Diuretics and calcium balance
- Richard H Sterns, MD
Richard H Sterns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Fluid and Electrolytes
- Professor of Medicine
- University of Rochester School of Medicine and Dentistry
Most of the filtered calcium is reabsorbed throughout the nephron. This process involves two basic steps: (1) calcium is reabsorbed passively in the proximal tubule and loop of Henle down the favorable electrochemical gradients created by sodium and water reabsorption; and (2) calcium transport is actively regulated according to changes in calcium balance in the distal tubule and adjacent connecting segment (a small segment between the distal tubule and cortical collecting tubule) [1,2]. Parathyroid hormone (PTH) and calcitriol, the most active form of vitamin D, which may act in part by enhancing the activity of PTH, appear to stimulate this active process [1,3,4].
Calcium reabsorption and urinary calcium excretion can be affected by the administration of diuretics. Calcium excretion is increased by loop diuretics and diminished by thiazide-type diuretics and amiloride. How these effects occur is related to the mechanisms of sodium, chloride, and calcium transport in the different diuretic-sensitive segments. Ions cannot directly cross epithelial cell membranes. As a result, transcellular reabsorption of ions requires either the presence of transmembrane carriers or channels  or passage through the paracellular space between the tubular cells.
LOOP OF HENLE AND LOOP DIURETICS
Filtered sodium chloride enters the cells in the thick ascending limb of the loop of Henle via Na-K-2Cl cotransporters in the luminal (or apical) membrane (figure 1) [5-7]. Although this process is electrically neutral, most of the reabsorbed potassium leaks back into the lumen to drive further sodium chloride transport . This movement of cationic potassium into the lumen plus the movement of reabsorbed chloride (via a chloride channel) out of the cell into the peritubular capillary generates a net positive current from the capillary into the lumen. The ensuing lumen electropositivity creates an electrical gradient that promotes the passive reabsorption of cations (sodium and, to a lesser degree, calcium and magnesium) via the paracellular pathway between the cells .
Loop diuretics act by competing for the chloride site on the Na-K-2Cl cotransporter [5,6]. Inhibiting sodium chloride reabsorption also inhibits the backleak of potassium and the generation of the lumen-positive potential. As a result, calcium excretion rises, an effect that may be exploited in the treatment of hypercalcemia in selected patients. (See "Treatment of hypercalcemia", section on 'Saline hydration'.)
In neonates, the calciuresis induced by a loop diuretic may be deleterious since it can lead to the development of nephrocalcinosis. (See "Nephrocalcinosis in neonates", section on 'Pathogenesis'.)
- Friedman PA, Gesek FA. Calcium transport in renal epithelial cells. Am J Physiol 1993; 264:F181.
- Hoenderop JG, Nilius B, Bindels RJ. Molecular mechanism of active Ca2+ reabsorption in the distal nephron. Annu Rev Physiol 2002; 64:529.
- Gesek FA, Friedman PA. On the mechanism of parathyroid hormone stimulation of calcium uptake by mouse distal convoluted tubule cells. J Clin Invest 1992; 90:749.
- Friedman PA, Gesek FA. Vitamin D3 accelerates PTH-dependent calcium transport in distal convoluted tubule cells. Am J Physiol 1993; 265:F300.
- Rose BD. Diuretics. Kidney Int 1991; 39:336.
- Haas M. The Na-K-Cl cotransporters. Am J Physiol 1994; 267:C869.
- Gamba G, Miyanoshita A, Lombardi M, et al. Molecular cloning, primary structure, and characterization of two members of the mammalian electroneutral sodium-(potassium)-chloride cotransporter family expressed in kidney. J Biol Chem 1994; 269:17713.
- Friedman PA. Basal and hormone-activated calcium absorption in mouse renal thick ascending limbs. Am J Physiol 1988; 254:F62.
- Plotkin MD, Kaplan MR, Verlander JW, et al. Localization of the thiazide sensitive Na-Cl cotransporter, rTSC1 in the rat kidney. Kidney Int 1996; 50:174.
- Lemann J Jr, Gray RW, Maierhofer WJ, Cheung HS. Hydrochlorothiazide inhibits bone resorption in men despite experimentally elevated serum 1,25-dihydroxyvitamin D concentrations. Kidney Int 1985; 28:951.
- Nijenhuis T, Vallon V, van der Kemp AW, et al. Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia. J Clin Invest 2005; 115:1651.
- Costanzo LS. Localization of diuretic action in microperfused rat distal tubules: Ca and Na transport. Am J Physiol 1985; 248:F527.
- Gesek FA, Friedman PA. Mechanism of calcium transport stimulated by chlorothiazide in mouse distal convoluted tubule cells. J Clin Invest 1992; 90:429.
- Lajeunesse D, Bouhtiauy I, Brunette MG. Parathyroid hormone and hydrochlorothiazide increase calcium transport by the luminal membrane of rabbit distal nephron segments through different pathways. Endocrinology 1994; 134:35.
- Shimizu T, Nakamura M, Yoshitomi K, Imai M. Interaction of trichlormethiazide or amiloride with PTH in stimulating Ca2+ absorption in rabbit CNT. Am J Physiol 1991; 261:F36.
- Friedman PA. Codependence of renal calcium and sodium transport. Annu Rev Physiol 1998; 60:179.
- Nijenhuis T, Hoenderop JG, Loffing J, et al. Thiazide-induced hypocalciuria is accompanied by a decreased expression of Ca2+ transport proteins in kidney. Kidney Int 2003; 64:555.
- Biner HL, Arpin-Bott MP, Loffing J, et al. Human cortical distal nephron: distribution of electrolyte and water transport pathways. J Am Soc Nephrol 2002; 13:836.
- Hoenderop JG, van der Kemp AW, Hartog A, et al. The epithelial calcium channel, ECaC, is activated by hyperpolarization and regulated by cytosolic calcium. Biochem Biophys Res Commun 1999; 261:488.
- Hoenderop JG, van Leeuwen JP, van der Eerden BC, et al. Renal Ca2+ wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest 2003; 112:1906.
- Bindels RJ, Ramakers PL, Dempster JA, et al. Role of Na+/Ca2+ exchange in transcellular Ca2+ transport across primary cultures of rabbit kidney collecting system. Pflugers Arch 1992; 420:566.
- LaCroix AZ, Wienpahl J, White LR, et al. Thiazide diuretic agents and the incidence of hip fracture. N Engl J Med 1990; 322:286.
- Felson DT, Sloutskis D, Anderson JJ, et al. Thiazide diuretics and the risk of hip fracture. Results from the Framingham Study. JAMA 1991; 265:370.
- Cauley JA, Cummings SR, Seeley DG, et al. Effects of thiazide diuretic therapy on bone mass, fractures, and falls. The Study of Osteoporotic Fractures Research Group. Ann Intern Med 1993; 118:666.
- Heidrich FE, Stergachis A, Gross KM. Diuretic drug use and the risk for hip fracture. Ann Intern Med 1991; 115:1.
- Jones G, Nguyen T, Sambrook PN, Eisman JA. Thiazide diuretics and fractures: can meta-analysis help? J Bone Miner Res 1995; 10:106.
- Christensson T, Hellström K, Wengle B. Hypercalcemia and primary hyperparathyroidism. Prevalence in patients receiving thiazides as detected in a health screen. Arch Intern Med 1977; 137:1138.
- Wermers RA, Kearns AE, Jenkins GD, Melton LJ 3rd. Incidence and clinical spectrum of thiazide-associated hypercalcemia. Am J Med 2007; 120:911.e9.
- Chandler PD, Scott JB, Drake BF, et al. Risk of hypercalcemia in blacks taking hydrochlorothiazide and vitamin D. Am J Med 2014; 127:772.
- Friedman PA, Gesek FA. Stimulation of calcium transport by amiloride in mouse distal convoluted tubule cells. Kidney Int 1995; 48:1427.