The mechanism of hypocalciuria with NaCl cotransporter inhibition.

Thiazide diuretics are used to prevent the recurrence of calcium-containing kidney stones. The ability of these drugs to reduce urinary calcium excretion has a key role in this process. Although studies have shown a reduction in the recurrence rate of calcium-containing stones in patients treated with thiazides, whether hypocalciuria results from increased calcium reabsorption in the proximal or distal nephron is still unclear. When extracellular fluid volume is considerably reduced, the proximal tubule is likely to have a major role in thiazide-induced hypocalciuria. This process frequently occurs when high doses of thiazides and sodium restriction are prescribed for the treatment of kidney stone disease. The distal tubule is predominantly involved in NaCl cotransporter inhibition-induced hypocalciuria when the extracellular fluid volume is not reduced, a clinical scenario observed in patients with Gitelman syndrome. In this Perspectives article, we discuss the evidence supporting the hypocalciuric effects of NaCl cotransporter inhibition in the proximal and distal nephron.

Proton pump inhibitors, osteoporosis, and osteoporosis-related fractures.

Proton pump inhibitors (PPIs) are among the most commonly prescribed medications today with an excellent short-term safety profile. Recently, a number of studies from a variety of data sources have reported an association between PPI use and hip fractures. However, there is not yet any direct evidence of a causal link between PPI use and the development of hip fracture. In the following paper, we will review the recent studies which have described this association between PPI use and hip fracture, and discuss the evidence supporting the likelihood of this association being causal, using data from previous work on the effects of surgical and pharmacological inhibition of gastric acid secretion on calcium absorption and bone mineral density. We will conclude by summarizing the current state of evidence on the relationship between gastric acid inhibition and the risk of fracture, and suggest management strategies for patients who require the long-term use of gastric acid inhibiting medications who also may be at risk for metabolic bone disease and fracture.

Drug-induced endocrine and metabolic disorders.

Complex interactions exist amongst the various components of the neuroendocrine system in order to maintain homeostasis, energy balance and reproductive function. These components include the hypothalamus-pituitary- adrenal and -gonadal axes, the renin-angiotensin-aldosterone system, the sympathetic nervous system and the pancreatic islets. These hormones, peptides and neurotransmitters act in concert to regulate the functions of many organs, notably the liver, muscles, kidneys, thyroid, bone, adrenal glands, adipocytes, vasculature, intestinal tract and gonads, through many intermediary pathways. Endocrine and metabolic disorders can arise from imbalance amongst numerous hormonal factors. These disturbances may be due to endogenous processes, such as increased secretion of hormones from a tumour, as well as exogenous drug administration. Drugs can cause endocrine abnormalities via different mechanisms, including direct alteration of hormone production, changes in the regulation of the hormonal axis, effects on hormonal transport, binding, and signalling, as well as similar changes to counter-regulatory hormone systems. Furthermore, drugs can affect the evaluation of endocrine parameters by causing interference with diagnostic tests. Common drug-induced endocrine and metabolic disorders include disorders of carbohydrate metabolism, electrolyte and calcium abnormalities, as well as drug-induced thyroid and gonadal disorders. An understanding of the proposed mechanisms of these drug effects and their evaluation and differential diagnosis may allow for more critical interpretation of the clinical observations associated with such disorders, better prediction of drug-induced adverse effects and better choices of and rationales for treatment.

Recent advances in renal tubular calcium reabsorption.

PURPOSE OF REVIEW: Knowledge of renal Ca2+ reabsorption has evolved greatly in recent years. This review focuses on two recent discoveries concerning passive and active Ca2+ reabsorption. RECENT FINDINGS: The thiazide diuretics are known for their hypocalciuric effect. Recently, it has been demonstrated that TRPV5-knockout mice, in which active Ca2+ reabsorption in the distal convoluted tubule is completely abolished, show the same sensitivity towards thiazides as wild-type mice. This indicates that thiazide affects Ca2+ reabsorption indirectly via contraction of the extracellular volume, independent of active Ca2+ reabsorption in the distal convoluted tubule, thereby increasing passive paracellular Ca2+ transport in the proximal tubule. Moreover, the antiaging hormone Klotho regulates Ca2+ reabsorption in the distal convoluted tubule via a novel molecular mechanism. Klotho stabilizes the TRPV5 Ca2+ channel in the plasma membrane by deglycosylation of the protein. SUMMARY: By showing that thiazide-induced hypercalciuria is due to increased passive Ca2+ reabsorption in the proximal tubule, a long-standing issue has been solved, underlining the importance of proximal paracellular Ca2+ reabsorption. Moreover, the molecular mechanism by which the antiaging hormone Klotho regulates TRPV5 activity may prove to be generally applicable in Klotho-mediated prevention of aging.

Vitamin D receptor modulators for inflammation and cancer.

1alpha, 25-Dihydroxyvitamin D3 [1,25-(OH)2D3], the biologically active form of vitamin D, is an important hormone that is critically required for the maintenance of mineral homeostasis and structural integrity of bones. 1,25-(OH)2D3 accomplishes this by facilitating calcium absorption from the gut and by a direct action on osteoblasts, the bone forming cells. Apart form its classical actions on the gut and bone, 1,25-(OH)2D3 and its synthetic analogs also possess potent anti-proliferative, differentiative and immunomodulatory activities. 1,25-(OH)2D3 exerts these effects through vitamin D receptor (VDR), a ligand-dependent transcription factor that belongs to the superfamily of steroid/thyroid hormone/retinoid nuclear receptors. The presence of VDR in various tissues other than gut and bone, along with their ability to exert differentiation, growth inhibitory and anti-inflammatory action, has set the stage for therapeutic exploitation of VDR ligands for the treatment of various inflammatory indications and cancer. However, the use of VDR ligands in clinic is limited by their major dose-related side effect, namely hypercalcemia/hypercalciuria. Efforts are being undertaken to develop vitamin D receptor modulators (VDRMs) that are tissue-selective and/or gene-selective in their action and these ligands may exhibit increased therapeutic indices. This review explores the recent advances in VDR biology, non-secosteroidal VDR ligands and the current and potential clinical applications of VDR ligands in inflammation and cancer.

Enhanced passive Ca2+ reabsorption and reduced Mg2+ channel abundance explains thiazide-induced hypocalciuria and hypomagnesemia.

Thiazide diuretics enhance renal Na+ excretion by blocking the Na+-Cl- cotransporter (NCC), and mutations in NCC result in Gitelman syndrome. The mechanisms underlying the accompanying hypocalciuria and hypomagnesemia remain debated. Here, we show that enhanced passive Ca2+ transport in the proximal tubule rather than active Ca2+ transport in distal convolution explains thiazide-induced hypocalciuria. First, micropuncture experiments in mice demonstrated increased reabsorption of Na+ and Ca2+ in the proximal tubule during chronic hydrochlorothiazide (HCTZ) treatment, whereas Ca2+ reabsorption in distal convolution appeared unaffected. Second, HCTZ administration still induced hypocalciuria in transient receptor potential channel subfamily V, member 5-knockout (Trpv5-knockout) mice, in which active distal Ca2+ reabsorption is abolished due to inactivation of the epithelial Ca2+ channel Trpv5. Third, HCTZ upregulated the Na+/H+ exchanger, responsible for the majority of Na+ and, consequently, Ca2+ reabsorption in the proximal tubule, while the expression of proteins involved in active Ca2+ transport was unaltered. Fourth, experiments addressing the time-dependent effect of a single dose of HCTZ showed that the development of hypocalciuria parallels a compensatory increase in Na+ reabsorption secondary to an initial natriuresis. Hypomagnesemia developed during chronic HCTZ administration and in NCC-knockout mice, an animal model of Gitelman syndrome, accompanied by downregulation of the epithelial Mg2+ channel transient receptor potential channel subfamily M, member 6 (Trpm6). Thus, Trpm6 downregulation may represent a general mechanism involved in the pathogenesis of hypomagnesemia accompanying NCC inhibition or inactivation.

Multiple electrolyte abnormalities after pamidronate administration.

Pamidronate constitutes a major advance in the treatment of tumor-associated hypercalcemia. However, transient electrolyte abnormalities have been reported after pamidronate administration. We describe here a patient with multiple myeloma and severe hypercalcemia who developed transient but significant electrolyte disturbances (mainly hypophosphatemia and hypomagnesemia) after a single dose of 90 mg of pamidronate, focusing on the underlying pathophysiological mechanisms.

Solanum malacoxylon: a toxic plant which affects animal calcium metabolism.

The "enteque seco" is a disease of calcinosis, i.e., pathological deposition of calcium phosphate in soft tissues, which occurs in grazing cattle in Argentina and is of considerable economic importance. The ingestion of leaves of Solanum malacoxylon has been identified as the cause of the disease. Hypercalcemia and/or hyperphosphatemia and mineralization of the cardiovascular and pulmonary systems are usually seen in bovines or experimental animals exposed to this plant. The symptoms of the disease resemble those of vitamin D intoxication. In agreement with these observations, a glycoside derivative of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the hormonally active form of vitamin D in animals, has been identified as the toxic principle of S. malacoxylon. Glycoside conjugates of its precursors, 25-hydroxyvitamin D3 and vitamin D3, may also be present. Recent studies indicate that the plant factor is modified in the rumen of bovines through cleavage of the glycosidic linkage and further conversion of the released 1,25(OH)2D3 to a more polar metabolite, possibly 1,24,25-trihydroxyvitamin D3. Excess free 1,25(OH)2D3 may alter extracellular and intracellular Ca homeostasis in intoxicated animals through a receptor-mediated mechanism and activation of membrane Ca channels. In addition, 1,24,25(OH)3D3 may potentiate the effects of 1,25(OH)2D3 on intestinal Ca transport.

Evaluation of factors associated with glucocorticoid-induced osteopenia in patients with rheumatic diseases.

In 161 ambulatory rheumatic disease patients receiving long-term prednisone therapy, diaphyseal mass (DM) and metaphyseal mass (MM) of the forearm were measured by single photon absorptiometry, and bone radiographs were reviewed when available. Multivariate analysis of treatment and patient characteristics demonstrated that glucocorticoid-induced osteopenia (defined as an elevated DM:MM ratio) and bone fractures occurred with similar frequency in patients of each sex, in whites and blacks, in patients with various rheumatic diseases, and in patients receiving different regimens of prednisone therapy. However, large cumulative doses of prednisone were associated with elevated DM:MM ratios as well as with bone fractures, and menopause or age greater than or equal to 50 years (males or females) was associated with bone fractures. We conclude that long-term therapy with various prednisone regimens results in glucocorticoid-induced osteopenia and fractures. This affect is cumulative, occurs in all patient groups, and results in more bone fractures in certain groups.

Oxalate absorption and postprandial urine supersaturation in an experimental human model of absorptive hypercalciuria.

The effect of 1.25-dihydroxyvitamin D [1,25-(OH)2D] on dietary oxalate absorption and postprandial urine supersaturation with calcium oxalate was determined in 11 normal subjects. 1,25-(OH)2D increased the urinary excretion of orally administered [14C]oxalate in the 8 h period after a liquid meal containing 1.875 mmol of calcium and 0.83 mmol of oxalate (P less than 0.01), and during a 48 h period when the subjects ingested a diet containing 25 mmol of calcium and 3.3 mmol of oxalate/day (P less than 0.01); however, 1,25-(OH)2D administration had no effect on [14C]oxalate excretion when calcium was removed from the liquid meal. 1.25-(OH)2D increased 24 h urinary oxalate excretion from 28.7 +/- 2.1 mmol/mol of creatinine to 36.8 +/- 2.6 mmol/mol of creatinine (P less than 0.05) on the 10 mmol/day calcium diet and from 26.4 +/- 2.9 to 33.2 +/- 2.2 mmol/mol of creatinine (P less than 0.1) on the 25 mmol/day calcium diet. A linear correlation (r = 0.72) was found between plasma 1,25-(OH)2D levels and urinary [14C]oxalate excretion after the liquid meal. 1,25-(OH)2D administration produced postprandial supersaturation of urine with calcium oxalate and calcium oxalate crystalluria. These studies suggest that 1,25-(OH)2D increases oxalate absorption (and urinary excretion) by increasing calcium absorption, which results in less binding of calcium to oxalate in the intestine; therefore more oxalate is available for absorption. The combined effect of increased calcium and oxalate absorption results in postprandial supersaturation of urine with calcium oxalate, with resultant crystalluria.

Calmodulin activity in corticosteroid-induced osteopenia.

A reproducible high-pressure liquid chromatography assay of calmodulin, a multifunctional calcium-dependent modulating protein, was developed for cartilage and bone by using cyclic nucleotide phosphodiesterase activity as the basis for standard curve determination. Calmodulin activity was then measured in rabbits that were made osteopenic by prednisolone injection in an effort to characterize in vivo cellular events. A significant rise in bone calmodulin levels was noted when this data was correlated with osteocyte and osteoblast content by quantitative histomorphometry. This suggests that calmodulin mediates steroid effects on the collagen matrix as well as on calcium homeostasis. Diminished calmodulin levels in weight-bearing cartilage of steroid-treated animals has as yet unresolved significance. Further characterization of calmodulin activity appears warranted in the study of osteopenic states at the subcellular level.

Reversal of vitamin-D2-induced hypercalciuria by chlorothiazide.

To 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 +/- 0.2 mg/dl; C, 6.0 +/- 0.2 mg/dl), serum creatinine concentration (A, 0.5 +/- 0.07 mg/dl; B, 0.52 +/- 0.08 mg/dl; C, 0.48 +/- 0.04 mg/dl), and creatinine clearance (A, 4.8 +/- 0.7 ml/min/kg; B, 5.2 +/- 1.2 ml/min/kg; C, 4.9 +/- 0.5 ml/min/kg). The administration of vitamin-D2 significantly increased the urinary calcium excretion from 6.7 +/- 1.0 mg/kg/day to 19.5 +/- 9.7 mg/kg/day (p less than 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 less than 0.02). Evaluation of the ratio of calcium/creatinine excretion (A, 0.19 +/- 0.03; B, 0.53 +/- 0.25; C, 0.20 +/- 0.07) and calcium/sodium excretion (A, 0.22 +/- 0.05; B, 0.48 +/- 0.25; C, 0.19 +/- 0.04) further 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 without hypercalcemia, and that this hypercalciuria can be effectively prevented by chlorothiazide.

[Particularly severe calcium metabolic disorder in nephropathy from analgesic abuse]. / Atteinte particulièrement sévère du métabolisme calcique dans la néphropathie par abus d'analgésiques.

Calcium (Ca) metabolism was compared in 2 groups of patients with chronic interstitial nephritis: in 21 patients (AAN-group) nephropathy was due to exposure for 5 to 50 years (mean 21.1) to phenacetin containing analgesics, whereas in 21 other patients (controls) it was due to exposure for 1 to 80 years (mean 21.4) (NS) to other causes. Patients were followed for 2.5 +/- 0.6 and 1.6 +/- 0.6 years respectively (mean +/- SEM) (NS). Blood Ca, P, protein, creatinine, alkaline phosphatase, parathyroid hormone (PTH), 25-hydroxyvitamin D (25-OH-D), together with arterial acid-base status and urinary excretion rate of Ca, P and creatinine were measured serially. For each patient the results were averaged for 2 degrees of renal failure, i.e. for creatinine levels below and above 400 mumol/l (logarithmic mean). Results were included only when P was maintained between 0.7 and 1.9 mmol/l. The range of creatinine levels studied was 95 to 1600 mumol/l. No differences were found between the 2 groups with respect to creatinine clearance, blood, P, protein, arterial pH and urinary excretion rates of Ca and P. There was a trend for blood HCO3 to be lower in the AAN group. Mean plasma Ca was significantly lower, and PTH was significantly higher, in the AAN than in the control group at both degrees of renal failure; mean plasma alkaline phosphatase activity was also significantly higher in the AAN group, but at severe degrees of renal failure only. Significant correlations were observed between individual values of both Ca and PTH (r = -0.747) and PTH and alkaline phosphatase (r = 0.603). The degree of hypocalcemia and of hyperparathyroidism was not related to the plasma level of 25-OH-D. It is concluded that at comparable degrees and duration of renal failure patients with AAN, when compared with patients with interstitial nephritis of other origins, have lower blood Ca and consequently higher PTH levels and alkaline phosphatase activities, suggesting more severe osteodystrophy.

Postanesthetic myonecrosis in horses.

Two horses died of massive myonecrosis following surgery. The hematological, biochemical and pathological changes are described and compared with those previously reported in the literature.

Effect of 1 alpha hydroxylated vitamin D on steroid induced calcium malabsorption.

As persistent bone loss is a major problem of chronic steroid therapy the effects of 3 weeks therapy with 1 alpha hydroxycholecalciferol were studied in 10 kidney transplant recipients on chronic steroid therapy. Treatment resulted in a significant increase in intestinal calcium absorption, paralleled by a significant decrease of serum iPTH, whereas neither plasma calcium nor urinary calcium excretion rose significantly, suggesting a positive calcium balance throughout the study. It is therefore suggested that administration of active vitamin D metabolites is an effective protection against one of the pathogenic mechanisms of steroid induced osteopenia.