Inhibitory effects of the transcription factor Ets-1 on the expression of type I collagen in TGF-ß1-stimulated renal epithelial cells.

Extracellular matrix (ECM) production and epithelial-mesenchymal transition (EMT) are important for phenotypic conversion in normal development and disease states such as tissue fibrosis. Transforming growth factor-ß1 (TGFß1) is one of the most potent inducers of ECM proteins, and its role in the pathogenesis of fibrosis is well established. Ets family is involved in a diverse array of biologic functions including cellular growth, migration, and differentiation. In the present study, we investigated whether Ets-1 has a role in ECM production and EMT in human renal tubuloepithelial cells (HKC cells). TGFß1 treatment increases Ets-1 expression and nuclear translocation in the HKC cells. Overexpression of recombinant Ets-1 suppressed transcription of α2(I) collagen (COL1A2) and type I collagen production in the TGFß1-activated HKC cells. From the experiments using specific inhibitors against Smad3 or mitogen-activated protein (MAP) kinase pathways, Ets-1 has an inhibitory role for COL1A2 transcription and the p38 MAPK pathway participates in the negative contribution of Ets-1 in TGFß1/Smad3-activated renal cells.

Vitamin D receptor agonist supplementation and suppression of inflammation may have advantage for all-cause mortality in hemodialysis patients.

BACKGROUND: Vitamin D deficiency is common in hemodialysis (HD) patients. The aim of this study was to determine whether HD patients with low 25-hydroxyvitamin D [25(OH)D] levels are at increased risk of mortality. METHODS: This was a prospective cohort study of Japanese HD patients. We selected all patients with measured serum 25(OH)D levels at the time of entry. We assessed the impact of low serum 25(OH)D levels on the long-term mortality of HD patients by performing Cox regression analyses. Associations between serum 25(OH)D levels and all-cause mortality were also investigated. RESULTS: Data from 100 patients (mean age 61.0 ± 11.8 years, 64 % males) were available. There was a high prevalence (55 %) of 25(OH)D insufficiency < 20 ng/ml, and 51 % of study subjects were treated with alfacalcidol. Twenty-four patients died during a follow-up period of 4.6 years. There were no significant associations between serum 25(OH)D levels and all-cause mortality (p = 0.777). After adjustments for possible confounders, the hazard ratio (with 95 % CI) for all-cause mortality was 1.091 (1.024-1.167) for age, 0.734 (0.566-1.167) for dialysis vintage, 1.012 (0.995-1.031) for serum total cholesterol values, 2.028 (1.093-3.701) for serum phosphate levels, and 0.291 (0.088-0.855) for treatment with alfacalcidol. A survival advantage of alfacalcidol treatment was observed (log-rank, p = 0.0150). The group of subjects whose serum (25(OH)D level was <20 ng/ml and who were not treated with alfacalcidol had the highest mortality rate. CONCLUSION: Vitamin D deficiency in HD patients who had not taken vitamin D receptor agonist (VDRA) is associated with an increased risk of all-cause mortality. VDRA supplementation may suppress chronic inflammation and have some advantage for mortality of HD patients with vitamin D deficiency.

Relationship between serum fibroblast growth factor-23 level and mortality in chronic hemodialysis patients.

BACKGROUND: Fibroblast growth factor-23 (FGF23) is a phosphate-regulating hormone and is found to be markedly increased in patients with chronic kidney disease. The aim of the present study was to evaluate the relationship between serum FGF23 levels and mortality, including the impact of gender and cardiovascular disease (CVD), in a Japanese cohort of chronic hemodialysis (HD) patients. METHODS: Ninety-two maintenance dialysis patients (58 men; mean age 60.3 years) were included. Serum intact FGF23, calcium, phosphate, albumin, intact parathyroid hormone (PTH), and C-reactive protein were measured at baseline. CVD was defined as clinical symptoms and/or a history of CVD. RESULTS: During a median follow-up time of 53.2 months, 24 patients (26 %) died. Serum FGF23 levels were positively correlated with serum levels of calcium (r = 0.5433, P < 0.0001), phosphate (r = 0.5048, P < 0.0001), calcium × phosphate product (r = 0.6801, P < 0.0001), and intact PTH (r = 0.2710, P = 0.0090) (r = 0.27, P < 0.0001). In Cox proportional hazard models, serum FGF23 level was not associated with increased mortality risk, neither in crude nor in multivariate-adjusted models. However, in a subgroup analysis of women with previous CVD, serum FGF23 level above median was associated with higher cardiovascular event risk in crude models (hazard ratio 9.52, 95 % confidence interval 1.56-86.11, P = 0.0129). Kaplan-Meier analysis stratifying for the presence of CVD demonstrated a significant higher mortality risk in patients with history of CVD and higher serum FGF23 levels (P < 0.0001). CONCLUSION: Serum FGF23 level was not associated with increased mortality risk in this cohort of prevalent HD patients. These results suggest that the impact of FGF23 on mortality may be modified by gender and previous CVD and is blunted in the grade of hyperphosphatemia.

Relation of carotid intima-media thickness and silent cerebral infarction to cardiovascular events and all-cause mortality in chronic hemodialysis patients.

OBJECTIVE: Silent cerebral infarction (SCI) and increased carotid intima-media thickness (IMT) have been found to be associated with future stroke in the general population. We investigated whether a combination of SCI and increased IMT is a predictor of cardiovascular events and all-cause mortality in chronic hemodialysis (HD) patients. METHODS: We performed a retrospective cohort study of 70 HD patients who had one or more risk factors for atherosclerosis but no history of cardiovascular disease. We performed cranial magnetic resonance imaging (MRI) and measured carotid IMT at baseline, and then evaluated the risks of cardiovascular events and all-cause mortality by using Cox proportional hazards models. The Kaplan-Meier method and a log-rank test were used to compare event-free survival. RESULTS: SCI was present in 25 patients (35.7%) at baseline. During an average follow-up of 46.3 ± 14.3 months (range: 19 to 56 months), 15 patients (21.4%) died and 16 (22.9%) experienced a new cardiovascular event. The presence of SCI in combination with increased carotid IMT at baseline was independently associated with cardiovascular events and all-cause mortality after adjustment for age, sex, duration of dialysis, and traditional vascular risk factors. CONCLUSION: SCI, similar to carotid IMT, is an independent predictor of cardiovascular events and all-cause mortality in chronic HD patients.

Flowcytometric analysis of lymphocytapheresis in a patient with recurrent FSGS after renal transplant.

Frequently, focal segmental glomerulosclerosis (FSGS) recurs after renal transplantation, resulting in poor graft survival. Pathological mechanisms of the recurrence are still unknown, but both B and T cell disorders are suspected based on much evidence. This supports theoretical benefits using plasma exchange (PE) and lymphocytapheresis (LCAP). A renal transplant was performed for a 35-year-old woman, who suffered steroid-resistant FSGS and developed to chronic kidney disease stage 5D at 31 years old. We treated the patient with recurrent FSGS by LACP and examined whether peripheral neutrophils were dynamically changed after the therapy. Further, we performed flowcytometric analysis to examine lymphocyte fractions before and after LCAP. The decrease of helper (CD4 positive) and memory (CD4 and CD45RO positive) T cells was prominent after LCAP. Although B cells were at the nadir because of rituximab treatment, LCAP also decreased peripheral B cells. These suggest that LCAP has the potential to suppress the activities of recurrent FSGS after renal transplant.