Effects of raloxifene on bone metabolism in hemodialysis patients with type 2 diabetes.

BACKGROUND: Osteoporosis and chronic kidney disease are common conditions in older adults, and often occur concurrently. Bone disease is caused by increased bone turnover accompanying secondary hyperparathyroidism, and by factors such as bone metabolic disorder accompanying kidney disease and postmenopausal or age-related osteoporosis, even in hemodialysis patients. Raloxifene is commonly used for the treatment of postmenopausal osteoporosis in the general population, and may be a treatment option for osteoporosis in hemodialysis patients. However, the effects of raloxifene in hemodialysis patients with type 2 diabetes have not been examined in detail. OBJECTIVES: This study was performed to investigate the effects of raloxifene on bone turnover markers and bone density in postmenopausal women with type 2 diabetes mellitus who were undergoing hemodialysis in Japan. PATIENTS AND METHODS: The subjects were 60 female patients on maintenance hemodialysis (non-diabetic, n=30; diabetic, n=30). Raloxifene hydrochloride (60 mg) was administered to 14 diabetic patients and 14 non-diabetic patients for one year, and these patients were compared with control groups (no raloxifene) of 16 diabetic patients and 16 non-diabetic patients. Serum levels of N-terminal cross-linking telopeptide of type I collagen (NTx), bone alkaline phosphatase, and intact parathyroid hormone (iPTH) were measured, and bone density was determined by quantitative heel ultrasound at the speed of sound (SOS) in the calcaneus during this period. RESULTS: There were no significant differences in the levels of bone turnover markers except for iPTH after treatment of diabetic and non-diabetic patients with raloxifene for one year. SOS increased after treatment with raloxifene, but was significantly decreased in the control groups. Treatment with raloxifene resulted in a significant decrease in NTx and a significant increase in SOS in both diabetic and non-diabetic patients. There were no significant differences between the diabetic and non-diabetic patients who received raloxifene. CONCLUSIONS: Treatment with raloxifene can suppress reduction in bone density in postmenopausal women with type 2 diabetes who are undergoing hemodialysis.

[Difficult hemodialysis induction due to subclavian steal syndrome in a patient with Takayasu's arteritis].

The patient was a 53-year-old woman who had bilateral renal arterial constriction due to Takayasu's arteritis, and developed end-stage renal failure. When transient loss of consciousness occurred in 2002, she was diagnosed with subclavian steal syndrome (SSS). The renal failure worsened in June 2004, and there was concern that the left SSS could become aggravated as a consequence of creating an arterio-venous (AV) shunt. Although peritoneal dialysis was strongly recommended, she elected to undergo hemodialysis. We confirmed that there was no reduction of cerebral blood flow using brain single photon emission computed tomography (SPECT). Right and left examinations indicated the site at which an AV shunt should be created and subsequently, the AV shunt was created on the left fore-arm. Brain SPECT findings were again confirmed after dialysis, at the time of hemodialysis induction, and again 2 years after hemodialysis induction, showing no reduction in cerebral blood flow. She has no apparent symptoms or signs of left SSS, to date. Although it is known that an SSS could arise after AV shunt creation, there has been no report of the creation of an AV shunt in a case of SSS. The present case suggests that cerebral blood flow measurement using brain SPECT is useful for evaluating cerebral hemodynamics before AV fistula creation among patients with Takayasu's arteritis.

The effects of raloxifene on bone turnover markers and bone mineral density in women on maintenance hemodialysis.

BACKGROUND: Bone disease is caused not only by increased bone turnover accompanying secondary hyperparathyroidism but also by factors such as bone metabolic disorder accompanying kidney disease and postmenopausal or age-related osteoporosis in hemodialysis patients. In this study, we investigated the effects of raloxifene on bone turnover markers and bone mineral density (BMD) in female hemodialysis patients to determine involvement of estrogen deficiency in bone disease. METHODS: The subjects were 47 female patients on maintenance hemodialysis. Raloxifene hydrochloride (60 mg) was administered to 21 patients for 1 year, and these patients were compared with a control group of 26 patients. Serum levels of N-terminal cross-linking telopeptide of type I collagen (NTx), bone alkaline phosphatase, and intact parathyroid hormone were measured, and BMD was determined by quantitative heel ultrasound as the speed of sound (SOS) in the calcaneus over this period. RESULTS: NTx decreased after treatment with raloxifene for 1 year, but significantly increased in the control group. SOS increased after treatment with raloxifene for 1 year, but significantly decreased in the control group. Treatment with raloxifene resulted in a significant decrease of NTx and a significant increase of SOS in subgroups of patients aged <60 and ≥ 60 years. CONCLUSIONS: Treatment with raloxifene can suppress a rise in NTx and increase bone mineral density in patients around the time of menopause and in postmenopausal patients of advanced age. A reduction in bone mineral density caused by estrogen deficiency may be involved in the development of bone disease in female hemodialysis patients.

Soluble fibrin augments spreading of fibroblasts by providing RGD sequences of fibrinogen in soluble fibrin.

We previously reported that fibroblasts were found to spread far more avidly on NaBr-solubilized fibrin monomer (FM) monolayers than on immobilized fibrinogen (Fbg), indicating that removal of fibrinopeptides by thrombin is a prerequisite for the fibrin-mediated augmentation of cell spreading [J. Biol. Chem. 272 (1997) 8824-8829]. Soluble fibrin (SF), a 1:2 complex of fibrin-monomer and fibrinogen, is known to be present in the circulating blood under the pathological condition in which blood coagulation is activated. However, its physiological roles are still incompletely known. Fibroblasts spread on immobilized purified soluble fibrin. Cells spreading on immobilized soluble fibrin were blocked by the exogenous addition of soluble fibrin and glycine-arginine-glycine-aspartic acid-serine-phenylalanine (GRGDSP)-synthetic peptide but not by the addition of fibrinogen or fibrin monomer. However, cell spreading activity was decreased in the surfaces coated with fragment X, whose Aalpha-chains lack carboxyl-terminal segments including arginine-glycine-aspartic acid (RGD)-2 domain, fibrin monomer complexes. It suggests that the RGD-2 domain of fibrinogen after being complexed with fibrin monomer plays a pivotal role for soluble fibrin-dependent cell spreading. Soluble fibrin in plasma derived from the patients of disseminated intravascular coagulation (DIC) was immuno-purified using the monoclonal antibody (mAb) which specifically recognizes the Ca(++)-dependent conformer of fibrinogen. The purified soluble fibrin consisted of desAA-fibrin monomer and two fibrinogen molecules and did show the cell spreading activity. Thus, soluble fibrin in plasma plays a role as the modulator of thrombogenic process in vivo.

Multimeric vitronectin in ascites is involved in fibroblast spreading of EPS in patients on CAPD therapy.

BACKGROUND: Although encapsulating peritoneal sclerosis (EPS) is a serious complication of continuous ambulatory peritoneal dialysis (CAPD) therapy, the mechanism of the fibroneogenesis in EPS remains unknown. Because fibroblast adhesion and spreading to the extracellular matrix is the first step in peritoneal fibrosis, we investigated fibroblast spreading factor in ascites obtained from patients with EPS (EPS ascites). METHODS: To analyze fibroblast spreading activity, various concentrations of EPS ascites obtained from two EPS patients were coated on culture plates, and then the number of human fibroblasts (TIG-3) that had spread was counted. Each fraction of gel-filtered EPS ascites was also analyzed by this activity. Next, we examined the effect of the addition of Arg-Gly-Asp (RGD) peptides, several antibodies against adhesion molecules, and heparin on the fibroblast spreading activity in the EPS ascites. RESULTS: The fibroblast spreading activity of EPS ascites was about four times greater than that in ascites from a patient with nephrotic syndrome. Two major peaks (peak I and II) of spread cells were obtained when ascites were gel-filtered. The fibroblast spreading activities of the two peaks were abolished by the addition of RGD peptides and polyclonal antibody against vitronectin (VN). Immunoblotting analysis revealed that the two peaks contained VN and that peak I contained multimeric VN. Heparin, at 10 microg/ml, augmented the fibroblast spreading activity of peak I to about three times greater than the control. CONCLUSIONS: The results indicate that multimeric VN in EPS ascites plays a potential role in peritoneal fibrogenesis in EPS and that heparin may participate in peritoneal fibrosis in EPS.

Ascites from patients with encapsulating peritoneal sclerosis augments NIH/3T3 fibroblast proliferation.

Encapsulating peritoneal sclerosis (EPS) remains one of the major causes of dropout in continuous ambulatory peritoneal dialysis by reducing ultrafiltration capacity. To demonstrate whether ascites from patients with EPS (EPS ascites) has fibroblast proliferation activity, we used NIH/3T3 fibroblasts to examine the effects of EPS ascites on fibroblast proliferation activity by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. Encapsulating peritoneal sclerosis ascites dose-dependently augmented NIH/3T3 fibroblast proliferation. The protein kinase C inhibitors and the tyrosine kinase inhibitors partially inhibited the stimulatory effects of EPS ascites on fibroblast proliferation activity. In EPS ascites, levels of interleukin (IL)-1beta, IL-6, IL-8, transforming growth factor (TGF)-beta1, hepatocyte growth factor (HGF), and platelet-derived growth factor (PDGF)-AB were elevated. The treatment with IL-1beta, HGF, TGF-beta1, and PDGF-AB alone or in combination at similar concentrations to those in EPS ascites exhibited small but significant fibroblast proliferation activities. We conclude that EPS ascites stimulate NIH/3T3 fibroblast proliferation via protein kinase C and tyrosine kinase. The elevated cytokine and growth factors partly contribute to the EPS ascites-induced fibroblast proliferation.