Idiopathic hypercalciuria: the contribution of Dr. Jacob Lemann, Jr.
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The original contributions of Jacob Lemann to mineral metabolism, especially calcium metabolism and idopathic hypercalciuria, are reviewed. One group of studies concern acid base balance and calcium loss, showing that acid loads increase calcium loss in the urine. Another group of studies concern the calciuria of glucose or carbohydrate ingestion, with the observation that stone patients, who as a population are enriched with hypercalciuria, respond with more exaggerated calciuria to glucose loads than do normal people. Yet another body of work shows that normal men, when given noncalcemic loads of calcitriol, exhibit two essential features of idiopathic hypercalciuria--hyperabsorptive hypercalciuria and bone mineral loss on a low-calcium diet. The final group of studies presented worked on the problem of thiazide hypocalciuric action, and where the calcium goes that does not appear in the urine, as well as the effects of potassium bicarbonate and sodium loads on mineral balance and acid base status. (+info)
Increased intestinal vitamin D receptor in genetic hypercalciuric rats. A cause of intestinal calcium hyperabsorption.
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In humans, familial or idiopathic hypercalciuria (IH) is a common cause of hypercalciuria and predisposes to calcium oxalate nephrolithiasis. Intestinal calcium hyperabsorption is a constant feature of IH and may be due to either a vitamin D-independent process in the intestine, a primary overproduction of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], or a defect in renal tubular calcium reabsorption. Selective breeding of spontaneously hypercalciuric male and female Sprague-Dawley rats resulted in offspring with hypercalciuria, increased intestinal calcium absorption, and normal serum 1,25(OH)2D3 levels. The role of the vitamin D receptor (VDR) in the regulation of intestinal calcium absorption was explored in 10th generation male genetic IH rats and normocalciuric controls. Urine calcium excretion was greater in IH rats than controls (2.9 +/- 0.3 vs. 0.7 +/- 0.2 mg/24 h, P < 0.001). IH rat intestine contained twice the abundance of VDR compared with normocalciuric controls (536 +/- 73 vs. 243 +/- 42 nmol/mg protein, P < 0.001), with no difference in the affinity of the receptor for its ligand. Comparable migration of IH and normal intestinal VDR on Western blots and of intestinal VDR mRNA by Northern analysis suggests that the VDR in IH rat intestine is not due to large deletion or addition mutations of the wild-type VDR. IH rat intestine contained greater concentrations of vitamin D-dependent calbindin 9-kD protein. The present studies strongly suggest that increased intestinal VDR number and normal levels of circulating 1,25(OH)2D3 result in increased functional VDR-1,25(OH)2D3 complexes, which exert biological actions in enterocytes to increase intestinal calcium transport. Intestinal calcium hyperabsorption in the IH rat may be the first example of a genetic disorder resulting from a pathologic increase in VDR. (+info)
Current status of vitamin D metabolism.
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In summary one can record that the biochemist has discovered a beautiful metabolic pathway for vitamin D which is probably as yet incomplete. Subsequently the medicinal chemist has provided numerous synthetic analogues. However, delays in the diagnosis and treatment of vitamin D disorders, due to lack of specific assays and inadequate supplies of therapeutic metabolites, still unfortunately exist. It is hoped that these problems will be rectified as soon as more plentiful supplies of the appropriate metabolites are available. (+info)
Disorders of the calcium-sensing receptor.
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The human calcium-sensing receptor (CaSR) is a 1078-amino-acid cell surface protein which is expressed in the parathyroids, thyroid cells and the kidney, and is a member of the family of G protein-coupled receptors. The CaSR allows regulation of parathyroid hormone (PTH) secretion and renal tubular calcium reabsorption in response to alterations in extracellular calcium concentrations. The human CaSR gene is located on chromosome 3q13.3-q21, and loss of function CaSR mutations have been reported in the hypercalcaemic disorders of familial benign (hypocalciuric) hypercalcaemia (FBH or FHH) and neonatal severe primary hyperparathyroidism (NSHPT). In addition, gain of function CaSR mutations have been observed in a novel familial syndrome of hypocalcaemia with hypercalciuria. The human CaSR gene on chromosome 3q13.3-q21 is likely to be one of several, as two other loci for FBH have been located on chromosome 19p and 19q13. Cloning and characterisation of these genes will help to further elucidate the mechanisms regulating extracellular calcium. (+info)