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      Macromolecules and Urolithiasis: Parallels and Paradoxes

      Nephron Physiology

      S. Karger AG

      Macromolecules, Calcium oxalate, Inhibitors, promoters, Urolithiasis

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          Long-standing interest in the possible role of macromolecules in urolithiasis stems from the observation that all human kidney stones consist of a complex amalgam of mineral and organic material. This review summarises what is currently known or is hypothesised about the influences of urinary macromolecules, especially proteins, on the formation of calcium oxalate crystals, their attachment to renal epithelial cells, and their subsequent destruction within those cells. Although a list is provided of proteins that have either been detected in stones or have been implicated by virtue of their effects on crystallization, only a select handful, which have been intensively studied, have been singled out for individual discussion. The review ends with a speculative discussion of the applicability of current knowledge to the investigation and treatment of urolithiasis.

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          Most cited references 15

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          Innovative materials processing strategies: a biomimetic approach.

          Many organisms construct structural ceramic (biomineral) composites from seemingly mundane materials; cell-mediated processes control both the nucleation and growth of mineral and the development of composite microarchitecture. Living systems fabricate biocomposites by: (i) confining biomineralization within specific subunit compartments; (ii) producing a specific mineral with defined crystal size and orientation; and (iii) packaging many incremental units together in a moving front process to form fully densified, macroscopic structures. By adapting biological principles, materials scientists are attempting to produce novel materials. To date, neither the elegance of the biomineral assembly mechanisms nor the intricate composite microarchitectures have been duplicated by nonbiological processing. However, substantial progress has been made in the understanding of how biomineralization occurs, and the first steps are now being taken to exploit the basic principles involved.
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            Calcium oxalate nephrolithiasis: effect of renal crystal deposition on the cellular composition of the renal interstitium.

            Urinary calcium oxalate (CaOx) crystals and crystal agglomerates are normally harmlessly excreted, but in nephrolithiasis they are retained by tubular epithelial cells and shifted into the renal interstitium. This crystalline material induces an inflammatory response consisting of an increase in the number of interstitial cells and an expansion of the extracellular matrix. The newly arrived cells either derive from the blood or the connective tissue or they are formed by local proliferation. Identification of the cells that surround the interstitial crystals is a first step in investigating the question of whether the interstitial cells could remove the crystalline material. Therefore, we performed an immunohistochemical study on the kidneys of rats made hyperoxaluric by ethylene glycol (EG) and ammonium chloride (AC). Attention was paid to expression of the leukocyte common antigen (LCA), which identifies all types of leukocytes, the ED1 antigen, which is specific for monocytes and macrophages, and the major histocompatibility class II antigen (MHC II), which is present on dendritic cells, B lymphocytes, and activated macrophages. The results obtained were compared with those seen in two human kidney specimens with acute and chronic oxalosis. In both rat and humans, macrophages and multinucleated giant cells are the major cells that encapsulate the interstitial crystals. This similarity in response underlines the relevance of the rat nephrolithiasis model. The rat experiments showed, furthermore, that the number of interstitial crystals and the amount of biochemically measured kidney-associated oxalate both decrease with time, if the nephrolithiatic agents EG and AC are omitted from the drinking water. Further studies must clarify whether macrophages and multinucleated giant cells are able to remove the interstitial crystals and how these cells are recruited at the inflammatory site.
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              Fibronectin as a potent inhibitor of calcium oxalate urolithiasis.

              Fibronectin (230 kD.) is a multifunctional alpha2-glycoprotein distributed throughout the extracellular matrix and body fluids. Many investigators have demonstrated that fibronectin, because of its cell adhesive action, is related to biological processes such as morphogenesis, wound healing and metastasis. Recent studies have shown that a variety of molecules, including fibronectin, inhibit endocytosis of calcium oxalate crystals in vitro. We investigated other roles of fibronectin in calcium oxalate stone formation. Immunoblotting of the crystal surface binding substance obtained from pooled healthy male urine samples was used to analyze whether fibronectin was adsorbed onto the surface of calcium oxalate crystals. To clarify the relationship between fibronectin and calcium oxalate crystals, we performed 6 experiments. Experiment 1 was immunohistochemical examination of fibronectin expression in stone forming rat model kidneys, and experiment 2 examined the fibronectin content of stone forming rat kidney models with the enzyme-linked immunosorbent assay. Experiment 3 was designed to determine fibronectin content of Madin-Darby canine kidney (MDCK) cells stimulated by addition of calcium oxalate crystals and experiment 4 identified the inhibitory effect of fibronectin on calcium oxalate crystal growth by the seed crystal method. For experiment 5 we used an aggregometer system to clarify the inhibitory effect of fibronectin on calcium oxalate crystal aggregation and experiment 6 examined the inhibitory effect of fibronectin on the adhesion of calcium oxalate crystals to MDCK cells. In the crystal surface binding substance immunoreactive bands at 230 kD., which correspond to the molecular weight of fibronectin, were detected by Western blot analysis. In stone forming rat kidneys strong expression of fibronectin was found on the renal tubules to which the crystals were attached. The fibronectin content of these kidneys was significantly greater than that of kidneys without calcium oxalate crystals. The fibronectin content of MDCK cells tended to increase in proportion to the concentration of calcium oxalate crystals added to the culture medium. The growth inhibition assay showed that the inhibitory effect of fibronectin on calcium oxalate crystal growth was small in relation to the quantity of fibronectin excreted. However, fibronectin had inhibitory effects on calcium oxalate crystal aggregation and adhesion of the crystals to MDCK cells. Fibronectin secretion can be stimulated by calcium oxalate crystals, and this protein, which is excreted from the tubular cells, may inhibit calcium oxalate crystal aggregation and attachment to cells.

                Author and article information

                Nephron Physiol
                Nephron Physiology
                S. Karger AG
                October 2004
                19 October 2004
                : 98
                : 2
                : p37-p42
                Department of Surgery, Flinders University School of Medicine, Flinders Medical Centre, Adelaide, Australia
                80262 Nephron Physiol 2004;98:p37–p42
                © 2004 S. Karger AG, Basel

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                Figures: 1, Tables: 2, References: 29, Pages: 1
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