Age at Transplant—One of the Factors Affecting Bone Mineral Density in Kidney Recipients—A Single-Center Retrospective Study

Abstract

Background: Osteoporosis/osteopenia after kidney transplantation is multifactorial, and the mechanism responsible for this condition is unclear. A cumulative steroid dose and female gender are two likely major risk factors for osteoporosis/osteopenia after transplantation, but there is no consensus as to which risk factors are most strongly associated with reduced bone mineral density (BMD). Methods: We assessed 84 kidney recipients who had received transplants at least 5 months prior to enrollment in the study. BMD at the lumbar spine, hip, and femoral neck was evaluated by dual-energy X-ray absorptiometry. We used the average BMD (BMDa), defined as the average of the sum of the lumbar spine, hip, and femoral neck mineral density values, as representative of body BMD. Results: This retrospective study revealed inverse correlations between the BMDa and creatinine level and age at transplant as well as a positive correlation with male gender. Osteoporosis occurred in transplantations where the duration since transplantation was longer. Conclusion: This retrospective study demonstrated that a decrease in BMD, reflecting a bone condition tending toward osteoporosis/osteopenia, is inversely correlated with male gender, creatinine level, and age at transplant in kidney recipients. Nonetheless, the time since transplant is higher in the osteoporosis group than in the osteopenia group.

Keywords:

• osteoporosis
• osteopenia
• kidney recipients
• dual-energy X-ray absorptiometry
• DEXA
• bone mineral density
• BMD

INTRODUCTION

Patients maintained on dialysis for end-stage renal disease exhibit severe mineral and bone problems. Multiple factors may contribute to the loss of bone mineral density (BMD) in chronic renal failure patients, including the duration of prior chronic renal failure and dialysis, persistent metabolic acidosis, hyperparathyroidism, diabetes mellitus (DM), and smoking.¹ Renal transplantation restores defective kidney function in patients with chronic renal disease and is expected to progressively correct established bone lesions. Although transplantation may resolve many of the biochemical imbalances associated with chronic renal failure, such as hyperparathyroidism, the associated steroid and other immunosuppressant therapy cause a continuing damage to bone.^2,3 Progressive loss of BMD in trabecular bone often occurs early in renal transplantation.⁴ Although a cumulative steroid dose and female gender are two likely major risk factors after transplantation,¹ there is no consensus as to which risk factors are most strongly associated with reduced BMD.^5,6 At present, biochemical markers of bone turnover in the serum or urine are not recommended for diagnosis.⁷ The World Health Organization (WHO) defines osteoporosis as a lumbar spine (LS), femoral neck (FN), or hip (H) BMD of 2.5 standard deviations (SDs) or more below the mean for healthy young adults, as measured by dual-energy X-ray absorptiometry (DEXA). Osteopenia is defined as a BMD between 1 and 2.5 SDs below the mean.⁷ In this study, we used the average BMD (BMDa), defined as the average of the sum of the LS, hip, and FN mineral density values, as representative of body BMD. The aim of this retrospective study was to evaluate the osteoporosis factors on BMDa values in renal transplantation recipients.

MATERIALS AND METHODS

Study Population

We enrolled 84 kidney recipients (40 males and 44 females) with transplant durations from 5 months to 274 months. BMD measurements of the LS, left hip, and FN were obtained by DEXA from September 2008 to March 2009. Bone condition was defined by the WHO criteria: osteoporosis was defined as a value of BMD >2.5 SD (T-score) below the young adult mean BMD and osteopenia was defined as a value BMD >1.0–2.5 SD below the young adult mean BMD. In this study, we tried to use the BMDa, defined as the average of the sum of the LS, hip, and FN mineral density values, as representative of body BMD. All subjects had received posttransplantation immunosuppression with prednisolone plus calcineurin inhibitors/sirolimus. Blood samples for serum creatinine (Cr), blood urea nitrogen (BUN), calcium, inorganic phosphate, and uric acid were obtained in a fasting state. DM, smoking frequency, alcohol intake, hepatitis B virus (HBV), hepatitis C virus (HCV), and cytomegalovirus (CMV) infections were assessed via the patients’ medical records. Determinations of 24 h urine total protein were obtained for all patients.

Statistical Analysis

Data are expressed as mean ± SD. The Pearson’s correlation coefficient was employed to evaluate the univariate association between the BMDa and the studied variables. Stepwise multiple linear regression analysis was performed to determine which variables were independently correlated with BMDa, LS-BMD, H-BMD, and FN-BMD. For the purpose of this analysis, the dependent variables were BMDa, LS-BMD, H-BMD, and FN-BMD; and the independent variables were age, age at transplantation, time since transplant, Cr, serum uric acid, serum calcium, inorganic phosphate concentrations, male gender, smoking, alcohol consumption, and status of DM, CMV, HBV, and HCV infections. Intergroup comparisons were performed with the Student’s t-test. A least significant difference one-way analysis of variance (ANOVA) was performed to compare the transplantation duration values of the various BMD types. The level of statistical significance was set at p < 0.05. All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) Version 12.0 for Windows (SPSS, Inc., Chicago, IL, USA).

RESULTS

Patient Characteristics

Of the 84 subjects enrolled in this study, 13 patients had a medical history of DM, 10 patients had HBV infection, 19 patients had HCV infection, and 16 patients had CMV infection. Moreover, 12 males were habitual users of tobacco, and 8 males and 1 female regularly consumed alcohol. Table 1 lists the characteristics of the study subjects. The BMDa did not differ between DM and non-DM (0.803 ± 0.12 vs. 0.797 ± 0.118, p = 0.865) but showed a significant increase in male subjects compared to female subjects (0.841 ± 0.127 vs. 0.751 ± 0.093, p < 0.001). The mean age of subjects was 50.6 ± 8.8 years. The mean BMDa was 0.79 ± 0.12 g/cm². The BMDa was negatively correlated with the 24 h urine total protein level, but this was not statistically significant.

Table 1. Characteristics of the kidney recipients.

N = 84	Mean	±SD
Gender (M/F)	40/44
Age	50.6	±8.8
Age at transplantation	42.9	±9.9
Time since transplant (months)	90.3	±66.3
LS-BMD (g/cm²^2)	0.89	±0.14
H-BMD (g/cm²^2)	0.79	±0.14
FN-BMD (g/cm²^2)	0.68	±0.11
BMDa (g/cm²^2)	0.79	±0.12
LS T-score	−1.61	±1.17
H T-score	−1.83	±0.96
FN T-score	−2.49	±0.98
Smoking	12/84
Alcohol	9/84
DM	13/84
BUN (mg/dL)	21.5	±14.1
Cr (mg/dL)	1.25	±0.61
Ca (mg/dL)	9.45	±0.56
P (mg/dL)	3.22	±0.56
Uric acid (mg/dL)	6.33	±1.72
HBV	10/84
HCV	19/84
CMV	16/84

Note: LS-BMD, lumbar spine bone mineral density; H-BMD, hip bone mineral density; FN-BMD, femoral neck bone mineral density; BMDa, bone mineral density in average; T-score, number of standard deviation (SD) above or below the mean value of a sex-matched young adult mean BMD; DM, diabetes mellitus; BUN, blood urea nitrogen; Cr, blood creatinine; Ca, serum calcium concentration; P, serum inorganic phosphate level; HBV, status of hepatitis B virus infection; HCV, status of hepatitis C virus infection; CMV, status of cytomegalovirus infection.

Table 2. Coefficients of correlation in the Pearson’s correlation analysis between BMDa and other clinical variables.

	Coefficients	p-Value
Gender (M/F)	0.378	<0.001
Age	−0.148	0.18
Age at transplantation	−0.089	0.42
Time since transplant (month)	−0.031	0.78
Smoking	0.137	0.22
Alcohol	0.177	0.11
DM	0.019	0.86
BUN	−0.27	0.01
Cr	−0.204	0.06
Ca	0.079	0.48
P	−0.215	0.05
Uric acid	−0.077	0.49
HBV	0.115	0.3
HCV	0.022	0.85
CMV	−0.11	0.33

Note: DM, diabetes mellitus; BUN, blood urea nitrogen; Cr, blood creatinine; Ca, serum calcium concentration; P, serum inorganic phosphate level; HBV, status of hepatitis B virus infection; HCV, status of hepatitis C virus infection; CMV, status of cytomegalovirus infection.

Table 3. Results of stepwise multiple regression analysis to assess the correlation of BMDa, LS-BMD, H-BMD, and FN-BMD with other variables.

Covariate	Standard β	Partial correlations	p-Value
BMDa
Male gender	0.38	0.4	<0.001
Cr (mg/dL)	−0.46	−0.43	<0.001
Age at transplant (years)	−0.25	−0.25	0.03
LS-BMD
Cr (mg/dL)	−0.25	−0.25	0.03
H-BMD
Male gender	0.39	0.41	<0.001
Cr (mg/dL)	−0.44	−0.42	<0.001
Age at transplant (years)	−0.27	−0.28	0.02
FN-BMD
Male gender	0.45	0.45	<0.001
Cr (mg/dL)	−0.31	−0.33	0.005

Note: BMDa, bone mineral density in average; LS-BMD, lumbar spine bone mineral density; H-BMD, hip bone mineral density; FN-BMD, femoral neck bone mineral density; Cr, serum creatinine levels.

BMDa and Other Clinical Parameters

Table 2 lists the coefficients of correlation in the Pearson’s correlation analysis between BMDa and other clinical variables. This analysis demonstrated that gender and BUN concentration correlated with BMDa. In a stepwise multiple linear regression analysis, we used the BMDa value, LS-BMD, H-BMD, and FN-BMD as the dependent variables, while using age, age at transplantation, time since transplant, Cr, serum uric acid, serum calcium, inorganic phosphate concentrations, male gender, smoking, alcohol consumption, and the status of DM, CMV, HBV, and HCV infections as independent variables. Table 3 shows the results of the stepwise multiple linear regression analysis between the representations of different BMD and the other clinical variables. Gender, Cr concentration, and age at transplantation were significant variables for BMDa. To further examine the possible influence of clinical features on bone condition, a one-way ANOVA was performed using the WHO criteria as an independent factor. In this study, the normal group contained 6 patients (time since transplant, 121.8 ± 58.7 months), the osteopenia group contained 30 patients (time since transplant, 68.6 ± 57.3 months), and the osteoporosis group contained 48 patients (time since transplant, 100.3 ± 69.7 months). Table 4 shows the clinical parameters of recipients between normal, osteopenia, and osteoporosis groups. Figure 1 illustrates the difference in time since transplantation among the osteopenia and osteoporosis groups.

Table 4. Clinical parameters of recipients between normal, osteopenia, and osteoporosis groups.

Parameter	Normal (n = 6)	Osteopenia (n = 30)	Osteoporosis (n = 48)
Gender (M/F)	4/2	16/14	20/28
Age (years)	49.2 ± 3.7	50.1 ± 9.1	51 ± 9.2
Age at transplantation (years)	38.1 ± 5.7	44.4 ± 10.1	42.5 ± 10.1
Time since transplant (months)	133.2 ± 57.7^a	68.5 ± 56.4	100.3 ± 69.7^a
Smoking	1	4	7
Alcohol	1	4	4
DM	1	6	6
BUN (mg/dL)	15 ± 2	18 ± 8^b	24.4 ± 17
Cr (mg/dL)	1.1 ± 0.2	1.1 ± 0.5^b	1.4 ± 0.7
Ca (mg/dL)	9.6 ± 0.6	9.5 ± 0.5	9.4 ± 0.6
P (mg/dL)	3.1 ± 0.3	3.2 ± 0.6	3.2 ± 0.6
Uric acid (mg/dL)	5.8 ± 2.1	6 ± 1.5	6.6 ± 1.8
HBV	1	3	6
HCV	3	4^c	12^c
CMV	1	4	11

Notes: DM, diabetes mellitus; BUN, blood urea nitrogen; Cr, blood creatinine; Ca, serum calcium concentration; P, serum inorganic phosphate level; HBV, status of hepatitis B virus infection; HCV, status of hepatitis C virus infection; CMV, status of cytomegalovirus infection.

^aSignificantly different from osteopenia group.

^bSignificantly different from osteoporosis group.

^cSignificantly different from normal group.

DISCUSSION

High bone mass loss after transplantation occurs when the patient already has a poor-quality skeleton and is additionally influenced by a number of factors, including iatrogenic ones.⁸ Most of the available information, including that on biochemical markers, has been obtained from patients without kidney disease, and the use of biochemical markers in the assessment of skeletal problems is extremely limited⁸; this study examined the feasibility of using the BMDa value for assessing the risk of osteoporosis/osteopenia and viral infection and as an indicator of daily urine total protein in kidney recipients. Our study is the first to demonstrate that the BMDa value is independently positively correlated with the male gender and negatively correlated with renal function and the age at transplant in kidney recipients.

Figure 1. Significant difference of time since transplant in patients with different bone conditions: A, normal; B, osteopenia; C, osteoporosis.

Notes: The number in parentheses indicates the number of patients in each group.

*p < 0.05 versus group B.

An increase in bone mass loss is multifactorial and is affected by age,⁹ female gender,^9–11 renal function, and duration of dialysis before transplantation.¹¹ A major influencing and well-known factor causing increased loss of bone mass is high-dose steroid therapy during the early period after transplantation and continuous long-term steroid administration.³ Bone mass loss in kidney recipients is a result of a combination of increased bone resorption and decreased bone formation, but the precise mechanisms involved are unknown.

Renal transplantation can be associated with dramatically reduced bone mass, the first 3–6 months after transplantation being the most critical period.^5,12,13 In a long-term study, the ongoing accelerated lumbar bone mass loss was approximately 1.7% ± 2.8% per year.¹⁴ Earlier prospective studies in glucocorticoid-induced osteoporosis suggested more rapid bone loss in the early weeks of steroid therapy that subsequently slowed in later weeks.¹⁵ In a cross-sectional study, the time since the transplant was shown to have a high correlation with the cumulative prednisolone dose.² Julian et al.⁵ documented a rapid decrease (6.8%) in lumbar BMD in the first 6 months after transplantation, with a slower decrease of 2.6% in the following 12 months. Horber et al.¹² reported a similar rapid decrease in lumbar bone mass during the first 5 months after renal transplantation. These studies explain why the time since transplant is longer in the osteoporosis group (n = 48, 100.3 ± 69.7 months) than in the osteopenia group (n = 30, 68.6 ± 57.3 months), as shown in Figure 1.

Age is a risk factor for osteoporosis, and women older than 65 years and men older than 70 years are recommended for osteoporosis screening in the general population.⁷ In this study, 92% of the study population (mean age, 51 ± 9 years) had osteopenia/osteoporosis resulting due to prior renal failure and posttransplant iatrogenic effects. Hung et al.⁹ reported that age was one of the factors for osteoporosis in kidney recipients; however, other studies^2,16 noted that the age of the kidney recipient was not a factor for osteoporosis. From these studies, it appears that the role of age in osteoporosis in kidney recipients is controversial. To our knowledge, the role of age at transplant has been less discussed with respect to osteoporosis in kidney recipients. In normal and in the kidney recipient population between the age of 20 and 70 years, the average LS-BMD and FN-BMD values are probably negatively correlated with age. It is interesting that 12 months following cardiac transplantation, the LS-BMD value was restored to the BMD value at the time of transplant.¹⁷ Twenty-four months after transplantation, the yearly loss of absolute BMD was parallel to the age-dependent physiological decline in absolute BMD,¹⁸ providing an explanation for why the age at transplant is an important factor determining bone condition of kidney recipients, as shown in our study.

Our study suffered from certain limitations, including retrospective observations, a lack of cumulative steroid and other immunosuppressant agent dosing, and so on. The effect of steroids on bone density has been shown in most studies investigating bone loss after kidney transplantation.³ However, the role of calcineurin inhibitors on bone density is controversial,^2,8,11 and at least one study has shown that cyclosporine might have a bone protective effect.¹⁹

In conclusion, despite the effect of immunosuppressant agents, this retrospective study has demonstrated that the BMDa value, reflecting bone condition, is positively correlated with the male gender and negatively correlated with the Cr value and the age at transplant in kidney recipients. Nonetheless, the time since transplant is higher in osteoporosis group than in osteopenia group. The negative association between BMDa and age at transplant in kidney recipients is interesting and warrants further investigation of the outcomes of kidney transplants in younger patients.

ACKNOWLEDGMENT

We thank the members of the Immune-Transplant Center in Chang Gung Memorial Hospital for their invaluable and dedicated assistance.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.