Hiroyuki Kobayakawa

Induction of Irreversible Glomerulosclerosis in the Rat by Repeated Injections of a Monoclonal Anti-Thy-1.1 Antibody

The present experiment demonstrated that an irreversible glomerulosclerosis could be induced in the rat through repeated intravenous administrations of OX-7 (a monoclonal anti-Thy-1.1 antibody). Rats were injected with 0.2 mg of affinity-purified OX-7 at 1-week intervals for a period of 4 weeks. Glomerular damage was periodically examined at light-microscopic level. Thirty-five days after the initial injection (7 days after the final injection), capillary aneurysms and expansion of the mesangial areas with hypercellularity were frequently observed. Similar glomerular damage was also observed in rats 7 days after they received a single injection of either 1.0 or 0.2 mg of OX-7. After repeated injections, 112 days from the initial administration (84 days after the final injection), approximately 60% of the glomeruli had expanded mesangial areas with an apparent increase in the mesangial matrix. The result contrasts sharply with that obtained from a single injection of OX-7 in that more than 85% of the glomeruli showed no abnormalities 84 days after the injection. This chronic model, as a result of repeated injections of the antibody, could serve as a potential for further investigation of the mechanisms involved in the development of chronic glomerulonephritis.

Effects of L-Carnitine Administration on Short-Chain Fatty Acid (Acetic Acid) and Long-Chain Fatty Acid Metabolism during Hemodialysis

The purpose of the study is to investigate the effects of L-carnitine on the exogenous acetate metabolism during hemodialysis together with the triglyceride and free fatty acid metabolism. Sixteen chronic renal failure patients on acetate dialysis were orally administered 1,200 mg of L-carnitine chloride per day for 12 weeks. Plasma triglyceride concentrations at 30 and 60 min following initiation of hemodialysis were significantly lower than before hemodialysis, while the plasma concentrations of free fatty acid at the same points into hemodialysis were significantly higher than before hemodialysis, whether L-carnitine chloride was being given or not. This is attributed to the enhanced degradation of triglyceride and the increased generation of the free fatty acid with heparin administration during hemodialysis. The L-carnitine chloride treatment did not affect the plasma triglyceride concentrations at 30 and 60 min into hemodialysis, whereas the free fatty acid concentrations at the same points into hemodialysis were significantly lower after L-carnitine chloride administration commenced than before it. This is attributed to the fact that fatty acid oxidation was enhanced following the L-carnitine chloride treatment. Compared to before the drug administration, the whole body clearance of exogenous acetate was significantly increased after the drug was given, and the plasma acetate level during hemodialysis fell accordingly. This is attributed to the fact that with L-carnitine chloride administration, the amount of accumulated acyl-CoA in the cytosol decreased and consequently the citrate cycle function increased.

The limit to which serum β2-MG level could be lowered by an intermittent hemopurification approach

我々はβ2-microglobulin (β2-MG) に関し, 間質及び血しょうスペースよりなるtwo pool kinetic modelを作製した. この際には以下の2点を前提とした. 1) β2-MG generation rateは血清β2-MG濃度の変動とは無関係に一定である. 2) β2-MG elimination rateは治療間けつ時には生体内クリアランスと血清濃度との積としてもとめられ, 治療時にはこれにダイアライザークリアランスと血清濃度との積を加え合わせた値として求められる. 次にこれを利用し, 治療時及び治療間けつ時における長期透析患者の血清β2-MG濃度の推移を2週間以上の期間に渡りシュミレートした.その結果, 1回4時間の, 血液透析施行直後に血清β2-MG濃度を劇的に低下させることは現在のダイアライザーの性能を考え可能なことであるが, 治療間けつ期は血清β2-MG濃度の緩徐な上昇, 即ちrebound現象があることがわかった. (間けつ治療におけるβ2-MGのkineticsは基本的にこのパターンの繰り返しである.) β2-MGクリアランスが50ml/minのダイアライザーを用い, 一回4時間の治療を週3回行うとするこのrebound現象のために, 治療前値が60, 40, 20mg/lの患者の2週間後の治療直前値はそれぞれ39.2, 30.8, 18.4mg/lにすぎない. (治療前値が60mg/lの患者の場合ある程度は下がるが, 治療前値が20mg/lである患者の場合, ほぼ元の値に戻ってしまうことに着目される.) 同様に, 治療前値が30mg/lの患者の場合, ダイアライザークリアランスをたとえ80ml/minに増大させたとしても2週間後の治療直前値に少しの差しか認められない. このことは (特に透析患者としては比較的血清濃度の低い患者で著名な傾向であるが,) 透析患者のβ2-MGを持続的に低下させることが現在の維持透析療法では困難であることを示唆する.