Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options.

Secondary hyperparathyroidism (SHPT) is a challenge frequently encountered in the management of patients with chronic kidney disease (CKD). Downregulation of the parathyroid vitamin D and calcium-sensing receptors represent critical steps that lead to abnormalities in mineral metabolism: high phosphate, low calcium, and vitamin D deficiency. These imbalances result in parathyroid hyperplasia and contribute to vascular calcification. New studies have established a central role for fibroblast growth factor 23 (FGF-23) in the regulation of phosphate-vitamin D homeostasis. FGF-23 concentration increases in CKD and contributes to SHPT. Achieving current targets for the key mineral parameters in the management of SHPT set by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines can be challenging. This review summarizes the current understanding and evidence supporting strategies for SHPT treatment in CKD patients. Treatment should include a combination of dietary phosphorus restriction, phosphate binders, vitamin D sterols, and calcimimetics. Parathyroidectomy is effective in suitable candidates refractory to medical therapy and the standard against which new approaches should be measured. Future strategies may focus on the stimulation of apoptotic activity of hyperplastic parathyroid cells.

[1]  Y. Tominaga,et al.  Parathyroidectomy for Secondary Hyperparathyroidism in the Era of Calcimimetics , 2008, Therapeutic apheresis and dialysis : official peer-reviewed journal of the International Society for Apheresis, the Japanese Society for Apheresis, the Japanese Society for Dialysis Therapy.

[2]  B. Garrett,et al.  A comparison of the calcium-free phosphate binder sevelamer hydrochloride with calcium acetate in the treatment of hyperphosphatemia in hemodialysis patients. , 1999, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[3]  G. Chertow,et al.  Mineral metabolism, mortality, and morbidity in maintenance hemodialysis. , 2004, Journal of the American Society of Nephrology : JASN.

[4]  K. O̸lgaard,et al.  Autoregulation in the parathyroid glands by PTH/PTHrP receptor ligands in normal and uremic rats. , 2003, Kidney international.

[5]  J. Muñoz-Castañeda,et al.  FGF23 fails to inhibit uremic parathyroid glands. , 2010, Journal of the American Society of Nephrology : JASN.

[6]  H. Takagi,et al.  Clonal Analysis of Nodular Parathyroid Hyperplasia in Renal Hyperparathyroidism , 1996, World Journal of Surgery.

[7]  S. Yano,et al.  Efficacy of direct injection of calcitriol into the parathyroid glands in uraemic patients with moderate to severe secondary hyperparathyroidism. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[8]  T. Craig,et al.  Evidence for a signaling axis by which intestinal phosphate rapidly modulates renal phosphate reabsorption , 2007, Proceedings of the National Academy of Sciences.

[9]  J. Silver,et al.  The calcium-sensing receptor regulates parathyroid hormone gene expression in transfected HEK293 cells , 2009, BMC Biology.

[10]  Keith C. Norris,et al.  K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease. , 2003, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[11]  S. Massry Is parathyroid hormone a uremic toxin? , 1977, Nephron.

[12]  Alex J. Brown,et al.  Vitamin D analogues for secondary hyperparathyroidism. , 2002, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[13]  M. Hernán,et al.  Activated injectable vitamin D and hemodialysis survival: a historical cohort study. , 2005, Journal of the American Society of Nephrology : JASN.

[14]  M. Mohammadi,et al.  The parathyroid is a target organ for FGF23 in rats. , 2007, The Journal of clinical investigation.

[15]  D. Batlle,et al.  Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. , 2003, Kidney international.

[16]  T. Drüeke,et al.  Cell biology of parathyroid gland hyperplasia in chronic renal failure. , 2000, Journal of the American Society of Nephrology : JASN.

[17]  K. Cao,et al.  Calcium-independent and 1,25(OH)2D3-dependent regulation of the renin-angiotensin system in 1alpha-hydroxylase knockout mice. , 2008, Kidney international.

[18]  M. Bia,et al.  Etiology of hypercalcemia in hemodialysis patients on calcium carbonate therapy. , 1990, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[19]  S. Cañadillas,et al.  Regulation of parathyroid function in chronic renal failure , 2005, Journal of Bone and Mineral Metabolism.

[20]  D. Rodríguez‐Puyol,et al.  Oral active vitamin D is associated with improved survival in hemodialysis patients. , 2008, Kidney international.

[21]  J. Silver,et al.  Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. , 2010, Kidney international.

[22]  K. Martin,et al.  CHAPTER 39 – The Parathyroids in Renal Disease: Pathophysiology , 2001 .

[23]  T. Akizawa,et al.  Guidelines for percutaneous ethanol injection therapy of the parathyroid glands in chronic dialysis patients. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[24]  D. Lacey,et al.  Pharmacodynamics of the Type II Calcimimetic Compound Cinacalcet HCl , 2004, Journal of Pharmacology and Experimental Therapeutics.

[25]  D. Lacey,et al.  Cinacalcet HCl attenuates parathyroid hyperplasia in a rat model of secondary hyperparathyroidism. , 2005, Kidney international.

[26]  Guilin Qiao,et al.  Cardiac hypertrophy in vitamin D receptor knockout mice: role of the systemic and cardiac renin-angiotensin systems. , 2005, American journal of physiology. Endocrinology and metabolism.

[27]  J. Muñoz-Castañeda,et al.  Upregulation of parathyroid VDR expression by extracellular calcium is mediated by ERK1/2-MAPK signaling pathway. , 2010, American journal of physiology. Renal physiology.

[28]  S. Moe,et al.  Management of Secondary Hyperparathyroidism: The Importance and the Challenge of Controlling Parathyroid Hormone Levels without Elevating Calcium, Phosphorus, and Calcium-Phosphorus Product , 2003, American Journal of Nephrology.

[29]  A. Levin,et al.  Vascular calcification in chronic kidney disease. , 2004, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[30]  G. London,et al.  Clinical Outcomes in Secondary Hyperparathyroidism and the Potential Role of Calcimimetics , 2008, NDT plus.

[31]  V. Torregrosa,et al.  The in vitro effect of calcitriol on parathyroid cell proliferation and apoptosis. , 2000, Journal of the American Society of Nephrology : JASN.

[32]  E. Fernández,et al.  Parathyroid function as a determinant of the response to calcitriol treatment in the hemodialysis patient. , 1999, Kidney international.

[33]  E. Nemeth,et al.  The calcium-sensing receptor: a key factor in the pathogenesis of secondary hyperparathyroidism. , 2005, American journal of physiology. Renal physiology.

[34]  F. J. Mendoza,et al.  Direct upregulation of parathyroid calcium-sensing receptor and vitamin D receptor by calcimimetics in uremic rats. , 2009, American journal of physiology. Renal physiology.

[35]  P. Aljama,et al.  Cinacalcet reduces the set point of the PTH-calcium curve. , 2008, Journal of the American Society of Nephrology : JASN.

[36]  P. Raggi,et al.  The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[37]  E. Ogata,et al.  Regression of parathyroid hyperplasia by calcitriol-pulse therapy in patients on long-term dialysis. , 1990, The New England journal of medicine.

[38]  E. Siendones,et al.  The calcimimetic R-568 increases vitamin D receptor expression in rat parathyroid glands. , 2007, American journal of physiology. Renal physiology.

[39]  F. J. Mendoza,et al.  The effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats. , 2008, Kidney international.

[40]  Supplemental Tables,et al.  KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). , 2009, Kidney international. Supplement.

[41]  E. Slatopolsky,et al.  Parathyroid hyperplasia in uremic rats precedes down-regulation of the calcium receptor. , 2001, Kidney international.

[42]  S. Rosansky,et al.  Long-term treatment of secondary hyperparathyroidism with the calcimimetic cinacalcet HCl. , 2005, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[43]  S. Massry Role of parathyroid hormone in the pathogenesis of the uremic manifestations , 1979, Klinische Wochenschrift.

[44]  J. Wetmore,et al.  Effects of cinacalcet and concurrent low-dose vitamin D on FGF23 levels in ESRD. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[45]  E. Ritz,et al.  1,25(OH)2 vitamin D3 inhibits parathyroid cell proliferation in experimental uremia. , 1989, Kidney international.

[46]  R. Vanholder,et al.  Inhibition of calcitriol receptor binding to vitamin D response elements by uremic toxins. , 1995, The Journal of clinical investigation.

[47]  M. Walling Intestinal Ca and phosphate transport: differential responses to vitamin D3 metabolites. , 1977, The American journal of physiology.

[48]  T. Shigematsu,et al.  Serum fibroblast growth factor-23 levels predict the future refractory hyperparathyroidism in dialysis patients. , 2005, Kidney international.

[49]  R. Kitazawa,et al.  Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. , 2010, Kidney international.

[50]  K. Kurokawa,et al.  Decreased 1,25-dihydroxyvitamin D3 receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. , 1993, The Journal of clinical investigation.

[51]  H Takagi,et al.  Molecular genetics of hyperparathyroid disease. , 1996, Current opinion in nephrology and hypertension.

[52]  R. Koerfer,et al.  Vitamin D and vascular calcification , 2007, Current opinion in lipidology.

[53]  Y. Miao,et al.  Endoscopic Total Parathyroidectomy and Partial Parathyroid Tissue Autotransplantation for Patients with Secondary Hyperparathyroidism: A New Surgical Approach , 2009, World Journal of Surgery.

[54]  F. Recio,et al.  Persistent downregulation of calcium-sensing receptor mRNA in rat parathyroids when severe secondary hyperparathyroidism is reversed by an isogenic kidney transplantation. , 2002, Journal of the American Society of Nephrology : JASN.

[55]  A. Teutonico,et al.  Does vitamin D receptor and calcium receptor activation therapy play a role in the histopathologic alterations of parathyroid glands in refractory uremic hyperparathyroidism? , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[56]  M. Fukagawa,et al.  FGF23-parathyroid interaction: implications in chronic kidney disease. , 2010, Kidney international.

[57]  M. Fukagawa,et al.  Cinacalcet effectively reduces parathyroid hormone secretion and gland volume regardless of pretreatment gland size in patients with secondary hyperparathyroidism. , 2010, Clinical journal of the American Society of Nephrology : CJASN.

[58]  A. Felsenfeld,et al.  PTH, FGF-23 and early CKD. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[59]  P. Raggi,et al.  Mortality effect of coronary calcification and phosphate binder choice in incident hemodialysis patients. , 2007, Kidney international.

[60]  N. Chen,et al.  Pathophysiology of Vascular Calcification in Chronic Kidney Disease , 2004, Circulation research.

[61]  M. Ketteler Fetuin-A and extraosseous calcification in uremia , 2005, Current opinion in nephrology and hypertension.

[62]  R. Baron,et al.  Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice. , 1998, Endocrinology.

[63]  G. Barsotti,et al.  Long-term treatment with cinacalcet and conventional therapy reduces parathyroid hyperplasia in severe secondary hyperparathyroidism , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[64]  N. Nagano,et al.  NPS R-568 halts or reverses osteitis fibrosa in uremic rats. , 1998, Kidney international.

[65]  E. Ogata,et al.  Serial evaluation of parathyroid size by ultrasonography is another useful marker for the long-term prognosis of calcitriol pulse therapy in chronic dialysis patients. , 1994, Nephron.

[66]  G. Chertow,et al.  Combined therapy with cinacalcet and low doses of vitamin D sterols in patients with moderate to severe secondary hyperparathyroidism. , 2008, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[67]  L. Quarles,et al.  Development and progression of secondary hyperparathyroidism in chronic kidney disease: lessons from molecular genetics. , 2008, Kidney international.

[68]  S. Libutti,et al.  Deletion of the vitamin D receptor specifically in the parathyroid demonstrates a limited role for the receptor in parathyroid physiology. , 2009, American journal of physiology. Renal physiology.

[69]  I. Narita,et al.  Pretreatment serum FGF-23 levels predict the efficacy of calcitriol therapy in dialysis patients. , 2005, Kidney international.

[70]  M. Wolf,et al.  Postprandial mineral metabolism and secondary hyperparathyroidism in early CKD. , 2008, Journal of the American Society of Nephrology.

[71]  E. Siendones,et al.  Regulation of parathyroid vitamin D receptor expression by extracellular calcium. , 2002, Journal of the American Society of Nephrology : JASN.

[72]  E. Brown Mechanisms underlying the regulation of parathyroid hormone secretion in vivo and in vitro. , 1993, Current opinion in nephrology and hypertension.

[73]  T. Sakaguchi,et al.  Calcimimetic compound upregulates decreased calcium-sensing receptor expression level in parathyroid glands of rats with chronic renal insufficiency. , 2004, Journal of the American Society of Nephrology : JASN.

[74]  B. Kiperova The treatment of glomerular disease--a compromise between the standard and the individual approach. , 2003, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[75]  M. Wolf,et al.  Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. , 2003, The New England journal of medicine.

[76]  A. Martín-Malo,et al.  Calcium-sensing receptor expression and parathyroid hormone secretion in hyperplastic parathyroid glands from humans. , 2005, Journal of the American Society of Nephrology : JASN.

[77]  R. Simpson,et al.  Characterization of heart size and blood pressure in the vitamin D receptor knockout mouse , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[78]  J. Delmez,et al.  Suppression of parathyroid hormone secretion in hemodialysis patients by a novel vitamin D analogue: 19-nor-1,25-dihydroxyvitamin D2. , 1998, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[79]  A. Felsenfeld,et al.  Development of parathyroid gland hyperplasia without uremia: role of dietary calcium and phosphate. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[80]  S. Fishbane,et al.  Cinacalcet HCl and concurrent low-dose vitamin D improves treatment of secondary hyperparathyroidism in dialysis patients compared with vitamin D alone: the ACHIEVE study results. , 2008, Clinical journal of the American Society of Nephrology : CJASN.

[81]  A. Macleod,et al.  Clinical Practice Guideline for the Diagnosis, Evaluation, Prevention, and Treatment of Chronic Kidney Disease- Mineral and Bone Disorder (CKD-MBD) , 2009 .

[82]  J. Delmez,et al.  Pathogenesis of secondary hyperparathyroidism. , 1999, Kidney international. Supplement.

[83]  G. Eknoyan,et al.  Bone metabolism and disease in chronic kidney disease , 2003 .

[84]  T. Sakaguchi,et al.  Direct injection of calcitriol or its analog into hyperplastic parathyroid glands induces apoptosis of parathyroid cells. , 2006, Kidney international. Supplement.

[85]  Sharon M Moe,et al.  Mechanisms of vascular calcification in chronic kidney disease. , 2008, Journal of the American Society of Nephrology : JASN.

[86]  E. Bedrick,et al.  Mortality risk among hemodialysis patients receiving different vitamin D analogs. , 2006, Kidney international.

[87]  David A. Martin,et al.  Can calcimimetics inhibit parathyroid hyperplasia? Evidence from preclinical studies. , 2007, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[88]  P. Raggi,et al.  Study design and subject baseline characteristics in the ADVANCE Study: effects of cinacalcet on vascular calcification in haemodialysis patients. , 2010, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[89]  E. Slatopolsky,et al.  Decreased calcium-sensing receptor expression in hyperplastic parathyroid glands of uremic rats: role of dietary phosphate. , 1999, Kidney international.

[90]  L. Schurgers,et al.  The Associations of Fibroblast Growth Factor 23 and Uncarboxylated Matrix Gla Protein With Mortality in Coronary Artery Disease: The Heart and Soul Study , 2010, Annals of Internal Medicine.

[91]  M. Lafage-Proust Does the downregulation of the FGF23 signaling pathway in hyperplastic parathyroid glands contribute to refractory secondary hyperparathyroidism in CKD patients? , 2010, Kidney international.