INTRODUCTION — 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.
PROXIMAL TUBULE — Calcium that is not bound to protein (approximately one-half of the calcium in plasma) is filtered at the glomerulus, and approximately two-thirds of the filtered calcium is reabsorbed in the proximal tubule. Most proximal reabsorption is a passive paracellular process, driven by active sodium transport, which creates an osmotic gradient across the leaky proximal tubular epithelium that results in water (and calcium) reabsorption. Osmotic diuretics such as mannitol interfere with paracellular water reabsorption from the proximal tubule and increase fractional excretion of calcium . Sodium reabsorption in the proximal tubule occurs primarily through sodium-hydrogen exchange, which then creates an osmotic force across the leaky proximal tubular epithelium that drives water. The carbonic anhydrase inhibitor acetazolamide, which impairs sodium-hydrogen exchange, increases urinary calcium excretion . Inhibitors of sodium-glucose co-transporter 2 (SGLT-2), which are increasingly used to treat diabetes, block sodium-glucose co-transport in the proximal tubule, eliciting a glucose-induced osmotic diuresis. As a result, SGLT-2 inhibitors decrease the luminal calcium concentration that drives paracellular calcium reabsorption in the proximal tubule. Decreased proximal reabsorption of calcium is the likely mechanism for the increase in calcium excretion caused by these agents .
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) [5,8,9]. 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 [5,8]. 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 'Volume expansion with isotonic saline'.)
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'.)
DISTAL TUBULE AND THIAZIDE DIURETICS — Transcellular calcium transport in the distal tubule occurs through the transient receptor potential vanilloid 5 (TRPV5) channel, which facilitates calcium uptake from the tubular lumen. Extrusion of calcium from the tubular cell to the blood is driven by the Na-Ca exchanger and plasma membrane Ca-ATPase . The thiazide-type diuretics decrease NaCl reabsorption in the distal tubule and connecting segment (a short segment connecting the distal and cortical collecting tubules) by inhibiting Na-Cl cotransporters in the luminal membrane that are responsible for the entry of luminal sodium and chloride into the cell (figure 2) [9,11].
The diuresis induced by a thiazide diuretic may be accompanied by a fall in urinary calcium excretion of as much as 50 to 150 mg (1.3 to 3.8 mmol) per day .
Proposed mechanisms — Two main mechanisms have been proposed to explain the effect of thiazides on calcium excretion, but their relative importance is uncertain:
●Increased proximal sodium and water reabsorption due to volume depletion, which leads to increased passive proximal calcium reabsorption .
●Increased distal calcium reabsorption at the thiazide-sensitive site in the distal tubule and connecting segment [14-17]. Postulated mechanisms for this effect include increased entry of luminal calcium into the tubular cell via TRPV5 in the luminal membrane, enhanced extrusion out of the tubular cell via the Na-Ca exchanger in the basolateral membrane, and decreased levels of calcium transport proteins in the kidney [6,18-23]. Although distal tubular calcium reabsorption may be increased acutely, the chronic hypocalciuric effect is probably mediated primarily by the associated volume depletion, which increases proximal sodium and therefore calcium reabsorption .
Clinical implications — The effect of thiazide diuretics on calcium balance has several important clinical implications. Perhaps most important, the hypocalciuric action probably accounts for the ability of thiazide diuretics to reduce the frequency of recurrent stone formation in patients with idiopathic hypercalciuria. (See "Kidney stones in adults: Prevention of recurrent kidney stones".)
The fall in calcium excretion also tends to induce positive calcium balance or to minimize the degree of negative calcium balance that is commonly seen in older patients . This may be manifested clinically by an increase in bone density and, in patients treated for more than two years, a reduction in the incidence of hip fracture [24-26]. The latter benefit has not been confirmed in all studies , although a meta-analysis suggested that long-term thiazide use led to a 20 percent reduction in fracture risk . Chronic use of a loop diuretic may have the opposite effect as negative calcium balance may enhance the risk of hip fracture . (See "Drugs that affect bone metabolism", section on 'Thiazide diuretics'.)
Thiazide diuretics also increase the plasma calcium concentration, although the effect is usually small since even slight degrees of hypercalcemia suppress parathyroid hormone (PTH) secretion . In some patients, however, the plasma calcium can reach 11.5 mg/dL (2.9 mmol/L). In addition to urinary calcium retention, an increased plasma albumin concentration caused by fluid loss may contribute to thiazide-induced hypercalcemia; hyperalbuminemia increases the physiologically inactive concentration of albumin-bound calcium  (see "Relation between total and ionized serum calcium concentrations"). Cessation of diuretic therapy in this setting leads to rapid normalization of the plasma calcium.
Underlying primary hyperparathyroidism or some other hypercalcemic state should be suspected if thiazide therapy is associated with a rise in plasma calcium above 12 mg/dL (3 mmol/L) or if hypercalcemia persists after cessation of thiazide therapy [29,30]. This was best shown in a study of 72 patients with thiazide-associated hypercalcemia . Among 33 patients who discontinued the thiazide, persistent hypercalcemia was noted in 21, of whom 20 had primary hyperparathyroidism. (See "Diagnostic approach to hypercalcemia".)
Vitamin D, which is commonly given as a supplement, increases calcium absorption from the gastrointestinal tract. Combined with a thiazide, vitamin D supplements could theoretically increase the risk of hypercalcemia. The risk of the combination in subjects without other predisposing conditions, such as sarcoidosis or hyperparathyroidism, appears to be low. A post-hoc analysis of a randomized, double-blind, placebo-controlled dose-finding trial of vitamin D supplementation in community-based Black patients found that only 5.9 percent of thiazide users experienced hypercalcemia with concurrent use of hydrochlorothiazide and vitamin D . There was no dose-response relationship (more subjects had hypercalcemia in the 1000 international unit group than in the higher-dose groups [2000 or 4000 international units] at one month) .
CORTICAL COLLECTING TUBULE AND POTASSIUM-SPARING DIURETICS — Potassium-sparing diuretics act on the aldosterone-responsive distal nephron, decreasing sodium reabsorption and potassium secretion. Amiloride and triamterene block sodium entry into the tubular cell by closing luminal sodium channels (called epithelial sodium channels). Spironolactone and eplerenone block the mineralocorticoid receptor. Amiloride increases distal calcium reabsorption and reduces urinary calcium excretion (figure 3) [6,14,17,32,33].
The hypocalciuric response to amiloride may involve both the connecting segment (in which sodium entry occurs via both sodium channels and thiazide-sensitive Na-Cl cotransporters in the luminal membrane)  and the initial cortical collecting tubule (in which sodium entry occurs only via luminal sodium channels) [14,17,23].
The mechanism by which amiloride reduces calcium excretion is incompletely understood. The inhibitory effect on sodium reabsorption may hyperpolarize the membrane, thereby promoting calcium entry into the cell via calcium channels in the luminal membrane . In support of this hypothesis, the increases in calcium entry and intracellular calcium activity induced by amiloride can be prevented by the calcium channel blocker, nifedipine, in isolated distal tubular cells.
Triamterene has not been shown to have a hypocalciuric effect; since the drug has been shown to cause kidney stones, it should not be used to treat hypercalciuria . Little is known of the effect of spironolactone and eplerenone on urinary calcium excretion in normal subjects. However, primary hyperaldosteronism is associated with increased urinary calcium excretion, secondary hyperparathyroidism, and reduced bone mineral density [35,36]; hypercalciuria is reduced by treatment with spironolactone or adrenalectomy .
SUMMARY — Most of the filtered calcium is reabsorbed, an effect that occurs throughout the nephron. Calcium reabsorption in the proximal tubule can be affected by the patient's volume status as enhanced proximal sodium and water reabsorption due to volume depletion leads to increased passive proximal calcium reabsorption. (See 'Proposed mechanisms' above.)
Calcium reabsorption 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). Parathyroid hormone (PTH) and calcitriol, the most active form of vitamin D, appear to stimulate this active process. (See 'Introduction' above.)
Diuretic therapy has variable effects on urinary calcium excretion according to the site of action:
●Calcium excretion is increased by loop diuretics due to diminished reabsorption. This effect may be beneficial in selected patients with hypercalcemia, but can be deleterious in neonates, leading to the development of nephrocalcinosis. (See 'Loop of Henle and loop diuretics' above.)
●Calcium excretion is diminished by thiazide-type diuretics by as much as 50 to 150 mg (1.3 to 3.8 mmol) per day due to increased reabsorption. The fall in calcium excretion can be beneficial in certain clinical settings, reducing the frequency of new stone formation in patients with hypercalciuria and, with prolonged therapy, increasing bone density and possibly reducing the incidence of fracture. Thiazides may also cause a rise in plasma calcium, but levels above 12 mg/dL (3 mmol/L) or persistent hypercalcemia after the cessation of therapy suggests underlying primary hyperparathyroidism or some other cause of hypercalcemia. (See 'Distal tubule and thiazide diuretics' above.)
●Calcium excretion is also diminished by amiloride therapy, which increases calcium reabsorption. (See 'Cortical collecting tubule and potassium-sparing diuretics' above.)