Changes in Serum and Urinary Calcium during Treatment with Hydrochlorothiazide: Studies on Mechanisms

Brickman, Arnold S.; Massry, Shaul G.; Coburn, Jack W.

doi:10.1172/jci106889

Cited by 219 publications

(95 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Creatinine clearance, Ca filtered load, and urine Na excretion were not altered by chronic TZ treatment. A modest drop in intravascular volume has been shown to occur after initiation of TZ in other studies (7,34), after which subjects come into balance at this new modestly decreased weight, and Na excretion returns to baseline; presumably volume depletion occurred in our subjects as well ( Table 1).…”

Section: Discussionsupporting

confidence: 66%

“…The mechanism of chronic TZ hypocalciuria is unclear. In short-term studies, administration of TZ causes modest Na depletion, which is associated with a fall in urine Ca excretion; the hypocalciuria can be prevented by administration of sodium chloride (6,7,30,32). However, these studies have rarely included subjects with IH and usually were limited to a week or less in duration.…”

mentioning

confidence: 99%

See 1 more Smart Citation

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

Bergsland

Worcester

Coe

2013

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

Bergsland KJ, Worcester EM, Coe FL. Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria. Am J Physiol Renal Physiol 305: F592-F599, 2013. First published May 29, 2013 doi:10.1152/ajprenal.00116.2013The most common metabolic abnormality found in calcium (Ca) kidney stone formers is idiopathic hypercalciuria (IH). Using endogenous lithium (Li) clearance, we previously showed that in IH, there is decreased proximal tubule sodium absorption, and increased delivery of Ca into the distal nephron. Distal Ca reabsorption may facilitate the formation of Randall's plaque (RP) by washdown of excess Ca through the vasa recta toward the papillary tip. Elevated Ca excretion leads to increased urinary supersaturation (SS) with respect to calcium oxalate (CaOx) and calcium phosphate (CaP), providing the driving force for stone growth on RP. Thiazide (TZ) diuretics reduce Ca excretion and prevent stone recurrence, but the mechanism in humans is unknown. We studied the effect of chronic TZ administration on renal mineral handling in four male IH patients using a fixed three meal day in the General Clinical Research Center. Each subject was studied twice: once before treatment and once after 4 -7 mo of daily chlorthalidone treatment. As expected, urine Ca fell with TZ, along with fraction of filtered Ca excreted. Fraction of filtered Li excreted also fell sharply with TZ, as did distal delivery of Ca. Unexpectedly, TZ lowered urine pH. Together with reduced urine Ca, this led to a marked fall in CaP SS, but not CaOx SS. Since CaOx stone formation begins with an initial CaP overlay on RP, by lowering urine pH and decreasing distal nephron Ca delivery, TZ might diminish stone risk both by reducing CaP SS, as well as slowing progression of RP. calcium oxalate; calcium phosphate; idiopathic hypercalciuria; kidney calculi; thiazide THE MOST COMMON METABOLIC abnormality found in calcium (Ca) stone formers is so-called idiopathic hypercalciuria (IH) (40). Patients with IH absorb more Ca from a given meal than normal people (N), but also have abnormally decreased renal tubule Ca reabsorption, so that they often excrete more Ca than they have absorbed, exhibit decreased bone density, and have a propensity for increased fractures (22,42). Elevated urine Ca excretion leads to increased urinary supersaturation (SS) with respect to both calcium oxalate (CaOx) and calcium phosphate (CaP), providing the driving force for kidney stone formation (36). In addition, urine Ca excretion is correlated with the amount of interstitial apatite deposits (called Randall's plaque) found on the surface of the renal papillae (19). These deposits are the attachment sites for most CaOx stones and appear to be critical for stone formation (14). A plausible mechanism by which increased Ca reaches the deep papillae is via washdown from reabsorption in the thick ascending limb; an increase in delivery of Ca to this site would tend to increase reabsorption and washdown into the papilla and potentially increase...

show abstract

Section: Discussionsupporting

confidence: 66%

mentioning

confidence: 99%

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

Bergsland

Worcester

Coe

2013

American Journal of Physiology-Renal Physiology

View full text Add to dashboard Cite

show abstract

“…Parfitt (18) and Higgins et al (12) reported that thiazides were effective in decreasing the amount of calcium in the urine of vitamin-D-treated patients. Yendt and Cohanim (24), Parfitt (19), and Brickman et al (3), who studied patients with hypoparathyroidism treated by vitamin-D, found that thiazide had no influence on the excretion of calcium; on the other hand, normal controls receiving vitamin-D studied by the last group (3) experienced reduction in calcium excretion rates under treatment. Harrison and Harrison (11) pressed for further controlled studies of thiazide therapy for vitamin-D-induced hypercalciuria before conclusions should be drawn about their applicability in man.…”

Section: Methodsmentioning

confidence: 99%

“…Previous attempts to evaluate the effect of thiazides on vitamin-D-induced hypercalciuria have RESULTS produced the conflicting claims that urine calcium excretion is reduced in some patients (12,18) but that it is not reduced in All rats consumed 16 2 g of the Purina chow and lost 2.1 * others (3,19,24). It has, therefore, been recommended that further 1.2% of their weight during the 12-day study, with no difference studies are needed ( I 1).…”

mentioning

confidence: 99%

Reversal of Vitamin-D2-Induced Hypercalciuria by Chlorothiazide

1983

View full text Add to dashboard Cite

Summarydaily subcutaneous injection of 0.2 ml of the vitamin-DzTo test the effects of chlorothiazide on vitamin-D2-induced hypercalciuria, we carried out 17 metabolic studies lasting 12 days each in adult Sprague-Dawley male rats. Three groups were studied: (A) control rats receiving only the vitamin-D2 vehicle; (B) vitamin-D2-treated rats receiving 50 IU/day; and (C) rats treated in the same manner as group B with the addition of chlorothiazide 20 mg/day for the last 6 days of the study. Urine was collected during the last 3 days, and a blood sample was obtained at the end of each study period. Analysis of the data showed that there were no significant differences between the groups in changes of serum calcium concentration (A, 6.1 + 0.1 mg/dl; B, 6.1 f 0.2 mg/dl; C, 6.0 f 0.2 mg/dl), serum creatinine concentration (A, 0.5 + 0.07 mg/dl; B, 0.52 f 0.08 mg/dl; C, 0.48 k 0.04 mg/dl), and creatinine clearance (A, 4.8 f 0.7 ml/min/kg; B, 5.2 + 1.2 ml/min/kg; C, 4.9 f 0.5 ml/min/kg). The administration of vitamin-D2 significantly increased the urinary calcium excretion from 6.7 f 1.0 mg/kg/ day to 19.5 f 9.7 mg/kg/day ( p < 0.02), but the calciuria was inhibited in group C rats by the addition of chlorothiazide, which restored urinary calcium excretion to 6.8 + 2.5 mg/kg/day ( p < confirmed these effects of vitamin-D2 and chlorothiazide on urine calcium excretion. We conclude that in rats conventional doses of vitamin-D2 consistently induce marked hypercalciuria, even witbout hypercalcemia, and that this hypercalciuria can be effectively prevented by chlorothiazide. vehicle only; Group B, the vitamin-Dz group was composed of six rats that were injected daily subcutaneously with 50 IU of vitamin-DP (Drisdol, Winthrop Laboratories, New York, NY); and Group C, the vitamin-Dz and chlorothiazide group included six rats that were treated in the same manner as those in Group B but additionally with chlorothiazide 20 mg/day injected intraperitoneally (Diuril, Merck Sharp and Dohme, West Point, PA) for the last six days. During the last 3 days of the study all urine was collected, mixed, and measured. At the end of the study a blood sample was obtained from each rat by aortic puncture.0The urine was analyzed for calcium, creatinine, and sodium, and the serum for calcium and creatinine. Calcium was determined by atomic absorption spectrophotometry, nonchromogen creatinine, and sodium by standard methods. Student's t test was used to determine the significance of the difference between the groups.

show abstract

“…Thiazide diuretic agents and analogous molecules such as chlorthalidone (Thz) reduce urine calcium excretion in normal people (22,23), patients with idiopathic hypercalciuria (24,25), hypoparathyroid people (26,27), and rats (28,29). Thiazide diuretics are commonly used to treat CaOx stone disease (1)(2)(3)(4)(5).…”

mentioning

confidence: 99%

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Bushinsky¹,

Asplin²

2005

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Over 59 generations, a strain of rats has been inbred to maximize urine calcium excretion. The rats now excrete eight to 10 times as much calcium as controls. These rats uniformly form calcium phosphate (apatite) kidney stones and have been termed genetic hypercalciuric stone-forming (GHS) rats. The addition of a common amino acid and oxalate precursor, hydroxyproline, to the diet of the GHS rats leads to formation of calcium oxalate (CaOx) kidney stones. Hydroxyproline-supplemented GHS rats were used to test the hypothesis that the thiazide diuretic chlorthalidone would decrease urine calcium excretion, supersaturation, and perhaps stone formation. All GHS rats received a fixed amount of a standard 1.2% calcium diet with 5% trans-4-hydroxy-L-proline (hydroxyproline) so that the rats would exclusively form CaOx stones. Half of the rats had chlorthalidone (Thz; 4 to 5 mg/kg per d) added to their diets. Urine was collected weekly, and at the conclusion of the study, the kidneys, ureters, and bladders were radiographed for the presence of stones. Compared with control, the addition of Thz led to a significant reduction of urine calcium and phosphorus excretion, whereas urine oxalate excretion increased. Supersaturation with respect to the calcium hydrogen phosphate fell, whereas supersaturation with respect to CaOx was unchanged. Rats that were fed Thz had fewer stones. As calcium phosphate seems to be the preferred initial solid phase in patients with CaOx kidney stones, the reduction in supersaturation with respect to the calcium phosphate solid phase may be the mechanism by which thiazides reduce CaOx stone formation.

show abstract

Changes in Serum and Urinary Calcium during Treatment with Hydrochlorothiazide: Studies on Mechanisms

Cited by 219 publications

References 27 publications

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

Role of proximal tubule in the hypocalciuric response to thiazide of patients with idiopathic hypercalciuria

Reversal of Vitamin-D2-Induced Hypercalciuria by Chlorothiazide

Thiazides Reduce Brushite, but not Calcium Oxalate, Supersaturation, and Stone Formation in Genetic Hypercalciuric Stone–Forming Rats

Contact Info

Product

Resources

About