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- Patients and Methods
Kidney transplant recipients have a higher incidence of fractures compared to the general population and compared to patients on dialysis [1-3]. In addition to affecting morbidity, fractures have been associated with decreased recipient survival . The high risk of fractures results from a combination of traditional factors, including immunosuppressive therapy, especially corticosteroids [4, 5], diabetes [4, 6, 7], female sex [4, 6, 8] and older age [2, 4, 7]. Moreover, preexisting osteodystrophy may also be involved, as suggested by the association between the duration of dialysis and the incidence of fractures [2, 7, 9]. After kidney transplantation, persistent hyperparathyroidism (pHPT) is common and contributes to bone loss [10-15]. High levels of serum intact parathyroid hormone (PTH) are associated with an increased risk of fracture in dialysis patients and in those with primary hyperparathyroidism [16, 17]. Nevertheless, the impact of pHPT in renal graft recipients on fractures has not yet been demonstrated.
Although the PTH level drops in the first posttransplant months with the reversal of uremia, it remains high in 17–50% of patients at 1 year [18-20]. The prevalence of pHPT varies largely between studies depending on the PTH assay used, the threshold of PTH chosen to define pHPT, the GFR [20, 21] and the 25-hydroxyvitamin D (25OHD) levels. pHPT can induce other mineral disorders such as hypophosphatemia, hypercalcemia [9, 22] and a high bone turnover state . Hypophosphatemia may also potentiate the fracture risk through osteomalacia . pHPT and hypercalcemia contribute to nephrocalcinosis and are associated with chronic allograft dysfunction [24-26]. The prevalence of these disorders many years after transplantation is not well documented. pHPT is due to a low or incomplete regression of parathyroid gland abnormalities induced by end-stage renal disease (ESRD) , and can be promoted by nonoptimal renal graft function and by native vitamin D insufficiency.
In contrast to the management of hyperparathyroidism in ESRD patients, there are no guidelines for optimal PTH levels after transplantation, and data regarding the clinical outcomes are lacking. The aim of this longitudinal study was to evaluate pHPT in kidney transplant recipients and its association with mineral disorders and fractures in the 5 posttransplant years.
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- Patients and Methods
Our series is the first longitudinal study to evaluate the impact of pHPT and mineral disorders on fractures after kidney transplantation. pHPT is common after kidney transplantation with 1-year rates varying among studies from 17% to 50% [18-20]. Its definition differs by author, and the optimal PTH level is not yet defined in renal graft recipients. In our study, pHPT was defined as an intact PTH level higher than twice the upper normal limit of the assay (130 ng/L). Our results consolidate this definition by the associated clinical outcome of fracture occurrence. pHPT was present in almost half of our patients at 3 months and in 41% at 1 year. In a recent study, the prevalence of pHPT with the same definition was lower at 1 year, at 24% . This difference could be explained by the higher PTH levels in our patients at the time of transplantation, as our population was not selected and was therefore more representative of a patient population in a clinical setting. The use of phosphate supplementations may also have led to an increase of PTH levels . However, the available evidence in the field is controversial; indeed, a study has suggested a potential muscular benefit of this supplementation without affecting the evolution of PTH levels . As previously shown, we observed that pHPT was associated with a longer dialysis duration , a high PTH level before transplantation [20, 32, 33], renal insufficiency [20, 21, 32, 33] and calcidiol deficiency [21, 34]. Patients with pHPT were also more likely to have a high BMI, which is consistent with recent studies on renal graft recipients , dialysis patients  and obese patients . Additionally, obesity may stimulate PTH secretion via leptin . After more than 1 year posttransplant, the persistence of HPT is less documented. In our study, one-third of patients presented a PTH level higher than twice the normal level at 5 years. Some authors speculate that the long-term PTH levels in patients with normal renal function should approach normal values to restore normal bone turnover . In our study, 42% of patients with normal renal function had PTH levels higher than normal (>65 ng/L) at 5 years posttransplant, although the majority of them had a calcidiol level in the target range. These data suggest an incomplete recovery from the parathyroid gland abnormalities induced by ESRD over the long term in a large subset of patients.
Mineral abnormalities induced by pHPT, such as hypercalcemia and hypophosphatemia, were also associated with fracture occurrence. Hypophosphatemia due to a reduced tubular reabsorption of phosphate was still observed in 14% of patients 5 years after transplantation. Renal phosphate wasting may also be a consequence of the persistence of excessive fibroblast growth factor 23 (FGF23) production by bone cells . In addition to affecting bone via hypophosphatemia, elevated FGF23 secretion may directly impact bone and inhibit mineralization .
Fractures occurred in 8% of our cohort in the first year and in 15% in 5 years, which is consistent with recent studies reporting 5-year fracture incidences of 12%  and 22% . We observed that patients with pHPT at 3 months had a greater risk of fracture in the 5 years posttransplant. Although several studies found that pHPT negatively impacts bone loss [10-15], fracture risk has been rarely evaluated. In a cross-sectional study of 125 patients on average 4 years after kidney transplantation, Giannini et al  showed that an elevated PTH level was related to an increased risk of vertebral fractures detected by systematic radiography. The contribution of hyperparathyroidism to fracture risk was also recently described in a large cohort of patients on hemodialysis , where PTH levels above 900 pg/mL were associated with an increased risk of any new hip fracture. This association was also reported in primary hyperparathyroidism . By contrast, hypoparathyroidism has been also associated with bone loss after renal transplantation [39, 40] as well as with fractures in patients on dialysis . In our study, no fracture occurred in subjects with PTH <130 ng/L at the time of transplantation; however, this result should be interpreted with caution because of the small sample size of this subgroup.
The impact of pHPT on bone may be mediated by the stimulation of bone turnover by PTH, as illustrated by the positive correlation between posttransplant PTH and bone turnover markers levels in our cohort and in other studies [15, 23]. Nevertheless, we did not find that fracture occurrence was associated with higher bone marker levels. Bone abnormalities induced by pHPT may be explained by the removal of skeletal resistance to PTH after kidney transplantation. In chronic kidney disease, bone becomes hyporesponsive to PTH. Many factors, such as phosphate loading, decreased calcitriol, antagonistic PTH fragments, the downregulation of PTH receptors and decreased pulsatility of PTH, lead to bone resistance to PTH . After transplantation, most of these factors decrease, most likely inducing an important bone response to PTH. In addition, in vitro studies have demonstrated that the bone response to PTH is enhanced by glucocorticoid treatment . The use of steroids in the presence of high PTH levels, particularly in the immediate posttransplant period, appears to have a cumulative deleterious effect on bone and may explain the early bone loss described in renal graft recipients.
An elevated risk of fracture was also observed for patients with pretransplant osteopenia. This finding is in accordance with a recent study showing that low BMD conferred an increased risk of fracture after kidney transplantation . Nevertheless, we were surprised to find no association between fractures and osteoporosis. This could be explained by different management protocols for recipients with osteoporosis, including the limited use of steroids, the use of calcium and vitamin D and preventive treatment with bisphosphonates. Indeed, some trials have shown a protective effect of bisphosphonates on early bone loss after transplantation [45, 46]. This study was not specifically designed to address the impact of pretransplant BMD; nevertheless, we found interesting to assess it in the routine pretransplant evaluation, to select patients in whom preventive treatment in the immediate posttransplant weeks can be beneficial. Larger randomized studies are required to evaluate the usefulness of bisphosphonates for the prevention of bone loss and fractures in selected patients, particularly in those with bone loss, pHPT and high levels of bone turnover markers. The KDIGO guidelines recommend caution when using bisphosphonates because fracture data are limited and an associated risk of adynamic disease has been described.
The present results also suggest that hypoalbuminemia was a risk factor for fractures. Hypoalbuminemia was associated with bone loss in a study of renal graft recipients  and with hip fracture in dialysis patients , suggesting that malnutrition and sarcopenia play roles in the pathogenesis of fracture. We also noted that female sex and pretransplant diabetes were associated with fractures, but these relationships were not significant, although this was most likely due to the small sample size. Other studies have not confirmed traditional risk factors, such as older age [2, 3, 6, 7] or diabetes . The use of corticosteroids is a recognized risk factor for fractures . Patients treated with prednisone at 1 year were more likely to develop fractures. This association was not significant, possibly because the dose of prednisone was not sufficiently different between subjects with or without steroids at 1 year, particularly in the first posttransplant months. In addition, all deaths occurred in the group of patients with pHPT (p = 0.006). This finding can be explained by the lower GFR, the longer dialysis duration and the trends of older age in this group. Although dialysis patients with hyperparathyroidism  and renal transplant recipients with hypercalcemia  have a greater risk of mortality, it is not clear whether hyperparathyroidism can be linked to an increased risk of death for transplant recipients. This result must be further evaluated in larger studies.
This study has some limitations due to its observational design. The timing between pretransplant BMD assessment and transplantation may have varied among the study participants (from several months to 3 years). Bone-specific therapies were administered in some patients. Corticosteroid sparing was most likely performed in some subjects, particularly in diabetic and osteoporotic patients. Another caveat is the lack of information on the cumulative corticosteroid dose for each patient; however, steroid exposure at specific time points did not differ significantly between groups. In addition, we may have missed some asymptomatic fractures particularly vertebral fractures. Nonetheless, this study provides new and longitudinal data on PTH levels after kidney transplantation, which are typically missing from large registry studies on fractures. A large and multicenter study controlling for treatments influencing mineral and bone disorders is warranted to corroborate our data.
With the aim to reduce fracture risk after kidney transplantation, this study identified a new risk factor represented by pHPT, which may better select recipients who could benefit from treatment. Better control of hyperparathyroidism after kidney transplantation should be considered in some patients using efficient treatments, such as calcium supplementation , native and active vitamin D, cinacalcet and parathyroidectomy. Previous studies suggest a bone protective effect of cinacalcet in dialysis patients. An analysis of four randomized studies showed that cinacalcet reduced the fracture risk in dialysis patients with intact PTH >300 ng/L . However, the recent EVOLVE trial did not support the protective effect of cinacalcet against the development of fractures . In any case, it should be noted that the intention-to-treat analysis of this trial had significant limitations (e.g. the results were unadjusted for baseline characteristics such as age and there was a high rate of treatment crossover). Moreover, it is noteworthy that in the prespecified analysis with lag censoring, there was a significant reduction in the risk of fractures among cinacalcet-treated patients . In two small studies of kidney transplantation, treatment with cinacalcet improved BMD in subjects with hypercalcemia secondary to pHPT [51, 52].
In conclusion, this study is the first to demonstrate that pHPT is an independent risk factor for fractures after kidney transplantation. This new risk factor has a high prevalence, particularly in the first year when the fracture rate is the highest. Better control of hyperparathyroidism before and after kidney transplantation should be beneficial. Randomized studies are needed to determine whether cinacalcet reduces the occurrence of fractures in recipients with pHPT.