Renal stones form in the late collecting duct in a complex milieu involving salts and protein components of the urine together with direct interactions at the epithelial cells lining the duct. The operation of newly discovered physiological controls that limit crystal formation by feedback mechanisms which sense the luminal environment are discussed. Adhesion at the epithelial surface and intracellular processing of crystals comprise a previously unrecognised mechanism for limiting crystal growth, which may be disrupted resulting in disease. Dent’s disease is discussed as a paradigm of a complex renal tubular disease resulting in renal stone formation. Defects in endosomal acidification, due to ablation of the CLC-5 voltage-gated Cl– channel, result in defects in both proximal and collecting duct endosomal traffic leading to stone formation.

Keywords:
Chloride channel, Crystals, Tubular epithelia, Collecting duct, Nephrocalcinosis
1.
Randall A: The origin and growth of renal calculi. Ann Surg 1937:105:1009.
2.
Kajander EO, Ciftcioglu N: Nanobacteria: An alternative mechanism for pathogenic intra- and extracellular calcification and stone formation. Proc Natl Acad Sci USA 1998;95:8274–8279.
3.
Brown EM, Pollak M, Hebert SC: The extracellular calcium-sensing receptor: Its role in health and disease. Annu Rev Med 1998;49:15–29.
4.
Sands JM, Flores FX, Kato A, Baum MA, Brown EM, Ward DT, Hebert SC, Harris HW: Vasopressin-elicited water and urea permeabilities are altered in IMCD in hypercalcemic rats. Am J Physiol 1998;274:F978–F985.
5.
Gruber AD, Elble RC, Ji HL, Schreur KD, Fuller CM, Pauli BU: Genomic cloning, molecular characterization, and functional analysis of human CLCA1, the first human member of the family of Ca2+-activated Cl– channel proteins. Genomics 1998;54:200–214.
6.
Boese SH, Glanville M, Aziz O, Gray MA, Simmons NL: Ca2+ and cAMP-activated Cl– conductances mediate Cl– secretion in a mouse renal inner medullary collecting duct cell line. J Physiol 2000;523:325–338.
7.
Shindo M, Simmons NL, Gray MA: Characterization of whole cell chloride conductances in a mouse inner medullary collecting duct cell line mIMCD-3. J Membr Biol 1996;149:21–31.
8.
Chen XZ, Vassilev PM; Basora N, Peng JB, Nomura H, Segal Y, Brown EM, Reeders ST, Hediger MA, Zhou J: Polycystin-L is a calcium-regulated cation channel permeable to calcium ions. Nature 1999;401:383–386.
9.
Asplin JR, Parks JH, Chen MS, Lieske JC, Toback FG, Pillay SN, Nakagawa Y, Coe FL: Reduced crystallization inhibition by urine from men with nephrolithiasis. Kidney Int 1999;56:1505–1516.
10.
Hess B: Tamm-Horsfall glycoprotein and calcium nephrolithiasis. Miner Electrolyte Metab 1994;20:393–398.
11.
Dent CE, Friedman M: Hypercalcuric rickets associated with renal tubular damage. Arch Dis Child 1964;39:240–249.
12.
Wrong OM, Norden AGW, Feest TG: Dent’s disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance. QJM 1994;87:473–493.
13.
Lloyd SE, Pearce SH, Fisher SE, Steinmeyer K, Schwappach B, Scheinman SJ, Harding B, Bolino A, Devoto M, Goodyer P, Rigden SP, Wrong O, Jentsch TJ, Craig IW, Thakker RV: A common molecular basis for three inherited kidney stone diseases. Nature 1996;379:445–449.
14.
Waldegger S, Jentsch TJ: From tonus to tonicity: Physiology of CLC chloride channels. J Am Soc Nephrol 2000;11:1331–1339.
15.
Devuyst O, Christie PT, Courtoy PJ, Beauwens R, Thakker RV: Intra-renal and subcellular distribution of the human chloride channel, CLC-5, reveals a pathophysiological basis for Dent’s disease. Hum Mol Genet 1999;8:247–257.
16.
Gunther W, Luchow A, Cluzeaud F, Vandewalle A, Jentsch TJ: ClC-5, the chloride channel mutated in Dent’s disease, colocalizes with the proton pump in endocytotically active kidney cells. Proc Natl Acad Sci USA 1998;95:8075–8080.
17.
Luyckx VA, Goda FO, Mount DB, Nishio T, Hall A, Hebert SC, Hammond TG, Yu AS: Intrarenal and subcellular localization of rat CLC5. Am J Physiol 1998;275:F761–F769.
18.
Piwon N, Gunther W, Schwake M, Bosl MR, Jentsch TJ: ClC-5 Cl– channel disruption impairs endocytosis in a mouse model for Dent’s disease. Nature 2000;408:369–373.
19.
Simon DB, Lu Y, Choate KA, Velazquez H, Al-Sabban E, Praga M, Casari G, Bettinelli A, Colussi G, Rodriguez-Soriano J, McCredie D, Milford D, Sanjad S, Lifton RP: Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption. Science 1999;285:103–106.
20.
Luyckx VA, Leclercq B, Dowland LK, Yu AS: Diet-dependent hypercalciuria in transgenic mice with reduced CLC5 chloride channel expression. Proc Natl Acad Sci USA 1999;96:12174–12179.
21.
Scheinman SJ: X-linked hypercalciuric nephrolithiasis: Clinical syndromes and chloride channel mutations. Kidney Int 1998;53:3–17.
22.
Obermüller N, Gretz N, Kriz W, Reilly RF, Witzgall R: The swelling-activated chloride channel ClC-2, the chloride channel ClC-3, and ClC-5, a chloride channel mutated in kidney stone disease, are expressed in distinct subpopulations of renal epithelial cells. J Clin Invest 1998;101:635–642.
23.
Stewart GS, Glanville M, Aziz O, Simmons NL, Gray MA: Regulation of an outwardly rectifying chloride conductance in renal epithelial cells by external and internal calcium. J Membr Biol 2001;180:49–64.
24.
Sayer JA, Stewart GS, Boese SH, Gray MA, Pearce SH, Goodship TH, Simmons NL: The voltage-dependent Cl(–) channel ClC-5 and plasma membrane Cl(–) conductances of mouse renal collecting duct cells (mIMCD-3). J Physiol 2001;536:769–783.
25.
Lieske JC, Deganello S, Toback FG: Cell-crystal interactions and kidney stone formation. Nephron 1999;81(suppl 1):8–17.
26.
Wang SS, Devuyst O, Courtoy PJ, Wang XT, Wang H, Wang Y, Thakker RV, Guggino S, Guggino WB: Mice lacking renal chloride channel, CLC-5, are a model for Dent’s disease, a nephrolithiasis disorder associated with defective receptor-mediated endocytosis. Hum Mol Genet 2000;9:2937–2945.
© 2002 S. Karger AG, Basel
2002
Copyright / Drug Dosage / Disclaimer
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.
You do not currently have access to this content.