Bone disease after renal transplantation

Because of increasing life expectancy after renal transplantation, the prevention of long-term complications, such as bone disease, has become an essential part of post-renal-transplant care. Bone disease is one of the possible long-term complications that can significantly influence quality of life. Compared to members of the normal population of the same age, the fracture rate in renal transplant patients is four times higher. In addition, there is a risk for avascular bone necrosis after transplantation, which mainly affects weight-bearing bone structures, such as femoral heads, and as a rule, can only be treated by hip replacement with endoprosthesis. Histological evidence of abnormal bone structure, osteodystrophy and osteopaenia is already present shortly after transplantation in almost all transplant recipients [1]. Bone disease after renal transplantation differs from bone disease after transplantation of non-renal solid organs. Bone disease after non-renal solid organs is often similar to steroid-induced osteoporosis. In addition, accessory factors such as low 25-hydrolylase activity in liver graft recipients may lead to osteomalacia. However, after renal transplantation, bone disease is in large part due to pre-existing bone damage acquired during dialysis therapy and renal insufficiency and because of factors that affect the bone to varying degrees after successful renal transplantation. Apart from immunosuppressive agents, metabolic factors such as hyperphosphaturia, persistent hyperparathyroidism with hypercalcaemia, disturbances to the acid–base balance and hypomagnesaemia also play an important role. Renal bone disease before transplantation has once again become the object of attention because of our better understanding of important pathogenic mechanisms underlying hyperparathyroidism and its regulation, bone metabolism and the impact of hyperphosphataemia and hypercalcaemia on cardiovascular mortality. In addition, new drugs have been developed, such as the calcium-free phosphate binders sevelamer and lanthanum carbonate, or the calcimimetic drug cinacalcet, which have broadened the range of available therapeutic options. Moreover, these pharmacological approaches provide new understanding of and therapy for bone disease after successful renal transplantation. These aspects will be described below. A retrospective analysis of 1572 kidney graft recipients showed a fracture incidence of 19.1% within an average observation period of 6.5 years, with 6.4% of all patients suffering multiple fractures [2]. After the exclusion of malleolar fractures (8.3%) and avascular bone necroses (5.0%), the cumulative fracture incidence was 12.0% after 5 years, 18.5% after 10 years and 23.0% after 15 years. Over 16% of the patients had deformations of the spine and vertebral fractures inappropriate for the force causing the injury [3]. Consequently, the long-term risk of fracture far exceeds that of the normal population, which is ∼1% in women 65 years of age and below and ∼6–10% in 75-year-old women [4]. What is the risk of fracture for patients on the waiting list for transplantation compared to renal transplant recipients? Retrospectively, 101 039 patients on the waiting list for renal transplantation were evaluated [5]. Of those, 41 095 (40.7%) had never received a transplant and could thus be compared with 59 944 (59.3%) transplant recipients. The mean follow-up duration was 2.98 years. In total, 971 patients had a hip fracture. In dialysis patients, the fracture rate was 2.9 fractures per 1000 patient-years versus 3.3 fractures in transplant recipients. Consequently, their risk was 34% higher. However, the risk of fracture in transplant recipients compared to patients on the waiting list decreases continuously over time. In the first 6 months after transplantation, the relative risk among transplant recipients is 1.34 times higher, but it decreases by 1% per month, so after ∼630 days, a similar risk is found in both groups. After this point, the risk of fracture for transplant recipients falls below that of patients from the waiting list (Figure 1). Calculated relative risk of fractures after renal transplantation in comparison with patients on the waiting list for renal transplantation (the interrupted line marks the 95% confidence interval) (Reprint with permission from American Medical Association [5]). To answer the question of how to avoid fractures and which type of prophylaxis is the most adequate, the pathogenesis of bone disease after renal transplantation will be reviewed. Special attention will be paid to the fact that the individual components of bone disease change over time. From these considerations, the appropriateness and timing of the respective therapies can be derived. Because the aim of an optimal prophylaxis is to reduce the fracture rate after transplantation, therapeutic interventions have to be proven in prospective, randomized, blinded studies. Most published studies cannot answer this question, either because of insufficient duration or number of patients. Studies based on the examination of histological changes in bone are also rare. Therefore, change in bone density is almost always chosen as a surrogate parameter, even though change in bone density does not provide any information on the architecture or histology of bone. Although stability of bone density or even an increase in bone density represents a good surrogate parameter for an effective prophylaxis of osteoporotic fractures [7,8]. Nonetheless, changes in bone density remain the standard parameter for most studies in regard to the efficacy of various prophylactic measures. Bone disease in transplant recipients is based on pre-existing damage to the bone acquired during the period of renal insufficiency, damage to the bone starting in the period of transplantation and modulating influences independent of renal disease or renal transplantation (Figure 2). Factors causing bone disease after transplantation [5,68]. Important factors comparatively independent of renal disease will not be discussed here in detail, even though they are significant. Some of these factors, such as smoking or physical inactivity, should be actively considered as a part of the preventive actions. The starting point for bone disease after transplantation is the period during pre-terminal renal insufficiency and renal replacement therapy. The different factors contributing to bone disease, including secondary hyperparathyroidism accompanied by hyperphosphataemia, decreased calcitriol concentrations and variable calcium concentrations can be identified to various degrees in biopsies of patients immediately after renal transplantation, thus reflecting the ‘baseline’ before other factors that affect the bone after transplantation have time to produce detectable changes. In a study on the effectiveness of bisphosphonates, 50% of the biopsies taken from patients immediately after transplantation showed bone with high turnover, with the dominant picture being osteitis fibrosa, while ∼30% had adynamic bone and ∼20% showed a mixed picture [9]. This distribution of bone disease shows geographic variation and is primarily subject to the therapeutic regimen that was in place prior to transplantation. Immediately after transplantation and along with the start of transplant function, many factors, which are responsible for the development of renal osteodystrophy, undergo some fundamental changes. Often as early as during the first post-transplant week, hyperphosphataemia-–one of the earliest factors to develop-–turns into hypophosphataemia because of marked hyperphosphaturia. The increase in parathyroid hormone excretion, which becomes autonomous over time, continues and calcitriol concentration, which varies widely in renal transplant recipients immediately after the procedure, is often accompanied by episodes of hypercalcaemia. To detect the developing changes at an early stage, monitoring according to the K/DOQI guidelines is recommended [10]. In addition to these factors, immunosuppressive regimens, especially the use of steroids, play a decisive role. Because all the above-mentioned factors act simultaneously on the bone-–which is already affected by a wide variety of pre-existing pathological changes-–while simultaneously interacting with each other, bone disease after transplantation manifests as a complex condition. For the prophylactic or therapeutic treatment of bone disease after transplantation in an individualized, targeted and rational manner, it is helpful to look at the individual factors acting on the bone after transplantation in greater detail. The lack of guidelines to define what is considered a ‘normal’ PTH concentration in kidney graft recipients is due to the lack of well-controlled studies that correlate PTH concentrations with alterations of the bone after transplantation. Most often, a target PTH concentration adjusted to the kidney function as in other patients with kidney diseases has been used. One must be aware of the possibility that this may not adequately reflect the complex situation in the transplant setting. Parathyroid function after renal transplantation has been evaluated in a number of studies. In about two-thirds of renal transplant recipients, increased parathyroid hormone levels are found immediately after transplantation [11]. The parathyroid hormone concentration falls by ∼50% within the first 2 weeks, followed by a more gradual decrease; as a result, approximately half of the renal transplant recipients with good transplant function have normal parathyroid hormone levels after about 3 months, and after 1 year, only between 10 and 50% of patients suffer from hyperparathyroidism [12]. In the further course, there is only a slight additional decrease in the hyperparathyroidism rate; 21% of the transplant recipients still show abnormally high levels of parathyroid hormone up to 15 years after transplantation [13]. Hyperparathyroidism is associated with a high percentage of hypercalcaemic episodes. During a post-renal-transplant follow-up period of up to 5 years, hypercalcaemic episodes were found in 46% of cases after 1 year, 40% after 3 years and 24% after 5 years [11]. The progression from secondary to tertiary hyperparathyroidism, i.e. the form that no longer responds to the normalization of calcium, phosphate and calcitriol, is promoted by both prolonged periods of hyperphosphataemia and delayed calcitriol therapy prior to transplantation, and is very difficult to reverse after transplantation. Tertiary hyperparathyroidism is based on somatic mutations in individual parathyroid gland cells finally resulting in clonal expansion and adenoma formation, which are associated with a depressed expression of calcium-sensing and vitamin D receptors [14]. Finally, impaired renal transplant function with far below normal performance in many patients is another factor that prevents normalization of hyperparathyroidism. The primary target of parathyroid hormone is osteoblasts. Osteoblasts, but not osteoclasts, express PTH receptors. PTH increases the number, activity and lifespan of osteoblasts and also protects osteoblasts against steroid-induced apoptosis [15]. The activation of osteoclasts by parathyroid hormone is an indirect effect based on cell–cell contacts with osteoblast-like cells. In addition, increasing evidence suggests a binding of intact PTH, but not PTH 1–34 to osteoclasts, possibly through the novel PTH receptors (CPTHRs) resulting in an increased osteoclast activity and number [16–18]. In physiological concentrations, PTH leads to increased bone remodelling and an increase in trabecular bone volume compared to cortical bone. In summary, bone damage caused by chronic hyperparathyroidism most closely resembles osteitis fibrosa. However, hyperparathyroidism and hypercalcaemia also correlate with interstitial microcalcifications in the transplant. Interstitial microcalcifications are, in turn, an indicator of poor prognosis regarding long-term function [19]. Thus, apart from bone disease, pathological changes in extraosseous organs also have to be taken into consideration. The development of hypophosphataemia as a result of hyperphosphaturia soon after renal transplantation is a common complication, observed in more than 90% of transplant patients [20]. Although the serum phosphate concentration normalizes in most patients after 1 year, this does not apply to hyperphosphaturia; increased fractional phosphate excretion can still be detected after 1 year [21]. Even hypophosphataemia can be detected up to 10 years after transplantation in some patients [22]. This hypophosphataemia is the result of impaired reabsorption of phosphate in the proximal tubule, where up to 80% of the filtered phosphate is reabsorbed. Tubular reabsorption can be decreased by various factors, including: hyperparathyroidism, calcitriol deficiency, corticosteroid therapy, phosphatonins (e.g. FGF23), hormones (e.g. insulin, thyroid hormones, glucagons), cytokines (e.g. insulin-like growth factor I, EGF), phosphate-rich diet, and metabolic acidosis. High parathyroid hormone levels can reduce phosphate reabsorption in the proximal tubule from 80 to 20%. Certainly, persistent hyperparathyroidism is not the only factor. In patients with normal kidneys, a primary hyperparathyroidism with very high parathyroid hormone levels is often only associated with mild hypophosphataemia or none at all. The underlying mechanism may also be the increased production of calcitriol as a result of the parathyroid hormone-induced stimulation of renal 1α-hydroxylase because calcitriol can increase the activity of the Na/Pi cotransporter, both in the intestines and in the proximal tubule [28,29]. Hypophosphataemia is associated with increased osteoblast apoptosis, diminished osteoblast activity and decreased osteoblastogenesis—factors also promoting the development of osteomalacia after transplantation. In summary, hypophosphataemia causes changes that most closely resemble osteomalacia. The standard immunosuppressive regimen after renal transplantation consists of a calcineurin or or an such as or and for or therapy may be to this immunosuppressive study on the of on bone is the effect of and is may to the development of osteomalacia by increasing hyperphosphaturia. 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