Calcium Kidney Stones

Pathogenesis, Evaluation, and Treatment Options

Helen L. Figge, RPh, PharmD, MBA


US Pharmacist 

In This Article

Stone Formation

Calcium stones form when urine is supersaturated with the constituent ions that comprise the stone. Hence, supersaturation with calcium and oxalate ions will promote the formation of calcium oxalate stones. Supersaturation of urine with calcium and phosphate ions will promote the formation of calcium phosphate stones. Supersaturation occurs when the product of the ionic activity of calcium [Ca2+]a and oxalate [Oxalate2−]aexceeds the solubility product for calcium oxalate (SP1); or the product of the ionic activity of calcium [Ca2+]a and phosphate [HPO4 2−]a exceeds the solubility product for calcium phosphate (SP2) (Figure 1).

Figure 1.

Solubility Product for Calcium Oxalate (SP1) and Calcium Phosphate (SP2)

Homogeneous nucleation occurs when calcium and oxalate ions complex to form small crystals that then grow to larger pure calcium oxalate stones. Heterogeneous nucleation occurs when calcium and phosphate ions complex to initially form small crystals of calcium phosphate. These small crystals form the substrate upon which calcium oxalate subsequently deposits. This results in a mixed calcium oxalate–calcium phosphate stone. Various factors contribute, including the concentrations of individual free (unbound) ions such as calcium and oxalate, the pH, and the presence or absence of other substances that can either accelerate or retard the formation of calcium stones. For example, citrate is a known inhibitor of calcium crystallization, because citrate forms soluble complexes with calcium, which then lowers the ionic activity of free calcium ions in the urine and decreases stone formation.[7] There are several known endogenous inhibitors of calcium crystallization including uropontin, pyrophosphate, and nephrocalcin.[8,9]

The formation of a stone and its growth are also dependent upon the ability of crystals to anchor to renal tubule epithelium. The anchoring typically occurs over patches of calcium phosphate in the form of apatite. Twenty-four hour collections of urine are often obtained to measure the concentrations of calcium, oxalate, and phosphate, to estimate risk of stone formation. However, patients with similar levels of supersaturation will have varying risk of calcium stone formation depending upon the activity of inhibitors.

Various anatomical abnormalities can contribute to stone formation. The horseshoe kidney malformation, polycystic kidney, or obstructions at the ureteropelvic junction can cause urinary stasis, which increases the risk of stone formation. Patients with a single functioning kidney in these circumstances are at high risk of developing acute renal failure.

Dietary Factors

Dietary factors can significantly influence the level of excreted calcium, phosphate, and oxalate ions. Increasing fluid intake to 2 L or more a day can greatly diminish stone formation,[10] since the relevant ions become more diluted in the urine, reducing the risk of supersaturation. Dietary sodium intake is also a relevant factor because increased sodium excretion leads to increased renal calcium excretion. Any condition that promotes metabolic acidosis also enhances renal calcium excretion. Excessive animal protein intake can increase the risk of calcium stone formation via multiple mechanisms, including development of a mild metabolic acidosis.

The effect of dietary calcium intake is more complex. One might think that a low-calcium diet would decrease the incidence of stone formation. This is not always observed in practice, because dietary calcium also binds oxalate in the gastrointestinal (GI) tract and prevents its absorption. Hence, inadequate calcium intake can lead to excessive GI absorption and renal excretion of oxalate. Age and sex-appropriate calcium intake along with a low-oxalate, low-sodium, low-animal-protein diet (with 2 to 3 L of water a day) has been shown in a randomized study to decrease the risk of calcium stone formation in comparison with a low-calcium diet.[11] On the other hand, excessive intake of calcium and vitamin D can increase the risk of stone formation.

Metabolic and Genetic Factors

Metabolic derangements can also increase the risk of developing a calcium stone. Idiopathic hypercalciuria is the most common biochemical abnormality found in patients with recurrent calcium stone formation. The hypercalciuria is typically familial but is significantly influenced by dietary calcium intake. Patients with idiopathic hypercalciuria may demonstrate increased GI absorption of calcium; however, serum calcium levels remain normal because the excess calcium is promptly excreted. The actual defects appear to be: 1) a greater-than-expected decrease in renal calcium reabsorption compared to normal control subjects; 2) increased intestinal calcium absorption; and 3) excessive bone demineralization.[12] There are no abnormalities of parathyroid hormone levels in these patients. Even on a low-calcium diet, the excretion of calcium is increased in these individuals, implying that calcium is mobilized from bone. The underlying genetic defect in the familial form of hypercalciuria has not yet been identified, but it is thought that this is a polygenic disorder. At the molecular level, this condition could be a dysregulation of a calcium transport mechanism. Numerous hypotheses regarding the underlying defect have been advanced, but the data are inconclusive.[13]

Another biochemical abnormality that should be excluded is primary hyperparathyroidism. In cases of primary hyperparathyroidism, serum calcium is elevated in association with elevated intact parathyroid hormone levels. Primary hyperparathyroidism can be diagnosed or excluded by simultaneous measurement of serum calcium and intact parathyroid hormone.[14]

Certain systemic disorders such as sarcoidosis can cause hypercalcemia and may also lead to hypercalciuria, which can increase the risk of stone formation.[15] Some GI disorders such as Crohn's disease are associated with small bowel dysfunction and nephrolithiasis.[16] Increased intestinal fat binds calcium, which is then not available to sequester oxalate in the GI tract. This results in increased oxalate absorption and increased urinary oxalate. Patients with Crohn's disease also demonstrate decreased urinary citrate.

There are also a number of rare genetic disorders such as X-linked hypercalciuric nephrolithiasis, which lead to hypercalciuria and stone formation.[17] This disorder is caused by mutations in a chloride channel. It is not understood how the molecular lesion leads to the clinical phenotype.

Primary hyperoxaluria type 1 is a rare genetic disorder due to mutations in the AGXT gene that encodes an enzyme that catalyzes the conversion of glyoxylate to glycine.[18] When the enzyme is inactive, glyoxylate is converted to oxalate, resulting in hyperoxaluria.

Drug-induced Factors

There are several medications that can increase the risk of calcium stone formation. These include acetazolamide, amphotericin B, calcium antacids, calcium supplements, glucocorticoids, loop diuretics, theophylline, and vitamin D.[19] Acetazolamide contributes to calcium stone formation in part by inducing a mild metabolic acidosis. Calcium antacids and supplements increase the load of absorbed calcium and hence increase the amount of excreted calcium. Loop diuretics directly stimulate urinary excretion of calcium.


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