Portacaval shunt causes apoptosis and liver atrophy in rats despite increases in endogenous levels of major hepatic growth factors

Background/Aims: The response to the liver damage caused by portacaval shunt (PCS) is characterized by low-grade hyperplasia and atrophy. To clarify mechanisms of this dissociation, we correlated the expression of 'hepatotrophic factors' and the antihepatotrophic and proapoptotic peptide, transforming growth factor (TGF)-β, with the pathologic changes caused by PCS in rats. Methods: PCS was created by side-to-side anastomosis between the portal vein and inferior vena cava, with ligation of the hilar portal vein. Hepatic growth mediators were measured to 2 months. Results: The decrease in the liver/body weight ratio during the first 7 days which stabilized by day 15, corresponded to parenchymal cell apoptosis and increases in hepatic TGF-β concentration that peaked at 1.4 × baseline at 15 days before returning to control levels by day 30. Variable increases in the concentrations of growth promoters (hepatocyte growth factor, TGF-α and augmenter of liver regeneration) also occurred during the period of hepatocellular apoptosis. Conclusions: The development of hepatic atrophy was associated with changes in TGF-β concentration, and occurred despite increased expression of multiple putative growth promoters. The findings suggest that apoptosis set in motion by TGF-β constrains the amount of hepatocyte proliferation independently from control of liver volume. © 2002 European Association for the Study of the Liver. Published by Elsevier Science B.V. All rights reserved

Erythropoietin improves long-term neurological outcome in acute ischemic stroke patients: a randomized, prospective, placebo-controlled clinical trial.

Mortality and disability following ischemic stroke (IS) remains unacceptably high with respect to the conventional therapies. This study tested the effect of erythropoietin (EPO) on long-term neurological outcome in patients after acute IS. This study aimed to evaluate the safety and efficacy of two consecutive doses of EPO (5,000 IU/dose, subcutaneously administered at 48 hours and 72 hours after acute IS) on improving the 90-day combined endpoint of recurrent stroke or death that has been previously reported. A secondary objective was to evaluate the long-term (that is, five years) outcome of patients who received EPO.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access

Effect of occasional epoetin use in combination with a stable darbepoetin dosage on anemia management in hemodialysis patients

Kazumasa Shimamatsu Shimamatsu Naika Iin (Clinic), Shiseikai Medical Corporation, Chikushino City, Japan Aim: Taking advantage of the characteristics of both darbepoetin (DA) and epoetin (EPO) might be a reasonable option for stabilizing hemoglobin (Hb) control in hemodialysis (HD) patients. The effect of DA assisted by EPO (DA/EPO) on Hb control was evaluated retrospectively in comparison with that of EPO monotherapy. Methods: Twenty-six HD patients whose annual mean Hb values were available for both an EPO monotherapy period and a DA/EPO period were selected for analysis. During the DA/EPO period, DA was given on the second HD day of a week, and EPO was given if needed on the first and third HD days. Under stable DA dosage, when Hb rose >12 g/dL, EPO was eliminated. When Hb decreased <10 g/dL, EPO was added again. The variability of annual mean Hb values from the 26 HD patients during the DA/EPO period was compared with that during the EPO period. Additionally, the distance in Hb (d-Hb; absolute value of difference) between the annual mean Hb values and the target Hb (11 g/dL) during the DA/EPO period was compared with that during the EPO period. Results: The variability of annual mean Hb values during the DA/EPO period was significantly smaller than that during the EPO period (11.2±0.25 g/dL versus [vs] 11.0±0.50 g/dL; the F-test for equality of variance, P<0.001). Additionally, the d-Hb during the DA/EPO period was significantly smaller than that during the EPO period (0.22±0.21 g/dL vs 0.38±0.31 g/dL, P<0.03). The total doses (as EPO equivalents) of DA with EPO were reduced to 82.2% of the baseline EPO dose during the EPO monotherapy period. The expenditure for the DA/EPO period was significantly reduced to 80.9% of that for the EPO monotherapy. Also, the annual total amount of intravenous iron supplementation during the DA/EPO period was significantly reduced compared with that during the EPO period (546±304 mg/year vs 684±314 mg/year, P<0.05). Conclusion: The occasional use of EPO in combination with a stable DA dosage may be useful for Hb control within a narrow range of the target level. Keywords: combination therapy, erythropoiesis-stimulating agents, hemoglobin cycling, hemoglobin S

Regulation of platelet count by erythropoiesis-stimulating agents – iron axis in hemodialysis patients

Kiyomi Koike,1,2 Kei Fukami,1 Atsushi Kawaguchi,2 Kazumasa Shimamatsu,3 Sho-ichi Yamagishi,4 Seiya Okuda1 1Division of Nephrology, Department of Medicine, Kurume University School of Medicine, Kurume, 2The Biostatistics Center, Kurume University, Kurume, 3Shimamatsu Naika Iin (Clinic), Shiseikai Medical Corporation, Chikushino, 4Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Fukuoka, Japan Abstract: Higher doses of erythropoiesis-stimulating agents (ESAs) contribute to atherothrombotic cardiovascular disease in hemodialysis (HD) patients. Thrombocytosis is associated with increased mortality in ESA-treated HD patients. We investigated variables affecting platelet count and its variability (platelet count increment [Δplatelet count]) in HD patients. This retrospective longitudinal and observational study of HD outpatients was carried out over 3 years. The outcome was independent determinants of platelet count and platelet count, which were associated with iron indices, ESA dose, and C-reactive protein. In univariate regression analysis, V-shaped relationship was observed between platelet count and transferrin saturation (TSAT), ferritin, serum iron, and hemoglobin (Hb) with the bottom of 0.21, 330 ng/mL, 49 µg/dL, and 10.3 g/dL, respectively. Mixed-effect multivariate regression analysis revealed that TSAT (inversely), Hb ≤10.3 g/dL (inversely), C-reactive protein, and ESA dose were independently associated with platelet count. Δplatelet count was independently and inversely correlated with ΔTSAT and directly correlated with Δferritin. TSAT was independently and inversely associated with ESA dose. ESA dose was directly correlated with iron dose and inversely correlated with TSAT, ferritin ≤330 ng/mL, and Hb ≤10.3 g/dL. ESA dose and TSAT were correlated in determining platelet count and Δplatelet count. Targets of iron indices that reflect iron supply sufficient to avoid platelet count increment and variability may be >21% of TSAT and 300 ng/mL of serum ferritin for appropriate ESA therapy in HD patients. Keywords: hemodialysis, platelet count, erythropoiesis-stimulating agents, iron deficienc