- Email: [email protected]
Introduction to Renal Osteodystrophy: Calcium Metabolism in Health and Uremia
Introduction to Renal Osteodystrophy: Calcium Metabolism In Health and Uremia KIYOSHI KUROKAWA, MO;
MASAFUMI FUKAGAWA, MO, PHD
C
alcium ion concentration of the extracellular fluid (ECF) is kept constant within a narrow range of ~ 1.25 /Lmol/L.1 This is mainly achieved by the actions of parathyroid hormone (PTH) and active 1,25-dihydroxyvitamin D (1,25D). The principal target organs of these hormones are bone, kidney, and intestine. When plasma calcium ion concentration decreases, the parathyroid glands sense the change via membrane-bound calcium sensor protein and secrete PTH immediately.2 PTH acts on the bone and releases calcium into ECF. At the same time, PTH also acts on the kidney and stimulates calcium reabsorption in the distal nephron, returning the calcium ion concentration to normal. Sufficient action of 1,25D has been suggested to be mandatory for these three steps to work appropriately.3 On the other hand, the kidney almost exclusively activates vitamin D. As a total system, interplay of PTH and vitamin D will set the ECF calcium ion at 5 mg/dL by adjusting the calcium set-point of PTH secretion in parathyroid, bone-ECF interphase, and renal tubular reabsorption. 4 Considering such central roles of the kidney and bone in the maintenance of calcium homeostasis, it is reasonable that altered metabolism of divalent ion and bone disease develop in patients with chronic renal failure. With the introduction of renal replacement therapy, longer history of uremia and additional modifications by the therapy itself have given rise to varieties of bone disease known as renal osteodystrophy (Table 1).5 Bone abnormalities in uremic patients were recognized as early as a century ago. 'Renal osteitis fibrosa cystica' or 'osteomalacia with parathyroid hyperplasia' were the names given to the types of bone disease initially recognized. 6,7 Later, it was revealed that the parathyroid hyperplasia was a sequela of renal failure. 8 In the early 1970s, it was
From the Tokai University School of Medicine, Isehara, Kanagawa (KK), and Division of Nephrology, Tokyo Teishin Hospital, Tokyo (MF), Japan. Correspondence: Kiyoshi Kurokawa, M.D., Dean, Tokai University School of Medicine, Boseidai, Isehara-shi, Kanagawa 259-11, Japan (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
suggested that stimulation of PTH secretion in uremia was hypocalcemia caused by phosphate retention (trade-off theory).9,10 High turnover bone disease is the result of such PTH hypersecretion and often progresses to osteitis fibrosa. The discovery of vitamin D activation in the kidneyll was a breakthrough in the research on and clinical treatment of renal osteodystrophy. Then, the role of the decreased production of 1,25D12 in the development of uremic hyperparathyroidism was recognized together with the role of phosphate on 1,25D production in the kidney.13 Active vitamin D sterols soon became available and were used routinely with favorable results. 14 In 1984, Slatopolsky et al reported that intravenous administration of 1,25D effectively suppressed PTH secretion without hypercalcemia in severe cases of hyperparathyroidism on chronic dialysis (1,25D pulse therapy),15 which suggests that the physiological plasma concentration of 1,25D may not be sufficient to control PTH secretion in uremia. Such resistance to 1,25D has been attributed to the decreased density of 1,25D receptor initially revealed by Korkor 16 and to the inhibition of 1,25Dreceptor complex with the target gene by uremic toxins as suggested by Hsu et alP Abnormal sensitivity of parathyroid cells to calcium has been also suggested to be the stimulus of PTH secretion in uremia,18 Cloning of the calcium-sensing receptor provided.a molecular basis for this mechanism 19 and has led to the development of calcimimetics. 20 In addition, direct effect of phosphate on parathyroid glands has been shown recently.21 Parathyroid hyperplasia is one of the originally recognized characteristics of renal osteodystrophy. Inspired by several clinical observations, the pathophysiology of parathyroid hyperplasia has been intensively studied at the cellular and molecular levels. Recent data suggest that large parathyroid glands usually represent nodular hyperplasia composed of monoclonally proliferating cells,22 with lower density of 1,25D receptor23 and calcium-sensing receptor, and 24 thus resistant to medical therapy. In some cases, genetic mutations have even been demonstrated. 25 In turn, these observations
355
Introduction
Table 1. Classification of Bone Diseases in Uremic Patients High-turnover bone disease Mild disease Osteitis fibrosa Low-turnover bone disease Adynamic bone disease Osteomalacia Mixed type bone disease Dialysis-related amyloid bone and joint disease
3. 4. 5. 6.
provide a rational basis for the new therapeutic modalities, such as percutaneous ethanol injection therapy. 26 An outbreak of fractures together with encephalopathy in the United Kingdom in 1978 attracted attention to the toxicity of aluminum in uremia for the first time.27 In this type of osteomalacia, aluminum deposit was noted along the mineralization front. Iron has been also implicated for the same abnormality. Recognition of this disease led to the purification of the water used for dialysates and later to the abandonment of aluminum gels used as phosphate binder.28 Recently, another type of lowturnover bone disease, known as aplastic or adynamic bone, has been recognized as a new entity. Although the long-term clinical consequences of this lesion are controversial, contribution of relatively low PTH levels for its genesis has been suggested. 29 In other words, higher PTH is necessary to maintain normal bone turnover in uremic patients. 3o The nature of such a resistance, which has been suggested for more than 2 decades, needs to be clarified in the near future. Dialysis-related amyloidosis is another type of bone and joint disease seen in patients with a long history of dialysis. The accumulation of a unique type of amyloid protein made of f32-microglobulin causes bone cysts, carpal tunnel syndrome, and arthropathy, including destructive spondyloarthropathy.32 In addition, it has been suggested that modification of accumulated f32-microglobulin plays a role, especially as advanced glycation end productS. 33 In this symposium issue, selected topics in the calcium homeostasis in uremia will be discussed both from biological and clinical standpoints. As can be seen from the history summarized above, careful clinical and experimental observations have contributed and made feedback to each other in this unique field in clinical medicine. Development of new and rational therapeutic modalities is highly expected after further studies at the molecular level.
7. 8. 9. 10. 11. 12. 13.
14.
15.
16. 17.
18. 19. 20. 21.
22. 23.
References 1. Kurokawa K. Calcium regulating hormones and the kidney. Kidney Int 1987;32:760-71. 2. Brown EM. Extracellular Ca 2 + sensing, regulation of parathyroid cell function, and role of Ca 2 + and other ions as
356
24.
extracellular (first) messengers. Physiol Rev 1991;71:371411. Yamamoto M, Kawanobe Y, Takahashi H, et al. Vitamin D deficiency and calcium transport in the rat. J Clin Invest 1984;74:507-13. Kurokawa K. The kidney and calcium homeostasis. Kidney Int 1994;45:897-8105. Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone diseases in end-stage renal failure-an evolving disorder. Kidney Int 1993;43:436-442. Albright F, Drake TG, Sulkowitch. Renal osteitis fibrosa cystica: Report of case with discussion of metabolic aspects. Johns Hopkins Med J 1937;60:377-385. Lucas RC. On a form of late rickets associated with albuminuria, rickets of adolescents. Lancet 1883;1:993-4. Langmead FS, Orr JW. Renal rickets associated with parathyroid hyperplasia, Arch Dis Child 1933;8:265-78. Bricker NS, Slatopolsky E, Reiss E, et al. Calcium, phosphorus and bone in renal disease and transplantation. Arch Int Med 1969;123:543-53. Slatopolsky E, Caglar S, Gradowska I, et al. On the pathogenesis of hyperparathyroidism in chronic experimental insufficiency in the dog. J Clin Invest 1971;50:492-9. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature 1970;228: 764-6. Mawer EB, Backhouse J, Taylor CM. Failure offormation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency. Lancet 1973;1:626-8. Portale AP, Booth BE, Halloran BP, et al. Effect of dietary phosphorus on circulating concentrations of 1,25dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984;73:1580-9. Brickman AS, Coburn JW, Norman AW. Action of 1,25dihydroxycholecalciferol, a potent kidney produced metabolite of vitamin D3 in uremic man. N Engl J Med 1972;287: 891-5. Slatopolsky EA, Weerts C, Thielan J, et al. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 1984;74:2136-43. Korkor AB. Reduced binding of [3Hll,25-dihydroxyvitamin D3 in the parathyroid glands of patients with renal failure. N Engl J Med 1987;316:1573-7. Brown EM. Four parameter model ofthe sigmoidal relationship between PTH release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983;56:572-81. Hsu CH, Patel SR, Young EW, et al. The biological action of calcitriol in renal failure. Kidney Int 1994;46:605-12. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca2 + -sensing receptor from bovine parathyroid. Nature 1993;366:575-80. Antonsen JE, Sherrard DJ, Andress DL. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney Int 1998;53:223-7. Slatopolsky E, Finch J, Denda M, et al. Phosphorus restriction prevents parathyroid gland growth: High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 1996;96:2534-40. Arnold A, Brown MF, Urena P, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia, J Clin Invest 1995;95:2047-53. Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993;92:1436-43. Kifor 0, Moore FD Jr, Wang P, et al. Reduced immunostaining for the extracellular Ca 2 + -sensing receptor in priJune 1999 Volume 317 Number 6
Kurokawa and Fukagawa
25. 26. 27. 28. 29.
mary and uremic secondary hyperp£'Tathyroidism. J Clin Endocrinol Metab 1996;81:1598-606. Falchetti A, Bale AE, Amorosi A, et al. Progression of uremic hyperparathyroidism involves alleic loss on chromosome 11. J Clin Endocrinol Metab 1993;76:139-44. Kitaoka M, Fukagawa M, Ogata E, et al. Reduction of functioning parathyroid cell mass by ethanol injection in chronic dialysis patients. Kidney Int 1994;46:1110-7. Ward MK, Feest TG, Ellis HA, et al. Osteomalacic dialysis osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminum. Lancet 1978;1:841-5. Berlyne GM, Ben-Ari J, Pest D, et al. Hyperaluminaemia from aluminum resins in renal failure. Lancet 1970;2:494-6. Hercz G, Pei Y Greenwood C. Aplastic osteodystrophy without aluminum: the role of "suppressed" parathyroid function. Kidney Int 1993;44:860-6.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
30. Quarles LD, Lobaugh B, Murphy G. Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia, J Clin Endocrinol Metab 1992;75:145-50. 31. Massry SG, Coburn JW, Lee DBN,. Skeletal resistance to parathyroid hormone in renal failure: study in 105 human subjects. Ann Int Med 1973;78:357-64. 32. Gejyo F, Yamada T, Odani S, et al. A new form of amyloid protein associated with chronic hemodialysis was identified as /32-microglobulin. Biochem Biophys Res Commun 1985; 129:701-6. 33. Miyata T, Oda 0, Inigi R, et al. /32-Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyioidosis. J Clin Invest 1993; 92:1243-52.
357
MASAFUMI FUKAGAWA, MO, PHD
C
alcium ion concentration of the extracellular fluid (ECF) is kept constant within a narrow range of ~ 1.25 /Lmol/L.1 This is mainly achieved by the actions of parathyroid hormone (PTH) and active 1,25-dihydroxyvitamin D (1,25D). The principal target organs of these hormones are bone, kidney, and intestine. When plasma calcium ion concentration decreases, the parathyroid glands sense the change via membrane-bound calcium sensor protein and secrete PTH immediately.2 PTH acts on the bone and releases calcium into ECF. At the same time, PTH also acts on the kidney and stimulates calcium reabsorption in the distal nephron, returning the calcium ion concentration to normal. Sufficient action of 1,25D has been suggested to be mandatory for these three steps to work appropriately.3 On the other hand, the kidney almost exclusively activates vitamin D. As a total system, interplay of PTH and vitamin D will set the ECF calcium ion at 5 mg/dL by adjusting the calcium set-point of PTH secretion in parathyroid, bone-ECF interphase, and renal tubular reabsorption. 4 Considering such central roles of the kidney and bone in the maintenance of calcium homeostasis, it is reasonable that altered metabolism of divalent ion and bone disease develop in patients with chronic renal failure. With the introduction of renal replacement therapy, longer history of uremia and additional modifications by the therapy itself have given rise to varieties of bone disease known as renal osteodystrophy (Table 1).5 Bone abnormalities in uremic patients were recognized as early as a century ago. 'Renal osteitis fibrosa cystica' or 'osteomalacia with parathyroid hyperplasia' were the names given to the types of bone disease initially recognized. 6,7 Later, it was revealed that the parathyroid hyperplasia was a sequela of renal failure. 8 In the early 1970s, it was
From the Tokai University School of Medicine, Isehara, Kanagawa (KK), and Division of Nephrology, Tokyo Teishin Hospital, Tokyo (MF), Japan. Correspondence: Kiyoshi Kurokawa, M.D., Dean, Tokai University School of Medicine, Boseidai, Isehara-shi, Kanagawa 259-11, Japan (E-mail: [email protected]). THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
suggested that stimulation of PTH secretion in uremia was hypocalcemia caused by phosphate retention (trade-off theory).9,10 High turnover bone disease is the result of such PTH hypersecretion and often progresses to osteitis fibrosa. The discovery of vitamin D activation in the kidneyll was a breakthrough in the research on and clinical treatment of renal osteodystrophy. Then, the role of the decreased production of 1,25D12 in the development of uremic hyperparathyroidism was recognized together with the role of phosphate on 1,25D production in the kidney.13 Active vitamin D sterols soon became available and were used routinely with favorable results. 14 In 1984, Slatopolsky et al reported that intravenous administration of 1,25D effectively suppressed PTH secretion without hypercalcemia in severe cases of hyperparathyroidism on chronic dialysis (1,25D pulse therapy),15 which suggests that the physiological plasma concentration of 1,25D may not be sufficient to control PTH secretion in uremia. Such resistance to 1,25D has been attributed to the decreased density of 1,25D receptor initially revealed by Korkor 16 and to the inhibition of 1,25Dreceptor complex with the target gene by uremic toxins as suggested by Hsu et alP Abnormal sensitivity of parathyroid cells to calcium has been also suggested to be the stimulus of PTH secretion in uremia,18 Cloning of the calcium-sensing receptor provided.a molecular basis for this mechanism 19 and has led to the development of calcimimetics. 20 In addition, direct effect of phosphate on parathyroid glands has been shown recently.21 Parathyroid hyperplasia is one of the originally recognized characteristics of renal osteodystrophy. Inspired by several clinical observations, the pathophysiology of parathyroid hyperplasia has been intensively studied at the cellular and molecular levels. Recent data suggest that large parathyroid glands usually represent nodular hyperplasia composed of monoclonally proliferating cells,22 with lower density of 1,25D receptor23 and calcium-sensing receptor, and 24 thus resistant to medical therapy. In some cases, genetic mutations have even been demonstrated. 25 In turn, these observations
355
Introduction
Table 1. Classification of Bone Diseases in Uremic Patients High-turnover bone disease Mild disease Osteitis fibrosa Low-turnover bone disease Adynamic bone disease Osteomalacia Mixed type bone disease Dialysis-related amyloid bone and joint disease
3. 4. 5. 6.
provide a rational basis for the new therapeutic modalities, such as percutaneous ethanol injection therapy. 26 An outbreak of fractures together with encephalopathy in the United Kingdom in 1978 attracted attention to the toxicity of aluminum in uremia for the first time.27 In this type of osteomalacia, aluminum deposit was noted along the mineralization front. Iron has been also implicated for the same abnormality. Recognition of this disease led to the purification of the water used for dialysates and later to the abandonment of aluminum gels used as phosphate binder.28 Recently, another type of lowturnover bone disease, known as aplastic or adynamic bone, has been recognized as a new entity. Although the long-term clinical consequences of this lesion are controversial, contribution of relatively low PTH levels for its genesis has been suggested. 29 In other words, higher PTH is necessary to maintain normal bone turnover in uremic patients. 3o The nature of such a resistance, which has been suggested for more than 2 decades, needs to be clarified in the near future. Dialysis-related amyloidosis is another type of bone and joint disease seen in patients with a long history of dialysis. The accumulation of a unique type of amyloid protein made of f32-microglobulin causes bone cysts, carpal tunnel syndrome, and arthropathy, including destructive spondyloarthropathy.32 In addition, it has been suggested that modification of accumulated f32-microglobulin plays a role, especially as advanced glycation end productS. 33 In this symposium issue, selected topics in the calcium homeostasis in uremia will be discussed both from biological and clinical standpoints. As can be seen from the history summarized above, careful clinical and experimental observations have contributed and made feedback to each other in this unique field in clinical medicine. Development of new and rational therapeutic modalities is highly expected after further studies at the molecular level.
7. 8. 9. 10. 11. 12. 13.
14.
15.
16. 17.
18. 19. 20. 21.
22. 23.
References 1. Kurokawa K. Calcium regulating hormones and the kidney. Kidney Int 1987;32:760-71. 2. Brown EM. Extracellular Ca 2 + sensing, regulation of parathyroid cell function, and role of Ca 2 + and other ions as
356
24.
extracellular (first) messengers. Physiol Rev 1991;71:371411. Yamamoto M, Kawanobe Y, Takahashi H, et al. Vitamin D deficiency and calcium transport in the rat. J Clin Invest 1984;74:507-13. Kurokawa K. The kidney and calcium homeostasis. Kidney Int 1994;45:897-8105. Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone diseases in end-stage renal failure-an evolving disorder. Kidney Int 1993;43:436-442. Albright F, Drake TG, Sulkowitch. Renal osteitis fibrosa cystica: Report of case with discussion of metabolic aspects. Johns Hopkins Med J 1937;60:377-385. Lucas RC. On a form of late rickets associated with albuminuria, rickets of adolescents. Lancet 1883;1:993-4. Langmead FS, Orr JW. Renal rickets associated with parathyroid hyperplasia, Arch Dis Child 1933;8:265-78. Bricker NS, Slatopolsky E, Reiss E, et al. Calcium, phosphorus and bone in renal disease and transplantation. Arch Int Med 1969;123:543-53. Slatopolsky E, Caglar S, Gradowska I, et al. On the pathogenesis of hyperparathyroidism in chronic experimental insufficiency in the dog. J Clin Invest 1971;50:492-9. Fraser DR, Kodicek E. Unique biosynthesis by kidney of a biologically active vitamin D metabolite. Nature 1970;228: 764-6. Mawer EB, Backhouse J, Taylor CM. Failure offormation of 1,25-dihydroxycholecalciferol in chronic renal insufficiency. Lancet 1973;1:626-8. Portale AP, Booth BE, Halloran BP, et al. Effect of dietary phosphorus on circulating concentrations of 1,25dihydroxyvitamin D and immunoreactive parathyroid hormone in children with moderate renal insufficiency. J Clin Invest 1984;73:1580-9. Brickman AS, Coburn JW, Norman AW. Action of 1,25dihydroxycholecalciferol, a potent kidney produced metabolite of vitamin D3 in uremic man. N Engl J Med 1972;287: 891-5. Slatopolsky EA, Weerts C, Thielan J, et al. Marked suppression of secondary hyperparathyroidism by intravenous administration of 1,25-dihydroxycholecalciferol in uremic patients. J Clin Invest 1984;74:2136-43. Korkor AB. Reduced binding of [3Hll,25-dihydroxyvitamin D3 in the parathyroid glands of patients with renal failure. N Engl J Med 1987;316:1573-7. Brown EM. Four parameter model ofthe sigmoidal relationship between PTH release and extracellular calcium concentration in normal and abnormal parathyroid tissue. J Clin Endocrinol Metab 1983;56:572-81. Hsu CH, Patel SR, Young EW, et al. The biological action of calcitriol in renal failure. Kidney Int 1994;46:605-12. Brown EM, Gamba G, Riccardi D, et al. Cloning and characterization of an extracellular Ca2 + -sensing receptor from bovine parathyroid. Nature 1993;366:575-80. Antonsen JE, Sherrard DJ, Andress DL. A calcimimetic agent acutely suppresses parathyroid hormone levels in patients with chronic renal failure. Kidney Int 1998;53:223-7. Slatopolsky E, Finch J, Denda M, et al. Phosphorus restriction prevents parathyroid gland growth: High phosphorus directly stimulates PTH secretion in vitro. J Clin Invest 1996;96:2534-40. Arnold A, Brown MF, Urena P, et al. Monoclonality of parathyroid tumors in chronic renal failure and in primary parathyroid hyperplasia, J Clin Invest 1995;95:2047-53. Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Invest 1993;92:1436-43. Kifor 0, Moore FD Jr, Wang P, et al. Reduced immunostaining for the extracellular Ca 2 + -sensing receptor in priJune 1999 Volume 317 Number 6
Kurokawa and Fukagawa
25. 26. 27. 28. 29.
mary and uremic secondary hyperp£'Tathyroidism. J Clin Endocrinol Metab 1996;81:1598-606. Falchetti A, Bale AE, Amorosi A, et al. Progression of uremic hyperparathyroidism involves alleic loss on chromosome 11. J Clin Endocrinol Metab 1993;76:139-44. Kitaoka M, Fukagawa M, Ogata E, et al. Reduction of functioning parathyroid cell mass by ethanol injection in chronic dialysis patients. Kidney Int 1994;46:1110-7. Ward MK, Feest TG, Ellis HA, et al. Osteomalacic dialysis osteodystrophy: Evidence for a water-borne aetiological agent, probably aluminum. Lancet 1978;1:841-5. Berlyne GM, Ben-Ari J, Pest D, et al. Hyperaluminaemia from aluminum resins in renal failure. Lancet 1970;2:494-6. Hercz G, Pei Y Greenwood C. Aplastic osteodystrophy without aluminum: the role of "suppressed" parathyroid function. Kidney Int 1993;44:860-6.
THE AMERICAN JOURNAL OF THE MEDICAL SCIENCES
30. Quarles LD, Lobaugh B, Murphy G. Intact parathyroid hormone overestimates the presence and severity of parathyroid-mediated osseous abnormalities in uremia, J Clin Endocrinol Metab 1992;75:145-50. 31. Massry SG, Coburn JW, Lee DBN,. Skeletal resistance to parathyroid hormone in renal failure: study in 105 human subjects. Ann Int Med 1973;78:357-64. 32. Gejyo F, Yamada T, Odani S, et al. A new form of amyloid protein associated with chronic hemodialysis was identified as /32-microglobulin. Biochem Biophys Res Commun 1985; 129:701-6. 33. Miyata T, Oda 0, Inigi R, et al. /32-Microglobulin modified with advanced glycation end products is a major component of hemodialysis-associated amyioidosis. J Clin Invest 1993; 92:1243-52.
357