植田 佐保子

Post-transplantation bone diseases negatively affect the quality of life of solid organ recipients. Secondary or tertiary hyperparathyroidism is a frequent complication in kidney transplantation (KTx) recipients. Treatment with immunosuppressive agents including glucocorticoids can lead to deterioration in bone metabolism in these patients. In the present study, we explored the effects of a three-year treatment period with oral alendronate (ALN) in long-term KTx recipients. Post-KTx recipients were recruited (n = 24, M/F = 12/12, mean age 52.0 +/- A 7.8 years) into this study. All patients were prescribed methylprednisolone (4.07 +/- A 0.86 mg/day) with various immunosuppressive agents. Before treatment with oral ALN (35 mg/week), the mean concentrations of intact parathyroid hormone (iPTH) and 25-hydroxyvitamin D were 139.2 +/- A 71.4 pg/mL and 20.8 +/- A 4.1 ng/mL, respectively. After 36 months of ALN treatment, mean iPTH levels increased slightly (+20.9 %). Treatment with ALN reduced bone-specific alkaline phosphatase (-35.4 %), serum type I collagen N-terminal telopeptide (-31.2 %) and osteocalcin (-55.6 %) levels. ALN did not increase bone mass after 24 months. Four patients with the highest baseline iPTH levels suffered a clinical osteoporotic fracture during the 36-month ALN treatment period. Higher iPTH levels with chronic kidney disease (CKD) at baseline were associated with the incidence of new clinical fractures during ALN treatment. In conclusion, anti-resorptive therapy with ALN can suppress bone turnover even when iPTH concentration is elevated in long-term KTx recipients. However, hyperparathyroidism with CKD seems to be associated with new clinical fractures during ALN treatment.

Background: Chronic elevation of cardiac troponin T (TnT) levels as measured by conventional assays is strongly associated with structural heart disease and cardiovascular events. A new high-sensitivity assay for TnT makes it possible to measure concentrations more than a factor of 5 lower than the limits of detection of conventional assays. We evaluated the utility of serum TnT as a risk marker of cardiovascular disease in 409 outpatients with type-2 diabetes mellitus (T2DM). Results: TnT was detectable (&gt 0. 002 ng/mL) in 80% of patients, and elevation in TnT levels (&gt 0. 014 ng/mL) was found in 19. 3%, suggesting a higher prevalence of structural heart diseases in T2DM patients. A history of cardiovascular disease was noted in 89 (22%) patients. Patients with diabetic microvascular complications and those with abnormal electrocardiogram including left ventricular hypertrophy had higher TnT levels. Patients with increased levels of TnT (&gt 0. 014 ng/mL) were older, had higher values of N-terminal pro-B-type natriuretic peptide (NT-proBNP), C-reactive protein, cystatin C, and urinary albumin/creatinine ratio, had lower values of hemoglobin and estimated glomerular filtration rate, and had a higher prevalence of cardiovascular disease compared with those without increased TnT levels. In stepwise logistic analysis, NT-proBNP (odds ratio 7. 40 per 10-fold increase, P &lt 0. 0001) and cystatin C (18. 0 per 1. 0 mg/L, P &lt 0. 0001) were independently associated with elevation of TnT levels. HsTnT level, cystatin C, and HDL-cholesterol were also independent risk factors for history of major cardiovascular diseases in T2DM patients. Conclusion: This new high-sensitivity TnT assay may be useful for stratifying cardiovascular risk in outpatients with T2DM. © 2011 The Japan Diabetes Society.

Serum 25-hydroxyvitamin D (25-OHD) concentrations are thought to accurately reflect vitamin D stores, and vitamin D deficiency causes secondary hyperparathyroidism, irreversible bone loss, and increased risk of fracture. Recent studies suggest that decrease of serum 25-OHD level in mothers could increase the risk of preeclampsia, cesarean section, and craniotabes. Furthermore, this deficiency may affect bone mass and the incidence of neuromuscular diseases of their children in the future. In the present study, the serum concentration of 25-OHD in 93 pregnant women after the 30th week of their gestation was determined by direct radioimmunoassay. Mean 25-OHD levels in spring, summer, fall, and winter were 14.3 +/- 5.1, 15.7 +/- 6.4, 13.7 +/- 5.1, and 13.9 +/- 4.2 ng/ml, respectively. Severe vitamin D deficiency (25-OHD < 10 ng/ml) was found in 10 of these 93 women. Overall, hypovitaminosis D, which was defined as serum 25-OHD concentration equal to or less than 20 ng/ml, was revealed in 85 mothers (89.5%). Serum 25-OHD levels were not associated with either intact parathyroid hormone or corrected calcium concentrations, but were negatively associated with serum type I collagen N-terminal telopeptide and bone-specific alkaline phosphatase in these subjects. Mothers with threatened premature delivery had significantly lower 25-OHD levels (11.2 +/- 3.2 ng/ml) than those in mothers with normal delivery (15.6 +/- 5.1 ng/ml). In conclusion, the present data suggest a high prevalence of hypovitaminosis D in perinatal pregnant Japanese women throughout the year, which seems to affect bone metabolism and to be associated with threatened premature delivery.

Sekiguchi S, Suzuki A, Asano S, Nishiwaki-Yasuda K, Shibata M, Nagao S, Yamamoto N, Matsuyama M, Sato Y, Yan K, Yaoita E, Itoh M. Phosphate overload induces podocyte injury via type III Na-dependent phosphate transporter. Am J Physiol Renal Physiol 300: F848-F856, 2011. First published February 9, 2011; doi:10.1152/ajprenal.00334.2010.-Uptake of Pi at the cellular membrane is essential for the maintenance of cell viability. However, phosphate overload is also stressful for cells and can result in cellular damage. In the present study, we investigated the effects of the transgenic overexpression of type III Pi transporter Pit-1 to explore the role of extracellular Pi in glomerular sclerosis during chronic renal disease. Pit-1 transgenic (TG) rats showed progressive proteinuria associated with hypoalbuminemia and dyslipidemia. Ultrastructural analysis of TG rat kidney by transmission electron microscopy showed a diffuse effacement of the foot processes of podocytes and a thickening of the glomerular basement membrane, which were progressively exhibited since 8 wk after birth. TG rats died at 32 wk of age due to cachexia. At this time, more thickening of the glomerular basement membrane and segmental sclerosis were observed in glomeruli of the TG rats. Immunohistochemical examination using anticonnexin 43 and anti-desmin antibodies suggested the progressive injury of podocytes in TG rats. TG rats showed higher Pi uptake in podocytes than wild-type rats, especially under low Pi concentration. When 8-wk-old wild-type and TG rats were fed a 0.6% normal phosphate (NP) or 1.2% phosphate (HP) diet for 12 wk, HP diet-treated TG rats showed more progressive proteinuria and higher serum creatinine levels than NP diet-treated TG rats. In conclusion, our findings suggest that overexpression of Pit-1 in rats induces phosphate-dependent podocyte injury and damage to the glomerular barrier, which result in the progression of glomerular sclerosis in the kidney.

The type III inorganic phosphate (Pi) transporter Pit-1 was previously found to be preferentially expressed in developing long bones. Several studies also described a regulation of its expression in cultured bone cells by osteotropic factors, suggesting a role of this transporter in bone metabolism. In the present study, we investigated the effects of the transgenic overexpression of Pit-1 in Wistar male rats on calcium phosphate and bone metabolism. A threefold increase and doubling of Pi transport activity were recorded in primary cultured osteoblastic cells derived from calvaria of two transgenic (Tg) lines compared with wild-type littermates (WT), respectively. Skeletal development was not affected by the transgene, and bone mass, analyzed by DXA, was slightly decreased in Tg compared with WT. Enhanced Pi uptake in calvaria-derived osteoblasts from Pit-1 Tg was associated with a significantly decreased expression of alkaline phosphatase activity and a normal deposition and calcification of the collagenous matrix. In 4-month-old adult Tg rats, serum Pi and renal Pi transport were increased compared with WT. The decrease of serum Ca concentration was associated with increased serum parathyroid hormone levels. Variations in serum Pi in Pit-1 Tg rats were negatively correlated with serum fibroblast growth factor-23, whereas 1,25-dihydroxyvitamin D(3) was not affected by Pit-1 overexpression. In conclusion, transgenic Pit-1 overexpression in rats affected bone and calcium phosphate metabolism. It also decreased alkaline phosphatase activity in osteoblasts without influencing bone matrix mineralization as well as skeletal development.

Inorganic phosphate (Pi) transport probably represents an important function of bone-forming cells in relation to extracellular matrix mineralization. In the present study, we investigated the effect of prostaglandin D-2 (PGD(2)) on Pi transport activity and its intracellular signaling mechanism in MC3T3-E1 osteoblast-like cells. PGD(2) stimulated Na-dependent Pi uptake time- and dose-dependently in MC3T3-E1 cells during their proliferative phase. A protein kinase C (PKC) inhibitor calphostin C partially suppressed the stimulatory effect of PGD(2) on Pi uptake. The selective inhibitors of mitogen-activated protein (MAP) kinase pathways such as ERK, p38 and Jun kinases suppressed PGD(2)-induced Pi uptake. The inhibitors of phosphaticlylinositol (PI) 3-kinase and S-6 kinase reduced this effect of PGD(2), while Akt kinase inhibitor did not. These results suggest that PGD(2) stimulates Na-dependent Pi transport activity in the phase of proliferation of osteoblasts. The mechanisms responsible for this effect are activation of PKC, MAP kinases, PI 3-kinase and S-6 kinase. (C) 2009 Elsevier Ltd. All rights reserved.