Low Sodium Diet Decreases Stone Formation in Genetic Hypercalciuric Stone-Forming Rats.

Background: Urine (u) calcium (Ca) excretion is directly dependent on dietary sodium (Na) intake leading to the recommendation for Na restriction in hypercalciuric kidney stone formers. However, there is no direct evidence that limiting Na intake will reduce recurrent stone formation.

Materials And Methods: We used genetic hypercalciuric stone-forming (GHS) rats, which universally form Ca phosphate (P) kidney stones, fed either a low Na (LNa, 0.

Modeling hypercalciuria in the genetic hypercalciuric stone-forming rat.

Purpose Of Review: In this review, we discuss how the genetic hypercalciuric stone-forming (GHS) rats, which closely model idiopathic hypercalciuria and stone formation in humans, provide insights into the pathophysiology and consequences of clinical hypercalciuria.

Recent Findings: Hypercalciuria in the GHS rats is due to a systemic dysregulation of calcium transport, as manifest by increased intestinal calcium absorption, increased bone resorption and decreased renal tubule calcium reabsorption. Increased levels of vitamin D receptor in intestine, bone and kidney appear to mediate these changes.

Effect of Potassium Citrate on Calcium Phosphate Stones in a Model of Hypercalciuria.

Potassium citrate is prescribed to decrease stone recurrence in patients with calcium nephrolithiasis. Citrate binds intestinal and urine calcium and increases urine pH. Citrate, metabolized to bicarbonate, should decrease calcium excretion by reducing bone resorption and increasing renal calcium reabsorption.

Persistence of 1,25D-induced hypercalciuria in alendronate-treated genetic hypercalciuric stone-forming rats fed a low-calcium diet.

Genetic hypercalciuric stone-forming (GHS) rats demonstrate increased intestinal Ca absorption, increased bone resorption, and reduced renal tubular Ca reabsorption leading to hypercalciuria and all form kidney stones. GHS have increased vitamin D receptors (VDR) at these sites of Ca transport. Injection of 1,25(OH)2D3 (1,25D) leads to a greater increase in urine (u)Ca in GHS than in control Sprague-Dawley (SD), possibly due to the additional VDR.

1,25(OH)₂D₃ induces a mineralization defect and loss of bone mineral density in genetic hypercalciuric stone-forming rats.

Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (u) calcium (Ca) excretion, demonstrate increased intestinal Ca absorption, increased bone Ca resorption, and reduced renal Ca reabsorption, all leading to elevated uCa compared to the parental Sprague-Dawley (SD) rats. GHS rats have increased numbers of vitamin D receptors (VDRs) at each site, with normal levels of 1,25(OH)₂D₃ (1,25D), suggesting their VDR is undersaturated with 1,25D. We have shown that 1,25D induces a greater increase in uCa in GHS than SD rats.

1,25(OH)₂D₃-enhanced hypercalciuria in genetic hypercalciuric stone-forming rats fed a low-calcium diet.

The inbred genetic hypercalciuric stone-forming (GHS) rats exhibit many features of human idiopathic hypercalciuria and have elevated levels of vitamin D receptors (VDR) in calcium (Ca)-transporting organs. On a normal-Ca diet, 1,25(OH)2D3 (1,25D) increases urine (U) Ca to a greater extent in GHS than in controls [Sprague-Dawley (SD)]. The additional UCa may result from an increase in intestinal Ca absorption and/or bone resorption.

Increased biological response to 1,25(OH)(2)D(3) in genetic hypercalciuric stone-forming rats.

Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (U) calcium (Ca) excretion, have increased intestinal Ca absorption and bone Ca resorption and reduced renal Ca reabsorption, leading to increased UCa compared with the Sprague-Dawley (SD) rats. GHS rats have increased vitamin D receptors (VDR) at each of these sites, with normal levels of 1,25(OH)(2)D(3) (1,25D), indicating that their VDR is undersaturated with 1,25D. We tested the hypothesis that 1,25D would induce a greater increase in UCa in GHS rats by feeding both strains ample Ca and injecting 1,25D (25 ng · 100 g body wt(-1) · day(-1)) or vehicle for 16 days.

Effect of metabolic and respiratory acidosis on intracellular calcium in osteoblasts.

In vivo, metabolic acidosis {decreased pH from decreased bicarbonate concentration ([HCO(3)(-)])} increases urine calcium (Ca) without increased intestinal Ca absorption, resulting in a loss of bone Ca. Conversely, respiratory acidosis [decreased pH from increased partial pressure of carbon dioxide (Pco(2))] does not appreciably alter Ca homeostasis. In cultured bone, chronic metabolic acidosis (Met) significantly increases cell-mediated net Ca efflux while isohydric respiratory acidosis (Resp) does not.

Metabolic acidosis increases intracellular calcium in bone cells through activation of the proton receptor OGR1.

Metabolic acidosis increases urine Ca without increasing intestinal absorption, leading to bone Ca loss. It is unclear how bone cells detect the increase in proton concentration. To determine which G protein-coupled proton sensing receptors are expressed in bone, PCR was performed, and products were detected for OGR1, TDAG8, G2A, and GPR4.

Regulation of COX-2 mediates acid-induced bone calcium efflux in vitro.

Unlabelled: Chronic metabolic acidosis induces net Ca efflux from bone; this osteoclastic bone resorption is mediated by increased osteoblastic prostaglandin synthesis. Cyclooxygenase, the rate-limiting enzyme in prostaglandin synthesis, is present in both constitutive (COX-1) and inducible (COX-2) forms. We report here that acidosis increases both osteoblastic RNA and protein levels for COX-2 and that genetic deficiency or pharmacologic inhibition of COX-2 significantly reduces acid-induced Ca efflux from bone.

Genetic hypercalciuric stone-forming rats.

Purpose Of Review: We will describe the pathophysiology of hypercalciuria and the mechanism of the resultant stone formation in a rat model and draw parallels to human hypercalciuria and stone formation.

Recent Findings: Through inbreeding we have established a strain of rats that excrete 8-10 times more urinary calcium than control rats. These genetic hypercalciuric rats absorb more dietary calcium at lower 1,25-dihydroxyvitamin D3 levels.

RANK ligand and TNF-alpha mediate acid-induced bone calcium efflux in vitro.

Chronic metabolic acidosis stimulates net calcium efflux from bone due to increased osteoclastic bone resorption and decreased osteoblastic collagen synthesis. Previously, we determined that incubation of neonatal mouse calvariae in medium simulating physiological metabolic acidosis leads to a significant, cyclooxygenase-dependent, increase in RNA for bone cell receptor activator of NF-kappaB ligand (RANKL) compared with incubation in neutral pH medium. In this study, we tested the hypothesis that the acid-mediated increase in RANKL expression is a primary mechanism for the stimulated osteoclastic resorption.

Mechanism of acid-induced bone resorption.

Purpose Of Review: This review presents our current understanding of the way metabolic acidosis induces calcium efflux from bone, and in the process, buffers additional systemic hydrogen ions associated with acidosis.

Recent Findings: Acid-induced changes in bone mineral are consistent with a role for bone as a proton buffer. In response to metabolic acidosis in an in-vitro bone organ culture system, we observed a fall in mineral sodium, potassium, carbonate and phosphate, which each buffer protons and in vivo should increase systemic pH towards the physiologic normal.

Cellular mechanisms of bone resorption induced by metabolic acidosis.

Metabolic acidosis increases urine calcium excretion without an increase in intestinal calcium absorption, resulting in a net loss of bone mineral. In vitro metabolic acidosis induces bone calcium efflux initially by physicochemical dissolution and subsequently by cell-mediated mechanisms involving inhibition of osteoblasts and stimulation of osteoclasts. In bone, prostaglandins (PGs) are important mediators of bone resorption and we have recently determined that acid-induced bone resorption is mediated by PGs.

Metabolic acidosis stimulates RANKL RNA expression in bone through a cyclo-oxygenase-dependent mechanism.

Unlabelled: Metabolic acidosis inhibits osteoblastic bone formation and stimulates osteoclastic resorption. To determine whether acidosis alters expression of RNA for the osteoclastic differentiation factor RANKL, mouse calvariae were incubated in neutral or physiologically acidic media. Acidosis resulted in a significant cyclo-oxygenase-dependent increase in RANKL RNA levels, which would be expected to induce the associated increase in bone resorption.

Cortisol inhibits acid-induced bone resorption in vitro.

Metabolic acidosis increases urine calcium excretion without an increase in intestinal calcium absorption, resulting in a net loss of bone mineral. In vitro, metabolic acidosis has been shown to initially induce physicochemical mineral dissolution and then enhance cell-mediated bone resorption. Acidic medium stimulates osteoblastic prostaglandin E(2) production, which mediates the subsequent stimulation of osteoclastic bone resorption.