69
Views
0
CrossRef citations to date
0
Altmetric
Review

Secondary hyperparathyroidism in chronic kidney disease: pathophysiology, current treatments and investigational drugs

, & ORCID Icon
Pages 775-789 | Received 14 Feb 2024, Accepted 13 Jun 2024, Published online: 19 Jun 2024

References

  • Goltzman D, Mannstadt M, Marcocci C. Physiology of the calcium-parathyroid hormone-vitamin D Axis. Vit D Clinic Med. 2018;50:1–13.
  • Habener JF. Regulation of parathyroid-hormone secretion and biosynthesis. Annu Rev Physiol. 1981;43(1):211–223. doi: 10.1146/annurev.ph.43.030181.001235
  • Wein MN, Kronenberg HM. Regulation of bone remodeling by parathyroid hormone. Cold Spring Harb Perspect Med. 2018 Aug;8(8):a031237. doi: 10.1101/cshperspect.a031237
  • Brenza HL, Kimmel-Jehan C, Jehan F, et al. Parathyroid hormone activation of the 25-hydroxyvitamin D3-1alpha-hydroxylase gene promoter. Proc Natl Acad Sci USA. 1998 Feb 17;95(4):1387–1391. doi: 10.1073/pnas.95.4.1387
  • Alexander RT, Dimke H. Effects of parathyroid hormone on renal tubular calcium and phosphate handling. Acta Physiol. 2023 May;238(1). doi: 10.1111/apha.13959
  • McCann LM, Beto J. Roles of calcium-sensing receptor and vitamin D receptor in the pathophysiology of secondary hyperparathyroidism. J Ren Nutr. 2010 May;20(3):141–150. doi: 10.1053/j.jrn.2010.01.004
  • Cunningham J, Locatelli F, Rodriguez M. Secondary hyperparathyroidism: pathogenesis, disease progression, and therapeutic options. Clin J Am Soc Nephrol. 2011 Apr;6(4):913–921. doi: 10.2215/CJN.06040710
  • Levin A, Bakris GL, Molitch M, et al. Prevalence of abnormal serum vitamin D, PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int. 2007 Jan;71(1):31–38. doi: 10.1038/sj.ki.5002009
  • Isakova T, Wahl P, Vargas GS, et al. Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease. Kidney Int. 2011 Jun;79(12):1370–1378. doi: 10.1038/ki.2011.47
  • Magagnoli L, Cozzolino M, Caskey FJ, et al. Association between CKD-MBD and mortality in older patients with advanced CKD—results from the EQUAL study. Nephrol Dialysis Transplantation. 2023 May;38(11):2562–2575. doi: 10.1093/ndt/gfad100
  • Floege J, Kim J, Ireland E, et al. Serum iPTH, calcium and phosphate, and the risk of mortality in a European haemodialysis population. Nephrol Dial Transplant. 2011 Jun;26(6):1948–1955. doi: 10.1093/ndt/gfq219
  • Noordzij M, Korevaar JC, Boeschoten EW, et al. The kidney disease outcomes quality initiative (K/DOQI) guideline for bone metabolism and disease in CKD: association with mortality in dialysis patients. Am J Kidney Diseases. 2005;46(5):925–932. doi: 10.1053/j.ajkd.2005.08.013
  • Tentori F, Blayney MJ, Albert JM, et al. Mortality risk for dialysis patients with different levels of serum calcium, phosphorus, and PTH: the dialysis outcomes and practice patterns study (DOPPS). Am J Kidney Dis. 2008 Sep;52(3):519–530. doi: 10.1053/j.ajkd.2008.03.020
  • Kovesdy CP, Ahmadzadeh S, Anderson JE, et al. Secondary hyperparathyroidism is associated with higher mortality in men with moderate to severe chronic kidney disease. Kidney Int. 2008 Jun;73(11):1296–1302. doi: 10.1038/ki.2008.64
  • Geng S, Kuang Z, Peissig PL, et al. Parathyroid hormone independently predicts fracture, vascular events, and death in patients with stage 3 and 4 chronic kidney disease. Osteoporos Int. 2019 Oct;30(10):2019–2025. doi: 10.1007/s00198-019-05033-3
  • Group KDIGOKC-MW. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. 2009;76:S1–S130.
  • Group KDIGOKC-MUW. KDIGO 2017 clinical practice guideline update for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int Suppl. 2017 Jul;7(1):1–59. doi: 10.1016/j.kisu.2017.04.001
  • Hassan A, Khalaily N, Kilav-Levin R, et al. Molecular mechanisms of parathyroid disorders in chronic kidney disease. Metabolites. 2022 Feb;12(2):111. doi: 10.3390/metabo12020111
  • Brown EM, Gamba G, Riccardi D, et al. Cloning And characterization of an extracellular Ca2±sensing receptor from bovine parathyroid. Nature. 1993 Dec;366(6455):575–580. doi: 10.1038/366575a0
  • Hofer AM, Brown EM. Extracellular calcium sensing and signalling. Nat Rev Mol Cell Biol. 2003 Jul;4(7):530–538. doi: 10.1038/nrm1154
  • Chavez-Abiega S, Mos I, Centeno PP, et al. Sensing extracellular calcium - an insight into the structure and function of the calcium-sensing receptor (CaSR). Calcium Signaling, 2nd Ed. 2020;1131:1031–1063.
  • Centeno PP, Herberger A, Mun HC, et al. Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion. Nat Commun. 2019 Oct 10;10(1). doi: 10.1038/s41467-019-12399-9
  • Chen RA, Goodman WG. Role of the calcium-sensing receptor in parathyroid gland physiology. Am J Physiol Renal Physiol. 2004 Jun;286(6):F1005–F1011. doi: 10.1152/ajprenal.00013.2004
  • Kifor O, Moore FD, Wang P, et al. Reduced immunostaining for the extracellular Ca sensing receptor in primary and uremic secondary hyperparathyroidism. J Clin Endocrinol Metab. 1996 Apr;81(4):1598–1606. doi: 10.1210/jc.81.4.1598
  • Brown AJ, Zhong M, Finch J, et al. Rat calcium-sensing receptor is regulated by vitamin D but not by calcium. Am J Physiol-Renal Fluid And Electrolyte Physiol. 1996 Mar;270(3):F454–F460. doi: 10.1152/ajprenal.1996.270.3.F454
  • Fetahua IS, Hummel DM, Manhardt T, et al. Regulation of the calcium-sensing receptor expression by 1,25-dihydroxyvitamin D3, interleukin-6, and tumor necrosis factor alpha in colon cancer cells. J Steroid Biochem Mol Biol. 2014 Oct;144:228–231. doi: 10.1016/j.jsbmb.2013.10.015
  • Canaff L, Hendy GN. Human calcium-sensing receptor gene - vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J Biol Chem. 2002 Aug;277(33):30337–30350. doi: 10.1074/jbc.M201804200
  • LaClair RE, Hellman RN, Karp SL, et al. Prevalence of calcidiol deficiency in CKD: a cross-sectional study across latitudes in the United States. Am J Kidney Diseases. 2005 Jun;45(6):1026–1033. doi: 10.1053/j.ajkd.2005.02.029
  • Nitta K, Nagano N, Tsuchiya K. Fibroblast growth factor 23/Klotho axis in chronic kidney disease. Nephron Clin Pract. 2014 Dec;128(1–2):1–10. doi: 10.1159/000365787
  • Baker AR, McDonnell DP, Hughes M, et al. Cloning and expression of full-length cDNA encoding human vitamin D receptor. Proc Natl Acad Sci, USA. 1988 May;85(10):3294–3298. doi: 10.1073/pnas.85.10.3294
  • Gallieni M, Cozzolino M, Fallabrino G, et al. Vitamin D: physiology and pathophysiology. Int J Of Artificial Organs. 2009 Feb;32(2):87–94. doi: 10.1177/039139880903200205
  • Bikle D, Christakos S. New aspects of vitamin D metabolism and action - addressing the skin as source and target. Nat Rev Endocrinol. 2020 Apr;16(4):234–252. doi: 10.1038/s41574-019-0312-5
  • Nishishita T, Okazaki T, Ishikawa T, et al. A negative vitamin D response DNA element in the human parathyroid hormone-related peptide gene binds to vitamin D receptor along with Ku antigen to mediate negative gene regulation by vitamin D. J Biol Chem. 1998 May;273(18):10901–10907. doi: 10.1074/jbc.273.18.10901
  • Dusso A, Cozzolino M, Lu Y, et al. 1,25-Dihydroxyvitamin D downregulation of TGFα/EGFR expression and growth signaling: a mechanism for the antiproliferative actions of the sterol in parathyroid hyperplasia of renal failure. J Steroid Biochem Mol Biol. 2004 May;89-90(1–5):507–511. doi: 10.1016/j.jsbmb.2004.03.061
  • Fukuda N, Tanaka H, Tominaga Y, et al. Decreased 1,25-dihydroxyvitamin-D(3) receptor density is associated with a more severe form of parathyroid hyperplasia in chronic uremic patients. J Clin Investig. 1993 Sep;92(3):1436–1443. doi: 10.1172/JCI116720
  • Penido M, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012 Nov;27(11):2039–2048. doi: 10.1007/s00467-012-2175-z
  • Wagner CA. The basics of phosphate metabolism. Nephrol Dialysis Transplantation. 2023;39(2):190–201. doi: 10.1093/ndt/gfad188
  • Bon N, Couasnay G, Bourgine A, et al. Phosphate (Pi)-regulated heterodimerization of the high-affinity sodium-dependent Pi transporters PiT1/Slc20a1 and PiT2/Slc20a2 underlies extracellular Pi sensing independently of Pi uptake. J Biol Chem. 2018 Feb;293(6):2102–2114. doi: 10.1074/jbc.M117.807339
  • Liu SG, Quarles LD. How fibroblast growth factor 23 works. J Am Soc Nephrol. 2007 Jun;18(6):1637–1647. doi: 10.1681/ASN.2007010068
  • Urakawa I, Yamazaki Y, Shimada T, et al. Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature. 2006 Dec;444(7120):770–774. doi: 10.1038/nature05315
  • Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Investig. 2007 Dec;117(12):4003–4008. doi: 10.1172/JCI32409
  • Krajisnik T, Bjorklund P, Marsel R, et al. Fibroblast growth factor-23 regulates parathyroid hormone and 1α-hydroxylase expression in cultured bovine parathyroid cells. J Endocrinol. 2007 Oct;195(1):125–131. doi: 10.1677/JOE-07-0267
  • Canalejo R, Canalejo A, Martinez-Moreno JM, et al. FGF23 fails to inhibit uremic parathyroid glands. J Am Soc Nephrol. 2010 Jul;21(7):1125–1135. doi: 10.1681/ASN.2009040427
  • Galitzer H, Ben-Dov IZ, Silver J, et al. Parathyroid cell resistance to fibroblast growth factor 23 in secondary hyperparathyroidism of chronic kidney disease. Kidney Int. 2010 Feb;77(3):211–218. doi: 10.1038/ki.2009.464
  • Komaba H, Goto S, Fujii H, et al. Depressed expression of Klotho and FGF receptor 1 in hyperplastic parathyroid glands from uremic patients. Kidney Int. 2010 Feb;77(3):232–238. doi: 10.1038/ki.2009.414
  • Kawakami K, Takeshita A, Furushima K, et al. Persistent fibroblast growth factor 23 signalling in the parathyroid glands for secondary hyperparathyroidism in mice with chronic kidney disease. Sci Rep. 2017 Jan 17;7(1):40534. doi: 10.1038/srep40534
  • Sela-Brown A, Silver J, Brewer G, et al. Identification of AUF1 as a parathyroid hormone mRNA 3′-untranslated region-binding protein that determines parathyroid hormone mRNA stability. J Biol Chem. 2000 Mar;275(10):7424–7429. doi: 10.1074/jbc.275.10.7424
  • Nechama M, Ben-Dov IZ, Briata P, et al. The mRNA decay promoting factor K-homology splicing regulator protein post-transcriptionally determines parathyroid hormone mRNA levels. FASEB J. 2008 Oct;22(10):3458–3468. doi: 10.1096/fj.08-107250
  • Nechama M, Uchida T, Yosef-Levi IM, et al. The peptidyl-prolyl isomerase Pin1 determines parathyroid hormone mRNA levels and stability in rat models of secondary hyperparathyroidism. J Clin Investig. 2009 Oct;119(10):3102–3114. doi: 10.1172/JCI39522
  • Shilo V, Ben-Dov IZ, Nechama M, et al. Parathyroid-specific deletion of dicer-dependent microRnas abrogates the response of the parathyroid to acute and chronic hypocalcemia and uremia. FASEB J. 2015 Sep;29(9):3964–3976. doi: 10.1096/fj.15-274191
  • Shilo V, Levi IMY, Abel R, et al. Let-7 and MicroRNA-148 regulate parathyroid hormone levels in secondary hyperparathyroidism. J Am Soc Nephrol. 2017 Aug;28(8):2353–2363. doi: 10.1681/ASN.2016050585
  • Wang Q, Palnitkar S, Parfitt AM. Parathyroid cell proliferation in the rat: Effect of age and of phosphate administration and recovery. Endocrinology. 1996 Nov;137(11):4558–4562. doi: 10.1210/endo.137.11.8895317
  • Tominaga Y, Kohara S, Namii Y, et al. Clonal analysis of nodular parathyroid hyperplasia in renal hyperparathyroidism. World J Surg. 1996 Sep;20(7):744–752. doi: 10.1007/s002689900113
  • Tokumoto M, Tsuruya K, Fukuda K, et al. Reduced p21, p27 and vitamin D receptor in the nodular hyperplasia in patients with advanced secondary hyperparathyroidism. Kidney Int. 2002 Oct;62(4):1196–1207. doi: 10.1111/j.1523-1755.2002.kid585.x
  • Arcidiacono MV, Yang J, Fernandez E, et al. Parathyroid-specific epidermal growth factor-receptor inactivation prevents uremia-induced parathyroid hyperplasia in mice. Nephrol Dialysis Transplantation. 2015 Mar;30(3):434–440. doi: 10.1093/ndt/gfu318
  • Volovelsky O, Cohen G, Kenig A, et al. Phosphorylation of ribosomal protein S6 mediates mammalian target of rapamycin complex 1-induced parathyroid cell proliferation in secondary hyperparathyroidism. J Am Soc Nephrol. 2016 Apr;27(4):1091–1101. doi: 10.1681/ASN.2015040339
  • Zhang QA, Qiu JS, Li HM, et al. Cyclooxygenase 2 promotes parathyroid hyperplasia in ESRD. J Am Soc Nephrol. 2011 Apr;22(4):664–672. doi: 10.1681/ASN.2010060594
  • Lou LM, Caverni A, Gimeno JA, et al. Dietary intervention focused on phosphate intake in hemodialysis patients with hyperphosphatemia. Clin Nephrol. 2012 Jun;77(6):476–483.
  • Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet. 2013 Oct;382(9900):1268–1277. doi: 10.1016/S0140-6736(13)60897-1
  • Pergola PE, Rosenbaum DP, Yang Y, et al. A randomized trial of tenapanor and phosphate binders as a dual-mechanism treatment for hyperphosphatemia in patients on maintenance dialysis (AMPLIFY). J Am Soc Nephrol. 2021 Jun;32(6):1465–1473. doi: 10.1681/ASN.2020101398
  • Lin T, Al-Makki A, Shepler B. Tenapanor: a new treatment option for hyperphosphatemia in end stage kidney disease. J Pharm Pharm Sci. 2022;25:77–83. doi: 10.18433/jpps32284
  • Daugirdas JT. Removal of phosphorus by hemodialysis. Semin Dial. 2015 Nov;28(6):620–623. doi: 10.1111/sdi.12439
  • Memmos DE, Eastwood JB, Talner LB, et al. Double-blind trial of oral 1,25-dihydroxy vitamin-D3 Versus placebo in asymptomatic hyperparathyroidism in patients receiving maintenance hemodialysis. Br Med J. 1981;282(6280):1919–1924. doi: 10.1136/bmj.282.6280.1919
  • Galassi A, Ciceri P, Porata G, et al. Current treatment options for secondary hyperparathyroidism in patients with stage 3 to 4 chronic kidney disease and vitamin D deficiency. Expert Opin Drug Saf. 2021 Nov;20(11):1333–1349. doi: 10.1080/14740338.2021.1931117
  • Cuppari L, Garcia-Lopes MG. Hypovitaminosis D in chronic kidney disease patients: prevalence and treatment. J Ren Nutr. 2009 Jan;19(1):38–43. doi: 10.1053/j.jrn.2008.10.005
  • Bischoff-Ferrari HA, Dawson-Hughes B, Stöcklin E, et al. Oral supplementation with 25(OH)D3 versus vitamin D3: Effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity. J Bone Mineral Res. 2012 Jan;27(1):160–169. doi: 10.1002/jbmr.551
  • Sprague SM, Crawford PW, Melnick JZ, et al. Use of extended-release calcifediol to treat secondary hyperparathyroidism in stages 3 and 4 chronic kidney disease. Am J Nephrol. 2016;44(4):316–325. doi: 10.1159/000450766
  • Martin KJ, González EA, Gellens M, et al. 19-nor-1-α-25-dihydroxyvitamin D2 (Paricalcitol) safely and effectively reduces the levels of intact parathyroid hormone in patients on hemodialysis. J Am Soc Nephrol. 1998 Aug;9(8):1427–1432. doi: 10.1681/ASN.V981427
  • Frazao JM, Elangovan L, Maung HM, et al. Intermittent doxercalciferol (1α-hydroxyvitamin D2) therapy for secondary hyperparathyroidism. Am J Kidney Diseases. 2000 Sep;36(3):550–561. doi: 10.1053/ajkd.2000.16193
  • Kazama JJ, Maruyama H, Narita I, et al. Maxacalcitol is a possible less phosphatemic vitamin D analog. Ther Apher Dial. 2005 Aug;9(4):352–354. doi: 10.1111/j.1744-9987.2005.00296.x
  • Nemeth EF, Fox J. Calcimimetic compounds: a direct approach to controlling plasma levels of parathyroid hormone in hyperparathyroidism. Trends Endocrinol Metab. 1999 Mar;10(2):66–71. doi: 10.1016/S1043-2760(98)00119-2
  • Block GA, Martin KJ, de Francisco ALM, et al. Cinacalcet for secondary hyperparathyroidism in patients receiving hemodialysis. N Engl J Med. 2004 Apr;350(15):1516–1525. doi: 10.1056/NEJMoa031633
  • Block GA, Bushinsky DA, Cunningham J, et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism two randomized clinical trials. JAMA-J Am Med Assoc. 2017 Jan;317(2):146–155. doi: 10.1001/jama.2016.19456
  • Hou YC, Zheng CM, Chiu HW, et al. Role of calcimimetics in treating bone and mineral disorders related to chronic kidney disease. Pharmaceuticals. 2022 Aug;15(8):952. doi: 10.3390/ph15080952
  • Franceschini N, Joy MS, Kshirsagar A. Cinacalcet HCI: a calcimimetic agent for the management of primary and secondary hyperparathyroidism. Expert Opin Investig Drugs. 2003 Aug;12(8):1413–1421. doi: 10.1517/13543784.12.8.1413
  • Ballinger AE, Palmer SC, Nistor I, et al. Calcimimetics for secondary hyperparathyroidism in chronic kidney disease patients. Cochrane Database Syst Rev. 2014;2014(12). doi: 10.1002/14651858.CD006254.pub2
  • Harris RZ, Salfi M, Posvar E, et al. Pharmacokinetics of desipramine HCl when administered with cinacalcet HCl. Eur J Clin Pharmacol. 2007 Feb;63(2):159–163. doi: 10.1007/s00228-006-0129-8
  • Block GA, Bushinsky DA, Cheng SF, et al. Effect Of etelcalcetide vs cinacalcet on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism a randomized clinical trial. JAMA-J Am Med Assoc. 2017 Jan;317(2):156–164. doi: 10.1001/jama.2016.19468
  • Fukagawa M, Shimazaki R, Akizawa T, et al. Head-to-head comparison of the new calcimimetic agent evocalcet with cinacalcet in Japanese hemodialysis patients with secondary hyperparathyroidism. Kidney Int. 2018 Oct;94(4):818–825. doi: 10.1016/j.kint.2018.05.013
  • Ni ZH, Liang XL, Wu CC, et al. Comparison of the oral calcimimetics evocalcet and cinacalcet in east asian patients on hemodialysis with secondary hyperparathyroidism. Kidney Int Rep. 2023 Nov;8(11):2294–2306. doi: 10.1016/j.ekir.2023.08.034
  • Sato H, Murakami S, Horii Y, et al. Upacicalcet is a novel secondary hyperparathyroidism drug that targets the amino acid binding site of calcium-sensing receptor. Mol Pharmacol. 2022 Oct;102(4):183–195. doi: 10.1124/molpharm.122.000522
  • Shigematsu T, Koiwa F, Isaka Y, et al. Efficacy and safety of upacicalcet in hemodialysis patients with secondary hyperparathyroidism a randomized placebo-controlled trial. CJASN. 2023 Sep;18(10):1300–1309. doi: 10.2215/CJN.0000000000000253
  • Lafrance JP, Cardinal H, Leblanc M, et al. Effect of cinacalcet availability and formulary listing on parathyroidectomy rate trends. BMC Nephrol. 2013 May 14;14(1). doi: 10.1186/1471-2369-14-100
  • Cianciolo G, Tondolo F, Barbuto S, et al. A roadmap to parathyroidectomy for kidney transplant candidates. Clin Kidney J. 2022 Jul;15(8):1459–1474. doi: 10.1093/ckj/sfac050
  • Lorenz K, Bartsch DK, Sancho JJ, et al. Surgical management of secondary hyperparathyroidism in chronic kidney disease—a consensus report of the European society of endocrine surgeons. Langenbecks Arch Surg. 2015 Dec;400(8):907–927. doi: 10.1007/s00423-015-1344-5
  • Hiramitsu T, Hasegawa Y, Futamura K, et al. Treatment for secondary hyperparathyroidism focusing on parathyroidectomy. Front Endocrinol. 2023 Apr 14;14. doi: 10.3389/fendo.2023.1169793
  • Dulfer RR, Koh EY, van der Plas WY, et al. Parathyroidectomy versus cinacalcet for tertiary hyperparathyroidism; a retrospective analysis. Langenbecks Arch Surg. 2019 Feb;404(1):71–79. doi: 10.1007/s00423-019-01755-4
  • Koh EY, van der Plas WY, Dulfer RR, et al. Outcomes of parathyroidectomy versus calcimimetics for secondary hyperparathyroidism and kidney transplantation: a propensity-matched analysis. Langenbecks Arch Surg. 2020 Sep;405(6):851–859. doi: 10.1007/s00423-020-01953-5
  • van der Plas WY, Dulfer RR, Engelsman AF, et al. Effect of parathyroidectomy and cinacalcet on quality of life in patients with end-stage renal disease-related hyperparathyroidism: a systematic review. Nephrol Dialysis Transplantation. 2017 Nov;32(11):1902–1908. doi: 10.1093/ndt/gfx044
  • Narayan R, Perkins RM, Berbano EP, et al. Parathyroidectomy versus cinacalcet hydrochloride-based medical therapy in the management of hyperparathyroidism in ESRD: a cost utility analysis. Am J Kidney Diseases. 2007 Jun;49(6):801–813. doi: 10.1053/j.ajkd.2007.03.009
  • Komaba H, Moriwaki K, Goto S, et al. Cost-effectiveness of cinacalcet hydrochloride for hemodialysis patients with severe secondary hyperparathyroidism in Japan. Am J Kidney Diseases. 2012 Aug;60(2):262–271. doi: 10.1053/j.ajkd.2011.12.034
  • Wang AY, Lo WK, Cheung SC, et al. Parathyroidectomy versus oral cinacalcet on cardiovascular parameters in peritoneal dialysis patients with advanced secondary hyperparathyroidism (PROCEED): a randomized trial. Nephrol Dial Transplant. 2023 Jul 31;38(8):1823–1835. doi: 10.1093/ndt/gfad043
  • Wang AY, Tang TK, Yau YY, et al. Impact Of parathyroidectomy versus oral cinacalcet on bone mineral density in patients on peritoneal dialysis with advanced secondary hyperparathyroidism: the PROCEED pilot randomized trial. Am J Kidney Dis. 2024 Apr;83(4):456–466.
  • Fukagawa M, Kitaoka M, Tominaga Y, et al. Guidelines for percutaneous ethanol injection therapy of the parathyroid glands in chronic dialysis patients. Nephrol Dial Transplant. 2003 Jun;18(Suppl 3):iii31–3. doi: 10.1093/ndt/gfg1008
  • Koiwa F, Hasegawa T, Tanaka R, et al. Indication and efficacy of PEIT in the management of secondary hyperparathyroidism. NDT Plus. 2008 Aug;1(Suppl 3):iii14–iii17. doi: 10.1093/ndtplus/sfn081
  • Fernández-Martín JL, Carrero JJ, Benedik M, et al. COSMOS: the dialysis scenario of CKD-MBD in Europe. Nephrol Dialysis Transplantation. 2013 Jul;28(7):1922–1935. doi: 10.1093/ndt/gfs418
  • Cozzolino M, Shilov E, Li Z, et al. Pattern Of laboratory parameters and management of secondary hyperparathyroidism in countries of Europe, Asia, the Middle East, and North America. Adv Ther. 2020 Jun;37(6):2748–2762. doi: 10.1007/s12325-020-01359-1
  • Sampson M, Faria N, Powell JJ, et al. Efficacy and safety of PT20, an iron-based phosphate binder, for the treatment of hyperphosphataemia: a randomized, double-blind, placebo-controlled, dose-ranging, Phase IIb study in patients with haemodialysis-dependent chronic kidney disease. Nephrol Dialysis Transplantation. 2021 Aug;36(8):1399–1407. doi: 10.1093/ndt/gfaa116
  • Wu-Wong JR, Chen YW, Wong JT, et al. Preclinical studies of VS-505: a non-absorbable highly effective phosphate binder. Br J Pharmacol. 2016 Jul;173(14):2278–2289. doi: 10.1111/bph.13510
  • Gan L, Zhuang B, Yang J, et al. ABSTRACT: SA-PO173: a dose escalation study to evaluate the tolerability, safety, and efficacy of VS-505 In hemodialysis patients with hyperphosphatemia. J Am Soc Nephrol. 2022;33(11S):650–650. doi: 10.1681/ASN.20223311S1650b
  • Zhuang B, Gan LY, Liu B, et al. Tolerability, safety, and efficacy of a novel phosphate binder VS-505 (AP301): a Phase 2 dose-escalation and dose-ranging study in patients undergoing maintenance hemodialysis. Nephrol Dialysis Transplantation. 2024 Mar. doi: 10.1093/ndt/gfae053
  • China’s NMPA clears phase 3 IND application for alebund pharmaceutical’s AP301, a new-generation iron-based phosphate binder, to treat hyperphosphatemia in dialysis patients. 2023 cited 2024 Jan 22. Available from: https://www.lillyasiaventures.com/blog/china-s-nmpa-clears-phase-3-ind-application-for-alebund-pharmaceutical-s
  • Tsuboi Y, Ohtomo S, Ichida Y, et al. EOS789, a novel pan-phosphate transporter inhibitor, is effective for the treatment of chronic kidney disease-mineral bone disorder. Kidney Int. 2020 Aug;98(2):343–354. doi: 10.1016/j.kint.2020.02.040
  • Tanifuji K, Shiozaki Y, Koike M, et al. Effects of EOS789, a novel pan-phosphate transporter inhibitor, on phosphate metabolism: comparison with a conventional phosphate binder. J Med Invest. 2023 Feb;70(1–2):260–270. doi: 10.2152/jmi.70.260
  • Gallant KMH, Stremke ER, Trevino LL, et al. EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients. Kidney Int. 2021 May;99(5):1225–1233. doi: 10.1016/j.kint.2020.09.035
  • Alebund Reports Update for AP306 (EOS789), a First-in-Class Pan-inhibitor of Sodium-dependent Phosphate Transporters. From a Completed Phase II clinical trial in patients with hyperphosphatemia on hemodialysis 2023. cited 2024 Jan 22. Available from: https://www.prnewswire.com/news-releases/alebund-reports-update-for-ap306-eos789-a-first-in-class-pan-inhibitor-of-sodium-dependent-phosphate-transporters-from-a-completed-phase-ii-clinical-trial-in-patients-with-hyperphosphatemia-on-hemodialysis-302013538.html
  • Locatelli F, Dimkovic N, Spasovski G. Colestilan for the treatment of hyperphosphatemia in chronic kidney disease patients on dialysis. Expert Rev Endocrinol Metab. 2015;10(2):131–142. doi: 10.1586/17446651.2015.1009368
  • Negri AL, Brandemburg VM. Calcitriol resistance in hemodialysis patients with secondary hyperparathyroidism. Int Urol Nephrol. 2014 Jun;46(6):1145–1151. doi: 10.1007/s11255-013-0637-2
  • Shevde NK, Plum LA, Clagett-Dame M, et al. A potent analog of 1α,25-dihydroxyvitamin D3 selectively induces bone formation. Proc Natl Acad Sci, USA. 2002 Oct;99(21):13487–13491. doi: 10.1073/pnas.202471299
  • Zella JB, Plum LA, Plowchalk DR, et al. Novel, selective Vitamin D analog suppresses parathyroid hormone in uremic animals and postmenopausal women. Am J Nephrol. 2014;39(6):476–483. doi: 10.1159/000362846
  • Pandey R, Zella JB, Zhu JG, et al. Pharmacokinetics of a new oral vitamin D receptor activator (2-methylene-19-nor-(20S)-1α,25-dihydroxyvitamin D3) in patients with chronic kidney disease and secondary hyperparathyroidism on hemodialysis. Drugs In R&D. 2017 Dec;17(4):597–605. doi: 10.1007/s40268-017-0210-z
  • DeLuca HF, Bedale W, Binkley N, et al. The vitamin D analogue 2MD increases bone turnover but not BMD in postmenopausal women with osteopenia: results of a 1-year phase 2 double-blind, placebo-controlled, randomized clinical trial. J Bone Miner Res. 2011 Mar;26(3):538–545. doi: 10.1002/jbmr.256
  • Pandey R, Zella J, Clagett-Dame M, et al. Use of 2MD, a novel oral calcitriol analog, in hemodialysis patients with secondary hyperparathyroidism. Am J Nephrol. 2016;43(3):213–220. doi: 10.1159/000445756
  • Thadhani R, Zella JB, Knutson DC, et al. 2MD (DP001), A single agent in the management of hemodialysis patients: a randomized trial. Am J Nephrol. 2017;45(1):40–48. doi: 10.1159/000452680
  • Ma JN, Owens M, Gustafsson M, et al. Characterization of highly efficacious allosteric agonists of the human calcium-sensing receptor. J Pharmacol Exp Ther. 2011 Apr;337(1):275–284. doi: 10.1124/jpet.110.178194
  • Leach K, Gregory KJ, Kufareva I, et al. Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor. Cell Res. 2016 May;26(5):574–592. doi: 10.1038/cr.2016.36
  • Dinh L, DeBono A, Keller AN, et al. Development of AC265347-inspired calcium-sensing receptor ago-positive allosteric modulators. ChemMedchem. 2021 Nov;16(22):3451–3462. doi: 10.1002/cmdc.202100368
  • Bone disease - 1. NDT Plus. 2009;2(suppl_2):ii2065–ii2065. doi: 10.1093/ndtplus/2.s2.32
  • Wilson BC, Patterson MS. The physics, biophysics and technology of photodynamic therapy. Phys Med Biol. 2008 May;53(9):R61–R109. doi: 10.1088/0031-9155/53/9/R01
  • Wachowska M, Muchowicz A, Firczuk M, et al. Aminolevulinic Acid (ALA) as a prodrug in photodynamic therapy of cancer. Molecules. 2011 May;16(5):4140–4164. doi: 10.3390/molecules16054140
  • Prosst RL, Willeke F, Schroeter L, et al. Fluorescence-guided minimally invasive parathyroidectomy: a novel detection technique for parathyroid glands. Surg Endosc. 2006 Sep;20(9):1488–1492. doi: 10.1007/s00464-005-0471-4
  • Miyakogawa T, Kanai G, Tatsumi R, et al. Feasibility of photodynamic therapy for secondary hyperparathyroidism in chronic renal failure rats. Clin Exp Nephrol. 2017 Aug;21(4):563–572. doi: 10.1007/s10157-016-1335-z
  • Wen Y, Zeng LY, Chen QT, et al. RNA-Seq-based transcriptomics analysis during the photodynamic therapy of primary cells in secondary hyperparathyroidism. Photochem Photobiol Sci. 2023 Apr;22(4):905–917. doi: 10.1007/s43630-023-00361-0
  • Martins WK, Belotto R, Silva MN, et al. Autophagy regulation and photodynamic therapy: insights to improve outcomes of cancer treatment. Front Oncol. 2021 Jan 10;10. doi: 10.3389/fonc.2020.610472
  • Zeng LY, Zou QY, Huang P, et al. Inhibition of autophagy with Chloroquine enhanced apoptosis induced by 5-aminolevulinic acid-photodynamic therapy in secondary hyperparathyroidism primary cells and organoids. Biomed Pharmacother. 2021 Oct;142:111994. doi: 10.1016/j.biopha.2021.111994
  • Friedrich M, Pracht K, Mashreghi MF, et al. The role of the miR-148/-152 family in physiology and disease. Eur J Immunol. 2017 Dec;47(12):2026–2038. doi: 10.1002/eji.201747132
  • Melkman-Zehavi T, Oren R, Kredo-Russo S, et al. miRNAs control insulin content in pancreatic β-cells via downregulation of transcriptional repressors. Embo J. 2011 Mar;30(5):835–845. doi: 10.1038/emboj.2010.361
  • Deng BP, Tang X, Wang Y. Role of microRNA-129 in cancer and non-cancerous diseases (Review). Exp Ther Med. 2021 Sep;22(3). doi: 10.3892/etm.2021.10350
  • Xu MZ, Li H, Bai YF, et al. miR-129 blocks secondary hyperparathyroidism-inducing Fgf23/αKlotho signaling in mice with chronic kidney disease. Am J Med Sci. 2021 May;361(5):624–634. doi: 10.1016/j.amjms.2020.09.013
  • Chesnaye NC, Carrero JJ, Hecking M, et al. Differences in the epidemiology, management and outcomes of kidney disease in men and women. Nat Rev Nephrol. 2024 Jan;20(1):7–20. doi: 10.1038/s41581-023-00784-z
  • Galassi A, Ciceri P, Fasulo E, et al. Management of secondary hyperparathyroidism in chronic kidney disease: a focus on the elderly. Drugs Aging. 2019 Oct;36(10):885–895. doi: 10.1007/s40266-019-00696-3
  • Magagnoli L, Galassi A, Cozzolino M. Beyond vessels and bones: can CKD-MBD treatment improve uraemic subjects’ minds? Nephrol Dialysis Transplantation. 2022 Oct;37(11):2039–2041. doi: 10.1093/ndt/gfac176

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.