Hypercalciuria, treatment

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 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). 

Burren, C. P., Curley, A., Christie, P., Rodda, C. P., and Thakker, R. V. (2005) A family with autosomal dominant hypocalcaemia with hypercalciuria (ADHH) mutational analysis, phenotypic variability and treatment challenges. J. Pediatr. Endocrinol. Metab. 18, 9-99. 

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. 

Calcipotriene (Dovonex), a synthetic vitamin D3 derivative, is indicated for the treatment of moderate plaque psoriasis. Its mechanism of action is unknown, although it competes for calcitriol receptors on keratinocytes and normalizes differentiation. It also has a variety of immunomodulatory effects in the skin. Although the drug can cause local irritation, the most serious toxicities are hypercalciuria and hypercalcemia, which are usually reversible. 

Thiazides inhibit NaCI reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Q transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria. 

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). 

Mild asymptomatic hypercalcemia is common during treatment with parathyroid hormone (15). The hypercalcemia is persistent, and requires dosage reduction in 3% of patients using 20 micrograms/day and in 11% using 40 micrograms/day (16). Transient mild hypercalciuria and increased serum phosphate are common but do not usually limit therapy. 

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. 

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. 

Q9 Thiazides are considered first-line drugs in the treatment of hypertension in older people. They are also used in mild heart failure and to inhibit kidney stone formation in hypercalciuria, in addition to their use in treatment of nephrogenic diabetes insipidus. 

Calcitonin is used in the treatment of Paget s disease (osteitis deformans), a chronic disorder characterized by increased bone remodeling, normocalcemia and normophosphatemia, frequent episodes of hypercalciuria leading to stone formation, and elevation of serum alkaline phosphatase and urinary hydroxyproline levels. The disease does not appear to be primarily a derangement of calcium metabolism. Calcitonin reduces the levels of serum alkaline phosphatase and urinary hydroxyproline, and may relieve other symptoms of the disease as well. Diphosphonates, especially etidronate disodium, also reduce bone resorption in this disease. Various cancers are accompanied by hypercalcemia and may respond to treatment with calcitonin. 

Sodium cellulose phosphate (SCP) is an insoluble, non-absorbable ester of cellulose containing 34% inorganic phosphate and 11% sodium. It is capable of binding calcium in the intestinal tract, reducing absorption of this ion, as well as magnesium. SCP is indicated only for the treatment of absorptive hypercalciuria type I with recurrent calcium oxalate or calcium phosphate nephrolitMasis. 

Sodium cellulose phosphate is used in the treatment of adsorptive hypercalciura and nephrocalcinosis (both a common cause of kidney stones). The ability of inorganic esters of cellulose to function as ion exchangers, described previously, is the key to the use of sodium cellulose phosphate in the treatment of adsorptive hypercalciuria. Hypercalciuria is an increased level of calcium in a patient s urine. This disorder commonly results in painful kidney stones. Sodium cellulose phosphate has been used to complex the calcium ions and thus remove them from the patient and minimize the risk of stone formation (50-54). 

Comparative studies The efficacy of high-dose intramuscular versus oral cholecalciferol therapy (600,000 lU/ day) in elderly patients deficient in vitamin D has been examined [43 ]. At 6weeks, hypercalciuria was reported in one patient in intramuscular group compared with three patients in the oral group and at 12 weeks three patients on intramuscular and one on oral cholecalciferol experienced hypercalciuria. No other adverse events were reported. In another 6-month study to evaluate the effectiveness of one-dose oral versus inframuscular cholecalciferol (300,000 lU) for treatment of hypovitaminosis D, no adverse effects were observed... 

Randomised trials A randomised, controlled trial of 6 months of parathyroid hormone treatment in combination with either concurrent or sequential ibandronate over 2 years [67 ] found that both treatment regimens were efficacious in increasing bone mineral density in postmenopausal women (N = 44). Seven women met the criteria for hypercalcaemia, with only one requiring reduction in treatment. Three women met the criteria for hypercalciuria. The most commonly reported adverse events were nausea (32%) and injection-site reactions (32%). 

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