Urinary calcium, magnesium and citrate levels are important in promoting or inhibiting renal stone formation. Here we review current information on the tubular handling of these ions. Most filtered calcium is reabsorbed in the proximal tubule and the thick ascending limb (TAL) of the loop of Henle, largely paracellularly; most of the remainder is reabsorbed in the distal tubule, transcellularly. Calcium reabsorption in the TAL and distal tubule is stimulated by parathyroid hormone and vitamin D; other factors influencing its renal handling include extracellular volume status and acid-base balance. Little filtered magnesium is reabsorbed in the proximal tubule; the bulk is reabsorbed paracellularly in the TAL, while most of the remainder is reabsorbed transcellularly in the distal tubule. Dietary intake, peptide hormones and chronic potassium depletion can all influence magnesium reabsorption in the TAL and distal tubule. Most filtered citrate is taken up across the apical membrane of the proximal tubule via a sodium-dicarboxylate co-transporter (NaDC-1). It also enters proximal tubular cells across the basolateral membrane; citrate contributes to the cells’ oxidative metabolism. Citrate excretion is affected by acid-base balance, acetazolamide treatment, chronic potassium depletion and urinary excretion of calcium and magnesium. Where possible, we have indicated the mechanisms of these complex interactions.

1.
Friedman PA: Renal calcium metabolism; in Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology, ed 3. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 1749–1789.
2.
Hebert SC: Extracellular calcium-sensing receptor: Implications for calcium and magnesium handling in the kidney. Kidney Int 1996;50:2129–2139.
3.
Magosci M, Yamaki M, Penniston JT, Dousa TP: Localization of mRNAs coding for isozymes of plasma membrane Ca2+-ATPase pump in rat kidney. Am J Physiol 1992;263:F7–F14.
4.
Hoenderop JGJ, Nilius B, Bindels RJM: Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol 2002;64:529–549.
5.
Nijenhuis T, Hoenderop JGJ, Loffing J, van der Kemp AWCM, van Os CH, Bindels RJM: Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney. Kidney Int 2003;64:555–564.
6.
Costanzo LS: Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985;248:F527–F535.
7.
Rizzo M, Capasso G, Bleich M, Pica A, Grimaldi D, Bindels RJM, Greger R: Effect of chronic metabolic acidosis on calbindin expression along the rat distal tubule. J Am Soc Nephrol 2000;11:203–210.
8.
Quamme GA, de Rouffignac C: Renal magnesium handling; in Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology, ed 3. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 1711–1729.
9.
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.
10.
Walder RY, Landau D, Meyer P, Shalev H, Tsolia M, Borochowitz Z, Boettger MB, Beck GE, Englehardt RK, Carmi R, Sheffield VC: Mutation of TRPM6 causes familial hypomagnesemia with secondary hypocalcemia. Nat Genet 2002;31:171–174.
11.
Dai L-J, Ritchie G, Kerstan D, Kang HS, Cole DEC, Quamme GA: Magnesium transport in the renal distal convoluted tubule. Physiol Rev 2001;81:51–84.
12.
Hamm LL: Renal handling of citrate. Kidney Int 1990;38:728–735.
13.
Brennan TS, Klahr S, Hamm LL: Citrate transport in rabbit nephron. Am J Physiol 1986;251:F683–F689.
14.
Pajor AM: Sodium-coupled transporters for Krebs cycle intermediates. Annu Rev Physiol 1999;61:663–682.
15.
Chen X, Tsukaguchi H, Chen X-Z, Berger UV, Hediger MA: Molecular and functional analysis of SDCT2, a novel rat sodium-dependent dicarboxylate transporter. J Clin Invest 1999;103:1159–1168.
16.
Dedmon RE, Wrong O: The excretion of organic anion in renal tubular acidosis with particular reference to citrate. Clin Sci 1962;22:19–32.
17.
Aruga S, Wehrli S, Kaissling B, Moe OW, Preisig PA, Pajor AM, Alpern RJ: Chronic metabolic acidosis increases NaDC-1 mRNA and protein abundance in rat kidney. Kidney Int 2000;58:206–215.
18.
Simpson DP: Citrate excretion: A window on renal metabolism. Am J Physiol 1983;244:F223–F234.
19.
Hamm LL, Hering-Smith KS: Pathophysiology of hypocitraturic nephrolithiasis. Endocrinol Metab Clins N Am 2002;31:885–893.
20.
Levi M, McDonald LA, Preisig PA, Alpern RJ: Chronic K depletion stimulates rat renal brush-border membrane Na-citrate cotransporter. Am J Physiol 1991;261:F767–F773.
21.
Soleimani M, Bergman JA, Hosford MA, McKinney TD: Potassium depletion increases luminal Na+/H+ exchange and basolateral Na+:CO3=:HCO3 co-transport in rat renal cortex. J Clin Invest 1990;86:1076–1083.
22.
Rudman D, Kutner MH, Redd SC, Waters WC, Gerron GG, Bleier J: Hypocitraturia in calcium nephrolithiasis. J Clin Endocrinol Metab 1982;55:1052–1057.
23.
Mossetti G, Vuotto P, Rendina D, Numis FG, Viceconti R, Giordano F, Cioffi M, Scopacasa F, Nunziata V: Association between vitamin D receptor gene polymorphisms and tubular citrate handling in calcium nephrolithiasis. J Intern Med 2003;253:194–200.
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.