Cystinuria Lysine

H2N (CH2]5 NH2. a syrupy fuming liquid, b.p. 178-180 - C. Soluble in water and alcohol. Cadaverine is one of the ptomaines and is found, associated with pulrescine, in putrefying tissues, being formed by bacterial action from the amino-acid lysine. It is found in the urine in some cases of the congenital disease cystinuria. The free base is poisonous, but its salts are not. 

Hyperargininemia. This defect is characterized by elevated blood and cerebrospinal fluid arginine levels, low erythrocyte levels of arginase (reaction 5, Figure 29-9), and a urinary amino acid pattern resembling that of lysine-cystinuria. This pattern may reflect competition by arginine with lysine and cystine for reabsorption in the renal tubule. A low-protein diet lowers plasma ammonia levels and abolishes lysine-cystinuria. 

There are numerous abnormalities of cysteine metabolism. Cystine, lysine, arginine, and ornithine are excreted in cystine-lysinuria (cystinuria), a defect in renal reabsorption. Apart from cystine calculi, cystinuria is benign. The mixed disulfide of L-cysteine and L-homocysteine (Figure 30-9) excreted by cystinuric patients is more soluble than cystine and reduces formation of cystine calculi. Several metabolic defects result in vitamin Bg-responsive or -unresponsive ho-mocystinurias. Defective carrier-mediated transport of cystine results in cystinosis (cystine storage disease) with deposition of cystine crystals in tissues and early mortality from acute renal failure. Despite... 

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. 

Fig. 2.1.2a-c A Urine amino acids in a patient with cystinuria assayed by an amino acid analyzer (AAA). The indicated peaks are 1 glycine, 2 cystine, 3 ammonia, 4 ornithine, 5 lysine, 6 arginine, i.s. internal standard (S-amino thyl-cysteine). Cystinuria treatment is best followed-up by analyzing an early morning urine specimen, which usually shows the highest amino acid concentrations. b-c see next page... 

Cystinuria is a disorder of the proximal tubule s reabsorption of filtered cystine and dibasic amino acids (lysine, ornithine, arginine). 

At least seven different systems are known for transporting amino acids into cells. In the inherited disorder cystinuria, the carrier system responsible for reabsorption of the amino acids cysteine, ornithine, arginine, and lysine in the proximal convoluted tubule of the kidney is defective. The inability to reabsorb cystine leads to kidney stones. 

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... 

Cystinuria has been known for a long time (A2, H18, Yl), but it was Dent and Rose (D12) who noticed, in 15 patients suffering from cystine caleulosis, that cystine was not the only amino acid abnormally abundantly excreted by the kidney. They observed that arginine and lysine were also excreted in abnormally large amounts, and Stein (S31) reported this to be true of ornithine as well. Bickel refers to the condition by using the expression lysine cystinuria, but this is in fact misleading because it infers that these are the only two amino acids concerned, whereas that is not the case. Taurine excretion, on the other hand, is low (S31). The cystine plasma level is either normal or low (D19, Fll). 

R3. Robson, E. B., and Rose, G. A., The effect of intravenous lysine on the renal clearances of cystine, arginine and ornithine in normal subjects, in patients with cystinuria and Fanconi syndrome and in their relatives. Clin. Sci. 16, 75-93 (1957). 

A number of amino acid transport disorders may be associated with one or several of the systems described in Table 20.4. These are characterized by the excretion of amino acids in the urine but no increase in amino acid levels in the bloodstream. They are usually of hereditary origin. The most common disorder is cystinuria, characterized by the excretion of cystine. Because cystine is only slightly water soluble, cystinuria is often accompanied by the deposition of cystine-containing stones in the genitourinary tract. Cystinuria is apparently caused by a defect in the cationic amino acid transport system. Another disease that affects this system is lysinuric protein intolerance, which is associated with a failure to transport lysine, ornithine, arginine, and citrulline across membranes. Citrulline and ornithine are urea cycle intermediates (see later), and a disruption of their interorgan traffic results in hyperammonemia. 

Cystinuria is an autosomal recessive condition in which there is excessive urinary excretion of cystine because of a defect in proximal renal tubular reabsorption. In the most common form of the disease there is also excess excretion of the dibasic amino acids (lysine, ornithine, and arginine). These share the same renal tubular transporter although their presence in excess in urine appears benign. More rarely, isolated cystinuria is seen. The reader should note that cystinuria should not be confused with cystinosis, which is a condition associated with intracellular accumulation of cystine but not excess urinary excretion of cystine. 

Cystinuria is a disorder of renal and gastrointestinal tract amino acid transport that also affects lysine, ornithine, and arginine. The four amino acids share a common transport mechanism (discussed above). Clinically, it presents as urinary stone disease because of the insolubility of cystine. In cystinosis, cystine crystals are deposited in tissues because of a transport defect in ATP-dependent cystine efflux from lysosomes (discussed above). 

Cystinuria An Increased excretion of the amino acids cystine, lysine, arginine and ornithine leads to an increased incidence of renal calculi. A defective carrier protein causes impaired renal tubular reabsorption of these amino acids from the glomerular filtrate... 

Cal Kulis passed a renal stone shortly after admission, with immediate relief of flank pain. Stone analysis showed its major component to be cystine. Normally, amino acids are filtered by the renal glomerular capillaries into the tubular urine but are almost entirely reabsorbed from this fluid back into the blood via transport proteins in the proximal tubular cells of the kidney. Cal Kulis has cystinuria, a genetically inherited amino acid substitution in the transport protein that normally reabsorbs cystine, arginine, and lysine from the kidney lumen back into the renal tubular cells. Therefore, his urine contained high amounts of these amino acids. Cystine, which is less soluble than other amino acids, precipitates in the urine to form renal stones (calculi). 

Cal Kulis. Mr. Knlis has cystinuria, a relatively rare disorder, with a () prevalence that ranges between 1 in 2,500 to 1 in 15,000 births, depending on the population stndied. It is a genetically determined disease with a complex recessive mode of inheritance resulting from allelic mutations. These mutations lead to a reduction in the activity of renal tubular cell transport proteins that normally carry cystine from the tubular lumen into the renal tubular cells. The transport of the basic amino acids (lysine, arginine, and ornithine, an amino acid... 

Cal Kulis and other patients with cystinuria have a genetically determined defect in the transport of cystine and the basic amino acids, lysine, arginine, and ornithine, across the brush-border membranes of cells in both their small intestine and renal tubules. However, they do not appear to have any symptoms of amino acid deficiency, in part because the amino acids cysteine (which is oxidized in blood and urine to form the disulfide cystine) and arginine can be synthesized in the body (i.e., they are "nonessential" amino acids). Ornithine (an amino acid that is not found in proteins but serves as an intermediate of the urea cycle) can also be synthesized. The most serious problem for these patients is the insolubility of cystine, which can form kidney stones that may lodge in the ureter, causing bleeding and severe pain. 

In patients with cystinuria, such as Cal Kulis, the inability to normally absorb cystine and basic amino acids from the gut and the increased loss of these amino acids in the urine would be expected to cause a deficiency of these compounds in the blood. However, because three of these amino acids can be synthesized in the body (i.e., they are nonessential amino acids), their concentrations in the plasma remain normal, and clinical manifestations of a deficiency state do not develop. It is not clear why symptoms related to a lysine deficiency have not been observed. 

Cystinuria and cystinosis are disorders involving two different transport proteins for cystine, the disulfide formed from two molecules of cysteine. Cystinuria is caused by a defect in the transport protein that carries cystine, lysine, arginine, and ornithine into intestinal epithelial cells and that permits resorption of these amino acids by renal tubular cells. Cystine, which is not very soluble in the urine, forms renal calculi (stones). Cal Kulis, a patient with cystinuria, developed cystine stones (see Chapter 37). 

Excessive urinary cysteine, ornithine, lysine, and arginine (cystinuria)... 

Other, more specific, transporter dysfunctions lead to distinct inborn errors of metabolism. Oxaluria and cystinuria, defects in oxalate and cysteine transport, respectively, manifest with renal stones. Cystinuria specifically presents with cysteine, ornithine, lysine, and arginine in the urine. The latter should not be confused with cystinosis. Lysinuric protein intolerance (LPI) is a defect in the dibasic amino acid transporter. This results in a specific amino aciduria pattern (ornithine, lysine, and arginine), which in turn results in secondary inhibition of the urea cycle. Individuals affected by LPI are at risk for hyperammonemia and also have a unique susceptibility to macrophage activation syndrome, an exaggerated systemic inflammatory response, and alveolar proteinosis. Renal damage... 

Cystinuria is an autosomal recessive disorder of renal mbular teab-sorption of cystine, ornithine, arginine and lysine (mnemonic COAL). Cystine (a dimer of cysteine Chapter 6) is sparingly soluble and accumulates in the tubular fluid, forming bladder and kidney stones (cystine urolithiasis). Cystine is so-called because cystine stones were discovered in the cyst (i.e. bladder). 

Cystinuria is a hereditary disease characterized by the excessive excretion of cystine, lysine, ornithine, and arginine in the urine, probably resulting from a deficiency in the renal tubular transport mechanism. Sir Archibald E. Garrod postulated that cystinuria resulted from a metabolic block involving the oxidation of cystine to sulfate. Later investigations of the pathogenesis of cystinuria demonstrated that the hereditary deficiency does not involve a metabolic block. If a metabolic impairment existed, cystine would be expected to accumulate in the plasma of cystinurics, but plasma levels of cystine are normal or low in cys-... 

A number of experimental procedures have established that the dibasic monocarboxylic acids lysine, arginine, and ornithine are transported in the intestines and kidneys by a common system. Moreover, the system that transports the dibasic monocarboxylic acid also transports cystine [170-172]. The transport mechanism just described is the one that is deficient in patients with cystinuria. 

An amino acid excreted in large amounts in the urine in the inborn error, cystinuria. This condition is due to a failure of the tubular reabsorption mechanism for the dibasic amino acids, cystine, ornithine, arginine and lysine. Two types of hyperlysinaemia... 

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