According to current concepts, renal ammonia synthesis may be attributed to the renal extraction and catabolism of certain plasma amino acids. In 1943, Van Slyke and associates demonstrated in the dog that the amide nitrogen of glutamine was removed from arterial plasma in quantities sufficient to account for approximately 60 per cent of the urinary ammonia excreted during metabolic acidosis (1). It was proposed that the remaining 40 per cent of urinary ammonia could be accounted for by the renal uptake of plasma a-amino nitrogen. In agreement with this hypothesis, many investigators have since shown that the administration of several amino acids other than glutamine is associated with an increased urinary ammonia excretion (2-4). Loading experiments of this type have indicated thatbesides glutamine-glycine, alanine, asparagine, leucine. and histidine may serve as precursors of urine ammonia. The demonstration of appropriate enzyme systems within renal tissue capable of forming ammonia from these substrates has been offered as additional support for the thesis that several plasma amino acids may participate normally in the renal production of ammonia. Nevertheless, the specific amino acids that serve as renal ammonia precursors have not been identified clearly in conditions associated with normal acid-base balance and normal plasma amino acid concentrations. The present study was undertaken for two principal reasons: first, to characterize the' typical patterns of uptake or release * Investigation supported in part by U. S. Public Health Service research grants A-5930 and A-6306 from the National Institutes of Health, Bethesda, Md., and by the Veterans Administration Clinical Investigator Program; presented in part at the annual meeting of the Southern Section, Amer. Fed. Clin. Research, New Orleans, La., January 18, 1962. of individual amino acids by the normal human kidney, and second, to determine whether or not the adaptive increase of renal ammonia production during metabolic acidosis could be attributed to chances in the renal extraction of certain plasma amino acids. METHODSTwelve renal clearance experiments were carried out on eleven healthy male volunteers between 21 and 38 years old. All studies were conducted with them in the recumbent position after an overnight fast. To facilitate the collection of timed urine specimens, urine flows of approximately 5 ml per minute were assured by the oral ingestion of 500 ml of tap water 1 hour before the test, followed immediately by a constant intravenous infusion of 5 per cent dextrose in water. After appropriate priming doses, an-intravenous maintainance infusion of a solution of inulin and para-aminohippurate (PAH) was begun 45 minutes before the first clearance period via a Bowman constant-infusion pump. During the equilibration period, a no. 7 or 8 cardiac catheter was introduced into a renal vein through either the right brachial or femoral vein under fluoroscopic control. An indwelling Cournand arterial needle was placed in the left brachial artery. Thr...

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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. METHODSNine patients without hepatic or renal disease were studied. All were hospitalized ambulatory males ranging in age from 28 to 49 years. Subj ects were studied in the recumbent position after an overnight fast. In order to initiate a water diuresis, 1,000 to 1,500 ml of water was ingested 30 minutes to 1 hour before each procedure. A constant intravenous infusion (Bowman pump) which delivered 14 to 18 mg of para-aminohippurate (PAH) per minute was maintained throughout the study period and was preceded by a priming dose calculated to provide plasma levels of approximately 2 mg per 100 ml. The water diuresis was maintained throughout the procedure by the intravenous infusion of 5 per cent dextrose and water at a rate of 15 to 20 ml per minute. Arterial samples were obtained from a brachial artery and renal venous samples from the * This investigation was supported (in part) by a research grant (Public Health Service A-3255) from the National Institutes of Health, Bethesda, Md. tThis paper was presented (in part) at the Southern Society for Clinical Research, New Orleans, La., January 23, 1960. right renal vein by way of a no. 8 catheter. Control voided urine specimens were collected during and after equilibration of the PAH infusion. Baseline arterial and renal venous samples were begun 45 to 60 minutes after the PAH infusion was started. Each patient received an intravenous infusion of 0.155 M ammonium lactate at a rate of 0.50 mEq of ammonia per minute for 30 minutes and 0.75 mEq of ammonia per minute for the subsequent 15 minutes. Serial arterial-renal venous ammonia differences were obtained at 15-minute intervals during the infusion and at the 15 minute post-infusion period. Voided urine samples collected in an oil-toluene mixture were obtained at 15-to 30-minute intervals during the infusion and in 4 subjects for 30 to 60 minutes after the infusion was terminated.Blood and urine ammonia was measured by a modification (6) of the microdiffusion method of Brown, Duda, Korkes and Handler (7). PAH concentration in blood and infusion media was determined by the method...

The intrarenal distribution of ammonia was evaluated in the dog during antidiuresis and osmotic (mannitol) diuresis at various levels of urine pH. During antidiuresis, the concentration of ammonia in renal tissue water rose progressively from the cortex to the tip of the papilla. In contrast, the corticomedullary ammonia gradient was completely obliterated by osmotic diuresis. In both experimental groups, a close relationship was observed between urine pH and the logarithm of the ratio between the urine and papillary concentrations of ammonia. The data are compatible with a proposal that a medullary countercurrent exchange system is responsible for medullary ammonia accumulation, and that diffusion equilibrium exists between the pNH3 of loop of Henle fluid, vasa recta blood, and collecting duct fluid.