JOURNAL OF DIALYSIS, 1(6), 545-558 (1977)
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CLINICAL ASPECTS OF HEMOFILTRATION
D. von Herrath, K. Schaefer, M. H u f l e r , G. Asmus and A. Hensel Mgdizinische A b t e i l u n g 11, S t . Joseph-Krankenhaus, Baumergl an 24, 1 B e r l i n 42 , German Federal Republic ABSTRACT We r e p o r t on c l i n i c a l experiences obtained i n 7 uremic p a t i e n t s t r e a t e d s i n c e January 1976 3 times weekly by c h r o n i c h e m f i l t r a t i o n . The observations which we c o l l e c t e d i n more than 300 treatments suggest t h a t h e m f i l t r a t i o n might be s u p e r i o r t o conventional hemod i a l y s i s . The main advantages of t h i s treatment a r e c h a r a c t e r i z e d by i t s b e t t e r c o n t r o l o f hypertension, hyperhydration, and p o s s i b l y o f uremic bone disease. Furthermore, t h e a p p l i e d a c r y l o n i t r i l e membrane allows t h e removal o f substances w i t h a molecular weight up t o 60,000, s i m i l a r t o t h e glomerular basement membrane. Addit i o n a l l y , we r e p o r t on methodological problems, on t h e c o m p a t i b i l i t y o f h e m f i l t r a t i o n , and f i n a l l y on i t s e f f i c i e n c y f o r removal o f d i f f e r e n t uremic solutes. Uremic t o x i n s a r e removed from t h e blood by d i f f u s i o n d u r i n g hemodialysis.
This means t h a t t h e clearance o f a substance i s i n -
v e r s l y c o r r e l a t e d w i t h i t s molecular weight.
I n contrast, hemofil-
t r a t i o n mimics t h e n a t u r a l f i l t r a t i o n process o f t h e glomerular basement membrane.
Thus, s o l u t e s can pass t h e h e m f i l t r a t i o n mem-
brane r e l a t i v e l y independently of t h e i r m l e c u l a r weight, so t h a t small and l a r g e r molecules are cleared---within t h e c h a r a c t e r i s t i c s of the membrane---with
a range given by
the same v e l o c i t y .
This c h a r a c t e r i s t i c d i f f e r e n c e between h e m f i l t r a t i o n and h e m d i a l y s i s could be o f t h e r a p e u t i c value i f t h e theory t h a t h i g h e r
545 Copyright 0 1977 by 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.
VON HERRATH ET AL.
546
molecular weight substances a r e i n v o l v e d i n uremic complications i s correct.
Another advantage, besides t h e more p h y s i o l o g i c a l f i l -
t r a t i o n process, i s t h e f a c t t h a t no d i a l y s a t e i s needed, thus avoidi n g t h e problems o c c u r r i n g w i t h t h e p r e p a r a t i o n o f t a p water and Ren Fail Downloaded from informahealthcare.com by McMaster University on 12/04/14 For personal use only.
d i a l y s a t e , as w e l l as problems w i t h b a c t e r i a l contamination.
Fur-
thermore, t h e h e m o f i l t r a t i o n machine can be moved e a s i l y from one place t o another and i s independent o f t h e water supply.
The
t h e o r e t i c a l advantages and t h e c l i n i c a l experiences obtained by Professor Q u e l lh o r s t ' 5 group (1 ) encouraged us t o h e m f i l t r a t e p a t i e n t s w i t h r e n a l i n s u f f i c i e n c y s i n c e January 1976, d e s p i t e the fact t h a t some t e c h n i c a l problems have n o t y e t been solved.
METHODS The hemof l t r a t i o n machine and t h e techn c a l procedures were a s described by H u f l e r e t a l . ( 2 ) .
The RP 6 d i a l y z e r o f Rhone-Poulenc
w i t h an a c r y l o n l ' t r i l e membrane ( t h i c k n e s s 30u, surface 1.03 m2) was used as t h e f i l t e r .
a t regular intervals. f i l t r a t e were obtained.
H e m f i l t r a t i o n was performed 3 times weekly Each procedure l a s t e d u n t i l 98 l i t e r s o f The b l o o d f l o w r a t e s and transmembrane
pressures a r e shown i n Table I . t l o n s o f the normal human kidney.
They a r e compared w i t h t h e condiI f one assumes t h a t the t o t a l
surface o f t h e human glornerular basement membrane i s about 7 m2
( 3 1 , as i n t h e RP 6 d i a l y z e r , i t i s remarkable t h a t t h e kidney needs only an e f f e c t i v e f i l t r a t i o n pressure o f 45 mn Hg t o e s t a b l i s h a
567
CLINICAL ASPECTS OF HEMOFILTRATION TABLE I
FILTRATION CHARACTERISTICS OF THE GLOMERULUS AND THE ACRYLONITRILE MEMBRANE AN 69
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Glomerular Basement Membrane
AN 69
Permeabi 1 i t y up t o molecu1 a r we igh t
80.000
4o,000-60,
Effective f i l t r a t ion pressure
45 nm Hg
500 nm Hg
Blood flow
1100 rnl/min
300 ml/min
Plasma flow (cortex)
610 ml/min Hct. 0.45
225 ml/rnin Hct. 0.25
Filtration rate
120 ml/min
66 ml/min
F i l t r a t i o n rate: Plasma flow
0.197
0.293
(cortex)
ooo
glomerular f i l t r a t i o n r a t e o f 45 n Hg t o establish a glomerular f i l t r a t i o n r a t e o f 120 ml/min.
However, a transmembrane pressure
o f 500 mn Hg has t o be created i n the r a t e o f about 66 ml/min.
RP 6 t o obtain a f i l t r a t i o n
This difference i s due t o the higher
blood flow rates i n the kidneys.
The Cimino f i s t u l a l i m i t s blood
flow t o a maximum of 300 ml/min i n extracorporeal hemofiltration, so t h a t higher pressures are needed t o obtain e f f e c t i v e f i l t r a t i o n .
In our hernofiltration device, we use a transmembrane pressure of 500 mm Hg a t blood flow rates between 250- 300 ml/min.
Under these
conditions, we achieve f i l t r a t i o n rates between 60 and 70 ml/min,
VON HERRATH ET AT.,=
548
which a r e comparable t o t h e f u n c t i o n of a normal kidney.
Because of
the lower hematocrit, t h e r e i s a r e l a t i v e l y h i g h plasma f l o w i n chronic uremic p a t i e n t s .
The achieved f i l t r a t i o n f r a c t i o n of 0.293
i s d i s t i n c t l y h i g h e r than i n t h e kidney.
The f i l t r a t e volume o f
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3 x 18 l i t e r s / w e e k i m p l i e s a h e m o f i l t r a t i o n r a t e o f 5.35 ml/min t h a t
can be added t o the r e s i d u a l kidney f u n c t i o n . We observed 15 membrane r u p t u r e s i n a t o t a l o f 309 treatments, presumably caused by mechanical s t r a i n .
However9 as these a r e nor-
m a l l y microleaks i n the membrane. and near t h e connections, we a r e
not f o r c e d t o change t h e f i l t e r .
On t h e o t h e r hand, we had a con-
s l d e r a b l e number o f ruptures, with extensive b l o o d l o s s i n 2 cases,
As s u b s t i t u t i o n f o r t h e removed f i l t r a t e , we a'nfused a s o l u t i o n containing, per 1 l i t e r : glucose 1.5 g, sodium 135 mEq, potassium 2.0 mEq, calcium 3.75 mEq, magnesium 1.5 mEq, c h l o r i d e 109 mEq, and l a c t a t e 33.75 mEq.
The balances o f t h e d i f f e r e n t s u b s t i t u t e d
solutes vary considerably w i t h t h e amount o f f l u i d removed.
How-
ever, the balance o f calcium remained p o s i t i v e i n a l l cases.
If
glucose-free s o l u t i o n s a r e used as s u b s t i t u t i o n , t h e r e is a 'loss o f about 15 g of glucose.
This i s w e l l t o l e r a t e d , w i t h o u t symptoms,
and can be compensated by e a t i n g . Patients.
Since January 11976, we have performed 309 hemofil-
t r a t i o n s in 7 p a t i e n t s : 4 females and 3 males, ages between 36 and
71 years ( f o e . . 23 p a t i e n t months o f h e m o f i l t r a t i o n , Table 11). Chronic g l o m e r u l o n e p h r l t i s was t h e u n d e r l y i n g disease t h a t l e d t o
C L I N I C A L ASPECTS OF AEElOFILTRATION
549
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TABLE I1 Weight
Creatinine C 1 . (ml bin)
Nr. of
Patient
%E
Sex -
0Disease
E.R.
50
F
48.5
cGN,diabetes me1 1 i t u s
3.57
103
E.W.
41
F
46.0
cGN, severe hypertension
2.73
70
D.Sch.
36
M
50.5
cGN, hypertens ion
5.48
49
M.G.
42
H
59 .O
cGN, alcohol ism
3 -32
42
5.28
22
HF
W.Sch.
41
F
61 .O
cGN, m a 1 ignant hypertens ion, miocard. i n f .
H.F.
71
M
57.5
cGN, polyneuropa thy
4.69
18
K.S.
64
F
52 .O
cGN hypotension dur. HD
3.10
5
TOTAL :
------------
309
cGN=chronic glomerulonephritis.
terminal renal insufficiency i n all patients, as f a r as i t could be clinically confirmed.
Three patients presented w i t h severe hyper-
tension, one of them w i t h a malignant course.
The patients D.Sch.
and W.Sch. had a relatively good residual renal function when they
were transferred t o the hemofiltration program to improve the hypertension.
Both patients had refused to take their antihypertensive
drugs because o f severe side effects.
The oldest patient (71 years)
VON HERRATH ET
550
was on r e g u l a r h e m d i a l y s i s f o r one y e a r p r i o r t o h e r n o f i l t r a t i o n . The reason f o r s t a r t i n g hemofil t r a t i o n was a r a p i d d e t e r i o r a t i o n i n h i s neuropathy.
I n a d d i t i o n , he o f t e n had severe hyperhydration,
and u l t r a f i l t r a t i o n d u r i n g h e m d i a l y s i s was n o t w e l l t o l e r a t e d .
Al-
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together, 3 p a t i e n t s had been h e m d i a l y z e d f o r several months p r i o r t o hemofi 1t r a t i on. One p a t i e n t d i e d from t h e consequences o f urosepsis.
An i n -
ocul a t l o n d u r i n g t h e h e m f i1t r a t i o n procedure c o u l d be excl uded by means o f b a c t e r o l o g i c a l examinations o f t h e i n f u s i o n s o l u t i o n s and the blood l i n e s .
RESULTS Compatibility o f H e m f i l t r a t i o n .
To summarize our present
c l i n i c a l observations, we have t h e impression t h a t treatment by h e m f i l t r a t i o n is t o l e r a t e d w i t h o u t major symptoms.
However, some-
times the p a t i e n t s experience a f e e l i n g o f i n n e r heat s h o r t l y a f t e r starting hemfiltration.
The symptom l a s t s o n l y f o r a few minutes
and i s not accompanied by a r i s e i n body temperature.
We assume
t h a t t h i s phenomenon i s due t o t h e p l a s t i c m a t e r i a l used, perhaps of t h e RP6.
Headache, nauseas and vomiting, w h i l e o c c u r r i n g o f t e n
i n hemodialysis, a r e unusual i n h e m o f i l t r a t i o n , and i n most cases
are caused by i n c o r r e c t i n f u s i o n balance.
P a t i e n t s t h a t had pre-
wiously been on hemodialysis p r e f e r hemofil t r a t i o n because o f i t s better compatibflity.
Whether o r n o t t h i s judgement o f t h e o l i g u r i s
CLINICAL ASPECTS OF HEMOFILTRATION
55 1
patients is based on the large filtration volume, w i t h i t s color so similar t o human urine, remains speculative.
However, we have the
strong feeling that hemofil tration could be considered as the best method t o treat severe hyperhydration i n terminal renal failure.
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Even large volumes (i.e., 1 - 2 liters/hour) can be removed without excessive f a l l s i n blood pressure and often without muscle cramps. Dehydration to such an extent cannot be performed by h m d i a l y s i s because of nmrous side effects.
T h i s good compatibility i s prob-
ably because of the isotonic dehydration.
Figure 1 shows a pro-
tocol of a hemfiltration treatment. Within only 5 hours, i t was
PATIENT E.R., 0.50 YEARS
FIGURE 1 P r o t o c o l of a h e r n o f i l t r a t i o n t r e a t m e n t w i t h remoVal of 6 . 1 kg of fluid w i t h i n 5 hours.
552
VON HERRATH ET
p o s s i b l e t o remove 6.3 kg o f edema f l u i d (11% o f t h e body weight) i n a severely overhydrated p a t i e n t w i t h o u t any problems i n cont r o l l i n g t h e blood pressure.
T h i s p a t i e n t was a b l e t o leave t h e
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h o s p i t a l a f t e r treatment. H e m o f i l t r a t i o n and Hypertension.
Henderson e t a1
. reported
on an anephric hypertensive p a t i e n t whose b l o o d pressure was normalized a f t e r a p e r i o d o f o n l y 4 weeks o f h e r n o f i l t r a t i o n treatment ( 4 ) Howevern s i n c e i n most cases t h e hypertension o f anephric p a t i e n t s can be improved by volume d e p l e t i o n , i t c o u l d n o t be decided whether
a r e d u c t i o n o f t h e e x t r a c e l l u l a r space o r t h e removal o f s t i l l unknown substances had been responsible f o r t h e permanent blood pressure lowering.
Although we have n o t observed such impressive i m -
provements, we c o u l d c o n f i r m these observations i n t h a t our 3 hypertensive p a t i e n t s had a lower b l o o d pressure under c h r o n i c h e m f i l tratl’on than before.
The numerous a n t i hypertensive drugs
c o u l d be reduced t o a reasonable l e v e l i n a l l cases a f t e r 3 t o 4 weeks.
F i g u r e 2 represents the c l i n i c a l course over a p e r i o d o f 6
months i n a p a t i e n t with severe hypertension.
The blood pressure
c o u l d n o t be i n f l u e n c e d b e f o r e h e r n o f i l t r a t i o n d e s p i t e i n t e n s i v e treatment.
-
__I__ I
The p a t i e n t s u f f e r e d from v e r t i g o , nausea, vomiting,
fatigue, and weakness.
We i n t e r p r e t e d these symptoms as r e s u l t i n g
from a combination o f hypertension, atotemia, anemia, and the s i d e effects o f t h e d i f f e r e n t drugs.
The p a t i e n t l o s t weight because o f
anorexia, thereby exacerbating azotemia.
The symptoms improved o n l y
2 weeks a f t e r beginning h e m f i l t r a t i o n , so t h a t t h e p a t i e n t was a b l e
553
CLINICAL ASPECTS OF HEMOFILTRATION PATIENT E.W., 9,41 YEARS
I
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Diet
-
t
0
I
l-bmfittration 3x weekly 18 1
2
1
3
a 4
5
6
MONTHS
FIGURE 2 Course of hypertensioL during a 6 months treatment period with hemofiltration.
to eat and thereby t o gain weight.
A t the same time, i t was pos-
sible t o reduce the antihypertensive drugs because the systolic and especially the diastolic
blood pressure values decreased. Blood
pressure could be easily controlled after 5 months o f hemofiltration w i t h small doses o f hydralatine and propranolol.
increased her weight a t t h a t time by 2 . 5 kg.
The patient had
Su mrizin g our limited
experience, we assume that especially volume-dependent hypertension can be better controlled by hemofil t r a t i o n than by hemodialysis. According t o our experience, this i s presently not valid for other
554
VON HEIERRATH ET. AL.
forms o f hypertension.
A t any r a t e , t h e b e t t e r c o m p a t i b i l i t y of
volume d e p l e t i o n d u r i n g h e m o f i l t r a t i o n i s a d i s t i n c t b e n e f i t , e5p e c i a l 1y f o r hypertensive pa t i en t s .
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E f f i c i e n c y o f Hemofil t r a t i o n .
i s demonstrated i n Table 111.
The e f f i c i e n c y o f hemofil t r a t i o n
The amount o f s o l u t e removed i s de-
pendent on i t s c o n c e n t r a t i o n i n t h e plasma, provided t h a t t h e f l o w
TABLE I I I REMOVAL OF DIFFERENT SMSVANCES BY HEMOFILTRATION SERUM UREA Start
(rng/!00 m I )
9 1 iters I8 1 iters
216 I64 128
-CREATlNlNE Start
12.8
9 liters 18 liters
FILTERED AMT. I
(g)
--_ 17.01 113 2
9.3
7.3 TOTAL:
1.737
TOTAL:
1.0117
URIC AClb
Start
9 iiters 18 liters
PHOSPHATE Start 9 1 i ters 19 liters
8.6 5 05 4.3
~ m o/L) l
2.181.67 1.49
CLINICAL ASPECTS OF HEMOFILTRATION r a t e o f the f i l t r a t e i s constant.
555 However, as the plasma concen-
t r a t i o n steadily decreases, the clearance o f a solute, a1 though valuable f o r comparing the e f f i c i e n c y o f d i f f e r e n t f i l t e r s and dialyzers, i s not a very meaningful measurement o f the e f f i c i e n c y
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o f hemofiltration i n a patient.
We believe t h a t the amount o f
solute removed per hour, o r per treatment, i s a b e t t e r i n d i x o f efficiency.
The few l i t e r s o f hemofiltrate formed, i n contrast t o
the large volumes o f dialysate, f a c i l i t a t e the d i r e c t measurement o f d i f f e r e n t f i l t e r e d substances.
As Table I11 shows, i t was pos-
s i b l e t o remove i n one o f our patients (H.F.),
i n 435 hours o r
18 l i t e r s o f h e m f i l t r a t e , 28 g o f urea, which represents twot h i r d s of the amount produced d a i l y by a healthy person,
Similar
data were obtained f o r creatinine, u r i c acid, and phosphate, which are not so w e l l dialyzed but reasonably f i l t e r e d .
Our experience
suggests t h a t the application o f drugs t h a t lower u r i c acid and phosphate could be avoided i n the majority o f patients.
However,
i t could not be determined how much h e m f i l t r a t i o n treatment i s
presently adequate.
It i s l i k e l y t h a t suggestions w i l l be a v a i l -
able i n the near future t h a t might enable us t o calculate adequate hemofiltration treatment, s i m i l a r t o the d i a l y s i s index (5).
The
characterics and the e f f i c i e n c y o f the f i l t e r s should be considered i n such an index, as well as the size o f the body compartments of the individual patient. Two of our patients who had a d i a l y s i s i n dex o f 1.2 before the beginning o f hemofiltration d i d not show any s i g n i f i c a n t increase i n t h e i r serum creatinine values.
VON HERRATB ET AL.
556 Neuropathy and Anemia.
We are p r e s e n t l y n o t a b l e t o judge
whether o r n o t h e m o f i l t r a t i o n i s a b l e t o prevent o r t o improve uremic neuropathy, s i n c e we consider a treatment p e r i o d o f 6 o r 9 months as tao s h o r t t o make any c o n e n t s on t h a t problem.
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time o f one o f our p a t i e n t s (H.F.) index o f 1.2.
The nerve conduction
deteriorated despite a d i a l y s i s
This was the reason f o r h i s t r a n s f e r t o our hemofil-
t r a t i o n program.
I t remains t o be e s t a b l i s h e d whether o r n o t the
scheduled h e m o f i l t r a t i o n time o f 3 x 1 8 l i t e r s w i l l improve h i s neuropathy. Statements concerning a p o s s i b l e i n f l u e n c e on uremic anemia r e = q u i r e f u r t h e r c l i n i c a l observations.
U n t i l now, we have n o t n o t i c e d
any s i g n i f i c a n t d i f f e r e n c e between hemof i1t r a t i o n and hemodial ys is as f a r as hemoglobin o r h e m t o c r i t i s concerned.
However, i t must
be r e a l i z e d t h a t more blood samples have been taken from the hemof i l t r a t i o n p a t i e n t s compared w i t h p a t i e n t s t h a t have been on hemod i a l y s i s f o r years. Future Aspects o f H e m o f i l t r a t i o n .
H a l f a y e a r ago, we consid-
ered the advantages and disadvantages o f h e m o f i l t r a t i o n a t a symposium i n Gstaad, Switzerland.
Table
I V summarizes t h e advantages
o f h e m o f i l t r a t i o n compared w i t h hemodialysis.
While t h e advantages a t t h a t time were s t i l l t h e o r e t i c a l , they have now beeng a t l e a s t i n p a r t , confirmed.
The questions concerning
costs cannot be answered u n t i l automatic h e m o f i l t r a t i o n machines and s p e c i a l membranes and f i l t e r s a r e a v a i l a b l e .
Whether o r not,
and i n what q u a n t i t y , middle molecules a r e removed by h e m f i l t r a -
t i o n i s p r e s e n t l y being studied.
557
CLINICAL ASPECTS OF KEMOFILTRATION
TABLE I V ADVANTAGES OF HEMOFILTRATION COMPARED W I T H HEMODIALYSIS
1.
Not dependent on water
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2 . No problems w i t h c o n d u c t i v i t y 3. E a s i l y moved from one place t o another 4. No s t e r i l i z a t i o n r e q u i r e d a f t e r treatment
5. A1 1 equipment disposable 6. Less reasons f o r i n f e c t i o n s 7. Lower costs f o r a machine 8.
Lower p r i c e s p e r treatment ( ? )
9.
More p h y s i o l o g i c a l removal o f uremic t o x i n s
10.
Removal o f middle molecules
11.
No problems with overhydrated p a t i e n t s
12.
Shortening o f treatment time t o 2 b e t t e r membranes developed
- 3 hours
i f and when
The disadvantages o f hemofil t r a t i o n compared with h e m d i a l y s i s t h a t were discussed i n t h e Gstaad symposium a r e s m r i z e d i n Table V. The disadvantages mentioned i n t o p i c s 1 and 2 o f Table V were t e c h n i c a l problems t h a t have been r e s o l v e d i n t h e meantime.
The
TABLE V DISADVANTAGES OF HEMOFILTRATION COMPARED WITH HEMODIALYSIS 1.
A t present, no m o n i t o r i n g o f b l o o d l e a k
2. 3.
I n f u s i o n r a t e a t present n o t monitored by f i l t r a t i o n r a t e Dependency on l a r g e i n f u s i o n volunes
4.
A t present, h i g h c o s t s f o r f i l t e r s
5. A t present, u n c e r t a i n t y on t h e amount o f f l u i d which should be removed
6.
Minimum blood f l o w 200 m l / m i n
VON HERRATH ET AL.
558
n e c e s s i t y o f l a r g e i n f u s i o n volumes i s n e c e s s i t a t e d by t h e p r i n c i p l e o f h e m f i l t r a t i o n ; however, i f one succeeds i n removing t h e d i f f e r e n t s o l u t e s from t h e h e r n o f i l t r a t e , i t should be p o s s i b l e t o r e infuse it.
A b l o o d f l o w o f 200 m l / m i n i s p r e s e n t l y necessary, u s i n g
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the a v a i l a b l e f i l t e r s , t o a v o i d a l o n g e r treatment time than i s necessary f o r hemodialysis.
REFERENCES
1.
Q u e l l h o r s t , E., Doht, B., and Rieger, J . , XI11 EDTA Congress, Hamburg, Germany, 1976; a b s t r a c t s , p. 30.
2.
H u f l e r , M., von Herrath, Do, Asmus, G., J, D i a l y s i s , 1977, t h i s volume.
3.
Goss, C . M . , Gra 's Anatom del phia, 196-
4.
Henderson, L.W., Ford, Ch.A., Lysaght, M.J. , Grosman, R . A . , and S i l v e r s t e i n , M.E., Kid. Int., l:S-413, 1975.
5.
Babb, A.L., Strand, M.J,, Kid. I n t . , I:S-23, 1975.
, 28th
Ed.,
U v e l l i , D.A.,
and Schaefer, K., Lea & Febiger, P h i l a -
M i l u t i n o v i c , J.,
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CLINICAL ASPECTS OF HEMOFILTRATION
D. von Herrath, K. Schaefer, M. H u f l e r , G. Asmus and A. Hensel Mgdizinische A b t e i l u n g 11, S t . Joseph-Krankenhaus, Baumergl an 24, 1 B e r l i n 42 , German Federal Republic ABSTRACT We r e p o r t on c l i n i c a l experiences obtained i n 7 uremic p a t i e n t s t r e a t e d s i n c e January 1976 3 times weekly by c h r o n i c h e m f i l t r a t i o n . The observations which we c o l l e c t e d i n more than 300 treatments suggest t h a t h e m f i l t r a t i o n might be s u p e r i o r t o conventional hemod i a l y s i s . The main advantages of t h i s treatment a r e c h a r a c t e r i z e d by i t s b e t t e r c o n t r o l o f hypertension, hyperhydration, and p o s s i b l y o f uremic bone disease. Furthermore, t h e a p p l i e d a c r y l o n i t r i l e membrane allows t h e removal o f substances w i t h a molecular weight up t o 60,000, s i m i l a r t o t h e glomerular basement membrane. Addit i o n a l l y , we r e p o r t on methodological problems, on t h e c o m p a t i b i l i t y o f h e m f i l t r a t i o n , and f i n a l l y on i t s e f f i c i e n c y f o r removal o f d i f f e r e n t uremic solutes. Uremic t o x i n s a r e removed from t h e blood by d i f f u s i o n d u r i n g hemodialysis.
This means t h a t t h e clearance o f a substance i s i n -
v e r s l y c o r r e l a t e d w i t h i t s molecular weight.
I n contrast, hemofil-
t r a t i o n mimics t h e n a t u r a l f i l t r a t i o n process o f t h e glomerular basement membrane.
Thus, s o l u t e s can pass t h e h e m f i l t r a t i o n mem-
brane r e l a t i v e l y independently of t h e i r m l e c u l a r weight, so t h a t small and l a r g e r molecules are cleared---within t h e c h a r a c t e r i s t i c s of the membrane---with
a range given by
the same v e l o c i t y .
This c h a r a c t e r i s t i c d i f f e r e n c e between h e m f i l t r a t i o n and h e m d i a l y s i s could be o f t h e r a p e u t i c value i f t h e theory t h a t h i g h e r
545 Copyright 0 1977 by 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.
VON HERRATH ET AL.
546
molecular weight substances a r e i n v o l v e d i n uremic complications i s correct.
Another advantage, besides t h e more p h y s i o l o g i c a l f i l -
t r a t i o n process, i s t h e f a c t t h a t no d i a l y s a t e i s needed, thus avoidi n g t h e problems o c c u r r i n g w i t h t h e p r e p a r a t i o n o f t a p water and Ren Fail Downloaded from informahealthcare.com by McMaster University on 12/04/14 For personal use only.
d i a l y s a t e , as w e l l as problems w i t h b a c t e r i a l contamination.
Fur-
thermore, t h e h e m o f i l t r a t i o n machine can be moved e a s i l y from one place t o another and i s independent o f t h e water supply.
The
t h e o r e t i c a l advantages and t h e c l i n i c a l experiences obtained by Professor Q u e l lh o r s t ' 5 group (1 ) encouraged us t o h e m f i l t r a t e p a t i e n t s w i t h r e n a l i n s u f f i c i e n c y s i n c e January 1976, d e s p i t e the fact t h a t some t e c h n i c a l problems have n o t y e t been solved.
METHODS The hemof l t r a t i o n machine and t h e techn c a l procedures were a s described by H u f l e r e t a l . ( 2 ) .
The RP 6 d i a l y z e r o f Rhone-Poulenc
w i t h an a c r y l o n l ' t r i l e membrane ( t h i c k n e s s 30u, surface 1.03 m2) was used as t h e f i l t e r .
a t regular intervals. f i l t r a t e were obtained.
H e m f i l t r a t i o n was performed 3 times weekly Each procedure l a s t e d u n t i l 98 l i t e r s o f The b l o o d f l o w r a t e s and transmembrane
pressures a r e shown i n Table I . t l o n s o f the normal human kidney.
They a r e compared w i t h t h e condiI f one assumes t h a t the t o t a l
surface o f t h e human glornerular basement membrane i s about 7 m2
( 3 1 , as i n t h e RP 6 d i a l y z e r , i t i s remarkable t h a t t h e kidney needs only an e f f e c t i v e f i l t r a t i o n pressure o f 45 mn Hg t o e s t a b l i s h a
567
CLINICAL ASPECTS OF HEMOFILTRATION TABLE I
FILTRATION CHARACTERISTICS OF THE GLOMERULUS AND THE ACRYLONITRILE MEMBRANE AN 69
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Glomerular Basement Membrane
AN 69
Permeabi 1 i t y up t o molecu1 a r we igh t
80.000
4o,000-60,
Effective f i l t r a t ion pressure
45 nm Hg
500 nm Hg
Blood flow
1100 rnl/min
300 ml/min
Plasma flow (cortex)
610 ml/min Hct. 0.45
225 ml/rnin Hct. 0.25
Filtration rate
120 ml/min
66 ml/min
F i l t r a t i o n rate: Plasma flow
0.197
0.293
(cortex)
ooo
glomerular f i l t r a t i o n r a t e o f 45 n Hg t o establish a glomerular f i l t r a t i o n r a t e o f 120 ml/min.
However, a transmembrane pressure
o f 500 mn Hg has t o be created i n the r a t e o f about 66 ml/min.
RP 6 t o obtain a f i l t r a t i o n
This difference i s due t o the higher
blood flow rates i n the kidneys.
The Cimino f i s t u l a l i m i t s blood
flow t o a maximum of 300 ml/min i n extracorporeal hemofiltration, so t h a t higher pressures are needed t o obtain e f f e c t i v e f i l t r a t i o n .
In our hernofiltration device, we use a transmembrane pressure of 500 mm Hg a t blood flow rates between 250- 300 ml/min.
Under these
conditions, we achieve f i l t r a t i o n rates between 60 and 70 ml/min,
VON HERRATH ET AT.,=
548
which a r e comparable t o t h e f u n c t i o n of a normal kidney.
Because of
the lower hematocrit, t h e r e i s a r e l a t i v e l y h i g h plasma f l o w i n chronic uremic p a t i e n t s .
The achieved f i l t r a t i o n f r a c t i o n of 0.293
i s d i s t i n c t l y h i g h e r than i n t h e kidney.
The f i l t r a t e volume o f
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3 x 18 l i t e r s / w e e k i m p l i e s a h e m o f i l t r a t i o n r a t e o f 5.35 ml/min t h a t
can be added t o the r e s i d u a l kidney f u n c t i o n . We observed 15 membrane r u p t u r e s i n a t o t a l o f 309 treatments, presumably caused by mechanical s t r a i n .
However9 as these a r e nor-
m a l l y microleaks i n the membrane. and near t h e connections, we a r e
not f o r c e d t o change t h e f i l t e r .
On t h e o t h e r hand, we had a con-
s l d e r a b l e number o f ruptures, with extensive b l o o d l o s s i n 2 cases,
As s u b s t i t u t i o n f o r t h e removed f i l t r a t e , we a'nfused a s o l u t i o n containing, per 1 l i t e r : glucose 1.5 g, sodium 135 mEq, potassium 2.0 mEq, calcium 3.75 mEq, magnesium 1.5 mEq, c h l o r i d e 109 mEq, and l a c t a t e 33.75 mEq.
The balances o f t h e d i f f e r e n t s u b s t i t u t e d
solutes vary considerably w i t h t h e amount o f f l u i d removed.
How-
ever, the balance o f calcium remained p o s i t i v e i n a l l cases.
If
glucose-free s o l u t i o n s a r e used as s u b s t i t u t i o n , t h e r e is a 'loss o f about 15 g of glucose.
This i s w e l l t o l e r a t e d , w i t h o u t symptoms,
and can be compensated by e a t i n g . Patients.
Since January 11976, we have performed 309 hemofil-
t r a t i o n s in 7 p a t i e n t s : 4 females and 3 males, ages between 36 and
71 years ( f o e . . 23 p a t i e n t months o f h e m o f i l t r a t i o n , Table 11). Chronic g l o m e r u l o n e p h r l t i s was t h e u n d e r l y i n g disease t h a t l e d t o
C L I N I C A L ASPECTS OF AEElOFILTRATION
549
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TABLE I1 Weight
Creatinine C 1 . (ml bin)
Nr. of
Patient
%E
Sex -
0Disease
E.R.
50
F
48.5
cGN,diabetes me1 1 i t u s
3.57
103
E.W.
41
F
46.0
cGN, severe hypertension
2.73
70
D.Sch.
36
M
50.5
cGN, hypertens ion
5.48
49
M.G.
42
H
59 .O
cGN, alcohol ism
3 -32
42
5.28
22
HF
W.Sch.
41
F
61 .O
cGN, m a 1 ignant hypertens ion, miocard. i n f .
H.F.
71
M
57.5
cGN, polyneuropa thy
4.69
18
K.S.
64
F
52 .O
cGN hypotension dur. HD
3.10
5
TOTAL :
------------
309
cGN=chronic glomerulonephritis.
terminal renal insufficiency i n all patients, as f a r as i t could be clinically confirmed.
Three patients presented w i t h severe hyper-
tension, one of them w i t h a malignant course.
The patients D.Sch.
and W.Sch. had a relatively good residual renal function when they
were transferred t o the hemofiltration program to improve the hypertension.
Both patients had refused to take their antihypertensive
drugs because o f severe side effects.
The oldest patient (71 years)
VON HERRATH ET
550
was on r e g u l a r h e m d i a l y s i s f o r one y e a r p r i o r t o h e r n o f i l t r a t i o n . The reason f o r s t a r t i n g hemofil t r a t i o n was a r a p i d d e t e r i o r a t i o n i n h i s neuropathy.
I n a d d i t i o n , he o f t e n had severe hyperhydration,
and u l t r a f i l t r a t i o n d u r i n g h e m d i a l y s i s was n o t w e l l t o l e r a t e d .
Al-
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together, 3 p a t i e n t s had been h e m d i a l y z e d f o r several months p r i o r t o hemofi 1t r a t i on. One p a t i e n t d i e d from t h e consequences o f urosepsis.
An i n -
ocul a t l o n d u r i n g t h e h e m f i1t r a t i o n procedure c o u l d be excl uded by means o f b a c t e r o l o g i c a l examinations o f t h e i n f u s i o n s o l u t i o n s and the blood l i n e s .
RESULTS Compatibility o f H e m f i l t r a t i o n .
To summarize our present
c l i n i c a l observations, we have t h e impression t h a t treatment by h e m f i l t r a t i o n is t o l e r a t e d w i t h o u t major symptoms.
However, some-
times the p a t i e n t s experience a f e e l i n g o f i n n e r heat s h o r t l y a f t e r starting hemfiltration.
The symptom l a s t s o n l y f o r a few minutes
and i s not accompanied by a r i s e i n body temperature.
We assume
t h a t t h i s phenomenon i s due t o t h e p l a s t i c m a t e r i a l used, perhaps of t h e RP6.
Headache, nauseas and vomiting, w h i l e o c c u r r i n g o f t e n
i n hemodialysis, a r e unusual i n h e m o f i l t r a t i o n , and i n most cases
are caused by i n c o r r e c t i n f u s i o n balance.
P a t i e n t s t h a t had pre-
wiously been on hemodialysis p r e f e r hemofil t r a t i o n because o f i t s better compatibflity.
Whether o r n o t t h i s judgement o f t h e o l i g u r i s
CLINICAL ASPECTS OF HEMOFILTRATION
55 1
patients is based on the large filtration volume, w i t h i t s color so similar t o human urine, remains speculative.
However, we have the
strong feeling that hemofil tration could be considered as the best method t o treat severe hyperhydration i n terminal renal failure.
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Even large volumes (i.e., 1 - 2 liters/hour) can be removed without excessive f a l l s i n blood pressure and often without muscle cramps. Dehydration to such an extent cannot be performed by h m d i a l y s i s because of nmrous side effects.
T h i s good compatibility i s prob-
ably because of the isotonic dehydration.
Figure 1 shows a pro-
tocol of a hemfiltration treatment. Within only 5 hours, i t was
PATIENT E.R., 0.50 YEARS
FIGURE 1 P r o t o c o l of a h e r n o f i l t r a t i o n t r e a t m e n t w i t h remoVal of 6 . 1 kg of fluid w i t h i n 5 hours.
552
VON HERRATH ET
p o s s i b l e t o remove 6.3 kg o f edema f l u i d (11% o f t h e body weight) i n a severely overhydrated p a t i e n t w i t h o u t any problems i n cont r o l l i n g t h e blood pressure.
T h i s p a t i e n t was a b l e t o leave t h e
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h o s p i t a l a f t e r treatment. H e m o f i l t r a t i o n and Hypertension.
Henderson e t a1
. reported
on an anephric hypertensive p a t i e n t whose b l o o d pressure was normalized a f t e r a p e r i o d o f o n l y 4 weeks o f h e r n o f i l t r a t i o n treatment ( 4 ) Howevern s i n c e i n most cases t h e hypertension o f anephric p a t i e n t s can be improved by volume d e p l e t i o n , i t c o u l d n o t be decided whether
a r e d u c t i o n o f t h e e x t r a c e l l u l a r space o r t h e removal o f s t i l l unknown substances had been responsible f o r t h e permanent blood pressure lowering.
Although we have n o t observed such impressive i m -
provements, we c o u l d c o n f i r m these observations i n t h a t our 3 hypertensive p a t i e n t s had a lower b l o o d pressure under c h r o n i c h e m f i l tratl’on than before.
The numerous a n t i hypertensive drugs
c o u l d be reduced t o a reasonable l e v e l i n a l l cases a f t e r 3 t o 4 weeks.
F i g u r e 2 represents the c l i n i c a l course over a p e r i o d o f 6
months i n a p a t i e n t with severe hypertension.
The blood pressure
c o u l d n o t be i n f l u e n c e d b e f o r e h e r n o f i l t r a t i o n d e s p i t e i n t e n s i v e treatment.
-
__I__ I
The p a t i e n t s u f f e r e d from v e r t i g o , nausea, vomiting,
fatigue, and weakness.
We i n t e r p r e t e d these symptoms as r e s u l t i n g
from a combination o f hypertension, atotemia, anemia, and the s i d e effects o f t h e d i f f e r e n t drugs.
The p a t i e n t l o s t weight because o f
anorexia, thereby exacerbating azotemia.
The symptoms improved o n l y
2 weeks a f t e r beginning h e m f i l t r a t i o n , so t h a t t h e p a t i e n t was a b l e
553
CLINICAL ASPECTS OF HEMOFILTRATION PATIENT E.W., 9,41 YEARS
I
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Diet
-
t
0
I
l-bmfittration 3x weekly 18 1
2
1
3
a 4
5
6
MONTHS
FIGURE 2 Course of hypertensioL during a 6 months treatment period with hemofiltration.
to eat and thereby t o gain weight.
A t the same time, i t was pos-
sible t o reduce the antihypertensive drugs because the systolic and especially the diastolic
blood pressure values decreased. Blood
pressure could be easily controlled after 5 months o f hemofiltration w i t h small doses o f hydralatine and propranolol.
increased her weight a t t h a t time by 2 . 5 kg.
The patient had
Su mrizin g our limited
experience, we assume that especially volume-dependent hypertension can be better controlled by hemofil t r a t i o n than by hemodialysis. According t o our experience, this i s presently not valid for other
554
VON HEIERRATH ET. AL.
forms o f hypertension.
A t any r a t e , t h e b e t t e r c o m p a t i b i l i t y of
volume d e p l e t i o n d u r i n g h e m o f i l t r a t i o n i s a d i s t i n c t b e n e f i t , e5p e c i a l 1y f o r hypertensive pa t i en t s .
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E f f i c i e n c y o f Hemofil t r a t i o n .
i s demonstrated i n Table 111.
The e f f i c i e n c y o f hemofil t r a t i o n
The amount o f s o l u t e removed i s de-
pendent on i t s c o n c e n t r a t i o n i n t h e plasma, provided t h a t t h e f l o w
TABLE I I I REMOVAL OF DIFFERENT SMSVANCES BY HEMOFILTRATION SERUM UREA Start
(rng/!00 m I )
9 1 iters I8 1 iters
216 I64 128
-CREATlNlNE Start
12.8
9 liters 18 liters
FILTERED AMT. I
(g)
--_ 17.01 113 2
9.3
7.3 TOTAL:
1.737
TOTAL:
1.0117
URIC AClb
Start
9 iiters 18 liters
PHOSPHATE Start 9 1 i ters 19 liters
8.6 5 05 4.3
~ m o/L) l
2.181.67 1.49
CLINICAL ASPECTS OF HEMOFILTRATION r a t e o f the f i l t r a t e i s constant.
555 However, as the plasma concen-
t r a t i o n steadily decreases, the clearance o f a solute, a1 though valuable f o r comparing the e f f i c i e n c y o f d i f f e r e n t f i l t e r s and dialyzers, i s not a very meaningful measurement o f the e f f i c i e n c y
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o f hemofiltration i n a patient.
We believe t h a t the amount o f
solute removed per hour, o r per treatment, i s a b e t t e r i n d i x o f efficiency.
The few l i t e r s o f hemofiltrate formed, i n contrast t o
the large volumes o f dialysate, f a c i l i t a t e the d i r e c t measurement o f d i f f e r e n t f i l t e r e d substances.
As Table I11 shows, i t was pos-
s i b l e t o remove i n one o f our patients (H.F.),
i n 435 hours o r
18 l i t e r s o f h e m f i l t r a t e , 28 g o f urea, which represents twot h i r d s of the amount produced d a i l y by a healthy person,
Similar
data were obtained f o r creatinine, u r i c acid, and phosphate, which are not so w e l l dialyzed but reasonably f i l t e r e d .
Our experience
suggests t h a t the application o f drugs t h a t lower u r i c acid and phosphate could be avoided i n the majority o f patients.
However,
i t could not be determined how much h e m f i l t r a t i o n treatment i s
presently adequate.
It i s l i k e l y t h a t suggestions w i l l be a v a i l -
able i n the near future t h a t might enable us t o calculate adequate hemofiltration treatment, s i m i l a r t o the d i a l y s i s index (5).
The
characterics and the e f f i c i e n c y o f the f i l t e r s should be considered i n such an index, as well as the size o f the body compartments of the individual patient. Two of our patients who had a d i a l y s i s i n dex o f 1.2 before the beginning o f hemofiltration d i d not show any s i g n i f i c a n t increase i n t h e i r serum creatinine values.
VON HERRATB ET AL.
556 Neuropathy and Anemia.
We are p r e s e n t l y n o t a b l e t o judge
whether o r n o t h e m o f i l t r a t i o n i s a b l e t o prevent o r t o improve uremic neuropathy, s i n c e we consider a treatment p e r i o d o f 6 o r 9 months as tao s h o r t t o make any c o n e n t s on t h a t problem.
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time o f one o f our p a t i e n t s (H.F.) index o f 1.2.
The nerve conduction
deteriorated despite a d i a l y s i s
This was the reason f o r h i s t r a n s f e r t o our hemofil-
t r a t i o n program.
I t remains t o be e s t a b l i s h e d whether o r n o t the
scheduled h e m o f i l t r a t i o n time o f 3 x 1 8 l i t e r s w i l l improve h i s neuropathy. Statements concerning a p o s s i b l e i n f l u e n c e on uremic anemia r e = q u i r e f u r t h e r c l i n i c a l observations.
U n t i l now, we have n o t n o t i c e d
any s i g n i f i c a n t d i f f e r e n c e between hemof i1t r a t i o n and hemodial ys is as f a r as hemoglobin o r h e m t o c r i t i s concerned.
However, i t must
be r e a l i z e d t h a t more blood samples have been taken from the hemof i l t r a t i o n p a t i e n t s compared w i t h p a t i e n t s t h a t have been on hemod i a l y s i s f o r years. Future Aspects o f H e m o f i l t r a t i o n .
H a l f a y e a r ago, we consid-
ered the advantages and disadvantages o f h e m o f i l t r a t i o n a t a symposium i n Gstaad, Switzerland.
Table
I V summarizes t h e advantages
o f h e m o f i l t r a t i o n compared w i t h hemodialysis.
While t h e advantages a t t h a t time were s t i l l t h e o r e t i c a l , they have now beeng a t l e a s t i n p a r t , confirmed.
The questions concerning
costs cannot be answered u n t i l automatic h e m o f i l t r a t i o n machines and s p e c i a l membranes and f i l t e r s a r e a v a i l a b l e .
Whether o r not,
and i n what q u a n t i t y , middle molecules a r e removed by h e m f i l t r a -
t i o n i s p r e s e n t l y being studied.
557
CLINICAL ASPECTS OF KEMOFILTRATION
TABLE I V ADVANTAGES OF HEMOFILTRATION COMPARED W I T H HEMODIALYSIS
1.
Not dependent on water
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2 . No problems w i t h c o n d u c t i v i t y 3. E a s i l y moved from one place t o another 4. No s t e r i l i z a t i o n r e q u i r e d a f t e r treatment
5. A1 1 equipment disposable 6. Less reasons f o r i n f e c t i o n s 7. Lower costs f o r a machine 8.
Lower p r i c e s p e r treatment ( ? )
9.
More p h y s i o l o g i c a l removal o f uremic t o x i n s
10.
Removal o f middle molecules
11.
No problems with overhydrated p a t i e n t s
12.
Shortening o f treatment time t o 2 b e t t e r membranes developed
- 3 hours
i f and when
The disadvantages o f hemofil t r a t i o n compared with h e m d i a l y s i s t h a t were discussed i n t h e Gstaad symposium a r e s m r i z e d i n Table V. The disadvantages mentioned i n t o p i c s 1 and 2 o f Table V were t e c h n i c a l problems t h a t have been r e s o l v e d i n t h e meantime.
The
TABLE V DISADVANTAGES OF HEMOFILTRATION COMPARED WITH HEMODIALYSIS 1.
A t present, no m o n i t o r i n g o f b l o o d l e a k
2. 3.
I n f u s i o n r a t e a t present n o t monitored by f i l t r a t i o n r a t e Dependency on l a r g e i n f u s i o n volunes
4.
A t present, h i g h c o s t s f o r f i l t e r s
5. A t present, u n c e r t a i n t y on t h e amount o f f l u i d which should be removed
6.
Minimum blood f l o w 200 m l / m i n
VON HERRATH ET AL.
558
n e c e s s i t y o f l a r g e i n f u s i o n volumes i s n e c e s s i t a t e d by t h e p r i n c i p l e o f h e m f i l t r a t i o n ; however, i f one succeeds i n removing t h e d i f f e r e n t s o l u t e s from t h e h e r n o f i l t r a t e , i t should be p o s s i b l e t o r e infuse it.
A b l o o d f l o w o f 200 m l / m i n i s p r e s e n t l y necessary, u s i n g
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the a v a i l a b l e f i l t e r s , t o a v o i d a l o n g e r treatment time than i s necessary f o r hemodialysis.
REFERENCES
1.
Q u e l l h o r s t , E., Doht, B., and Rieger, J . , XI11 EDTA Congress, Hamburg, Germany, 1976; a b s t r a c t s , p. 30.
2.
H u f l e r , M., von Herrath, Do, Asmus, G., J, D i a l y s i s , 1977, t h i s volume.
3.
Goss, C . M . , Gra 's Anatom del phia, 196-
4.
Henderson, L.W., Ford, Ch.A., Lysaght, M.J. , Grosman, R . A . , and S i l v e r s t e i n , M.E., Kid. Int., l:S-413, 1975.
5.
Babb, A.L., Strand, M.J,, Kid. I n t . , I:S-23, 1975.
, 28th
Ed.,
U v e l l i , D.A.,
and Schaefer, K., Lea & Febiger, P h i l a -
M i l u t i n o v i c , J.,
