Mechanism of chronic hypercalciuria with furosemide: increased calcium absorption

1986 ◽  
Vol 251 (1) ◽  
pp. F17-F24 ◽  
Author(s):  
D. A. Bushinsky ◽  
M. J. Favus ◽  
C. B. Langman ◽  
F. L. Coe
Keyword(s):  
Calcium Absorption ◽  
Chronic Administration ◽  
Urinary Calcium ◽  
Intestinal Calcium Absorption ◽  
Calcium Excretion ◽  
Calcium Balance ◽  
Urine Calcium ◽  
Calcium Diet ◽  
Filtered Load ◽  
Urine Calcium Excretion

Furosemide produces chronic hypercalciuria. The source of the additional urinary calcium is not known but must be either bone mineral or calcium absorbed by the intestine. Without bone calcium dissolution or increased absorption the filtered load of calcium would fall and urinary calcium excretion would return to pretreatment levels. To determine whether furosemide alters intestinal calcium absorption, we fed furosemide (75 mg . kg body-1 wt . day-1) to 11 rats eating 15 g/day of a 0.60% calcium diet. Compared with 11 control rats, furosemide increased urine calcium (15.6 +/- 0.8 mg/5 days vs. 4.1 +/- 0.3, P less than 0.001). Fecal calcium excretion fell (194 +/- 7 mg/5 days vs. 223 +/- 12, P less than 0.05), indicating an increase in intestinal calcium absorption sufficient to sustain the hypercalciuria. The increase in absorption occurred without an increase in the level of serum 1,25-dihydroxycholecalciferol (180 +/- 20 pg/ml vs. 220 +/- 16, furosemide vs. control, respectively, P = NS). To determine whether the intestinal effect of furosemide persists after the initial sodium diuresis abates, we analyzed only the last 3 days of balance. Again, rats fed furosemide had increased urine excretion and intestinal absorption of calcium, so that net calcium balance was not different from that of controls. Twelve additional rats were fed a 0.02% calcium diet to which 35 mg . kg body wt-1 . day-1 of furosemide was added. Compared with eleven controls, urine calcium increased and fecal calcium excretion again fell, but balance was not different. Chronic administration of furosemide increases intestinal calcium absorption enough to permit urine calcium excretion to remain elevated without the necessity for bone dissolution.

Mechanism of chronic hypocalciuria with chlorthalidone: reduced calcium absorption

1984 ◽  
Vol 247 (5) ◽  
pp. F746-F752 ◽  
Author(s):  
D. A. Bushinsky ◽  
M. J. Favus ◽  
F. L. Coe
Keyword(s):  
Serum Calcium ◽  
Calcium Absorption ◽  
Chronic Administration ◽  
Intestinal Calcium Absorption ◽  
Male Rats ◽  
Calcium Excretion ◽  
Urine Calcium ◽  
X 24 ◽  
Filtered Load ◽  
Urine Calcium Excretion

Chlorthalidone, like other benzothiadiazides, lowers urine calcium excretion chronically. If intestinal calcium absorption did not fall or bone accretion did not increase, serum calcium and the filtered load of calcium would increase and urine calcium would return to pretreatment levels. To determine whether overall intestinal calcium absorption fell, we fed chlorthalidone (5 mg X kg body wt-1 X 24 h-1) to 10 adult male rats eating 15 g/day of a 0.6% calcium diet. Compared with 10 control rats, chlorthalidone reduced urine calcium [2.1 +/- 0.1 (SE) vs. 5.8 +/- 0.5 mg/6 days; P less than 0.001]. Fecal calcium rose (307 +/- 9 vs. 257 +/- 12; P less than 0.005) because percent intestinal calcium absorption fell (41 +/- 2 vs. 52 +/- 2; P less than 0.002). Twenty other rats given the same diet were injected subcutaneously with 1,25(OH)2D3 (50 ng/day). In these rats, chlorthalidone reduced urine calcium (23 +/- 3 vs. 59 +/- 3; P less than 0.001) and percent intestinal calcium absorption (60 +/- 1 vs. 66 +/- 1; P less than 0.01). With or without 1,25(OH)2D3, chronic administration of chlorthalidone reduces intestinal calcium absorption, and this reduction seems to be the mechanism that permits urine calcium excretion to remain low.

Effect of Hydrochlorothiazide on 1,25-dihydroxyvitamin D3-induced Changes in Calcium Metabolism in Experimental Hypoparathyroidism in Rats

1981 ◽  
Vol 60 (1) ◽  
pp. 101-107 ◽  
Author(s):  
R. Rizzoli ◽  
K. Hugi ◽  
H. Fleisch ◽  
J.-P. Bonjour
Keyword(s):  
Calcium Absorption ◽  
Kinetic Studies ◽  
Chronic Administration ◽  
Plasma Calcium ◽  
Intestinal Calcium Absorption ◽  
Calcium Deposition ◽  
Calcium Excretion ◽  
Calcium Balance ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3

1. Chronic administration of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] can normalize plasma calcium in human hypoparathyroidism and in thyroparathyroidectomized animals. The effect of 1,25(OH)2D3 on plasma calcium is associated with an increase in urinary calcium excretion. In an attempt to prevent this increase, thyroparathyroidectomized rats receiving 1,25(OH)2D3 were also treated with hydrochlorothiazide for 9–11 days. 2. Calcium clearance studies show that hydrochlorothiazide stimulated the tubular reabsorption of calcium in thyroparathyroidectomized rats treated with 1,25(OH)2D3. 3. Calcium balance and kinetic studies indicated that hydrochlorothiazide decreased 1,25(OH)2D3-induced hypercalciuria in thyroparathyroidectomized rats. Hydrochlorothiazide did not affect the 1,25(OH)2D3-induced increase in plasma calcium. The hypocalciuric effect of hydrochlorothiazide was not associated with significant changes in calcium deposition into or release from bone. 4. In thyroparathyroidectomized rats treated with 1,25(OH)2D3 the hypocalciuric effect of hydrochlorothiazide was associated with a fall in intestinal calcium absorption. Overall, the calcium balance was unaffected. 5. Thus it appears that hydrochlorothiazide reduces the 1,25(OH)2D3-induced hypercalciuria in parathyroid hormone-deficient animals by decreasing intestinal calcium absorption. Despite the decreased absorption, hydrochlorothiazide does not reduce the 1,25(OH)2D3-induced increase in plasma calcium.

Urinary calcium indices in primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH): which test performs best?

2020 ◽  
pp. postgradmedj-2020-137718
Author(s):  
Muhammad Fahad Arshad ◽  
James McAllister ◽  
Azhar Merchant ◽  
Edmund Rab ◽  
Jacqueline Cook ◽  
...  
Keyword(s):  
Primary Hyperparathyroidism ◽  
International Workshop ◽  
Significant Proportion ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Clearance Ratio ◽  
Urine Calcium ◽  
Genetic Studies ◽  
Urine Calcium Excretion ◽  
Control Study

AimPrimary hyperparathyroidism (PHPT) is much more common than familial hypocalciuric hypercalcaemia (FHH), but there is considerable overlap in biochemical features. Urine calcium indices help with the differential diagnosis, but their reliability in making this distinction is not clear. The aim of this study was to compare urinary calcium values in patients with PHPT and FHH.MethodsThis was a case–control study of patients with PHPT who had successful surgery and genetically proven FHH between 2011 and 2016. Due to low FHH numbers, patients from neighbouring hospitals and outside study period (2017–2019) were allowed to improve power. Data on demographics and urinary calcium were obtained from electronic records and compared between the two groups.ResultsDuring the study period, 250 patients underwent successful PHPT surgery, while in the FHH arm, 19 genetically proven cases were included. The median (IQR) 24-hour urine calcium excretion (UCE) in the PHPT group was 8.3 (5.6–11.2) mmol/24 hours compared with 3.2 (2.1–6.1) mmol/24 hour in the FHH group (p<0.001). Median (IQR) calcium to creatinine clearance ratio (CCCR) in the PHPT and FHH groups was 0.020 (0.013–0.026) and 0.01 (0.002–0.02), respectively (p=0.001). The sensitivity of urinary tests for PHPT was 96% for UCE (cut-off ≥2.5 mmol/24 hour) and 47% for CCCR (cut-off >0.02). The specificity of the urinary tests for FHH was 29.4% for UCE (cut-off <2.5 mmol/24 hour) and 93% for CCCR (cut-off <0.02).Conclusions24-hour UCE is more sensitive in diagnosing PHPT; however, it is less specific in ruling out FHH as compared with CCCR, when the cut-offs suggested by the International guidelines from the fourth international workshop are used. A significant proportion of patients with PHPT would have also required genetic studies if the guidelines were followed.

Increased sensitivity to 1,25(OH)2D3 in bone from genetic hypercalciuric rats

1996 ◽  
Vol 271 (1) ◽  
pp. C130-C135 ◽  
Author(s):  
N. S. Krieger ◽  
V. M. Stathopoulos ◽  
D. A. Bushinsky
Keyword(s):  
Bone Resorption ◽  
Calcium Absorption ◽  
Immunoblot Analysis ◽  
Calcium Excretion ◽  
Sprague Dawley ◽  
Urine Calcium ◽  
Fourfold Increase ◽  
Low Calcium Diet ◽  
Slot Blot Analysis ◽  
Urine Calcium Excretion

As a model of human hypercalciuria, we have selectively inbred genetic hypercalciuric stone-forming (GHS) Sprague-Dawley rats whose mean urine calcium excretion is eight to nine times greater than that of controls. A large component of this excess urine calcium excretion is secondary to increased intestinal calcium absorption, which is not due to an elevation in serum 1,25(OH)2D3, but appears to result from an increased number of intestinal 1,25(OH)2D3 receptors (VDR). When GHS rats are fed a low-calcium diet, the hypercalciuria is only partially decreased and urine calcium excretion exceeds intake, suggesting that an additional mechanism contributing to the hypercalciuria is enhanced bone demineralization. To determine if GHS rat bones are more sensitive to exogenous 1,25(OH)2D3, we cultured calvariae from neonatal (2- to 3-day-old) GHS and control rats with or without 1,25(OH)2D3 or parathyroid hormone (PTH) for 48 h at 37 degrees C. There was significant stimulation of calcium efflux from GHS calvariae at 1 and 10 nM 1,25(OH)2D3, whereas control calvariae showed no significant response to 1,25(OH)2D3 at any concentration tested. In contrast, PTH induced similar bone resorption in control and GHS calvariae. Immunoblot analysis demonstrated a fourfold increase in the level of VDR in GHS calvariae compared with control calvariae, similar to the increased intestinal receptors described previously. There was no comparable change in VDR RNA levels as measured by slot blot analysis, suggesting the altered regulation of the VDR occurs posttranscriptionally. That both bone and intestine display an increased amount of VDR suggests that this may be a systemic disorder in the GHS rat and that enhanced bone resorption may be responsible, in part, for the hypercalciuria in the GHS rat.

scholarly journals Inhibition of calbindin D28K expression by cyclosporin A in rat kidney: the possible pathogenesis of cyclosporin A-induced hypercalciuria.

1998 ◽  
Vol 9 (8) ◽  
pp. 1416-1426
Author(s):  
C W Yang ◽  
J Kim ◽  
Y H Kim ◽  
J H Cha ◽  
S Y Mim ◽  
...  
Keyword(s):  
Cyclosporin A ◽  
Serum Calcium ◽  
Protein Level ◽  
Rat Kidney ◽  
Urinary Calcium ◽  
Calcium Handling ◽  
Calcium Excretion ◽  
Urine Calcium ◽  
Calbindin D28k ◽  
Urine Calcium Excretion

A recent study by Steiner et al. (Biochem Pharmacol 51: 253-258, 1996) demonstrated a decreased calbindin D28K expression in the kidneys of cyclosporin A (CsA)-treated rats. To evaluate the association of renal calcium handling with calbindin D28K expression in CsA-treated rats, two separate experiments (vehicle [VH] versus CsA groups, 1,25-dihydroxyvitamin D3 [VitD] versus VitD + CsA groups) were done simultaneously. CsA (25 mg/kg per d, subcutaneously) and VitD (0.5 microg/kg per d, subcutaneously) were given for 7 d. The CsA group showed decreased serum calcium, increased urine calcium excretion, and decreased calbindin D28K protein level and immunoreactivity compared with the VH group. The VitD + CsA treatment decreased serum calcium, increased urine calcium excretion, and decreased calbindin D28K protein level and immunoreactivity compared with the VitD alone. CsA treatment did not affect the serum parathyroid hormone and VitD levels. This study demonstrates an association of calbindin D28K expression with the urinary calcium excretion in CsA-treated rats, and suggests that decreased calbindin D28K expression may play a role in renal calcium wasting.

The Causes of Hypocalcaemia in Chronic Renal Failure

1971 ◽  
Vol 40 (4) ◽  
pp. 305-315 ◽  
Author(s):  
M. Cochran ◽  
B. E. C. Nordin
Keyword(s):  
Renal Failure ◽  
Serum Calcium ◽  
Sodium Excretion ◽  
Calcium Concentration ◽  
Calcium Absorption ◽  
Calcium Excretion ◽  
Urine Calcium ◽  
Serum Calcium Concentration ◽  
Glomerular Filtrate ◽  
Urine Calcium Excretion

1. Serum calcium and phosphate, calcium absorption and calcium excretion were measured in twenty-seven cases of chronic renal failure. 2. Hypocalcaemia was present in thirteen cases and tended to be more severe in patients with the most severe degree of renal failure. 3. The hypocalcaemia could not be attributed to hyperphosphataemia since many of the patients with hypocalcaemia had normal serum phosphate concentrations. 4. Malabsorption of calcium was observed in all but three patients, and was significantly related to the degree of renal failure, but there was only a weak correlation between absorption and the serum calcium concentration. The 24 h calcium excretion was not significantly related to creatinine clearance or to calcium absorption. 5. The relation between serum calcium concentration and fasting urine calcium excretion, expressed in mg per 100 ml of glomerular filtrate, was grossly abnormal. Instead of the positive correlation previously established in normal subjects, plasma calcium and urine calcium expressed in this way were inversely related, signifying a severe reduction in the tubular reabsorption of calcium. 6. Calcium and sodium excretion (each expressed in units per 100 ml of glomerular filtrate) were significantly related, but calcium excretion and serum bicarbonate were not. However, examination of the urine calcium/sodium relationship at urine sodium excretion rates below 1·5 mEq per 100 ml of glomerular filtrate indicated that, within this range, urine calcium excretion was inversely related to serum bicarbonate concentration and positively related to urine sodium excretion. 7. We conclude that there is reduced tubular reabsorption of calcium in renal failure, and this is attributable both to metabolic acidosis and to the increased rate of sodium excretion per nephron, and that it could be a significant contributory factor in the hypocalcaemia which may be observed in renal failure without hyperphosphataemia.

The effect of diabetes mellitus on urinary calcium excretion in pregnant rats and their offspring

1995 ◽  
Vol 145 (1) ◽  
pp. 11-18 ◽  
Author(s):  
T J Birdsey ◽  
S M Husain ◽  
H O Garland ◽  
C P Sibley
Keyword(s):  
Diabetes Mellitus ◽  
Calcium Homeostasis ◽  
Calcium Absorption ◽  
Maternal Diabetes ◽  
Urinary Calcium ◽  
Urinary Calcium Excretion ◽  
Calcium Excretion ◽  
Calcium Balance ◽  
Pregnant Rats ◽  
Total Body Calcium

Abstract The effect of maternal diabetes mellitus on renal calcium excretion in pregnant rats and their offspring has been examined in order to ascertain the role of the kidney in the disturbed calcium homeostasis of infants born to diabetic mothers. Diabetic pregnant (DP) rats exhibited severe hypercalciuria which greatly exceeded the urinary calcium losses (UCaV) in non-diabetic pregnant (CP) or non-pregnant diabetic (D) rats. Means ± s.e.m. for UCaV at day 21 (mmol/24 h) were: DP=1·12± 0·09 (n=7); CP=0·06±0·01 (n=7); D=0·63±0·06 (n=7) (P<0·001 DP vs CP and DP vs D). The profile for urinary calcium excretion in the three groups was different from that of other measured ions. The degree of natriuresis, for example, was comparable in DP and D rats at all stages studied. Although magnesium output was significantly greater in DP than D rats on days 14 and 21, this appeared to result from an additive effect of the magnesiuresis seen when pregnancy and diabetes were studied separately. The marked renal calcium wasting of diabetic pregnancy will have implications for overall calcium balance in the mother. For example, an enhanced intestinal calcium absorption was seen in DP rats in the second half of gestation. Means ± s.e.m. for day 21 (mmol/24 h) were: DP=3·8±0·8 (n=7); CP=1·4±0·3 (n=7); D=1·6±0·3 (n=7) (P<0·05 DP vs CP and DP vs D). The hypercalciuria may also contribute to the disturbed calcium homeostasis of the neonate if it reduces the amount of calcium available for transfer to the fetus. In contrast to their mothers, the offspring of DP rats did not show a raised UCaV compared with CP pups. Means ± s.e.m. at day 1 postpartum (nmol/2 h per pup) were: DP=47·2±15·7 (n=4 litters); CP=72·2±14·1 (n=7 litters) (not significant). Changes in neonatal renal function are therefore unlikely to contribute to their disturbed calcium balance. In fact, their slightly reduced urinary calcium output may be an attempt to compensate for their lowered total body calcium as reported elsewhere. Journal of Endocrinology (1995) 145, 11–18

scholarly journals Calcium and caffeine interaction in increased calcium balance in ovariectomized rats

2013 ◽  
Vol 26 (3) ◽  
pp. 313-322
Author(s):  
Sandra Tavares da Silva ◽  
Neuza Maria Brunoro Costa ◽  
Frederico Souzalima Caldoncelli Franco ◽  
Antônio José Natali
Keyword(s):  
Calcium Intake ◽  
Calcium Absorption ◽  
Urinary Calcium ◽  
Deionized Water ◽  
Ovariectomized Rats ◽  
Caffeine Intake ◽  
Calcium Excretion ◽  
Calcium Balance ◽  
Negative Effects ◽  
Ad Libitum

OBJECTIVE: This study investigated the effects of caffeine intake associated with inadequate or adequate calcium intake in laparotomized or ovariectomized rats by means of the calcium balance. Forty adults Wistar rats were ovariectomized or laparotomized. METHODS: The animals (n=40) were randomly placed in eight groups receiving the AIN-93 diet with 100% or 50% of the recommended calcium intake with or without added caffeine (6mg/kg/day). The animals were kept in individuals metabolic cages at a temperature of 24°±2ºC, light/dark cycles of 12/12 hours, and deionized water available ad libitum. On the 8th week of the experiment, food consumption was measured and 24-hour urine and 4-day feces were collected to determine calcium balance [Balance=Ca intake-(Urinary Ca+Fecal Ca)]. RESULTS: Animals with adequate calcium intake presented higher balances and rates of calcium absorption and retention (p<0.05) than those with inadequate calcium intake, regardless of caffeine intake (p<0.05). Caffeine intake did not affect urinary calcium excretion but increased balance (p<0.05) in the groups with adequate calcium intake. CONCLUSION: Adequate calcium intake attenuated the negative effects of estrogen deficiency and improved calcium balance even in the presence of caffeine.

Metabolic, but not respiratory, acidosis increases bone PGE2 levels and calcium release

2001 ◽  
Vol 281 (6) ◽  
pp. F1058-F1066 ◽  
Author(s):  
David A. Bushinsky ◽  
Walter R. Parker ◽  
Kristen M. Alexander ◽  
Nancy S. Krieger
Keyword(s):  
Metabolic Acidosis ◽  
Calcium Release ◽  
Calcium Absorption ◽  
Respiratory Acidosis ◽  
Urinary Calcium ◽  
Calcium Excretion ◽  
Calcium Efflux ◽  
Bicarbonate Concentration ◽  
Blood Ph ◽  
Urine Calcium Excretion

First published July 12, 2001; 10.1152/ajprenal.00355.2001.— A decrease in blood pH may be due to either a reduction in bicarbonate concentration ([HCO[Formula: see text]]; metabolic acidosis) or to an increase in Pco 2 (respiratory acidosis). In mammals, metabolic, but not respiratory, acidosis increases urine calcium excretion without altering intestinal calcium absorption, indicating that the additional urinary calcium is derived from bone. In cultured bone, chronic metabolic, but not respiratory, acidosis increases net calcium efflux ( J Ca), decreases osteoblastic collagen synthesis, and increases osteoclastic bone resorption. Metabolic acidosis increases bone PGE2production, which is correlated with J Ca, and inhibition of PGE2 production inhibits this acid-induced J Ca. Given the marked differences in the osseous response to metabolic and respiratory acidosis, we hypothesized that incubation of neonatal mouse calvariae in medium simulating respiratory acidosis would not increase medium PGE2 levels, as observed during metabolic acidosis. To test this hypothesis, we determined medium PGE2 levels and J Ca from calvariae incubated at pH ∼7.1 to model either metabolic (Met; [HCO[Formula: see text]] ∼11 mM) or respiratory (Resp; Pco 2 ∼83 Torr) acidosis, or at pH ∼7.5 as a control (Ntl). We found that after 24–48 and 48–51 h in culture, periods when cell-mediated J Capredominates, medium PGE2 levels and J Ca were increased with Met, but not Resp, compared with Ntl, and there was a direct correlation between medium PGE2 levels and J Ca. Thus metabolic, but not respiratory, acidosis induces the release of bone PGE2, which mediates J Ca from bone.

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