Bone remodeling after renal transplantation

Several studies have indicated that bone alterations after transplantation are heterogeneous. Short-term studies after transplantation have shown that many patients exhibit a pattern consistent with adynamic bone disease. In contrast, patients with long-term renal transplantation show a more heterogeneous picture. Thus, while adynamic bone disease has also been described in these patients, most studies show decreased bone formation and prolonged mineralization lag-time faced with persisting bone resorption, and even clear evidence of generalized or focal osteomalacia in many patients. Thus, the main alterations in bone remodeling are a decrease in bone formation and mineralization up against persistent bone resorption, suggesting defective osteoblast function, decreased osteoblastogenesis, or increased osteoblast death rates. Indeed, recent studies from our laboratory have demonstrated that there is an early decrease in osteoblast number and surfaces, as well as in reduced bone formation rate and delayed mineralization after transplantation. These alterations are associated with an early increase in osteoblast apoptosis that correlates with low levels of serum phosphorus. These changes were more frequently observed in patients with low turnover bone disease. In contrast, PTH seemed to preserve osteoblast survival. The mechanisms of hypophosphatemia in these patients appear to be independent of PTH, suggesting that other phosphaturic factors may play a role. However, further studies are needed to determine the nature of a phosphaturic factor and its relationship to the alterations of bone remodeling after transplantation.     

Infrared spectroscopy indicates altered bone turnover and remodeling activity in renal osteodystrophy

Renal osteodystrophy alters metabolic activity and remodeling rate of bone and also may lead to different bone composition. The objective of this study was to characterize the composition of bone in high‐turnover renal osteodystrophy patients by means of Fourier transform infrared spectroscopic imaging (FTIRI). Iliac crest biopsies from healthy bone (n = 11) and patients with renal osteodystrophy (ROD, n = 11) were used in this study. The ROD samples were from patients with hyperparathyroid disease. By using FTIRI, phosphate‐to‐amide I ratio (mineral‐to‐matrix ratio), carbonate‐to‐phosphate ratio, and carbonate‐to‐amide I ratio (turnover rate/remodeling activity), as well as the collagen cross‐link ratio (collagen maturity), were quantified. Histomorphometric analyses were conducted for comparison. The ROD samples showed significantly lower carbonate‐to‐phosphate (p < .01) and carbonate‐to‐amide I (p < .001) ratios. The spatial variation across the trabeculae highlighted a significantly lower degree of mineralization (p < .05) at the edges of the trabeculae in the ROD samples than in normal bone. Statistically significant linear correlations were found between histomorphometric parameters related to bone‐remodeling activity and number of bone cells and FTIRI‐calculated parameters based on carbonate‐to‐phosphate and carbonate‐to‐amide I ratios. Hence the results suggested that FTIRI parameters related to carbonate may be indicative of turnover and remodeling rate of bone. © 2010 American Society for Bone and Mineral Research     

Silent urothelial cancer detected by sonography after renal transplantation

OBJECTIVES: Organ transplantation increases the incidence of cancer through unclear mechanisms. In our observation, urothelial cancer happens much more frequently in Chinese people. We reviewed the detection of urothelial cancer in our series after renal transplantation. METHODS: From July 1981 to June 2005, we performed 620 renal transplantations. We do graft and native kidney sonography survey annually even if the patient is asymptomatic. During this period, 10 urothelial tumors were detected. Herein we have reviewed the findings in these cases, along with their management and outcomes. RESULTS: Moderate to severe hydronephrosis of native kidneys was observed in 14 patients, including 9 (64.3%) who had cancer including eight asymptomatic and only one with flank pain and lymph nodes metastasis succumbing in 10 months with a functioning graft. Three patients showed similar degrees of graft hydronephrosis and graft ureteral cancer was diagnosed in one. Mean time from transplantation was 5.09 years. There was a female predominance (7:3). The bladder-to-renal pelvis-to-ureter ratio was 2:5:7, which was distinct from the usual 51:3:1 distribution. In native ureter cancer, we found the left ureter more prone to develop cancer than the right (8:1). CONCLUSION: The pattern of cancer in renal transplant patients is thoroughly different from the general population, namely female predominance, with a higher incidence of ureteral and renal pelvis versus bladder cancer. In our observation, routine periodic sonography survey even in asymptomatic patients is important for urothelial tumor detection, as the incidence of cancer is surprisingly high.     

The fate of bone after renal transplantation

Post-transplantation bone disease is a multifactorial, complex condition. It derives in a significant part from pre-existing renal osteodystrophy, but it is aggravated by factors emerging after renal transplantation. Among the latter factors, the key pathophysiological contributor to bone disease is immunosuppressive agent application (especially glucocorticoids (GC)). Post-transplantation bone disease is detectable even years after renal transplantation in the vast majority of patients, and potentially it never resolves completely. Due to post-transplantation bone disease, a rapid reduction of bone mineral density (BMD) develops that can exceed 10% in the first 12 months. Subsequently, the bone loss slows down or even a secondary increase occurs. Post-transplantation bone disease results in a significantly elevated fracture risk, which largely contributes to the increased morbidity in transplant patients. Currently, vitamin D metabolites and bisphosphonates are the most extensively tested therapeutic agents against this accelerated bone loss. Both substances have proven effective. However, it is yet unproven that they reduce the fracture risk. In patients with adynamic bone disease, bisphosphonate usage cannot be recommended, since this group of drugs could oversuppress bone metabolism.     

Bisphosphonates are effective prophylactic of early bone loss after renal transplantation

INTRODUCTION: Rapid bone loss and fractures occur early after solid organ transplantation. We examined the preliminary results of a prospective study evaluating the efficacy of prophylactic use of bisphosphonates in renal allograft recipients. METHODS: Bone mineral density (BMD) was measured at the lumbar spine and the hip by dual energy X-ray absorptiometry at 1, 6, 12 months. Alendronian or risedronian were initiated for patients with osteopenia or osteoporosis at 1 month who had no contraindications to bisphosphonates. The treatment lasted at least 6 months. Sixty-six patients were included in the study; 39 were treated with bisphosphonates (A), and 27 were drug-free (B). Presently, 24 group A and 13 group B patients have completed the 12-month observation period. RESULTS: In group A 53.8% (21) subjects had osteoporosis and 46.2% (18), osteopenia. Mean T-score L(2)-L(4) in group A at 1, 6, and 12 months were: (-)2.22 +/- 1.06; (-)2.07 +/- 1.25; (-)1.89 +/- 1.07, respectively. The T-score increase between 6 and 12 months was significant (P = 0.0014). The relative rise in BMD L(2)-L(4) between 1 and 12 months was 2.26%. In group B mean T-score L(2)-L(4) at 1, 6, and 12 months were: (-)0.26 +/- 1.34; (-)0.80 +/- 1.19; (-)1.2 +/- 1.59, respectively. The T-score decrease between 1 and 12 months in group B was significant (P = .0082). The 12-month relative decrease in femoral neck and trochanter BMD in group B was (-)2.1% and (-)2.75%, respectively. CONCLUSION: Bisphosphonates are effective for prophylaxis of rapid bone loss early after renal transplantation.     

Effect of bisphosphonates on bone mineral density after renal transplantation as assessed by bone mineral densitometry

INTRODUCTION: Steroid-induced osteoporosis is a major problem after organ transplantation. There is considerable evidence that bisphosphonates are effective in decreasing osteoporosis. AIM: This prospective study was carried out to see the effects of bisphosphonates on bone mineral density (BMD) after successful renal transplantation. MATERIAL AND METHODS: Fifty consecutive patients of successful renal transplantation were randomized into two groups. Group A (n = 27) received 35 mg/wk of Alendronate for 6 months after transplantation. Group B (n = 23) did not receive Alendronate and served as a control. Both groups underwent a pretransplant baseline dual-energy X-ray absorptiometry (DEXA) scan of their hips and lumber spines. Both groups received oral calcium and vitamin D supplement. Both groups were matched for the regimen and dose of immunosuppressive drugs. BMD was measured at 3 months and 6 months after transplantation. RESULTS: Both groups showed a decline in BMD in early months posttransplantation. However, the 6-month DEXA scans showed a significant rise in BMD in group A as compared to group B. CONCLUSION: Bisphosphonates appear to have a beneficial effect on steroid-induced bone loss.     

Aseptic bone necrosis after renal transplantation

Osteonecrosis is a common complication of renal transplantation and is an obstacle to rehabilitation. While prednisone has long been implicated as causative, the sporadic nature of aseptic necrosis (ASN) is poorly understood. Four hundred forty-four patients received kidney transplants (TX) between January 1978 and December 1984. Fifty-two patients (16%) have developed ASN. This retrospective study was developed in an attempt to define potential etiologic factors. Age, sex, donor, source, primary renal disease, duration of dialysis, and pre-TX parathyroidectomy did not correlate with ASN. Prednisone administration and duration of use prior to transplantation was equally common in ASN and control patients. Black recipients had a twofold frequency of ASN, although this association did not quite reach significance (p = 0.07). Pretransplant x-ray evidence of either osteopenia or renal osteodystrophy was significant (p less than 0.01) and apparent in 23 of 52 patients (44%). ASN was associated with a history of early acute rejection (p less than 0.02), higher final serum creatinine (p = 0.07), and greater mean prednisone (p less than 0.0001). The mean linear trend of daily prednisone dose was also significant (p less than 0.03). This study suggests that ASN is three times more likely to occur if radiographic evidence is apparent before TX. Rejection and higher daily steroid dosage correlate with a greater incidence of ASN, and blacks appear to be at greater risk.     

Renal osteodystrophy after successful renal transplantation: a histomorphometric analysis in 57 patients

Renal transplantation is the treatment of choice for patients with end-stage renal disease. It corrects most of the metabolic abnormalities that cause renal osteodystrophy. Nevertheless, renal osteodystrophy persists in many transplant recipients. The aim of this study was to investigate frequency and histomorphometric pattern of bone disease after renal transplantation. Bone biopsy specimens were taken from the iliac crest of 57 patients, including 28 women (26-70 years old) and 29 men (27-67 years old). Indications for biopsy were hypercalcemia, elevation of parathyroid hormone, and, in 19 cases, without suspected bone abnormalities based on laboratory parameters. The mean time of dialysis prior to renal transplantation was 43 months (range, 6-91 months in women and 10-111 months in men) and the mean interval between transplantation and bone biopsy was 53.5 months (range, 4-191 months in women and 5-90 months in men). Fourteen patients were treated with either 25-hydroxyvitamin D3 and/or 1-alpha hydroxyvitamin D3 or 1,25 dihydroxyvitamin D3, 3 with phosphate-binding agents. The immunosuppression consisted of cyclosporine, azathioprine, and prednisolone. The cumulative dosage of corticosteroids was 5569+/-5305 mg. For static and dynamic histomorphometry, we used American Society of Bone and Mineral Research nomenclature. Mild osteitis fibrosa and osteitis fibrosa, the most frequent forms of renal osteodystrophy, were observed in 13. (22.8%) and 14 patients (24.6%), respectively. Mixed uremic osteodystrophy was found in 7 patients (12.3%), adynamic renal bone disease in 3 patients (5.3%), and osteomalacia in 2 patients (3.5%). In 13 patients (22.8%), reduced bone mass and structural damage without typical signs of renal osteodystrophy, such as endosteal fibrosis or osteoclasia, were detected, and 5 patients (8.7%) showed normal histomorphometric parameters. We concluded that renal osteodystrophy, especially forms with high bone turnover, persisted in many patients after successful renal transplantation. This finding may be due to preexisting conditions, such as duration of dialysis and degree of hyperparathyroidism. Bone disease is increased by corticosteroid and immunosuppressive therapy after renal transplantation and requires close monitoring.     

Avascular necrosis of bone after renal transplantation

Summary: Avascular necrosis (AVN) of bone is the most debilitating musculoskeletal complication that can follow renal transplantation, and has been reported in 3-41% of patients. In this unit 351 renal transplants have been done on 285 recipients. Five (1.8%) of these patients (mean age 41.6 years; range 22-57 years; four female; all cadaveric kidneys) developed AVN which affected both hip joints. the mean duration of renal failure before dialysis was 18.2 months (range 5-36). All five were on dialysis for a mean of 16.2 months (range 4-29) pre-transplant. No patient had radiological evidence of renal osteodystrophy prior to transplantation. the first 116 patients were immunosuppressed with prednisone/azathioprine and four (3.5%) developed AVN. the subsequent 169 patients were treated with prednisone/azathioprine/ cyclosporine and one (0.6%) developed AVN. Only two of the five patients needed treatment for acute rejection (methylprednisolone 3 g and 6 g). the mean time from transplantation to onset of joint pain was 45.4 months (range 6-108). Total hip replacement (THR) was undertaken on all 10 joints with the first side being operated on after a mean of 73.2 months (range 23-124) from transplantation and the contralateral side after 88.4 months (range 24–144). Total hip replacement resulted in relief of pain in all joints: three surgical revisions were required, two for dislocation and one for a fractured prosthesis. This study has shown a low prevalence of AVN after renal transplantation. Possible explanations include careful control of renal osteodystrophy while on dialysis and the use of low dose prednisone in the immunosuppressive regimen.     

The role of multiple pharmaco-therapy in the pathogenesis of hyperlipidemia after renal transplantation

A study was undertaken in 54 renal allograft recipients to evaluate the multiple factors contributing to the pathogenesis of hyperlipidemia after renal transplantation. Serum triglyceride concentrations were found to correlate positively with the cummulative prednisolone dose, and with abdominal skin fold thickness. Serum cholesterol concentrations correlated significantly with serum creatinine concentrations. Patients on beta adrenergic blocking agents had lower plasma free fatty acid concentrations and patients on diuretics had higher serum triglyceride concentrations. The implication of these findings are discussed.     

Percutaneous bone biopsy in the diagnosis of renal osteodystrophy

Renal failure is associated with many complex bone and mineral complications. The spectrum of diseases is wide, encompassing defects in bone turnover, remodeling, and mineralization. Disease is currently defined in terms of whether a high or low turnover lesion is present. Measurement of serum parathyroid hormone levels (PTH) remains an important aspect in the management of renal bone disease, however, is limited by its lack of sensitivity in many clinical settings. Multiple biochemical markers are also available both commercially and experimentally to assist in assessing the degree of bone formation or resorption. However, when definitive diagnosis is important, when the clinical setting is confusing or complex, or when parathyroidectomy is being considered, the use of percutaneous bone biopsy is an essential tool in the understanding of underlying bone pathology and in directing therapy intervention.