and healthy volunteers. 3)The similarity in amino acid uptake and lipid esterification values by duodenal mucosa from patients with Whipples disease and nontropical sprue has been discussed in light of the recognized lack of morphological alteration in the mucosal epithelial cell of patients with Whipples disease as contrasted with the consistent epithelial cell changes seen in nontropical sprue.

Intra-renal distribution of free amino acids in antidiuretic ruminants☆

Abstract 1. 1. The difference between “measured” and “calculated” values for tissue osmolality was determined in the several zones of kidneys from the antidiuretic sheep, goat and dog on differing dietary intakes of nitrogen. 2. 2. The intra-renal distribution and potential contribution of twenty-five free amino acids to tissue osmolality were established. 3. 3. “Measured” tissue osmolality was always higher than “calculated” osmolality, the difference being most pronounced in the inner medullary zone. 4. 4. Free amino acids accounted for the difference between “measured” and “calculated” osmotic concentration in cortex, but only for a small percentage of the “solute gap” in the inner medullary zone. In antidiuretic sheep and goats, solutes other than urea, electrolytes and free amino acids must contribute to medullary hypertonicity.

Kidney as a source of blood ammonia: effect of chlorothiazide.

Summary The effect of intravenous chlorothiazide on arterial ammonia concentration and release of ammonia into renal vein was studied in 7 patients with Laennecs cirrhosis. Rapid and significant increases in quantity of ammonia released into the renal vein were observed along with progressive rise in arterial ammonia concentration. The data demonstrate the kidneys importance in the pathogenesis of hyperammonemia which follows intravenous chlorothiazide.

THE EFFECT OF ACUTE ALKALOSIS ON RENAL METABOLISM OF AMMONIA IN CIRRHOTICS

The kidney consistently releases ammonia into the renal venous circulation of normal subjects and patients with compensated liver disease (1-4). Under conditions of normal acid-base balance, the quantity released usually approximates the amount of ammonia excreted into urine (3, 4). From determinations of arteriovenous ammonia differences across various organs, it has become apparent that the release of ammonia into the renal vein represents a major source of the normal ammonia concentration in blood (5). Of possible clinical importance in this regard is the observation that under certain conditions patients with liver disease may increase their renal contribution of ammonia to the systemic circulation. The increase of blood ammonia concentration seen after the intravenous administration of acetazolamide and chlorothiazide can be adequately explained by concomitant increases in release of ammonia into renal vein (3, 6). It has been suggested that the alterations in renal ammonia release seen during carbonic anhydrase inhibition may result from a shift in the normal partition of ammonia between urine and renal venous blood because of a disproportionate increase in pH of urine as compared with that of peritubular fluid (3). The present study deals with acute metabolic and respiratory alkalosis and was designed to obtain additional information on the role of the kidney in the regulation of the ammonia concentration in blood and to evaluate the effects of acute systemic alkalosis on total bidirectional renal release of ammonia.

Unusual liver pathology associated with xanthomatosis and jaundice. Report of a case.

SummaryA 56-year-old man developed insidious progressive jaundice with xanthomatosis. The laboratory findings indicated biliary obstruction but the biliary outflow tract was patent. Serial biopsies and postmortem examination of the liver revealed the centrilobular deposition of collagen-like material. The resemblance of the clinical picture to primary biliary cirrhosis and the possibile relationship of hepatic changes to cardiac failure are discussed, but the etiology of the findings in this case is unknown.