Nephrocalcinosis: molecular insights into calcium precipitation within the kidney

Abstract

Nephrocalcinosis may be defined as a generalized increase in the calcium content of the kidneys. This renal calcification may occur at a molecular, microscopic or macroscopic level leading to progressive amounts of renal damage. The major causes include those associated with an increase in urinary levels of calcium, oxalate and phosphate. Under these conditions, urine concentration and supersaturation leads to calcium crystal precipitation, which may be an intratubular event or initiate within the renal interstitium. The focus of discussion concerning renal calcification is often limited to factors that lead to renal stones (calculi and nephrolithiasis); however, nephrocalcinosis is a more sinister event, and often implies a serious metabolic defect. This review will discuss the hypotheses concerning initiating lesions of nephrocalcinosis using available laboratory and clinical studies and will examine whether new understanding of the molecular basis of tubulopathies, that lead to nephrocalcinosis, has given further insights.

Adverse Renal and Metabolic Effects Associated with Oral Sodium Phosphate Bowel Preparation

“…In many cases, the initial event in the development of both nephrocalcinosis and nephrolithiasis may be the formation of calcium-phosphate deposits in the thin limb of Henle, called "Randall's plaques," which form largely due to supersaturation of calcium and phosphate in that portion of the tubule (66,67). When these plaques rupture into the urinary space, they serve as a nidus for calcium-oxalate crystallization, and nephrocalcinosis results when the urothelium overgrows and encapsulates the crystals (63,68). The observation that most calcium-oxalate stones contain some calcium-phosphate supports this mechanism (61,66).…”

“…Calcium phosphate crystals are not birefringent, whereas calcium oxalate crystals are birefringent upon examination under polarized light. Hypercalciuria is a wellestablished risk factor for calcium crystal deposition, but nephrocalcinosis can occur in the setting of normal calcium excretion, particularly in the presence of primary or secondary hyperoxaluria (63). Patients with primary hyperoxaluria overproduce oxalate due to inherited enzyme defects and develop severe nephrocalcinosis and nephrolithiasis (64).…”

The Calcium-Sensing Receptor Promotes Urinary Acidification to Prevent Nephrolithiasis

“…[12][13][14] The formation of less acidic urine predisposes to urolithiasis as the crystallization of Ca 2ϩ -phosphate occurs via the conversion of phosphate to its divalent form (HPO 4 2Ϫ ) in an alkaline rather than in an acidic environment. 15,16 Previously, insufficient urinary acidification was demonstrated in recurrent stone formers. 17,18 Currently, no clinical trials have documented the description of the prevention of stone formation by stimulating urinary acidification.…”

Crystal Retention in Renal Stone Disease

“…It is not clear how these compounds (and phosphate) can become so high in the papillary interstitium. Perhaps they are actively pumped into the interstitium by membrane transport proteins (156,157). Despite their extremely high concentrations, poorly soluble calcium salts do not precipitate continuously in the papillary interstitium.…”