NEFROLOGÍA. Vol. XXIII. Suplemento 2. 2003 Bone loss in pediatric renal transplant recipients A. A. El-Husseini, A. E. El-Agroudy, M. A. Sobh y M. A. Ghoneim Mansoura Urology & Nephrology Center. Mansoura University. Mansoura, Egypt. SUMMARY The factors that affect bone mineral density (BMD) and the long term progress of BMD after transplantation in children is still unknown. Therefore we performed a cross-sectional study to determine BMD in 83 recipients who received living renal allotransplants in Mansoura Urology & Nephrology Center between 1981 and 2001 (mean age at transplantation 13.2 ± 3.1 years) by dual energy x-ray absorptiometry at various time intervals up to 16 years after transplantation (mean duration after transplantation was 48 ± 34 months, range 6-192 months). The Z-score for lumbar spine was -2.28 ± 2.06 and -1.44 ± 1,44 for the total body. Osteopenia/osteoporosis were present in about two thirds of our kidney transplant recipients. The significant predictors for osteopenia/osteoporosis by univariate analysis were cyclosporine based immunosuppression, the cumulative steroid dose/m2 surface area, graft dysfunction and the urinary deoxypyridinoline. Using logistic regression analysis the cumulative steroid dose/m2 surface area and the urinary deoxypyridinoline were the major significant predictors for bone loss. Key words: Bone loss. Children. Renal transplant. PÉRDIDA ÓSEA EN RECEPTORES PEDIÁTRICOS DE TRASPLANTE RENAL RESUMEN Los factores que afectan a la Densidad mineral ósea (BMD) y lo que ocurre a largo plazo con la BMD después del trasplante en niños es todavía desconocido. Por ello realizamos un estudio transversal para determinar la BMD en 83 receptores que recibieron un allotrasplante renal de vivo en Mansoura Urology and Nephology Center entre 1981 y 2001 (media de edad al trasplante 13,2 ± 3,1 años) por densitometría radiológica de doble energía, en varios intervalos de tiempo hasta 16 años después del trasplante (media de duración después del trasplante fue 48 ± 34 meses, rango de 6-192 meses). El valor de Z-score en columna lumbar fue de ­2,28 ± 2,06 y de -1,44 ± 1,44 en cuerpo total. Osteopenia/osteoporosis estuvo presente en dos tercios de nuestros receptores de trasplante renal. Los predictores significativos para osteopenia/osteoporosis por análisis univariante fueron la inmunosupresión basada en ciclosporina, la dosis de esteroides acumulativa por m2 de área de superficie, disfunción del injerto y la deoxypyridinolina urinaria. Usando análisis de regresión logística la dosis acumulativa de esteroides por m2 de área de superficie y la deoxypyridinolina urinaria fueron los mayores predictores para pérdida de masa ósea. Palabras clave: Pérdida ósea. Niños. Trasplante renal. Correspondence: Dr. Mohamed A. Sobh Urology and Nephrology Center Mansoura University, Egypt Postal code: 35516 Fax: 020-50-2283717 E-mail: profmsobh@netscape.net 131 AMR A. EL-HUSSEINI y cols. MATERIAL AND METHODS A total of 83 pediatric renal graft recipients presented for routine transplant examination at various time intervals after transplantation were evaluated by bone densitometry between 2000 and 2001. The selection criteria were patients with functioning graft at least 6 months post renal transplantation. Patients with a prior history of parathyroidectomy or treatment with fluoride, calcitonin or bisphosphonates were excluded. All patients received living renal allotransplants at Mansoura Urology & Nephrology Center between 1981 and 2001. All subjects underwent bone mineral densitometry and a biochemical evaluation of their renal allograft function, calcium metabolism and bone turnover. Measurement of BMD was performed by DEXA using lunar DFXMD 7517 machine, US. The BMD results were expressed as Z-score. The BMD was measured on the lumbar spine at L2-L4 and for the total body. RESULTS Our study included 83 renal transplant patients who underwent renal transplantation at the age of 17 years or less. All patients received live donor transplant, fifty three were males while thirty were females. At the time of the study the mean age of our cases was 16.3 ± 3.2 years, the mean serum creatinine was 1.9 ± 3.8 mg / dl, the mean corrected creatinine clearance was 62 ± 25.9 ml/min. Bone loss was common in the study population at both lumbar spine and the total body. About 2/3 of our cases had osteopenia/osteoporosis. The significant risk factors for osteopenia/osteoporosis by univariate analysis were the cyclosporine based immunosuppressive regimen, cumulative dose of steroids/m2 surface area, the graft dysfunction and the urinary deoxypyridinoline. A multiple regression model was performed using the logistic regression analysis. Only the cumulative steroid dose/m2 surface area and the urinary de- Table I. Effects of pre and post-transplant parameters on whole boy BMD of 83 pediatric transplants Number Age 13 years or less More than 13 years Sex Male Female Original kidney disease Hypoplastic kidney Glomerular disease Tubulointerstitial disease Hereditary nephritis Unknown Pretransplant dialysis No Yes Immunosuppressive regimen Cyclosporine based Tacrolimus based Acute rejection episode No Yes Chronic rejection No Yes Alternate-day steroid No Yes Cumulative steroid dose 16 g/m2 or less More than 16 g/m2 Cumulative steroid index 10 g/m2 or less More than 10 g/m2 BMD < -1 P. value 40 43 53 30 22 22 20 10 9 22 61 63 8 51 32 67 16 62 21 47 36 42 41 22 (55.00%) 32 (74.82%) 38 (71.70%) 16 (53.33%) 4 17 12 5 6 (63.64%) (77.27%) (60.00 %) (50.00%) (66.67%) 0.064 0.092 0.609 0.084 0.022 0.302 0.130 0.379 0.231 0.046 11 (50.00%) 43 (70.49%) 45 (71.43%) 7 (38.89%) 31 (60.78%) 23 (71.19%) 41 (61.19%) 13 (81.25%) 42 (67.74%) 12 (57.14%) 28 (59.57%) 26 (72.22%) 23 (54.76%) 31 (75.61%) 132 BONE LOSS IN PEDIATRIC RENAL TRANSPLANT RECIPIENTS oxypyridinoline were significant predictors for bone loss. Table 1 shows that all of the pre-transplant variables were not significant as risk factors for osteopenia /osteoporosis. Only the cyclosporine based therapy and cumulative steroid dose more than 10 g/m surface area were significant post-transplant risk factors for osteopenia/osteoporosis. Table 2 shows that the graft function and the urinary deoxypyridinoline were significant post-transplant risk factors for BMD. DISCUSSION Post-transplant bone disease seems to be a universal finding in adult transplant recipients, and is most probably related to steroids. Reports on bone mineral density in children after renal transplantation are not uniform1. There was a decreased in BMD in both lumbar spine and the total body BMD with more affection of the lumbar spine (Z-score= -2.28 ± 2.06 versus -1,44 ± 1,44). Feber et al, explain the greater spinal bone loss by the high metabolic activity of the vertebral trabecular bone, which is also more prone to the side effects of steroids2. Two thirds of our cases had decreased bone density. Feber et al, found significant demineralization in 62% of children2. Moderate to severe osteopenia in children following transplantation was also reported by other authors3,4. The significant risk factors for osteopenia/osteoporosis were use of cyclosporine based therapy, cumulative steroid dose/m2 surface area, renal dysfunction and urinary deoxypyridinoline. Both cyclosporine and tacrolimus have been demonstrated to cause high-turnover bone loss in animal studies5 but, not yet proven to occur in human6. Although it is well established that pharmacological doses of steroids have a powerful inhibitory effect on bone formation, they probably do not directly stimulate bone resorption7. In most studies bone mineral density was related to cumulative dose of steroids8,9. However, in some no correlation between BMD loss and steroids was f o u n d 10,2. Although osteopenia has been reported in some studies in patients with renal insufficiency in renal transplant patients7,11, others have reported no diminution in bone density with renal dysfunction12. In conclusion, osteopenia and osteoporosis are common in pediatric and adolescent renal transplant patients. The cumulative steroid dose/m2 surface area and the urinary deoxypyridinoline were the major predictors for bone loss. REFERENCES 1. Feber J, Cochat P, Braillon P: Bone mineral density in children after renal transplantation. Pediatr Nephrol 14: 654-657, 2000. 2. Feber J, Cochat P, Braillon P, Castelo F, Martin X, Glastre C, Chapuis F, David L, Meunier PJ: Bone mineral density after renal transplantation in children. J Pediatr 125: 870-875, 1994. 3. Boot AM, Nauta J, Hokken-Koelega AC, Pols HA, De Ridder MA, De Muinck Keizer-Schrama SM: Renal transplantation and osteoporosis. Arch Dis Child 72: 502-506, 1995. 4. Melgosa MM, Romero MD, Garcia MC y cols.: Value of bone densitometry in pediatric renal transplantation. An Esp Pediatr 47: 373-377, 1997. 5. Epstein S: Post-transplantation bone disease: the role of immunosuppressive agents and the skeleton. J Bone Miner Res 11: 1-6, 1996. 6. Wilmink JM, Bras J, Surachno S, Van Heyst JL, Van der Horst JM: Bone repair in cyclosporine treated renal transplant patients. Transplant Proc 21: 1492-1494, 1989. 7. Canalis E: Mechanisms of glucocorticoid action in bone. Implications to glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 81: 441-3446, 1996. Table 2. Effects of posttransplant laboratory parameters on whole body BMD of 83 pediatric transplants Normal BMD (number = 29) S.cr (mg/dl) Cr.cl. (ml/min) S. Calcium (mg/dL) S. phosphorus (mg/dL) S. Albumin (g/dL) Alkaline phosphatase (IU/L) Intact PTH (pg/ml) Osteocalcin (ng/ml) Urine deoxypyridinoline Urine Ca/cr 1.68 73.83 9.59 3.66 3.87 140.76 7.66 44.80 71.32 0.05 ± ± ± ± ± ± ± ± ± ± 1.78 21.88 0.76 1.00 0.48 85.32 8.63 20.65 64.30 0.07 Reduced BMD (number = 54) 2.48 52.46 9.29 3.94 3.87 141.77 10.67 46.83 123.86 0.04 ± ± ± ± ± ± ± ± ± ± 2.74 20.99 0.74 1.05 0.42 66.89 12.65 23.52 61.20 0.06 P. Value 0.030 0.040 0.606 0.693 0.928 0.253 0.328 0.662 0.002 0.657 133 AMR A. EL-HUSSEINI y cols. 8. Wolpaw T, Deal CL, Fleming-Brooks S, Bartucci MR, Schulak JA, Hricik DE: Factors influencing vertebral bone density after renal transplantation. Transplantation 58: 1186-1189, 1994. 9. Grotz WH, Mundinger FA, Rasenack J, Speidel L, Olschewski M, Exner VM, Schollmeyer PJ: Bone loss after kidney transplantation: a longitudinal study in 115 graft recipients. Nephrol Dial Transplant 10: 2096-2100, 1995. 10. Kwan JTC, Almond MK, Evans K, Cunningham J: Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation. Miner Electrolyte Metab 18: 166-168, 1992. 11. Stein MS, Packham D, Ebeling P, Wark JD, Becker GJ: Prevalence and risk for osteopenia in dialysis patients. Am J Kid Dis 28: 515-520, 1996. 12. Fletcher S, Jones RG, Rayner HC: Assessment of renal osteodystrophy in dialysis patients: use of bone alkaline phosphatase, bone mineral density and parathyroid ultrasound in comparison with bone histology. Nephron 75: 412-416, 1997. 134