Shuji Iida

Carbonic-adsorbent AST-120 reduces overload of indoxyl sulfate and the plasma level of TGF-β1 in patients with chronic renal failure

BackgroundWe previously reported a significant increase in plasma TGF-β1 in patients with chronic renal failure (CRF). Progression of CRF may be caused by persistent renal production of TGF-β1. In CRF rat models, an oral carbonic absorbent (AST-120) reduces the expression of the TGF-β1 gene in the kidney, and delays the progression of CRF, in part by alleviating the overload of indoxyl sulfate. The aim of this study was to evaluate the effect of AST-120 on plasma levels of indoxyl sulfate and TGF-β1 in CRF patients.MethodsTen CRF patients (aged 59.3 ± 9.5 years, 5 men, serum creatinine 4.37 ± 1.72 mg/dl) were enrolled in this study. All patients maintained a regular dietary therapy and the same medication throughout the study. AST-120 was added at a dose of 6 g/day. Parameters including the slope of the reciprocal of the serum creatinine – time plot, plasma indoxyl sulfate level, and plasma and urinary levels of TGF-β1 were compared before and after the treatment with AST-120. The mean observation periods before and after the treatment were 9.7 ± 2.8 and 6.5 ± 2.9 months, respectively.ResultsAdministration of AST-120 significantly reduced the plasma levels of indoxyl sulfate (1.42 ± 1.50 vs. 1.26 ± 1.40 mg/dl, P < 0.05) and TGF-β1 (17.9 ± 7.2 vs. 10.6 ± 4.7 ng/ml, P < 0.05) and improved the slope of the reciprocal of serum creatinine (−0.061 ± 0.041 vs. −0.032 ± 0.055 dl/mg/year, P < 0.05).ConclusionsThese results support the notion that indoxyl sulfate and TGF-β1 may be involved in the progression of CRF, and that the oral adsorbent AST-120 may suppress the progression, at least in part, by reducing overproduction of TGF-β1.

Polymorphonuclear Leukocytes May Impair Endothelial Function Results of Crossover Randomized Study of Lipid-Lowering Therapies

Objectives—To examine whether polymorphonuclear leukocytes (PMNs) in hypercholesterolemia (HC) are activated to generate large amount of superoxide in vivo and hence impair endothelial function and, if so, whether statins, which possess anti-inflammatory properties, may restore PMN-mediated endothelial dysfunction. Methods and Results—At baseline, subjects with HC showed impaired endothelial function (P<0.001), estimated by flow-mediated vasodilation of the brachial artery, and increased susceptibility of low-density lipoprotein (LDL) to oxidation (P<0.0001) compared with control subjects. PMNs obtained from HC produced greater amount of superoxide (P<0.0001), showed higher adhesiveness to cultured endothelial cells (HUVECs) (P<0.0001), and impaired endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation of HUVECs compared with controls (P<0.001). Crossover administration of fluvastatin or colestimide for 3 months lowered LDL to the same levels (P<0.001 for both). Endothelial function was restored (P<0.0001). LDL oxidation (P<0.0001) and superoxide release from PMNs (P<0.0001) were diminished only in fluvastatin but not in colestimide arm. Fluvastatin attenuated PMN adhesion to HUVECs (P<0.0001) and restored eNOS Ser1177 phosphorylation of HUVECs (P<0.001). Conclusion—Statins may improve endothelial function at least in part by inactivating neutrophils independently of LDL reduction. Our results raise a novel concept that polymorphonuclear leukocytes may attack endothelia and play a pivotal role in the pathogenesis of atherosclerosis.

Involvement of iron-evoked oxidative stress in smoking-related endothelial dysfunction in healthy young men.

Background Oxidative stress and smoking contribute to endothelial dysfunction. Iron might also play a role in oxidative stress generation and endothelial dysfunction. However, the involvement of iron in smoking-induced endothelial dysfunction in healthy smokers remains unclear. Therefore, we examined here whether (1) intravenous iron infusion impaired endothelial function evaluated by flow-mediated vasodilatation (FMD) in non-smokers, and (2) deferoxamine, a potent iron chelator, ameliorated endothelial dysfunction in healthy smokers. Methods Eight healthy young male non-smokers (23±4 years old) received intravenous injection of saccharated ferric oxide (0.7 mg/kg body weight), while 10 age-matched healthy male smokers received deferoxamine mesylate (8.3 mg/kg body weight). At baseline, 5 and 20 minutes after treatment with iron or deferoxamine, biochemical variables were measured, including serum iron and marondialdehyde (MDA), a marker of lipid oxidation, and endothelial function was simultaneously evaluated by FMD. Results Compared with non-smokers, FMD was significantly lower in smokers. Iron and MDA levels were significantly increased, whereas FMD was impaired by iron infusion in non-smokers. Conversely, deferoxamine treatment significantly decreased iron and MDA levels and restored the decreased FMD in smokers. Baseline serum iron and MDA levels in all 18 subjects (non-smokers and smokers) were correlated with each other. There was a significant inverse correlation between the changes in MDA values and FMD from baseline in 18 men. Endothelium-independent vasodilation by glyceryl trinitrate was unaltered by either treatment. Conclusions Our present study suggests that iron-evoked oxidative stress might play a role in endothelial dysfunction in healthy smokers.

Usefulness of bone uptake ratio of bone scintigraphy in hemodialysis patients.

ObjectiveIt is important to estimate the bone metabolism in patients with renal osteodystrophy. The methods of estimation must be noninvasive, accurate, and able to measure repeatedly.MethodsThe regions of interest on bone scintigraphy were drawn over the radius in 22 hemodialysis patients (10 males, 12 females). The bone/soft tissue ratio (B/ST ratio) was calculated for all patients. The bone soft tissue ratio of both skull (S) and radius (R) was obtained from the resultant count ratios. We investigated the correlation between intact parathyroid hormone (PTH), alkaline phosphatase (ALP) and the uptake ratios S and R.ResultsIntact PTH had a significantly linear correlation with R (r = 0.745, p < 0.0001) and S (r = 0.702, p = 0.0001). ALP also had a significantly linear correlation with R (r = 0.537, p = 0.009) and S (r = 0.772, p < 0.0001).ConclusionThe measurement of the bone soft tissue ratio of radius on bone scintigraphy was crucial for estimating renal osteodystrophy.