Cystinuria Cystine stone

Fig. 3-66. Cystinuria. Cystine stone assuming shape of calices...

D-Penicillamine can promote the elimination of copper (e.g., in Wilson disease) and of lead ions. It can be given orally. Two additional indications are cystinuria and rheumatoid arthritis. In cystinuria, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In rheumatoid arthritis, penicillamine can be used as a basal regimen (p.332). The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters p. 74), nephrotoxicity, bone marrow depression, and taste disturbances. 

The normal urinary excretion of cystine has been reported to be 4.81 to 48.1mg/24 hours (40 to 400p.mol/24 hours).Its relatively low limit of solubility, 18.0mg/dL (1500 LlmoI/L), is exceeded in many patients with cystin-uria, resulting in the formation of hexagonal crystals and, ultimately, cystine stones. Cystine stones are usually only seen in homozygotes, although there is some evidence that heterozygotes are at increased risk of stone formation. Cystinuria may present at any age from infancy to old age, although presentation is most common in the second and third decades. 

The finding of a cystine stone should prompt confirmation of cystinuria by urinary analysis. It could be argued, however, that aU stone formers should be screened for cystinuria at least 10% of cystinurics form stones in which cystine cannot be detected, presumably because of epitaxis. The index of suspicion shordd be increased in patients who are relatively young stone formers and in those with a positive family history. Once a cystinuric patient is diagnosed, it is important to screen all members of the family, particularly to detect affected siblings. 

Cystine stones are rare except in cases of an inborn error of metabolism (cystinuria). Cystine, like uric acid, is more soluble in alkaline urine that in acidic urine. Xanthine stones are very rare except in cases of an inborn error of metabolism (xanthinuria). 

Tiopronin, a thiol compound that stabilizes the cystine moiety, is used in prevention of urinary cystine stone formation in patients with severe homozygous cystinuria (urinary cystine excretion exceeding 500 mg daily) unresponsive to other therapies. 

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). 

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. Penicillamine reduces excess cystine excretion in cystinuria. Penicillamine with conventional therapy decreases crystalluria and stone formation, and may decrease the size of or dissolving existing stones. This is achieved by disulfide interchange between penicillamine and cystine, resulting in a substance more soluble than cystine and readily excreted. 

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. 

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... 

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. 

Understanding and mimicking of the cellular transport processes are both challenging and rewarding from scientific and technological point of view. For example in certain inherited diseases (such as cystinuria), specific transport systems are either defective or missing [1]. Cystinuria is a human disease characterized by the absence of a transport system that carries cystine and other amino acids into kidney cells. Kidney cells normally reabsorb these amino acids from the urine and return them to the blood, but a person inflicted with cystinuria develops painful stones from amino acids that accumulate and crystallize in the kidneys. Similarly, there are many technological applications of these transport processes, e.g., bioseparations, bioextractions, and synthetic nano-bioreactors. 

Ascorbic acid 4 g/day increases uric acid clearance in volunteers (23), although it does not reduce protein-bound uric acid in blood. Ascorbic acid 4-12 g/day causes acidification of the urine, which can cause precipitation of urate and cystine and consequently formation of urate stones or cystinuria. Ascorbic acid is excreted largely as oxalate, and hyperoxaluria results when large doses are... 

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). 

Transport of molecules across plasma membranes is a critical function of all organisms. A single genetic mutation in a transport protein can give rise to disease. In cystinuria, for example, dietary cysteine can be taken up in the intestine in the form of small polypeptides and subsequently released into the bloodstream as the free amino acid which would normally be taken up by the tissues. In cystinuria, however, the import of cystine into cells cannot occur due to a genetic defect in the transport protein and the cystine in the blood is passed into the kidney where renal reabsorption is defective and the cystine precipitates as kidney stones. 

Free cysteine occurs only in very low amounts in the blood. Most of the potential free cysteine occurs as cystine where the two SH groups are oxidized to a disulfide bond. This compound can be reduced to cysteine where and when needed. Normally, the kidney reabsorbs both cysteine and cystine. In the disease cystinuria, the transport of cystine into many cells is defective. This causes an increase in plasma cystine, resulting in a spillage of cystine in the urine. Cystine is rather insoluble and forms stones in the kidney, bladder, and ureter, which can be extremely painful. Cystine has a lower solubility as pH decreases. 

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 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. 

Two human genetic diseases are known which involve this disulphide amino acid. In one, cystinuria , there is a transport defect in the intestine and kidney. This results in abnormally high levels of cystine in the urine and can result in the precipitation of cystine crystals and kidney stone formation. In cystinosis, cystine crystals form within cells and eventually cause severe kidney damage. The nature of the primary biochemical lesion is unknown all known cystine reduction systems of the cell appear to be normal. 

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