Calcium Hypercalciuria

As intestinal absorption of calcium increases, urinary calcium excretion also increases. When the latter exceeds 300 mg/d, formation of calcium phosphate or calcium oxalate stones (urolithiasis) may occur. Hypercalciuria may result from decreased reabsorption of calcium due to a renal tubular defect or from increased intestinal absorption of calcium. Hypercalciuria may be due to an intrinsic defect in the intestinal mucosa or secondary to increased synthesis of 1,25-(OH)2D in the kidney. Disordered regulation of 1,25-(0H)2D synthesis is relatively common in idiopathic hypercalciuria. Treatment usually includes reduction in dietary calcium. Increased vitamin D intake, hyperparathyroidism, and other disorders can also cause hypercalciuria and urolithiasis. 

The overall effect in most animals is to stimulate intestinal absorption of calcium with a concomitant increase in semm calcium and a reduction in parathyroid hormone (PTH). Modest hypercalcemia allows the glomerular filtration rate to remain stable and hypercalciuria to occur because of increased filtered load of calcium and reduction of tubular resorption of calcium with reduced PTH. However, with further increases in semm calcium, the glomerular filtration rate decreases, resulting in an even more rapid increase in semm calcium and the subsequent fall in urinary calcium. 

A number of factors can limit calcium absorption, and special consideration must be given to calcium dosing to maximize absorption. Large amounts of calcium taken at once cannot be absorbed. Supplement doses should be limited to 500 to 600 mg of elemental calcium per dose. Calcium intake greater than 2500 mg/day should be avoided due to increased risk of toxicity, including hypercalciuria and hypercalcemia. 

Vitamin D is often combined in varying amounts with calcium salts. A multiple vitamin is another good source of vitamin D. Most multivitamins contain 400 IU per tablet. Vitamin D is also available as a single entity. Doses above 2000 IU/day should be avoided owing to the risk of hypercalciuria and hypercalcemia. Ergocalciferol (vitamin D2) and... 

Many animal species excrete more calcium if fed an acid or acidforming compounds. In the calf, Steenbock and coworkers (13) observed hypercalciuria and acidic urine after feeding hydrochloric acid to the calf. Stehle (14) pointed out that calcium represented the main long-term fixed base to be lost in the urine of the dog loaded with excessive amounts of hydrochloric acid. Walzer and Browder (15) demonstrated that when infused with a sulfate containing solution, the dog excreted several fold more acid and calcium than saline-infused controls the increased calcium loss returned to normal upon removal of the sulfate. Marone, et al. (16) demonstrated increased excretion of calcium in the acidotic dog. Correction of the acidosis reduced the excessive fractional calcium excretion rate, but did not alter sodium excretion. 

The rat has been used rather widely to study the relation between dietary protein, or acid salt feeding, and calcium loss. Barzel and Jowsey (19) showed that the rat fed a control diet supplemented with ammonium chloride excreted excessive urinary calcium, and experienced a concomitant loss of fat-free bone tissue. Draper, et al. (20) extending this work, reported an inverse relation between dietary phosphate and loss of bone calcium and dry, fat-free tissue. In subsequent studies (21), they reported that this process was accompanied by reduced serum calcium levels the high phosphorus, low calcium diet increased urinary calcium loss. Whereas, increasing the phosphorus content of the diet stopped the excessive urinary calcium loss. To test possible zinc loss that might result from this sort of acid salt feeding, Jacob and her coworkers (22) fed rats a supplement of ammonium chloride and then measured urinary zinc and calcium. The hypercalciuria occurred exclusive of an effect upon urinary zinc loss. 

Acidosis induced by salt feeding to humans influenced urinary calcium loss as effectively as feeding whole foods. Martin and Jones (25), for example, fed adult subjects a diet supplemented with ammonium chloride which resulted in marked hypercalciuria and an acidified urine. In a follow-up trial, feeding alkali as sodium bicarbonate, they also demonstrated that human hypercalciuria could be prevented by adding an alkaline supplement to the diet. 

None of these earlier animal studies had been rigorously for protein, calcium, or acid output. The data of the present study demonstrated that the acid nature of the diet, fed at constant levels, and to the same subjects, induced hypercalciuria in the meat period. 

This phenomenon also had been reported in human subjects fed acid ash foods. Farquharson, et al. (33) fed a high-protein (200 g) diet to human subjects who promptly excreted more urinary acid and calcium. This occurred whether the protein level was raised to 200 g, or an equivalent amount of ammonium chloride was fed. If, on the other hand, the acid ash in the protein were neutralized with sodium bicarbonate, the hypercalciuria did not occur. 

During the last decade, a number of investigators have attempted to elucidate the mechanism by which protein consumption induces hypercalciuria. In our previous research, the calciuria could not be explained by increased intestinal absorption of calcium, complexing with sulfur amino acids, or urinary acid production. 

From preliminary in vitro experiments using rat renal slices, it appears that the hormone directly affects renal calcium transport. If insulin is the mediator of the hypercalciuria, it might be possible to reduce urinary calcium loss by lowering the intake of in-sulinogenic foods. This would be especially important in those individuals with a marked calciuric response to such foods. 

We have tested the hypothesis that insulin inhibits the stimulatory effect of parathyroid hormone (PTH) on calcium reabsorption in the distal nephron. PTH is known to enhance calcium transport in renal cells, probably by stimulation of adenylate cyclase and subsequent increases in 3 5 cyclic AMP productoin. Since insulin had been observed to inhibit PTH-stimulated increases in kidney cyclic AMP levels in vitro (24) we investigated whether insulin-mediated hypercalciuria was dependent on the presence of PTH in vivo. 

It has been well established that the ingestion of high dietary protein levels results in hypercalciuria in man, and that hypercalciuria is frequently accompanied by negative calcium balance (1-3). In a summary of data from nutritional surveys in the U.S., Pao (4J showed that dietary protein intake was well above the Recommended Dietary Allowances (RDA) for both men and women regardless of age (1). Although dietary calcium intakes are generally at the RDA for men, women below the age of 50 yr consume only 75% of the RDA (4J. Women above the age of 50 yr consume only two-thirds of the RDA for calcium (4). These low consumptions become critical when we consider the reduced ability for calcium absorption demonstrated in both men and women over the age of 60 yr (6). 

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 this study, the protein-induced calciuric effect was rather modest. Such could be the response early in life or it may be due to the natural protein sources, which are reported (13, 14) to be less calciuric than purified protein sources. Proteins differ in their calciuric effect and combining them can render them less calciuric. The relative (to calcium) excess of dietary phosphorus, a hypocal-ciuric agent (14) may have also mitigated pronounced hypercalciuria due to excessive protein. 

The suppression of PTH secretion from the parathyroid gland that accompanies the constitutive activation of the CASR makes the disorder difficult to recognize and treat. In some cases, it has been reported that seizures can be intractable. The abnormal set point of calcium regulation complicates treatment with calcitriol and dietary calcium supplementation because the CASR expressed in the kidney controls calcium excretion. The constitutively activated CASR mutant induces hypercalciuria, which may compound the hypocalcemia (42). 

Cellulose phosphate esters are produced from reaction with phosphoric acid and urea. The products are used to treat hypercalciuria because of its ability to bind calcium. It has also been used for the treatment of kidney stones. 

Mithramycin (also known as MIT and plicamy-cin) is an antibiotic that binds to DNA to regulate transcription. It attaches to specific regions of DNA that are rich in guanine and cytosine. It appears to lower serum calcium concentrations by blocking the hypercalcemic action of Vitamin D. After IV administration about 25% of the drug is excreted in the urine after 2 hours, and 40% after 15 hours. The main indications are treatment of testicular tumors and control of hypercalcemia and hypercalciuria. 

It is a potent antacid with rapid acid neutralizing capacity, but on long term use, it can cause hypercalcemia, hypercalciuria and formation of calcium stones in the kidney. 

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. 

Approximately two thirds of kidney stones contain Ca2+ phosphate or Ca2+ oxalate. Many patients with such stones exhibit a defect in proximal tubular Ca2+ reabsorption that causes hypercalciuria. This can be treated with thiazide diuretics, which enhance Ca2+ reabsorption in the distal convoluted tubule and thus reduce the urinary Ca2+ concentration. Salt intake must be reduced in this setting, since excess dietary NaCI will overwhelm the hypocalciuric effect of thiazides. Calcium stones may also be caused by increased intestinal absorption of Ca2+, or they may be idiopathic. In these situations, thiazides are also effective, but should be used as adjunctive therapy with other measures. 

People with idiopathic hypercalciuria, characterized by hypercalciuria and nephrolithiasis with normal serum calcium and... 

Cholecalciferol Regulate gene transcription via the vitamin D receptor Stimulate intestinal calcium absorption, bone resorption, renal calcium and phosphate reabsorption decrease parathyroid hormone (PTH) promote innate immunity inhibit adaptive immunity Osteoporosis, osteomalacia, renal failure, malabsorption Hypercalcemia, hypercalciuria the vitamin D preparations have much longer half-life than the metabolites and analogs... 

Renal calcinosis can develop as a result of hypercalciuria and is a major concern in the treatment of infantile spasms with corticotropin. In 16 infants, corticotropin, often associated with anticonvulsants, results in increased urinary excretion of calcium and phosphate, with increased parathormone serum concentrations and in some cases generalized aminoaciduria (26). This makes it imperative that the dose of corticotropin and the duration of treatment be kept to the minimum required to ensure efficacy. In one case in which calcified stones were removed surgically, recurrence was apparently prevented, despite the presence of a Cushingoid state, by long-term chlorothiazide (27). 

A patient with psoriasis developed hypercalcemia and hypercalciuria after 28 days of treatment with tacalcitol (1208). He had been taking long-term thiazide therapy for his hypertension. When he used topical tacalcitol ointment his serum calcium concentration and urinary calcium excretion gradually increased to 3.55 mmol/1 and 0.475 g/day respectively. Within 7 days of withdrawal of tacalcitol, the serum calcium concentration had normalized. 

Carling, T, Szabo, E, Bai, M, Ridefelt, P, Westin, G, Gustavsson, P, Trivedi, S, Heilman, P, Brown, EM, Dahl, N and Rastad, J, 2000, Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor, J Clin Endocrinol Metab 85 2042-2047... 

Pearce, SH, Williamson, C, Kifor, O, Bai, M, Coulthard, MG, Davies, M, Lewis-Bamed, N, McCredie, D, Powell, H, Kendall-Taylor, P, Brown, EM and Thakker, RV, 1996, A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor [see comments], N Engl J Med 335 1115-1122... 

Yamamoto, M, Akatsu, T, Nagase, T and Ogata, E, 2000, Comparison of hypocalcemic hypercalciuria between patients with idiopathic hypoparathyroidism and those with gain-of-function mutations in the calcium-sensing receptor is it possible to differentiate the two disorders , J Clin Endocrinol Metab... 

Renal hypercalciuria (kidney stones). Thiazide diuretics such as metolazone (Zaroxolyn) that increase calcium levels in the body are used in the treatment of kidney stones. 

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