https://www.amjmed.com/article/0002-9343(82)90567-8/pdf

Effects of low-calcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects

https://www.kidney-international.org/article/S0085-2538(15)54823-0/pdf

Nephrolithiasis-associated bone disease: pathogenesis and treatment options

The effect of long-term thiazide therapy (hydrochlorothiazide, 50 mg twice/day) on intestinal calcium (Ca) absorption and serum 1 alpha,25-dihydroxyvitamin D [1 alpha,25-(OH)2D] concentration was examined in 10 patients with renal hypercalciuria (RH), many of whom had hyperabsorption of Ca, and in 11 cases of absorptive hypercalciuria (AH), all of whom had intestinal hyperabsorption of Ca. In patients with RH, the intestinal Ca absorption decreased significantly during thiazide therapy (mean treatment period of 15 mo) from 0.68 +/- 0.09 SD to 0.56 +/- 0.10 (p less than 0.01), commensurate with the "correction" of the renal leak of Ca and secondary hyperparathyroidism. Furthermore, serum 1 alpha,25-(OH)2D decreased significantly from 5.2 +/- 2.2 SD ng/dl to 3.7 +/- 0.8 ng/dl (p less than 0.025) during thiazide therapy. In patients with AH, the intestinal hyperabsorption of calcium persisted during thiazide treatment (0.69 +/- 0.07 versus 0.69 +/- 0.06), despite restoration of normal urinary Ca. Serum 1 alpha,25-(OH)2D was virtually unchanged during treatment (4.5 +/- 1.4 ng/dl versus 4.7 +/- 0.9 ng/dl). The results support the hypothesis that the intestinal hyperabsorption of Ca in RH is a result of increased serum concentration of 1 alpha,25-(OH)2D secondary to the hyperparathyroid state, while that in AH may not be totally dependent on increased concentrations of 1 alpha,25-(OH)2D.

Selective effects of thiazide therapy on serum 1α,25-dihydroxyvitamin D and intestinal calcium absorption in renal and absorptive hypercalciurias

In humans, idiopathic hypercalciuria is associated with stone formation. In order to study the mechanisms that are responsible for excess urine calcium excretion, in ways that are difficult or impossible in humans, we have developed a rat model of hypercalciuria. Spontaneously hypercalciuric rats have been successively inbred for over 50 generations to produce a strain in which urine calcium excretion is over 10 times greater than that of controls, and all rats form kidney stones. Analysis of the model has revealed that the rats not only exhibit increased intestinal calcium reabsorption but an independent defect in renal tubular calcium resorption and an increased tendency for bone resorption. These findings closely parallel those in patients with idiopathic hypercalciuria. In the intestine, bone and kidney there is an increased number of vitamin D receptors which are hyperresponsive to 1,25-dihydroxyvitamin D3. Whether the increased number of vitamin D receptors is directly responsible for the hypercalciuria and whether the same abnormality is present in humans with idiopathic hypercalciuria is under investigation. Hypercalciuric rats appear to be an excellent model to provide insights into the mechanisms causing hypercalciuria, and to delineate treatments for stone disease.

Genetic hypercalciuric stone-forming rats

Hypercalciuria in genetic hypercalciuric stone-forming (GHS) rats is accompanied by intestinal Ca hyperabsorption with normal serum 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) lev- els, elevation of intestinal, kidney, and bone vitamin D re- ceptor (VDR) content, and greater 1,25(OH) 2 D 3 -induced bone resorption in vitro. To test the hypothesis that hyperre- sponsiveness of VDR gene expression to 1,25(OH) 2 D 3 may mediate these observations, male GHS and wild-type Sprague- Dawley normocalciuric control rats were fed a normal Ca diet (0.6% Ca) and received a single intraperitoneal in- jection of either 1,25(OH) 2 D 3 (10-200 ng/100 g body wt) or vehicle. Total RNAs were isolated from both duodenum and kidney cortex, and the VDR and calbindin mRNA levels were determined by Northern blot hybridization using spe- cific cDNA probes. Under basal conditions, VDR mRNA levels in GHS rats were lower in duodenum and higher in kidney compared with wild-type controls. Administration of 1,25(OH) 2 D 3 increased VDR gene expression significantly in GHS but not normocalciuric animals, in a time- and dose-dependent manner. In vivo half-life of VDR mRNA was similar in GHS and control rats in both duodenum and kidney, and was prolonged significantly (from 4-5 to . 8 h) by 1,25(OH) 2 D 3 administration. Neither inhibition of gene transcription by actinomycin D nor inhibition of de novo protein synthesis with cycloheximide blocked the upregula- tion of VDR gene expression stimulated by 1,25(OH) 2 D 3 ad- ministration. No alteration or mutation was detected in the sequence of duodenal VDR mRNA from GHS rats com- pared with wild-type animals. Furthermore, 1,25(OH) 2 D 3 administration also led to an increase in duodenal and renal calbindin mRNA levels in GHS rats, whereas they were ei- ther suppressed or unchanged in wild-type animals. The re- sults suggest that GHS rats hyperrespond to minimal doses of 1,25(OH) 2 D 3 by an upregulation of VDR gene expression. This hyperresponsiveness of GHS rats to 1,25(OH) 2 D 3 ( a ) occurs through an increase in VDR mRNA stability without involving alteration in gene transcription, de novo protein synthesis, or mRNA sequence; and ( b ) is likely of functional significance, and affects VDR-responsive genes in 1,25(OH) 2 D 3 target tissues. This unique characteristic suggests that GHS rats may be susceptible to minimal fluctuations in serum 1,25(OH) 2 D 3 , resulting in increased VDR and VDR-respon- sive events, which in turn may pathologically amplify the actions of 1,25(OH) 2 D 3 on Ca metabolism that thus contrib- ute to the hypercalciuria and stone formation. ( J. Clin. In- vest. 1998. 101:2223-2232.) Key words: vitamin D receptor • gene expressionrat • 1,25(OH) 2 D 3 • hypercalciuria

/pdf/hyperresponsiveness-of-vitamin-d-receptor-gene-expression-to-2r6rvyd65f.pdf

Hyperresponsiveness of vitamin D receptor gene expression to 1,25-dihydroxyvitamin D3. A new characteristic of genetic hypercalciuric stone-forming rats.

The effect of long-term thiazide therapy on the intestinal Ca absorption was measured in 10 well-defined cases of absorptive hypercalciuria with intestinal hyperabsorption of Ca and 8 with renal hypercalciuria (“renal leal” of CA), many of whom had hyperabsorption of Ca. In most cases of absorptive hypercalciuria, the intestinal hyperabsorption of Ca persisted during treatment, despite restoration of normal urinary Ca. In contrast, the intestinal Ca absorption decreased significantly during thiazide therapy in 7 of 8 patients with renal hypercalciuria commensurate with the “correction” of the renal leak of Ca and secondary hyperparathyroidism. The results support the hypothesis that the intestinal hyperabsorption of Ca in absorptive hypercalciuria may be primary, whereas that in renal hypercalciuria may be associated with the hyperparathyroid state.

Selective effects of thiazide on intestinal absorption of calcium in absorptive and renal hypercalciurias

Primary hyperparathyroidism is a major cause of calcium urolithiasis and is easily recognised when it is classically manifested. However, subtle presentations of primary hyperparathyroidism may cause confusion with other causes of calcium stone disease or cause diagnostic difficulty. Several pitfalls of parathyroid evaluation and treatment are illustrated by four cases of calcium urolithiasis. Cases 1 and 2 represent ineffective or useless parathyroid surgery rendered for renal hypercalciuria and absorptive hypercalciuria, respectively. Cases 3 and 4 had mild or intermittent hypercalcaemia. The correct diagnosis of primary hyperparathyroidism was made in Case 3 by parathyroid venous sampling and bone densitometry. In Case 4, the thiazide provocative test was used to establish the diagnosis of primary hyperparathyroidism.

Pitfalls in parathyroid evaluation in patients with calcium urolithiasis

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Selective effects of thiazide on intestinal absorption of calcium in absorptive and renal hypercalciurias

Pitfalls in parathyroid evaluation in patients with calcium urolithiasis