bone diseases; clinical nephrology; hyperparathyroidism; kidney transplantation; mineral metabolism; Minerals; Steroids; Bone Density; Female; Humans; Male; Middle Aged; Prospective Studies; Bone Diseases; Kidney Transplantation/adverse effects; alkaline phosphatases; bone histomorphometry; chronic kidney disease; mineral and bone disorder; parathyroid hormone; tartrate-resistant acid phosphatase; Nephrology; General Medicine
Abstract :
[en] ("[en] BACKGROUND: Knowledge of the effect of kidney transplantation on bone is limited and fragmentary. The aim of this study was to characterize the evolution of bone disease in the first post-transplant year.
METHODS: We performed a prospective, observational cohort study in patients referred for kidney transplantation under a steroid-sparing immunosuppressive protocol. Bone phenotyping was done before, or at the time of, kidney transplantation, and repeated at 12 months post-transplant. The phenotyping included bone histomorphometry, bone densitometry by dual-energy x-ray absorptiometry, and biochemical parameters of bone and mineral metabolism.
RESULTS: Paired data were obtained for 97 patients (median age 55 years; 72% male; 21% of patients had diabetes). Bone turnover remained normal or improved in the majority of patients (65%). Bone histomorphometry revealed decreases in bone resorption (eroded perimeter, mean 4.6% pre- to 2.3% post-transplant; P<0.001) and disordered bone formation (fibrosis, 27% pre- versus 2% post-transplant; P<0.001). Whereas bone mineralization was normal in all but one patient pretransplant, delayed mineralization was seen in 15% of patients at 1 year post-transplant. Hypophosphatemia was associated with deterioration in histomorphometric parameters of bone mineralization. Changes in bone mineral density were highly variable, ranging from -18% to +17% per year. Cumulative steroid dose was related to bone loss at the hip, whereas resolution of hyperparathyroidism was related to bone gain at both spine and hip.
CONCLUSIONS: Changes in bone turnover, mineralization, and volume post-transplant are related both to steroid exposure and ongoing disturbances of mineral metabolism. Optimal control of mineral metabolism may be key to improving bone quality in kidney transplant recipients.
CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Evolution of Bone Histomorphometry and Vascular Calcification Before and After Renal Transplantation, NCT01886950.","[en] ","")
Disciplines :
Laboratory medicine & medical technology Urology & nephrology
Author, co-author :
Jørgensen, Hanne Skou ; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium ; Department of Kidney Diseases, Aarhus University Hospital, Aarhus, Denmark
Behets, Geert ; Laboratory of Pathophysiology, University of Antwerp, Wilrijk, Belgium
Bammens, Bert; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium ; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Claes, Kathleen; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium ; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Meijers, Bjorn; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium ; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Naesens, Maarten ; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium ; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Sprangers, Ben ; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium ; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Kuypers, Dirk R J; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium ; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Cavalier, Etienne ; Centre Hospitalier Universitaire de Liège - CHU > > Service de chimie clinique
D'Haese, Patrick; Laboratory of Pathophysiology, University of Antwerp, Wilrijk, Belgium
Evenepoel, Pieter; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium Pieter.Evenepoel@uzleuven.be ; Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
Language :
English
Title :
Natural History of Bone Disease following Kidney Transplantation.
ERA - European Renal Association – European Dialysis and Transplant Association [GB] Augustinus Foundation [DK]
Funding text :
Financial Disclosure: CUST_FINANCIAL_DISCLOSURE :No data available. BB reports consultancy from Otsuka Pharmaceutical and Baxter; Research Funding: Dept. of Nephrology, Dialysis and Renal Transplantation, Roche, Otsuka Pharma, Amgen, Astellas, and Novartis; and Honoraria: Speaker's fees from Baxter. KC reports support from Astellas, Astra Zeneca, Sanofi, and Alexion; Scientific Advisor or Membership: Alexion, Astellas; and Other Interests/Relationships: speaker's fee from Menarini, and Fresenius Medical Care. BM reports consultancy from Nipro, Astra Zeneca, Baxter, and Bayer Fresenius, Novartis, Vifor Fresenius; Research Funding: Ionis, Bayer, Nipro; Honoraria: Nipro, Fresenius, VIFOR, Baxter; Scientific Advisor or Membership: Editorial board BMC nephrology, editorial board Toxins; and Speakers Bureau: Baxter. EC is consultant for IDS, DiaSorin, Fujirebio, Nittobo. PE reports consultancy from Amgen and Vifor Pharma; Research Funding: Sanofi, ViforFMC; Honoraria: Amgen, Vifor-FMC; Scientific Advisor or Membership: Editorial board Kidney International, NDT; and Speakers Bureau: Amgen, Vifor-FMC. H. Joergensen reports Other Interests/Relationships: Long-term fellowship from the European Renal Association for work within their CKD-MBD working group for 2020. B. Sprangers reports Scientific Advisor or Membership: expert ad hoc for the European Medicines Agency (EMA). D. Kuypers reports Consultancy Agreements: Astellas Company, CSL Behring, UCB, HANSA, GSK; Research Funding: Astellas Inc.; Honoraria: Astellas; CSL Behring, UCB, HANSA, GSK; Scientific Advisor or Membership: Associate editor Transplantation, Editorial board member Transplantation Reviews, Therapeutic Drug Monitoring, Current Clinical Pharmacology; and Speakers Bureau: Astellas. P. D'Haese reports Research Funding: Inositec, Shire Pharmaceuticals, ViforPharma, and Rockwell Medical. Remaining authors report no conflicts of interest.HSJ was supported by an ERA long-term fellowship within the CKD-MBD working group during this work and received further financial support from the Augustinus Foundation and Kornings Fund. BS and MN are senior clinical investigators of The Research Foundation Flanders (1842919N and 1844019N, respectively). The authors would like to acknowledge the excellent assistance of Marc Dekens and Henriette de Loor at the KU Leuven Lab of Nephrology and Albert Herelixka and Herman Borghs at UZ Leuven, as well as Pierre Lukas at the Clinical Chemistry Laboratory of the CHU de Liège. We thank the centers of the Leuven Collaborative Group for Renal Transplantation, the clinicians, surgeons, and nursing staff assisting in data collection, and above all, the patients who participated in this study.
Nikkel LE, Hollenbeak CS, Fox EJ, Uemura T, Ghahramani N. Risk of fractures after renal transplantation in the United States. Transplantation. 2009;87(12):1846-1851. doi:10.1097/TP.0b013e3181a6bbda
Hansen D, Olesen JB, Gislason GH, Abrahamsen B, Hommel K. Risk of fracture in adults on renal replacement therapy: a Danish national cohort study. Nephrol Dial Transplant. 2016;31(10):1654- 1662. doi:10.1093/ndt/gfw073
Iseri K, Carrero JJ, Evans M, et al. Fractures after kidney transplantation: Incidence, predictors, and association with mortality. Bone. 2020;140:115554. doi:10.1016/j.bone.2020.115554
Pippias M, Stel VS, Abad Diez JM, et al. Renal replacement therapy in Europe: a summary of the 2012 ERA-EDTA Registry Annual Report. Clin Kidney J. 2015;8(3):248-261. doi:10.1093/ckj/sfv014
Salter ML, Liu X, Bae S, et al. Fractures and Subsequent Graft Loss and Mortality among Older Kidney Transplant Recipients. J Am Geriatr Soc. 2019;67(8):1680-1688. doi:10.1111/jgs.15962
Iyer SP, Nikkel LE, Nishiyama KK, et al. Kidney transplantation with early corticosteroid withdrawal: paradoxical effects at the central and peripheral skeleton. J Am Soc Nephrol. 2014;25(6):1331-1341. doi:10.1681/ASN.2013080851
Batteux B, Gras-Champel V, Lando M, et al. Early steroid withdrawal has a positive effect on bone in kidney transplant recipients: a propensity score study with inverse probability-of-treatment weighting. Ther Adv Musculoskelet Dis. 2020;12:1759720X2095335. doi:10.1177/1759720X20953357
Nikkel LE, Mohan S, Zhang A, et al. Reduced Fracture Risk With Early Corticosteroid Withdrawal After Kidney Transplant. Am J Transplant. 2012;12(3):649-659. doi:10.1111/j.1600- 6143.2011.03872.x
Evenepoel P, Claes K, Meijers B, et al. Natural history of mineral metabolism, bone turnover and bone mineral density in de novo renal transplant recipients treated with a steroid minimization immunosuppressive protocol. Nephrol Dial Transplant. 2020;35(4):697-705. doi:10.1093/ndt/gfy306
Aleksova J, Kurniawan S, Elder GJ. The trabecular bone score is associated with bone mineral density, markers of bone turnover and prevalent fracture in patients with end stage kidney disease. Osteoporos Int. 2018;29(6):1447-1455. doi:10.1007/s00198-018-4468-y
Evenepoel P, Claes K, Meijers B, et al. Bone mineral density, bone turnover markers, and incident fractures in de novo kidney transplant recipients. Kidney Int. 2019;95(6):1461-1470. doi:10.1016/j.kint.2018.12.024
Heimgartner N, Graf N, Frey D, Saleh L, Wüthrich RP, Bonani M. Predictive Power of Bone Turnover Biomarkers to Estimate Bone Mineral Density after Kidney Transplantation with or without Denosumab: A post hoc Analysis of the POSTOP Study. Kidney Blood Press Res. 2020;45(5):758- 767. doi:10.1159/000510565
Moe S, Drüeke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: A position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69(11):1945-1953. doi:10.1038/sj.ki.5000414
Keronen S, Martola L, Finne P, Burton IS, Kröger H, Honkanen E. Changes in bone histomorphometry after kidney transplantation. Clin J Am Soc Nephrol. 2019;14(6):894-903. doi:10.2215/CJN.09950818
Evenepoel P, Behets GJ, Viaene L, D'Haese PC. Bone histomorphometry in de novo renal transplant recipients indicates a further decline in bone resorption 1 year posttransplantation. Kidney Int. 2017;91(2):469-476. doi:10.1016/j.kint.2016.10.008
Sprague SM, Bellorin-Font E, Jorgetti V, et al. Diagnostic Accuracy of Bone Turnover Markers and Bone Histology in Patients With CKD Treated by Dialysis. Am J Kidney Dis. 2016;67(4):559-566. doi:10.1053/j.ajkd.2015.06.023
Monier-Faugere MC, Mawad H, Qi Q, Friedler RM, Malluche HH. High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol. 2000;11(6):1093-1099. doi:DOI: 10.1681/ASN.V1161093
Neves CL, Dos Reis LM, Batista DG, et al. Persistence of bone and mineral disorders 2 years after successful kidney transplantation. Transplantation. 2013;96(3):290-296. doi:10.1097/TP.0b013e3182985468
Rojas E, Carlini RG, Clesca P, et al. The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling. Kidney Int. 2003;63(5):1915-1923. doi:10.1046/j.1523-1755.2003.00938.x
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150(9):604-612. doi:10.7326/0003-4819-150-9-200905050-00006
Bouillon R, Coopmans W, Degroote DE, Radoux D, Eliard PH. Immunoradiometric assay of parathyrin with polyclonal and monoclonal region-specific antibodies. Clin Chem. 1990;36(2):271- 276.
Bouillon R, Van Herck E, Jans I, Tan BK, Van Baelen H, De Moor P. Two direct (nonchromatographic) assays for 25-hydroxyvitamin D. Clin Chem. 1984;30(11):1731-1736.
Dempster DW, Compston JE, Drezner MK, et al. Standardized nomenclature, symbols, and units for bone histomorphometry: A 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res. 2013;28(1):2-17. doi:10.1002/jbmr.1805
Moe S, Drüeke T, Cunningham J, et al. Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int. 2006;69(11):1945-1953. doi:10.1038/sj.ki.5000414
Jørgensen HS, Behets G, Viaene L, et al. Static histomorphometry allows for a diagnosis of bone turnover in renal osteodystrophy in the absence of tetracycline labels. Bone. 2021;152:116066. doi:10.1016/j.bone.2021.116066
Bhan A, Qiu S, Rao SD. Bone histomorphometry in the evaluation of osteomalacia. Bone Reports. 2018;8:125-134. doi:10.1016/j.bonr.2018.03.005
Baim S, Wilson CR, Lewiecki EM, Luckey MM, Downs RW, Lentle BC. Precision Assessment and Radiation Safety for Dual-Energy X-Ray Absorptiometry. J Clin Densitom. 2005;8(4):371-378. doi:10.1385/JCD:8:4:371
Marques IDB, Araújo MJCLN, Graciolli FG, et al. A randomized trial of zoledronic acid to prevent bone loss in the first year after kidney transplantation. J Am Soc Nephrol. 2019;30(2):355-365. doi:10.1681/ASN.2018060656
Malluche H, Faugere M-C. Renal bone disease 1990: An unmet challenge for the nephrologist. Kidney Int. 1990;38(2):193-211. doi:10.1038/ki.1990.187
Evenepoel P, Cavalier E, D'Haese PC. Bone biomarkers in de novo renal transplant recipients. Clin Chim Acta. 2020;501(September 2019):179-185. doi:10.1016/j.cca.2019.10.035
Cavalier E, Lukas P, Carlisi A, Gadisseur R, Delanaye P. Aminoterminal propeptide of type I procollagen (PINP) in chronic kidney disease patients: the assay matters. Clin Chim Acta. 2013;425:117-118. doi:10.1016/j.cca.2013.07.016
Salam S, Gallagher O, Gossiel F, Paggiosi M, Khwaja A, Eastell R. Diagnostic accuracy of biomarkers and imaging for bone turnover in renal osteodystrophy. J Am Soc Nephrol. 2018;29(5):1557-1565. doi:10.1681/ASN.2017050584
Jørgensen HS, Behets G, Viaene L, et al. Diagnostic Accuracy of Noninvasive Bone Turnover Markers in Renal Osteodystrophy. Am J Kidney Dis. Published online October 2021. doi:10.1053/j.ajkd.2021.07.027
Soeiro EMD, Castro L, Menezes R, et al. Association of parathormone and alkaline phosphatase with bone turnover and mineralization in children with CKD on dialysis: effect of age, gender, and race. Pediatr Nephrol. 2020;35(7):1297-1305. doi:10.1007/s00467-020-04499-2
Malluche HH, Mawad HW, Monier-Faugere MC. Renal osteodystrophy in the first decade of the new millennium: Analysis of 630 bone biopsies in black and white patients. J Bone Miner Res. 2011;26(6):1368-1376. doi:10.1002/jbmr.309
Bhadada SK, Rao SD. Role of Phosphate in Biomineralization. Calcif Tissue Int. 2020;(0123456789). doi:10.1007/s00223-020-00729-9
Jørgensen HS, Behets G, Bammens B, et al. Patterns of renal osteodystrophy 1 year after kidney transplantation. Nephrol Dial Transplant. 2021;36(11):2130-2139. doi:10.1093/ndt/gfab239
Evenepoel P, Naesens M, Claes K, Kuypers D, Vanrenterghem Y. Tertiary "hyperphosphatoninism" accentuates hypophosphatemia and suppresses calcitriol levels in renal transplant recipients. Am J Transplant. 2007;7(5):1193-1200. doi:10.1111/j.1600-6143.2007.01753.x
Evenepoel P, Meijers BKI, de Jong H, et al. Recovery of hyperphosphatoninism and renal phosphorus wasting one year after successful renal transplantation. Clin J Am Soc Nephrol. 2008;3(6):1829-1836. doi:10.2215/CJN.01310308
Sirilak S, Chatsrisak K, Ingsathit A, et al. Renal phosphate loss in long-term kidney transplantation. Clin J Am Soc Nephrol. 2012;7(2):323-331. doi:10.2215/CJN.06380611
Levi M. Post-transplant hypophosphatemia. Kidney Int. 2001;59(6):2377-2387. doi:10.1046/j.1523- 1755.2001.00755.x
Evenepoel P, Claes K, Kuypers D, Maes B, Bammens B, Vanrenterghem Y. Natural history of parathyroid function and calcium metabolism after kidney transplantation: A single-centre study. Nephrol Dial Transplant. 2004;19(5):1281-1287. doi:10.1093/ndt/gfh128
van Londen M, Aarts BM, Sanders JSF, et al. Tubular maximum phosphate reabsorption capacity in living kidney donors is independently associated with one-year recipient GFR. Am J Physiol - Ren Physiol. 2018;314(2):F196-F202. doi:10.1152/ajprenal.00287.2017
Tantiyavarong P, Kramer A, Heaf JG, et al. Changes in clinical indicators related to the transition from dialysis to kidney transplantation-data from the ERA-EDTA Registry. Clin Kidney J. 2019;13(2):188-198. doi:10.1093/ckj/sfz062
Evenepoel P, Cooper K, Holdaas H, et al. A randomized study evaluating cinacalcet to treat hypercalcemia in renal transplant recipients with persistent hyperparathyroidism. Am J Transplant. 2014;14(11):2545-2555. doi:10.1111/ajt.12911
Julian BA, Laskow DA, Dubovsky J, Dubovsky E V, Curtis JJ, Quarles LD. Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med. 1991;325(8):544-550. doi:10.1056/NEJM199108223250804
Casez J-P, Lippuner K, Horber FF, Montandon A, Jaeger P. Changes in bone mineral density over 18 months following kidney transplantation: the respective roles of prednisone and parathyroid hormone. Nephrol Dial Transplant. 2002;17(7):1318-1326. doi:10.1093/ndt/17.7.1318
Grotz WH, Mundinger FA, Muller CB, et al. Trabecular bone architecture in female renal allograft recipients-assessed by computed tomography. Nephrol Dial Transplant. 1997;12(3):564-569.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Update Work Group. 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;7(1):1- 59. doi:10.1016/j.kisu.2017.04.001
Weinstein RS, Jilka RL, Michael Parfitt A, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts end osteocytes by glucocorticoids potential mechanisms of their deleterious effects on bone. J Clin Invest. 1998;102(2):274-282. doi:10.1172/JCI2799
Abdelhadi M, Nordenström J. Bone mineral recovery after parathyroidectomy in patients with primary and renal hyperparathyroidism. J Clin Endocrinol Metab. 1998;83(11):3845-3851. doi:10.1210/jcem.83.11.5249
Lu KC, Ma WY, Yu JC, Wu CC, Chu P. Bone turnover markers predict changes in bone mineral density after parathyroidectomy in patients with renal hyperparathyroidism. Clin Endocrinol (Oxf). 2012;76(5):634-642. doi:10.1111/j.1365-2265.2011.04265.x [doi]
Lin R, Vucak-Dzumhur M, Elder GJ. Changes to bone mineral density, the trabecular bone score and hip structural analysis following parathyroidectomy: a case report. BMC Nephrol. 2020;21(1):513. doi:10.1186/s12882-020-02168-y
Yajima A, Ogawa Y, Takahashi HE, Tominaga Y, Inou T, Otsubo O. Changes of bone remodeling immediately after parathyroidectomy for secondary hyperparathyroidism. Am J Kidney Dis. 2003;42(4):729-738. doi:10.1016/S0272-6386(03)00909-0
Yajima A, Inaba M, Tominaga Y, Nishizawa Y, Ikeda K, Ito A. Increased osteocyte death and mineralization inside bone after parathyroidectomy in patients with secondary hyperparathyroidism. J Bone Miner Res. 2010;25(11):2374-2381. doi:10.1002/jbmr.126
Evenepoel P, Cunningham J, Ferrari S, et al. European Consensus Statement on the diagnosis and management of osteoporosis in chronic kidney disease stages G4-G5D. Nephrol Dial Transplant. 2021;36(1):42-59. doi:10.1093/ndt/gfaa192
Park WY, Han S, Choi BS, et al. Progression of Osteoporosis After Kidney Transplantation in Patients With End-Stage Renal Disease. Transplant Proc. 2017;49(5):1033-1037. doi:10.1016/j.transproceed.2017.03.038
Haarhaus M, Evenepoel P. Differentiating the causes of adynamic bone in advanced chronic kidney disease informs osteoporosis treatment. Kidney Int. 2021;100(3):546-558. doi:10.1016/j.kint.2021.04.043
Evenepoel P, D'Haese P, Bacchetta J, et al. Bone biopsy practice patterns across Europe: the European renal osteodystrophy initiative-a position paper. Nephrol Dial Transplant. 2017;32(10):1608-1613. doi:10.1093/ndt/gfw468
