Akio Imada

Significantly rapid relief from steroid-resistant nephrotic syndrome by LDL apheresis compared with steroid monotherapy

Rapid amelioration of hypercholesterolemia by LDL apheresis (LDL-A) was performed for long-standing nephrotic syndrome (NS) with hyperlipidemia due to focal segmental glomerulosclerosis (FGS) and the clinical data and prognosis were compared between LDL-A-treated and nontreated groups. Seventeen steroid-resistant NS patients treated with LDL-A (LDL-A group) and 10 NS patients treated with steroids only (steroid-monotherapy (SM) group) were compared. Serum cholesterol and phospholipid levels were significantly lowered only in the LDL-A group (p < 0.01, respectively). The LDL-A group showed a significant decrease of urinary protein (UP, p < 0.01) and increase of serum albumin (p < 0.05). Average time needed to achieve a decrease of UP to less than nephrotic range (< 3.5 g/day) was significantly shorter in the LDL-A group than in the SM group (p < 0.01). Although this is not a prospective study, it is highly expected that a rapid improvement of hypercholesterolemia by LDL-A in steroid-resistant NS will provide more rapid relief from NS than steroid therapy alone.

Clinical effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in hemodialysis patients

Orthostatic hypotension is one of the major factors interfering with everyday activities in hemodialysis patients, but there has been no effective agent for treating it. In order to clarify the clinical effects of L-threo-3,4-dihydroxyphenylserine (L-DOPS) on orthostatic hypotension of hemodialysis patients, we conducted a randomized, double-blind comparative trial. 149 regular hemodialysis patients with orthostatic hypotension were randomly allocated to three groups and L-DOPS at doses of 400 mg, 200 mg or placebo was orally administrated to each group 30 min before starting every hemodialysis for 4 weeks. Changes of blood pressure (BP) in orthostatic hypotension immediately after completion of hemodialysis and symptoms related to orthostatic hypotension were compared between the three groups. In the 400-mg group, systolic and diastolic BP after standing increased significantly and the drop of mean BP after standing was also reduced compared with pretreatment levels. No such changes were observed in the placebo group. Fatiguability, malaise/weakness, dizziness and light-headed feeling, the interdialytic symptoms commonly observed in hemodialysis patients who developed orthostatic hypotension, were improved to a significant extent in the L-DOPS group compared with the placebo group. In particular, the improvement was more remarkable for the L-DOPS 400-mg group than the placebo group in patients with diabetic nephropathy, lower systolic BP after standing, and the long duration type of orthostatic hypotension. The incidence of adverse events was comparable between the three groups, and all recovered after discontinuation of L-DOPS or concomitantly administered drugs, or without any treatment. These findings indicate that L-DOPS taken before hemodialysis prevents orthostatic hypotension in patients undergoing hemodialysis, and is also effective for the interdialytic symptoms related to orthostatic hypotension.

Effects of L-threo-3,4-dihydroxyphenylserine on orthostatic hypotension in hemodialysis patients.

Background: Orthostatic hypotension (OH) is a serious complication observed in hemodialysis (HD) patients after HD as well as during the interdialytic period. L-Threo-3,4-dihydroxyphenylserine (L-DOPS) is a nonphysiological neutral amino acid that is directly converted to the neurotransmitter norepinephrine by aromatic L-amino acid decarboxylase. Methods: A placebo-controlled double-blind study for 4 consecutive weeks and a long-term study (24–52 weeks) were conducted to evaluate the efficacy of L-DOPS for OH after HD. The drug was administered orally 30 min before the start of each HD period in both studies. Doses of 400 mg of L-DOPS or placebo were given to HD patients with OH (45 and 41 patients, respectively) in the double-blind study, and doses of 200 or 400 mg of L-DOPS were given to 74 HD patients in the long-term study. Results: In the double-blind study, L-DOPS significantly ameliorated subjective symptoms related to OH, including dizziness/light-headed feeling, and malaise, throughout the interdialytic period. For 19 patients with delayed-type OH, hypotension with the lowest blood pressure recorded 10 min after standing, the decrease in blood pressure was suppressed significantly after L-DOPS treatment (10 patients) as compared with the placebo-treated group (9 patients). In the long-term study, the efficacy of L-DOPS was not attenuated, and the marked fluctuations in the plasma L-DOPS and norepinephrine levels were not noted after long-term use, without increases in incidence or severity of adverse reactions. Conclusions: These results indicate that L-DOPS is effective for improving OH-related interdialytic subjective symptoms in HD patients after short-term as well as after long-term administration.

Anti-Glomerular Basement Membrane Nephritis after Extracorporeal Shock Wave Lithotripsy

Rapidly progressive glomerulonephritis was observed in a 37-year-old woman following the administration of extracorporeal shock wave lithotripsy (ESWL) for a single stone in her right kidney. The renal biopsy specimen showed diffuse cellular crescents in all glomeruli, with linear deposits of immunoglobulin G and complement component C3 along the glomerular basement membrane (GBM). Circulating anti-GBM antibodies were detected by enzyme-linked immunosorbent assay. Thus, the patient was diagnosed with anti-GBM nephritis. It is suggested that ESWL produced an alteration in the GBM leading to the production of anti-GBM antibodies.

Comparative Study of the Pharmacokinetics of Various β-Lactams after Intravenous and Intraperitoneal Administration in Patients Undergoing Continuous Ambulatory PeritoneaL Dialysis

Since continuous ambulatory peritoneal dialysis (CAPO) allows patients to return to society, the therapy is now widely employed in many countries as an ideal treatment for end-stage renal disease (ESRD). The major complication which limits this home therapy is bacterial peritonitis. Knowledge of the pharmacokinetic properties of the [1-lactams, which are most frequently used in the treatm ent of peritonitis complicating CAPD, is very important for their appropriate use, since the pharmacokinetics in patients undergoing CAPO and in CAPD patients with peritonitis are different from the properties in subjects with normal renal function. CAPD therapy will be more widely employed ifit becomes possible for patients to be given optimal antibiotic therapy to treat peritonitis (under the direction of a physician) while undergoing CAPO at home.

Pharmacokinetics of Cefotaxime and Desacetylcefotaxime in Renal Failure Patients Undergoing Continuous Arteriovenous Haemofiltration

In patients with acute renal failure or renal and multiple organ failure circulatory problems such as hypotension often develop. Accordingly, it is difficult to carry out conventional haemodialysis. Recently, the technique of continuous arteriovenous haemofiltration (CAVH) developed by Kramer et al. (1977) has come to be applied clinically for the treatment of such renal failure patients. CAVH differs from conventional haemodialysis and haemofiltration in that no pump is employed for circulation, and blood taken from an artery is passed immediately through a CAVH filter and then returned to a vein. It is common for renal failure patients undergoing CAVH to receive antibiotics. Therefore, it is important that the pharmacokinetics of the administered antibiotic are clearly understood during CAVH. In this study the pharmacokinetics of cefotaxime were investigated in renal failure patients undergoing CAVH.

Neuronal changes of hypokalemic myopathy: A light- and electron-microscopic study on muscle biopsy

Hypokalemic myopathy has been observed in various clinical conditions. There are many studies of the pathomorphological changes of muscle fibers but alterations in intramuscular nerves and motor end-plates are seldom mentioned. The present authors observed biopsied muscle from a 51-year-old housewife who had suffered from gradually increasing muscle weakness. Laboratory examinations revealed a severe hypokalemia of 1.5 mEq/1, 18304 U/1 of CPK, 1300 U/1 of LDH, 343 U/1 of SGOT and 297 IU/1 of adolase. Light-microscopic examination showed changes previously described, including twin-peaked distribution in the histogram of type I, IIA and IIB fibers, ballooning and thickening of terminal axon, and 2 or 3 end-plates closely spaced along the length of muscle fibers. The electron-microscopic examination revealed empty folds of basement membrane in end-plate regions, reduced secondary synaptic clefts, interposition of Schwann cell processes between nerve ending and primary synaptic cleft, and an increase of disarranged microtubules and neurofilaments in terminal axons. The findings suggest that severe hypokalemia primarily produces structural alterations of intramuscular peripheral nerves and motor end-plates as well as of muscle fibers.

Influence of pH and osmotic pressure of dialysis fluid and protective effect of phosphatidylcholine on cultured mesothelial cells.

標準CAPD療法を長期間継続した症例の中には, 溶質除去能は保たれているのに, 除水量が減少する症例がある. 一方, 生体内のリン脂質の大部分を占めるphosphatidylcholine (PC) の投与により, 減少した除水量が改善したことが報告されている. しかし常時腹腔内に貯液されている透析液の腹膜に対する傷害性やPCの防御効果についての詳細はまだ不明な点が多い. そこで, 透析液のpHと浸透圧が腹膜に与える影響およびPCの防御効果を知るために, 培養ヒト腹膜中皮細胞を用いて実験的にそれらを検討してみた. 外科手術時に得たヒト大網から細胞を剥離し, ヒト腹膜中皮細胞を培養した. それらに51Crをラベルして, 培養液の代わりに, pHや浸透圧がそれぞれ異なる測定液を作製して加えた. 4時間後にその上清中の51Crの放射活性を測定して, 放出率を算定することで細胞傷害性を検討した. 同様の方法で種類の異なる精製されたPCを測定液に一定量添加して, 最も防御効果のあるPCの種類とその濃度を検討した. さらにPCの防御効果の機序を検討するために, 培養液とPC添加後の測定液上清中のリン脂質濃度を調べた. その結果, 酸性の方が中性の透析液より細胞傷害性は有意に強く, 浸透圧が高くなるほど傷害性も強くなる傾向が認められた. またdipalmitoyl-phosphatidylcholine (DPPC) を50および100mg/lの濃度で透析液に添加したときにのみ培養ヒト腹膜中皮細胞の傷害性は抑制された. さらにDPPC添加培養液を使用すると培養上清中のリン脂質濃度は相対的に低下した. 従って, DPPCを投与することで腹膜中皮細胞の状態が変化したことが考えられた. 以上の実験結果から, 酸性あるいは高張透析液が腹膜中皮細胞に傷害を与えていることと, 透析液中にDPPCが50-100mg/l存在することで腹膜中皮細胞は保護される可能性が示唆された.

Treatment of hemodialysis-induced hypotension with oral droxidopa.

血液透析 (HD) 中の低血圧発作 (HIH) は深刻な合併症である. ドロキシドパ (DOPS) は, 経口投与が可能なnorepinephrine (NE) 前駆アミノ酸で, Shy-Drager症候群などに見られる起立性低血圧に臨床応用されている. 我々はすでに, HD患者においてもDOPSが有効に吸収されNEに変換し, HIHに対して有効例の存在することを報告した. そこで今回, 多施設における初期第II相試験を行い, 用量設定に関しても検討した. 5施設において, 処置を要するHIHを呈した週3回の慢性HD患者34例 (男14例, 糖尿病性腎不全〔DM〕12例) を対象とした. DOPSはHD開始1時間前に200mgから服用させ, 効果に応じて1週毎に100mgずつ, 400mgまで増量し6週継続した. 本試験中透析条件は一定とし, 一定の透析経過記載表を用い, 観察項目, HIHに対する処置を統一した. 全症例の比較でも, 透析中の最低血圧時, 透析終了時, 終了後立位時の血圧がいずれも有意に上昇した. また, HIHに対する補液量, 処置回数も有意に減少した.個々の症例の検討でも, 67.6%に有用性が認められ, 透析中の自覚症状の改善が73.5%に, 透析終了後の改善が64.7%に得られた. 副作用は3例に見られたが, 減量後消失し, DOPSの継続は可能であった. 最終投与量は200mg13例, 300mg7例, 400mg14例で, 400mg群の有用性は200, 300mg群に比べ有意に低値であった. 年齢, 透析期間と有効性には関連はないが, HIHの軽症な患者, HD前収縮期血圧の低い患者に有用率が高い. また, DM患者の有用率は慢性糸球体腎炎患者に比べ有意に低値であったが, 補液量, 処置回数は, 両者とも有意に減少した. HD前NE濃度は有用性と関連が認められなかった. 以上, HIHを呈する慢性HD患者の約2/3の症例にDOPSの有用性を確認した.

Hemodialysis in cadaveric renal transplantation with acute renal failure.

腎移植は末期慢性腎不全に対する唯一の根治療法であり, 特に死体腎移植の普及が望まれる. 死体腎移植の場合, 移植腎機能の発現まで透析による補助療法を必要とする症例が多い. そこで, 透析療法を必要とする症例およびその離脱の条件を検討した. 当院で1980年から1988年までの9年間に死体腎移植が施行された年齢14-56歳 (平均33.8±8.4歳) の男性21例, 女性11例の計32例を対象とした. 対象症例のうち23例が透析療法を必要とし, 血液透析が19例, 腹膜透析が4例に施行された. これらの症例を透析療法を施行しなかった群 (非透析群), 透析療法を施行したが腎機能が発現し離脱可能であった群 (離脱群) および離脱が不可能であった群 (非離脱群) の3群に分けた. 3群の阻血時間に統計学的な有意の差は認めなかった. 透析離脱群の透析施行期間は2-31日, 温阻血時間は1-40分で両者の間にはr=0.53 (p<0.005) で正の相関が認められた. また, 移植腎機能の発現時期を2週で分け阻血時間を比較したところ, 2週以上の群に阻血時間の長い傾向が認められたが統計学的に有意の差は認められなかった. 透析療法施行のための指標を調べるために, 移植術後の臨床検査値を比較した. その結果, 透析療法を必要としなかった群は移植直後から利尿が得られ, 尿量の増加とともに血清クレアチニンの低下を認めた. 一方移植後2日目までに利尿を認めなかった症例は全例透析療法が必要であった. したがって, 透析療法を必要とするかどうかの指標には, 移植後の利尿および尿量がよいと思われた. すなわち移植後2日目までに利尿が得られない場合には透析療法の施行を考えカリウムや水分の厳重な管理を行うことが必要だと考えられた. また, 尿量が1,000mlを越えていれば透析療法からの離脱が可能であったことから, 透析離脱には開始する場合と同様に尿量を指標にするのがよいと思われた. さらに, 透析療法の施行には, 血液凝固系の活性化を防止するよう工夫された血液回路と抗血栓性のあるEVA膜を用いることで, 無抗凝固薬透析が可能であった. 本邦の死体腎移植は心停止後に腎の摘出が行われるため虚血による急性尿細管壊死が発生し無尿状態となる. したがって透析療法は不可欠な補助療法であるが, 移植後の状態を考え施行する時にはその時期や透析法を考慮することが大切である. しかし, 移植後透析療法を避けるためには脳死状態からの腎の提供を一般化することが重要だと思われる.