Bone complications of kidney transplantation

Renal osteodystrophy is the most complex, multifactorial metabolic bone disease. Different exposures to these factors result in a spectrum of histological changes. Types of renal osteodystrophy are based on the bone formation rate, presence of fibrosis or increased osteoid, and amount of aluminum staining. These types do not necessarily correspond to the bone density or the risk of fracture. Low bone density may be associated with either low bone formation rates or with secondary hyperparathryoidism and high bone formation rates. Furthermore, many patients have hyperparathyroidism, which increases the trabecular bone volume while it decreases the cortical bone volume, so that the effects on bone density depend on the site that is measured. Estrogen protects the bone from the resorbing effects of PTH, so that hyperparathyroidism may particularly enhance bone loss in women with estrogen deficiency.

Changes after kidney transplant
Renal transplants have been performed for 30 years, and there is now long-term data about the bone disease in these patients. Although many aspects of renal osteodystrophy improve, the bone density and strength may worsen due to the adverse effects of immunosuppression.

Fracture rates
Symptomatic fractures are reported in 4 to 11% of patients, with average first fracture 2 to 5 years after transplantation. Some prospective studies have not seen fractures in any patients during the first year after transplant, but measurement of vertebral compression had not been done.

A large retrospective survey showed 33 of 432 patients had a symptomatic fracture (7.6%). Fractures of the feet accounted for 40% of the fractures. The average time from transplant to fracture was 20 months.

Bone density
Graph of bone loss in renal transplant patients Bone density decreases in patients after renal transplantation, although there is some variation in reported rates of loss. This may reflect the underlying variability in types of renal osteodystrophy that exist prior to transplantation. Ongoing studies suggest that the rate of loss is greatest in the first year, but after several years the rate of loss is about 1-2%/year.

Bone histology
Bone biopsies frequently show abnormalities after kidney transplantation. The findings are variable, which is not surprising because there is such a wide spectrum of abnormalities before transplantation. Bone formation and resorption are often very high before transplantation. Thus, these rates may decrease after transplantation and still be higher than normal. The osteoid surface is higher in those taking cyclosporine. Osteomalacia is not generally encountered after transplantation, even in cases of hypophosphatemia. The bone density may reflect differences in bone histology; in mixed or hyperparathryoid disease the spine BMD z-score was -0.3, in adynamic disease is was -0.4, and in those with normal histology it was +0.8.

Hyperparathyroidism usually improves after transplantation, since the new kidney can excrete phosphate and produce 1,25-dihydroxyvitamin D in appropriate amounts. About 1/3 of patients develop hypercalcemia after a transplant; this persists in 7% and requires parathyroid surgery in about 2%. The PTH may continue to gradually decrease for 7 years after surgery.

Higher pre-transplant PTH and longer time on dialysis predict higher post-transplant PTH. The persistence of high PTH is related to the size of the parathyroid glands. Each parathyroid cell continues to secrete a basal level of PTH, and even with maximal metabolic inhibition, the total PTH secretion may be too high. This problem may resolve after several years, but some patients with hypercalcemia require partial parathyroidectomy. The late-term increase in PTH may be related to corticosteroids, which may cause secondary hyperparathyroidism.

Osteitis fibrosis may persist in the bone, but in other cases it may resolve. Radiographic studies of hyperparathyroidism also may improve after transplantation. In some of the larger studies PTH levels are directly correlated to decreases in bone density.

Aluminum deposition
Aluminum intoxication is not seen as frequently now that nephrologists monitor dialysate water aluminum and limit oral aluminum intake. Older studies reported worsening of aluminum-associated dementia after a kidney transplant; this was probably because the stress of the surgery, the corticosteroids, and the postoperative bedrest increased bone resorption, releasing aluminum that worsened the neurological disease. In more moderate cases, aluminum toxicity is reversed by transplantation, because aluminum is easily cleared by the new kidney. The bone aluminum content decreases dramatically, for example, in one study mean stainable aluminum decreased from 48 to 11% of the bone surface within 2 years, in another the content decreased from 63 to 36 mcg/kg. Aluminum may be found within the cement lines after transplant, indicating new bone formation that buries the aluminum, reducing the toxicity. Osteomalacia is not typically seen in post-transplant patients.

Oxalate accumulates in all dialysis patients, but it is unusual to see crystal deposition in the bone. Whether small amounts of oxalate increase bone resorption is not known. After transplantation, oxalate is cleared.

Patients receiving long-term hemodialysis accumulate 2microglobulin, which can aggregate into amyloid deposits in the bones and joints. After transplantation the pain associated with these deposits improves quickly, but the cysts and subchondral bone erosions remain. After four years the cysts persist, but no enlargement or new cysts develop. The pain relief may be due to the steroids, suggesting an inflammatory component to amyloid bone disease.

Gonadal steroids
Estradiol levels measured prospectively following transplantation may not increase, likely as a consequence of corticosteroid use. However, in many women menses return and fertility is restored. Testosterone remains low in approximately half the males.

Avascular necrosis is a common skeletal problem, seen an average of 3 years after kidney transplantation. The reported incidence varies from 1% to 30% of patients. Some of this variation is due to different anti-rejection regimens: higher prednisone doses are associated with a higher incidence of AVN. The incidence is also higher in those studies which report asymptomatic findings on radiographic studies. Abnormal changes seen on MRI surveys can resolve spontaneously in half the cases in which the bone scan is normal. Most patients with abnormalities in both a bone scan and MRI have symptoms, and 80% of symptomatic patients require hip replacement within 5 years to manage the pain.

There are little data on treatment of bone disease in patients after kidney transplantation. One reason is that the spectrum of post-transplant disease reflects the complexity of renal osteodystrophy, and many aspects of bone physiology improve with no specific management. Commonly used anti-resorbing medications such as alendronate or calcitonin could worsen hyperparathyroidism. This is frequently a problem in patients following kidney transplant, which is not seen in patients after other transplantation. Although clinical data are lacking, it makes physiological sense to be sure PTH is controlled before starting such treatment. Patients may still require calcitriol, but doses would be lower than in dialysis patients. Hypercalciuria and hypercalcemia could occur with too much calcitriol.

Because this is a relatively new procedure, there is little information about the bone disease in these patients. However available studies have shown fracture rates of 15 to 45%, and bone density is frequently low. Diabetes itself may contribute to low bone formation rate, but patients who have high body mass index tend to have high bone density. After transplantation, acidosis may complicate the bone disease. Also, diabetic neuropathy enhances the likelihood of stress fractures in the feet and ankles, which account for a large proportion of the fractures in this group of patients.
Table of literature review

More literature review


Almond, M. K.(1994). Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 66(1): 52-7.

Aroldi, A.(1997). Effects of three immunosuppressive regimens on vertebral bone density in renal transplant recipients: a prospective study. Transplantation 63(3): 380-6.

Bagni, B.(1994). Continuing loss of vertebral mineral density in renal transplant recipients. Eur J Nucl Med 21(2): 108-12.

Bardin, T.(1995). Dialysis arthropathy: outcome after renal transplantation [see comments]. Am J Med 99(3): 243-8.

Behnke, B.(1996). Bone mineral density in pediatric patients after renal transplantation. Clin Nephrol 46(1): 24-9.

Berenson, J. R.(1997). Pharmacokinetics of pamidronate disodium in patients with cancer with normal or impaired renal function. J Clin Pharmacol 37(4): 285-90.

Boot, A. M.(1995). Renal transplantation and osteoporosis. Arch Dis Child 72(6): 502-6.

Braun, W. E.(1999). The incidence and management of osteoporosis, gout, and avascular necrosis in recipients of renal allografts functioning more than 20 years (Level 5A) treated with prednisone and azathioprine. Transplantation Proceedings 31(1-2): 1366-1369.

Briner, V. A.(1995). Prevention of cancellous bone loss but persistence of renal bone disease despite normal 1,25 vitamin D levels two years after kidney transplantation. Transplantation 59(10): 1393-400.

Chao, S. H.(1994). Bone mineral density profile in uremic and renal transplant patients. Transplant Proc 26(4): 2009-11.

Cueto-Manzano, A. M.(1999). Bone loss in long-term renal transplantation: histopathology and densitometry analysis [In Process Citation]. Kidney Int 55(5): 2021-9.

Davenport, A.(1993). Treatment of hypercalcaemia with pamidronate in patients with end stage renal failure. Scand J Urol Nephrol 27(4): 447-51.

David-Neto, E.(1993). Reversal of aluminum-related bone disease after renal transplantation. Am J Nephrol 13(1): 12-7.

Dissanayake, I. R.(1998). The fate of bone after renal transplantation. Current Opinion in Nephrology and Hypertension 7(4): 389-395.

Elmstedt, E.(1981). Avascular bone necrosis in the renal transplant patient: a discriminant analysis of 144 cases. Clin Orthop(158): 149-57.

Elmstedt, E.(1982). Incidence of skeletal complications in renal graft recipients. Effect of changes in pharmacotherapy. Acta Orthop Scand 53(6): 853-6.

Elmstedt, E.(1982). Spontaneous fractures in the renal graft recipient: a discriminant analysis of 144 cases. Clin Orthop(162): 195-201.

Feber, J.(1994). Bone mineral density after renal transplantation in children. J Pediatr 125(6 Pt 1): 870-5.

Grotz, W. H.(1994). Bone fracture and osteodensitometry with dual energy X-ray absorptiometry in kidney transplant recipients. Transplantation 58(8): 912-5.

Grotz, W. H.(1995). Bone loss after kidney transplantation: a longitudinal study in 115 graft recipients. Nephrol Dial Transplant 10(11): 2096-100.

Grotz, W. H.(1995). Bone mineral density after kidney transplantation. A cross-sectional study in 190 graft recipients up to 20 years after transplantation. Transplantation 59(7): 982-6.

Grotz, W. H.(1998). Treatment of osteopenia and osteoporosis after kidney transplantation. Transplantation 66(8): 1004-8.

Grotz, W.(1998). Treatment of bone pain after kidney transplantation. Transplant Proc 30(5): 2114-6.

Horber, F. F.(1994). Changes in bone mass early after kidney transplantation. J Bone Miner Res 9(1): 1-9.

Hung, C. J.(1996). Clinical implication of hormone treatment in postmenopausal kidney transplants. Transplant Proc 28(3): 1548-50.

Hurst, G.(1998). Stabilization of bone mass after renal transplant with preemptive care. Transplant Proc 30(4): 1327-8.

Isiklar, I.(1998). Changes in bone mineral density after renal transplantation. Transplant Proc 30(3): 814-5.

Julian, B. A.(1991). Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 325(8): 544-50.

Kalef-Ezra, J. A.(1994). Bone mineral status after renal transplantation. Assessment by noninvasive techniques. Invest Radiol 29(2): 127-33.

Kim, M. S.(1998). Effect of deflazacort on bone mineral density in renal transplant recipients. Transplant Proc 30(7): 3041-2.

Kim, H.(1998). Bone mineral density after renal transplantation. Transplant Proc 30(7): 3029-30.

Klaus, G.(1998). Weight-/height-related bone mineral density is not reduced after renal transplantation. Pediatr Nephrol 12(5): 343-8.

Kwan, J. T.(1992). Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation. Miner Electrolyte Metab 18(2-5): 166-8.

Lausten, G. S.(1998). Necrosis of the femoral head after kidney transplantation. Clinical Transplantation 12(6): 572-574.

Lindsay, R.(1976). The value of bone density measurements in predicting the risk of developing avascular necrosis following renal transplantation. Calcif Tissue Res 21 Suppl: 242-6.

Lippuner, K.(1998). Effects of deflazacort versus prednisone on bone mass, body composition, and lipid profile: a randomized, double blind study in kidney transplant patients. J Clin Endocrinol Metab 83(11): 3795-802.

Machado, C. E.(1996). Safety of pamidronate in patients with renal failure and hypercalcemia. Clin Nephrol 45(3): 175-9.

Massari, P. U.(1997). Disorders of bone and mineral metabolism after renal transplantation. Kidney International 52(5): 1412-1421.

McIntyre, H. D.(1995). Long-term bone loss after renal transplantation: comparison of immunosuppressive regimens. Clin Transplant 9(1): 20-4.

Messa, P.(1998). Persistent secondary hyperparathyroidism after renal transplantation. Kidney Int 54(5): 1704-13.

Moore, L. W.(1996). Clinical observations of metabolic changes occurring in renal transplant recipients receiving ketoconazole. Transplantation 61(4): 537-41.

Pichette, V.(1996). Long-term bone loss in kidney transplant recipients: a cross-sectional and longitudinal study. Am J Kidney Dis 28(1): 105-14.

Ramsey-Goldman, R.(1999). Increased risk of fracture in patients receiving solid organ transplants. Journal of Bone and Mineral Research 14(3): 456-463.

Sanchez, C. P.(1998). Bone disease in children and adolescents undergoing successful renal transplantation. Kidney Int 53(5): 1358-64.

Sellers, E.(1998). The use of pamidronate in three children with renal disease. Pediatr Nephrol 12(9): 778-81.

Setterberg, L.(1996). Bone demineralization after renal transplantation: Contribution of secondary hyperparathyroidism manifested by hypercalcaemia. Nephrology Dialysis Transplantation 11(9): 1825-1828.

Smets, Y. F.(1998). Low bone mass and high incidence of fractures after successful simultaneous pancreas-kidney transplantation. Nephrol Dial Transplant 13(5): 1250-5.

Smets, Y. F.(1998). Pattern of bone loss after simultaneous pancreas-kidney transplantation: a prospective study. Transplant Proc 30(2): 326.

Svahn, T.(1975). Avascular necrosis of the bone in 99 renal allograft recipients. Scand J Urol Nephrol(29 Suppl): 135-7.

Talalaj, M.(1996). Efficiency of preventive treatment of glucocorticoid-induced osteoporosis with 25-hydroxyvitamin D3 and calcium in kidney transplant patients. Transplant Proc 28(6): 3485-7.

Torregrosa, J. V.(1995). Factors involved in the loss of bone mineral density after renal transplantation. Transplant Proc 27(4): 2224-5.

Torregrosa, J. V.(1995). Evolution of bone mineral density after renal transplantation: related factors. Nephrol Dial Transplant 10 Suppl 6: 111-3.

Tyrrell, C. J.(1994). Intravenous pamidronate: infusion rate and safety. Ann Oncol 5 Suppl 7: S27-9.

Valimaki, M. J.(1999). A prospective study of bone loss and turnover after allogeneic bone marrow transplantation: effect of calcium supplementation with or without calcitonin. Bone Marrow Transplantation 23(4): 355-361.

Velasquez-Forero, F.(1996). Adynamic bone lesion in renal transplant recipients with normal renal function. Nephrol Dial Transplant 11 Suppl 3: 58-64.

Wolpaw, T.(1994). Factors influencing vertebral bone density after renal transplantation. Transplantation 58(11): 1186-9.

Yap, A. S.(1990). Use of aminohydroxypropylidene bisphosphonate (AHPrBP, "APD") for the treatment of hypercalcemia in patients with renal impairment [see comments]. Clin Nephrol 34(5): 225-9.

Yazawa, K.(1998). Positive effects of kidney transplantation on bone mass. Transplant Proc 30(7): 3031-3.

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