Iwakazu Kaneko

Effects of internal filtration on the solute removal efficiency of a dialyzer.

To improve solute removal efficiency, several types of dialyzers with enhanced internal filtration were introduced for clinical application. In these dialyzers, enhanced internal filtration increased convective transport of the solute, in addition to diffusive transport. In this study, the effects of internal filtration on solute removal efficiency were examined by both analytic and experimental studies. Internal filtration is affected by blood (QB) and dialysate (QD) flow rates; the patient’s hematocrit and plasma level of total protein; and the effective length (Leff), inner diameter (D), and density ratio (DR) of the hollow fibers. An analytic model was introduced for the estimation of the changes in mass and momentum along the dialyzer. It clarified the effects of these parameters on maximum internal filtration flow rate (QIF) and clearance (K) of urea (60 daltons), vitamin B12 (1,355), and myoglobin (17,000). As a result of the analytic study, QIF was increased, resulting in a smaller D, a longer Leff, and a larger DR value. Several types of dialyzers with the same cellulose triacetate membrane, produced by Toyobo Co, Ltd., Ohtsu, Japan, and Nissho Corporation, Kusatsu, Japan, were used for the experimental study. An in vitro evaluation using myoglobin solution showed the same trends as found in the analytic study. For example, a dialyzer with 150 &mgr;m of D has a 72.0 ml/min myoglobin K value, much higher than that of 53.7 ml/min for a dialyzer with 200 &mgr;m of D under constant QB (300 ml/min) and DR (50%) values. Development of a dialyzer with enhanced internal filtration, however, should take the patient’s safety into account, and hemolysis and endotoxin invasion from the dialysate to the patient should be avoided.

Solute removal characteristics of continuous recirculating peritoneal dialysis in experimental and clinical studies.

Continuous recirculating peritoneal dialysis (CRPD) was introduced to enhance solute removal efficiency in conventional peritoneal dialysis (PD) therapies such as continuous ambulatory peritoneal dialysis (CAPD). In CRPD, a portion of the dwell dialysate in the patients peritoneal cavity is drained through a double-lumen catheter and purified by an extracorporeal dialyzer. In this study, solute removal characteristics and safety of CRPD are examined in ex vivo and clinical studies. Recirculation dialysis experiments using nine dogs (13.6 +/- 2.5 kg of body weight) were carried out for 240 min in the ex vivo study, whereas another seven dogs (12.1 +/- 2.8 kg) received conventional peritoneal dialysis (CPD) (120 min dwelling x 2) and six additional dogs (11.9 +/- 2.7 kg) received a Tidal PD (20 min dwelling x 12; 50% of tidal volume ratio) as controls. The ex vivo study revealed that CRPD has a higher efficiency for solute removal than CPD and is equivalent to Tidal PD. In the BUN reduction rate, the 19.4 +/- 5.5% in 240 min CRPD (n = 9) was significantly higher (p < 0.05) than the 3.5 +/- 3.6% in 240 min CPD (n = 7) and equivalent to the 17.3 +/- 4.7% in 240 min Tidal PD (n = 6). Continuous recirculating peritoneal dialysis maintained a low UN level in the peritoneal cavity due to dialysis with an extracorporeal dialyzer. This tendency was also seen in creatinine removal. In the clinical study, CRPD (n = 10) and CPD (n = 5) treatments were used in three renal failure patients. Higher solute removal efficiency was shown in CRPD than in CPD treatments, and the urea peritoneal clearance was 14.1 +/- 4.4 ml/min in CRPD (n = 10), significantly higher (p < 0.05) than the 7.3 +/- 2.1 ml/min in CPD (n = 5). No fibrin formation occurred during CRPD treatments.

In vitro Study of Removal of Protein-Bound Toxins

Protein-bound toxins are not efficiently removed by conventional hemodialysis techniques. In order to improve the removal of protein-bound toxins, we performed an in vitro study to evaluate the effects of dilution and pH change on the dissociation of protein-bound toxins from albumin. Human plasma harvested by therapeutic apheresis treatment was diluted with saline or isotonic NaHCO3 solution, and the amounts of the free fractions of indoxyl sulfate (IS) and homocysteine were determined. The results suggested that IS was dissociated easily from albumin by dilution and pH change; higher dilution was associated with more effective removal and a greater increase of the free fraction of IS. However, these methods did not facilitate dissociation of homocysteine from albumin. Effective removal of some protein-bound toxins may be achieved by applying dilution and pH change methods to blood purification techniques, such as pre-dilution on-line hemodiafiltration.

Can cytokines be removed by hemofiltration or hemoadsorption

To study the removability of pro-inflammatory cytokines by hemofiltration (HF), we performed experimental HF with various high-flux membranes (HFM) using a closed circuit system filled with monocyte-free human plasma, which contained TNF&agr;, IL-1&bgr;, and IL-6. Plasma and filtrate samples were taken before and 1, 2, 3, and 4 hours after the initiation of HF, and each cytokine was determined by enzyme-linked immunosorbent assay. IL-1&bgr; was well removed through filtration during experimental HF using HFM (PAN>CTA>PMMA>PS). TNF&agr; and IL-6 were only minimally filtered out by HF using HFM. TNF&agr; was removed to some extent by using PS, and IL-6 was partially removed by using PMMA during experimental HF through other mechanisms, such as adsorption, than the filtration. IL-1&bgr; and IL-6 were effectively removed by HA using charcoal adsorbent column, especially during the first 2 hours, while TNF&agr; was only partly removed.

Preliminary study on the removal of protein-bound toxins using dilution and pH change

蛋白結合性尿毒素は，その分子量の大きさから，通常の血液透析では除去困難な尿毒素として認識されている．今回，血漿成分に対して希釈効果およびpH変化を付与することにより，蛋白結合性尿毒素をアルブミンなどの蛋白から解離させ，除去することを目的とした基礎検討を行ったので報告する．腎不全患者から得たアフェレシス廃棄血漿を用いて，ホモシステインおよびインドキシル硫酸を対象としたin vitro実験を行った．その結果，生理食塩液やリン酸緩衝溶液による希釈効果によって，インドキシル硫酸では比較的容易に蛋白から解離させることができ，遊離率の上昇（蛋白結合率の低下）が認められた．また，希釈倍率が大きいほど，その解離は顕著であった．一方，ホモシステインでは，ほとんど解離が認められなかった．今後，蛋白結合性尿毒素の種類に応じた効果的な解離方法を検討する必要がある．

Validity of water removal control by the blood volume monitor (BVM) of a dialysis machine, Fresenius 4008S

Fresenius社製個人用透析装置4008Sのblood volume monitor (BVM) による除水コントロール機能 (BVM-HD) を8症例に対し施行し, 相対血液量 (relative blood volume: RBV) の変動や血圧の推移を均等除水 (Normal-HD: N-HD) と比較した. 今回, 治療中におけるRVB変動の指標の一つとしてplasma refilling rate (PRR) をultrafiltration rate (UFR) で除した値 (PRR/UFR値) を用いた. この指標によりUFRが連続的に変化する本治療法においても, 除水コントロールに対するPRRやRBVへの影響を客観的に評価できると考えられた. PRR/UFR値 (mean±SD) の全体の平均値は, BVM-HDおよびN-HDでそれぞれ, 0.83±0.02, 0.72±0.03 (p<0.01) とBVM-HDがN-HDに比較して高値を示したことから, RBV低下に対する除水コントロール機能の有用性が示唆された. また透析終了時の最終RBV値はBVM-HDおよびN-HDでそれぞれ0.79±0.04, 0.76±0.07 (NS) と有意差は得られなかったものの, BVM-HDがN-HDに比べ高値を示した. 血圧の推移は, 治療条件の相違による影響が否定できないが, 治療後半の血圧低下に対してBVM-HDが有効と思われる症例もみられた. これらの結果から, 治療後半において血圧低下をきたす患者に対して, 4008Sの除水コントロール機能によるBVM-HDは, 血圧の安定化が図れる可能性が示唆された. 今後の課題として, BVMによる除水コントロール機能をさらに有効に活用するために, 患者個々に対し治療開始時における適切な除水速度 (UFRSET) の設定や相対血液量限度値 (critical-relative blood volume: C-RBV) 定義法の確立が望まれる.

Perioperative managenent of patients with end-stage renal failure undergoing cardiac surgery

1977年より1986年に東京女子医大で心臓・大血管手術を施行した37例の透析患者のうち, 開心術あるいはaortocoronary bypass graft (ACB) を施行した12例について術中, 術後の管理上の問題点を血液浄化法を中心に検討した.症例は不安定狭心症5例 (全例3枝病変でうち1例は腹部大動脈瘤を合併), 急性心筋梗塞および中隔穿孔1例, 肺動脈狭窄, 心房・心室中隔欠損, 僧帽弁閉鎖不全1例, 亜急性心内膜炎, 大動脈炎, 大動脈弁・僧帽弁閉鎖不全1例, 僧帽弁狭窄2例, 僧帽弁閉鎖不全1例, 心房中隔欠損1例であり, 施行した手術はACB (2枝バイパス) 5例 (うち1例は腹部大動脈瘤切除・人工血管移植術も施行), 心室瘤切除, 中隔穿孔閉鎖1例, 肺動脈拡張, 心房・心室中隔欠損閉鎖1例, 心房中隔欠損閉鎖1例, 大動脈弁・僧帽弁置換1例, 僧帽弁置換1例, 交連切開術2例であった.直死例は2例 (16.7%) で, 1例は原疾患の心内膜炎が術後敗血症に進展したもので, 他の1例は術直後の低拍出量症候群によるものであった.6例の虚血性心疾患のうち5例にACB (全例2枝バイパス) を施行し, 1例が術後51日目に出血性脳梗塞で死亡した. 術後は10例に腹膜灌流 (PD) を行い, 循環動態の安定, 出血性合併症の予防の点で有効であった. その後7例は血液透析 (HD) に変更したが, うち2例は変更直後に出血性合併症で死亡した. 術前よりcontinuous ambulatory peritoneal dialysis (CAPD) に導入し, 術後もcontinuous PDで維持した4症例は全例術後経過は良好であった. また8例において術中人工心肺にHD, 血液濾過を併用したが, 術中術後の水分管理, 電解質・酸塩基平衡の補正, 高窒素血症の予防に有効であった.透析患者の心臓手術については早期に手術を行うこと, 適切な血液浄化法を施行することによりその成績の改善が期待される.

Development of a system for passive and active CAVH

当施設においてcontinuous arteriovenous hemofiltration (CAVH) を31症例について施行した. これらの症例を分類し, なおかつ臨床経験をもとにCAVHの問題点について検討を行った.その結果は濾液・補充液バランス装置を用いて積極的に溶質除去を行うactive CAVH (mildなHF) が31症例 (52%), 通常のCAVH (passive CAVH) が11例 (35%) となり, passiveとactive CAVHの併用症例が4例 (13%) であった. 血液ポンプの使用をした症例は全体の71%となった. またこの治療が長時間に及ぶため夜間の管理, フィルター内における血液凝固が血液回路にまでおよびblood accessの閉塞が惹起されることも多い. われわれはこれらの問題を解消するためpassiveおよびactive CAVH用システムを開発した. システムとしては血液駆動部, 濾液・補充液バランス部とblood acess確保部により構成されている. Passiveおよびactive CAVHに使用した濾過器はAmicon社製Diafilter-20, Gambro社製FH-101, 旭メディカル社製PAN-50, 60Pとニプロ社製UF-50である. 濾過器の性能を濾過係数 (LP) とふるい係数 (SC) で表わしたところLP 22.6±8.6ml/hr/m/mmHgでSCは尿素0.98±0.02, クレアチニン0.94±0.06, イヌリン0.65±0.12でアルブミンは0であった. 体外回路の血液充填量は24mlである.治療時間数は1日-47日で平均の治療時間は8.3日であった. 濾過についてはpassive CAVHの平均濾過量は350ml/hrとなり, active CAVHの置換液量は350-1,000ml/hrであった. 抗凝固薬は全体の65%がヘパリンを用い投薬量は8U/hr/kgとした.われわれはactive CAVHに必要なシステムを開発したが, 本システムはpassive CAVHに切り換えが可能であり, CAVHの特長を最大に生かした装置といえる.