Urinary calcium excretion effect

Thiazide diuretics decrease urinary calcium excretion and may decrease bone turnover. However, their effects on bone mineral density and fracture rates have not been studied in controlled trials. Thiazide diuretics are not recommended solely for potential beneficial effects in osteoporosis. 

Since the early 1970 s, research has been directed at identifying the mechanism by which the calciuria is induced. Attention was given first to the question of whether the elevated urinary calcium excretion was caused by an increase in the intestinal absorption of calcium. Results of calcium balance studies in human subjects showed that protein ingestion either had no effect on calcium absorption (4) or that the effect was insufficient to account for the calciuria (5j. Consequently, negative calcium balance is a frequent observation in human studies when high protein diets are fed, and this situation is not improved by high calcium intakes (4 ). 

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. 

While our data using this technique are still preliminary, we have observed that 25 yU/ml insulin inhibits the rate of calcium efflux from renal slices (28). This effect of insulin was gradually reduced at the higher concentrations of insulin. The effects of insulin on calcium exchange appear to be localized in the mitochondrial compartment. Further work is needed to determine whether insulin affects specific enzyme systems which are known to play a role in renal calcium transport, and which cellular or subcellular compartments are involved. This would substantially increase our understanding of the regulation of urinary calcium excretion, and of ways in which excessive loss of calcium by this route might be avoided. 

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. 

Table III. Postprandial Effects of Protein Level and Source on Urinary Calcium Excretion of Men...

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. 

Prentice, A., Jaqou, L. M., Cole, T. J., Stirling, D. M., Dibba, B., and Fairweather-Tait, S. (1995). Calcium requirements of lactating Gambian mothers Effects of a calcium supplement on breast-milk calcium concentration, maternal bone mineral content, and urinary calcium excretion. Am. J. Clin. Nutr. 62, 58-67. 

Four children with the nephrotic syndrome developed transient hypercalciuria and intraluminal calcification in renal histopathological specimens without radiological evidence of renal calcification. These children were resistant to corticosteroids and were receiving furosemide plus albumin for the management of edema (10). This result stresses the pervasive effect of furosemide, and probably all loop diuretics, in increasing urinary calcium excretion, with resultant nephrocalcinosis. Whenever possible, steps should be taken to limit the hypercalciuric effect of loop diuretics. Such maneuvers could include limiting the sodium content of the diet and/or combining the loop diuretic with a thiazide diuretic. 

Diuretics have been shown to have variable effects in relationship to urinary calcium excretion and supersaturation, most notably including loop diuretic induced hypercalciuria and attenuation of urinary calcium excretion by thiazide diuretics. The factors contributing to nephrotoxicity are most commonly associated with multiple factors that favor calcium salt or uric acid deposition at the tubulo-interstitial level. Management of renal stone formation and nephrocalcinosis therefore presents a unique clinical challenge, balancing factors that increase risk for abnormal calcium salt deposition or crystallization, and factors that reduce this risk. 

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... 

Adverse effects of oral calcium and vitamin D supplementation include hypercalcemia and hypercalciuria, especially in the hy-poparathyroid patient, in whom the renal calcium-sparing effect of parathyroid hormone is absent. Hypercalciuria may increase the risk of calcium stone formation and nephrolithiasis in susceptible patients. One maneuver to help prevent calcium stones is to maintain the calcinm at a low normal concentration. Monitoring 24-hour urine collections for total calcium concentrations (goal <300 mg/24 h) may also minimize the occurrence of hypercalciuria. The addition of thiazide dinretics for patients at risk for stone formation may result in a reduc-tionof both urinary calcium excretion and vitamin D requirements." ... 

The thiazide diuretics, which reduce urinary calcium excretion, also may reduce the rate of bone loss (33). This protective effect has been shown to vanish within 4 to 5 months after discontinuation of the thiazide. 

Knapen, M.H., Hamulyak, K., and Vermeer, C. (1989). The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion, Ann. Intern. Med., Ill, 1001. 

Acutely, the use of saline infusion accompanied by administration of loop diuretics enhances urinary calcium excretion. Calcitonin, mithramycin and corticosteroids decrease calcium movement from bone. Reduced intake of calcium and corticosteroids decrease intestinal absorption of calcium. Short-term hemodialysis or peritoneal dialysis is effective for the rapid removal of calcium from the blood in crisis situations, especially in patients with renal failure or congestive heart failure. Prolonged hemodialysis, however, is not a therapeutic solution because of its impracticality and high complication rate. 

A single dose of 500 ml cranberry juice had no effect on urinary oxalate secretion but significantly increased mean urinary calcium levels (Brinkley et al. 1981). A significant increase in urinary calcium excretion was observed in a small study after consumption of 2 pints of cranberry juice (Kahn et al. 1967). Consumption of 2 pints daily of cranberry juice for 1 month reduced urinary ionized calcium by 50% (Light et al. 1973). A study on dietary intake and urinary excretion of oxalates indicated that cranberry juice had no effect on oxalate excretion (Massey et al. 1993). 

Hypocalcemia has previously been described in connection with deferoxamine in an 8-month-old infant with aluminium overload related to parenteral nutrition, without increased urinary calcium excretion, suggesting bone uptake of calcium after chelation of aluminium [21 ]. A similar hypocalcemic effect has been observed in two patients with dialysis-related aluminium-induced osteomalacia treated with deferoxamine 12 ... 

If the semm calcium is greater than 11 mg/dL, the patient has nephrolithiasis, or the serum creatinine is elevated, dmg therapy is usually required. The drug of choice is prednisone at an initial daily dose of 20 to 40 mg/day (183). Corticosteroids cause a rapid decline in serum calcium within 5 days and in urinary calcium excretion in 7 to 10 days (183). Failure of the serum calcium to normalize within two weeks on this corticosteroid regimen should alert the clinician to an alternate or coexisting disorder such as hyperparathyroidism, lymphoma, carcinoma, and myeloma (183). Once the calcium disorder is brought under control, the corticosteroid dose can be lowered over four to six weeks (183). The serum calcium and urinary calcium excretion rate should be closely monitored. If the patient develops intolerable corticosteroid side effects or fails to respond, chloroquine (184), hydroxychloroquine (185), and ketoco-nizole (186) have been used successfully. 

Leaf DE, Korets R, Taylor EN, Tang J, Asplin JR, Goldferb DS, et aL Effect of vitanun D repletion on urinary calcium excretion among kidney stone formers. Clin J Am Soc Nephrol May 2012 7(5) 829-34. 

Collectively, the possible effects of high dietary intakes of protein and phosphate on urinary calcium excretion and enhanced bone resorption, respectively, along with the possibility of reduced calcium absorption with advancing age, argue for recommending an ample intake of calcium. 

Dietary calcium has a relatively small impact on urinary calcium (e.g., only 6-8% of an increase in dietary calcium intake will appear in the urine). The major food components that affect urinary calcium are protein, phosphorus, caffeine, and sodium. For each 50-g increment in dietary protein, approximately 1.5 mmol (60 mg) of additional calcium is lost in urine. The higher amounts of phosphorus consumed concurrently with a high-protein diet can blunt, but not eliminate, this phenomenon. Dietary phosphorus (as well as intravenously administered phosphorus) increases PTH synthesis and subsequently stimulates renal calcium reabsorption and reduces the urinary excretion of calcium. Caffeine causes a reduction in renal reabsorption of calcium and a subsequently increased loss of urinary calcium soon after it is consumed. It has been shown repeatedly in animals and humans that dietary sodium, in the form of salt (NaCl), increases urinary calcium excretion. On average, for every 100 mmol (2300 mg) of sodium excreted in urine, there is an approximately 0.6-1 mmol (24-40 mg) loss of calcium in free-living healthy populations of various ages. Because most of the urinary calcium is of bone origin, it is commonly hypothesized that those nutrients or food components that are hypercalciuretic are also detrimental to the skeleton. On the other hand, thiazide medications are hypocalciuric and, as such, may have modest positive effects on bone. 

Epidemiologic studies have consistently documented that increased potassium intake is associated with greater bone mineral density. In trials, supplemental potassium bicarbonate reduced bone turnover as manifest by less urinary calcium excretion and by biochemical evidence of greater bone formation and reduced bone resorption. However, no trial has tested the effect of increased potassium or diets rich in potassium on bone mineral density or clinical outcomes related to osteoporosis. 

In a study with 40 healthy men and women, average age 63.7 years, who were randomized to either an alkali diet (meat plus fruits and vegetables) or an acid diet (meat plus cereal grains) (Jajoo and others 2006), altering the renal net acid excretion over a period of 60 days affected several biochemical markers of bone turnover and calcium excretion. The acidity of the diet had a significant effect on increasing NTX, a urinary marker of bone breakdown, and increasing the amount of calcium excreted in the urine. 

In attempting to reconcile these findings, it should be pointed out that rats may not be appropriate models for the study of calcium metabolism in humans. Unlike humans, the rat does not undergo epiphyseal plate closure and does not have a significant haversian remodeling sequence (21) Furthermore, rats excrete only l-270 of their calcium intake in their urine whereas humans excrete approximately 20-30% or more. This fact is especially significant, since most of the known effects of phosphates on calcium retention in humans are effected by alterations in urinary calcium. 

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. 

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