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Successful Renal Transplantation, Bone Mineral Densitometry, and Affecting Factors
Successful Renal Transplantation, Bone Mineral Densitometry, and Affecting Factors M.B. Canoza, D. Yavuza, A. Altunoglua,*, R. Yavuzb, T. Colaka, and M. Haberalc a Nephrology, Bas¸kent University Faculty of Medicine, Ankara, Turkey; bMedical Education, Ondokuz Mayıs University Faculty of Medicine, Samsun, Turkey; and cGeneral Surgery, Bas¸kent University Faculty of Medicine, Ankara, Turkey
ABSTRACT Background. Successful renal transplantation corrects many disorders of bone and mineral metabolism owing to the normalization of serum levels of calcium and phosphorus and restoration of calcitriol production. However, successful transplantation does not guarantee complete resolution of the pre-transplantation osteopathy. Methods. This study evaluated 100 patients who underwent successful renal transplantation. We determined the possible risk factors for osteoporosis among 72 male and 28 female renal transplant patients of mean age 32.3 10.0 years with 81% of them recipients of living-related grafts. Bone mineral densitometry (BMD) was performed in all patients before and 1 year after transplantation. Routine test results and demographic data were recorded. Results. At the time of transplantation 76% of the patients had osteoporosis or osteopeni and only 24% of them had normal BMD in 4 regions (femur neck, lumber, radius, and ultradistal). After transplantation, 70% of them had osteopororosis or osteopeni and 30% were normal. After renal transplantation, BMD scores increased (P > .05) although the diagnosis of the bone disease did not change (P < .05). Only preexisting osteodystrophy and smoking were found to be important risk factors for post-transplantation osteoporosis. Conclusions. After renal transplantation, BMD scores increased whereas the diagnosis of bone disease did not change statistically. We found that medical management of osteopenia/osteoporosis before transplantation and smoking habit are the main factors to prevent post-transplantation osteoporosis. Further long-term studies may be more helpful for evaluating the risk factors of post-transplantation osteoporosis.
S
ECONDARY hyperparathyroidism, adynamic bone disease, osteomalacia, the use of corticosteroids, and chronic acidosis may all decrease bone density and increase the risk of fractures in patients with end-stage renal disease (ESRD) [1,2]. Compared with dialysis, renal transplantation may be more beneficial in improving the problems that develop due to uremia in patients with ESRD, although the success rate declines in disorders of the bone metabolism. Histologic evidences of osteodystrophy and osteopenia are commonly detected in most patients with successful kidney transplants. Osteoporosis may also develop in early phases owing to the loss of the bone mass. Moreover, many patients experience the risk of avascular necrosis within the 1st 2 years after transplantation [3]. Ongoing hyperparathyroidism, hypercalcemia, and hyperphosphatemia after renal transplantation also are risk factors
for the deterioration of existing bone diseases [4]. Various studies in renal transplant patients with osteopenia indicated the existence of many histologic structures that were not related to hyperparathyroidism. Low-turnover bone lesions similar to osteoporosis [5] and even osteomalacia were detected in bone biopsies [6]. High doses of tacrolimus in patients with kidney transplants, as well as cyclosporine, which is known to reduce osteoclast formation and inhibit osteoclastic bone resorption, enhance the loss of bone mass [7]. A consensus on the reduction of *Address correspondence to Alpaslan Altunoglu, Nephrology Specialist, Bas¸kent University Faculty of Medicine, 5 Sok, No: 48 06490 Bahçelievler, Ankara, Turkey. E-mail: alpaltinoglu@yahoo. com
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.05.006
Transplantation Proceedings, 47, 1813e1819 (2015)
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CANOZ, YAVUZ, ALTUNOGLU ET AL Table 1. Descriptive Characteristics of the Patients Characteristic
Median age at transplantation: 32.3 10.0 y Sex Female Male Etiology of renal failure Hypertension Glomerulonephritis VUR PCKD FMF Unknown Pre-transplantation dialysis modality Hemodialysis Peritoneal dialysis Donation Living donation Cadaver Familial status 1st degree 2nd degree 3rd degree Marriage Acute rejection history Yes No Immunsuppression protocols Azathioprine þ prednisolone þ tacrolimus Azathioprine þ prednisolone þ sirolimus MMF þ prednisolone þ cyclosporine MMF þ prednisolone þ tacrolimus MMF þ prednisolone þ sirolimus Hepatitis B virus Positive Negative Hepatitis C virus Positive Negative Smoking Yes No Body mass index (kg/m2) Underweight (<18.5) Healthy weight (18.5e24.9) Overweight (25.0e29.9) Obese (30)
%*
28.0 72.0 13.0 27.0 5.0 2.0 5.0 48.0 87.0 13.0 81.0 19.0 83 4 2 11 11.0 89.0 5 2 40 42 11 10.0 90.0 10.0 90.0 27.0 73.0 2 48.0 36.0 14.0
Abbreviations: VUR, vesicoureteral reflux; PCKD, polycystic kidney disease; FMF, familial Mediterranean fever; MMF, mycophenolate mofetil. *The number of patients is 100, so the percentages are the same as the numbers.
osteoblast formation and precipitation of the loss of the bone mass by the use of glucocorticoids after renal transplantation has recently been achieved [8]. The increase in osteocalcin levels due to the effects of cyclosporine after renal transplantation contributes to the low-turnover bone disease developing under the action of glucocorticoids [9]. Rapid loss of the bone mass in patients with kidney transplants can not yet be prevented. Post-transplantation osteodystrophy (mostly osteoporosis) and osteonecrosis are
among the most important causes of long-term morbidity in patients with kidney transplants. Therefore, we investigated the factors that influence bone mineral density (BMD) after successful renal transplantation. METHODS One hundred patients who received kidney transplants in Baskent University, Ankara, Turkey, were randomly included in this study (72 men, 28 women). The descriptive characteristics of the patients are summarized in Table 1. Pre- and post-transplantation BMD scores as well as the means of some biochemical parameters are presented in Table 2. Inclusion criteria were: absence of hyperparathyroidism at the time of transplantation (intact parathyroid hormone [PTH] <600 ng/mL); no history of parathyroidectomy; and absence of a comorbid disease that affects bone metabolism, such as hyperthroidism, Cushing syndrome, or advanced liver disease. Patients were excluded if they displayed poor renal function, namely, serum creatinine value >2 mg/dL or proteinuria >1,000 mg/d. None of the patients received vitamin D or analogues during the post-transplantation period. Bone mineral densitometry was performed on all patients at the 1st year after renal transplantation with the use of dual-energy x-ray absorptiometry (DEXA-Hologic, model QDR 1500A, Watham, Massachusetts). Osteoporosis was defined by the World Health Organization criteria as a T score of 2.5 or more below the SD. Osteopenia and normal values were defined as T scores from 1.5 to 2.5 SD and over 1.5 SD, respectively. Patients were divided into 3 groups according to BMD results: group 1 with normal values (T score greater than 1.5 SD), group 2 with osteopenia (T score from 1.5 to 2.5 SD), and group 3 with osteoporosis (T score less than 2.5 SD). We analyzed differences in pre- and post-transplantation T score values, as well as clinical, laboratory, and demographic data. Patients received prednisone, azathioprine, mycophenolate mofetil, and cyclosporine for maintenance immunosuppression. Cyclosporine was initiated at a dose of 8e10 mg/kg/d orally in 2 divided doses and then adjusted to maintain whole-blood levels of 100e200 ng/mL with the use of a modular ISE 900 machine (Cedia Cyclosporine Assay; Roche Diagnostic Corp, Indianapolis, Indiana) with a homogeneous enzyme immunoassay system. Prednisolone was initiated at 1e2 mg/kg/ d orally and tapered over 6 months to a maintenance dosage of 10 mg/d. An acute rejection episode was suspected based on clinical and biochemical parameters and confirmed by means of renal allograft biopsy. It was initially treated with intravenous pulse methylprednisolone. Steroid-resistant acute rejection episodes were treated with OKT3. Laboratory parameters were performed with the use of standard laboratory techniques. Statistical analyses were performed with the use of SPSS software (Statistical Package for the Social Sciences, version 15.0; SPSS, Chicago, Illinois). All numeric variables, such as biochemical parameters and BMD scores, are expressed as mean SD. The values of categoric variables (history of smoking, sex, menopausal status, body mass index [BMI] scores, dialysis modality, the presence of hepatitis B virus [HBV] or hepatitis C virus [HCV] seropositivity, BMD-associated diagnoses, donor of transplantation, acute rejection, immunosuppressive protocol) are presented as n (%). McNeamar test was used for showing the differences of pre- and post-transplantation BMD-associated diagnoses. We analyzed the values of variables such as age, alkaline phosphatase (ALP), phosphorus, and duration of dialysis with the use of Pearson correlation analysis technique. All numeric variables are expressed as mean SD. Intergroup differences were compared by means of the Student t, Mann-Whitney U, 1-way analysis of variance, or
Pre-transplantation BMD Normal
Osteopenia
Osteoporosis
Post-transplantation BMD, n (%*) Normal
Osteoporosis
Normal
e 5 (3.3)
2 (3.3) 2 (1.3)
9 (64.3) 21 (55.3)
5 (35.7) 15 (39.5)
e 2 (5.3)
2 (5.3) 10 (10.1)
e 1 (1.7) 1 (7.1) e 1 (9.1) 2 (1.9)
2 (9.5) e e e e 2 (1.9)
3 (42.9) 9 (60) e e e 18 (62.1)
3 (42.9) 5 (33.3) 1 (100) e e 11 (37.9)
1 (14.3) 1 (6.7) e e e e
2 (8.3) 2 (5.7) 1 (20) e 2 (22.2) 5 (8.5)
5 (2.7) e
4 (2.2) e
27 (55.1) 3 (100.0)
20 (40.8) e
2 (4.1) e
10 (8.8) 2 (8.3)
26 (23.0) 6 (25)
77 (68.1) 16 (66.7)
3 (1.7) 2 (5.3)
3 (1.7) 1 (2.6)
27 (58.7) 3 (50)
17 (37) 3 (50)
2 (4.3)
12 (10.6) e
25 (22.1) 7 (29.2)
76 (67.3) 17 (70.8)
3 (2) e e e
2 (1.4) e e 1 (5.6)
24 1 1 1
(61.5) (100) (33.3) (33.3)
14 (35.9) d 2 (66.7) 1 (33.3)
1 (2.6) e e 1 (33.3)
9 (10.1) e 1 (25) 2 (13.3)
21 1 2 1
59 4 1 12
1 (4.5) 4 (2.1)
e 4 (2.1)
5 (62.5) 25 (56.8)
3 (37.5) 17 (38.6)
e 2 (4.5)
e e 2 (2.6) 3 (3.3) e
e 1 (20) 1 (1.3) 2 (2.2) e
2 1 13 10 4
2 (1.7) 3 (4.3) e
2 (1.7) 1 (1.4) 1 (3.8)
3 (1.9) 2 (3.7) e e
(66.7) (50) (56.5) (52.6) (80)
Osteopenia
1 1 9 9
Osteoporosis
Normal
1 (7.1) 11 (8.9)
Osteopenia
Osteoporosis
10 (26.3) 22 (22.2)
26 (68.4) 67 (67.7)
6 5 1 1 4 15
16 28 3 4 3 39
(25) (14.3) (20) (20) (44.4) (25.4)
(23.6) (20) (50) (6.7)
(66.7) (80) (60) (80) (33.3) (66.1)
(66.3) (80) (25) (80)
5 (35.7) 27 (22)
8 (57.1) 85 (69.1)
(33.3) (50) (39.1) (47.4) e
e e 1 (4.3) e 1 (20)
1 (16.7) e 8 (13.3) 3 (5.3) e
1 (16.7) e 11 (18.3) 16 (28.1) 4 (30.8)
4 1 41 38 9
20 (74.1) 9 (42.9) 1 (25)
6 (22.2) 12 (57.1) 2 (50)
1 (3.7) e 1 (25)
1 (1.7) 7 (13.2) 4 (15.4)
15 (25.9) 10 (18.9) 7 (26.9)
42 (72.4) 36 (67.9) 15 (57.7)
4 (2.5) e
17 (50) 13 (72.2)
15 (44.1) 5 (27.8)
2 (5.9) e
23 (22.89) 9 (25)
68 (67.3) 25 (69.4)
e 2 (4.4)
3 (60.0) 6 (66.7)
2 (40.0) 3 (33.3)
e e
8 (40.0) 2 (11.1)
10 (50.0) 16 (88.9)
Abbreviations: Aza, azathioprine; Pred, prednisone; Tac, tacrolimus; Sir, sirolimus; CsA, cyclosporine; other abbreviations as in Table 1. *Percentages of patients with pre-transplantation normal, osteopenia, or osteoporosis.
10 (9.9) 2 (5.6) 2 (10.0) e
(66.7) (100) (68.3) (66.7) (69.2)
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Sex Female 58 (96.7) Male 144 (95.4) Etiology of renal failure Hypertension 19 (90.5) Glomerulonephritis 57 (98.3) VUR 13 (92.9) PCKD 3 (100) FMF 10 (90.9) Unknown 100 (96.2) Pre-transplantation dialysis modality Hemodialysis 177 (95.2) Peritoneal dialysis 25 (100.0) Donation Living donation 167 (96.5) Cadaver 35 (92.1) Familial status 1st degree 143 (96.6) 2nd degree 6 (100) 3rd degree 1 (100) Marriage 17 (94.4) Acute rejection history Yes 21 (95.5) No 181 (95.8) Immunosuppression protocols AzaþPredþTac 11 (100) AzaþPredþSir 4 (80) MMFþPredþTac 74 (96.1) MMFþPred þCsA 87 (94.6) MMFþPredþSir 26 (100) Body mass index Low or normal 111 (96.5) Overweight 66 (94.3) Obese 25 (96.2) Smoking No 150 (95.5) Yes 52 (96.3) Menopause Yes 15 (100.0) No 43 (95.6)
Osteopenia
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Table 2. Pre- and Post-transplantation Bone Minderal Density (BMD) Measurements in All Patients From All 4 Areas Taken Together Into Consideration (400 Measurements in 100 Patients)
1816 Kruskal-Wallis tests. Nominal parameters were analyzed by means of the chi-square test. A value for P of <.05 was considered to be statistically significant.
RESULTS
The median and mean durations from the time of the transplantation to the last BMD measurement were 6 years (range, 2e8 years) and 5.7 1.6 years. There was no correlation between the change between the 2 BMD measurements and the duration from the time of transplantation to the last BMD measurement (P > .05). Moreover, when the patients were evaluated in 2 groups according to the time from transplantation to the last BMD measurement (<5 years or 5 years), BMD scores did not exhibit any statistically significant difference between the 2 groups (P > .05). At the pre-transplantation period, no statistical correlations could be observed between BMI, type of the dialysis received, etiology of ESRD, menopausal status in females, use of any treatments for osteoporosis, or presence of HBV or HCV seropositivity and BMD values (P > .05). Stratification of the study groups according to sex revealed that 60.7% of the women and 81.9% of the men were osteopenic and/or osteoporotic (P < .05). The rates for osteopenia/ osteoporosis among nonsmokers and smokers were 69.9% and 92.6%, respectively (P < .05). Similarly, no statistically significant correlations could be revealed for the post-transplantation period between the use of any treatments for osteoporosis, the type of the dialysis treatment previously received, the presence of HBV or HCV seropositivity, the type of the immunosuppressive treatment protocol administered, the age of the patient at the time of transplantation, or any earlier history of acute rejection and the post-transplantation BMD values (P > .05). The rate of the patients whose BMD scores from any of the 4 regions (lumbar, femoral neck, radius, and ultradistal radius) corresponded to osteopenia/osteoporosis was 70%, whereas the rate of the patients whose BMD scores from all 4 regions were evaluated as “normal” was 30%. Osteopenia/osteoporosis was more common in men than in women in this study group (79.2% vs 46.4%, respectively) (P < .05). The rate of osteopenia/osteoporosis among the smokers was also higher than that among the nonsmokers (96.3% vs 60.3%, respectively; P < .05). Significantly lower levels of serum PTH were detected in patients after renal transplantation (P < .0001). Acute rejection occurred in 11% of the patients involved in this study, and those patients were treated with the use of pulse steroids. Only 1 of those patients received the diagnosis of acute rejection a 2nd time. No correlations could be shown between the existence of acute rejection and osteoporosis in this study (P > .05). Statistically significant correlations were observed when all BMD scores measured both before and after transplantation in all patients were carefully compared. BMD scores of all 4 areas were shown to be increased after transplantation (P < .0001; Table 2). When stratification based on patient BMD scores was performed and a comparison was made according to
CANOZ, YAVUZ, ALTUNOGLU ET AL
osteopenia/osteoporosis diagnoses, pre-transplantation diagnoses were found to be significantly different from the posttransplantation ones (P < .0001; Table 2). Accordingly, when pre- and post-transplantation BMD measurements in all patients from all 4 areas were taken together into consideration, and therefore 400 measurements in 100 patients were evaluated, 78.3% of the pre-transplantation diagnoses remained the same after transplantation, whereas 7.5% converted from osteopenia to normal BMD, 3% transformed from osteoporosis to normal BMD, and 8% changed from osteoporosis to osteopenia. However, 0.5% of the patients who were diagnosed with osteopenia before transplantation were later evaluated as having osteoporosis. This change in BMD scores was statistically significant (P < .0001; Table 2). All women with normal pre-transplantation BMD values had similarly normal post-transplantation BMD values, whereas 93.5% of all men with normal pre-transplantation BMD values had normal post-transplantation BMD values; 3.6% of the men with normal pre-transplantation BMD values developed osteopenia after transplantation and 2.9% of the men with normal pre-transplantation BMD values developed osteoporosis following transplantation. This difference was statistically significant (P < .05; Table 2). When the changes in BMD scores for all 4 areas were evaluated according to sex, no statistically significant differences could be demonstrated between the groups (P > .05). Only the changes in radial scores were shown to be significantly different when the changes in BMD scores were evaluated according to the relevant etiology. The differences in pre- and post-transplantation BMD scores in patients with polycystic kidney disease (PCKD) were significantly higher than those in patients with other etiologies, and the changes were toward lower BMD scores (P < .05; Table 2). The type of the dialysis received, the source of the donor organ (cadaveric vs living donors), the use of any post-transplantation medications for osteoporosis treatment, and the development of acute rejection were all associated with the changes in BMD scores (P > .05; Table 2). This study also demonstrated that smoking affected the changes in BMD scores obtained from the lumbar and femoral neck areas. The changes in the mean BMD scores of the nonsmoker patients were higher than those of the smokers, and the changes were toward higher BMD scores (P < .05; Table 2). Smoking was identified as an important determinant of both pre- and post-transplantation changes in BMD scores. Accordingly, nonsmoker patients with normal BMD scores before transplantation were more likely to maintain normal BMD scores after transplantation than smokers with normal BMD scores before transplantation (Table 2). Smokers with osteopenia and/or osteoporosis before transplantation were prone to more severe osteopenia and/or osteoporosis after transplantation (P < .05; Table 2). The changes in BMD scores from the lumbar 1e4 and femoral neck areas were found to be significantly associated with menopausal status when menstruating and postmenopausal women are compared. Correspondingly, the changes in post-menopausal women were significantly higher
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than those in menstruating women (P < .05; Table 2). Patient blood groups, BMI, type of the immunosuppressive treatment, and HBV and HCV seropositivity were shown not to be associated with changes in BMD scores (P > .05; Table 2). DISCUSSION
This study indicates that although BMD scores increase after successful renal transplantation, the pre-transplantation and post-transplantation BMD-associated diagnoses remain the same in general when BMD-associated diagnoses are considered. Successful renal transplantation was shown to have beneficial effects on bone metabolism, including the reestablishment of calcitriol synthesis and reduction in PTH levels, as well as beneficial effects on phosphorus and aluminum metabolism. However, the disorders of bone and mineral metabolism due to pre-existing uremia (residual hyperparathyroidism, low- or high-turnover osteodystrophy) as well as immobilization during the early post-transplantation period and the subsequent use of immunosuppressive treatments may have detrimental effects on bone mass [10]. Although the appearance of the bone loss within the 1st year after transplantation is well documented, data about the loss in the bone mass at later periods are controversial in the literature. Spiechowicz et al demonstrated that 50% of the patients were osteopenic and 20% osteoporotic at the 4th year after transplantation [11]. Babarykin et al investigated a total of 52 recipients who were within their post-transplantation 1st year (early-term), within the 1st and the 5th years (mid-term), and were transplanted >5 years before (long-term). They stated that 50% of the early-term recipients were osteopenic and 8.3% osteoporotic, whereas the loss in the bone mass was diminished in the mid-term recipients (32% osteopenic and 4% osteoporotic) and again enhanced in the long-term recipients (46.7% osteopenic and 26.7% osteoporotic) [12]. However, our results indicated that 30% of the recipients had totally normal BMD scores from all 4 measurement areas (lumbar 1e4, femoral neck, radius, and ultradistal radius), whereas in 70% of the recipients, BMD measurements from any of the 4 areas corresponded to either osteopenia or osteoporosis. Moreover, when the patients were evaluated in 2 groups according to the time from transplantation to the last BMD measurement (<5 years or 5 years), BMD scores did not exhibit any statistically significant difference between the 2 groups. The reason for the lower rate of osteopenia and osteoporosis in the femur than in the lumbar spinal area can be explained by the fact that the trabecular bone is the most metabolically active bone type and that lumbar vertebrae are the first bones affected in the disorders of bone metabolism. In the present study, the rate of the detection of osteopenia and/or osteoporosis by the related post-transplantation lumbar and femoral neck BMD values were 42% and 14%, respectively. In contrast, another study claimed that the rate of the detection of osteopenia and/or osteoporosis in the lumbar spinal area was lower than that in the femoral neck in 20 kidney
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transplant patients with a mean post-transplantation follow-up of 4 years [13]. However, similarly to our study, Pichette et al reported that osteopenia was detected more in the lumbar area than in the femoral area (33% vs 10%) at the posttransplantation 8th year [14]. Conflicting data exist in the literature regarding the relationship between recipient age and post-transplantation osteoporosis development. Kusec et al suggested that recipient age and post-transplantation long-term BMD values are negatively correlated [15]. However, in a recent study by Marcen et al, no correlations could be shown between the ages and lumbar BMD values of the transplant recipients during a follow-up of 10 years [16]. Our study did not reveal any statistically significant associations between post-transplantation BMD score and recipient age. Considering that the mean age of the patients involved in this study was 32.3 10 at the time of the transplantation, we think that the younger patient group included in our study compared with those included in other studies where significant associations between age and BMD values were found was the main reason for the lack of any documented associations. Obesity is known to influence BMD favorably during the adulthood. As BMI increases, serum estrone and estradiol levels increase by the conversion of androstenedione into estrone in the adipose tissue. Literature data suggests that increased BMI influences the bone mass favorably during the post-transplantation period [17e19]. Yet some authors failed to document any significant associations between BMI and BMD values in renal transplant patients during long-term follow-up [17]. In a prospective study covering 4 years, Marcen et al did not find a significant association between BMI and changes in BMD [18]. Similarly in the present study, we were unable to show any statistically significant associations between BMI and the rate of the changes in post-transplantation BMD values. Various results are reported related to the duration of post-transplantation follow-up in the literature. The use of steroids was suggested to be the main cause of the reported negative correlation between bone volume and time after renal transplantation [12]. On the other hand, it was demonstrated in some other studies that the lumbar and femoral neck areas were not significantly affected during the post-transplantation period, whereas the trabecular bonee rich radius area was negatively influenced by the time after the transplantation [19]. Yet it was reported in some studies that the time after the transplantation had no influence on the bone mass [17]. Kusec et al indicated that changes in BMD values did not differ significantly between the end of the 1st year and 19 years after transplantation [15]. Our study also did not reveal any significant associations between changes in BMD and the time after transplantation. This may be due to the early recognition and therefore medical treatment and replenishment of bone loss. A number of studies in the literature suggest that the duration of dialysis during the pre-transplantation period has negative influences on BMD [20]. It is known that in patients with ESRD-secondary hyperparathyroidism, chronic acidosis
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and aluminum-containing phosphate binders that were commonly used in earlier years as well as decreased physical activity may decrease bone density and increase the risk of fractures. However, Marcen et al and Vang et al reported that no associations could be demonstrated between duration and type of dialysis, postmenopausal status, or recipient age at the time of renal transplantation and osteoporosis development [18,20]. Our study also could not assign any significant relationships between duration of dialysis and BMD. This lack of relationship may be the result of regular testing and treatment of patients on dialysis for osteoporosis. The present study did not reveal any statistically significant associations between the sex of the patients and the pre- or post-transplantation changes in BMD scores. A significant sex-dependent difference appeared for the postmenopausal women in this study. Many studies suggest that being in the postmenopausal period is a risk factor for osteoporosis development [21]. In our study, the rate of the changes in post-transplantation BMD scores was significantly higher in postmenopausal women than in menstruating women. However, it should be noted that only the changes in scores were significantly different between the postmenopausal and menstruating women, not the rates of osteoporosis. Limited data are available in the literature regarding the etiology of chronic renal failure (CRF) and posttransplantation BMD changes. Conley et al could not report any statistically significant differences between various CRF etiologies in patients with severe osteoporosis that could cause fragility fractures [22]. Similarly, our study did not reveal any significant associations between pre-transplantation BMD levels and different CRF etiologies. Although CRF patients in whom glomerulonephritis was the main causative disorder received long-term steroid treatment, patients on steroids were closely followed for osteoporosis development and were medically treated when necessary to prevent steroid-induced osteoporosis. We think that is the reason that there were no significant associations between BMD levels and various etiologies of CRF. The same was also true for the duration of dialysis and menopausal status of women. Considering the changes in post-transplantation BMD scores, a negative correlation could be demonstrated only between the patients with PCKD and BMD scores from the radius area in this study. We think that this correlation was not significant because there were only 2 PCKD patients included in the study. The relationship between the risk of osteoporosis and post-transplantation steroid dose as well as the presence of acute rejection was documented in numerous studies [23]. Still, the results from those studies may vary depending on the study design. For example, Heaf et al reported that the time after transplantation had no influence on bone mass in 125 patients with a mean post-transplantation follow-up of 5.7 years. That result was ascribed to the reduction of the administered steroid dose during the post-transplantation period [24].
CANOZ, YAVUZ, ALTUNOGLU ET AL
No significant relationships between the development of acute rejections and post-transplantation BMD scores as well as BMD changes could be detected in the present study, either. This was probably due to the low number of patients with acute rejection and the administration of lower doses of pulse steroids within a short period of time (1e2 g/ total). The influence of the cumulative steroid dose on osteoporosis development was not noted in this study, because for all patients the maintenance steroid treatment was the same (5 mg/d) and the immunosuppressive therapy protocols included steroids. Only a few studies have investigated the relationship between smoking and the development of osteoporosis in patients with CRF and kidney transplants, and the reported results were similar. Smoking during the post-transplantation period was shown to be a risk factor for osteoporosis development in one study [25]. Similarly, the results of the present study demonstrated that the rate of osteoporosis before transplantation was higher in smokers than in nonsmokers. Moreover, our study revealed that smoking affected the preand post-transplantation changes in BMD. Accordingly, the rate of conversion to osteopenia and/or osteoporosis was higher in the smokers with normal pre-transplantation BMD levels than that in the nonsmokers with normal pretransplantation BMD levels. We also investigated the changes in BMD scores after stratification of the study group depending on the source of the donor organ, either cadaveric or living donor. No associations could be documented between the changes in BMD scores and the source of the donor organ as well as the degree of consanguinity of the donors. To the best of our knowledge, the related literature lacks detailed studies investigating the relationship between the changes in BMD and the source of the donor organs. Different results related to the associations between the post-transplantation bone loss and immunosuppressive agents other than steroids were reported in various studies in the literature [24]. Heaf et al suggested an inverse correlation between the serum cyclosporine levels and bone mass [24]. A limited number of studies comparatively investigating the use of sirolimus, mycophenolate mofetil, and azathioprine demonstrated that their effects on the bone mass were only minimal [26]. No relationships could be demonstrated between the immunosuppressive therapy protocols used and the posttransplantation BMD scores measured as well as the posttransplantation BMD-associated diagnoses in our study. This may be due to the regular treatment of patients for osteoporosis during the post-transplantation period. After the introduction of the stimulation of PTH secretion by decreased calcium absorption due to post-transplantation administration of steroids, the idea that serum PTH levels alone were not sufficient to reflect bone turnover began to be increasingly accepted [27]. Basic mechanisms of the changes in bone remodeling are described with factors that appear during the post-transplantation period, such as hypophosphatemia and the effects of glucocorticoids [28]. Although the posttransplantation levels of serum PTH, phosphorus, blood
SUCCESSFUL RENAL TRANSPLANTATION
urea nitrogen, creatinine, and ALP decreased significantly in our study, no statistically significant associations could be documented between that decrease and the changes in BMD. The main reason for the persisting BMD-associated diagnoses after transplantation despite the improvements in the biochemical parameters that influence bone formation and resorption may be the post-transplantation activation of additional factors that result in osteoporosis. In conclusion, this study revealed that despite the increase in BMD scores after transplantation, this improvement in BMD scores was not reflected in the BMD-associated diagnoses in general, and pre- and post-transplantation BMDassociated diagnoses did not differ significantly in patients with kidney transplants. The most important factor that influences the development of osteopenia and/or osteoporosis after renal transplantation is the pre-transplantation BMD value. Therefore, it is essential to closely and regularly follow patients for pre-transplantation BMD and to administer the appropriate medical treatment when necessary. REFERENCES [1] Tanko LB, Bagger YZ, Christiansen C. Low bone mineral density in the hip as a marker of advanced atherosclerosis in elderly women. Calcif Tissue Int 2003;73:15e20. [2] Stehman-Breen CO, Sherrard DJ, Alem AM, et al. Risk factors for hip fracture among patients with end-stage renal disease. Kidney Int 2000;58:2200e5. [3] El-Agroudy AE, El-Husseini AA, El-Sayed M, et al. A prospective randomized study for prevention of postrenal transplantation bone. Kidney Int 2005;67:2039e45. [4] Traindl O, Langle F, Reading S, et al. Secondary hyperparathyroidism and acute tubular necrosis following renal transplantation. Nephrol Dial Transplant 1993;8:173e6. [5] Velasquez-Forero F, Mondragon A, Herrero B, et al. Adynamic bone lesion in renal transplant recipients with normal renal function. Nephrol Dial Transplant 1996;11(Suppl 3):58e64. [6] Felsenfeld AJ, Gutman RA, Drezner M, et al. Hypophosphatemia in long-term renal transplant recipients: effects on bone histology and 1,25-dihydroxycholecalciferol. Miner Electrolyte Metab 1986;12:333e41. [7] Orcel P, Denne MA, de Vernejoul MC. Cyclosporin-A in vitro decreases bone resorption, osteoclast formation, and the fusion of cells of the monocyte-macrophage lineage. Endocrinology 1991;128:1638e46. [8] Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: Pathogenesis and management. Ann Intern Med 1990;112: 352e64. [9] Westeel FP, Mazouz H, Ezaitouni F, et al. Cyclosporine bone remodeling effect prevents steroid osteopenia after kidney transplantation. Kidney Int 2000;58:1788e96.
1819 [10] Sadideen Hazim, Covic Adrian, Goldsmith David. Mineral and bone disorder after renal transplantation. Int Urol Nephrol 2008;40:171e84. [11] Spiechhowicz U, Kokot F, Wiecek A. Markers of calciumphophate metabolism and bone alterations in long term kidney transplant patients. Przegl Lek 2003;60:690e4. [12] Babarykin D, Adamsone I, Amerika D, et al. Disorders of calcium metabolism at various times after renal transplantation. Ann Transplant 1999;4:46e53. [13] Carlini RG, Rojas E, Arminio A, et al. What are the bone lesions in patients with more than four years of a functioning renal transplant? Nephrol Dial Transplant 1998;13(Suppl 3): 103e4. [14] Pichette V, Bonnardeux A, Prudhomme L. Long term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study. Am J Kidney Dis 1996;28:105e14. [15] Kusec V, Smalcelj R, Cvijetic S. Parathyroid hormone and bone mass after kidney transplantation. Acta Med Croatica 2002;56:17e20. [16] Marcen R, Caballero C, Uriol O. Prevalence of osteoporosis, osteopenia, and vertebral fractures in long-term renal transplant recipients. Transplant Proc 2007;39:2256e8. [17] Parker CR, Freemont AJ, Blackwell PJ, et al. Crosssectional analysis of renal transplantation osteoporosis. J Bone Miner Res 1999;14:1943e51. [18] Marcen R, Caballero C, Pascual J. Lumbar bone mineral density in renal transplant patients on neoral and tacrolimus: a fouryear prospective study. Transplantation 2006;81:826e31. _ Turan M, Erdal R, [19] Ugur A, Güvener N, Is¸ıklar I, Haberal M. Osteoporosis after renal transplantation: single center experience. Transplantation 2001;71:645e9. [20] Wang H, Chang C, Chu S. Osteoporosis after kidney transplantaion: prelimary report from a single center. Transplant Proc 2008;40:2412e3. [21] Patel S, Kwan JT, McCloskey E, et al. Prevalence and causes of low bone density and fractures in kidney transplant patients. J Bone Miner Res 2001;16:1963e70. [22] Conley E, Muth B, Samaniego M. Biphosphonates and bone fractures in long term kidney transplant recipients. Transplantation 2008;86:231e7. [23] Trabulus S, Apaydın S, Altıparmak MR, et al. Osteoporosis after renal transplantation. Nefrologia 2003;23(Suppl 2):127e30. [24] Heaf J, Tvedegaard E, Kanstrup IL, et al. Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease. Clin Transplant 2000;14:457e63. [25] Taal MW, Masud T, Gren D, Cassidy MJ. Risk factors for reduced bone density in hemodialysis patients. Nephrol Dial Transplant 2004;14:1922e8. [26] Aroldi A, Tarantino A, Montagnino G, et al. Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients: a prospective study. Transplantation 1997;63:380e6. [27] Sperschneider H, Stein G. Bone disease after renal transplantation. Nephrol Dial Transplant 2003;18:874e7. [28] Bellorin-Font E, Rojas E, Carlini RG, et al. Bone remodeling after renal transplantation. Kidney Int Suppl 2003;85: 125e8.
ABSTRACT Background. Successful renal transplantation corrects many disorders of bone and mineral metabolism owing to the normalization of serum levels of calcium and phosphorus and restoration of calcitriol production. However, successful transplantation does not guarantee complete resolution of the pre-transplantation osteopathy. Methods. This study evaluated 100 patients who underwent successful renal transplantation. We determined the possible risk factors for osteoporosis among 72 male and 28 female renal transplant patients of mean age 32.3 10.0 years with 81% of them recipients of living-related grafts. Bone mineral densitometry (BMD) was performed in all patients before and 1 year after transplantation. Routine test results and demographic data were recorded. Results. At the time of transplantation 76% of the patients had osteoporosis or osteopeni and only 24% of them had normal BMD in 4 regions (femur neck, lumber, radius, and ultradistal). After transplantation, 70% of them had osteopororosis or osteopeni and 30% were normal. After renal transplantation, BMD scores increased (P > .05) although the diagnosis of the bone disease did not change (P < .05). Only preexisting osteodystrophy and smoking were found to be important risk factors for post-transplantation osteoporosis. Conclusions. After renal transplantation, BMD scores increased whereas the diagnosis of bone disease did not change statistically. We found that medical management of osteopenia/osteoporosis before transplantation and smoking habit are the main factors to prevent post-transplantation osteoporosis. Further long-term studies may be more helpful for evaluating the risk factors of post-transplantation osteoporosis.
S
ECONDARY hyperparathyroidism, adynamic bone disease, osteomalacia, the use of corticosteroids, and chronic acidosis may all decrease bone density and increase the risk of fractures in patients with end-stage renal disease (ESRD) [1,2]. Compared with dialysis, renal transplantation may be more beneficial in improving the problems that develop due to uremia in patients with ESRD, although the success rate declines in disorders of the bone metabolism. Histologic evidences of osteodystrophy and osteopenia are commonly detected in most patients with successful kidney transplants. Osteoporosis may also develop in early phases owing to the loss of the bone mass. Moreover, many patients experience the risk of avascular necrosis within the 1st 2 years after transplantation [3]. Ongoing hyperparathyroidism, hypercalcemia, and hyperphosphatemia after renal transplantation also are risk factors
for the deterioration of existing bone diseases [4]. Various studies in renal transplant patients with osteopenia indicated the existence of many histologic structures that were not related to hyperparathyroidism. Low-turnover bone lesions similar to osteoporosis [5] and even osteomalacia were detected in bone biopsies [6]. High doses of tacrolimus in patients with kidney transplants, as well as cyclosporine, which is known to reduce osteoclast formation and inhibit osteoclastic bone resorption, enhance the loss of bone mass [7]. A consensus on the reduction of *Address correspondence to Alpaslan Altunoglu, Nephrology Specialist, Bas¸kent University Faculty of Medicine, 5 Sok, No: 48 06490 Bahçelievler, Ankara, Turkey. E-mail: alpaltinoglu@yahoo. com
ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.05.006
Transplantation Proceedings, 47, 1813e1819 (2015)
1813
1814
CANOZ, YAVUZ, ALTUNOGLU ET AL Table 1. Descriptive Characteristics of the Patients Characteristic
Median age at transplantation: 32.3 10.0 y Sex Female Male Etiology of renal failure Hypertension Glomerulonephritis VUR PCKD FMF Unknown Pre-transplantation dialysis modality Hemodialysis Peritoneal dialysis Donation Living donation Cadaver Familial status 1st degree 2nd degree 3rd degree Marriage Acute rejection history Yes No Immunsuppression protocols Azathioprine þ prednisolone þ tacrolimus Azathioprine þ prednisolone þ sirolimus MMF þ prednisolone þ cyclosporine MMF þ prednisolone þ tacrolimus MMF þ prednisolone þ sirolimus Hepatitis B virus Positive Negative Hepatitis C virus Positive Negative Smoking Yes No Body mass index (kg/m2) Underweight (<18.5) Healthy weight (18.5e24.9) Overweight (25.0e29.9) Obese (30)
%*
28.0 72.0 13.0 27.0 5.0 2.0 5.0 48.0 87.0 13.0 81.0 19.0 83 4 2 11 11.0 89.0 5 2 40 42 11 10.0 90.0 10.0 90.0 27.0 73.0 2 48.0 36.0 14.0
Abbreviations: VUR, vesicoureteral reflux; PCKD, polycystic kidney disease; FMF, familial Mediterranean fever; MMF, mycophenolate mofetil. *The number of patients is 100, so the percentages are the same as the numbers.
osteoblast formation and precipitation of the loss of the bone mass by the use of glucocorticoids after renal transplantation has recently been achieved [8]. The increase in osteocalcin levels due to the effects of cyclosporine after renal transplantation contributes to the low-turnover bone disease developing under the action of glucocorticoids [9]. Rapid loss of the bone mass in patients with kidney transplants can not yet be prevented. Post-transplantation osteodystrophy (mostly osteoporosis) and osteonecrosis are
among the most important causes of long-term morbidity in patients with kidney transplants. Therefore, we investigated the factors that influence bone mineral density (BMD) after successful renal transplantation. METHODS One hundred patients who received kidney transplants in Baskent University, Ankara, Turkey, were randomly included in this study (72 men, 28 women). The descriptive characteristics of the patients are summarized in Table 1. Pre- and post-transplantation BMD scores as well as the means of some biochemical parameters are presented in Table 2. Inclusion criteria were: absence of hyperparathyroidism at the time of transplantation (intact parathyroid hormone [PTH] <600 ng/mL); no history of parathyroidectomy; and absence of a comorbid disease that affects bone metabolism, such as hyperthroidism, Cushing syndrome, or advanced liver disease. Patients were excluded if they displayed poor renal function, namely, serum creatinine value >2 mg/dL or proteinuria >1,000 mg/d. None of the patients received vitamin D or analogues during the post-transplantation period. Bone mineral densitometry was performed on all patients at the 1st year after renal transplantation with the use of dual-energy x-ray absorptiometry (DEXA-Hologic, model QDR 1500A, Watham, Massachusetts). Osteoporosis was defined by the World Health Organization criteria as a T score of 2.5 or more below the SD. Osteopenia and normal values were defined as T scores from 1.5 to 2.5 SD and over 1.5 SD, respectively. Patients were divided into 3 groups according to BMD results: group 1 with normal values (T score greater than 1.5 SD), group 2 with osteopenia (T score from 1.5 to 2.5 SD), and group 3 with osteoporosis (T score less than 2.5 SD). We analyzed differences in pre- and post-transplantation T score values, as well as clinical, laboratory, and demographic data. Patients received prednisone, azathioprine, mycophenolate mofetil, and cyclosporine for maintenance immunosuppression. Cyclosporine was initiated at a dose of 8e10 mg/kg/d orally in 2 divided doses and then adjusted to maintain whole-blood levels of 100e200 ng/mL with the use of a modular ISE 900 machine (Cedia Cyclosporine Assay; Roche Diagnostic Corp, Indianapolis, Indiana) with a homogeneous enzyme immunoassay system. Prednisolone was initiated at 1e2 mg/kg/ d orally and tapered over 6 months to a maintenance dosage of 10 mg/d. An acute rejection episode was suspected based on clinical and biochemical parameters and confirmed by means of renal allograft biopsy. It was initially treated with intravenous pulse methylprednisolone. Steroid-resistant acute rejection episodes were treated with OKT3. Laboratory parameters were performed with the use of standard laboratory techniques. Statistical analyses were performed with the use of SPSS software (Statistical Package for the Social Sciences, version 15.0; SPSS, Chicago, Illinois). All numeric variables, such as biochemical parameters and BMD scores, are expressed as mean SD. The values of categoric variables (history of smoking, sex, menopausal status, body mass index [BMI] scores, dialysis modality, the presence of hepatitis B virus [HBV] or hepatitis C virus [HCV] seropositivity, BMD-associated diagnoses, donor of transplantation, acute rejection, immunosuppressive protocol) are presented as n (%). McNeamar test was used for showing the differences of pre- and post-transplantation BMD-associated diagnoses. We analyzed the values of variables such as age, alkaline phosphatase (ALP), phosphorus, and duration of dialysis with the use of Pearson correlation analysis technique. All numeric variables are expressed as mean SD. Intergroup differences were compared by means of the Student t, Mann-Whitney U, 1-way analysis of variance, or
Pre-transplantation BMD Normal
Osteopenia
Osteoporosis
Post-transplantation BMD, n (%*) Normal
Osteoporosis
Normal
e 5 (3.3)
2 (3.3) 2 (1.3)
9 (64.3) 21 (55.3)
5 (35.7) 15 (39.5)
e 2 (5.3)
2 (5.3) 10 (10.1)
e 1 (1.7) 1 (7.1) e 1 (9.1) 2 (1.9)
2 (9.5) e e e e 2 (1.9)
3 (42.9) 9 (60) e e e 18 (62.1)
3 (42.9) 5 (33.3) 1 (100) e e 11 (37.9)
1 (14.3) 1 (6.7) e e e e
2 (8.3) 2 (5.7) 1 (20) e 2 (22.2) 5 (8.5)
5 (2.7) e
4 (2.2) e
27 (55.1) 3 (100.0)
20 (40.8) e
2 (4.1) e
10 (8.8) 2 (8.3)
26 (23.0) 6 (25)
77 (68.1) 16 (66.7)
3 (1.7) 2 (5.3)
3 (1.7) 1 (2.6)
27 (58.7) 3 (50)
17 (37) 3 (50)
2 (4.3)
12 (10.6) e
25 (22.1) 7 (29.2)
76 (67.3) 17 (70.8)
3 (2) e e e
2 (1.4) e e 1 (5.6)
24 1 1 1
(61.5) (100) (33.3) (33.3)
14 (35.9) d 2 (66.7) 1 (33.3)
1 (2.6) e e 1 (33.3)
9 (10.1) e 1 (25) 2 (13.3)
21 1 2 1
59 4 1 12
1 (4.5) 4 (2.1)
e 4 (2.1)
5 (62.5) 25 (56.8)
3 (37.5) 17 (38.6)
e 2 (4.5)
e e 2 (2.6) 3 (3.3) e
e 1 (20) 1 (1.3) 2 (2.2) e
2 1 13 10 4
2 (1.7) 3 (4.3) e
2 (1.7) 1 (1.4) 1 (3.8)
3 (1.9) 2 (3.7) e e
(66.7) (50) (56.5) (52.6) (80)
Osteopenia
1 1 9 9
Osteoporosis
Normal
1 (7.1) 11 (8.9)
Osteopenia
Osteoporosis
10 (26.3) 22 (22.2)
26 (68.4) 67 (67.7)
6 5 1 1 4 15
16 28 3 4 3 39
(25) (14.3) (20) (20) (44.4) (25.4)
(23.6) (20) (50) (6.7)
(66.7) (80) (60) (80) (33.3) (66.1)
(66.3) (80) (25) (80)
5 (35.7) 27 (22)
8 (57.1) 85 (69.1)
(33.3) (50) (39.1) (47.4) e
e e 1 (4.3) e 1 (20)
1 (16.7) e 8 (13.3) 3 (5.3) e
1 (16.7) e 11 (18.3) 16 (28.1) 4 (30.8)
4 1 41 38 9
20 (74.1) 9 (42.9) 1 (25)
6 (22.2) 12 (57.1) 2 (50)
1 (3.7) e 1 (25)
1 (1.7) 7 (13.2) 4 (15.4)
15 (25.9) 10 (18.9) 7 (26.9)
42 (72.4) 36 (67.9) 15 (57.7)
4 (2.5) e
17 (50) 13 (72.2)
15 (44.1) 5 (27.8)
2 (5.9) e
23 (22.89) 9 (25)
68 (67.3) 25 (69.4)
e 2 (4.4)
3 (60.0) 6 (66.7)
2 (40.0) 3 (33.3)
e e
8 (40.0) 2 (11.1)
10 (50.0) 16 (88.9)
Abbreviations: Aza, azathioprine; Pred, prednisone; Tac, tacrolimus; Sir, sirolimus; CsA, cyclosporine; other abbreviations as in Table 1. *Percentages of patients with pre-transplantation normal, osteopenia, or osteoporosis.
10 (9.9) 2 (5.6) 2 (10.0) e
(66.7) (100) (68.3) (66.7) (69.2)
1815
Sex Female 58 (96.7) Male 144 (95.4) Etiology of renal failure Hypertension 19 (90.5) Glomerulonephritis 57 (98.3) VUR 13 (92.9) PCKD 3 (100) FMF 10 (90.9) Unknown 100 (96.2) Pre-transplantation dialysis modality Hemodialysis 177 (95.2) Peritoneal dialysis 25 (100.0) Donation Living donation 167 (96.5) Cadaver 35 (92.1) Familial status 1st degree 143 (96.6) 2nd degree 6 (100) 3rd degree 1 (100) Marriage 17 (94.4) Acute rejection history Yes 21 (95.5) No 181 (95.8) Immunosuppression protocols AzaþPredþTac 11 (100) AzaþPredþSir 4 (80) MMFþPredþTac 74 (96.1) MMFþPred þCsA 87 (94.6) MMFþPredþSir 26 (100) Body mass index Low or normal 111 (96.5) Overweight 66 (94.3) Obese 25 (96.2) Smoking No 150 (95.5) Yes 52 (96.3) Menopause Yes 15 (100.0) No 43 (95.6)
Osteopenia
SUCCESSFUL RENAL TRANSPLANTATION
Table 2. Pre- and Post-transplantation Bone Minderal Density (BMD) Measurements in All Patients From All 4 Areas Taken Together Into Consideration (400 Measurements in 100 Patients)
1816 Kruskal-Wallis tests. Nominal parameters were analyzed by means of the chi-square test. A value for P of <.05 was considered to be statistically significant.
RESULTS
The median and mean durations from the time of the transplantation to the last BMD measurement were 6 years (range, 2e8 years) and 5.7 1.6 years. There was no correlation between the change between the 2 BMD measurements and the duration from the time of transplantation to the last BMD measurement (P > .05). Moreover, when the patients were evaluated in 2 groups according to the time from transplantation to the last BMD measurement (<5 years or 5 years), BMD scores did not exhibit any statistically significant difference between the 2 groups (P > .05). At the pre-transplantation period, no statistical correlations could be observed between BMI, type of the dialysis received, etiology of ESRD, menopausal status in females, use of any treatments for osteoporosis, or presence of HBV or HCV seropositivity and BMD values (P > .05). Stratification of the study groups according to sex revealed that 60.7% of the women and 81.9% of the men were osteopenic and/or osteoporotic (P < .05). The rates for osteopenia/ osteoporosis among nonsmokers and smokers were 69.9% and 92.6%, respectively (P < .05). Similarly, no statistically significant correlations could be revealed for the post-transplantation period between the use of any treatments for osteoporosis, the type of the dialysis treatment previously received, the presence of HBV or HCV seropositivity, the type of the immunosuppressive treatment protocol administered, the age of the patient at the time of transplantation, or any earlier history of acute rejection and the post-transplantation BMD values (P > .05). The rate of the patients whose BMD scores from any of the 4 regions (lumbar, femoral neck, radius, and ultradistal radius) corresponded to osteopenia/osteoporosis was 70%, whereas the rate of the patients whose BMD scores from all 4 regions were evaluated as “normal” was 30%. Osteopenia/osteoporosis was more common in men than in women in this study group (79.2% vs 46.4%, respectively) (P < .05). The rate of osteopenia/osteoporosis among the smokers was also higher than that among the nonsmokers (96.3% vs 60.3%, respectively; P < .05). Significantly lower levels of serum PTH were detected in patients after renal transplantation (P < .0001). Acute rejection occurred in 11% of the patients involved in this study, and those patients were treated with the use of pulse steroids. Only 1 of those patients received the diagnosis of acute rejection a 2nd time. No correlations could be shown between the existence of acute rejection and osteoporosis in this study (P > .05). Statistically significant correlations were observed when all BMD scores measured both before and after transplantation in all patients were carefully compared. BMD scores of all 4 areas were shown to be increased after transplantation (P < .0001; Table 2). When stratification based on patient BMD scores was performed and a comparison was made according to
CANOZ, YAVUZ, ALTUNOGLU ET AL
osteopenia/osteoporosis diagnoses, pre-transplantation diagnoses were found to be significantly different from the posttransplantation ones (P < .0001; Table 2). Accordingly, when pre- and post-transplantation BMD measurements in all patients from all 4 areas were taken together into consideration, and therefore 400 measurements in 100 patients were evaluated, 78.3% of the pre-transplantation diagnoses remained the same after transplantation, whereas 7.5% converted from osteopenia to normal BMD, 3% transformed from osteoporosis to normal BMD, and 8% changed from osteoporosis to osteopenia. However, 0.5% of the patients who were diagnosed with osteopenia before transplantation were later evaluated as having osteoporosis. This change in BMD scores was statistically significant (P < .0001; Table 2). All women with normal pre-transplantation BMD values had similarly normal post-transplantation BMD values, whereas 93.5% of all men with normal pre-transplantation BMD values had normal post-transplantation BMD values; 3.6% of the men with normal pre-transplantation BMD values developed osteopenia after transplantation and 2.9% of the men with normal pre-transplantation BMD values developed osteoporosis following transplantation. This difference was statistically significant (P < .05; Table 2). When the changes in BMD scores for all 4 areas were evaluated according to sex, no statistically significant differences could be demonstrated between the groups (P > .05). Only the changes in radial scores were shown to be significantly different when the changes in BMD scores were evaluated according to the relevant etiology. The differences in pre- and post-transplantation BMD scores in patients with polycystic kidney disease (PCKD) were significantly higher than those in patients with other etiologies, and the changes were toward lower BMD scores (P < .05; Table 2). The type of the dialysis received, the source of the donor organ (cadaveric vs living donors), the use of any post-transplantation medications for osteoporosis treatment, and the development of acute rejection were all associated with the changes in BMD scores (P > .05; Table 2). This study also demonstrated that smoking affected the changes in BMD scores obtained from the lumbar and femoral neck areas. The changes in the mean BMD scores of the nonsmoker patients were higher than those of the smokers, and the changes were toward higher BMD scores (P < .05; Table 2). Smoking was identified as an important determinant of both pre- and post-transplantation changes in BMD scores. Accordingly, nonsmoker patients with normal BMD scores before transplantation were more likely to maintain normal BMD scores after transplantation than smokers with normal BMD scores before transplantation (Table 2). Smokers with osteopenia and/or osteoporosis before transplantation were prone to more severe osteopenia and/or osteoporosis after transplantation (P < .05; Table 2). The changes in BMD scores from the lumbar 1e4 and femoral neck areas were found to be significantly associated with menopausal status when menstruating and postmenopausal women are compared. Correspondingly, the changes in post-menopausal women were significantly higher
SUCCESSFUL RENAL TRANSPLANTATION
than those in menstruating women (P < .05; Table 2). Patient blood groups, BMI, type of the immunosuppressive treatment, and HBV and HCV seropositivity were shown not to be associated with changes in BMD scores (P > .05; Table 2). DISCUSSION
This study indicates that although BMD scores increase after successful renal transplantation, the pre-transplantation and post-transplantation BMD-associated diagnoses remain the same in general when BMD-associated diagnoses are considered. Successful renal transplantation was shown to have beneficial effects on bone metabolism, including the reestablishment of calcitriol synthesis and reduction in PTH levels, as well as beneficial effects on phosphorus and aluminum metabolism. However, the disorders of bone and mineral metabolism due to pre-existing uremia (residual hyperparathyroidism, low- or high-turnover osteodystrophy) as well as immobilization during the early post-transplantation period and the subsequent use of immunosuppressive treatments may have detrimental effects on bone mass [10]. Although the appearance of the bone loss within the 1st year after transplantation is well documented, data about the loss in the bone mass at later periods are controversial in the literature. Spiechowicz et al demonstrated that 50% of the patients were osteopenic and 20% osteoporotic at the 4th year after transplantation [11]. Babarykin et al investigated a total of 52 recipients who were within their post-transplantation 1st year (early-term), within the 1st and the 5th years (mid-term), and were transplanted >5 years before (long-term). They stated that 50% of the early-term recipients were osteopenic and 8.3% osteoporotic, whereas the loss in the bone mass was diminished in the mid-term recipients (32% osteopenic and 4% osteoporotic) and again enhanced in the long-term recipients (46.7% osteopenic and 26.7% osteoporotic) [12]. However, our results indicated that 30% of the recipients had totally normal BMD scores from all 4 measurement areas (lumbar 1e4, femoral neck, radius, and ultradistal radius), whereas in 70% of the recipients, BMD measurements from any of the 4 areas corresponded to either osteopenia or osteoporosis. Moreover, when the patients were evaluated in 2 groups according to the time from transplantation to the last BMD measurement (<5 years or 5 years), BMD scores did not exhibit any statistically significant difference between the 2 groups. The reason for the lower rate of osteopenia and osteoporosis in the femur than in the lumbar spinal area can be explained by the fact that the trabecular bone is the most metabolically active bone type and that lumbar vertebrae are the first bones affected in the disorders of bone metabolism. In the present study, the rate of the detection of osteopenia and/or osteoporosis by the related post-transplantation lumbar and femoral neck BMD values were 42% and 14%, respectively. In contrast, another study claimed that the rate of the detection of osteopenia and/or osteoporosis in the lumbar spinal area was lower than that in the femoral neck in 20 kidney
1817
transplant patients with a mean post-transplantation follow-up of 4 years [13]. However, similarly to our study, Pichette et al reported that osteopenia was detected more in the lumbar area than in the femoral area (33% vs 10%) at the posttransplantation 8th year [14]. Conflicting data exist in the literature regarding the relationship between recipient age and post-transplantation osteoporosis development. Kusec et al suggested that recipient age and post-transplantation long-term BMD values are negatively correlated [15]. However, in a recent study by Marcen et al, no correlations could be shown between the ages and lumbar BMD values of the transplant recipients during a follow-up of 10 years [16]. Our study did not reveal any statistically significant associations between post-transplantation BMD score and recipient age. Considering that the mean age of the patients involved in this study was 32.3 10 at the time of the transplantation, we think that the younger patient group included in our study compared with those included in other studies where significant associations between age and BMD values were found was the main reason for the lack of any documented associations. Obesity is known to influence BMD favorably during the adulthood. As BMI increases, serum estrone and estradiol levels increase by the conversion of androstenedione into estrone in the adipose tissue. Literature data suggests that increased BMI influences the bone mass favorably during the post-transplantation period [17e19]. Yet some authors failed to document any significant associations between BMI and BMD values in renal transplant patients during long-term follow-up [17]. In a prospective study covering 4 years, Marcen et al did not find a significant association between BMI and changes in BMD [18]. Similarly in the present study, we were unable to show any statistically significant associations between BMI and the rate of the changes in post-transplantation BMD values. Various results are reported related to the duration of post-transplantation follow-up in the literature. The use of steroids was suggested to be the main cause of the reported negative correlation between bone volume and time after renal transplantation [12]. On the other hand, it was demonstrated in some other studies that the lumbar and femoral neck areas were not significantly affected during the post-transplantation period, whereas the trabecular bonee rich radius area was negatively influenced by the time after the transplantation [19]. Yet it was reported in some studies that the time after the transplantation had no influence on the bone mass [17]. Kusec et al indicated that changes in BMD values did not differ significantly between the end of the 1st year and 19 years after transplantation [15]. Our study also did not reveal any significant associations between changes in BMD and the time after transplantation. This may be due to the early recognition and therefore medical treatment and replenishment of bone loss. A number of studies in the literature suggest that the duration of dialysis during the pre-transplantation period has negative influences on BMD [20]. It is known that in patients with ESRD-secondary hyperparathyroidism, chronic acidosis
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and aluminum-containing phosphate binders that were commonly used in earlier years as well as decreased physical activity may decrease bone density and increase the risk of fractures. However, Marcen et al and Vang et al reported that no associations could be demonstrated between duration and type of dialysis, postmenopausal status, or recipient age at the time of renal transplantation and osteoporosis development [18,20]. Our study also could not assign any significant relationships between duration of dialysis and BMD. This lack of relationship may be the result of regular testing and treatment of patients on dialysis for osteoporosis. The present study did not reveal any statistically significant associations between the sex of the patients and the pre- or post-transplantation changes in BMD scores. A significant sex-dependent difference appeared for the postmenopausal women in this study. Many studies suggest that being in the postmenopausal period is a risk factor for osteoporosis development [21]. In our study, the rate of the changes in post-transplantation BMD scores was significantly higher in postmenopausal women than in menstruating women. However, it should be noted that only the changes in scores were significantly different between the postmenopausal and menstruating women, not the rates of osteoporosis. Limited data are available in the literature regarding the etiology of chronic renal failure (CRF) and posttransplantation BMD changes. Conley et al could not report any statistically significant differences between various CRF etiologies in patients with severe osteoporosis that could cause fragility fractures [22]. Similarly, our study did not reveal any significant associations between pre-transplantation BMD levels and different CRF etiologies. Although CRF patients in whom glomerulonephritis was the main causative disorder received long-term steroid treatment, patients on steroids were closely followed for osteoporosis development and were medically treated when necessary to prevent steroid-induced osteoporosis. We think that is the reason that there were no significant associations between BMD levels and various etiologies of CRF. The same was also true for the duration of dialysis and menopausal status of women. Considering the changes in post-transplantation BMD scores, a negative correlation could be demonstrated only between the patients with PCKD and BMD scores from the radius area in this study. We think that this correlation was not significant because there were only 2 PCKD patients included in the study. The relationship between the risk of osteoporosis and post-transplantation steroid dose as well as the presence of acute rejection was documented in numerous studies [23]. Still, the results from those studies may vary depending on the study design. For example, Heaf et al reported that the time after transplantation had no influence on bone mass in 125 patients with a mean post-transplantation follow-up of 5.7 years. That result was ascribed to the reduction of the administered steroid dose during the post-transplantation period [24].
CANOZ, YAVUZ, ALTUNOGLU ET AL
No significant relationships between the development of acute rejections and post-transplantation BMD scores as well as BMD changes could be detected in the present study, either. This was probably due to the low number of patients with acute rejection and the administration of lower doses of pulse steroids within a short period of time (1e2 g/ total). The influence of the cumulative steroid dose on osteoporosis development was not noted in this study, because for all patients the maintenance steroid treatment was the same (5 mg/d) and the immunosuppressive therapy protocols included steroids. Only a few studies have investigated the relationship between smoking and the development of osteoporosis in patients with CRF and kidney transplants, and the reported results were similar. Smoking during the post-transplantation period was shown to be a risk factor for osteoporosis development in one study [25]. Similarly, the results of the present study demonstrated that the rate of osteoporosis before transplantation was higher in smokers than in nonsmokers. Moreover, our study revealed that smoking affected the preand post-transplantation changes in BMD. Accordingly, the rate of conversion to osteopenia and/or osteoporosis was higher in the smokers with normal pre-transplantation BMD levels than that in the nonsmokers with normal pretransplantation BMD levels. We also investigated the changes in BMD scores after stratification of the study group depending on the source of the donor organ, either cadaveric or living donor. No associations could be documented between the changes in BMD scores and the source of the donor organ as well as the degree of consanguinity of the donors. To the best of our knowledge, the related literature lacks detailed studies investigating the relationship between the changes in BMD and the source of the donor organs. Different results related to the associations between the post-transplantation bone loss and immunosuppressive agents other than steroids were reported in various studies in the literature [24]. Heaf et al suggested an inverse correlation between the serum cyclosporine levels and bone mass [24]. A limited number of studies comparatively investigating the use of sirolimus, mycophenolate mofetil, and azathioprine demonstrated that their effects on the bone mass were only minimal [26]. No relationships could be demonstrated between the immunosuppressive therapy protocols used and the posttransplantation BMD scores measured as well as the posttransplantation BMD-associated diagnoses in our study. This may be due to the regular treatment of patients for osteoporosis during the post-transplantation period. After the introduction of the stimulation of PTH secretion by decreased calcium absorption due to post-transplantation administration of steroids, the idea that serum PTH levels alone were not sufficient to reflect bone turnover began to be increasingly accepted [27]. Basic mechanisms of the changes in bone remodeling are described with factors that appear during the post-transplantation period, such as hypophosphatemia and the effects of glucocorticoids [28]. Although the posttransplantation levels of serum PTH, phosphorus, blood
SUCCESSFUL RENAL TRANSPLANTATION
urea nitrogen, creatinine, and ALP decreased significantly in our study, no statistically significant associations could be documented between that decrease and the changes in BMD. The main reason for the persisting BMD-associated diagnoses after transplantation despite the improvements in the biochemical parameters that influence bone formation and resorption may be the post-transplantation activation of additional factors that result in osteoporosis. In conclusion, this study revealed that despite the increase in BMD scores after transplantation, this improvement in BMD scores was not reflected in the BMD-associated diagnoses in general, and pre- and post-transplantation BMDassociated diagnoses did not differ significantly in patients with kidney transplants. The most important factor that influences the development of osteopenia and/or osteoporosis after renal transplantation is the pre-transplantation BMD value. Therefore, it is essential to closely and regularly follow patients for pre-transplantation BMD and to administer the appropriate medical treatment when necessary. REFERENCES [1] Tanko LB, Bagger YZ, Christiansen C. Low bone mineral density in the hip as a marker of advanced atherosclerosis in elderly women. Calcif Tissue Int 2003;73:15e20. [2] Stehman-Breen CO, Sherrard DJ, Alem AM, et al. Risk factors for hip fracture among patients with end-stage renal disease. Kidney Int 2000;58:2200e5. [3] El-Agroudy AE, El-Husseini AA, El-Sayed M, et al. A prospective randomized study for prevention of postrenal transplantation bone. Kidney Int 2005;67:2039e45. [4] Traindl O, Langle F, Reading S, et al. Secondary hyperparathyroidism and acute tubular necrosis following renal transplantation. Nephrol Dial Transplant 1993;8:173e6. [5] Velasquez-Forero F, Mondragon A, Herrero B, et al. Adynamic bone lesion in renal transplant recipients with normal renal function. Nephrol Dial Transplant 1996;11(Suppl 3):58e64. [6] Felsenfeld AJ, Gutman RA, Drezner M, et al. Hypophosphatemia in long-term renal transplant recipients: effects on bone histology and 1,25-dihydroxycholecalciferol. Miner Electrolyte Metab 1986;12:333e41. [7] Orcel P, Denne MA, de Vernejoul MC. Cyclosporin-A in vitro decreases bone resorption, osteoclast formation, and the fusion of cells of the monocyte-macrophage lineage. Endocrinology 1991;128:1638e46. [8] Lukert BP, Raisz LG. Glucocorticoid-induced osteoporosis: Pathogenesis and management. Ann Intern Med 1990;112: 352e64. [9] Westeel FP, Mazouz H, Ezaitouni F, et al. Cyclosporine bone remodeling effect prevents steroid osteopenia after kidney transplantation. Kidney Int 2000;58:1788e96.
1819 [10] Sadideen Hazim, Covic Adrian, Goldsmith David. Mineral and bone disorder after renal transplantation. Int Urol Nephrol 2008;40:171e84. [11] Spiechhowicz U, Kokot F, Wiecek A. Markers of calciumphophate metabolism and bone alterations in long term kidney transplant patients. Przegl Lek 2003;60:690e4. [12] Babarykin D, Adamsone I, Amerika D, et al. Disorders of calcium metabolism at various times after renal transplantation. Ann Transplant 1999;4:46e53. [13] Carlini RG, Rojas E, Arminio A, et al. What are the bone lesions in patients with more than four years of a functioning renal transplant? Nephrol Dial Transplant 1998;13(Suppl 3): 103e4. [14] Pichette V, Bonnardeux A, Prudhomme L. Long term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study. Am J Kidney Dis 1996;28:105e14. [15] Kusec V, Smalcelj R, Cvijetic S. Parathyroid hormone and bone mass after kidney transplantation. Acta Med Croatica 2002;56:17e20. [16] Marcen R, Caballero C, Uriol O. Prevalence of osteoporosis, osteopenia, and vertebral fractures in long-term renal transplant recipients. Transplant Proc 2007;39:2256e8. [17] Parker CR, Freemont AJ, Blackwell PJ, et al. Crosssectional analysis of renal transplantation osteoporosis. J Bone Miner Res 1999;14:1943e51. [18] Marcen R, Caballero C, Pascual J. Lumbar bone mineral density in renal transplant patients on neoral and tacrolimus: a fouryear prospective study. Transplantation 2006;81:826e31. _ Turan M, Erdal R, [19] Ugur A, Güvener N, Is¸ıklar I, Haberal M. Osteoporosis after renal transplantation: single center experience. Transplantation 2001;71:645e9. [20] Wang H, Chang C, Chu S. Osteoporosis after kidney transplantaion: prelimary report from a single center. Transplant Proc 2008;40:2412e3. [21] Patel S, Kwan JT, McCloskey E, et al. Prevalence and causes of low bone density and fractures in kidney transplant patients. J Bone Miner Res 2001;16:1963e70. [22] Conley E, Muth B, Samaniego M. Biphosphonates and bone fractures in long term kidney transplant recipients. Transplantation 2008;86:231e7. [23] Trabulus S, Apaydın S, Altıparmak MR, et al. Osteoporosis after renal transplantation. Nefrologia 2003;23(Suppl 2):127e30. [24] Heaf J, Tvedegaard E, Kanstrup IL, et al. Bone loss after renal transplantation: role of hyperparathyroidism, acidosis, cyclosporine and systemic disease. Clin Transplant 2000;14:457e63. [25] Taal MW, Masud T, Gren D, Cassidy MJ. Risk factors for reduced bone density in hemodialysis patients. Nephrol Dial Transplant 2004;14:1922e8. [26] Aroldi A, Tarantino A, Montagnino G, et al. Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients: a prospective study. Transplantation 1997;63:380e6. [27] Sperschneider H, Stein G. Bone disease after renal transplantation. Nephrol Dial Transplant 2003;18:874e7. [28] Bellorin-Font E, Rojas E, Carlini RG, et al. Bone remodeling after renal transplantation. Kidney Int Suppl 2003;85: 125e8.