Using HR-PQCT, an accurate and non-invasive with low radiation exposure technique for bone evaluation, we find satisfactory results on bone quantity and quality in 19 adolescent Tx recipients with tightly controlled bone biomarkers at the time of Tx compared to matched HC. We observe a slight degradation of trabecular microarchitecture 6 months after Tx at the radius. We also describe the evolution of mineral and bone biomarkers after Tx.
Major changes in serum mineral metabolism occur immediately after Tx [20]. PTH levels usually decrease but persistent secondary hyperparathyroidism is described in 10 to 60% of patients 12 months after Tx [27–29], hyperparathyroidism being an independent risk factor for allograft dysfunction in pediatric Tx [30]. In our series, 6 months after Tx, 53% patients still display elevated PTH levels (but always < 2 ULN). Hyperparathyroidism and persistent elevated circulating FGF-23 levels can promote renal phosphate wasting and low calcitriol levels [31]. Indeed, up to 10% of patients may present with hypophosphatemia 12 months after Tx, correlated with FGF23 levels [30]. Nearly 60% of our patients require phosphate supplementation 6 months after Tx, and a quarter of patients present with elevated FGF23 levels. The interest of phosphate supplementation in this setting remains debated, but one should not forget that hypophosphatemia is a main driver of mineralization defects; alternatively, giving too much phosphate on a renal transplant with normal or near-normal renal function may also induce secondary hyperparathyroidism, thus justifying a close and regular control of CKD-MBD parameters after pediatric Tx. Of note, even though the interest of cinacalcet after pediatric Tx has been discussed [32], none of the patients here received cinacalcet during the study period.
Shroff et al describe 25-OH vitamin D deficiency in half of pediatric Tx recipients [33]. Only one of our patients has vitamin D within the target range 6 months after Tx, despite native vitamin D supplementation. Given the fact that vitamin D is also a natural inhibitor of the mTor pathway [34], and that native vitamin D supplementation is able to prevent the onset of hyperparathyroidism in pediatric CKD [35], these data highlight the need of a close follow-up of 25D levels and an adequate correction of vitamin D deficiency if necessary [36]. They also highlight that CKD-MBD is closely controlled in dialysis, but maybe less after Tx, because of concomitant other comorbidities and specific post-Tx follow-up. Metabolic acidosis is found in 30% of patients whereas it is associated with altered growth hormone axis, protein degradation and glucocorticoid production [37]. Although these various parameters are poorly correlated with bone histomorphometry, they should be regularly monitored after transplantation in accordance with KDIGO guidelines, with particular interest in the evolution of trends [38–39]. Although, not recommended in daily practice for the follow-up of pediatric CKD-MBD [10], our DXA follow up revealed a significant increase in lean body mass, likely reflecting renutrition.
Few pediatric studies describe HR-pQCT post Tx [18–21]. In a cross-sectional study including 55 adolescent Tx recipients in 2000, Rüth et al identify a decrease in cortical thickness, at an average of 4.9 years after transplantation [21]. More recently, a study including 14 adolescent Tx recipients reveals significantly lower trabecular BMD Z-score 12 months after Tx in association with greater glucocorticoid exposure [19]. This study also describes cortical bone loss at transplantation associated with hyperparathyroidism severity and a significant increase of cortical BMD Z-score 12 months after Tx, correlated with low glucocorticoid exposure and lower PTH levels. However, this study is characterized by high median PTH level (3.6 ULN) at baseline and a high fracture rate in the first 6 months post Tx (10% within 6 months post Tx). This study is, therefore, not comparable with our series since our patients are better controlled in terms of median PTH levels at the time of Tx, i.e., 1.9 ULN; moreover, we did not observe any fracture during the 6-month follow up.
We surprisingly describe higher total and trabecular densities and better trabecular bone at the time of Tx compared with HC. These findings are probably due to a very rigorous control of mineral biomarkers pre-transplantation, notably for PTH (1.9 ULN) and phosphate levels (0.5SDS), as illustrated by the data obtained “randomly at the time of transplantation in patients receiving mostly transplants from deceased donors and therefore being drawn “without notice” in these patients. More than that, the strict nutritional control in pre-dialysis and dialysis, mainly focusing on calcium intake as recommended in international guidelines [40–41] likely provides more calcium intake than in healthy adolescent. We previously showed in our Vitados cohort a significant proportion of calcium deficiency, the median (range) calcium intake in this cohort indeed being of 812 (132–1382) mg [22]. Using the same HR-pQCT technique in the 32 adolescent from Lyon included in the 4C study (median GFR of 33 mL/min per 1.73m2), we already provided reassuring data concerning bone health in these children with moderate CKD, and, again tightly controlled mineral biomarkers (median PTH 1.2 ULN) [14].
Puberty is a crucial period for the acquisition of optimal bone mass, which has an impact on the risk of osteoporosis later in life [42–43]. In the general adolescent population, physical activity and its associated osteogenic effects have been shown to modify bone strength and quality during this particular period in various studies using DXA and HR-pQCT [44–46]. However, compared with the general population, physical activity levels are lower in pediatric kidney recipients and do not always improve after transplantation [47–48]. We show here that TEE tended to improve 6 months post-transplant and that TEE 6 months post Tx correlated with lean body mass and cortical bone parameters. This provides a rationale to promote early physical activity after transplantation, likely having beneficial effects on bone to prevent fractures on the long-term.
We observe a slight degradation of trabecular microarchitecture 6 months after Tx at the radius. Such impairment may be partly explained by a less rigorous control of mineral metabolism but also by the combination of bone risk factors that is maximal in the early post-Tx period, such as the use of corticosteroids and calcineurin inhibitors, and the presence (even if supplemented) of hypophophosphatemia and acidosis.
The limitations of our study include a small sample size, which limits our statistical power to demonstrate a potential impact of corticosteroids, a short follow-up period post Tx and the use of a self-administered questionnaire for assessing physical activity—chosen for its practicality over more complex methods like double-labeled water techniques or pedometer. It would be valuable to conduct a supplementary study involving HR-pQCT scans one year or more after transplantation. Despite these limitations, our study provides valuable and reassuring data on bone health in adolescent transplant recipients with tightly control bone biomarkers at Tx, presenting a thorough and rarely performed three-dimensional bone evaluation in this specific population.