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Bone mineral density after renal transplantation: long-term follow-up
Bone Mineral Density After Renal Transplantation: Long-Term Follow-Up A. Moreno, J.V. Torregrosa, F. Pons, J.M. Campistol, M.J. Martı´nez de Osaba, and F. Oppenheimer
R
ENAL OSTEODYSTROPHY is a relevant complication of chronic renal failure. Successful renal transplantation usually corrects the etiologic factors of renal osteodystrophy but preexisting secondary hyperparathyroidism can persist for a prolonged period.1,2 On the other hand, immunosuppressive therapy has a deleterious effect on bone metabolism, especially steroid therapy.3 Then, in some recipients, there is a marked bone loss immediately after renal transplantation associated with a higher incidence of bone fracture.4,5 In the present study we evaluated prospectively the long-term evolution of bone mineral density after renal transplantation and correlated it with several clinical and biochemical parameters. MATERIALS AND METHODS One hundred two allograft recipients (61 males, 41 females) with a mean age of 45 ⫾ 14 years were included. All the recipients were on hemodialysis before transplantation, with a mean time of 57 ⫾ 43 months. Primary renal disease was chronic glomerulonephritis in 31 cases, chronic interstitial nephritis in 24, polycystic disease in 21, unknown in 16, and nephroangiosclerosis in 10. Twenty-two patients had PTHi ⬎ 240 pg/mL (HPT) before transplantation. No patient had been parathyroidectomized. Immunosuppressive therapy consisted on cyclosporine (CyA) and prednisone in 83 patients and CyA monotherapy in 19 patients. The dose of prednisone was 1 mg/kg per day for the first 3 days after transplantation and then gradually reduced to 0.15 to 0.25 mg per day by 6 months. The initial dose of CyA was 10 mg/kg per day, gradually reduced according to CyA blood levels. Thirty-two patients suffered from acute rejection and received pulses of steroids (methylprednisolone 1 g ⫻ 3 days) gradually reduced according to the previous dose, and 19 of them also received OKT3 or ALG. None of the included patients received, during the study period, other drugs that could modify bone metabolism. Immediately before renal transplantation and at 6, 12, 24, 36, 48, and 60 months after transplantation, the following studies were performed: lumbar spine x-ray; measurements of bone mineral density of the lumbar spine and femoral neck; and blood determinations of PTHi, calcium, phosphorus, alkaline phosphatase, 1,25(OH)2D3 and serum creatinine. Bone mineral density (BMD) in the lumbar spine (LS) and the femoral neck (FN) were measured with a dual-energy x-ray absorptiometer (Lunar-DPX-L). Scans were made of three lumbar vertebrae (L2–L4) and the right proximal femur. BMD values were compared with the reference data in our geographic area and also were expressed as t-score (number of
standard deviations compared with a population between 20 to 40 years) and z-score (corrected for age and sex and expressed as the number of standard deviations). Results were expressed as mean ⫾ standard deviation. Statistical analysis was performed using Student’s t test, Fischer’s test, the chi-square test, and regression analysis. A P value ⬍.05 was considered significant.
RESULTS
At transplant time, mean BMD in LS and FN (z-score: ⫺0.01 ⫾ 0.4 in LS and ⫺0.52 ⫾ 1.8 in FN) was not significantly different to the control group population except for patients with HPT (z-score: ⫺0.83 ⫾ 0.5 in LS and ⫺1.14 ⫾ 1.4 in FN) (P ⬍ .05). During the first 6 months a decrease of the BMD was observed in all recipients (zscore: ⫺0.38 ⫾ 0.9 in LS and ⫺0.6 ⫾ 0.7 in FN). The decrease was more severe in patients receiving high steroids doses (z-score: ⫺1.84 ⫾ 1.1 in LS and ⫺1.32 ⫾ 0.6 in FN) (P ⬍ .01 and P ⬍ .05, respectively) and the patients with hyperparathyroidism receiving steroids reachs a worse BMD (z-score: ⫺1.92 ⫾ 0.4 in LS and ⫺1.42 ⫾ 0.7 in FN). The degree of BMD loss was significantly correlated with the cumulative dose of steroids (P ⬍ .05). Between 6 and 60 months posttransplant a progressive recovery of BMD was observed in all patients (z-score at 60 months: ⫺0.3 ⫾ 1.3 in LS and ⫺0.74 ⫾ 1.1 in FN), but the patients receiving steroids (z-score at 60 months: ⫺0.79 ⫾ 1.2 in LS and ⫺0.76 ⫾ 1.2 in FN) or with persistent hyperparathyroidism (z-score at 60 months: ⫺0.71 ⫾ 1.3 in LS and ⫺0.79 ⫾ 1.4 in FN) showed worse BMD recovering. The patients receiving immunosuppression with CyA monotherapy had a minimal but persistent loss of BMD (z-score at 6 months: ⫺0.06 ⫾ 1.08 in LS and ⫺0.79 ⫾ 1.09 in FN; z-score at 60 months: ⫺0.48 ⫾ 1.2 in LS and ⫺0.68 ⫾ 1.26 in FN). There was no significant correlation between BMD loss and age, gender, time on dialysis before transplantation, or renal function.
From Renal Transplant Unit (A.M., J.V.T., J.M.C., F.O.), Nuclear Medicine Service (F.P.), and Hormonal Laboratory (M.J.M.), Hospital Clinic, University of Barcelona, Barcelona, Spain. Address reprint requests to Dr J.V. Torregrosa, Hospital Clinic, Renal Transplant Unit, Villarroel 170, 08036 Barcelona, Spain.
0041-1345/99/$–see front matter PII S0041-1345(99)00360-7
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
2322
Transplantation Proceedings, 31, 2322–2323 (1999)
BONE MINERAL DENSITY AFTER RENAL TRANSPLANT
DISCUSSION
Bone loss after renal transplantation represents a serious and frequent complication in many transplant recipients. Successful renal transplantation usually corrects the mineral metabolism disturbances that lead to renal osteodystrophy, but preexisting secondary hyperparathyroidism and immunosuppressive agents, specially steroids, have a deleterious effect on bone metabolism. Our results corroborate that there is an acute loss of BMD after renal transplantation, clearly correlated with steroids treatment and previous HPT. After this acute loss of BMD, a progressive recovering was observed. HPT causes a more severe loss and a worse BMD recovering. The patients receiving immunosuppression with CyA monotherapy had a minimal loss of BMD, but the lower BMD persisted during the study period without changes.
2323
An immunosuppressive regimen without steroids and a better control of secondary hyperparathyroidism before the renal transplantation seems to be the best options to prevent the loss of BMD.
REFERENCES 1. Massari PU: Kidney Int 52:1412, 1997 2. Torregrosa JV, Campistol JM, Montesinos M, et al: Nephrol Dial Transplant 10:111, 1995 3. Epstein S: J Bone Miner Res 11:1, 1996 4. Julian B, Laskow D, Dubowsky J, et al: N Eng J Med 325:544, 1991 5. Almond M, Kwan J, Evans K, et al: Nephron 66:52, 1994
R
ENAL OSTEODYSTROPHY is a relevant complication of chronic renal failure. Successful renal transplantation usually corrects the etiologic factors of renal osteodystrophy but preexisting secondary hyperparathyroidism can persist for a prolonged period.1,2 On the other hand, immunosuppressive therapy has a deleterious effect on bone metabolism, especially steroid therapy.3 Then, in some recipients, there is a marked bone loss immediately after renal transplantation associated with a higher incidence of bone fracture.4,5 In the present study we evaluated prospectively the long-term evolution of bone mineral density after renal transplantation and correlated it with several clinical and biochemical parameters. MATERIALS AND METHODS One hundred two allograft recipients (61 males, 41 females) with a mean age of 45 ⫾ 14 years were included. All the recipients were on hemodialysis before transplantation, with a mean time of 57 ⫾ 43 months. Primary renal disease was chronic glomerulonephritis in 31 cases, chronic interstitial nephritis in 24, polycystic disease in 21, unknown in 16, and nephroangiosclerosis in 10. Twenty-two patients had PTHi ⬎ 240 pg/mL (HPT) before transplantation. No patient had been parathyroidectomized. Immunosuppressive therapy consisted on cyclosporine (CyA) and prednisone in 83 patients and CyA monotherapy in 19 patients. The dose of prednisone was 1 mg/kg per day for the first 3 days after transplantation and then gradually reduced to 0.15 to 0.25 mg per day by 6 months. The initial dose of CyA was 10 mg/kg per day, gradually reduced according to CyA blood levels. Thirty-two patients suffered from acute rejection and received pulses of steroids (methylprednisolone 1 g ⫻ 3 days) gradually reduced according to the previous dose, and 19 of them also received OKT3 or ALG. None of the included patients received, during the study period, other drugs that could modify bone metabolism. Immediately before renal transplantation and at 6, 12, 24, 36, 48, and 60 months after transplantation, the following studies were performed: lumbar spine x-ray; measurements of bone mineral density of the lumbar spine and femoral neck; and blood determinations of PTHi, calcium, phosphorus, alkaline phosphatase, 1,25(OH)2D3 and serum creatinine. Bone mineral density (BMD) in the lumbar spine (LS) and the femoral neck (FN) were measured with a dual-energy x-ray absorptiometer (Lunar-DPX-L). Scans were made of three lumbar vertebrae (L2–L4) and the right proximal femur. BMD values were compared with the reference data in our geographic area and also were expressed as t-score (number of
standard deviations compared with a population between 20 to 40 years) and z-score (corrected for age and sex and expressed as the number of standard deviations). Results were expressed as mean ⫾ standard deviation. Statistical analysis was performed using Student’s t test, Fischer’s test, the chi-square test, and regression analysis. A P value ⬍.05 was considered significant.
RESULTS
At transplant time, mean BMD in LS and FN (z-score: ⫺0.01 ⫾ 0.4 in LS and ⫺0.52 ⫾ 1.8 in FN) was not significantly different to the control group population except for patients with HPT (z-score: ⫺0.83 ⫾ 0.5 in LS and ⫺1.14 ⫾ 1.4 in FN) (P ⬍ .05). During the first 6 months a decrease of the BMD was observed in all recipients (zscore: ⫺0.38 ⫾ 0.9 in LS and ⫺0.6 ⫾ 0.7 in FN). The decrease was more severe in patients receiving high steroids doses (z-score: ⫺1.84 ⫾ 1.1 in LS and ⫺1.32 ⫾ 0.6 in FN) (P ⬍ .01 and P ⬍ .05, respectively) and the patients with hyperparathyroidism receiving steroids reachs a worse BMD (z-score: ⫺1.92 ⫾ 0.4 in LS and ⫺1.42 ⫾ 0.7 in FN). The degree of BMD loss was significantly correlated with the cumulative dose of steroids (P ⬍ .05). Between 6 and 60 months posttransplant a progressive recovery of BMD was observed in all patients (z-score at 60 months: ⫺0.3 ⫾ 1.3 in LS and ⫺0.74 ⫾ 1.1 in FN), but the patients receiving steroids (z-score at 60 months: ⫺0.79 ⫾ 1.2 in LS and ⫺0.76 ⫾ 1.2 in FN) or with persistent hyperparathyroidism (z-score at 60 months: ⫺0.71 ⫾ 1.3 in LS and ⫺0.79 ⫾ 1.4 in FN) showed worse BMD recovering. The patients receiving immunosuppression with CyA monotherapy had a minimal but persistent loss of BMD (z-score at 6 months: ⫺0.06 ⫾ 1.08 in LS and ⫺0.79 ⫾ 1.09 in FN; z-score at 60 months: ⫺0.48 ⫾ 1.2 in LS and ⫺0.68 ⫾ 1.26 in FN). There was no significant correlation between BMD loss and age, gender, time on dialysis before transplantation, or renal function.
From Renal Transplant Unit (A.M., J.V.T., J.M.C., F.O.), Nuclear Medicine Service (F.P.), and Hormonal Laboratory (M.J.M.), Hospital Clinic, University of Barcelona, Barcelona, Spain. Address reprint requests to Dr J.V. Torregrosa, Hospital Clinic, Renal Transplant Unit, Villarroel 170, 08036 Barcelona, Spain.
0041-1345/99/$–see front matter PII S0041-1345(99)00360-7
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
2322
Transplantation Proceedings, 31, 2322–2323 (1999)
BONE MINERAL DENSITY AFTER RENAL TRANSPLANT
DISCUSSION
Bone loss after renal transplantation represents a serious and frequent complication in many transplant recipients. Successful renal transplantation usually corrects the mineral metabolism disturbances that lead to renal osteodystrophy, but preexisting secondary hyperparathyroidism and immunosuppressive agents, specially steroids, have a deleterious effect on bone metabolism. Our results corroborate that there is an acute loss of BMD after renal transplantation, clearly correlated with steroids treatment and previous HPT. After this acute loss of BMD, a progressive recovering was observed. HPT causes a more severe loss and a worse BMD recovering. The patients receiving immunosuppression with CyA monotherapy had a minimal loss of BMD, but the lower BMD persisted during the study period without changes.
2323
An immunosuppressive regimen without steroids and a better control of secondary hyperparathyroidism before the renal transplantation seems to be the best options to prevent the loss of BMD.
REFERENCES 1. Massari PU: Kidney Int 52:1412, 1997 2. Torregrosa JV, Campistol JM, Montesinos M, et al: Nephrol Dial Transplant 10:111, 1995 3. Epstein S: J Bone Miner Res 11:1, 1996 4. Julian B, Laskow D, Dubowsky J, et al: N Eng J Med 325:544, 1991 5. Almond M, Kwan J, Evans K, et al: Nephron 66:52, 1994