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
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
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
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.

Amyloid
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.

AVN
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.

Treatment
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.

Kidney-pancreas
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.

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