Nephrolithiasis
Calcium Stones
Approximately 70% of all kidney stones contain calcium and are composed of calcium oxalate or calcium phosphate or both (Table 1) . Pure calcium oxalate stones occur more frequently than pure calcium phosphate stones. Once a patient forms a calcium-containing stone, another stone will generally form in less than 7 years, with a decreasing time interval to subsequent stone events [3] . Pregnancy increases urine calcium excretion but does not increase stone formation [12] . Calcium stones may form in urine that is supersaturated secondary to excess calcium, oxalate, or uric acid excretion, or the stones may form without a discernible cause.
Excess Calcium Excretion
Idiopathic Hypercalciuria
Patients with idiopathic hypercalciuria have a normal concentration of serum calcium; however, their urine calcium excretion exceeds the maximum of 300 mg/24 h in men, 250 mg/24 h in women, or 4 mg/kg in either sex [13] . These patients lack a definable disorder that would cause the observed elevation of urine calcium excretion. Idiopathic hypercalciuria tends to be familial, it is more prevalent in men, and initial stone formation often occurs in the third decade of life.
Although the cause of idiopathic hypercalciuria is obviously not known, it may result from disordered regulation of calcium handling at sites where large fluxes of calcium must be tightly regulated [1] [14] [15] [16] (Figure 1) . This disordered regulation may occur in the intestine, the kidney, or in the bone, resulting in an increase in urine calcium excretion (Table 4) . Increased intestinal calcium absorption may occur either by a direct mechanism or through excess 1,25-dihydroxyvitamin D3 (1,25(OH)2 D3 )-mediated calcium absorption. The increase in intestinal calcium absorption will result in a slight increase in serum calcium, a fall in parathyroid hormone, and an increase in the calcium filtered by the glomerulus and entering the renal tubule. Because parathyroid hormone increases renal tubule calcium reabsorption, a fall in parathyroid hormone coupled to an increase in the filtered load of calcium will result in hypercalciuria. Decreased renal reabsorption of either calcium or phosphorus, the latter through a hypophosphatemia-induced increase in 1,25(OH)2 D3 , will result in hypercalcemia. A primary increase in bone mineral resorption will increase serum calcium, suppress parathyroid hormone, and result in hypercalciuria.
Patients with idiopathic hypercalciuria cannot easily be characterized into any of these specific diagnostic groups [13] . Although there are expected serum and urine values for the alternative mechanisms of hypercalciuria (Table 4) , in formal metabolic studies there has been enough collection-to-collection variation among individual patients to preclude specific categorization [17] . Among large groups of patients, there appear to be smooth transitions in various metabolic parameters between the patients, which again precludes biologically significant grouping. However, several general concepts have emerged from studies of patients with idiopathic hypercalciuria. Most investigators agree that patients have an increase in net intestinal calcium absorption, have increased 1,25(OH)2 D3 levels, have increased intestinal calcium absorption relative to the 1,25(OH)2 D3 levels, and have mild decreases in bone mineral density [1] [14] [18] . These abnormalities appear to point to a systemic disregulation of the effect of 1,25(OH)2 D3 acting on the intestine, bone, and possibly kidney.
Genetic Hypercalciuric Stone-Forming Rats.
To more fully understand idiopathic hypercalciuria in humans, we have developed an animal model of this disorder [15] [16] [19] [20] [21] [22] [23] [24] [25] . Through more than 46 generations of successive inbreeding of the most hypercalciuric progeny of hypercalciuria Sprague Dawley rats, we have established a strain of rats, each of which excrete abnormally large amounts of urinary calcium (Figure 2) . As in humans, the principal mechanism for the excessive calcium excretion in these rats appears to be an increase in intestinal calcium absorption [15] . The increased intestinal calcium absorption appears to be mediated not by an increase in the serum level of 1,25(OH)2 D3 , but by an increase in the number of intestinal vitamin D receptors [25] . When these hypercalciuric rats are fed a very low calcium diet, their urine calcium excretion remains elevated compared with that of similarly treated control rats, indicating a defect in renal calcium reabsorption and/or an increase in bone resorption [24] , again similar to observations in humans [2] . When exposed to increasing amounts of 1,25(OH)2 D3 [22] , the bone of these hypercalciuric rats releases more calcium compared with bone of control rats. In addition, a primary defect in renal calcium reabsorption is observed during clearance studies [21] . We have shown that both the bone and kidney of hypercalciuric
| Parameter | Increased Intestinal Ca Absorption | Decreased Renal Reabsorption | Enhanced Bone Demineralization | ||
|---|---|---|---|---|---|
| Direct | Excess 1,25(OH)2 D3 | Calcium | Phosphorus | ||
| Ca absorption | Primary  |
|
|
|
 |
| Serum 1,25(OH)2 D3 | |
Primary |
|
|
|
| Serum PTH | |
|
|
|
|
| Bone Ca | nl | nl to |
nl to |
nl to |
Primary |
| Fasting serum Ca | nl to |
nl to |
|
nl to |
nl to |
| Fasting serum P | nl | nl to |
nl to |
|
nl to |
| Fasting urine Ca | nl | |
Primary |
|
|
| Urine Ca after low Ca diet | nl | nl to |
|
nl to |
|
a Ca, calcium; 1,25(OH)2 D3 , 1,25 dihydroxyvitamin D3 ; PTH, parathyroid hormone; P, phosphorus; , increase; , decrease; nl, normal.
rats also have an increased number of vitamin D receptors [22] [25] . Thus, these hypercalciuric rats appear to have a systemic abnormality in calcium homeostasis; they absorb more intestinal calcium, they resorb more bone, and they fail to adequately reabsorb filtered calcium. Because each of these hypercalciuric rats forms renal stones, we have termed the rats genetic hypercalciuric stone-forming (GHS) rats [16] [19] . Additional studies in GHS rats may help elucidate the mechanism of idiopathic hypercalciuria in humans.
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