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.

Krapf, Reto; Vetsch, R; W, Vetsch; Hulter, Henry N.

doi:10.1172/jci116137

Cited by 92 publications

(51 citation statements)

References 54 publications

(55 reference statements)

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“…Diet nitrogen was verified by direct analysis. Nitrogen intake by direct assay was found to be higher than the value of 14.2 g estimated previously from nutrition tables (22).…”

Section: Methodscontrasting

confidence: 78%

“…Albumin synthesis rates and urinary nitrogen excretion were measured in eight healthy male subjects in a dedicated metabolic room with controlled regular intake of meals, that were part of another metabolic study (22), before and during NH4Cl-induced metabolic acidosis. All subjects ingested a constant metabolic diet for at least 5 d before the base-line measurements and throughout the experiment.…”

Section: Methodsmentioning

confidence: 99%

“…Plasma albumin concentrations were determined with bromcresol purple. Plasma acid-base composition was determined in arterialized venous blood samples as described previously (22,32,33).…”

Section: Methodsmentioning

confidence: 99%

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Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.

Ballmer¹,

McNurlan²,

Hulter³

et al. 1995

J. Clin. Invest.

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341

183

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Chronic metabolic acidosis has been previously shown to stimulate protein degradation. To evaluate the effects of chronic metabolic acidosis on nitrogen balance and protein synthesis we measured albumin synthesis rates and urinary nitrogen excretion in eight male subjects on a constant metabolic diet before and during two different degrees of chronic metabolic acidosis (NH4Cl 2.1 mmol/kg body weight, low dose group, and 4.2 mmol/kg body weight, high dose group, orally for 7 d). Albumin synthesis rates were measured by intravenous injection of [2H5ring]phenylalanine (43 mg/kg body weight, 7.5 atom percent and 15 atom percent, respectively) after an overnight fast. In the low dose group, fractional synthesis rates of albumin decreased from 9.9±1.0% per day in the control period to 8.4±0.7 (n.s.) in the acidosis period, and from 8.3±1.3% per day to 6.3±1.1 (P < 0.001) in the high dose group. Urinary nitrogen excretion increased significantly in the acidosis period (EA 634 mmol in the low dose group, 2,554 mmol in the high dose group). Plasma concentrations of insulin-like growth factor-I, free thyroxine and tri-iodothyronine were significantly lower during acidosis. In conclusion, chronic metabolic acidosis causes negative nitrogen balance and decreases albumin synthesis in humans. The effect on albumin synthesis may be mediated, at least in part, by a suppression of insulin-like growth factor-I, free thyroxine and tri-iodothyronine. (J. Clin. Invest. 1995. 95:39-45.) Key words: albumin * metabolic acidosis A protein synthesis * nitrogen balance * insulin-like growth factor-I

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“…Diet nitrogen was verified by direct analysis. Nitrogen intake by direct assay was found to be higher than the value of 14.2 g estimated previously from nutrition tables (22).…”

Section: Methodscontrasting

confidence: 78%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.

Ballmer¹,

McNurlan²,

Hulter³

et al. 1995

J. Clin. Invest.

Self Cite

341

183

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“…Electrolyte values in plasma and urine were determined as described previously. [35][36][37] Blood and urine pH and PCO 2 were measured with a Radiometer (Copenhagen model ABL 500 or 700) and HCO 3 calculated. Urinary ammonium was analyzed by ion chromatography.…”

Section: Discussionmentioning

confidence: 99%

The Human Response to Acute Enteral and Parenteral Phosphate Loads

Scanni

vonRotz

Jehle

et al. 2014

Journal of the American Society of Nephrology

104

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The human response to acute phosphate (PO4) loading is poorly characterized, and it is unknown whether an intestinal phosphate sensor mechanism exists. Here, we characterized the human mineral and endocrine response to parenteral and duodenal acute phosphate loads. Healthy human participants underwent 36 hours of intravenous (IV; 1.15 [low dose] and 2.30 [high dose] mmol of PO4/kg per 24 hours) or duodenal (1.53 mmol of PO4/kg per 24 hours) neutral sodium PO4 loading. Control experiments used equimolar NaCl loads. Maximum PO4 urinary excretory responses occurred between 12 and 24 hours and were similar for low-dose IV and duodenal infusion. Hyperphosphatemic responses were also temporally and quantitatively similar for low-dose IV and duodenal PO4 infusion. Fractional renal PO4 clearance increased approximately 6-fold (high-dose IV group) and 4-fold (low-dose IV and duodenal groups), and significant reductions in plasma PO4 concentrations relative to peak values occurred by 36 hours, despite persistent PO4 loading. After cessation of loading, frank hypophosphatemia occurred. The earliest phosphaturic response occurred after plasma PO4 and parathyroid hormone concentrations increased. Plasma fibroblast growth factor-23 concentration increased after the onset of phosphaturia, followed by a decrease in plasma 1,25(OH)2D levels; a-Klotho levels did not change. Contrary to results in rodents, we found no evidence for intestinal-specific phosphaturic control mechanisms in humans. Complete urinary phosphate recovery in the IV loading groups provides evidence against any important extrarenal response to acute PO4 loads. Plasma phosphate (PO4) concentration is regulated within narrow limits and is the result of intestinal absorption, influx into and efflux from bone, renal excretion, and modest intestinal secretion. 1 Rapid changes in transcellular distribution are effected primarily by systemic acid-base equilibrium and hormones such as insulin and catecholamines. 2 1,25(OH) 2 D stimulates intestinal PO4 absorption, 4 while parathyroid hormone (PTH) and osteocytederived fibroblast growth factor-23 (FGF-23) are the best-characterized phosphaturic factors. Both inhibit proximal tubular sodium-dependent PO4 reabsorption (via Na/PO4 cotransport, NaPi2a and NaPi2c). 5,6 In addition, a-Klotho is a renal transmembrane and secreted protein that functions as an FGF-23 coreceptor and is phosphaturic independently of However, the relative roles of other phosphaturic agents, such as secreted frizzled related protein (sFRP-4), matrix extracellular phosphoglycoprotein, and FGF-8 are not yet defined in humans.1,25(OH) 2 D, PTH, and FGF-23 regulate PO4 metabolism within a complex system of positive and negative feedback mechanisms (for review, see Bergwitz and Jüppner 8 ). Increases in plasma PO4 concentration stimulate PTH secretion, while proximal tubule 1a-hydroxylase and, therefore,

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“…Our results, including the negative effect of CMA on osteocalcin, also provide evidence for a net adverse effect of CMA on bone formation rate and are in line with histomorphometric evidence of decreased bone formation rate shown in rat studies (17). The potential role of increased corticosterone secretion (in rodents) to contribute to the findings of the present study, or to hypercortisolism to explain potential CMA effects in human bone, requires further investigation (5,12,16,21).…”

Section: Ajp-renal Physiolmentioning

confidence: 95%

Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats

Gasser

Hulter

Imboden

et al. 2014

American Journal of Physiology-Renal Physiology

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Gasser JA, Hulter HN, Imboden P, Krapf R. Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats. Am J Physiol Renal Physiol 306: F517-F524, 2014. First published December 19, 2013 doi:10.1152/ajprenal.00494.2013.-Chronic metabolic acidosis (CMA) might result in a decrease in vivo in bone mass based on its reported in vitro inhibition of bone mineralization, bone formation, or stimulation of bone resorption, but such data, in the absence of other disorders, have not been reported. CMA also results in negative nitrogen balance, which might decrease skeletal muscle mass. This study analyzed the net in vivo effects of CMA's cellular and physicochemical processes on bone turnover, trabecular and cortical bone density, and bone microarchitecture using both peripheral quantitative computed tomography and CT. CMA induced by NH4Cl administration (15 mEq/kg body wt/day) in intact and ovariectomized (OVX) rats resulted in stable CMA (mean ⌬ [HCO 3 Ϫ ]p ϭ 10 mmol/l). CMA decreased plasma osteocalcin and increased TRAP5b in intact and OVX animals. CMA decreased total volumetric bone mineral density (vBMD) after 6 and 10 wk (week 10: intact normal ϩ2.1 Ϯ 0.9% vs. intact acidosis Ϫ3.6 Ϯ 1.2%, P Ͻ 0.001), an effect attributable to a decrease in cortical thickness and, thus, cortical bone mass (no significant effect on cancellous vBMD, week 10) attributed to an increase in endosteal bone resorption (nominally increased endosteal circumference). Trabecular bone volume (BV/TV) decreased significantly in both CMA groups at 6 and 10 wk, associated with a decrease in trabecular number. CMA significantly decreased muscle cross-sectional area in the proximal hindlimb at 6 and 10 wk. In conclusion, chronic metabolic acidosis induces a large decrease in cortical bone mass (a prime determinant of bone fragility) in intact and OVX rats and impairs bone microarchitecture characterized by a decrease in trabecular number. osteoporosis; mineral density; metabolic acidosis; overiectomy CHRONIC METABOLIC ACIDOSIS (CMA) is one of the cardinal acidbase disorders, characterized by a primary decrease in body base content and diagnosed clinically by measuring decreased plasma [HCO 3 Ϫ ] and blood pH. The disorder can be caused by increased production or decreased elimination of protons (such as in organic forms of metabolic acidosis or chronic renal failure) or by base losses (such as intestinal bicarbonate loss in diarrhea or bicarbonaturia in proximal tubular acidosis). Metabolic acidosis is regarded as the most common acid-base disorder due to the high worldwide prevalence of chronic diarrheal disease.Bone serves as an important proton buffer in metabolic acidosis and, thus, exhibits a homeostatic role by attenuating the severity of metabolic acidosis. Bone exposed to acidic media in vitro undergoes physicochemical mineral dissolution leading to a fall in mineral sodium, potassium, carbonate, calcium, and phosphate. In this process, calcium released from the bone leads to hypercalciuria, the magnitude of w...

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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.

Cited by 92 publications

References 54 publications

Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.

Chronic metabolic acidosis decreases albumin synthesis and induces negative nitrogen balance in humans.

The Human Response to Acute Enteral and Parenteral Phosphate Loads

Effect of chronic metabolic acidosis on bone density and bone architecture in vivo in rats

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