Masanori Kishino

Effect of vitamin E on lipid metabolism and atherosclerosis in ESRD patients

BACKGROUND Oxidative stress is enhanced in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). Bioincompatibility represents an important source of reactive oxygen species. HD patients exhibit altered anti-oxidative defences and anti-oxidative vitamins such as vitamin E and C are altered in uremia. Frequently, HD patients also suffer from atherosclerotic cardiac disease. We have previously reported that low density lipoprotein (LDL) of HD patients is rich in malondialdehyde (MDA), an end product of lipid peroxidation. MDA rich LDL is thought to be an atherogenic lipoprotein due to its enhancement of macrophage foam cell formation. METHODS We conducted a controlled study for two years comparing the effects of a vitamin E coated cellulose membrane dialyzer and an ordinary cellulose membrane dialyzer on lipid metabolism and the progress of atherosclerosis. LDL-MDA and oxidized LDL (ox-LDL) were measured in HD patients using these two types of dialyzers. Plasma vitamin E and lipid concentrations were also evaluated. The aortic calcification index (ACI) was evaluated by CT scan to assess the progress of atherosclerosis before and for every year after treatment. RESULTS Use of a vitamin E coated cellulose membrane dialyzer for six months, one year and two years resulted in a significant reduction in LDL-MDA and ox-LDL compared to the ordinary cellulose membrane dialyzer. Treatment with a vitamin E-coated dialyzer significantly reduced the percentage increase in ACI after 24 months compared to the control. There were no significant changes in plasma vitamin E and lipid concentrations between the two groups. CONCLUSIONS These results suggest that the oxidative stress could be one of the stimulating factors of abnormal lipid metabolism and atherosclerosis in ESRD patients.

Deletion of the kinase domain in death-associated protein kinase attenuates tubular cell apoptosis in renal ischemia-reperfusion injury

Death-associated protein kinase (DAPK) is a calcium/calmodulin-dependent serine/threonine kinase localized to renal tubular epithelial cells. To elucidate the contribution of DAPK activity to apoptosis in renal ischemia-reperfusion (IR) injury, wild-type (WT) mice and DAPK-mutant mice, which express a DAPK deletion mutant that lacks a portion of the kinase domain, were subjected to renal pedicle clamping and reperfusion. After IR, DAPK activity was elevated in WT kidneys but not in mutant kidneys (1785.7 +/- 54.1 pmol/min/mg versus 160.7 +/- 60.6 pmol/min/mg). Furthermore, there were more TUNEL-positive nuclei and activated caspase 3-positive cells in WT kidneys than in mutant kidneys after IR (24.0 +/- 5.9 nuclei or 9.4 +/- 0.6 cells per high-power field [HPF] versus 6.3 +/- 2.2 nuclei or 4.4 +/- 0.7 cells/HPF at 40 h after ischemia). In addition, the increase in p53-positive tubule cells after IR was greater in WT kidney than in mutant kidneys (9.9 +/- 1.4 cells/HPF versus 0.8 +/- 0.4 cells/HPF), which is consistent with the theory that DAPK activity stabilizes p53 protein. Finally, serum creatinine levels after IR were higher in WT mice than in mutant mice (2.54 +/- 0.34 mg/dl versus 0.87 +/- 0.24 mg/dl at 40 h after ischemia). Thus, these results indicate that deletion of the kinase domain from DAPK molecule can attenuate tubular cell apoptosis and renal dysfunction after IR injury.

A Rheumatic patient with secondary amyloidosis developed severe gastrointestinal bleeding after hemodialysis.

慢性関節リウマチ (RA) に続発する全身性アミロイドーシスにて透析導入後著明な消化管症状を呈した症例を報告する.症例は40歳の女性. 約10年のRA罹病期間の後, 尿蛋白の増加および腎機能不全を呈し, 透析導入に至った. 導入後, 嘔気嘔吐の消化管症状が増強し, かつ難治性の下痢および下血の出現をみた. 胃カメラおよび大腸ファイバーにて消化管アミロイドーシスを疑ったが, その後も治療困難な下血が続き, 透析導入後約1か月で死亡した. 死後の組織検査にて, AA型アミロイドーシスと組織診断された.RAに伴うアミロイドーシスは, 急激な尿蛋白の増加, または腎機能の急激な低下が初期徴候として現われることが多い. このような状況においては, できる限り早急に腎生検を施行し, 確定診断の後早期に治療を試みることが望ましいと考える.