[Effects of tacrolimus vs cyclosporin-A on bone metabolism after kidney transplantation: a cross-sectional study in 28 patients]. / Comparaison des effets de la ciclosporine-A et du tacrolimus sur le métabolisme osseux des patients transplantés rénaux: une étude transversale chez 28 patients.

BACKGROUND: Controversy exists about the effects of calcineurin inhibitors on bone metabolism. We decided to compare the effects of CyA vs FK506 on bone metabolism of kidney recipients. PATIENTS AND METHODS: From 94 patients grafted at the University Hospital of Nice between 1996 and 1999 treated either by CyA (N=49) or by FK506 (N=45), we selected 14 pairs (18 M, 10F), matched for gender, BMI, time lapsed since transplantation and gonadal status in females. Patients with>1 transplantation or>1 rejection episode were excluded. Cumulative dose of steroids was recorded. Bone mineral density (BMD) was mesured at heel and forearm, as well as serum concentration of calcium, phosphate, parathyroid hormone (PTH), vitamin D metabolites, C-telopeptide (CTX), creatinine, estradiol as well as Bone Alkaline Phosphatase (BAP) activity. RESULTS: Despite the matching, time on hemodialysis was longer in FK506 group. Cumulative dose of steroids was similar between groups. There was no difference between groups in BMD and biochemical parameters except for estradiol serum levels which were dramatically lower in FK506 than in CsA (P=0,02) and for a trend (p=0,08) for BAP and CTX to be higher in FK506 than in CsA. CONCLUSIONS: BMD is not lower in FK506- than in CsA-treated patients although exposure to hyperparathyroidism was longer and estradiol levels were lower in the FK506 than in the CsA group. These data suggest that FK506 may have a favorable bone effect to compensate for these deleterious factors. This hypothesis remains to be tested in longitudinal studies.

Vitamin B6 metabolites in idiopathic calcium stone formers: no evidence for a link to hyperoxaluria.

Vitamin B6 metabolites and their potential correlates to urinary oxalate excretion in idiopathic calcium stone formers (ICSF) compared with healthy subjects were investigated. This clinical study was performed in a population of male ICSF with (Hyperoxalurics, n=55) or without hyperoxaluria (Normooxalurics, n=57) as well as in 100 healthy male control subjects. Pyridoxal 5'-phosphate serum concentration (S-pyridoxal 5'P) and 24-h urinary excretion of 4-pyridoxic acid (U-4pyridoxic acid) were measured using HPLC; 24-h urinary excretion of oxalate (U-oxalate) was measured concurrently. A subgroup of subjects (40 Hyperoxalurics, 15 Normooxalurics and 50 controls) underwent the same measurements before and after 7-day pyridoxine loading per os (pyridoxine hydrochloride, 300 mg/d). Under usual conditions, U-4pyridoxic acid was similar in the three groups, whereas mean S-pyridoxal 5'P was significantly lower ( p<0.0001) in the Hyperoxalurics (59.6+/-21.2 nmol/L) and in the Normooxalurics (64.9+/-19.7 nmol/L) than in the controls (86.0+/-31.0 nmol/L). No correlation could be found between U-oxalate and U-4pyridoxic acid or S-pyridoxal 5'P. After B6 loading, S-pyridoxal 5'P was still significantly lower in the Hyperoxalurics (415+/-180 nmol/L, p<0.001) and in the Normooxalurics (429+/-115 nmol/L, p=0.036) than in the controls (546+/-180 nmol/L), although there was no difference between groups for U-4pyridoxic acid. No correlation in any group could be found between changes in U-oxalate and changes in U-4pyridoxic acid or S-pyridoxal 5'P. Although there is no vitamin B6 deficiency in ICSF with or without hyperoxaluria, these patients, on average, have lower levels of S-pyridoxal 5'P than healthy subjects. However, this slight decrease does not seem to account for idiopathic hyperoxaluria.

1,25-(OH)2-16ene-23yne-D3 reduces secondary hyperparathyroidism in uremic rats with little calcemic effect.

OBJECTIVES: To compare the effects of vitamin D analogs versus calcitriol on serum levels of Ca, P and parathyroid hormone (PTH). A compound better than calcitriol should increase the Ca x P product less than calcitriol for an equivalent decrease in PTH levels. METHODS: Biological activity of 4 vitamin D analogs, 1,25-(OH)(2)-16ene- D(3) (RO(1)), 1,25-(OH)(2)-16ene-23yne-D(3) (RO(2)), 1,25-(OH)(2)-26,27-hexafluoro-16ene-23yne-D(3) (RO(3)) and 1,25-(OH)(2)-16ene-23yne-26,27-hexafluoro-19nor-D(3) (RO(4)) was tested vs. calcitriol in parathyroidectomized rats. In a second set of experiments, the effects of RO(2), RO(4) and calcitriol were studied in 5/6 nephrectomized rats with secondary hyperparathyroidism. RESULTS: In parathyroidectomized rats, all analogs (250 pmol/day) led calcemia to rise after 7 days. In uremic rats, all treatments reduced PTH levels. RO(4) revealed toxicity. RO(2) was as effective as calcitriol in suppressing PTH in a dose dependent manner. Mean plasma ionized calcium did not change from baseline to day 14 and day 28 on RO(2) (250 or 500 pmol/day) whereas it increased significantly on RO(2) (1,000 pmol/day) and calcitriol (125 or 250 pmol/day). Increasing the dose of calcitriol led Ca x P to rise more dramatically than increasing the dose of RO(2), which appears to have a wider therapeutic window than calcitriol. CONCLUSION: 1,25-(OH)(2)-16ene-23yne-D(3) (RO(2)) may represent a novel candidate for the treatment of renal osteodystrophy in humans.

Changes in bone mineral density over 18 months following kidney transplantation: the respective roles of prednisone and parathyroid hormone.

BACKGROUND: Prednisone is a major factor of bone loss after kidney transplantation. The role of hyperparathyroidism and immunosuppressors is less clear. METHODS: Thirty-three patients (14 men, 19 women) with ESRD were followed prospectively for 18 months after kidney transplantation. All patients received prednisone and cyclosporin A (CyA) with (n=18) or without azathioprine. Rejection episodes were treated with boluses of methylprednisolone. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry for the spine, hip and whole body (total, trunk, limbs) at 1, 12, 24, 36, 60 and 75 weeks after kidney transplantation. At the same time, blood was assayed for calcium, phosphorus, intact-PTH, alkaline phosphatase, creatinine and CyA, and 24-h urine was assayed for Ca and P. RESULTS: BMD at baseline was low at all skeletal sites in women, but not in men. BMD decreased significantly at the spine (-7.0+/-0.9%, week 24), trunk (-4.8+/-0.5%, week 24), total hip (-4.3+/-1.0%, week 36), whole body (-2.2+/-0.4%, week 36) and limbs (-1.0+/-0.7%, week 74). BMD changes over time followed three different patterns: no change or gain, continuous loss, and NADIR. For the spine and trunk, two thirds of patients had a NADIR pattern with recovery at the end of the study, and one-quarter of patients had continuous bone loss. For the limbs, BMD rose or remained stable (n=20), decreased continuously (n=8) or had a NADIR pattern (n=5). Neither gender nor time on dialysis prior to transplantation influenced BMD changes. Patients with PTH serum concentrations below the median value 1 week after kidney transplantation (109 pg/ml) had continuous bone loss at the whole body or limbs but not at other sites. The cumulative dose of prednisone correlated negatively with BMD changes at the spine (r=-0.39, P<0.03), hip (r=-0.50, P=0.005) and trunk (r=-0.52, P=0.002), but not at the whole body or limbs. CyA levels in blood did not correlate with BMD changes. BMD for the whole body and limbs did not change in the patients receiving azathioprine (n=16; -2.7+/-0.7%, P=0.013) but decreased in the others (-2.8+/-0.9%, P<0.0002). CONCLUSIONS: High cumulative prednisone doses are deleterious for the axial skeleton. Low levels of PTH observed 1 week after kidney transplantation are predictive of continuous cortical bone loss.