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Renal Transplantation Decreases Osteoprotegerin Levels
Renal Transplantation Decreases Osteoprotegerin Levels A.S. Bargnoux, A.M. Dupuy, V. Garrigue, S. Deleuze, J.P. Cristol, and G. Mourad ABSTRACT Vascular calcifications are an important risk factor for cardiovascular mortality and morbidity in patients with chronic renal failure. Osteoprotegerin, a soluble decoy receptor for receptor activator NFkB ligand, has emerged as an independent predictive factor of atherosclerosis and vascular calcification in hemodialysis patients. Sparse data are available on the evolution of osteoprotegerin after renal transplantation. The aim of this study was to follow the evolution of serum osteoprotegerin levels and biochemical risk factors after renal transplantation. Forty patients were included. Blood samples for analysis were collected before and 3 months after renal transplantation. Besides the expected diminution in calcium-phosphate product, we have shown an early normalization of osteoprotegerin (10.05 ⫾ 4.77 pmol/L to 4.59 ⫾ 2.26 pmol/L). This study demonstrates that kidney transplantation improves this risk factor for vascular calcifications. However, these preliminary results should be confirmed and extended by the follow-up of vascular calcifications in the long term.
C
ARDIOVASCULAR MORTALITY is the first leading cause of death in patients with end-stage renal disease (ESRD) treated with hemodialysis or kidney transplantation.1,2 Vascular calcifications are now recognized as an important risk factor for uremia-induced cardiovascular disease. Increased calcium ⫻ phosphate (CaxPO4) product and secondary hyperparathyroidism were initially considered to be a crucial event in passive deposition of calcium in soft and vascular tissues. Recently, clinical and experimental data have suggested that vascular calcification is an active, cell-mediated process secondary to transdifferentiation of vascular smooth muscle cells into osteoblast-like cells.3 In this context, regulating molecules such as osteoprotegerin (OPG) and receptor activator of NFkB ligand (RANKL) have been identified as biological risk factors.4,5 However, the evolution of these nontraditional risk factors remains poorly investigated during renal transplantation. The aim of this study was to follow the kinetic of osteoprotegerin and other biochemical cardiovascular risk factors after kidney transplantation.
PATIENTS AND METHODS Forty patients (27 men and 13 women) who underwent a renal transplantation between March and December 2004 were enrolled in this study. Mean patient age was 46 ⫾ 11.5 years. The subjects were eight preemptive kidney transplant patients and 32 hemodialysis patients with a mean duration of dialysis of 4.9 ⫾ 5.6 years.
The immunosuppressive protocol used steroids, calcineurin inhibitors, and mycophenolic acid. Blood samples were collected before and 3 months after renal transplantation. Urea and creatinine were determined using standard laboratory methods. Parathyroid hormone was measured by immunoradiometric assay (N-Tact PTH SP IRMA Kit, DiaSorin, Minn, USA). Osteoprotegerin was measured with an enzyme immunoassay (ELISA Biovendor Laboratory Medicine, Brno, Czech Republic; normal range previously obtained in the laboratory 3.83 ⫾ 2.25 pmol/L) and RANKL was estimated using an ELISA kit from Biomedica (Wien, Austria). All data were analyzed using Student’s paired t test for comparison of mean values before and 3 months after renal transplantation. P ⬍ .05 was considered significant.
RESULTS
Three months after transplantation, renal function was stable (creatinine 138 ⫾ 41 mol/L; urea 10.5 ⫾ 3.08 mmol/L). The calcium-phosphate balance was improved as demonstrated by the decrease in phosphatemia (0.81 ⫾ 022 From the Department of Biochemistry (A.S.B., A.M.D., J.P.C.) and Department of Nephrology (V.G., S.D., G.M.), Transplantation and Peritoneal Dialysis, University hospital Lapeyronie, Montpellier, France. Address reprint requests to Georges Mourad, MD, Department of Nephrology, Transplantation and Dialysis, Hôpital Lapeyronie, Montpellier University Hospital, 34295 Montpellier cédex 5, France. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.126
Transplantation Proceedings, 38, 2317–2318 (2006)
2317
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mmol/L vs 1.68 ⫾ 0.49 mmol/L, P ⬍ .01), calcium-phosphate product (1.94 ⫾ 0.49 vs 4.05 ⫾ 1.18, P ⬍ .01), and parathyroid hormone (88 ⫾ 86 pg/mL vs 203 ⫾ 200 pg/mL, P ⬍ .01). OPG levels were elevated before renal transplantation (10.05 ⫾ 4.77 pmol/L) and decreased significantly at 3 months (4.59 ⫾ 2.26 pmol/L, P ⬍ .05) to reach laboratory norms (Fig 1). No variations in RANKL levels were observed (0.23 ⫾ 0.1 U/L after vs 0.24 ⫾ 0.12 before transplantation). DISCUSSION
An early normalization of OPG levels was observed 3 months after successful renal transplantation. Since osteoprotegerin levels increased along with the reduction of renal function6 and were correlated with time on dialysis,7 it could be postulated that decrease in OPG is linked to the amelioration of renal function.7,8 However, the weak tendency observed between creatinine levels and OPG levels do not reach significance (P ⫽ .15), suggesting that other factors such as immunosuppressive therapy may play a role. Glucocorticoid administration has been implicated in re-
Fig 1. Transplantation improves calcium metabolism and OPG levels.
BARGNOUX, DUPUY, GARRIGUE ET AL
ducing circulating osteoprotegerin levels after 4 weeks of treatment in patients with stable renal function.9 In addition, in vitro studies suggested that cyclosporine, rapamycin, and tacrolimus inhibited the production of OPG by the human marrow stromal cell line.10 In contrast, rapamycin increased OPG production by mature osteoblastic cells, and cyclosporine increased OPG production by vascular cells.10 In conclusion, our study demonstrates that kidney transplantation results in a dramatic improvement of both calcium and phosphorus metabolism and regulatory molecules of osteoblast metabolism such as OPG. The clinical significance of the rapid fall in OPG levels after renal transplantation is currently being investigated in our center by a long-term follow-up study of vascular calcification in kidney transplant recipients.
REFERENCES 1. Magee CC, Pascual M: Update in renal transplantation. Arch Intern Med 164:1373, 2004 2. Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108:2154, 2003 3. Tintut Y, Demer LL: Recent advances in multifactorial regulation of vascular calcification. Curr Opin Lipidol 12:555, 2001 4. Nitta K, Akiba T, Uchida K, et al: Serum osteoprotegerin levels and the extent of vascular calcification in haemodialysis patients. Nephrol Dial Transplant 19:1886, 2004 5. Morena M, Terrier N, Jaussent I, et al: Plasma osteoprotegerin is associated with mortality in hemodialysis patients. J Am Soc Nephrol 17:262, 2006 6. Kazama J: Osteoprotegerin and bone mineral metabolism in renal failure. Curr Opin Nephrol Hypertens 13:411, 2004 7. Moe S, Reslerova M, Ketteler M, et al: Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease. Kidney Intern 67:2295, 2005 8. Sato T, Tominaga Y, Iwasaki Y, et al: Osteoprotegerin level before and after renal transplantation. Am J Kidney Dis 38(suppl 1):S175, 2001 9. Sasaki N, Kusano E, Ando Y, et al: Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephro Dial Transplant 16:479, 2001 10. Hofbauer L, Shui C, Riggs B, et al: Effects of immunosuppressants on receptor activator of NF-B Ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun 280:334, 2001
C
ARDIOVASCULAR MORTALITY is the first leading cause of death in patients with end-stage renal disease (ESRD) treated with hemodialysis or kidney transplantation.1,2 Vascular calcifications are now recognized as an important risk factor for uremia-induced cardiovascular disease. Increased calcium ⫻ phosphate (CaxPO4) product and secondary hyperparathyroidism were initially considered to be a crucial event in passive deposition of calcium in soft and vascular tissues. Recently, clinical and experimental data have suggested that vascular calcification is an active, cell-mediated process secondary to transdifferentiation of vascular smooth muscle cells into osteoblast-like cells.3 In this context, regulating molecules such as osteoprotegerin (OPG) and receptor activator of NFkB ligand (RANKL) have been identified as biological risk factors.4,5 However, the evolution of these nontraditional risk factors remains poorly investigated during renal transplantation. The aim of this study was to follow the kinetic of osteoprotegerin and other biochemical cardiovascular risk factors after kidney transplantation.
PATIENTS AND METHODS Forty patients (27 men and 13 women) who underwent a renal transplantation between March and December 2004 were enrolled in this study. Mean patient age was 46 ⫾ 11.5 years. The subjects were eight preemptive kidney transplant patients and 32 hemodialysis patients with a mean duration of dialysis of 4.9 ⫾ 5.6 years.
The immunosuppressive protocol used steroids, calcineurin inhibitors, and mycophenolic acid. Blood samples were collected before and 3 months after renal transplantation. Urea and creatinine were determined using standard laboratory methods. Parathyroid hormone was measured by immunoradiometric assay (N-Tact PTH SP IRMA Kit, DiaSorin, Minn, USA). Osteoprotegerin was measured with an enzyme immunoassay (ELISA Biovendor Laboratory Medicine, Brno, Czech Republic; normal range previously obtained in the laboratory 3.83 ⫾ 2.25 pmol/L) and RANKL was estimated using an ELISA kit from Biomedica (Wien, Austria). All data were analyzed using Student’s paired t test for comparison of mean values before and 3 months after renal transplantation. P ⬍ .05 was considered significant.
RESULTS
Three months after transplantation, renal function was stable (creatinine 138 ⫾ 41 mol/L; urea 10.5 ⫾ 3.08 mmol/L). The calcium-phosphate balance was improved as demonstrated by the decrease in phosphatemia (0.81 ⫾ 022 From the Department of Biochemistry (A.S.B., A.M.D., J.P.C.) and Department of Nephrology (V.G., S.D., G.M.), Transplantation and Peritoneal Dialysis, University hospital Lapeyronie, Montpellier, France. Address reprint requests to Georges Mourad, MD, Department of Nephrology, Transplantation and Dialysis, Hôpital Lapeyronie, Montpellier University Hospital, 34295 Montpellier cédex 5, France. E-mail: [email protected]
© 2006 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/06/$–see front matter doi:10.1016/j.transproceed.2006.06.126
Transplantation Proceedings, 38, 2317–2318 (2006)
2317
2318
mmol/L vs 1.68 ⫾ 0.49 mmol/L, P ⬍ .01), calcium-phosphate product (1.94 ⫾ 0.49 vs 4.05 ⫾ 1.18, P ⬍ .01), and parathyroid hormone (88 ⫾ 86 pg/mL vs 203 ⫾ 200 pg/mL, P ⬍ .01). OPG levels were elevated before renal transplantation (10.05 ⫾ 4.77 pmol/L) and decreased significantly at 3 months (4.59 ⫾ 2.26 pmol/L, P ⬍ .05) to reach laboratory norms (Fig 1). No variations in RANKL levels were observed (0.23 ⫾ 0.1 U/L after vs 0.24 ⫾ 0.12 before transplantation). DISCUSSION
An early normalization of OPG levels was observed 3 months after successful renal transplantation. Since osteoprotegerin levels increased along with the reduction of renal function6 and were correlated with time on dialysis,7 it could be postulated that decrease in OPG is linked to the amelioration of renal function.7,8 However, the weak tendency observed between creatinine levels and OPG levels do not reach significance (P ⫽ .15), suggesting that other factors such as immunosuppressive therapy may play a role. Glucocorticoid administration has been implicated in re-
Fig 1. Transplantation improves calcium metabolism and OPG levels.
BARGNOUX, DUPUY, GARRIGUE ET AL
ducing circulating osteoprotegerin levels after 4 weeks of treatment in patients with stable renal function.9 In addition, in vitro studies suggested that cyclosporine, rapamycin, and tacrolimus inhibited the production of OPG by the human marrow stromal cell line.10 In contrast, rapamycin increased OPG production by mature osteoblastic cells, and cyclosporine increased OPG production by vascular cells.10 In conclusion, our study demonstrates that kidney transplantation results in a dramatic improvement of both calcium and phosphorus metabolism and regulatory molecules of osteoblast metabolism such as OPG. The clinical significance of the rapid fall in OPG levels after renal transplantation is currently being investigated in our center by a long-term follow-up study of vascular calcification in kidney transplant recipients.
REFERENCES 1. Magee CC, Pascual M: Update in renal transplantation. Arch Intern Med 164:1373, 2004 2. Sarnak MJ, Levey AS, Schoolwerth AC, et al: Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation 108:2154, 2003 3. Tintut Y, Demer LL: Recent advances in multifactorial regulation of vascular calcification. Curr Opin Lipidol 12:555, 2001 4. Nitta K, Akiba T, Uchida K, et al: Serum osteoprotegerin levels and the extent of vascular calcification in haemodialysis patients. Nephrol Dial Transplant 19:1886, 2004 5. Morena M, Terrier N, Jaussent I, et al: Plasma osteoprotegerin is associated with mortality in hemodialysis patients. J Am Soc Nephrol 17:262, 2006 6. Kazama J: Osteoprotegerin and bone mineral metabolism in renal failure. Curr Opin Nephrol Hypertens 13:411, 2004 7. Moe S, Reslerova M, Ketteler M, et al: Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease. Kidney Intern 67:2295, 2005 8. Sato T, Tominaga Y, Iwasaki Y, et al: Osteoprotegerin level before and after renal transplantation. Am J Kidney Dis 38(suppl 1):S175, 2001 9. Sasaki N, Kusano E, Ando Y, et al: Glucocorticoid decreases circulating osteoprotegerin (OPG): possible mechanism for glucocorticoid induced osteoporosis. Nephro Dial Transplant 16:479, 2001 10. Hofbauer L, Shui C, Riggs B, et al: Effects of immunosuppressants on receptor activator of NF-B Ligand and osteoprotegerin production by human osteoblastic and coronary artery smooth muscle cells. Biochem Biophys Res Commun 280:334, 2001