Clinical Investigation

Kidney International (1993) 43, 1104–1109; doi:10.1038/ki.1993.155

Parathyroid sensing of the direction of change of calcium in uremia

Jonathan TC Kwan1, Jeanette C Beer1, Kate Noonan1 and John Cunningham1

1Departments of Nephrology and Clinical Biochemistry, The Royal London Hospital and Medical College, London, England, United Kingdom

Correspondence: Dr John Cunningham, Department of Nephrology, The Royal London Hospital, Whitechapel, London E1 1BB, England, United Kingdom.

Received 26 August 1992; Revised 19 October 1992; Accepted 19 October 1992.

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Abstract

Parathyroid sensing of the direction of change of calcium in uremia. It could be advantageous for the parathyroids to be able to sense not only the absolute concentration of extracellular Ca2+, but also the rate and direction of change of Ca2+, thereby allowing the parathyroids to respond earlier to threats to Ca2+ homeostasis. By using high and low Ca2+ dialysis in a single session, we examined the parathyroid response to direction of change of Ca2+ during acute Ca2+ perturbation in nine hemodialysis patients. Separate PTH/ionized calcium (PTH/iCa) response curves were generated for rising Ca2+ and falling Ca2+. Significant directional hysteresis (higher PTH level during falling than during rising Ca2+) was found. During hypercalcemia, PTH levels were between 2.2 and 1.6 times higher at iCa concentrations of between 0 and +0.1 mM above the baseline iCa, when Ca2+ was falling than when it was rising. During the phase of induced hypocalcemia, parathyroid fatigue was seen in six of the nine patients. Fatigue patients tended to have higher basal PTH (1-84) levels than those not showing fatigue. The existence of fatigue provides an explanation for directional hysteresis during hypocalcemia, and therefore parathyroid sensing of the direction of change of Ca2+ could not be assessed during hypocalcemia. These studies demonstrate a capacity of the parathyroids to sense the direction of movement of Ca2+ during hypercalcemia.

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References

  1. Sherwood LM, Potts JTJ, Care AD, Mayer GP, Aurbach GD: Evaluation by radioimmunoassay of factors controlling the secretion of parathyroid hormone: Intravenous infusions of calcium and wthylenediamine tetracetic acid in the cow and the goat. Nature 209:52–55, 1966 | Article | PubMed | ChemPort |
  2. Sherwood LM, Mayer GP, Ramberg CF, Kronfeld DS, Aurbach GD, Potts JTJ: Regulation of parathyroid hormone secretion: Proportional control by calcium, lack of effect of phosphate. Endocrinology 83:1043–1051, 1968 | PubMed | ISI | ChemPort |
  3. Chertow BD, Baylink DJ, Wergedal JE, Su MH, Norman AW: Decrease in serum immunoreactive parathroid hormone in rats and in parathyroid hormone secretion in vitro by 1,25-dihydroxycholecalciferol. J Clin Invest 56:668–678, 1975
  4. Silver J, Naveh-Many T, Mayer H, Schmeizer HJ, Povtzer MM: Regulation by vitamin D metabolites of parathyroid hormone gene transcription in vivo in the rat. J Clin Invest 78:1296–1301, 1986 | PubMed | ISI | ChemPort |
  5. Brown EM, Gardner DG, Aurbach GD: Calcium-regulated parathyroid hormone release in primary hyperparathyroidism. Studies in vitro with dispersed parathyroid cells. Am J Med 66:923–931, 1977
  6. Rudberg C, Akerstrom G, Ljunghall S, Grimelius L, Johannson H, Pertroft H, Wide L: Regulation of parathyroid hormone release in primary and secondary hyerparathyroidism—Studies in vivo and in vitro. Acta Endocrinol 101:408–413, 1982
  7. Brown EM: Four-parameter model of the sigmoidal relationship between parathyroid hormone release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 56:572–581, 1983 | PubMed | ISI | ChemPort |
  8. LeBoff MS, Shoback D, Brown EM, Thatcher J, Leombruno R, Beaudoin D, Henry M, Wilson R, Pallotta J, Marynick S, Stock J, Leight G: Regulation of parathyroid hormone release and cytosolic calcium by extracellular calcium in dispersed and cultured bovine and pathological human parathyroid cells. J Clin Invest 75:49–57, 1985
  9. Mayer GP, Hurst JG: Sigmoidal relationship between parathyroid hormone secretion rate and plasma calcium concentration in calves. J Clin Invest 57:678–683, 1978
  10. Rudberg C, Akerstrom G, Johansson H, Ljunghall S, Malmaeus J, Wide L: Effects of 1,25- and 24,25-dihydroxycholecalciferol on parathyroid hormone release from human parathyroid cells in vitro. Acta Endocrinol Copenh 105:354–359, 1984
  11. Brent GA, LeBoff MS, Seely EW, Conlin PR, Brown EM: Relationship between the concentration and rate of change of calcium and serum intact parathyroid hormone levels in normal humans. Clin Endocrinol Metab 67:944–950, 1988
  12. Blum JW, Treschel U, Born W, Tobler PH, Taylor CM, Binswanger U, Fischer JA: Rapidity of plasma 1,25-dihydroxyvitamin D responses to hypo- and hypercalcemia in steers. Endocrinology 113:523–526, 1983 | PubMed | ISI | ChemPort |
  13. Felsenfeld AJ, Rodriguez M, Coleman M, Ross D, Llach F: Desferrioxamine therapy in hemodialysis patients with aluminum-associated bone disease. Kidney Int 35:1371–1378, 1989 | PubMed |
  14. Felsenfeld AJ, Rodriguez M, Dunlay R, Llach F: A comparison of parathyroid-gland function in haemodialysis patients with different forms of renal osteodystrophy. Nephrol Dial Transplant 6:244–251, 1991 | PubMed | ISI | ChemPort |
  15. Felsenfeld AJ, Ross D, Rodriguez M: Hysteresis of the parathyroid hormone response to hypocalcemia in hemodialysis patients with low turnover aluminum bond disease. J Am Soc Nephrol 21:1136–1143, 1991
  16. Dunlay R, Rodriguez M, Felsenfeld A, Llach F: Direct inhibitory effect of calcitriol on parathyroid function (sigmoidal curve) in dialysis patients. Kidney Int 36:1093–1098, 1989 | PubMed | ISI | ChemPort |
  17. Delmez JA, Tindira C, Grooms P, Dusso A, Windus DW, Slatopolsky E: Parathyroid hormone suppression by intravenous 1,25-dihydroxyvitamin D. J Clin Invest 83:1349–1355, 1989 | PubMed | ISI | ChemPort |
  18. Kwan JTC, Almond MA, Beer JC, Noonan K, Evan SJW, Cunningham J: "Pulse" oral calcitriol in uraemic patients: Rapid modification of parathyroid response to calcium. Nephrol Dial Transplant 7:829–834, 1992 | PubMed | ISI | ChemPort |
  19. Adami S, Muirhead N, Manning RM, Gleed JH, Papapoulos SE, Sandler LM, Catto GRD, O'Riordan JLH: Control of secretion of parathyroid hormone in secondary hyperparathyroidism. Clin Endocrinol 16:463–473, 1982
  20. Cunningham J, Altmann P, Gleed JH, Butter KS, Marsh FP, O'Riordan JLH: Effect of direction and rate of change of calcium on parathyroid hormone secretion in uraemia. Nephrol Dial Transplant 4:339–344, 1989 | PubMed | ChemPort |
  21. Grant FD, Conlin PR, Brown EM: Rate and concentration dependence of parathyroid hormone dynamics during stepwise changes in serum ionized calcium in normal humans. Clin Endocrinol Metab 71:370–378, 1990
  22. Conlin PR, Fajtova VT, Mortensen RM, LeBoff MS, Brown EM: Hysteresis in the relationship between serum ionized calcium and intact parathyroid hormone during recovery form induced hyper- and hypocalcemia in normal humans. J Clin Endocrinol Metab 69:593–599, 1989 | PubMed | ChemPort |
  23. Raman A: The calcium fractions of normal serum. Clin Biochem 4:141–146, 1971 | PubMed | ISI | ChemPort |
  24. D'Haese PC, van de Vyver FL, de Wolf FA, de Broe ME: Measurement of aluminium in serum, blood, urine and tissue of chronic hemodialyzed patients by use of electrothermal atomic absorption spectrometry. Clin Chem 31:24–29, 1985 | PubMed | ChemPort |
  25. Brown EM: Extracellular Ca2+ sensing, regulation of parathyroid cell function, and role of Ca2+ and other ions as extracellular (first) messengers. Physiol Rev 71:371–411, 1991 | PubMed | ISI | ChemPort |
  26. Nemeth EF: Regulation of cytosolic calcium by extracellular divalent cations in C-cells and parathyroid cells. Cell Calcium 11:323–327, 1990 | Article | PubMed | ChemPort |
  27. Fitzpatrick LA, Aurbach GD: Calcium inhibition of parathyroid hormone secretion is mediated via a guanine nucleotide regulatory protein. Endocrinology 119:2700–2703, 1986
  28. Chen CJ, Barnett JV, Congo DA, Brown EM: Divalent cations suppress 3',5'-adenosine monophosphate accumulation by stimulating a pertussis toxin-sensitive guanine nucleotide-binding protein in cultured bovine parathyroid cells. Endocrinology 124:233–239, 1989
  29. Brown EM, Enyedi P, Leboff M, Rotberg J, Preston J, Chen C: High extracellular Ca2+ and Mg2+ stimulate accumulation of inositol phosphates in bovine parathyroid cells. FEBS Lett 218:113–118, 1987 | Article | PubMed | ISI | ChemPort |
  30. Shoback DM, Membreno LA, McGhee JM: High calcium and other divalent cations increase inositol triphosphate in bovine parathyroid cells. Endocrinology 123:282–289, 1988
  31. Brown EM, Gardner DG, Windeck RA, Aurbach GD: Relationship of intracellular 3',5'-adenosine monophosphate accumulation to parathyroid hormone release from dispersed bovine parathyroid cells. Endocrinology 103:2323–2333, 1978 | PubMed | ChemPort |
  32. Shoback DM, Thatchem J, Leombruno R, Brown EM: Effects of extracellular Ca++ and Mg++ in dispersed bovine parathyroid cells. Endocrinology 113:424–426, 1983 | PubMed | ISI | ChemPort |
  33. Juhlin C, Lundgren S, Johansson H, Lorentzen J, Rask L, Larsson E, Rastad J, Akerstrom G, Klareskog L: 500 Kilodalton calcium sensor regulating cytoplasmic Ca2+ in cytotrophoblast cells of human placenta. J Biol Chem 265:8275–8280, 1990 | PubMed | ISI | ChemPort |
  34. Cohn DV, MacGregor RR: The biosynthesis, intracellular processing and secretion of parathormone. Endocrinol Rev 2:1–26, 1981
  35. Habener JF, Potts JT Jr: Parathyroid hormone: Biochemical aspects of biosynthesis, secretion, action, and metabolism. Physiol Rev 64:985–1053, 1984 | PubMed | ISI | ChemPort |
  36. Schwarz P, Sørensen HA, McNair P, Transbøl I: Induced hyocalcaemia and intact PTH responsiveness in patients with primary hyperparathyroidism, primary hypoparathyroidism and normal man. (abstract) Bone Miner 17:129, 1992
  37. Yamamoto M, Igarishi T, Muramatsu M, Fukagawa M, Motokura T, Ogata E: Hypocalcemia increases and hypercalcemia devreases the steady state level of parathyroid hormone messenger RNA in the rat. J Clin Invest 83:1053–1056, 1989 | PubMed | ISI | ChemPort |
  38. Russell J, Lettieri D, Sherwood LM: Direct regulation by calcium of cytoplasmic messenger ribonucleic acid coding for preproparathyroid hormone in isolated bovine parathyroid cells. J Clin Invest 72:1851–1855, 1983 | PubMed | ISI | ChemPort |

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