JOURNAL OF DIALYSIS, 1(3), 285-310
(1977)
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HEMODIALYZER PERFORMANCE: AN ASSESSMENT OF CURRENTLY AVAILABLE UNITS
P.W.E. Hone*, R.A. Ward*, J . F . Mahonyt, P . C . F a r r e l l * .
*
School of Chemical Engineering and Centre f o r Biomedical E n g i n e e r i n g , U n i v e r s i t y of New South Wales, P.O.Box 1, Kensington, N.S.W. 2033, Aus t r a l i a .
t Renal U n i t , Sydney H o s p i t a l , Sydney, N.S.W. 2 0 0 0 , A u s t r a l i a . ABSTRACT The performance c h a r a c t e r i s t i c s of n i n e currently available disposable parallel-flow dialyzers were a s s e s s e d , b o t h b e f o r e and immediately f o l l o w i n g d i a l y s i s , by measuring: (i)
(ii) fiii)
i n v i t r o c l e a r a n c e s o f C" l a b e l e d u r e a , c r e a t i n i n e , and s u c r o s e and H 3 l a b e l e d vitamin B I 2 a t standard co n d i t i o n s , u l t r a f i l t r a t i o n r a t e s i n s a l i n e a t 37C,and l o s s i n t h e mass t r a n s f e r c o e f f i c i e n t membrane a r e a p r o d u c t (hoA) , f o l l o w i n g a single dialysis.
P a r a l l e l - p l a t e d i a l y z e r s underwent c o n s i d e r a b l e membrane s t r e t c h i n g d u r i n g d i a l y s i s and e x h i b i t e d g r e a t e r v a r i a b i l i t y , p a r t i c u l a r l y regarding vitamin B I Z c l e a r a n c e and u l t r a f i l t r a t i o n a b i l i t y , t h a n d i d c a p i l l a r y d i a l y z e r s . The v a r i a b i l i t y i n p l a t e u n i t s was greater f o r l a r g e - a r e a d i a l y z e r s where t h e r e were 25 t o 26 blood c h a n n e l s . However, d e s p i t e
285 Copyright 0 1977 hy Marcel Dekker, Inc. All Rights Reserved. Neither this work nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming. and recording, or by any information storage and retrieval system, without permission in writing from the publisher.
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c o n s i d e r a b l e d i f f e r e n c e s i n performance c h a r a c t e r i s t i c s , a l l d i a l y z e r s were judged t o be c l i n i c a l l y a c c e p t a b l e i n terms o f b o t h s o l u t e c l e a r a n c e and u l t r a f i l t r a t i o n characteristics.
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INTRODUCTION Hemodialyzers a r e t r a d i t i o n a l l y e v a l u a t e d in v i t r o . However, c o n s i d e r a b l e c a u t i o n must be e x e r c i s e d when e x t r a p o l a t i n g from i n v i t r o t o a n t i c i p a t e d i n v i v o performance ( 1 ) . For example; ( I ) t h e r a t e of d i f f u s i o n f o r most s o l u t e s i s lower i n bPood t h a n i n aqueous s o l u t i o n ( Z ) , and ( i i ) t h e r e is t h e p o s s i b i l i t y o f s i g n i f i c a n t b i n d i n g o f some s o l u t e s t o plasma p r o t e i n s (39. Bsth f a c t o r s can cause s i g n i f i c a n t d i f f e r e n c e s between i n vivo and in v i t r o performance. I n a d d i t i o n , thrombus f o r m a t i o n on t h e d i a l y t e r membrane may cause i n v i v o performance t o d e v i a t e from t h a t i n v i t r o due t o changes i n flow geometry, e f f e c t i v e membrane a r e a and p e r m e a b i l i t y (1). The s o l u t e P e r m e a b i l i t y of r e g e n e r a t e d c e l l u l o s e d i a l y s i s membranes i s similar i n s a l i n e , human serum albumin and plasma e n v i r o n ments ( 4 1 , b u t t h i s i s u n l i k e l y t o apply t o p o l y a c r y l o n i t r i l e (PAN) , o r p o l y c a r b o n a t e membranes because of t h e i r h y d r o p h o b i c i t y . A technique f o r e s t i m a t i n g d i a l y z e r a r e a l o s s ,
f o l l o w i n g thrombus d e p o s i t i o n , h a s been proposed ( 5 ) . This t e c h n i q u e , based on p r e and p o s t d i a l y s i s s o l u t e c l e a r a n c e , assumes t h a t t h e o v e r a l l mass t r a n s f e r c o e f f i c i e n t (R,) remains c o n s t a n t , w h i l e t h e e f f e c t i v e membrane a r e a i s reduced by f i b r i n and/or formed-element d e p o s i t i o n . The a r e a loss in hollow f i b e r d i a l y z e r s was e s t i m a t e d , a f t e r
HEMODIALYZER
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m u l t i p l e r e u s e , from c l e a r a n c e s of a m o l e c u l a r w e i g h t range o f s o l u t e s and was shown t o c o r r e l a t e w e l l w i t h a r e a l o s s p r e d i c t e d from s a l i n e r i n s e measurements ( 5 ) . D i a l y z e r i n v i t r o performance and an e s t i m a t e of t h e e f f e c t of i n v i v o f a c t o r s (such as thrombus d e p o s i t i o n and h i g h transmembrane p r e s s u r e which c a u s e s membrane s t r e t c h i n g ) on performance a r e both i m p o r t a n t when s e l e c t i n g a d i a l y s i s regimen. I n t h i s s t u d y , t h e o v e r a l l magnitude o f t h e s e i n v i v o f a c t o r s has been e v a l u a t e d f o r some c u r r e n t l y a v a i l a b l e hemodialyzers (Table 1 ) u s i n g t h e above technique.
MATERIALS AND METHODS I n v i t r o d i a l y z e r c l e a r a n c e s were measured €or a spectrum of r a d i o a c t i v e s o l u t e s (Table 2 ) u s i n g p r e v i o u s l y described s i n g l e - p a s s procedures ( 6 ) . Dual c l o s e d - l o o p d i a l y s i s (7) was n o t used f o r e s t i m a t i n g v i t a m i n B 1 2 c l e a r a n c e because of s i g n i f i cant u l t r a f i l t r a t i o n . Experiments were conducted a t 37 f 0 . 1 C (mean 2 SD) w i t h 0.15 M s a l i n e flowing c o u n t e r c u r r e n t l y i n b o t h blood and d i a l y s a t e compartments a t flow r a t e s of 2 0 0 and 500 (t 2 % ) ml/min, r e s p e c t i v e l y . C o n c e n t r a t i o n s were determined f o r C’ “ - l a b e l e d s o l u t e s by b l e n d i n g 5 m l o f I n s t a g e l R (Packard, Downers Gove, I l l i n o i s ) c o c k t a i l w i t h 0 . 5 gm (weighed on an a n a l y t i c a l b a l a n c e ) of t e s t s o l u t i o n i n a low potassium c o u n t i n g v i a l and c o u n t i n g f o r 1 0 min i n a T r i - C a r b Model 3380 a u t o m a t i c s c i n t i l l a t i o n c o u n t e r (Packard,
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a 0 0 0
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TABLE 2
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SOLUTES SELECTED FOR IN VITRO DIALYZER EVALUATION
Solute"
5
creatinine
113
5
sucrose
342
5
urea
6'
el"H'
-
C a r r i e r Conc. mg/100 m l
60
C1'4-
Molecular W t .
vitamin B I Z (cyanocobalamin)
I
I 1
I
1355
I
1
I
I I
" s e l e c t e d from recommended s o l u t e s (1)
I Downers Grove, I l l i n o i s ) . F o r H 3 - l a b e l e d s o l u t e s , 10 m l o f c o c k t a i l were blended w i t h 1 m l of s o l u t i o n and counted for 50 min. Before e v a l u a t i o n , a i r was e l i m i n a t e d from both b l o o d and d i a l y s a t e compartments o f a l l d i a l y z e r s by r i n s i n g w i t h s a . l i n e . The b l o o d compartments o f a l l p a r a l l e l - p l a t e d i a l y z e r s were r e p e a t e d l y p r e s s u r i s e d t o 2 0 0 mmHg t o a s s i s t i n d e a e r a t i o n . The transmembrane p r e s s u r e (TMP) and hence t h e u l t r a f i l t r a t i o n r a t e (UFR) were m a i n t a i n e d a t z e r o d u r i n g t h e e v a l u a t i o n o f hollow f i b e r d i a l y z e r s P a r a l l e l - p l a t e d i a l y z e r s were o p e r a t e d w i t h a TMP
.
HPIODIALY ZER
291
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o f 45 t 5 mmHi (UFR 1 - 3 ml/min e x c e p t i n RP6 where UFR was approximately 28 ml/min) t o e n s u r e expanded blood envelopes and p r e v e n t b l o o d - s i d e c h a n n e l i n g w i t h a s s o c i a t e d r e d u c t i o n i n e f f e c t i v e membrane area. For u r e a , c r e a t i n i n e and s u c r o s e , b l o o d - s i d e s o l u t e c o n c e n t r a t i o n was m a i n t a i n e d a t 5 mg/100 m l ( i n 0.15 M s a l i n e ) l a b e l e d w i t h 1 2 p C i / l of C". To p r e v e n t c o l o r quenching of v i t a m i n B 1 2 ( 8 ) , c a r r i e r c o n c e n t r a t i o n was l i m i t e d t o 1 mg/100 m l . Because of t h e low counting e f f i c i e n c y o f H3 (305) compared w i t h C" ( 9 4 % ) , combined w i t h t h e slow d i f f u s i v e t r a n s f e r of v i t a m i n B 1 2 , 50 p C i / l of H3-vitamin B I 2 were u s e d ,
UFR was measured a t 37 2 0 . 1 C i n i s o t o n i c (0.15 M) s a l i n e u s i n g a s t a t i c t e c h n i q u e (6). The d i a l y z e r was p l a c e d i n a c o n s t a n t t e m p e r a t u r e b a t h (37 C) and a s t a t i c , b u t a d j u s t a b l e , p r e s s u r e a p p l i e d t o t h e blood compartment. TMP was measured by e i t h e r c a l i b r a t e d Bourdon gauges o r mercury manometer connected between blood and d i a l y s a t e compartments. The d i a l y z e r was d e a e r a t e d , as d e s c r i b e d above, and allowed t o r e a c h thermal e q u i l i b r i u m w i t h t h e b a t h . UFR was measured a t TMPs r a n g i n g from 70 t o 1 4 0 mmHg. Membrane t r a n s m i t t a n c e c o e f f i c i e n t s were measured u s i n g a p r e v i o u s l y d e s c r i b e d t e c h n i q u e ( 6 ) . Experiments were conducted i n a c o n s t a n t l y s t i r r e d u l t r a f i l t r a t i o n c e l l (Amicon C o r p o r a t i o n , Lexington, Massachusetts) w i t h s t e r i l e s a l i n e (0.15 M)containing t h e above c o n c e n t r a t i o n s of s u c r o s e and v i t a m i n B I Z . Temperature was m a i n t a i n e d a t 3 7 f 0 . 1 C w h i l e t h e u l t r a f i l t r a t i o n f l u x i n t h e c e l l was 70 f 7 ml/min/m2.
292
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The d i a l y z e r s , c h a r a c t e r i s e d a s above and s t o r e d w i t h 2.5% formaldehyde i n s t e r i l e s a l i n e i n b o t h compartments , were used f o r r o u t i n e c l i n i c a l d i a l y s i s before being re-evaluated i n iritro l e s s than 1 2 hrs a f t e r use. E i g h t p a t i e n t s w i t h t o t a l and permanent r e n a l f a i l u r e ( c r e a t i n i n e c l e a r a n c e L 0.5 ml/min) p a r t i c i p a t e d i n t h e s t u d y . T h e i r mean age and p r e d i a l y s i s weight were 40 t 11 y e a r s and 6 7 t 1 0 kg, r e s p e c t i v e l y . Heparin (mucous, Weddell P h a r m a c e u t i c a l s Sydney) was a d m i n i s t e r e d d u r i n g a l l d i a l y s e s i n a c o n s t a n t dosage f o r each p a t i e n t . The mean l o a d i n g dosage was 10,000 f 4 , 0 0 0 I n t e r n a t i o n a l U n i t s (XU) and t h e subsequent c o n t i n u o u s i n f u s i o n was 950 i 2 5 0 IU/hr. In a d d i t i o n , two p a t i e n t s had e x t e r n a l a r t e r i o v e n o u s s h u n t s and r e c e i v e d c o n s t a n t w a r f a r i n dosage d u r i n g t h e s t u d y . P r e v i o u s l y d e s c r i b e d p r o c e d u r e s were a d o p t e d f o r d i a l y s i s ( 9 ) e x c e p t t h a t no p l a t e l e t i n h i b i t i n g drugs were used. The 8 p a t i e n t s , where p o s s i b l e , were d i a l y s e d w i t h one of each d i a l y z e r t y p e . Large-area d i a l y z e r s (CDAK 5, BF % , 6 and GLM) were used f o r 4 h r s w h i l e t h e o t h e r u n i t s were used f a r 6 h r s . Blood flow r a t e , e s t i m a t e d
from bubble t r a n s i t time o v e r a measured l e n g t h of t u b i n g , averaged 165 f 3 4 m l / m i n and was m a i n t a i n e d c o n s t a n t for e a c h p a t i e n t . In v i m TMP ( t a k e n as venous r e t u r n p r e s s u r e p l u s d i a l y s a t e n e g a t i v e p x e s s u r e ) was v a r i e d t o s u i t volume l o s s r e q u i r e m e n t s of' each i n d i v i d u a l p a t i e n t .
HEMODIALYZER
293
THEORY
Clearance a t any UFR i s given by
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.. Eq.1 where
.. Eq.2 Clearances were c a l c u l a t e d from both blood and d i a l y s a t e samples and 9 9 % of a l l mass balance e r r o r s were l e s s than 2 % . Some d i f f i c u l t y was experienced i n o b t a i n i n g a c c e p t a b l e vitamin B 1 2 mass balances and 5% of mass balance e r r o r s exceeded 2 8 . However, a c c e p t a b l e r e p r o d u c i b i l i t y (t 1%f o r CDAK 4) was achieved between m u l t i p l e vitamin B 1 2 c l e a r a n c e s . The o v e r a l l mass t r a n s f e r r a t e was considered as being-composed of convective and d i f f u s i v e terms: M = Mc
+
MD
.. Eq.3
The convective mass t r a n s f e r r a t e i s dependent on average blood-side s o l u t e c o n c e n t r a t i o n , membrane t r a n s m i t t a n c e c o e f f i c i e n t and UFR, t h u s ,
.. Eq. D i f f u s i v e mass t r a n s f e r r a t e i s a f u n c t i o n of t h e o v e r a l l mass t r a n s f e r c o e f f i c i e n t , e f f e c t i v e
4
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membrane a r e a and t h e l o g a r i t h m i c mean c o n c e n t r a t i o n . For c o u n t e r c u r r e n t o p e r a t i o n :
The mass t r a n s f e r c o e f f i c i e n t by a r e a (hoA) was c a l c u l a t e d from e x p e r i m e n t a l d a t a u s i n g e q u a t i o n s 2 - 5 . Clearance (KO> a t zero UFR f o r c o u n t e r c u r r e n t o p e r a t i o n was c a l c u l a t e d (10) from
.. Eq.
U l t r a f i l t r a t i o n d a t a were analysed by l i n e a r r e g r e s s i o n and t h e i n t e r c e p t a t 1 0 0 mmHg TMP o b t a i n e d , A l l r e g r e s s i o n c o e f f i c i e n t s were b e t t e r t h a n 0.998.
NOMENCLATURE
w
e f f e c t i v e mass t r a n s f e r a r e a (m2>
CB
s o l u t e c o n c e n t r a t i o n i n blood (mg/ml)
CD
s o l u t e c o n c e n t r a t i o n i n d i a l y s a t e (mg/ml)
ho
o v e r a l l mass transfer c o e f f i c i e n t ( m l / m i n / n s 2 >
K
c l e a r a n c e a t any UFR (ml/min>
6
REMODIALYZKR
KO
c l e a r a n c e a t zero UFR (ml/min)
M
o v e r a l l mass t r a n s f e r r a t e (mg/min)
MC
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295
convective mass t r a n s f e r r a t e (mg/min)
MD
d i f f u s i v e mass t r a n s f e r r a t e (mg/min)
QB
blood flow r a t e (ml/min)
QD
d i a l y s a t e flow r a t e (ml/min)
Tr
transmittance c o e f f i c i e n t (solute concentration i n filtrate/concentration i n retentate)
U
u l t r a f i l t r a t i o n r a t e , UFR (ml/min)
Subscript: i
denotes an i n l e t v a r i a b l e
o
denotes an o u t l e t v a r i a b l e
RESULTS AND DISCUSSION 1. S o l u t e Clearances. I n v i t r o c l e a r a n c e s f o r each d i a l y z e r type a r e l i s t e d i n Table 3 . Blood ( s a l i n e ) and d i a l y s a t e f l o w r a t e s , while approximately a d j u s t e d (within 2 9 ) during experimental work have been normalized (equation 6 ) t o 200 and 500 ml/min, r e s p e c t i v e l y , and, where a p p r o p r i a t e , c o r r e c t e d t o zero UFR. CDAK 5 s o l u t e c l e a r a n c e s a r e e x c e l l e n t over t h e e n t i r e molecular weight range r e f l e c t i n g t h e d i a l y z e r ' s l a r g e membrane s u r f a c e a r e a ( 2 . 5 m'). CDAK 4 performance i s i n f e r i o r t o t h e CDAK 5 because of r e d u c t i o n i n membrane a r e a (1.3 c f . 2 . 5 m2)
.
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M
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31.6 f 5 . 3
QB 200 ml/min, QD 500 ml/min, UFR 0 and temperature 37C. t n refers t o t h e number o f d i a l y z e r s t e s t e d and b t o the number o f b a t c h e s . ** Actual clearance data measured a t UFRs ranging from 24.3 t o 28.3 ml/min.
*
133
16 2
140
RP6** (n-1)
--
5
116
f
145
164
RP6 (n-1)
(n=5, b = l )
PF 1 . 6
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298
HONE ET AL, An i n c r e a s e i n f i b e r i n s i d e diameter ( I D )
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i n c r e a s e s t h e b l o o d - f i l m r e s i s t a n c e i n hollow f i b e r s (11 j hence small molecule ( u r e a and c r e a t i n i n e ) c l e a r a n c e s , which a r e s t r o n g l y dependent on l i q u i d f i l m - d i f f u s i o n a l r e s i s t a n c e , are d i m i n i s h e d i n t h e HF 130 (ID,300 pm) compared w i t h t h e CDAK 4 (ID, 2 2 4 um). On t h e o t h e r hand, membrane r e s i s t a n c e , which i s d i r e c t l y p r o p o r t i o n a l t o membrane t h i c k n e s s , and a r e a , s t r o n g l y i n f l u e n c e s t h e c l e a r a n c e o f large molecules ( 1 2 ) . The d e c r e a s e i n hollow f i b e r w a l l t h i c k n e s s i n t h e HF 130 ( 2 0 um), compared w i t h t h e CDAK 4 (35-40 pm), c o n t r i butes t o the higher vitamin B I Z clearance i n the former. Any i n c r e a s e i n c l e a r a n c e , a c h i e v e d by changing from 1 7 um t o 1 3 , s um cuprophan membrane i n G L N d i a l y z e r s , i s n o t a p p a r e n t due t o c l e a r a n c e v a r i a t i o n s from c l i a l y z e r t o d i a l y z e r . T h i s v a r i a b i l i t y i n Gambro d i a l y z e r s has been r e c o g n i s e d ( 1 3 ) and i s p r o b a b l y r e l a t e d t o v a r i a t i o n s i n membrane p e r m e a b i l i t y . V a r i a b i l i t y h a s been shown t o e x i s t between (14) as w e l l a5 w i t h i n ( 1 2 ) b a t c h e s of cuprophan. The improved performance o f t h e GLM, compared w i t h t h e GLN If, i s n o t as g r e a t f o r v i t a m i n B I Z a s would be a n t i c i p a t e d . The 5 0 % i n c r e a s e i n membrane a r e a would be e x p e c t e d t o produce a s i m i l a r i n c r e a s e i n v i t a m i n B I Z c l e a r a n c e . However, as t h i s i s n o t s o , i t s u g g e s t s t h a t t h e r e i s more channeling w i t h a Larger p e r c e n t a g e r e d u c t i o n i n GLM e f f e c t i v e membrane a r e a t h a n i s p r e s e n t i n t h e GLN 1 3 . The PF 1 small molecule c l e a r a n c e s a r e comparable w i t h t h o s e of t h e HF 1 3 0 , w h i l e i t s v i t a m i n B n z c l e a r a n c e i s s i m i l a r t o the GLN s e r i e s . The improve-
HEMODIALYZW
299
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ment i n PF 1 . 6 performance compared w i t h t h e PF 1 i s due t o t h e 6 0 % i n c r e a s e i n s u r f a c e a r e a . The high clearance v a r i a b i l i t y i n both Para Flo d i a l y z e r s i s most l i k e l y a r e f l e c t i o n of cuprophan membrane variability. The RP6 was t h e o n l y d i a l y z e r e v a l u a t e d t h a t does n o t u s e a c e l l u l o s i c membrane. I t s h i g h l y permeable PAN membrane i s r e s p o n s i b l e f o r t h e h i g h vitamin B I Z clearance.
2. U l t r a f i l t r a t i o n Rates. I n v i t r o d i a l y z e r u l t r a f i l t r a t i o n c h a r a c t e r i s t i c s f o r s a l i n e a t 37 C a r e shown i n Table 4. A l l d i a l y z e r s appear c l i n i c a l l y a b l e t o c o n t r o l p a t i e n t w e i g h t . The RP6 (PAN membrane) i s extremely permeable r e q u i r i n g t h e use of t h e Rhodial 7 5 p r o p o r t i o n i n g u n i t (Rhone-Poulenc, P a r i s ) . f o r general c l i n i c a l use.
The v a r i a t i o n i n u l t r a f i l t r a t i o n c h a r a c t e r i s t i c s o f Gambro d i a l y z e r s has been a t t r i b u t e d t o v a r i a b i l i t y i n cuprophan membrane (14). S i m i l a r v a r i a t i o n s may a l s o e x p l a i n t h e l a r g e s t a n d a r d d e v i a t i o n s i n UFRs of b o t h P a r a F l o d i a l y z e r s . 3.
Changes i n H A
( i ) Support Masking a t High TMPs. I t has been r e c o g n i s e d t h a t e f f e c t i v e membrane area may b e s i g n i f i c a n t l y reduced by h i g h TMP induced s u p p o r t masking ( 1 2 ) , ( 1 5 ) ( F i g u r e 1 ) . S t u d i e s have shown t h a t s t r e t c h i n g a l t e r s membrane t h i c k n e s s and p e r m e a b i l i t y (16). Uniform b i - d i r e c t i o n a l s t r e t c h i n g
300
fIONE ET ALo
TABLE 4 COMPARISON OF IN VITRO ULTRAFILTRATION CFARACTERISTICS FOR NEW DIALYZERS" Dialyzer
UFR
f
SD a t 100 mmHg
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TMP (ml/hr) CDAK 4
182
f
9
306
f
14
[n=P4, b=49
CDAK 5 (n-8
b=6)
HF I30
261
(n=I>
255 f 4
GLM 1 7
(n= 3, b= 1) GEN 1 3 ( n = 1 7 , b=4)
307 f 29
GEM (n=5, b=l)
461
?
33
PF f
231
_c
28
(n-8
b= 2 )
PF 1 , 6 C R = ~ ,b=19
402 f 67
WPQ (n-1)
3240
"measured i n 0.15 M s a l i n e a t 3 7 C .
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HEMODIALY ZER
301
1. LOW TRANSMEMBRANE. PRESSURE
2 HIGH TRANSMEMBRANE PRESSURE
FIG. 1
Support masking of d i a l y s e r membranes
3U L
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mainly i n c r e a s e s p o r e s i z e w h i l e u n i - d i r e c t i o n a l s t r e t c h i n g a l t e r s p o r e shape (16). The e f f e c t on c l e a r a n c e of t h e membrane t h i c k n e s s - s u p p o r t c o n f i g u r a t i o n combinations used i n Gambro and P a r a F l o d i a l y z e r s has been e v a l u a t e d i n v i t r o w i t h d i a l y z e r s d e a e r a t e d o n l y by r i n s i n g w i t h s a l i n e . Vitamin B 1 2 c l e a r a n c e , which i s s t r o n g l y dependent on membrane a r e a , was measured i n i t i a l l y a t 45 f 3 mmHg TMP, t h e n a t 1 6 2 f 3 mmHg 'FMP, and f i n a l l y a t 4 3 5 6 mmHg TMP t o e s t a b l i s h t h e o v e r a l l e f f e c t of i n c r e a s e d p e r m e a b i l i t y and membrane masking induced by o p e r a t i o n a t t h e h i g h e r TMP. A p p l i c a t i o n o f high TMP t o GLN 1 3 and GLN d i a l y z e r s r e s u l t e d i n a s l i g h t but s i g n i f i c a n t (paired-sample t - t e s t , p < O . l ) , i n c r e a s e i n v i t a m i n R e z hoA (Figure 2 ) Because t h e s e d i a l y z e r s Rave u n i - d i r e c t i o n a l membrane s u p p o r t s o r i e n t e d i n t h e e x t r u s i o n d i r e c t i o n of t h e cuprophan membrane s t r e t c h i n g occurs i n t h e t r a n s v e r s e d i r e c t i o n , improving p o r e c o n f i g u r a t i o n as w e l l a s i n c r e a s i n g t h e a r e a a v a i l a b l e f o r s o l u t e t r a n s f e r . The permanent improvement i n h A (p