Kidney Amino acid excretion

Aminoaciduria, proteinuria and morphological kidney lesions can be induced in rats with a single [420] dose of NiCl2 (2-5 mg Ni/kg intraperitoneally). Amino-acid protein excretions consistently returned to normal by day 5 after exposure. 

In aquatic animals, ammonia diffuses out of the body through the skin, but land animals excrete excess ammonia either as urea or uric acid. Ammonia is excreted by humans on high meat diets as a strategy to conserve Na+ and K +. Excess PO4- and SO4- produced from phosphoproteins and S-containing amino acids are excreted as ammonium salts Na+ and K+ are exchanged for NH in the kidney. The excretion of urea requires a plentiful supply of water, as it is normally excreted in solution, whereas uric acid is very insoluble and is excreted as a solid by birds and reptiles. Thus, in animals in which weight, or the conservation of water, is important (e.g., birds), excess ammonia is excreted as uric acid. 

Much that is known about renal reabsorption mechanisms has been learned from the study of various forms of aminoaciduria. Three types of aminoaciduria have been identified (1) overflow aminoaciduria occurs when the plasma level of one or more amino acids exceeds the renal threshold (tubular capacity for reabsorption) (2) renal aminoaciduria occurs when plasma levels are normal but the renal transport system has a congenital or acquired defect and (3) no-threshold aminoaciduria occurs when excessive amounts of an amino acid, arising from an inherited metabolic block, are present in urine, but plasma levels are essentially normal because ah the amino acid is excreted. The no-threshold aminoacidurias, such as homocystinuria, are not due to congenital or acquired kidney defects but solely to saturation of the normal renal tubular reabsorption mechanisms. 

Patients with cystinuria and Hart- I nup disease have defective transport proteins in both the intestine and the kidney. These patients do not absorb the affected amino acids at a normal rate from the digestive products in the intestinal lumen. They also do not readily resorb these amino acids from the glomerular filtrate into the blood. Therefore, they do not have a hyperaminoacidemia (a high concentration in the blood). Normally, only a few percent of the amino acids that enter the glomerular filtrate are excreted in the urine most are resorbed. In these diseases, much larger amounts of the affected amino acids are excreted in the urine, resulting in a hyperaminoaciduria. 

A condition in which abnormally large amounts of amino acids are excreted in the urine. This disorder is usually due to one or more defects in the processes by which the kidneys prevent such urinary loss. 

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

Atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) are members of a family of so-called natriuretic peptides, synthesized predominantly in the cardiac atrium, ventricle, and vascular endothelial cells, respectively (G13, Y2). ANP is a 28-amino-acid polypeptide hormone released into the circulation in response to atrial stretch (L3). ANP acts (Fig. 8) on the kidney to increase sodium excretion and glomerular filtration rate (GFR), to antagonize renal vasoconstriction, and to inhibit renin secretion (Ml). In the cardiovascular system, ANP antagonizes vasoconstriction and shifts fluid from the intravascular to the interstitial compartment (G14). In the adrenal cortex, ANP is a powerful inhibitor of aldosterone synthesis (E6, N3). At the hypothalamic level, ANP inhibits vasopressin secretion (S3). It has been shown that some of the effects of ANP are mediated via a newly discovered hormone, called adreno-medullin, controlling fluid and electrolyte homeostasis (S8). The diuretic and blood pressure-lowering effect of ANP may be partially due to adrenomedullin (V5). 

There are seven membrane forms of GC, designated GC-A to GC-G [33], Two forms, GC-A and GC-B (Mr = 120kDa), serve as receptors for atrial natriuretic peptide (ANP) and related peptides. ANP is a 28-amino-acid peptide isolated originally from cardiac atria as an important factor in the regulation of sodium excretion and blood pressure. GC-A binds ANP, as well as brain natriuretic peptide (BNP), and is located in vascular tissue and kidney. 

Hormones are intercellular messengers. They are typically (1) steroids (e.g., estrogens, androgens, and mineral corticoids, which control the level of water and salts excreted by the kidney), (2) polypeptides (e.g., insulin and endorphins), and (3) amino acid derivatives (e.g., epinephrine, or adrenaline, and norepinephrine, or noradrenaline). Hormones maintain homeostasis—the balance of biological activities in the body for example, insulin controls the blood glucose level, epinephrine and norepinephrine mediate the response to the external environment, and growth hormone promotes normal healthy growth and development. 

Amino groups released by deamination reactions form ammonium ion (NH " ), which must not escape into the peripheral blood. An elevated concentration of ammonium ion in the blood, hyperammonemia, has toxic effects in the brain (cerebral edema, convulsions, coma, and death). Most tissues add excess nitrogen to the blood as glutamine. Muscle sends nitrogen to the liver as alanine and smaller quantities of other amino acids, in addition to glutamine. Figure I-17-1 summarizes the flow of nitrogen from tissues to either the liver or kidney for excretion. The reactions catalyzed by four major enzymes or classes of enzymes involved in this process are summarized in Table T17-1. 

Proteins are constantly being lost via the intestine and, to a lesser extent, via the kidneys. To balance these inevitable losses, at least 30 g of protein have to be taken up with food every day. Although this minimum value is barely reached in some countries, in the industrial nations the protein content of food is usually much higher than necessary. As it is not possible to store amino acids, up to 100 g of excess amino acids per day are used for biosynthesis or degraded in the liver in this situation. The nitrogen from this excess is converted into urea (see p. 182) and excreted in the urine in this form. The carbon skeletons are used to synthesize carbohydrates or lipids (see p. 180), or are used to form ATP. 

The kidneys main function is excretion of water and water-soluble substances (1). This is closely associated with their role in regulating the body s electrolyte and acid-base balance (homeostasis, 2 see pp.326 and 328). Both excretion and homeostasis are subject to hormonal control. The kidneys are also involved in synthesizing several hormones (3 see p. 315). Finally, the kidneys also play a role in the intermediary metabolism (4), particularly in amino acid degradation and gluconeo-genesis (see p. 154). 

Uric acid is the end product of the purine metabolism. When uric acid excretion via the kidneys is disturbed, gout can develop (see p. 190). Creatinine is derived from the muscle metabolism, where it arises spontaneously and irreversibly by cyclization of creatine and creatine phosphate (see p. 336). Since the amount of creatinine an individual excretes per day is constant (it is directly proportional to muscle mass), creatinine as an endogenous substance can be used to measure the glomerular filtration rate. The amount of amino acids excreted in free form is strongly dependent on the diet and on the ef ciency of liver function. Amino acid derivatives are also found in the urine (e.g., hippu-rate, a detoxification product of benzoic acid). 

Animal studies indicate that the primary toxic effect of uranium exposure is on the kidney, with particular damage to the proximal tubules. Functionally, this may result in increased excretion of glucose and amino acids. Structurally the necrosis of tubular epithelium leads to formation of cellular casts in the urine. If exposure is insufficient to cause death from renal failure, the mbular lesion is reversible with epithelial regeneration. Although bone is the other major site of deposition, there is no evidence of toxic or radiocarcinogenic effects to bone or bone marrow from experimental studies. ... 

The disease is characterized by excessive excretion of cystine and the dibasic amino acids arginine, lysine, and ornithine by the kidneys that may lead to precipitation of some of these compounds in the form of kidney stones. 

The answer is D. The patient s symptoms are consistent with a kidney stone, which is confirmed by the radiographic finding. The etiology of the stone is indicated by the urinalysis data, which suggest cystinuria. The cells of this patient s renal proximal tubules would be deficient in a transporter responsible for the reabsorptive uptake of cystine and the basic amino acids, arginine, lysine, and ornithine. Failure of the tubules to reabsorb these amino acids from the ultrafiltrate causes them to be excreted at high concentration in the urine. 

Valsartan (2) is a nonheterocyclic antagonist in which the imidazole of losartan has been replaced with an acylated amino acid. It is a very potent ATj antagonist (IC50 =1.6 nM). There is only one metabolite, valeryl 4-hydroxy valsartan, and it is inactive. The enzymes responsible for valsartan metabolism have not been identihed, but do not seem to be P450 CYP isozymes. Food decreases the absorption by 40%. Valsartan (2) is excreted in the bile (70%) and by the kidneys (30%). [See Chiolero and Burnier (1998).]... 

Parathyroid hormone is a single-chain polypeptide of 84 amino acids which is produced in the parathyroid glands. It increases serum calcium and decreases serum phosphate. In bone it promotes resorption of calcium. It indirectly increases osteoclastic activity by promoting the action of osteoblasts. It has been shown that in low doses PTH may even increase bone formation without stimulating bone resorption. In the kidney PTH increases resorption of calcium and it increases excretion of phosphate. An other important activity in the kidney is the enhanced synthesis of 1,25-dihydroxyvitamin D. An increased serum calcium level inhibits PTH secretion and increased serum phosphate decreases free serum calcium and thus stimulates PTH secretion. 

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. 

Although bile acid conjugates with amino acids are normally excreted into bile, amino acid conjugates of xenobiotics are usually excreted into urine. Conjugation with endogenous amino acids facilitates urinary excretion because of the organic anion transport systems located in the kidney tubules. 

Cysteine and cystine are relatively insoluble and are toxic in excess.450 Excretion is usually controlled carefully. However, in cystinuria, a disease recognized in the medical literature since 1810,451 there is a greatly increased excretion of cystine and also of the dibasic amino acids.451 452 As a consequence, stones of cystine develop in the kidneys and bladder. Patients may excrete more than 1 g of cystine in 24 h compared to a normal of 0.05 g, as well as excessive amounts of lysine, arginine, and ornithine. The defect can be fatal, but some persons with the condition remain healthy indefinitely. Cystinuria is one of several human diseases with altered membrane transport and faulty reabsorption of materials from kidney tubules or from the small intestine. Substances are taken up on one side of a cell (e.g., at the bottom of the cell in Fig. 1-6) and discharged into the bloodstream from the other side of the cell. In another rare hereditary condition, cystinosis, free cystine accumulates within lyso-somes.453... 

Parathyroid hormone (PTH) is an 84-amino acid peptide secreted by the parathyroid glands, and is the principal regulator of extracellular calcium levels [44, 45]. The effects of PTH on extracellular calcium are mediated directly or indirectly through effects on bone, kidney, and intestine. A decrease in extracellular calcium causes an increase in PTH secretion. As a consequence, the rise in PTH levels causes increased bone resorption and the release of calcium from bone, decreased calcium excretion by the kidney, and increased intestinal calcium absorption. The therapeutic application of PTH has centered on the bone effects as an anabolic treatment for osteoporosis. PTH increases the activity of both osteoblasts (which form bone) and osteoclasts (which mediate bone resorption). The desirable anabolic effects of PTH on osteoblasts appear to be highly dependent on dose schedule and the duration of daily exposure. 

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