Metabolic acidosis, ammonia

Excretion into urine of ammonia produced by renal mbu-lar cells facilitates cation conservation and regulation of acid-base balance. Ammonia production from intracellular renal amino acids, especially glutamine, increases in metabolic acidosis and decreases in metabolic alkalosis. 

As kidney function declines, bicarbonate reabsorption is maintained, but hydrogen excretion is decreased because the ability of the kidney to generate ammonia is impaired. The positive hydrogen balance leads to metabolic acidosis, which is characterized by a serum bicarbonate level of 15 to 20 mEq/L (15 to 20 mmol/L). This picture is generally seen when the GFR declines below 20 to 30 mL/minute.38... 

Ammonia can diffuse freely into the urine through the tubule membrane, while the ammonium ions that are formed in the urine are charged and can no longer return to the cell. Acidic urine therefore promotes ammonia excretion, which is normally 30-50 mmol per day. In metabolic acidosis (e.g., during fasting or in diabetes mellitus), after a certain time increased induction of glutaminase occurs in the kidneys, resulting in increased NH3 excretion. This in turn promotes H"" release and thus counteracts the acidosis. By contrast, when the plasma pH value shifts towards alkaline values alkalosis), renal excretion of ammonia is reduced. 

As a pantothenic acid analogue, hopantenate can affect lactate generation, glucose metabolism, and ammonia disposal, and there have been two fatal cases in elderly people who developed disturbances of consciousness with lactic acidosis, hypoglycemia, and hyperammonemia (903). 

The pH-buffering of extracellular fluid depends in part on the carbon dioxide/ bicarbonate equilibrium so that the intake of sodium bicarbonate is followed by a brief alkalosis and an increased excretion of sodium carbonate in the urine. Depending on its carbonate concentration, the pH of the urine may rise to 8.07. Large doses (80—100 g/day) of sodium bicarbonate were needed if the pH of stomach contents was to be maintained at 4 or over in patients with duodenal ulcers8. Oxidation of organic anions in the body to carbon dioxide and water permits the use of sodium citrate, lactate or tartrate instead of sodium bicarbonate. In an analogous manner the ingestion of ammonium chloride induces a brief acidosis as a result of the metabolic conversion of ammonia to urea and lowers the pH of the urine. 

Dog No. 3 was omitted because of insufficient data. It is apparent that a marked uptake of ammonia occurs in tissues in metabolic acidosis. In alkalosis the uptake by tissues is only slightly greater than normal, and the arterial levels of ammonia are comparable with normal values. The elevation of blood ammonia which occurs on vigorous acidification of the animal might not be due to a drop in permeability with pH, but might be due to a phenomenon reported by Krebs and Henseleit (K4). Urea synthesis by liver slices is directly proportional to the pH and C02 content of the medium. Table 2, constructed from data reported in this paper, shows this dependence. 

Also, respiratory distress with lung disorders osteomalacia on anti-convulsants metabolic acidosis/ coma in renal deficiency/diabetic nephropathy ammonia poisoning with cirrhosis hypo-potassium enhanced trough levels of cyclosporine. 

The kidney plays a major role in the maintenance of acid-base homeostasis, particiilarly with respect to metabolic acidosis. In response to metabolic acidosis, the kidney is able to increase its production of ammonia resulting in enhanced urinary ammonium excretion, a process linked to proton excretion and the generation of... 

In contrast to the studies of glutamine transport, several studies have suggested a potential role for the malate/a-ketoglutarate transporter in chronic acidosis [135,297]. Although Cheema-Dhadli and Halperin [135] were unable to demonstrate activation of the dicarboxylate (malate/phosphate) transporter in kidney cortex mitochondria from rats with chronic metabolic acidosis, Brosnan et al. [297] demonstrated that the malate/a-ketoglutarate carrier was activated in chronic acidosis. Additional studies are required to characterize this effect fully and to determine its role in the overall process of augmented ammonia formation in metabolic acidosis. However, it is... 

Studies of the role of metabolic transporters in the control and modulation of metabolic fluxes have provided somewhat ambiguous results in the case of respiration and gluconeogenesis. The role of the glutamate transporter in the acute control of ammonia formation seems clear at this time, and a proposed role of the malate/a-ketoglutarate carrier in chronic acidosis is an intriguing possibility. 

Hypoventilation causes retention of C02 by the lungs, which can lead to a respiratory acidosis. Hyperventilation can cause a respiratory alkalosis. Metabolic acidosis can result from accumulation of metabolic acids (lactic acid or the ketone bodies p-hydroxybutyric acid and acetoacetic acid), or ingestion of acids or compounds that are metabolized to acids (methanol, ethylene glycol). Metabolic alkalosis is due to increased HC03, which is accompanied by an increased pH. Acid-base disturbances lead to compensatory responses that attempt to restore normal pH. For example, a metabolic acidosis causes hyperventilation and the release of C02, which tends to lower the pH. During metabolic acidosis, the kidneys excrete NH4+, which contains H+ buffered by ammonia. 

The kidneys respond to respiratory acidosis similar to the way that they do to metabolic acidosis namely, with (1) increased exchange, (2) increased ammonia forma-... 

Ammonia arises in the body principally from the oxidative deamination of amino acids. In addition to its uptake in the reactions mentioned above, ammonia is also excreted in the urine as ammonium salts. This is not derived directly from the blood ammonia but is formed by the kidney from glutamine by the action of glutaminase. In metabolic acidosis, ammonia production and excretion by the kidney is greatly increased, and conversely it is decreased in metabolic alkalosis. This may be an important means of excreting excess ammonia. It must be remembered that ammonia formed by the action of intestinal bacteria on the protein hydrolyzates in the intestine can be also absorbed. The contribution of the ammonia formed in this way to the total ammonia in the body is unknown. Since this ammonia drains into the portal circulation, it is promptly removed by the liver. 

Last, ammonia is excreted in the urine in the form of ammonium salts. Normally, however, this is relatively small, but it may be increased in metabolic acidosis, if kidney tubular function is normal. Ammonia is synthesized from glutamine by the kidney as required in order to conserve fixed base, e.g., sodium or potassium or to neutralize excessive amounts of acid excreted in the urine as, for example, in acidosis. 

Ammonia is particularly toxic to brain but not to other tissues, even though levels in those tissues may increase under normal physiological conditions (e.g., in muscle during heavy exercise in kidney during metabolic acidosis). Several hypotheses have been suggested to explain the mechanism of neurotoxicity. 

Generation of ammonia from glutamine and its excretion as NH4 is an important mechanism for elimination of protons, particularly during severe metabolic acidosis, when it becomes a significant mode of nitrogen excretion. Most renal glutamine is derived from muscle (Chapters 17 and 22). Glutamine provides two molecules of NH3 ... 

Acidification of urine is affected in renal tubular acidosis. This condition may be due to an inborn error of metabolism or to an acquired tubular lesion. The defect may be related either to the secretion of hydrogen ions or to the diffusion of hydrogen ions into the blood as a result of increased permeability of the distal tubule cell wall to secreted hydrogen ions. Because renal tubular acidosis is primarily a defect in hydrogen ion secretion, the formation of ammonia by tubule cells is not affected. 

Hematological Effects. No information was located regarding the hematological effects of ammonia or ammonium compounds in humans following oral exposure. Repeated exposure to ammonium chloride in animals resulted in metabolic acidosis with related changes in bone metabolism and serum calcium. 

Lotspeich WD. 1965. Renal hypertrophy in metabolic acidosis and its relation to ammonia excretion. Am J Physiol 208 1135-1142. 

---