tacrolimus and Hyperparathyroidism--Secondary

Transplantation is an established therapy for end-stage diseases of kidney, lung, liver, and heart among others. Osteoporosis and fragility fractures are serious complications of organ transplantation, particularly in the first post-transplant year. Many factors contribute to the pathogenesis of osteoporosis following organ transplantation. This review addresses the mechanisms of bone loss that occurs both in the early and late post-transplant periods, including the contribution of the immunosuppressive agents as well as the specific features to bone loss after kidney, lung, liver, cardiac, and bone marrow transplantation. Prevention and treatment for osteoporosis in the transplant recipient are also discussed.

Topics: Animals; Bone Marrow Transplantation; Glucocorticoids; Heart Transplantation; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Organ Transplantation; Osteoporosis; Osteoporotic Fractures; Tacrolimus; Vitamin D Deficiency

Early after renal transplantation (RT) a rapid decrease in bone mineral density at the lumbar spine, femoral neck, and femoral shaft has been documented. In addition, an appreciable proportion of patients still remain losing bone late after RT. As a consequence, RT patients are at a high risk of bone fractures as compared to general population. Most fractures involve appendicular skeleton, particularly the feet and ankles, and the diabetic patient is at increased risk of fractures. Thus, early institution of preventive measures and treatment of established osteoporosis are central. The major cause of post-transplantation bone loss is corticosteroid treatment, and this should be used at the lower dose compatible with graft survival. Preexisting hyperparathyroidism also affects the early cancellous bone loss at the spine, and post-transplantation bone loss reflects variable individual susceptibility, resembling the polygenic determination of bone mineral density in general. Clinical trials have demonstrated that bisphosphonates or vitamin D plus calcium supplementation, prevent post-transplantation bone loss during the first 6-12 months. However, their role in preventing bone fractures has not been proven. Finally, recommendations for management, prevention and treatment, are summarized.

Topics: Absorptiometry, Photon; Adrenal Cortex Hormones; Animals; Biomarkers; Bone and Bones; Bone Density; Calcineurin Inhibitors; Calcium; Diphosphonates; Diuretics; Female; Fractures, Spontaneous; Genetic Predisposition to Disease; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Male; Osteoporosis; Postoperative Complications; Prospective Studies; Rats; Renal Dialysis; Risk; Tacrolimus; Vitamin D

Secondary hyperparathyroidism and immunosuppressive treatments are the most important pathogenetic factors for bone disease after kidney transplantation. The aim of study was to compare the influence of vitamin D receptor (VDR) genotype on the PTH level and bone mineral density (BMD) in 67 patients, including 45 immunosuppressed with cyclosporine (CsA) and 22 with tacrolimus (Tac) versus 147 healthy volunteers. Two VDR polymorphisms: BsmI and FokI were assayed with RFLP-PCR. Scantibodies were utilized to evaluate 1-84 PTH. BMD was measured by DEXA. Hormone levels were measured on the third day and sixth month after transplantation. BMD was examined at the third and ninth month. The distribution of FokI genotype differed, but the BsmI genotypes did not differ between the transplant patients and the control group. All transplanted patients showed an elevated tPTH at the first examination. The highest PTH values, which were observed in bb genotype, significantly decreased after the transplant procedure. Patients with the FF genotype who were treated with CsA showed higher levels of tPTH than those with the Ff genotype. At 6 months, a decrease in tPTH occurred in both the CsA and the Tac patients. A low BMD at the third month was more frequent among patients of the BB genotype treated with CsA. The Z-score remained low at the third month and at the ninth month. In conclusion, kidney graft recipients show overrepresentation of the Ff genotype. Our preliminary data suggest that the bb genotype exhibits a protective effect on bone loss after renal transplantation.

Topics: Adult; Bone Density; Cyclosporine; Follow-Up Studies; Genotype; Graft Rejection; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Parathyroid Hormone; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptors, Calcitriol; Tacrolimus

Because tacrolimus is predominantly metabolized by CYP3A, the blood concentration/dose (C/D) ratio is affected by CYP3A5 polymorphism. Parathyroid hormone (PTH) expression increases in secondary hyperparathyroidism, which is frequently associated with end-stage renal disease. Recently, PTH has been shown to downregulate CYP3A expression at mRNA level. In this study, we examined the influence of CYP3A5 polymorphism on and association of serum intact-PTH (iPTH) level with blood tacrolimus concentration in patients with end-stage renal disease just before kidney transplantation. Forty-eight patients who satisfied the selection criteria were analyzed. Subjects were classified into two phenotype subgroups: CYP3A5 expressor (CYP3A5*1/*1 and *1/*3; n = 15) and CYP3A5 nonexpressor (CYP3A5*3/*3; n = 33). The blood tacrolimus C/D (per body weight) ratio was significantly lower in CYP3A5 expressors than that in CYP3A5 nonexpressors. A significant positive correlation was found between tacrolimus C/D and iPTH concentrations (r = 0.305, p = 0.035), and the correlation coefficient was higher after excluding 20 patients co-administered CYP3A inhibitor or inducer (r = 0.428, p = 0.023). A multiple logistic regression analysis by stepwise selection identified CYP3A5 polymorphism and serum iPTH level as significant factors associated with tacrolimus C/D. These results may suggest the importance of dose design considering not only the CYP3A5 phenotype but also serum iPTH level when using tacrolimus in patients who undergo renal transplantation.

Topics: Adult; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Female; Graft Rejection; Humans; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Parathyroid Hormone; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Retrospective Studies; Tacrolimus

In the setting of kidney transplantation, cinacalcet has been given, mainly, once daily, but also twice daily. The aims of this prospective study were to assess the acute pharmacodynamic effect of cinacalcet administrated once or twice daily to kidney transplant patients with normal renal function and persisting hypercalcaemia due to hyperparathyroidism and to evaluate 1-year efficacy and tolerance of cinacalcet given at a dose of 30 mg b.i.d.. Eleven patients, who received a transplant 6 (6-59) months previously, were included in the study. A first kinetic was done after administration of 60 mg of cinacalcet at 8 a.m. After a washout period of 1 week, the second kinetic was performed with cinacalcet given at 30 mg b.i.d within a 12-h period.. During both kinetics, serum calcium (sCa), ionized calcium (sCa(2+)), albumin-corrected Ca and parathyroid hormone (PTH) levels decreased significantly. At 24 h after the second kinetic, sCa(2+) was significantly lower. After 1 year of cinacalcet treatment, given at the dose of 30 mg b.i.d., there was a significant decrease in sCa, sCa(2+), PTH levels and calcium x phosphorus (Ph) product. In contrast, Ph levels increased significantly. There was no significant change in renal function.. Once- or twice-daily acute administration of cinacalcet to kidney-transplant patients has similar efficacy. One-year administration of cinacalcet, given as two daily doses, is safe and efficient.

Topics: Adult; Aged; Calcium; Cinacalcet; Cyclosporine; Dose-Response Relationship, Drug; Female; Humans; Hypercalcemia; Hyperparathyroidism, Secondary; Kidney Failure, Chronic; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Naphthalenes; Parathyroid Hormone; Phosphorus; Prospective Studies; Tacrolimus

Topics: Adult; Aged; Calcium; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Parathyroidectomy; Tacrolimus

Topics: Adult; Aged; Calcium; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Parathyroidectomy; Tacrolimus

Parathyroid surgery (PTX) in patients with tertiary hyperparathyroidism (tHPT) may endanger the long-term survival of transplanted renal grafts. The mechanism by which graft function deteriorates is unknown. We reviewed our experience in regard to the operative procedures and postoperative outcome.. Sixty-nine patients were operated on for tHPT between 1987 and 2006 at our institution. Serum (s) calcium, s-creatinine, and levels of intact parathyroid hormone (PTH) were measured before and after PTX. The Modification of Diet in Renal Disease (MDRD) equation was used to estimate glomerular filtration rate (GFR).. The entire patient group developed a deterioration of kidney graft function after PTX. Nineteen of 69 patients developed a decrease in GFR of more than 20% during the hospital stay, persisting for more than one year after PTX. Ten of them had to restart dialysis during the first year after PTX. Mean preoperative s-creatinine was 4.4 +/- 0.6 mg/dl in these patients. When divided according to the surgical procedure performed, only the subgroup who underwent total parathyroidectomy showed a significant worsening of graft function when compared to subtotal or reoperative PTX.. PTX is an efficient way to treat tHPT but represents a risk for impairing graft function, especially for patients that already demonstrate poor kidney function at the time of surgery. In the aim to prevent transient hypoparathyroidism, which may provoke reduced graft perfusion, as one possible cause of kidney graft deterioration associated with PTX, one should consider subtotal instead of total parathyroidectomy.

Topics: Adult; Aged; Calcium; Creatinine; Cyclosporine; Female; Glomerular Filtration Rate; Humans; Hyperparathyroidism, Secondary; Kidney Transplantation; Male; Middle Aged; Parathyroidectomy; Retrospective Studies; Tacrolimus

Cinacalcet is a calcimimetic drug that has been approved for treatment of secondary and tertiary hyperparathyroidism in patients with renal failure requiring renal replacement therapy. A few cases of successful treatment in renal transplant patients immunosuppressed with cyclosporine have been reported. Herein we have reported the case of a 48-year-old renal transplant recipient presenting with secondary hypercalcemic hyperparathyroidism (parathyroid hormone [PTH] 896 pg/mL; total calcium, up to 3.3 mmol/L) under immunosuppressive therapy with tacrolimus. Owing to substantial comorbidity and a high operative risk, we decided to initiate a therapeutic trial with cinacalcet. Using a daily dose of 30 mg of Cinacalcet, normal calcium levels and a mild fall in PTH levels (decline of 62 pg/mL) were achieved within the first week of treatment. At this point, we also observed a marked decrease in tacrolimus levels (from 6.3 to 2.6 mg/dL) without any change in concomitant medications. Thus, we adapted the tacrolimus dosage. Concurrent with cinacalcet therapy, there was a rise in serum creatinine levels (from 3.9 to 4.9 mg/dL before discontinuation of cinacalcet), which was not reversible after termination of 3 weeks of treatment with cinacalcet, but continued. Cinacalcet and tacrolimus are both metabolized via cytochrome P 450. The documented decrease in tacrolimus serum levels, suggested a drug-drug interaction between tacrolimus and cinacalcet. The irreversible deterioration in renal function may be attributed to nephrotoxic properties of cinacalcet, but may also indicate an acceleration of the natural course of chronic allograft nephropathy.

Topics: Cinacalcet; Creatinine; Drug Interactions; Drug Therapy, Combination; Female; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Naphthalenes; Tacrolimus

In this article, we present a case in which marked intratubular calcification occurred in the transplanted kidney. The patient received living renal transplantation without control of severe secondary hyperparathyroidism, and the tacrolimus hydrate was used as an immunosuppressive agent, the adverse effects of which can induce intratubular calcification. Biopsy of the renal allograft revealed many intratubular calcifications in the cortex region of the specimen, although the histological grade was borderline for the Banff classification. The pathogenic causes of intratubular calcification were difficult to distinguish from the adverse effects of tacrolimus and the uncontrolled hyperparathyroidism.

Topics: Biopsy; Female; Humans; Hyperparathyroidism, Secondary; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Middle Aged; Nephrocalcinosis; Tacrolimus