Nephrolithiasis
Treatment
The treatment of patients with idiopathic hypercalciuria involves reduction of urine calcium excretion, especially using long-acting thiazide diuretics, in association with increasing fluid intake, both in an effort to decrease supersaturation with respect to the calcium-containing solid phases [2] [3] [13] [14] . Oral fluids, especially water, should be increased so that patients excrete more than 2 L of urine each day, and periods of dehydration must be avoided. Most clinicians use a long-acting thiazide diuretic such as chlorthalidone to reduce calcium excretion. Indapamide may be preferable in patients at risk for arterial plaque formation because it does not increase serum lipids. Patients should be monitored for hypokalemia and, if necessary, supplemented with potassium or a potassium-sparing diuretic such as amiloride. Triamterene should be avoided as it may, itself, cause stones.
Limitation of sodium and protein intake has theoretical advantages in decreasing urine calcium excretion. Limitation of calcium intake, in general, is not prudent because intestinal calcium will not be present to bind oxalate, resulting in enhanced oxalate absorption, excretion, and an increased propensity for stone formation. In a large epidemiologic study, decreased calcium intake was associated with increased stone formation [26] . In addition, patients with nephrolithiasis are often found to have decreased bone mineral density, and limitation of calcium intake could potentially worsen this osteopenia [14] . For these reasons, age- and gender-appropriate calcium intake should be maintained. Often, the recommendation that the patient consume calcium requires extensive reeducation, because many have been advised, on numerous occasions, to studiously avoid calcium.
Hormonal Hypercalciuria
Patients with hyperparathyroidism have an elevated serum calcium concentration and urine calcium excretion and a decrease in serum phosphorus concentration due to an increase in the serum level of parathyroid hormone [27] . The elevation in serum calcium may be very slight and may be in the upper range of normal; measurement of ionized calcium is often helpful to support the diagnoses. Especially in the presence of any degree of renal insufficiency, it is important to use the newer, immunoradiometric assays to determine the serum level of parathyroid hormone, because older methods may give false elevations due to the accumulation of biologically inactive metabolites [28] . This disorder is most common in elderly women, and at surgery they are generally found to have a single parathyroid adenoma [29] . Patients with hyperparathyroidism most commonly form hydroxyapatite or calcium oxalate stones.
Parathyroid hormone increases renal tubular calcium reabsorption, increases bone resorption, and increases the synthesis of 1,25(OH)2 D3 [27] . Excess, unregulated secretion of parathyroid hormone will result in hypercalcemia leading to an increase in the filtered load of calcium. When the increased filtered load of calcium exceeds threshold for renal tubule calcium reabsorption, which is increased by parathyroid hormone, hypercalciuria ensues. Parathyroid hormone also decreases the threshold for renal tubule phosphate reabsorption, resulting in hyperphosphaturia and hypophosphatemia despite the increased 1,25(OH)2 D3 -mediated phosphate absorption. A reduction in serum phosphate results in further elevations of 1,25(OH)2 D3 -mediated calcium absorption, worsening the hypercalcemia and hypercalciuria.
There are other hormonally mediated, hypercalcemic disorders that can occasionally lead to stone formation. Granulomatous tissue found in sarcoidosis and tuberculosis converts 25-hydroxyvitamin D3 to 1,25-dihydroxyvitamin D3 , resulting in hypercalcemia and hypercalciuria; however, levels of parathyroid hormone are depressed [30] . Excess vitamin D supplementation, especially with ample calcium intake, will result in hypercalciuria. Levels of parathyroid hormone again will be depressed. Lithium therapy may directly increase parathyroid hormone secretion and result in hypercalcemia and hypercalciuria. Malignant cells can secrete parathyroid hormone-related peptide, which acts in a similar manner to parathyroid hormone; however, it is not detected on standard parathyroid hormone assays [31] . Specific assays for parathyroid hormone-related peptide are currently available.
Renal Tubular Acidosis
Approximately two-thirds of patients with classical distal renal tubular acidosis (type I), either of the spontaneous or inherited variety, appear to have nephrocalcinosis or nephrolithiasis or both [32] . The stones are generally composed of calcium phosphate. Patients with proximal renal tubular acidosis (type II) generally do not have nephrocalcinosis or stones, but appear to have osteomalacia or rickets.
The mechanism of stone formation in patients with distal renal tubular acidosis is multifactorial; patients have increased urine calcium and phosphorus excretion, have a high urine pH, and decreased citrate excretion [33] . Increased urine calcium excretion appears due to a direct effect of acidosis to decrease renal tubule calcium reabsorption [34] . There is no concomitant increase in intestinal calcium absorption so that the increased urine calcium excretion must be derived from the bone mineral [35] [36] . Increased urine pH decreases the solubility of calcium phosphate complexes, resulting in greater urine supersaturation at any urine calcium and phosphorus concentration. Citrate is freely filtered by the glomerulus and reabsorbed in the proximal tubule. Acidosis increases proximal tubule citrate absorption and decreases its excretion. Citrate binds urine calcium, lowering its concentration, and acts as an inhibitor of crystallization. Thus, an acidosis-induced reduction in urinary citrate excretion not only increases the available calcium, raising supersaturation with respect to calcium phosphate complexation, but decreases an important crystallization inhibitor. Alkali administration reduces nephrocalcinosis and nephrolithiasis by decreasing calcium and increasing citrate excretion despite maintenance of an elevated urine pH.
Decreased Citrate Excretion
Urinary citrate is decreased in many patients who form calcium stones [37] [38] . The decreased urinary citrate excretion is often secondary to excessive dietary protein intake, which leads to increased endogenous acid production and increased net acid excretion. Patients with chronic diarrhea have an ongoing loss of base and often have decreased urinary citrate excretion. Decreasing dietary protein intake and, if necessary, administering base such as potassium bicarbonate or potassium citrate will increase citrate excretion and may help prevent stone formation. The sodium salt of the base should be avoided because sodium, but not potassium, will increase urine calcium excretion [39] . Patients often prefer tablets to potassium-containing liquids.
Excess Oxalate Excretion
Hyperoxaluria
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