Skip to main content

Advertisement

Log in

Bone Mineral Disease After Kidney Transplantation

  • Review
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Chronic kidney disease-mineral bone disorder (CKD-MBD) after kidney transplantation is a mix of pre-existing disorders and new alterations. The final consequences are reflected fundamentally as abnormal mineral metabolism (hypercalcemia, hypophosphatemia) and bone alterations [high or low bone turnover disease (as fibrous osteitis or adynamic bone disease), an eventual compromise of bone mineralization, decrease bone mineral density and bone fractures]. The major cause of post-transplantation hypercalcemia is the persistence of severe secondary hyperparathyroidism, and treatment options include calcimimetics or parathyroidectomy. On turn, hypophosphatemia is caused by both the persistence of high blood levels of PTH and/or high blood levels of FGF23, with its correction being very difficult to achieve. The most frequent bone morphology alteration is low bone turnover disease, while high-turnover osteopathy decreases in frequency after transplantation. Although the pathogenic mechanisms of these abnormalities have not been fully clarified, the available evidence suggests that there are a number of factors that play a very important role, such as immunosuppressive treatment, persistently high levels of PTH, vitamin D deficiency and hypophosphatemia. Fracture risk is four-fold higher in transplanted patients compared to general population. The most relevant risk factors for fracture in the kidney transplant population are diabetes mellitus, female sex, advanced age (especially > 65 years), dialysis vintage, high PTH levels and low phosphate levels, osteoporosis, pre-transplant stress fracture and high doses or prolonged steroids therapy. Treatment alternatives for CKD-MBD after transplantation include minimization of corticosteroids, use of calcium and vitamin D supplements, antiresorptives (bisphosphonates or Denosumab) and osteoformers (synthetic parathyroid hormone). As both mineral metabolism and bone disorders lead to increased morbidity and mortality, the presence of these changes after transplantation has to be prevented (if possible), minimized, diagnosed, and treated as soon as possible.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Wolf RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY et al (1999) Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 341(23):1725–1730

    Google Scholar 

  2. Torres A, Lorenzo V, Salido E (2002) Calcium metabolism and skeletal problems after transplantation. J Am Soc Nephrol 13:551–558

    PubMed  Google Scholar 

  3. Weisinger JR, Carlini RG, Rojas E, Bellorin-Font E (2006) Bone disease after renal transplantation. Clin J Am Soc Nephrol 1:1300–1313

    CAS  PubMed  Google Scholar 

  4. Kalantar-Zadeh K, Molnar MZ, Kovesdy CP, Mucsi I, Bunnapradist S (2012) Management of mineral and bone disorder after kidney transplantation. Curr Opin Nephrol Hypertens 21:389–403

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Torres A, Torregrosa JV, Marcen R et al (2016) Mineral metabolism disorders, vertebral fractures and aortic calcifications in stable kidney transplant recipients: The role of gender (EMITRAL study). Nefrologia 36:255–267

    PubMed  Google Scholar 

  6. Evenepoel P, Van der Bergh B, Naesens M, De Jonge H, Bammens B, Claes K et al (2009) Calcium metabolism in the early posttransplantation period. Clin J Am Soc Nephrol 4:665–672

    CAS  PubMed  PubMed Central  Google Scholar 

  7. van der Plas WY, Gomes Neto AW, Berger SP et al (2020) Association of time-updated plasma calcium and phosphate with graft and patient outcomes after kidney transplantation. Am J Transplant. https://doi.org/10.1111/ajt.16457

    Article  PubMed  Google Scholar 

  8. Torregrosa JV, Bergua C, Martínez de Osaba MJ, Oppenheimer F, Campistol JM (2009) Evolution of secondary hyperparathyroidism after kidney transplantation in patients receiving cinacalcet on diálisis. Transplant Proc 41:2396–2398

    CAS  PubMed  Google Scholar 

  9. Evenepoel P, Sprangers B, Lerut E et al (2012) Mineral metabolism in renal transplant recipients discontinuing cinacalcet at the time of transplantation: a prospective observational study. Clin Transplant 26:393–402

    CAS  PubMed  Google Scholar 

  10. Torres A, Rodríguez AP, Concepción MT, García S, Rufino M, Martín B et al (1998) Parathyroid function in long-term renal transplant patients: importance of pre-transplant PTH concentrations. Nephrol Dial Transplant 13:94–97

    PubMed  Google Scholar 

  11. Bouquegneau A, Salam S, Delanaye P, Eastell R, Khwaja A (2016) Bone disease after kidney transplantation. Clin J Am Soc Nephrol 11:1282–1296

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Evenepoel P (2013) Recovery versus persistence of disordered mineral metabolism in kidney transplant recipients. Semin Nephrol 33:191–203

    CAS  PubMed  Google Scholar 

  13. Ozdemir FN, Afsar B, Akgul A, Usluogullari C, Akçay A, Haberal M (2006) Persistent hypercalcemia is a significant risk factor for graft dysfunction in renal transplantation recipients. Transplant Proc 38:480–482

    CAS  PubMed  Google Scholar 

  14. Egbuna OI, Taylor JG, Bushinsky DA (2007) Elevated calcium phosphate product after renal transplantation is a risk factor for graft failure. Clin Transplant 21:558

    PubMed  Google Scholar 

  15. Gwinner W, Suppa S, Mengel M, Hoy L, Kreipe HH, Haller H et al (2005) Early calcification of renal allografts detected by protocol biopsies: causes and clinical implications. Am J Transplant 5:1934–1941

    PubMed  Google Scholar 

  16. Evenepoel P, Lerut E, Naesens M et al (2009) Localization, etiology and impact of calcium phosphate deposits in renal allografts. Am J Transplant 9:2470–2478

    CAS  PubMed  Google Scholar 

  17. Torregrosa JV, Barros X (2013) Management of hypercalcemia after renal transplantation. Nefrologia 33:751–757

    PubMed  Google Scholar 

  18. Serra AL, Schwarz AA, Wick FH (2005) Succesful treatment of hypercalcemia with cinacalcet in renal transplant recipients with persistent hyperparthyroidism. Nephrol Dial Transplant 20:1315–1317

    CAS  PubMed  Google Scholar 

  19. Bergua C, Torregrosa JV, Cofán F, Oppenheimer F (2007) Cinacalcet for the treatment of hypercalcemia in renal transplanted patients with secondary hyperparathyroidism. Transplant Proc 39(7):2254–2255

    CAS  PubMed  Google Scholar 

  20. Kruse AE, Eisenberger U, Frey FL, Mohaupt MG (2007) Effect of cinacalcet cessation in renal transplant recipients with persistent hyperparathyroidism. Nephrol Dial Transplant 22:2362–2365

    CAS  PubMed  Google Scholar 

  21. Schwarz A, Rustien G, Merkel S, Radermacher J, Haller H (2007) Decreased renal transplant function after parathyroidectomy. Nephrol Dial Transplant 22:584–591

    PubMed  Google Scholar 

  22. Yang RL, Freeman K, Reinke CE et al (2012) Tertiary hyperparathyroidism in kidney transplant recipients: characteristics of patients selected for different treatment strategies. Transplantation 94:70–76

    CAS  PubMed  Google Scholar 

  23. Triponez F, Clark OH, Vanrenthergem Y, Evenepoel P (2008) Surgical treatment of persistent hyperparathyroidism after renal transplantation. Ann Surg 248:18–30

    PubMed  Google Scholar 

  24. Cruzado JM, Moreno P, Torregrosa JV et al (2016) A randomized study comparing parathyroidectomy with cinacalcet for treating hypercalcemia in kidney allograft recipients with hyperparathyroidism. J AM Soc Nephrol 27:2487–2494

    CAS  PubMed  Google Scholar 

  25. Torregrosa JV, Felez I, Fuser D (2010) Usefulness of imaging techniques in secondary hyperparathyroidism. Nefrologia 30:158–167

    CAS  PubMed  Google Scholar 

  26. Chen J, Jia X, Kong X et al (2017) Total parathyroidectomy with autotransplantation versus subtotal parathyroidectomy for renal hyperparathyroidism: a systematic review and meta-analysis. Nephrology 22:388–396

    PubMed  Google Scholar 

  27. Liu M-E, Qiu N-C, Zha S-L et al (2017) To assess the effects of parathyroidectomy (TPTX versus TPTX+AT) for secondary hyperparathyroidism in chronic renal failure: a systematic review and meta-analysis. Int J Surg 44:353–362

    CAS  PubMed  Google Scholar 

  28. Fülöp T, Koch CA, Farah Musa AR et al (2018) Targeted surgical parathyroidectomy in end-stage renal disease patients and long-term metabolic control: a single-center experience in the current era. Hemodial Int 22:394–404

    PubMed  Google Scholar 

  29. Levi M (2001) Posttransplant hypophosphatemia. Kidney Int 59:2377–2387

    CAS  PubMed  Google Scholar 

  30. Seeherunvong W, Wolf M (2011) Tertiary excess of fibroblast growth factor 23 and hypophosphatemia following kidney transplantation. Pediatr Transplant 15:37–46

    PubMed  Google Scholar 

  31. Barros X, Torregrosa JV, Martínez de Osaba MJ, Casals G, Paschoalin R, Durán CE et al (2012) EarlierdecreaseofFGF-23andless hypophosphatemiainpreemptivekidneytransplantrecipients. Transplantation 94:830–836

    CAS  PubMed  Google Scholar 

  32. Evenepoel P, Meijers BK, de Jonge H, Naesens M, Bammens B, Claes K et al (2008) Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation. Clin J Am Soc Nephrol 3:1829–1836

    PubMed  PubMed Central  Google Scholar 

  33. Malluche HH, Monier-Faugere MC, Herberth J (2010) Bone disease after renal transplantation. Nat Rev Nephrol 6(32–40):9

    Google Scholar 

  34. Chadban S, Chan M, Fry R et al (2010) The CARI guideline Nutritional management of hypophosphatemia in adult kidney transplant recipients. Nephrology 15:S48-51

    PubMed  Google Scholar 

  35. Caravaca F, Fernandez MA, Ruiz-Calero R et al (1998) Effectos of oral phosphorus supplementation on mineral metabolism of renal transplant recipients. Nephrol Dial Transplant 13:2605–2611

    CAS  PubMed  Google Scholar 

  36. Ambühl PM, Meier D, Wolf B et al (1999) Metabolic aspects of phosphate replacement therapy for hypophosphatemia after renal transplantation: impact on muscular phosphate content, mineral metabolism and acid/base homeostasis. Am J Kidney Dis 34:875–883

    PubMed  Google Scholar 

  37. Riella LV, Rennke HG, Grafals M et al (2011) Hypophosphatemia in kidney transplant recipients: report of acute phosphate nephropathy as a complication of therapy. Am J Kidney Dis 57:641–645

    PubMed  Google Scholar 

  38. Balal M, Paydas S, Seyrek N et al (2005) Dipyridamole for renal phosphate leak in successfully renal transplanted hypophosphatemic patients. Clin Nephrol 63:87–91

    CAS  PubMed  Google Scholar 

  39. Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD (1991) Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 325:544–550

    CAS  PubMed  Google Scholar 

  40. Evenepoel P, Behets GJ, Viaene L, D’Haese PC (2017) Bone histomorphometry in de novo renal transplant recipients indicates a further decline in bone resorption 1 year posttransplantation. Kidney Int 91:469–476

    PubMed  Google Scholar 

  41. Marques IDB, Araujo M, Graciolli FG et al (2019) A randomized trial of zoledronic acid to prevent bone loss in the first year after kidney transplantation. J Am Soc Nephrol 30:355–365

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Keronen S, Martola L, Finne P, Burton IS, Kroger H, Honkanen E (2019) Changes in bone histomorphometry after kidney transplantation. Clin J Am Soc Nephrol 14:894–903

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Patel S, Kwan JT, McCloskey E, McGee G, Thomas G, Johnson D et al (2001) Prevalence and causes of low bone density and fractures in kidney transplant patients. J Bone Miner Res 16:1863–1870

    CAS  PubMed  Google Scholar 

  44. Ketteler M, Block GA, Evenepoel P et al (2017) Executive summary of the 2017 KDIGO chronic kidney disease-mineral and bone disorder (CKD-MBD) guideline update: what’s changed and why it matters. Kidney Int 92(1):26–36

    PubMed  Google Scholar 

  45. Torregrosa JV, Bover J, Cannata-Andia J et al (2011) Spanish society of nephrology recommendations for controlling mineral and bone disorder in chronic kidney disease patients. Nefrologia 31(suppl 1):3–32

    PubMed  Google Scholar 

  46. Brandenburg VM, Politt D, Ketteler M, Fassbender WJ, Heussen N, Westenfeld R et al (2004) Early rapid loss followed by long-term consolidation characterizes the development of lumbar bone mineral density after kidney transplantation. Transplantation 77:1566–1571

    PubMed  Google Scholar 

  47. Torregrosa JV, Campistol JM, Montesinos M, Fenollosa B, Pons F, Martínez de Osaba MJ et al (1995) Factorsinvolvedinthelossofbone mineral density after renal transplantation. Transplant Proc 27:2224–2225

    CAS  PubMed  Google Scholar 

  48. O’Brien CA, Jia D, Plotkin LI, Bellido T, Powers CC, Stewart SA et al (2004) Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength. Endocrinology 145:1835–1841

    PubMed  Google Scholar 

  49. Aroldi A, Tarantino A, Montagnino G, Cesana B, Cocucci C, Ponticelli C (1997) Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients. Transplantation 63:380–386

    CAS  PubMed  Google Scholar 

  50. Singha UK, Jiang Y, Yu S, Luo M, Lu Y, Zhang J et al (2008) Rapamycin inhibits osteoblast proliferation and differentiation in MC3T3-E1 cells and primary mouse bone marrow stromal cells. J Cell Biochem 103:434–446

    CAS  PubMed  Google Scholar 

  51. Kneissel M, Luong-Nguyen NH, Baptist M, Cortesi R, Zumstein- Mecker S, Kossida S et al (2004) Everolimus suppresses cancellous bone loss, bone resorption, and cathepsin K expression by osteoclasts. Bone 35:1144–1156

    CAS  PubMed  Google Scholar 

  52. Bonarek H, Merville P, Bonarek M et al (1999) Reduced parathyroid functional mass after successful kidney transplantation. Kidney Int 56:642–649

    CAS  PubMed  Google Scholar 

  53. Torregrosa JV, Fuster D, Duran CE et al (2015) Set point of calcium in severe secondary hyperparathyroidism is altered and does not change after successful kidney transplantation. Endocrine 48:709–711

    CAS  PubMed  Google Scholar 

  54. Evenepoel P, Claes K, Kuypers D et al (2004) Natural history of parathyroid function andcalcium metabolism after kidney transplantation: a single-centre study. Nephrol Dial Transplant 19:1281–1287

    CAS  PubMed  Google Scholar 

  55. Perrin P, Caillard S, Javier RM et al (2013) Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation. Am J Transplant 13:2653–2663

    CAS  PubMed  Google Scholar 

  56. Almond MK, Kwan JTC, Evans K, Cunningham J (1994) Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 66:52–57

    CAS  PubMed  Google Scholar 

  57. Carlini RG, Rojas E, Weisinger JR, Lopez M, Martinis R, Arminio A et al (2000) Bone disease in patients with long-term renal transplantation and normal renal function. Am J Kidney Dis 36:160–165

    CAS  PubMed  Google Scholar 

  58. Roe SD, Porter CJ, Godber IM, Hosking DJ, Cassidy MJ (2005) Reduced bone mineral density in male renal transplant recipients: evidence for persisting hyperparathyroidism. Osteoporos Int 16:142–148

    PubMed  Google Scholar 

  59. Abdelhadi M, Nordenstrom J (1998) Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab 83:3845–3851

    CAS  PubMed  Google Scholar 

  60. Bergua C, Torregrosa JV, Fuster D, Gutierrez-Dalmau A, Oppenheimer F, Campistol JM (2008) Effect of cinacalcet on hypercalcemia and bone mineral density in renal transplanted patients with secondary hyperparathyroidism. Transplantation 86:413–417

    CAS  PubMed  Google Scholar 

  61. Rojas E, Carlini RG, Clesca P, Arminio A, Suniaga O, De Elguezabal K et al (2003) The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling. Kidney Int 63:1915–1923

    PubMed  Google Scholar 

  62. Naylor KL, Li AH, Lam NN, Hodsman AB, Jamal SA, Garg AX (2013) Fracture risk in kidney transplant recipients: a systematic review. Transplantation 95:1461–1470

    PubMed  Google Scholar 

  63. Sidibe A, Auguste D, Desbiens LC et al (2019) Fracture risk in dialysis and kidney transplanted patients: a systematic review. JBMR Plus 3:45–55

    PubMed  Google Scholar 

  64. Evenepoel P, Claes K, Meijers B et al (2019) Bone mineral density, bone turnover markers, and incident fractures in de novo kidney transplant recipients. Kidney Int 95:1461–1470

    PubMed  Google Scholar 

  65. Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N (2009) Risk of fractures after renal transplantation in the United States. Transplantation 87(12):1846–1851

    PubMed  Google Scholar 

  66. Akaberi S, Simonsen O, Lindergård B, Nyberg G (2008) Can DXA predict fractures in renal transplant patients? Am J Transplant 8(12):2647–2651

    CAS  PubMed  Google Scholar 

  67. Buckley L, Humphrey MB (2018) Glucocorticoid-Induced Osteoporosis. N Engl J Med 379:2547–2556

    PubMed  Google Scholar 

  68. De Sévaux RG, Hoitsma AJ, Corstens FH, Wetzels JF (2002) Treatment with vitamin D and calcium reduces bone loss after renal transplantation: a randomized study. J Am Soc Nephrol 13:1608–1614

    PubMed  Google Scholar 

  69. Torres A, García S, Gómez A, González A, Barrios Y, Concepción MT et al (2004) Treatment with intermittent calcitriol and calcium reduces bone loss after renal transplantation. Kidney Int 65:705–712

    CAS  PubMed  Google Scholar 

  70. Marcén R, del Castillo D, Capdevila L (2009) Achieving chronic kidney disease treatment targets in renal transplant recipients: results from a cross-sectional study in Spain. Transplantation 87(9):1340–1346

    PubMed  Google Scholar 

  71. Cianciolo G, Galassi A, Capelli I et al (2016) Vitamin D in kidney transplant recipients: mechanisms and therapy. Am J Nephrol 43(6):397–407

    CAS  PubMed  Google Scholar 

  72. Maraka S, Kennel KA (2015) Bisphosphonates for the prevention and treatment of osteoporosis. BMJ 351:h3783

    PubMed  Google Scholar 

  73. Wang J, Yao M, Xu JH et al (2016) Bisphosphonates for prevention of osteopenia in kidney-transplant recipients: a systematic review of randomized controlled trials. Osteoporos Int 27:1683–1690

    PubMed  Google Scholar 

  74. Torregrosa JV, Fuster D, Monegal A, Gentil MA, Bravo J, Guirado L et al (2011) Efficacy of low doses of pamidronate in osteopenic patients administered in the early post-renal transplant. Osteoporos Int 22(1):281–287

    CAS  PubMed  Google Scholar 

  75. Torregrosa JV, Fuster D, Gentil MA, Marcen R, Guirado L, Zarraga S et al (2010) Open-label trial: effect of weekly risedronate immediately after transplantation in kidney recipients. Transplantation 89(12):1476–1481

    CAS  PubMed  Google Scholar 

  76. Cummings SR, San Martin J, McClung MR et al (2009) Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Eng J Med 361:756–756

    CAS  Google Scholar 

  77. Jamal S, Ljunggren O, Stehman-Breen C, Cummings SR, McClung MR, Goemaere S et al (2011) Effects of denosumab on fractures and bone mineral density by level of kidney function. J Bone Miner Res 26(8):1829–1835

    CAS  PubMed  Google Scholar 

  78. Bonani M, Frey D, Brockmann J et al (2016) Effect of twice-yearly denosumab on prevention of bone mineral density loss in de novo kidney transplant recipients: a randomized controlled trial. Am J Transplant 16:1882–1891

    CAS  PubMed  Google Scholar 

  79. Bonani M, Frey D, de Rougemont O et al (2017) Infections in De novo kidney transplant recipients treated with the RANKL inhibitor denosumab. Transplantation 101:2139–2145

    CAS  PubMed  Google Scholar 

  80. Palmer SC, Chung EY, McGregor DO et al (2019) Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev. 10(10):CD005015

    PubMed  Google Scholar 

  81. Lindsay R, Krege JH, Marin F, Jin L, Stepan JJ (2016) Teriparatide for osteoporosis importance of the full course. Osteoporos Int 27(8):2395–2410

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Cejka D, Benesch T, Krestan C, Roschger P, Klaushofer K, Pietschmann P et al (2008) Effect of teriparatide on early bone loss after kidney transplantation. Am J Transplant 8:1864–1870

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Josep-Vicent Torregrosa.

Ethics declarations

Disclosure

Josep-Vicent Torregrosa has no conflict of interest, and Ana Carina Ferreira reports personal fees from Amgen and Vifor Pharma, outside the submitted work. David Cucchiari has no conflict of interest. Aníbal Ferreira reports personal fees, grants and participation in advisory boards from Abbvie, Astellas, Amgen, Baxter, Merck Sharp and Dhome, Mundipharma, Nephrocare-Fresenius Medical Care, Sanofi and Vifor Pharma, outside the submitted work.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Torregrosa, JV., Ferreira, A.C., Cucchiari, D. et al. Bone Mineral Disease After Kidney Transplantation. Calcif Tissue Int 108, 551–560 (2021). https://doi.org/10.1007/s00223-021-00837-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-021-00837-0

Keywords

Navigation