Renal disease cystinuria

Diseases of the kidney that are discussed in this section include (1) the uremic syndrome, (2) chronic kidney disease, (3) end-stage renal disease, (4) diabetic nephropathy, (5) hypertensive nephropathy, (6) glomerular diseases, (7) interstitial nephritis, (8) polycystic Iddney disease, (9) polycystic kidney disease, (10) toxic nephropathy, (11) obstructive uropathy, (12) tubular diseases, (13) renal calculi, and (14) cystinuria. In addition, this section also includes discussions on (1) prostaglandins and NS AIDS in kidney disease, (2) monoclonal light chains and kidney disease, and (3) urinary osmolality. 

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... 

A number of inherited conditions are now known in which some degree of renal aciduria has been found. These include diseases as diverse as cystinuria, galactosemia, and Wilson s disease. In the last of these the aminoaciduria is probably a consequence of renal tubular damage secondary to excessive copper deposition (H2). 

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. 

Inherited defects in amino acid transport affect epithelial cells of the gastrointestinal tract and renal tubules. Some affect transport of neutral amino acids Hartnup disease), others that of basic amino acids and ornithine and cystine (cystinuria), or of glycine and proline (Chapter 12). Cystinosis is an intracellular transport defect characterized by high intralysosomal content of free cystine in the reticuloendothelial system, bone marrow, kidney, and eye. After degradation of endocytosed protein to amino acids within lysosomes, the amino acids normally are transported to the cytosol. The defect in cystinosis may reside in the ATP-dependent efflux system for cystine transport, and particularly in the carrier protein. 

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). 

D-penicillamine is so named because it was first isolated as an amine, from the degradation products of penicillin by Abraham et al [87]. Later studies showed the characteristic chemical behavior of D-penicillamine which involve three types of reactions, formation of disulphide links, formation of thiazolidine rings, and formation of metal complexes and chelates [67]. It was first used in 1956 in the treatment of Wilson s disease [88]. D-penicillamine has since been used in the treatment of many diseases, such as cystinuria [89], rheumatoid arthritis [90-92], systemic sclerosis [93], primary bdiary cirrhosis [94], heavy metal poisoning due to lead [95], cadmium [%], and mercury [97], and hyperviscosity syndrome [99]. In rheumatoid arthritis, D-peni-cdlamine has been widely accepted as an effective second line treatment. Despite of its effectiveness, it causes many adverse effects, such as skin rashes [99,100], taste abnormalities [100,101], hepatic dysfunction [102-104], gastrointestinal toxiciiy [99,105], proteinuria [100,106], hematuria [107, 108], thrombocytopenia [92, 109], aplastic anemia [110], lupus-like syndrome [111, 112], Goodpasture s-tike pulmonary renal syndrome [113-115], vasculitis [116,117], myasthenia gravis [118-122], polymyositis [123, 124], and dermatomyositis [125]. 

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. 

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... 

Hartnup disease Is another genetically determined and relatively rare autosomal recessive disorder. It is caused by a defect in the transport of neutral amino acids across both intestinal and renal epithelial cells. The signs and symptoms are, in part, caused by a deficiency of essential amino acids (see Clinical Comments). Cystinuria and Hartnup disease involve defects in two different transport proteins. In each case, the defect is present both in intestinal cells, causing malabsorption of the amino acids from the digestive products in the intestinal lumen and in kidney tubular cells, causing a decreased resorption of these amino acids from the glomerular filtrate. 

Ilie clinical aiqylications of this amuoach are best represented in a study by Sampson ef cd. (1985) of measurement of the urinary disulfides cystine and cystdnyl-penicillamine in cystinuria patients. In order to diagnose this disease and monitor patient treatnient, it is necessary to monitor the relatively insoluble disulfides responsible for formation of these urinary tract calculi. Urine samples were simply deproteinized with sulfosalicyclic acid and diluted before injection. For patients treated with penicillamine to increase disulfide solubility in the renal tract, the cysteine-penicillamine... 

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-... 

The sulfur amino acids are methionine, homocyst(e)ine, cystathionine, cyst(e)ine, and taurine. Defects in several of the enzymatic steps of their metabolism are known some, but not all, result in human disease. The re-methylation of homocysteine to methionine is closely dependent on folate and cobalamin cofactors, and relevant defects of their metabolism are therefore included in this chapter. Cystinuria and cystinosis, defects of renal tubular and lysosomal transport of cystine, respectively, are described in Chap. 13. 

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