Calcium excretion response

The importance of insulin as a mediator of the hypercalciuric effect of arginine infusion was also evident from studies conducted in chronically diabetic rats, where diabetes was induced by strepto-zotocin (23). Animals were injected with streptozotocin prior to arginine infusion 100 mg/kg i.p. was given on the seventh day before, followed by 25 mg/kg six days before the arginine infusion and renal clearance studies. In contrast to non-diabetic controls, diabetic animals did not increase their urinary calcium excreted (per ml glomerular filtrate) in response to the arginine infusion, nor did the arginine stimulate insulin secretion. 

The above experiments strongly suggest to us that a linear relationship exists between serum or plasma insulin levels over a wide physiological range, and urinary calcium excretion. The calciuric response to arginine or glucose infusion does not occur if insulin secretion is prevented, as evidenced by the data obtained from animals made acutely insulinopenic by mannoheptulose, or more chronically diabetic by streptozotocin. 

As anticipated, arginine infusion caused a large (221 percent) increase in calcium excretion in sham-operated animals. Parathyroidectomy had no effect on the calciuric response to arginine uri-ary calcium increases in PTX control and arginine-infused animals were 299 and 302 percent respectively. These results persisted when data were corrected for differences in GFR. The data illustrate that neither PTH activity nor secretion is involved in insulin impairment of renal calcium transport. 

The urinary calcium response to high levels of protein from beef showed some reduction in urinary total calcium excretion (P < 0.06). Similarly, the excretion of urinary free calcium, was also depressed when a meal containing high levels of beef was ingested (Table III). 

The effects of varying either the calcium or phosphorus level in conjunction with a high beef meal on the urinary calcium excretion of men are shown in Table IV. Urinary calcium excretion (total and ionized) was significantly elevated (P < 0.005) when the high protein beef meal contained 466 mg rather than 166 mg calcium. Increasing the phosphorus level from 308 mg to 700 mg in the high beef meal reduced both total and ionized calcium excretion in the urine, but the response was not statistically significant. Serum levels of calcium (ionized and total) and phosphorus were within normal limits and were unaffected by any of the dietary treatments. 

Increasing the dietary calcium level in the high beef meal resulted in hypercalciuria. This effect was obtained in the absence of an altered insulin response which suggests that factors other than or in addition to serum insulin were involved in the control of urinary calcium excretion. 

In lithium treated subjects, there is no evidence of reduced bone mass at any of the measured sites in relation to that of control subjects. The mechanism responsible for the maintenance of bone mass despite biochemical evidence of hyperparathyroidism is not clear [45]. We suspect that it is due to renal calcium retention. Indeed, in dogs lithium administration for only 3 days causes a striking decrease in urinary calcium excretion which is independent of the presence of parathyroid hormone and occurs despite the concurrent development of metabolic acidosis [Batlle D, Arruda J, and Kurtzman NA 1981 unpublished observations]. 

A striking and unexpected outcome of the Cadmibel study was the clear-cut interference of fhe low-level Cd exposure with calcium metabolism. For example, when urinary Cd excretion increased twofold, serum alkaline phosphatase activity and urinary calcium excretion rose by 3-4% and 0.25 mmol/24h respectively [142]. The dose (CdU)-response rate of increased calciuria (>9.8 mmol/24h) suggested a 10% prevalence of hy-percalciuria when CdU exceeded 1.9 pg Cd/24h [38]. Hypercalciuria should be considered an early adverse tubulotoxic effect, because it may exacerbate the development of osteoporosis, especially in the elderly. A prospective study from 1992-1995 (median follow-up of 6.6 years) in the above-mentioned Cadmibel subcohort from the rural area showed for a two-fold increase in urinary Cd a significant (p<0.02) decrease of 0.01 g/ cm in forearm bone density in post-menopausal women. In addition, the relative risks associated with doubled urinary Cd were 1.73 (95% Cl 1.16-2.57 p=0.007) for fractures in women and 1.60 (0.94-2.72 p=0.08) for height loss in men. Cadmium excretion in the four... 

Since unresolved nephrocaldnosis may lead to residual abnormalities in the kidney induding microscopic hematuria, hypercalciuria, and impaired tubular function [109, 113, 114], renal ultrasonography within a few months of initiating loop diuretics may be warranted [109,113]. If long-term diuretic therapy is needed, a thiazide diuretic alone or in combination with furosemide may reduce the risk of renal calcifications by decreasing urinary calcium and oxalate excretion [109, 111, 113,117,118]. However, two studies of premature infants failed to show a reduction in either urinary oxalate or calcium excretion when thiazides were added to furosemide therapy [116,119]. The lack of beneficial response may have been due to replacement of the infants sodium losses with large amounts of supplemental sodium. 

Since excess dietary protein and excess phosphorus have opposing effects on urinary calcium, the natural association of these nutrients in the human diet tends to ameliorate the effect of both on calcium excretion and bone loss. Whether the relative amounts of protein and phosphorus in high protein diets are always compatible with calcium homeostasis is unclear. This question is not amenable to study in rodents because feeding excess protein has no effect on calcium balance. Excess phosphorus causes bone loss irrespective of the protein content of the diet. Hence, adult rodents and adult humans differ with respect to their skeletal response to both excess protein and excess phosphorus. 

Hydroxy vitamin D pools ia the blood and is transported on DBF to the kidney, where further hydroxylation takes place at C-1 or C-24 ia response to calcium levels. l-Hydroxylation occurs primarily ia the kidney mitochondria and is cataly2ed by a mixed-function monooxygenase with a specific cytochrome P-450 (52,179,180). 1 a- and 24-Hydroxylation of 25-hydroxycholecalciferol has also been shown to take place ia the placenta of pregnant mammals and ia bone cells, as well as ia the epidermis. Low phosphate levels also stimulate 1,25-dihydtoxycholecalciferol production, which ia turn stimulates intestinal calcium as well as phosphoms absorption. It also mobilizes these minerals from bone and decreases their kidney excretion. Together with PTH, calcitriol also stimulates renal reabsorption of the calcium and phosphoms by the proximal tubules (51,141,181—183). 

As renal function declines in patients with CKD, decreased phosphorus excretion disrupts the balance of calcium and phosphorus homeostasis. 0 The parathyroid glands release PTH in response to decreased serum calcium and increased serum phosphorus levels. The actions of PTH include ... 

Decrease blood calcium Increase blood calcium decrease blood phosphate activation of vitamin D 3 "Fight-or-flight" response reinforces effects of the sympathetic nervous system Reabsorption of sodium excretion of potassium... 

Two renal responses are unique to the thiazide and thiazidehke diuretics. With these compounds, Na+ excretion is increased, while Ca++ excretion is decreased, primarily and directly because of increased distal Ca++ reabsorption, secondarily and indirectly because of a compensatory elevation of proximal solute absorption, making this class of diuretics useful in treating hypercal-ciuria. This effect, which may not be evident upon initial administration of the drug, is particularly benehcial in individuals who are prone to calcium stone formation. 

Phosphaturia and hypercalciuria occur during the bicarbonaturic response to inhibitors of carbonic anhydrase. Renal excretion of solubilizing factors (eg, citrate) may also decline with chronic use. Calcium salts are relatively insoluble at alkaline pH, which means that the potential for renal stone formation from these salts is enhanced. 

The most potent type of diuretic, loop diuretics are named after the loop of Henle, a component of a nephron. The nephrons are the filtering units of the kidney, and are responsible for moving fluids and waste out of the bloodstream, resulting in urine formation. The loop of Henle is a branch within each nephron where sodium and potassium are reabsorbed back into the bloodstream instead of being filtered into the urine. Loop diuretics inhibit this action and promote excretion of the sodium and potassium instead, along with calcium and magnesium. Since excess sodium causes excess fluid build-up, this results in fluid loss. Furosemide (Lasix), bumetanide (Bumex), torsemide (Demadex), and ethacryinic acid (Edecrin) are all loop diuretics. 

Some diuretics have direct vasodilating effects in addition to their diuretic action. Indapamide is a nonthiazide sulfonamide diuretic with both diuretic and vasodilator activity. As a consequence of vasodilation, cardiac output remains unchanged or increases slightly. Amiloride inhibits smooth muscle responses to contractile stimuli, probably through effects on transmembrane and intracellular calcium movement that are independent of its action on sodium excretion. 

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