“Early” Withdrawal of Glucocorticosteroids Is Well Tolerated by Kidney Transplant Recipients Without Increasing Allograft Rejection While Preserving Bone Integrity

Systemic bone demineralization is a frequent consequence of chronic kidney disease (CKD) caused by both reduced renal synthesis of 1,25 dihydroxy vitamin D3 plus secondary hyperparathyroidism stimulated by reciprocal hypocalcemia induced by diminished renal phosphate excretion. Recently, fibroblast growth factor 23 (FGF23) and klotho have been recognized as important regulators of bone mineral metabolism. Klotho deficiency associated with elevated circulating FGF23 levels signals the onset of secondary hyperparathyroidism in patients with CKD. Both FGF23 and parathyroid hormone levels rise as CKD progresses both to maintain mineral homeostasis and to overcome end-organ resistance. It is hard to define when the increase of both hormones becomes maladaptive inducing metabolic bone disease which is associated with adverse outcomes including cardiovascular disease and increased mortality (1). Although a functioning kidney transplant corrects both perturbations of uremia, glucocorticosteroids administered to prevent allograft rejection further challenge bone integrity adding to the risk of bone fractures as judged by reported low bone mineral density (BMD) measurements. That nephrologists are gaining control over bone complications in kidney transplant recipients was signaled by Naylor et al.’s previous report that only 6.3% of kidney transplant recipients on current regimens experienced a “major osteoporotic fracture” over 10 years (2). This surprising “Good News” is analyzed in the present report of 326 adult kidney transplant recipients in Manitoba, Canada, performed between 1996 and 2011, of mean age 45 years, of whom 61% are men. During follow-up, over a mean of 8.2 years, recipients bone integrity was monitored for a mean of 8.2 years by equal or less than two posttransplant dual energy X-ray absorptiometry examinations for which BMD was expressed as Z scores (standard deviation above/below sex-matched and age-matched reference data for which the main outcome was change in BMD which, in fact, remained stable or improved as judged by mean values that were “average for age and sex” (3). Hyperparathyroidism that persists after successful kidney transplantation is often proposed as an independent “major risk factor” for bone fractures after kidney transplantation (4). To assess the validity of this belief, a retrospective analysis of 143 consecutive adult patients who underwent kidney transplantation between 2004 and 2006 was performed (excluding nine with incomplete data, five who died, and four others) at Strasbourg University Hospital (France). Biochemical parameters were measured at the time of transplantation and at 3, 12, and 60 months after transplantation. At the time of transplantation, the median intact parathyroid hormone level was 334 ng/L decreasing to 123 ng/L at 3 months. A total of 30 fractures occurred in 22 patients. The authors assert that their study was “the first to demonstrate that persistent hyperparathyroidism 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.” Focused attention to detect and treat hyperparathyroidism before and after kidney transplantation is advocated to reduce the adverse impact of bone fractures. Reducing the dose of corticosteroids early after surgically successful kidney transplantation may be sufficient to avoid the bone complications and fractures that have been attributed, as an unavoidable component, of immunosuppression (5). Encouragingly, in a retrospective analysis of 34 kidney transplant recipients who had their glucocorticoid dose reduced to 4 mg per day within 1 month after kidney transplantation, no significant decrease in BMD of the lumbar spine was noted during their first year after transplantation. The allograft rejection rate was 15% after 3 years. It was concluded that mineral and bone disorder, a major complication after kidney transplantation, may very well be a “temporary” risk that could be largely avoided by early lowering the hazard imposed by corticosteroids without negatively altering the fate of the transplanted kidney. Attempts to discontinue corticosteroids as a component of the immunosuppressive regimen in stable kidney transplant recipients have been repeatedly reported. Over a decade ago, Maes et al. documented the safety and favorable outcome of stopping corticosteroids in 311 stable kidney transplant recipients in Belgium with successful “permanent” withdrawal effected in 274 (6). Steroid withdrawal was unsuccessful in 12% of patients with adrenal cortical deficiency resulting in 3% and acute rejection noted in 1.6%. Although pleased with the overall result, the authors stressed the need for longer follow-up, terming their overall outcome as reassuring that steroids can be withdrawn “to diminish the long-term morbidity” associated with corticosteroid therapy. It is reasonable now to consider a multicenter trial of steroid withdrawal, initially in uncomplicated stable transplant recipients, which, if positive, would serve to stimulate derivative studies in carefully selected and closely monitored complicated patients whose outcome is not yet predictable.

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