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Pathogenesis of primary hypercalciuria: Primary Hyperparathyroidism

Primary Hyperparathyroidism

In PHPT, a hypersecretion of PTH from a benign solitary parathyroid adenoma (80%) or multiglandular parathyroid hy- perplasia (15%) produces excessive bone resorption. Under normal circumstances, an increase in circulating ionized calci­um is followed by a rapid decrease in PTH secretion. In PHPT with adenoma, this feedback control is impaired, resulting in hypersecretion of PTH. In PHPT caused by hyperplasia, the sensitivity to circulating calcium is relatively intact but the num­ber of parathyroid cells is increased, enhancing PTH secretion. In either case, the PTH excess increases the number of active osteoclasts on the bone surface, stimulating bone resorption. The resulting rise in serum calcium increases the renal filtered load of calcium, causing hypercalciuria. Although PTH aug­ments renal tubular reabsorption of calcium, hypercalciuria en­sues from the greatly increased filtered load of calcium and from a suppressive effect of hypercalcemia on calcium reab- sorption. Cheap canadian drugs 

PTH also induces the renal 25-hydroxyvitamin D3-1a-hydroxy- lase; thus, serum 1,25(OH)2D3 concentration is often high in PHPT. The enhanced 1,25(OH)2D3 synthesis stimulates osteo- clastic bone resorption and, more importantly, raises intestinal calcium absorption. These effects further increase the circulat­ing concentration of calcium and contribute to hypercalciuria. Thus, hypercalciuria of PHPT is primarily resorptive and secon­darily absorptive in origin.

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Pathogenesis of primary hypercalciuria: Clinical Conditions Associated with Renal Hypercalciuria

High Animal Protein Diet. A high animal protein diet has long been known to cause hypercalciuria. Several mechanisms have been invoked. It may partly be due to enhanced bone loss (see Resorptive Hypercalciuria). Hypercalciuria of dietary acid excess does not appear to be intestinal in origin since there is no change in intestinal calcium absorption. High dietary protein intake causes glomerular hyperfiltration, which causes increased filtered load of calcium. The hypercalciuria, however, is above and beyond that of an increased filtered load to the kidney, indicating that a high dietary protein intake also causes a direct inhibition of calcium reabsorption in the kidneys. The possibility that hypercalciuria of animal pro­tein excess is due to an acid-mediated renal calcium leak is supported by studies to be described below. Dietary Acid Load. On a daily basis, the normal Western diet generates about 1 mEq/kg of acid in adult human beings. The kidney is responsible for clearing the systemic acid load. How­ever, there is a gradual reduction in overall renal function with age, which reduces the ability of the kidneys to excrete acid. When combined with a continued intake of animal pro­teins (contain acid-generating components such as methionine or cystine), a slight but significant acidemia may persist in the elderly. Even in younger individuals, overindulgence of animal proteins, can produce a degree of systemic acidity. The ensu­ing metabolic acidosis or acid load can produce marked hyper- calciuria. cialis professional discount drugs online

In a recent clinical study, a high protein-low carbohydrate weight reducing diet increased net acid excretion by 54 mEq/day and reduced urinary pH by 0.5 unit. While urinary calcium increased by 90 mg/day, intestinal calcium absorption was not altered and changes in bone markers were unremark­able. In another study, an animal model of animal protein ex­cess was produced in rats by feeding a high casein diet. Compared with a low casein diet, urinary calcium was 3-4 fold greater on a high casein diet that was high in acid ash content. In a preliminary study (unpublished observations, Preisig et al.), the neutralization of the acid load by co-administration of potassium citrate completely abrogated the rise in urinary calci­um from the high casein diet.

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Pathogenesis of primary hypercalciuria: Regulators of Calcium Transport in the Nephron

Although the active transcellular reabsorption of calcium in the distal nephron accounts for only about 20% of total reabsorbed calcium, it is the major target for regulation by key factors impli­cated in the development of hypercalciuria.

Luminal pH. Using patch-clamp electrophysiological recording of recombinant EcaC1 channels expressed in cultured cells, low extracellular pH directly inhibited ECaC1 channel activity with an apparent pK of 6.55 which is within the physiologic range of luminal pH of the distal nephron. The direct inhibition oc­curred as a result of extracellular proton titration of glutamate- 522 (rabbit ECaC1) in an extracellular loop. The ECaC1 activity was inhibited by 16% for a drop in extracellular pH of 0.4. cialis professional online we care about you health

1.25(OH)oD33 and Estrogen. 1,25(OH)2D3 stimulates calcium re­absorption via genomic mechanisms analogous to classical steroid hormones. It increases the mRNA levels of both cal- bindin-D28K and the Na+/Ca2+ exchanger in a time frame that requires a genomic mechanism. While not expressed as high a level as calbindin-D28K, calbindin-D9K is also expressed in the kidney and upregulated at the mRNA level by 1, 25(OH)2D3. Recently, 1,25(OH)2D3 was shown to regulate the expression of ECaC2 in the kidney (24). 1,25(OH)2D3 may also influence calcium reabsorption by altering the expression levels of the PTH receptor and 25-hydroxyvitamin D3– 2 4 – h y- droxylase.

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Pathogenesis of primary hypercalciuria: Sarcoidosis

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 cialis professional 20 mg

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. cialis professional 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. cialis professional 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

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 cialis professional

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.


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