Studies of the Mechanism by Which Chronic Metabolic Acidosis Augments Urinary Calcium Excretion in Man*

Lemann, Jacob; Litzow, John R.; Lennon, Edward J.

doi:10.1172/jci105624

Cited by 341 publications

(93 citation statements)

References 15 publications

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“…3 A), consistent with our previous observations in another group ofhumans (25). However, other studies in humans have not reported consistent acidosis-induced changes in plasma phosphate concentration, which was found to be either unchanged (35)(36)(37) or decreased (38,39). Similar inconsistencies are reported in previous animal studies (rat, dog, and chick; references 12, 16-18, 33, 40-44).…”

Section: Resultssupporting

confidence: 69%

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

Krapf¹,

Vetsch²,

W³

et al. 1992

J. Clin. Invest.

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IntroductionChronic metabolic acidosis results in metabolic bone disease, calcium nephrolithiasis, and growth retardation. The pathogenesis of each of these sequelae is poorly understood in humans. We therefore investigated the effects ofchronic extrarenal metabolic acidosis on the regulation of 1,25-(OH)2D, parathyroid hormone, calcium, and phosphate metabolism in normal humans. Chronic extrarenal metabolic acidosis was induced by administering two different doses of NH4CI 12.1 (low dose) and impaired conversion of 25-(OH)D to 1,25-(OH)2D ( 15).However, the results of measurements of serum 1,25-(OH)2D concentration during experimentally induced metabolic acidosis have not been consistent: reported values have ranged from increased to unchanged to decreased mean concentrations (15)(16)(17)(18)(19). These inconsistencies may have been due in part to the experimental difficulties in controlling acidosisinduced alterations in the plasma concentrations of known modulators of 1,25-(OH)2D production: phosphate (20-22), calcium (23), and parathyroid hormone (23,24

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Section: Resultssupporting

confidence: 69%

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

Krapf¹,

Vetsch²,

W³

et al. 1992

J. Clin. Invest.

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“…Although chronic expansion of the extracellular fluid volume produces hypercalciuria, it is unlikely that such a mechanism is operative in phosphate depletion since hypercalciuria persists when depleted animals are placed on a salt-free diet (1). Chronic metabolic acidosis also is associated with increased urinary calcium excretion (24). Previous studies have been unable to document consistent changes in acid-base status in phosphate depletion (1,4), and measurement of arterial pH in our animals did not reveal evidence of metabolic acidosis.…”

mentioning

confidence: 49%

Renal tubular effects of chronic phosphate depletion.

Goldfarb¹,

Westby²,

Goldberg³

et al. 1977

J. Clin. Invest.

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A B S T R A C T The effects ofchronic phosphate depletion on renal tubular function were evaluated by micropuncture and free water clearance studies in the dog. Proximal tubular punctures demonstrated that chronic hypophosphatemia led to a reduction in ratio of tubular fluid to plasma inulin in late superficial tubules from 1.59+0.08 in control animals to 1.29±0.06 in phosphate-depleted dogs, with proportional inhibitior, of calcium and sodium reabsorption. The chronic decrease in proximal tubular fluid reabsorption was confirmed by the analysis of sustained water diuresis in conscious, phosphate-depleted dogs, before and after repletion of body P04 stores, and in control animals. Urine flow rate/100 ml glomerular filtration rate (V/GFR) was significantly higher in P04 depletion than control (15.8±1.1 vs. 10.7±0.82). In addition, acetazolamide infusion did not increase V/GFR in phosphate-depleted dogs (15.8±1.1 vs. 17.16±0.9), supporting the conclusion that inhibition of proximal tubular fluid reabsorption was responsible for the elevated urine flow rate. P04 repletion over 5 days reduced V/GFR to 9.2±0.7 despite no change in urine osmolality and no change in GFR, further suggesting a specific reversible alteration in proximal tubular reabsorption in phosphate depletion.Although hypercalciuria was a constant finding in phosphate depletion (fractional excretion of calcium of 2.04±0.4% vs. 0.47±0.13% in controls), the enhanced distal delivery of calcium was not a crucial factor; acute phosphate infusion reduced urinary calcium excretion to control values without affecting the reduced proximal tubular reabsorption in either intact or thyroparathyroidectomized phosphate-depleted dogs. The change in distal nephron calcium reabsorp-

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“…If the low renal clearance of calcium in FHH does not represent an exaggerated anticalciuric response to PTH, other extra or intracellular factors must account for this feature. Among the factors that may affect renal calcium clearance are phosphate loading or depletion (21,22), acidbase status (23), urinary sodium excretion (7), vitamin D related sterols (24) and serum concentration of calcium. Urinary phosphorus excretion and serum phosphorus concentration were comparable in the two groups, with the exception of subject 4 with persistently normal serum phosphorus and normal renal handling of phosphorus, despite other evidence of hypo- in some studies increase renal tubular reabsorption of calcium, this effect has not been found consistently and even opposite effects have been found (24).…”

Section: Resultsmentioning

confidence: 99%

Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism

et al. 1983

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A B S T R A C T Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant trait comprising hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium. We evaluated the role of parathyroid hormone in the relative hypocalciuria of FHH and characterized the renal transport of calcium in this disorder using three previously hypercalcemic FHH patients with surgical hypoparathyroidism and three controls with surgical hypoparathyroidism. Intravenous infusion of calcium chloride in two patients with FHH and in three controls increased serum calcium from a mean basal of 5.0 to a mean peak of 6.8 meq/liter in two FHH patients and from 4.2 to 5.7 in three control subjects. Urinary calcium in a third FHH patient was studied without calcium infusion during recovery from hypercalcemia of vitamin D intoxication. At all serum concentrations of calcium, calcium clearance was lower in FHH than in controls; at base-line serum calcium, the ratio of calcium clearance to inulin clearance (CCa/CIN) in FHH subjects was 32% of that in controls and decreased to 19% during hypercalcemia. Calcium infusion increased the ratio of sodium clearance to inulin clearance in controls from a base line of 0.020 to 0.053 at peak concentrations of calcium in serum, but did not affect this parameter in FHH (0.017 at baseline serum calcium vs. 0.019 at peak). When calcium infusion studies were performed (in two patients with FHH and one control) during administration of acetazolamide, a drug whose principal renal action causes inhibition of proximal transport of solute, CCa/CIN in the patients with FHH was 29 and 7% of that of the control at base-line and peak serum calcium, respectively. In contrast, ethacrynic acid, a diuretic that acts in the ascending limb of the loop of Henle, increased CCa/CIN more in the FHH patients than in the control subject; CCa/CIN was 65% at baseline and 47% at peak serum calcium, compared with that of the control subject. The greater calciuric response to ethacrynic acid than to acetazolamide or calcium infusion alone in FHH indicates that a major renal locus of abnormal calcium transport in this disorder may be the ascending limb of the loop of Henle.Decreased clearance of calcium in patients with FHH and hypoparathyroidism when compared with hypoparathyroid controls indicates that relative hypocalciuria in FHH is not dependent on hyperparathyroidism. Since the parathyroid glands in FHH are not appropriately suppressed by calcium, this implies that FHH represents a disorder of abnormal transport of, and/or response to, extracellular calcium in at least two organs, parathyroid gland and kidney.

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Studies of the Mechanism by Which Chronic Metabolic Acidosis Augments Urinary Calcium Excretion in Man*

Cited by 341 publications

References 15 publications

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

Chronic metabolic acidosis increases the serum concentration of 1,25-dihydroxyvitamin D in humans by stimulating its production rate. Critical role of acidosis-induced renal hypophosphatemia.

Renal tubular effects of chronic phosphate depletion.

Urinary calcium excretion in familial hypocalciuric hypercalcemia. Persistence of relative hypocalciuria after induction of hypoparathyroidism

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