Pathogenesis of primary hypercalciuria: Sarcoidosis

Sarcoidosis is a granuloma-forming disorder characterized by mild to severe hypercalcemia in 10% of patients, with hypercal­ciuria occurring in up to 50% of patients at some time during the course of their disease. For many years, it was believed that hy­percalcemia and/or hypercalciuria resulted from increased sen­sitivity to the biological effects of vitamin D. Subsequently, the circulating concentrations of 1,25(OH)2D₃ was found to be high, due to its extrarenal synthesis by macrophages in sarcoid gran- ulomata. Thus, the increased 1,25(OH)₂D₃ synthesis caus­es hypercalcemia and hypercalciuria by stimulating intestinal calcium absorption and stimulating bone resorption. The distinction between AH and sarcoidosis is best exemplified by the glucocorticoid response. Glucocorticoids are effective in the management of hypercalcemia of vitamin D toxicity and hy- percalciuria associated with sarcoidosis and other granuloma- tous conditions. Among patients with sarcoidosis, prednisolone treatment significantly decreased serum 1,25(OH)₂D₃ and in­testinal calcium absorption, whereas this treatment was uni­formly ineffective among patients with AH. Cheap generic drugs online mycanadianhealthcare.com

General Description

Renal hypercalciuria is an uncommon cause of hypercalciuric nephrolithiasis. It is believed to result from a primary impair­ment in the renal tubular reabsorption of calcium. The re­sulting transient decline in serum calcium concentration stimu­lates parathyroid function, which in turn enhances 1,25(OH)₂D₃ synthesis and intestinal calcium absorption. Biochemically, serum calcium is normal and fasting urinary calcium is high co­incident with elevated serum PTH, indicative of secondary hy­perparathyroidism from renal calcium leak. A disturbed function of renal proximal tubule was suggested by exaggerated calci- uric response to carbohydrate ingestion, and accentuated natri- uresis to thiazide challenge. Unlike in AH, the correction of renal calcium leak by thiazide restores normal parathyroid function and intestinal calcium absorption.

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Pathogenesis of primary hypercalciuria: Genetic Studies in Human Beings with AH

AHRAC Gene. Prior studies have indicated that the inheritance of AH is compatible with an autosomal dominant trait. Reed et al. identified a locus on chromosome 1q23.3-24 in three kin­dreds with phenotypically well-defined AH. Within this re­gion, they identified a candidate gene, the absorptive hypercal- ciuria-related adenylyl cyclase (AHRAC), on account of its as­sociation with AH and the cyclase function in the soluble cytosolic cellular fraction described in its rat ortholog. The gene is ubiquitously expressed in humans and a number of base changes have been identified. While some of these base substitutions in AHRAC can be found in the normal population, the frequency in base changes was higher in patients with AH. Figure 1 summarizes the allelic frequency of all the base changes combined. Although one can easily find single base changes in normal subjects, most patients with >4 base changes have clinical AH. canadian-medshop-247.com canadian drugstore

Past studies have shown that AHRAC clearly encodes an adenylyl cyclase and is expressed in the intestine. However, it is not well understood at present how AHRAC regulates intesti­nal calcium transport and how the various polymorphic variants lead to hyperabsorption of calcium. At the empirical level, the intestinal absorption is positively correlated with the number of base changes in AHRAC (Fig. 2). This finding strongly sug­gests that AHRAC may control intestinal calcium absorption. It is important to state that intestinal calcium absorption is a con­tinuous variable under polygenic as well as non-genetic con­trol. The elucidation of the function of wild type and variant AHRAC in the gut should advance our knowledge of the patho­physiology of AH.

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Pathogenesis of primary hypercalciuria: General Description

Absorptive hypercalciuria (AH) describes a stone-forming con­dition in which the primary defect is presumed to be enhanced intestinal absorption of calcium. The increased absorbed calcium transiently raises serum calcium and suppresses parathyroid function. Hypercalciuria ensues from the increased renal filtered load of calcium, and decreased renal tubular re- absorption of calcium due to parathyroid suppression. In the classic presentation (AH Type I), the syndrome is character­ized biochemically by normocalcemia, normal or low serum parathyroid hormone (PTH), high intestinal calcium absorption, and hypercalciuria. Urinary calcium is high (>200 mg/day) on a diet restricted in calcium (400 mg/day) and sodium (100 mEq/day), and remains high (>300 mg/day) on a high calcium diet. In normal subjects, it is <200 mg/day on a low calcium diet and rarely exceeds 250 mg/day on a high calcium diet. Fasting urinary calcium is normal, and is appropriate for the level of parathyroid function. The intestinal hyperabsorption of calcium is unaffected by reduction of urinary calcium by thi­azide, or alteration of 1,25-dihydroxyvitamin D [1,25(OH)₂D₃] synthesis or sensitivity by orthophosphate or steroid. AH may present itself in a less severe form (AH Type II), wherein urinary calcium is normal on a calcium-restricted diet, though elevated on a high calcium diet. canadian-healthcare-shop.com online pharmacy

It may also occur in a severe form (fasting hypercalciuria), in which fasting urinary calcium is high. Fasting hypercalciuria may reflect inadequate duration of fast, incomplete renal clearance of absorbed calci­um or reduced renal tubular reabsorption of calcium from sup­pressed parathyroid function. In some patients, however, fast­ing hypercalciuria may be reflective of concomitant bone loss. Although radial shaft bone density is spared, spinal bone den­sity has been reported to be reduced in AH type I and fasting hypercalciuria. Read the rest of this entry »

Pathogenesis of primary hypercalciuria

Introduction

Hypercalciuria is clinically important since it often accompanies the formation of calcium-containing kidney stones. Among pa­tients with idiopathic calcium oxalate nephrolithiasis, hypercal­ciuria is the main determinant for the formation of calcium phosphate nidus (in the thin loops of Henle of the nephron) that may initiate calcium oxalate crystallization. The correction of hypercalciuria by thiazide or indapamide has been reported to reduce the rate of recurrent stone formation. In a risk analysis, hypercalciuria confers a higher risk for stone forma­tion than hyperoxaluria. 1 Internet Online Drugstore cad-pharmacy.com

The pathophysiologic basis for hypercalciuria is multifactorial, involving disturbance in calcium handling at three organs – in­testine, kidneys and bone. Accordingly, hypercalciuria has been classified into absorptive, renal and resorptive forms, de­pending on whether the principal defect is intestinal hyperab- sorption of calcium, “renal leak” of calcium or excessive bone resorption. This article will review recent advances in the pathophysiology of each of three main causes of hypercalciuria. It is understood, however, that a primary defect in calcium handling in one organ system may produce a secondary distur­bance in other organ system. Moreover, in some conditions, calcium handling may be primarily disturbed in more than one organ systems.