Kidney, ammonia metabolism

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. 

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... 

Figure 8.29 The initial reactions of glutamine metabolism in kidney, intestine and cells of the immune system. The initial reaction in all these tissues is the same, glutamine conversion to glutamate catalysed by glutaminase the next reactions are different depending on the function of the tissue or organ. In the kidney, glutamate dehydrogenase produces ammonia to buffer protons. In the intestine, the transamination produces alanine for release and then uptake and formation of glucose in the liver. In the immune cells, transamination produces aspartate which is essential for synthesis of pyrimidine nucleotides required for DNA synthesis otherwise it is released into the blood to be removed by the enterocytes in the small intestine or by cells in the liver.

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. 

Urea is a colorless, odorless crystalline substance discovered by Hilaire Marin Rouelle (1718—1779) in 1773, who obtained urea by boiling urine. Urea is an important biochemical compound and also has numerous industrial applications. It is the primary nitrogen product of protein (nitrogen) metabolism in humans and other mammals. The breakdown of amino acids results in ammonia, NH3, which is extremely toxic to mammals. To remove ammonia from the body, ammonia is converted to urea in the liver in a process called the urea cycle. The urea in the blood moves to the kidney where it is concentrated and excreted with urine. 

In contrast to transamination reactions that transfer amino groups, oxidative deamination by gutamate dehydrogenase results in the lib eration of the amino group as free ammonia (Figure 19.11). These reactions occur primarily in the liver and kidney. They provide a-ketoacids that can enter the central pathway of energy metabolism, and ammonia, which is a source of nitrogen in urea synthesis. 

One of the major products of amino acid metabolism is ammonia (NLI3), a molecule known to be highly toxic to higher organisms. In the liver, ammonia and carbon dioxide are used to produce a water-soluble form of nitrogen, urea, via the urea cycle. The liver passes this urea to the blood, which carries it to the kidneys to be filtered out and excreted in the urine. Since one function of the kidney is to collect and excrete urea, increases in the concentration of this compound in the blood are an indicator of poor kidney function. Since urea is formed in the liver, low blood urea nitrogen is often the consequence of impaired liver function due to disease or as the result of infection (hepatitis). 

Second, modified microorganisms could correct errors of metabolism resulting from either gastric or intestinal enzyme deficiencies (e.g., lipase or lactase) [11] or organ failure (by removing urea in the case of kidney failure or ammonia in the case of liver failure) [12,13]. This could constitute an alternative to current therapy such as renal dialysis, which is time consuming and uncomfortable for the patient. 

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... 

Several cysteine conjugates are metabolized by p-lyase to produce thiols, ammonia, and pyruvate. Cytosolic p-lyases have been isolated from the kidney, liver, and intestinal microflora. Since it has become clear that p-lyases can play a decisive role in the bioactivation of cysteine conjugates (such as those from hexachloro-1,3-butadiene or other halogenated al-kenes) to nephrotoxic agents, the scientific interest in this enzyme has increased considerably (Elfarra and Anders, 1984 Commandeur et al., 1987). 

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. 

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