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- Materials and Methods
Children with chronic kidney disease (CKD) have multiple risk factors for impaired bone accrual including growth failure, abnormal mineral metabolism, malnutrition, muscle deficits and secondary hyperparathyroidism. Successful renal transplantation corrects many of the abnormalities contributing to bone disease; however, glucocorticoid therapy and persistent hyperparathyroidism may impair recovery. Dual energy X-ray absorptiometry (DXA) is widely available for bone health assessment. The International Society for Clinical Densitometry (ISCD) recommended lumbar spine and whole body (WB) DXA scans for children with chronic diseases that impact bone metabolism . However, ISCD and Kidney Disease Improving Global Outcomes (KDIGO) guidelines  cautioned against the use of DXA in CKD for two reasons. First, DXA is a two-dimensional technique that summarizes superimposed trabecular and cortical bone mass within the projected bone area and may not capture opposing parathyroid hormone (PTH) effects to increase and decrease trabecular and cortical bone mass . Second, the utility of DXA to predict fracture in advanced CKD remains unproven .
In contrast, peripheral quantitative computed tomography (pQCT) is a three-dimensional technique that distinguishes between cortical and trabecular bone and provides measures of volumetric bone mineral density (vBMD) and cortical dimensions. We recently reported changes in tibia pQCT outcomes in pediatric renal transplant recipients . At transplantation, trabecular vBMD was elevated in younger recipients and decreased significantly in association with greater glucocorticoid exposure. Cortical vBMD increased significantly in association with greater glucocorticoid exposure and greater improvements in PTH levels. The baseline deficits in cortical dimensions did not improve, despite rapid recovery of muscle deficits and significant improvements in PTH levels. DXA scans were also obtained in this cohort.
The objectives of these analyses were to: (1) assess changes in DXA measures of spine-BMD, WB bone mineral content (WB-BMC), and body composition (lean mass [LM] and fat mass [FM]) in children and adolescents over 12 months after transplantation; (2) examine associations between DXA measures, disease characteristics, PTH levels and glucocorticoid exposure; (3) examine correlations between pQCT and DXA results; and (4) examine relations between changes in WB-BMC and LM as an index of the functional muscle-bone unit . These analyses employed a novel method to adjust for the short stature that frequently confounds DXA measures in childhood CKD [7, 8].
- Top of page
- Materials and Methods
DXA is the most widely used method to assess bone health. However, DXA has unique limitations in the setting of CKD. The wide spectrum of bone turnover abnormalities in CKD may differentially affect the superimposed trabecular and cortical compartments in the two-dimensional DXA image, yielding potentially misleading results. For example, PTH excess has generally catabolic effects on cortical bone with decreases in cortical vBMD and cortical thickness, and generally anabolic effects on trabecular bone with increases in trabecular thickness [3, 23]. Accordingly, KDIGO guidelines recommended against routine DXA BMD testing in patients with CKD stages 3–5 because “BMD does not predict the type of renal osteodystrophy” (2, . However, KDIGO did recommend measuring DXA BMD in the first 3 months after kidney transplantation in patients with an eGFR > 30 mL/min/1.73 m2 if treated with glucocorticoids.
Poor growth and decreased LM in pediatric CKD pose additional challenges in the interpretation of DXA areal BMD results. DXA is a two-dimensional projection technique that does not account for bone depth; therefore, DXA areal BMD and BMC relative to age are systematically underestimated in children with low height-for-age Z-scores . The ISCD recommends that DXA Z-scores should be adjusted for short stature . This study used a novel unbiased method developed in the Bone Mineral Density in Childhood Study to adjust for the decreased height Z-scores in the transplant recipients . The ISCD guidelines also noted that body composition measures in conjunction of WB-BMC results may be helpful in evaluating patients with chronic conditions. As muscles increase during growth, bones adapt by increasing dimensions and strength. This capacity of bone to respond to mechanical loading with increased bone strength is greatest during childhood . Therefore, we examined the relations between changes in WB LM and BMC in this cohort.
Prior DXA studies of bone health in pediatric renal transplant recipients yielded inconsistent results [26-34], largely related to varying use of methods to adjust for low height Z-scores, lack of reference data, differences in measurement sites, and inclusion of participants at highly variable (and frequently unspecified) intervals following transplantation. To our knowledge, this is the first study to assess changes in DXA measures of bone health and body composition in an incident cohort of pediatric renal transplant recipients, with adjustment for low height Z-scores based on robust reference data and inclusion of measures of PTH levels and glucocorticoid exposure. The study is also the first to compare pQCT and DXA results in children or adults.
The greater decreases in spine-BMD Z-scores in association with higher glucocorticoid doses and greater declines in iPTH levels were consistent with known effects of glucocorticoids and PTH to decrease and increase trabecular BMD, respectively. The observation of higher spine-BMD Z-scores in the younger compared with older participants at the time of transplantation was consistent with our pQCT results in this cohort where the mean (SD) trabecular BMD Z-scores in the tibia metaphysis were +2.10 (1.97) and −0.16 (1.51) in those recipients <13 and ≥13 years of age, respectively . The significant, but smaller magnitude of the age differences for the baseline DXA results (Table 3) compared with pQCT results may be due to the superimposed cortical bone in the DXA image, potentially concealing PTH-induced increases in trabecular vBMD. In our prior pQCT studies in pretransplant CKD [11, 13], we detected a significant interaction between PTH levels and age whereby the positive association between PTH levels and trabecular vBMD was more pronounced in younger participants. Prior pQCT studies by other investigators also documented greater trabecular BMD in the younger participants with CKD . The reason is unknown, but may relate to impaired resorption of secondary spongiosa in advanced CKD .
Despite high-dose glucocorticoid exposure in the majority, spine-BMD Z-scores remained significantly greater in younger transplant recipients at 12 months, compared with reference participants. The spine-BMD Z-scores in the older participants were similar to reference participants. In contrast, the pQCT results revealed significant trabecular deficits in the older transplant recipients at 12 months, with a mean vBMD Z-score of −0.54. The superimposed cortical bone (with significant increases in cortical vBMD following transplantation, as described below) may have concealed trabecular deficits in the DXA scans. The observation that the decreases in pQCT trabecular vBMD Z-scores were significantly greater than the declines in spine-BMD Z-scores in this study is consistent with this theory. Importantly, these explanations are speculative since the DXA scans were obtained in the spine and the pQCT scans in the tibia metaphysis. Future studies using spine QCT and DXA are necessary to provide comparisons at the same anatomic site.
Cortical bone comprises approximately 80% of the skeletal bone mass, and thus DXA WB-BMC is largely a function of cortical vBMD and cortical dimensions. This study demonstrated that glucocorticoid exposure was negatively associated with changes in WB-BMC Z-scores. We conclude that this was due to glucocorticoid effects to impair bone formation and accrual of cortical dimensions. This is consistent with our pQCT data in this cohort demonstrating that greater glucocorticoid doses were associated with greater decreases in periosteal circumference Z-scores . That is, periosteal surface did not contract; rather, the periosteal circumference did not expand to the extent expected relative to concurrent increases in tibia length. In contrast, greater glucocorticoid exposure was significantly associated with greater increases in pQCT cortical vBMD in this transplant cohort, as well as in other childhood diseases [37-39]. Glucocorticoids therefore have competing effects on total cortical bone mass due to increases in cortical vBMD but inhibition of cortical expansion. In order to assess the impact of these opposing effects, we assessed the relative contribution of cortical dimensions and vBMD to cortical BMC on pQCT scans using linear regression. Within our healthy controls, a 1.0 SD lower cortical vBMD Z-score was associated with a 0.20 SD lower cortical BMC Z-score, while a 1.0 SD lower cortical cross-sectional area Z-score was associated with a 0.97 SD lower cortical BMC Z-score. Therefore, we submit that WB-BMC provides an index of cortical dimensions with minimal impact of disease or treatment effects on cortical BMD. The highly significant correlation between changes in DXA WB-BMC and pQCT cortical area Z-scores (and lack of correlation with pQCT cortical vBMD Z-scores) following transplantation is consistent with this interpretation. The association between glucocorticoids and lower WB-BMC may also have been due to glucocorticoid effects to decrease the trabecular component that makes up approximately 20% of WB-BMC. The lack of an association between changes in PTH levels and WB-BMC Z-scores may also be due to the inability of WB-BMC to capture effects on cortical vBMD. Our prior pQCT data in these transplant recipients documented an association between declines in PTH and gains in cortical vBMD but no association between changes in PTH levels and cortical dimensions.
A novel finding in this study is the significant positive association between gains in height and WB-BMC Z-scores. The association was not observed for spine-BMD. Given that the WB-BMC Z-scores at each visit were adjusted for height Z-score, this indicates that greater linear growth is associated with greater gains in WB-BMC than can be explained by the gains in height alone. Periods of growth may provide a unique opportunity to recover cortical dimensions, such that strategies to promote accrual of cortical dimensions should target intervals of greatest growth. We previously reported that gains in calf muscle were not associated with the expected gains in cortical structure following transplantation in this cohort . The results reported here confirm these findings using WB DXA. The clinical significance of this observation is unknown; however, these findings warrant further study. Potential mechanisms include physical inactivity, poor muscle quality and function or glucocorticoid effects.
This study has multiple limitations. First, the absence of bone biopsy data prohibited any correlations of DXA results with bone microarchitecture, turnover or mineralization. Second, the DXA and pQCT scans were not obtained in the same anatomic location. Third, the study did not include lateral spine X-rays for the assessment of vertebral fractures. This is an important limitation in light of recent reports of vertebral compression fractures in pediatric solid organ transplant recipients [27, 40]. While the relations between DXA Z-score and fracture risk have not been characterized in pediatric renal transplant recipients, prospective studies have demonstrated that lower WB-BMC predicted fractures in healthy children  and lower lumbar spine-BMD was associated with fractures in children treated with glucocorticoids [42, 43]. Furthermore, DXA studies in adult renal transplant recipients demonstrated that lower BMD was associated with increased fracture risk . Additional studies are needed to determine if the DXA results observed here are associated with clinically important increases in short- and long-term fracture risk.
In summary, these data suggest that both WB and spine DXA provide insight into bone health following renal transplantation in children and adolescents. The spine-BMD Z-scores captured the expected independent effects of PTH and glucocorticoids on trabecular bone. The WB-BMC results illustrated the utility of this outcome to monitor impairment of cortical bone accrual, particularly accrual of cortical dimensions. The recent availability of population based DXA reference data [45, 46] along with prediction equations to adjust WB and spine scans for short stature may pave the way for use of these outcomes in clinical practice .