Blood pressure control and satisfaction of hypertensive patients following a switch to combined drugs of an angiotensin receptor blocker and a calcium channel blocker in clinical practice of nephrology.

BACKGROUND: Combination drugs containing an angiotensin receptor blocker and a calcium channel blocker have been widely commercialized in recent years, and their advantages, such as improvements in adherence, and reductions in medication costs, have been greatly emphasized. However, the actual situations and the impact of switching to combination drugs in clinical practice of nephrology are not fully understood. METHODS: This study was conducted in outpatients of nephrology who received antihypertensive medicines, and who switched to combination drugs. Changes in the potency of the antihypertensive drugs, and blood pressure were examined retrospectively before and after changing treatments. In addition, the study also involved patients' questionnaire, which examined changes in blood pressure at home, the presence or absence of missed doses, the impact on medication-related expenses, and the level of patients' satisfaction with regard to combination drugs. RESULTS: Survey results from 90 participants revealed that changing to combination drugs resulted in a reduction of missed doses, a decrease in blood pressure measured in an outpatient setting, and a reduction in medication-related expenses in total patients, non-chronic kidney disease (CKD) patients, and CKD patients. CONCLUSION: Our study shows that switching to combination antihypertensive drugs resulted in an improvement in adherence and a reduction in medication-related expenses, and revealed that patient satisfaction was high. Combination drugs for hypertensive patients may be beneficial in both medical and economical viewpoints.

Lipoxygenase mediates invasion of intrametastatic lymphatic vessels and propagates lymph node metastasis of human mammary carcinoma xenografts in mouse.

In individuals with mammary carcinoma, the most relevant prognostic predictor of distant organ metastasis and clinical outcome is the status of axillary lymph node metastasis. Metastases form initially in axillary sentinel lymph nodes and progress via connecting lymphatic vessels into postsentinel lymph nodes. However, the mechanisms of consecutive lymph node colonization are unknown. Through the analysis of human mammary carcinomas and their matching axillary lymph nodes, we show here that intrametastatic lymphatic vessels and bulk tumor cell invasion into these vessels highly correlate with formation of postsentinel metastasis. In an in vitro model of tumor bulk invasion, human mammary carcinoma cells caused circular defects in lymphatic endothelial monolayers. These circular defects were highly reminiscent of defects of the lymphovascular walls at sites of tumor invasion in vivo and were primarily generated by the tumor-derived arachidonic acid metabolite 12S-HETE following 15-lipoxygenase-1 (ALOX15) catalysis. Accordingly, pharmacological inhibition and shRNA knockdown of ALOX15 each repressed formation of circular defects in vitro. Importantly, ALOX15 knockdown antagonized formation of lymph node metastasis in xenografted tumors. Furthermore, expression of lipoxygenase in human sentinel lymph node metastases correlated inversely with metastasis-free survival. These results provide evidence that lipoxygenase serves as a mediator of tumor cell invasion into lymphatic vessels and formation of lymph node metastasis in ductal mammary carcinomas.

Defective glycosylation of α-dystroglycan contributes to podocyte flattening.

In addition to skeletal muscle and the nervous system, α-dystroglycan is found in the podocyte basal membrane, stabilizing these cells on the glomerular basement membrane. Fukutin, named after the gene responsible for Fukuyama-type congenital muscular dystrophy, is a putative glycosyltransferase required for the post-translational modification of α-dystroglycan. Chimeric mice targeted for both alleles of fukutin develop severe muscular dystrophy; however, these mice do not have proteinuria. Despite the lack of a functional renal defect, we evaluated glomerular structure and found minor abnormalities in the chimeric mice by light microscopy. Electron microscopy revealed flattening of podocyte foot processes, the number of which was significantly lower in the chimeric compared to wild-type mice. A monoclonal antibody against the laminin-binding carbohydrate residues of α-dystroglycan did not detect α-dystroglycan glycosylation in the glomeruli by immunoblotting or immunohistochemistry. In contrast, expression of the core α-dystroglycan protein was preserved. There was no statistical difference in dystroglycan mRNA expression or in the amount of nephrin and α3-integrin protein in the chimeric compared to the wild-type mice as judged by immunohistochemistry and real-time RT-PCR. Thus, our results indicate that appropriate glycosylation of α-dystroglycan has an important role in the maintenance of podocyte architecture.

Podocyte foot process effacement in very early phase of passive Heymann nephritis is not a prerequisite for proteinuria.

BACKGROUND: Although foot process effacement is a characteristic alteration of podocytes in the proteinuric state, whether this is the cause or the result of proteinuria is not understood. We studied the morphology and molecular background of foot process effacement in relation to proteinuria, using the passive Heymann nephritis (PHN) model. METHODS: Foot process effacement was evaluated by electron microscopy. C3 deposition and the expression of alpha 3-integrin, a major adhesion molecule of podocytes, and actin cytoskeleton were examined by immunofluorescent staining. alpha 3-Integrin was also evaluated by immunoelectron microscopy. Western blotting was performed to examine whether anti-Fx1A recognizes alpha 3 beta 1-integrin. RESULTS: Foot process effacement accompanied by decreased expression of alpha 3-integrin was already observed from day 1 after the injection of anti-Fx1A, but albuminuria was not observed until day 5. Complement activation, a key pathogenesis in PHN, was estimated to occur from day 2 after the appearance of foot process effacement. The degree of foot process effacement had not changed before the onset of albuminuria, while after the onset of albuminuria it significantly deteriorated with increased expression of actin. By immunoelectron microscopy, alpha 3-integrin decreased exclusively at the site of deposits. Western blotting showed anti-Fx1A recognizing beta1-integrin. CONCLUSIONS: These findings indicate that complement-independent foot process effacement related to decreased expression of alpha 3 beta 1-integrin in a very early phase of PHN is not a prerequisite for proteinuria, and the deterioration of foot process effacement related to actin reorganization after the onset of albuminuria might be a secondary response to proteinuria.

A low-protein diet concomitant with high calorie intake preserves renal function and structure in diabetic OLETF rats.

BACKGROUND: Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a spontaneous type 2 diabetes model, were used to clarify whether and how a low-protein diet prevents progressive diabetic nephropathy, in terms of functional and structural parameters. METHODS: A low-protein diet (LPD) with 11% protein content, was compared to the normal 24% protein diet (NPD) without keeping isocaloric conditions. Daily food intake, body weight, and blood and urine chemistry were serially measured in rats from 10 through 60 weeks of age, and renal clearance studies and histological evaluations were performed at 40 and 60 weeks of age. RESULTS: Daily calorie intake was higher in the OLETF rats fed on the LPD than in those fed on the NPD throughout the experiment. Due to this hyperphagia, fasting blood glucose and hemoglobin (Hb)A1c were dramatically increased in the LPD-fed OLETF rats at 30 weeks and thereafter, whereas urinary protein excretion was decreased by more than half after 26 weeks in the LPD group. Plasma concentrations of total cholesterol and triglyceride were decreased in the LPD-fed OLETF rats at 40 and 60 weeks. Inulin clearance in the LPD group was higher only at 60 weeks of age. The glomerular sclerosis index (GSI) and tubulointerstitial index (TII) were preserved in the LPD group. The LPD induced a decrease in tubulointerstitial macrophage infiltration as compared with the NPD at both 40 and 60 weeks of age, but glomerular macrophage infiltration was not alleviated. CONCLUSIONS: A low-protein diet, despite the worsening hyperglycemia caused by hyperphagia, not only reduced proteinuria but also ameliorated hyperlipidemia in OLETF rats, thereby preserving renal function and structure in diabetic nephropathy, probably via a macrophage-mediated mechanism.