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      Kidney Models of Calcium Oxalate Stone Formation

      Nephron Physiology

      S. Karger AG

      Urolithiasis, Kidney model, Calcium, Oxalate

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          Abstract

          This review compares and contrasts three mathematical models used to describe the flow of urine through the renal tubule and the composition of tubular fluid throughout the length of the nephron. From these data the relative supersaturation of tubular fluid with respect to calcium oxalate (CaOx) is calculated at various points along the tubule. This shows that glomerular filtrate is well undersaturated with respect to CaOx and is still undersaturated at the end of the proximal tubule. By the end of the descending limb of the loop of Henle, it is highly supersaturated as a result of water reabsorption and CaOx may nucleate in this region, particularly when the tubular concentration of oxalate is increased. Supersaturation falls slightly by the end of the ascending limb and becomes briefly undersaturated again in the short distal tubule. The final water adjustment in the collecting tubules causes the supersaturation to rise to a very high value by the end of the collecting duct and spontaneous CaOx crystalluria is likely to occur. The review also examines the probability of these crystals growing large enough to be trapped at some point in the nephron within the transit time of tubular fluid from glomerular capsule to ducts of Bellini. All three models agree that, under normal conditions, the likelihood of individual crystals growing large enough to be trapped within the measured urine transit time of 3–4 min is very small. It is concluded that either there has to be aggregation of crystals or some other factor that delays the passage of crystals for them to grow large enough to become lodged at some point in the nephron. Three new hydrodynamic factors are introduced that may lead to delay of crystal passage: (a) fluid drag close to the tubule walls; (b) the drag effect of tubular walls on particles travelling close to the tubule walls, and (c) the effect of gravity on particles travelling in upward-draining sections of tubule. When these factors are introduced into the mathematical model of urine flow and tubular concentration, it is shown that any crystals that form at the end of the descending limb of the loop of Henle and which travel close to the tubular walls may be delayed long enough to grow large enough to become trapped further down the nephron, particularly in upward-draining sections of the nephron. This possibility becomes increasingly significant as urinary oxalate concentration increases. Crystals that nucleate in the late collecting duct, however, are readily passed as small crystals and are at no risk of being trapped in the tubular system. These predictions are used to explain data on the effects of oxalate loading on CaOx crystalluria in stone formers and normal controls. The data are interpreted as showing that if the additional hydrodynamic factors are added to the mathematical model of nephron function, then the ‘free-particle’ model of calcium stone formation is still possible. This possibility will be further enhanced if crystal aggregation also takes place during the period when crystal passage is delayed by these factors.

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          Most cited references 8

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          Oxalate toxicity in LLC-PK1 cells: role of free radicals.

          Oxalate, the most common constituent of kidney stones, is an end product of metabolism that is excreted by the kidney. During excretion, oxalate is transported by a variety of transport systems and accumulates in renal tubular cells. This process has been considered benign; however, recent studies on LLC-PK1 cells suggested that high concentrations of oxalate are toxic, inducing morphological alterations, increases in membrane permeability to vital dyes and loss of cells from the monolayer cultures. The present studies examined the basis for oxalate toxicity, focusing on the possibility that oxalate exposure might increase the production/availability of free radicals in LLC-PK1 cells. Free radical production was monitored in two ways, by monitoring the reduction of nitroblue tetrazolium to a blue reaction product and by following the conversion of dihydrorhodamine 123 (DHR) to its fluorescent derivative, rhodamine 123. Such studies demonstrated that oxalate induces a concentration-dependent increase in dye conversion by a process that is sensitive to free radical scavengers. Specifically, addition of catalase or superoxide dismutase blocked the oxalate-induced changes in dye fluorescence/absorbance. Addition of these free radical scavengers also prevented the oxalate-induced loss of membrane integrity in LLC-PK1 cells. Thus it seems likely that free radicals are responsible for oxalate toxicity. The levels of oxalate that induced toxicity in LLC-PK1 cells (350 microM) was only slightly higher than would be expected to occur in the renal cortex. These considerations suggest that hyperoxaluria may contribute to the progression of renal injury in several forms of renal disease.
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            Activation of c-myc gene mediates the mitogenic effects of oxalate in LLC-PK1 cells, a line of renal epithelial cells.

            Recent studies on LLC-PK1 cells demonstrated that oxalate, a simple dicarboxylic acid, acts as a mitogen for these renal epithelial cells. Exposure to oxalate initiates DNA synthesis, induces the expression of one of the early growth response genes c-myc and stimulates proliferation of quiescent cultures of LLC-PK1 cells. The present studies examined the possibility that expression of the c-myc protooncogene is obligatory for this mitogenic response. Specifically we determined whether pretreatment with c-myc antisense oligonucleotides would block the proliferative effects of oxalate in LLC-PK1 cells. Quiescent cultures of LLC-PK1 cells were exposed to oxalate in the presence and absence of c-myc antisense and the effects of oxalate on c-myc protein expression (Myc), DNA synthesis and cell growth were assessed. Exposure of cells to oxalate alone increased the expression of Myc within two hours. Pretreatment with c-myc antisense abolished this response. Further, pretreatment of cells with c-myc antisense but not nonsense oligonucleotides blocked the oxalate-induced initiation of DNA synthesis. Increases in cell number in response to oxalate (measured after 72 hr exposure) were also blocked by exposure to c-myc antisense. These findings suggest that c-myc gene expression is critical for the mitogenic effects of oxalate in LLC-PK1 cells.
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              Crystal agglomeration is a major element in calcium oxalate urinary stone formation

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                Author and article information

                Journal
                NEP
                Nephron Physiol
                10.1159/issn.1660-2137
                Nephron Physiology
                S. Karger AG
                978-3-8055-7852-3
                978-3-318-06156-7
                1660-2137
                2004
                October 2004
                19 October 2004
                : 98
                : 2
                : p21-p30
                Affiliations
                University College London, Institute of Urology and Nephrology, London, UK
                Article
                80260 Nephron Physiol 2004;98:p21–p30
                10.1159/000080260
                15499211
                © 2004 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, Tables: 1, References: 21, Pages: 1
                Product
                Self URI (application/pdf): https://www.karger.com/Article/Pdf/80260
                Categories
                Paper

                Cardiovascular Medicine, Nephrology

                Kidney model, Oxalate, Urolithiasis, Calcium

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