Hypercalciuria diuretics

Thiazides inhibit NaCI reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Q transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria. 

See Table 15-5. The major indications for thiazide diuretics are (1) hypertension, (2) heart failure, (3) nephrolithiasis due to idiopathic hypercalciuria, and (4) nephrogenic diabetes insipidus. Use of the thiazides in each of these conditions is described in Clinical Pharmacology of Diuretic Agents. 

Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate. Many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption that causes hypercalciuria. This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the distal convoluted tubule and thus reduce the urinary Ca2+ concentration. Salt intake must be reduced in this setting, since excess dietary NaCI will overwhelm the hypocalciuric effect of thiazides. Calcium stones may also be caused by increased intestinal absorption of Ca2+, or they may be idiopathic. In these situations, thiazides are also effective, but should be used as adjunctive therapy with other measures. 

Renal hypercalciuria (kidney stones). Thiazide diuretics such as metolazone (Zaroxolyn) that increase calcium levels in the body are used in the treatment of kidney stones. 

Idiopathic hypercalciuria, a common cause of renal stone disease, may be reduced by thiazide diuretics... 

Four children with the nephrotic syndrome developed transient hypercalciuria and intraluminal calcification in renal histopathological specimens without radiological evidence of renal calcification. These children were resistant to corticosteroids and were receiving furosemide plus albumin for the management of edema (10). This result stresses the pervasive effect of furosemide, and probably all loop diuretics, in increasing urinary calcium excretion, with resultant nephrocalcinosis. Whenever possible, steps should be taken to limit the hypercalciuric effect of loop diuretics. Such maneuvers could include limiting the sodium content of the diet and/or combining the loop diuretic with a thiazide diuretic. 

Diuretics have been shown to have variable effects in relationship to urinary calcium excretion and supersaturation, most notably including loop diuretic induced hypercalciuria and attenuation of urinary calcium excretion by thiazide diuretics. The factors contributing to nephrotoxicity are most commonly associated with multiple factors that favor calcium salt or uric acid deposition at the tubulo-interstitial level. Management of renal stone formation and nephrocalcinosis therefore presents a unique clinical challenge, balancing factors that increase risk for abnormal calcium salt deposition or crystallization, and factors that reduce this risk. 

Some individuals with hypercalciuria (an elevated urinary concentration of calcium) are prune In the formation of Ca -enniaining. stnnes within the urinary tract. Becau.se Inng-temi use of thiazide and thiazide-like diuretics de-crea.ses the urinary excretion rate of Ca". they may help prevent Ca" -containing stone fnrmation. "... 

Since unresolved nephrocaldnosis may lead to residual abnormalities in the kidney induding microscopic hematuria, hypercalciuria, and impaired tubular function [109, 113, 114], renal ultrasonography within a few months of initiating loop diuretics may be warranted [109,113]. If long-term diuretic therapy is needed, a thiazide diuretic alone or in combination with furosemide may reduce the risk of renal calcifications by decreasing urinary calcium and oxalate excretion [109, 111, 113,117,118]. However, two studies of premature infants failed to show a reduction in either urinary oxalate or calcium excretion when thiazides were added to furosemide therapy [116,119]. The lack of beneficial response may have been due to replacement of the infants sodium losses with large amounts of supplemental sodium. 

An established interaction. The incidence is unknown but the reports cited suggest that it can be considerable if the intake of vitamin D and calcium are high. Concurrent use need not be avoided thiazides have been used clinically to reduce vitamin-D induced hypercalciuria, but the serum calcium levels should be regularly monitored to ensure that they do not become exeessive. Patients should be warned about the ingestion of very large amounts of calcium carbonate (readily available without prescription) if they are taking thiazide diuretics. 

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