Abstract
Background: Chronic metabolic acidosis (CMA) is known to induce renal phosphate wasting and hypophosphatemia
by enhancing bone resorption and inhibiting renal phosphate reabsorption. However,
nothing is known regarding changes in the plasma levels of phosphate-regulating hormones
during CMA, especially in humans with normal kidney function.
Methods: Fifteen healthy Thai female volunteers were given NH4 Cl orally for 7 days to induce CMA with or without oral phosphate supplementation.
Blood and 24-h urine specimens were collected prior to and after CMA induction. Plasma
concentrations and fractional excretion of calcium and inorganic phosphate as well
as plasma levels of fibroblast growth factor (FGF) 23, 25(OH)D3 , 1,25(OH)2 D3 and intact parathyroid hormone (iPTH) were determined.
Results: CMA led to hypophosphatemia and hypocalcemia with increases in the fractional excretion
of calcium and phosphate. Plasma concentrations of FGF23, 25(OH)D3 and iPTH were decreased, whereas that of 1,25(OH)2 D3 was increased. After oral phosphate supplementation, CMA-induced changes in the concentrations
of the studied ions, FGF23 and 25(OH)D3 , but not those of 1,25(OH)2 D3 and iPTH, were diminished.
Conclusions: The CMA-induced hypophosphatemia was likely to initiate a negative feedback response,
thereby leading to reduction in the plasma levels of hyperphosphaturic hormones, FGF23
and PTH. An increase in the plasma 1,25(OH)2 D3 level, despite diminishing 25(OH)D3 storage pool, may help enhance the intestinal phosphate absorption. Oral phosphate
supplementation abolished the effects of CMA on FGF23 and 25(OH)D3 levels, suggesting that the plasma phosphate concentration is the primary regulator
of the plasma levels of these hormones during CMA.
Key words
acidemia - ammonium chloride - fibroblast growth factor 23 (FGF23) - parathyroid hormone
References
1
Ambühl PM, Zajicek HK, Wang H. et al .
Regulation of renal phosphate transport by acute and chronic metabolic acidosis in
the rat.
Kidney Int.
1998;
53
1288-1298
2
Bushinsky DA, Krieger NS, Geisser DI. et al .
Effects of pH on bone calcium and proton fluxes in vitro.
Am J Physiol.
1983;
245
F204-F209
3
Bushinsky DA, Nalbantian-Brandt C, Favus MJ.
Elevated Ca2+ does not inhibit the 1,25(OH)2 D3 response to phosphorus restriction.
Am J Physiol.
1989;
256
F285-F289
4
Bushinsky DA, Smith SB, Gavrilov KL. et al .
Chronic acidosis-induced alteration in bone bicarbonate and phosphate.
Am J Physiol Renal Physiol.
2003;
285
F532-F539
5
Charoenphandhu N, Tudpor K, Pulsook N. et al .
Chronic metabolic acidosis stimulated transcellular and solvent drag-induced calcium
transport in the duodenum of female rats.
Am J Physiol Gastrointest Liver Physiol.
2006;
291
G446-G455
6
Charoenphandhu N, Wongdee K, Tudpor K. et al .
Chronic metabolic acidosis upregulated claudin mRNA expression in the duodenal enterocytes
of female rats.
Life Sci.
2007;
80
1729-1737
7
Cunningham J, Bikle DD, Avioli LV.
Acute, but not chronic, metabolic acidosis disturbs 25-hydroxyvitamin D3 metabolism.
Kidney Int.
1984;
25
47-52
8
Eto N, Tomita M, Hayashi M.
NaPi-mediated transcellular permeation is the dominant route in intestinal inorganic
phosphate absorption in rats.
Drug Metab Pharmacokinet.
2006;
21
217-221
9
Feldman GM, Charney AN.
Effect of acute metabolic alkalosis and acidosis on intestinal electrolyte transport
in vivo.
Am J Physiol.
1980;
239
G427-G436
10
Felsenfeld AJ, Rodriguez M.
Phosphorus, regulation of plasma calcium, and secondary hyperparathyroidism: a hypothesis
to integrate a historical and modern perspective.
J Am Soc Nephrol.
1999;
10
878-890
11
Fukumoto S.
Physiological regulation and disorders of phosphate metabolism – pivotal role of fibroblast
growth factor 23.
Intern Med.
2008;
47
337-343
12
Ghishan FK.
Phosphate transport by plasma membranes of enterocytes during development: role of
1,25-dihydroxycholecalciferol.
Am J Clin Nutr.
1992;
55
873-877
13
Goldhaber P, Rabadjija L.
H+ stimulation of cell-mediated bone resorption in tissue culture.
Am J Physiol.
1987;
253
E90-E98
14
Hoenderop JG, Nilius B, Bindels RJ.
Calcium absorption across epithelia.
Physiol Rev.
2005;
85
373-422
15
Hu MS, Kayne LH, Jamgotchian N. et al .
Paracellular phosphate absorption in rat colon: a mechanism for enema-induced hyperphosphatemia.
Miner Electrolyte Metab.
1997;
23
7-12
16
Kinoshita Y, Masuoka K, Miyakoshi S. et al .
Vitamin D insufficiency underlies unexpected hypocalcemia following high dose glucocorticoid
therapy.
Bone.
2008;
42
226-228
17
Kleger GR, Turgay M, Imoberdorf R. et al .
Acute metabolic acidosis decreases muscle protein synthesis but not albumin synthesis
in humans.
Am J Kidney Dis.
2001;
38
1199-1207
18
Kolek OI, Hines ER, Jones MD. et al .
1α,25-Dihydroxyvitamin D3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal
axis that controls phosphate transport.
Am J Physiol Gastrointest Liver Physiol.
2005;
289
G1036-G1042
19
Koyama H, Nishizawa Y, Inaba M. et al .
Impaired homologous upregulation of vitamin D receptor in rats with chronic renal
failure.
Am J Physiol.
1994;
266
F706-F712
20
Lin SH, Halperin ML.
Hypokalemia: a practical approach to diagnosis and its genetic basis.
Curr Med Chem.
2007;
14
1551-1565
21
Litkowski LJ, Wilson TL.
Effect of protein on titrimetry of bicarbonate, titratable acid, and ammonium in urine.
Clin Chem.
1979;
25
362-365
22
Lund B, Sørensen OH, Bishop JE. et al .
Stimulation of 1,25-dihydroxyvitamin D production by parathyroid hormone and hypocalcemia
in man.
J Clin Endocrinol Metab.
1980;
50
480-484
23
Nijenhuis T, Renkema KY, Hoenderop JG. et al .
Acid-base status determines the renal expression of Ca2+ and Mg2+ transport proteins.
J Am Soc Nephrol.
2006;
17
617-626
24
Nowik M, Picard N, Stange G. et al .
Renal phosphaturia during metabolic acidosis revisited: molecular mechanisms for decreased
renal phosphate reabsorption.
Pflügers Arch.
2008;
457
539-549
25
Osther PJ.
Effect of acute acid loading on acid-base and calcium metabolism.
Scand J Urol Nephrol.
2006;
40
35-44
26
Perwad F, Azam N, Zhang MY. et al .
Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin
D metabolism in mice.
Endocrinology.
2005;
146
5358-5364
27
Perwad F, Zhang MY, Tenenhouse HS. et al .
Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and
suppresses 25-hydroxyvitamin D-1α-hydroxylase expression in vitro.
Am J Physiol Renal Physiol.
2007;
293
F1577-F1583
28
Razzaque MS, Lanske B.
The emerging role of the fibroblast growth factor-23-klotho axis in renal regulation
of phosphate homeostasis.
J Endocrinol.
2007;
194
1-10
29
Riccardi D, Traebert M, Ward DT. et al .
Dietary phosphate and parathyroid hormone alter the expression of the calcium-sensing
receptor (CaR) and the Na+ -dependent Pi transporter (NaPi-2) in the rat proximal tubule.
Pflügers Arch.
2000;
441
379-387
30
Rizzo M, Capasso G, Bleich M. et al .
Effect of chronic metabolic acidosis on calbindin expression along the rat distal
tubule.
J Am Soc Nephrol.
2000;
11
203-210
31
Rodriguez M, Canadillas S, Lopez I. et al .
Regulation of parathyroid function in chronic renal failure.
J Bone Miner Metab.
2006;
24
164-168
32
Saito H, Maeda A, Ohtomo S. et al .
Circulating FGF-23 is regulated by 1α,25-dihydroxyvitamin D3 and phosphorus in vivo.
J Biol Chem.
2005;
280
2543-2549
33
Shaikh A, Berndt T, Kumar R.
Regulation of phosphate homeostasis by the phosphatonins and other novel mediators.
Pediatr Nephrol.
2008;
23
1203-1210
34
Stauber A, Radanovic T, Stange G. et al .
Regulation of intestinal phosphate transport. II. Metabolic acidosis stimulates Na+ -dependent phosphate absorption and expression of the Na+ -Pi cotransporter NaPi-IIb in small intestine.
Am J Physiol Gastrointest Liver Physiol.
2005;
288
G501-G506
35
Wiederkehr M, Krapf R.
Metabolic and endocrine effects of metabolic acidosis in humans.
Swiss Med Wkly.
2001;
131
127-132
Correspondence
N. Charoenphandhu MD, PhD and N. KrishnamraPhD
Consortium for Calcium and Bone Research
Faculty of Science, Mahidol University
Rama VI Road
Bangkok 10400
Thailand
Telefon: +66/2/354 71 54
Fax: +66/2/354 71 54
eMail: naratt@narattsys.com (NC)
eMail: scnks@mahidol.ac.th (NK)