Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate. Although there are numerous medical conditions (hyperparathyroidism, hypervitaminosis D, sarcoidosis, malignancies, etc) that cause hypercalciuria, many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption. This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the DCT and thus reduce the urinary Ca2+ concentration. Fluid intake should be increased, but salt intake must be reduced, since excess dietary NaCl will overwhelm the hypocalciuric effect of thiazides. Dietary Ca2+ should not be restricted, as this can lead to negative total body Ca2+ balance. 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.
Hypercalcemia can be a medical emergency (see Chapter 42). Because loop diuretics reduce Ca2+ reabsorption significantly, they can be quite effective in promoting Ca2+ diuresis. However, loop diuretics alone can cause marked volume contraction. If this occurs, loop diuretics are ineffective (and potentially counterproductive) because Ca2+ reabsorption in the proximal tubule would be enhanced. Thus, saline must be administered simultaneously with loop diuretics if an effective Ca2+ diuresis is to be maintained. The usual approach is to infuse normal saline and furosemide (80–120 mg) intravenously. Once the diuresis begins, the rate of saline infusion can be matched with the urine flow rate to avoid volume depletion. Potassium chloride may be added to the saline infusion as needed.
Diabetes insipidus is due to either deficient production of ADH (neurogenic or central diabetes insipidus) or inadequate responsiveness to ADH (nephrogenic diabetes insipidus [NDI]). Administration of supplementary ADH or one of its analogs is effective only in central diabetes insipidus. Thiazide diuretics can reduce polyuria and polydipsia in nephrogenic diabetes insipidus, which is not responsive to ADH supplementation. Lithium, used in the treatment of manic-depressive disorder, is a common cause of NDI, and thiazide diuretics have been found to be helpful in treating it. This seemingly paradoxical beneficial effect of thiazides was previously thought to be mediated through plasma volume reduction, with an associated fall in GFR, leading to enhanced proximal reabsorption of NaCl and water and decreased delivery of fluid to the downstream diluting segments. However, in the case of Li+-induced NDI, it is now known that HCTZ causes increased osmolality in the inner medulla (papilla) and a partial correction of the Li+-induced reduction in aquaporin-2 expression. HCTZ also leads to increased expression of Na+ transporters in the DCT and CCT segments of the nephron. Thus, the maximum volume of dilute urine that can be produced is significantly reduced by thiazides in NDI. Dietary sodium restriction can potentiate the beneficial effects of thiazides on urine volume in this setting. Serum Li+ levels must be carefully monitored in these patients, because diuretics may reduce renal clearance of Li+ and raise plasma Li+ levels into the toxic range (see Chapter 29). Lithium-induced polyuria can also be partially reversed by amiloride, which blocks Li+ entry into collecting duct cells, much as it blocks Na+ entry. As mentioned above, thiazides are also beneficial in other forms of nephrogenic diabetes insipidus. It is not yet clear whether this is via the same mechanism that has been found in Li+-induced NDI. Acetazolamide has also shown efficacy in treating polyuria in nephrogenic diabetes insipidus with fewer adverse events.