Physicochemical basis for formation of renal stones of calcium phosphate origin: calculation of the degree of saturation of urine with respect to brushite.

Brushite (CaHPO(4).2H(2)O) was considered to govern the formation of renal calculus of calcium phosphate origin. The degree of saturation of urine with respect to this phase was therefore calculated. This value was obtained from the ratio of the activity product of Ca(++) and HPO(4) (m) (K(sp)) before and after incubation of urine with brushite. The errors in the calculation of K(sp) were largely eliminated by this procedure.The urine of patients with idiopathic hypercalciuria and recurrent calcium-containing renal calculi was supersaturated with respect to brushit largely because of the high urinary concentration of Ca(++). The urine of normocalciuric subjects was undersaturated except at high urinary pH. This technique of estimating the degree of saturation of urine should allow a quantitative assessment of the various therapeutic regimens recommended for patients with nephrolithiasis.

Calcification of collagen by urine in vitro: dependence on the degree of saturation of urine with respect to brushite.

A state of supersaturation of urine with respect to brushite is considered to be important in the formation of renal stones composed of calcium phosphate. 56 supersaturated urine specimens and 44 undersaturated specimens were incubated with collagen (Sigma collagen). Most of the supersaturated specimens calcified the collagen, whereas none of the undersaturated ones did so. Among samples which calcified the collagen, whereas none of the undersaturated ones did so. Among samples which calcified the collagen, the activity product of Ca(++) and HPO(4) (=) after incubation with collagen was essentially the same as that after incubation of the same specimen with brushite; it usually differed from that obtained after incubation with octacalcium phosphate or hydroxyapatite. The molar calcium-to-phosphorus ratio of the solid phase in collagen was approximately 1. These results suggested that the solid phase formed in collagen is brushite. This conclusion was confirmed by the direct identification of brushite in collagen by X-ray diffraction.

The hypercalciurias. Causes, parathyroid functions, and diagnostic criteria.

The causes for the hypercalciuria and diagnostic criteria for the various forms of hypercalciuria were sought in 56 patients with hypercalcemia or nephrolithiasis (Ca stones), by a careful assessment of parathyroid function and calcium metabolism. A study protocol for the evaluation of hypercalciuria, based on a constant liquid synthetic diet, was developed. In 26 cases of primary hyperparathyroidism, characteristic features were: hypercalcemia, high urinary cyclic AMP (cAMP, 8.58+/-3.63 SD mumol/g creatinine; normal, 4.02+/-0.70 mumol/g creatinine), high immunoreactive serum parathyroid hormone (PTH), hypercalciuria, the urinary Ca exceeding absorbed Ca from intestinal tract (Ca(A)), high fasting urinary Ca (0.2 mg/mg creatinine or greater), and low bone density by (125)I photon absorption. The results suggest that hypercalciuria is partly secondary to an excessive skeletal resorption (resorptive hypercalciuria). The 22 cases with renal stones had normocalcemia, hypercalciuria, intestinal hyperabsorption of calcium, normal or low serum PTH and urinary cAMP, normal fasting urinary Ca, and normal bone density. Since their Ca(A) exceeded urinary Ca, the hypercalciuria probably resulted from an intestinal hyperabsorption of Ca (absorptive hypercalciuria). The primacy of intestinal Ca hyperabsorption was confirmed by responses to Ca load and deprivation under a metabolic dietary regimen. During a Ca load of 1,700 mg/day, there was an exaggerated increase in the renal excretion of Ca and a suppression of cAMP excretion. The urinary Ca of 453+/-154 SD mg/day was significantly higher than the control group's 211+/-42 mg/day. The urinary cAMP of 2.26+/-0.56 mumol/g creatinine was significantly lower than in the control group. In contrast, when the intestinal absorption of calcium was limited by cellulose phosphate, the hypercalciuria was corrected and the suppressed renal excretion of cAMP returned towards normal. Two cases with renal stones had normocalcemia, hypercalciuria, and high urinary cAMP or serum PTH. Since Ca(A) was less than urinary Ca, the hypercalciuria may have been secondary to an impaired renal tubular reabsorption of Ca (renal hypercalciuria). Six cases with renal stones had normal values of serum Ca, urinary Ca, urinary cAMP, and serum PTH (normocalciuric nephrolithiasis). Their Ca(A) exceeded urinary Ca, and fasting urinary Ca and bone density were normal. The results support the proposed mechanisms for the hypercalciuria and provide reliable diagnostic criteria for the various forms of hypercalciuria.

Mechanism for calcium urolithiasis among patients with hyperuricosuria: supersaturation of urine with respect to monosodium urate.

Since monosodium urate (NaU) may play an important etiologic role in the formation of renal stones containing Ca in patients with hyperuricosuria, the current studies were undertaken to define some of the physiocochemical factors which determine the formation of NaU. In solutions containing Na, uric acid was rapidly transformed to NaU at pH greater than 6. The results indicated that NaU, and not uric acid, was the stable phase above this pH. A reliable and simple method for the calculation of the state of saturation of urine with respect to NaU was developed from the ratio of concentration products of Na and total dissolved urate (Upi) in the ambient fluid before and after incubation of urine with synthetic NaU. The concentration product ratio closely approximated the ratio of activity products of Na+ and acid urate ion. In contrast, the relative saturation ratio, or the ratio of activity product of original sample and the thermodynamic solubility product of NaU, often differed from the activity product ratio in the individual urine samples. With the concentration product rate, it was found in 45 urine samples that a critical determinant for the supersaturated state with respect to NaU was the high concentration of UT. At UT greater than 300 mg/liter, urine samples were invariably supersaturated with respect to NaU. These results suggest that the nidus of NaU could potentially form in the urine of patients with hyperuricosuria and Ca stones.

Jejunal absorption and secretion of calcium in patients with chronic renal disease on hemodialysis.

10 patients with chronic renal disease on hemodialysis and 8 normals were studied by constant jejunal perfusion of calcium gluconate solutions, using polyethylene glycol as a nonabsorbable marker. Results in normals indicated that calcium absorption from 1 and 5 mM calcium solutions is mainly active. Absorption from 5, 15, and 20 mM solutions was a linear function of luminal calcium concentration, suggesting that the active transport carrier is saturated when luminal calcium concentration is greater than 5 mM and indicating that the increment in absorption at higher luminal concentrations is mainly the result of passive absorption. With 1 mM calcium, normals absorbed calcium against a concentration gradient, whereas the patients secreted calcium. Absorption in the patients was much less than normal with 5, 15, and 20 mM luminal calcium concentrations; however, the slope of this linear (passive) portion of the curve was normal. Unidirectional calcium fluxes were measured with calcium-47. Flux out of the lumen was depressed 2.5-fold in the patients, but flux into the lumen was normal. Xylose, urea, and tritiated water were absorbed normally, indicating no generalized abnormality of jejunal transport in these patients. Endogenous calcium secretion, estimated by the amount of calcium added to a calcium-free solution, was normal in the dialysis patients. These results indicate that active calcium absorption is markedly depressed in patients with chronic renal disease who are receiving hemodialysis therapy. On the other hand, passive calcium movement and endogenous calcium secretions are normal.

The role of 1 alpha, 25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyperparathyroidism and absorptive hypercalciuria.

The cuase for the intestinal hyperabsorptionof calcium (Ca) in various forms of hypercalciurias was explored by a careful measurement of plasma 1 alpha, 25-dihydroxycholecalciferol [1 alpha, 25-(OH)I D] and by an assessment of intestinal Ca absorption and of parathyroid function. In 18 cases of primary hyperparathyroidism (PHPT), the mean plasma concentration of 1 alpha, 25-(OH)2D was significantly increased (4.9 +/- 2.2 SD ng/dl vs. 3.4 +/- 0.9 ng/dl for the control group), and was significantly correlated with fractional Ca absorption (alpha) (r = 0.80, P less than 0.001). Plasma 1 alpha, 25-(OH)2D was also correlated with urinary Ca (P less than 0.05), but not with serum Ca or phosphorus (P), P clearance, urinary cyclic AMP, or serum immunoreactive parathyroid hormone. In 21 cases of absorptive hypercalciuria (AH), plasma 1 alpha, 25-(OH)2D was elevated in one-third of cases, and the mean value of 4.5 +/- 1.1 ng/dl was significantly higher than that of the control group (P less than 0.01). Since relative hypoparathyroidism may be present, the normal absolute value of plasma 1 alpha, 25-(OH)2D, found in two-thirds of cases of AH, may be considered to be inappropriately high. Moreover, in the majority of cases of AH, the data points relating plasma 1 alpha, 25-(OH)2D and alpha fell within 95% confidence limits of values found in non-AH groups (including PHPT). The results suggest that the intestinal hyperabsorption of Ca in PHPT aw AH may be vitamin D dependent. However, the disturbance in vitamin D metabolism may not be the sole cause for the high Ca absorption in AH, since in some patients with AH, the intestinal Ca absorption appears to be inapp

Magnesium absorption in the human small intestine. Results in normal subjects, patients with chronic renal disease, and patients with absorptive hypercalciuria.

Magnesium absorption was studied in the normal human jejunum and ileum by in vivo intestinal perfusion, using test solutions containing from 0 to 20 mM Mg (as MgCl2). As luminal Mg concentration was increased, the rate of absorption in the jejunum rose progressively with a tendency towards saturation at the higher concentrations. The kinetics and rates of Mg absorption in the ileum were comparable to those in the jejunum, with the exception that at higher luminal concentrations the ileal absorptive process was fully saturated. Using test solutions containing various combinations of Ca and Mg, we found that Ca had little or no influence on Mg absorption, even through Mg depressed Ca absorption to a modest extent. Patients with end-stage renal disease, who had a reduced rate of Ca absorption (presumably due to deficiency of 1,25-dihydroxycholecalciferol) were found to have a severe depression of Mg absorption. On the other hand, patients with absorptive hypercalciuria and nephrolithiasis, who had an increased rate of Ca absorption, were found to absorb Mg normally. These results suggest that Mg absorption in the human is mediated by a transport process different from that which facilitates Ca absorption, and that normal Mg absorption may be dependent on vitamin D. Our results do not establish whether or not the normal intestine can absorb Mg against an electrochemical gradient.

Jejunal and ileal absorption in patients with chronic renal disease. Effect of 1alpha-hydroxycholecalciferol.

Calcium absorption in 30-cm segments of small intestine was measured by constant perfusion of test solutions containing different concentrations of calcium gluconate. In both the jejunum and ileum, calcium absorption rates increased progressively as luminal calcium concentration was increased stepwise between 1 and 20 mM. Although calcium transport was not saturable within these limits, unidirectional flux ratios of calcium (47Ca) suggest that calcium absorption is active in both the jejunum and ileum. Calcium absorption in patients with chronic renal disease was markedly depressed in both regions of the small intestine. This was due to decreased flux out of the lumen; flux in the reverse direction was normal. Flux ratios in the renal disease patients showed no evidence for active calcium transport. Treatment of these patients for 1 wk within 2 mug/day of 1alpha-hydroxycholecalciferol [1alpha-(OH)-D3] restored net calcium absorption and unidirectional calcium flux out of the lumen to normal values in the jejunum; in the ileum, 1alpha-(OH)-D3 increased calcium absorption 60-83% of normal at the various luminal calcium concentrations. 1alpha(OH)-D3 had no effect on unidirectional calcium flux into the lumen or on xylose and electrolyte absorption in either area of the small intestine.

Jejunal and ileal adaptation to alterations in dietary calcium: changes in calcium and magnesium absorption and pathogenetic role of parathyroid hormone and 1,25-dihydroxyvitamin D.

Previous balance studies have shown that fractional calcium absorption is increased by a low and reduced by a high calcium diet. The present studies were done to determine which segment of the small intestine is most sensitive to alterations in dietary calcium, and to see if dietary calcium intake has an effect on the intestinal absorption of another divalent cation, magnesium. Absorption was measured during constant perfusion of 30-cm segments of jejunum and ileum of normal subjects after 4 or 8 wk of a high (1,900 mg/d) or a low (20 mg/d) calcium diet. We found that calcium absorption rate was higher when subjects had been on a low than when they had been on a high calcium diet; the ileum responded more rapidly and more completely than the jejunum. Similar results were obtained with magnesium, but only the difference in the ileum was statistically significant. Sodium and xylose absorption were not influenced by dietary calcium intake. The serum concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D were higher on the low than on the high calcium diet. We conclude that the ileum is more sensitive than the jejunum to changes in dietary calcium intake, and that ileal adaptation probably plays a major role in protecting the body against a deficiency or excess of body calcium that otherwise would occur when dietary calcium is abnormally low or high. Calcium intake influences ileal magnesium absorption in a similar fashion; it is not known whether or not this serves a protective function. Our data are compatible with the concept that adaptation to dietary calcium intake is mediated by changes in the serum concentrations of parathyroid hormone and 1,25-dihydroxyvitamin D.

Role of cyclosporin A in macromolecular synthesis of beta-cells.

Wistar rats developed hypoinsulinemia and hyperglycemia within 7 days when treated daily with 40 mg/kg body wt of cyclosporin A (CsA) and recovered from the metabolic alteration within 1 wk when CsA treatment was terminated. By light microscopy, there was no lymphocytic infiltration, but cytoplasmic vacuolization in the islets of Langerhans from the CsA-treated rats was seen. By electron microscopy, severe degranulation, cytoplasmic vacuolization, and dilation of endoplasmic reticulum were clearly seen in the pancreatic beta-cells. Islet cells isolated from the CsA-treated rats showed greater than 50% reduction in mRNA synthesis. A similar inhibitory pattern of mRNA synthesis was observed in in vitro CsA-treated (10 micrograms/ml) human pancreatic islet cells from one biopsy sample and in similarly treated rat insulinoma cells (RINm5F). The inhibitory effect of CsA on mRNA synthesis in RINm5F cells was dose dependent, with a 50%-inhibiting dose of 5 micrograms/ml. In addition to the inhibition of mRNA synthesis, CsA also inhibited protein and DNA syntheses, although the inhibitory effect on these macromolecular syntheses was significantly less than that on mRNA synthesis. However, there was only a minor effect of CsA on in vitro transcription and translation compared with that on RINm5F and islet cells. It is concluded that CsA-induced degranulation of the beta-cells in Wistar rats, accompanied by hypoinsulinemia and hyperglycemia, may be due to indirect, reversible interference of the cellular function primarily involved in mRNA synthesis.

Genetic control of organ-reactive autoantibody production in mice by obesity (ob) diabetes (db) genes.

Inbred strains of mice exhibited genetic and sex-dependent differences in spontaneous production of organ-reactive autoantibodies detected by indirect immunofluorescence. Antitestis autoreactivity was found primarily in sera from C57BL/6J (B6) mice, whereas antigastric autoreactivity was common to both CBA/J and 129/J strains. Autoantibodies against islet cell cytoplasmic antigens (ICAs) were uniquely expressed by C57BL/KsJ (BKs) males. Introduction of the diabetes (db) mutation into these various inbred-strain backgrounds induced expression of ICA, with stronger induction observed in males. The stress imposed by the db or obesity (ob) mutation induced ICA in BKs mice at a higher frequency than in B6 mice; this differential sensitivity was somehow related to a gene linked to the H-2 complex because BKs.B6 H-2b congenic mice resembled B6 mice. The db3J mutation increased the expression of these autoantibodies in 129/J mice, which, like B6, were H-2b and therefore presumably possessed the same H-2-linked inducibility allele as BKs. Cytotoxic autoantibodies against islet cell surface antigens were only observed in C3HeB/FeJ db/db males, and their presence was correlated with beta-cell necrosis. It is concluded that db and/or ob genes appear to play an important role in the production of autoantibodies to islet cells, and sex-linked factor(s) may modify the phenotypic expression of the autoantibodies.

Preferential infiltration of macrophages during early stages of insulitis in diabetes-prone BB rats.

The subpopulation of lymphoid cells at the different stages of insulitis in BB rats was determined by immunohistochemical techniques with various monoclonal antibodies, including the recently developed OX41, which distinguishes macrophages from T-lymphocytes, OX19 for pan-T-lymphocytes, W3/25 for both helper T-lymphocytes and macrophages, OX8 for cytotoxic T-lymphocytes and natural killer cells, and OX12 for B-lymphocytes. The major population of infiltrated cells found during the early stages of insulitis appeared to be macrophages. This preceded invasion by a mixed population of cells, including both T- and B-lymphocytes and/or natural killer cells. The preferential infiltration of macrophages during the early stages of insulitis strongly suggested that there might be an initial change in the target beta-cells that precedes their immune destruction, although the amplification of immune response by activated T-lymphocytes and natural killer cells at a later stage seemed to be required for the clinical expression of the disease.

Effects of polypeptide and protein hormones on lipid monolayers. I. Effect of insulin and parathyroid hormone on monomolecular films of monooctadecyl phosphate and stearic acid.

Insulin in low concentrations inhibits the uptake of Ca(++) by the monooctadecyl (stearyl) phosphate monolayer (at air-water interface) and facilitates the release of Ca(++) adsorbed to the monolayer. These effects of insulin are more pronounced at higher insulin concentrations. Evidence is presented that a relatively intact insulin molecule competes with Ca(++) for the free phosphate group of the monolayer. Albumin has a slight inhibitory action on calcium uptake and parathyroid hormone has no observable action on calcium uptake or release.

Anabolic effects of fluoride on bone.

Fluoride exerts a biphasic action at the level of osteoblasts, on bone mineral, on bone structure and function, and in the treatment of osteoporosis. At low circulating concentrations, skeletal uptake of fluoride is limited and the effects are beneficial. At higher concentrations and greater skeletal uptake, fluoride may cause the formation of abnormally mineralized bone of impaired quality. A new treatment program entailing intermittent slow release sodium fluoride (SR-NaF) with continuous calcium citrate may capture desirable qualities of fluoride without toxic effects, and be therapeutically efficacious in postmenopausal osteoporosis.

Successful treatment of hyperuricosuric calcium oxalate nephrolithiasis with potassium citrate.

Calcium stone (renal) formation in patients with hyperuricosuria has been ascribed to the urate-induced crystallization of calcium oxalate. Citrate (0.5mM), added to synthetic medium metastably supersaturated with respect to calcium oxalate, was shown to inhibit heterogeneous nucleation of calcium oxalate by monosodium urate (2 mg/mL). Long-term trial with potassium citrate (60 to 80 mEq/day) was therefore undertaken to determine whether induced hypercitraturia would prevent calcium oxalate stone formation in 19 patients with hyperuricosuria. The treatment produced a sustained rise in urinary pH by 0.55 to 0.85 to the high normal range (6.5 to 7.0). Urinary citrate levels rose by 249 to 402 mg/day to approximate the normal mean value of 643 mg/day. Commensurate with these changes, urinary saturation of calcium oxalate (relative saturation ratio) and the amount of undissociated uric acid declined significantly. However, the urinary uric acid and saturation of monosodium urate remained elevated. Stone formation declined from 1.55 +/- 2.70 per patient-year to 0.38 +/- 1.22 per patient-year during mean treatment period of 2.35 +/- 0.88 years. Stones ceased to form in 16 of 19 patients during treatment. The results provide physicochemical and clinical evidence for the utility of potassium citrate in the management of hyperuricosuric calcium oxalate nephrolithiasis.

Antihypertensive comparison of furosemide with hydrochlorothiazide for black patients.

Furosemide and hydrochlorothiazide were compared for treatment of black patients with mild to moderate hypertension in a randomized, open-label, crossover study design. Hydrochlorothiazide produced a significantly greater fall in mean arterial (24.7 vs 16.0 mm Hg, P less than .01) and diastolic (17.3 vs 10.1 mm Hg, P less than .01) blood pressure (BP) in 16 patients. Addition of methyldopa in nine patients produced a significantly greater fall in mean arterial (38.8 vs 31.9 mm Hg, P less than .05) and diastolic (28.9 vs 23.4 mm Hg, P less than .05) BP with hydrochlorothiazide vs furosemide. Renin status was categorized before and after treatment. Patients with low and normal renin activity were equally responsive to both diuretics. Hydrochlorothiazide caused a greater reduction in plasma potassium (0.26 mEg/L). Serum parathyroid hormone was not chronically elevated with furosemide. In this study, hydrochlorothiazide was more effective than furosemide for treatment of mild to moderate hypertension in black patients; renin classification did not predict diuretic responsiveness.

Sustained-release sodium fluoride in the treatment of the elderly with established osteoporosis.

BACKGROUND: We ascertained the safety and efficacy of fluoride in augmenting spinal bone mass and reducing spinal fractures in older women with established osteoporosis. We compared a combination of sustained-release sodium fluoride, calcium citrate, and cholecalciferol (SR-NaF group) with calcium and cholecalciferol alone (control group). METHODS: Eighty-five ambulatory women aged 65 years or older with 1 or more nontraumatic vertebral compression fractures were enrolled in a 42-month randomized, double-blind, placebo-controlled trial. Primary outcome measures were vertebral fracture rate, bone mass, and safety. RESULTS: The vertebral fracture rate determined by means of computer assistance in the SR-NaF group was significantly lower than that in the control group (relative risk [RR], 0.32; 95% confidence interval [CI], 0.14-0.73; P =.007). Results of visual adjudicated inspection also confirmed a significant reduction in fracture rate (RR, 0.40; 95% CI, 0.17-0.95; P =.04). Bone mineral density in L2 through L4 increased significantly from baseline in the SR-NaF group by 5.4% (95% CI, 2.7%-8.2%; P<.001), and by 3.2% in the control group (95% CI, 0.8%-5.6%; P =.01). The between-group differences in bone mineral density were not significant. The femoral neck and total hip bone mineral density remained stable in the SR-NaF group and was not significantly different from that of the control group. There were no significant differences in adverse effects between groups. CONCLUSION: The SR-NaF group significantly decreased the risk for vertebral fractures and increased spinal bone mass without reducing bone mass at the femoral neck and total hip.

Inhibition by citrate of spontaneous precipitation of calcium oxalate in vitro.

Effect of citrate on the spontaneous precipitation of calcium oxalate was examined in synthetic media. Citrate significantly increased the formation product of calcium oxalate. This "direct" measure of inhibitor activity, representing activity product at the point of nucleation, rose by 76% by the addition of citrate sufficient to provide trivalent citrate concentration of 1.49 mM. Moreover, citrate inhibited calcium oxalate crystallization by complexing calcium and lowering calcium oxalate saturation. This "indirect" measure of inhibitor activity was assessed from the concentration product of calcium oxalate at the point of nucleation, since this measure should provide a reflection of both ion pair formation and direct inhibitor activity of citrate. The concentration product exceeded the formation product at all ionic (trivalent) citrate concentrations, particularly at high ionic citrate levels. At the ionic citrate concentration of 1.49 mM, the rise in the concentration product was 373%, which was nearly fivefold that observed for the formation product. The presence of ferric or aluminum cations at a physiologic concentration of 2 mg/l did not modify the increase in formation product produced by citrate. Thus, citrate inhibits calcium oxalate crystallization, largely by complexing citrate, but also by directly affecting nucleation. Presence of ferric or aluminum cations at a physiological concentration does not modify the inhibitor action of citrate.

Effect of intermittent therapy with a slow-release fluoride preparation.

Long-term clinical effects of intermittent sodium fluoride (slow-release) therapy were assessed in 71 patients with primary osteoporosis. In Group I (receiving 1,25-(OH)2D3 2 micrograms/day for 2 weeks before 3 months of sodium fluoride treatment 25 mg twice a day, in each 5-month cycle), vertebral (L2-L4) bone mineral content did not change significantly. However, the L2-L4 bone mineral content significantly increased by 3.1% in Group II (those who did not receive 1,25-(OH)2D3 during 5-month cycle), 3.5% per patient year in Group III (combined NaF 25 mg twice a day with 1,25-(OH)2D3 0.5 micrograms/day for 12 months in each 13-month cycle), and by 7.8% per patient year in Group IV (combined NaF with calcium citrate for 12 months in each 13-month cycle). The rise in vertebral bone mineral content was sustained, with an annual increment of 4.2% during the third year compared with 4.4% during the first year. The vertebral fracture rate declined significantly from the pretreatment value in all groups, but comparison with a placebo control group was not available. There was no significant change in the bone density of the radial shaft or of the proximal femur. The rate of hip fracture (nontraumatic) during treatment was 1.8% per patient year, the same as before treatment. The drug was well tolerated with only minor infrequent gastrointestinal and rheumatic side effects. Thus, intermittent slow-release sodium fluoride treatment with adequate calcium supplementation augments spinal bone mass and apparently inhibits vertebral fractures, with a satisfactory safety of usage; however, it has no effect on appendicular bone mass or on hip fracture rate.(ABSTRACT TRUNCATED AT 250 WORDS)

A model system for assessing physicochemical factors affecting calcium absorbability from the intestinal tract.

An in vitro model system was utilized to critically examine physicochemical factors that could play a role in determining the amount of potentially absorbable ionic calcium as well as soluble complexes in the proximal jejunum following ingestion of tricalcium dicitrate, calcium carbonate, or tricalcium diphosphate. The solubility of calcium salts (500 mg calcium each) was tested in 300 ml water containing varying amounts of hydrochloric acid (0, 0.72, 2.4, 7.26, and 24.2 mEq) intended to mimic achlorhydric to peak acid secretory states. Whereas 20% of calcium citrate dissolved in the absence of hydrochloric acid, a negligible amount of calcium carbonate and calcium phosphate underwent dissolution. In solutions containing 0.72-7.26 mEq hydrochloric acid, calcium citrate was more than twofold soluble than calcium carbonate, and calcium phosphate had intermediate solubility. At simulated peak acid secretion, all three salts were completely soluble, or nearly so. To simulate pancreatic bicarbonate secretion, the filtrates obtained from solubility studies were titrated to pH 5, 6, and 7 with sodium hydroxide. Reprecipitation of calcium citrate and calcium carbonate did not occur. However, substantial calcium phosphate reprecipitation took place especially at high pH and in filtrates derived from high hydrochloric acid content. In filtrates derived from reprecipitation experiments (at pH 6 and 7), anionic complexation of calcium was calculated in order to estimate the amount of ionic and complexed calcium. Considerable amount of calcium from dissolved calcium citrate was complexed (60-65%), principally as soluble CaCit-, whereas calcium complexation was negligible in the calcium carbonate and calcium phosphate systems.