Biocompatibility of haemodialysis membranes

BIOCOMPATIBILITY OF HAEMODIALYSIS MEMBRANES N.A

Hoenich,

D. Levett,

S. Fawcett,

C. Woffindin

and

D.N.S.

Kerr*

INTRODUCTION

HAEMODIALYSIS

Haemodialvsis is an established and widely used mode of treatment for renal failure, and its therapeutic benefits are well recognized. However, treatment is associated with a number of adverse effects, such as rapid and transient fall of white cells, activation of the complement system and a fall in arterial oxygenation, eosinophilia and infrequentlv with anaphylactoid reactions.

Leucopenia associated with haemodialysis occurs during the first hour of treatment. Its duration is short with the nadir being reached between lo-20 min after the commencement of treatment, and is followed by a gradual return to pie-dialysis levels by the end of the first hour.

These reactions to haemodialysis have, until recently, received little attention, possibly for two reasons. First, the membranes used are based principally upon cellulose which was derived from a single source, thereby giving little opportunity to modify these observations. Second, due to the general acceptance of the statement made by Kaplow and Goffinet’ who, in their original description of the white cell changes associated with haemodialysis, stated that ‘the transient neutropenia introduced by haemodialysis is the most profound yet reported in man, and is without svmptoms or apparent sequelae’. More recently, modified cellulose membranes as well as synthetic alternatives have become available and this has intensified interest and rewakened research activity in this aspect of haemodialysis. The purpose of this review is to describe the interrelationship between leucopenia, complement activation and hypoxia observed during haemodialysis, to assess the role of the haemodialysis membrane and to discuss the clinical implications of the phenomena Drpartmcnt of Medicine, Universitv of Newcastfc upon l’vnr and ’ Royal Postgraduate Medical School. Univrrsity of London Reprints from Dr N.A. Hoenich. Department of Medic-k, The MedIcal School, Framlington Place. Newcastle upon Tyw, NE!! 4 H H, UK

0

1986 Butterworth

8c Co (Publishers)

0141-5425/86/010003-06

$03.00

Ltd

LEUCOPENIA

Studies by Toren and Goffinet2 established that the main cause of this leucopenia was the sequestration of leucocyctes in the pulmonary vasculature, an observation recently confirmed by Dodd3. The sequestered polymorphs return to the circulation later in dialysis and account for the return of the white cell count to predialysis levels. In some instances, an overshoot leucocytosis has been observed; this is probably a consequence of the release of neutrophils from the bone marrot\t’q5. Differential counts performed during the phenomenon demonstrated that the leucopenia is due mainly to a fall in neutrophil and monocyte counts5*6. Lymphocyte counts remain stable throughout the dialysis but eosinophil counts may fall and rise in parallel with the total white count’; however, this eosinophilia is probably a result of an allergic response to a treatment specific antigen such as ethylene oxid?. COMPLEMENT

SYSTEM

ACTIVATION

Activation of the complement system occurs during haemodialysis and may be demonstrated by a fall in the total complement activity of serum (CH50), or by falls in the concentration of complement components such as C3 and Factor B. Craddock et a1.9 demonstrated that this activation of complement was a direct consequence of the

3~o~am~at~bilit~ of ~a~modia~?s~s membranes:

N.A. Hoenxh

blood membrane contact during haemodialysis. They based their hypothesis on the fact that polysaccharides whtch are similar in structure to cellulose are capable of activating complement by the alternative pathway, with depletion of both C3 and Factor B. Furthermore, they showed that contact between the plasma and the membrane releases a granulocyte aggregant (C5a) which increases the stickiness of leucocytes and causes them to adhere to the first vascular surface with which they come into contact after passing through the haemodi~yser, namely the pulmona~ capillaries.

HYPOXIA Patients receiving dialysis treatment experience a fall in arterial oxygen tension (Pao,); this fall, which occurs over the same time span as leucopenia, ranges between 5-25% lo. The onset of hypoxia is rapid, but unlike leucopenia it persists throughout treatment with the arterial oxygen tension not returning to its predialysis levels until the termination of the dialysis session.

RE~TIONSHIP BETWEEN LEUCOPENIA AND COMPLEMENT ACTIVATION A link between leucopenia and complement activation was proposed by Craddock et aI9 who suggested that complex carbohydrates, which are similar in their structure tocellulose based haemodialys~s membranes, activate the complement system via the alternative pathway. This hypothesis was formulated on the basis of clinical and laboratory evidence demonstrating that activation of complement occurs during haemodialysis in patients developing leucopenia Studies by the same group demonstrated the release of a granulocyte aggregant derived from C5 (C5a) which they suggested as being responsible for the leucopenia Chenoweth”, while agreeing with Craddock’s hypothesis, suggested that leucopenia was associated with C3a formation. Although Craddock’s hypothesis is indisputably elegant, a number of studies have cast doubt on it. Studies by Aljama’*, JonesI and De Vinuesa” have suggested that the two ph.enomena may be independent but occur simultaneously. Their disagreement with Craddock’s hypothesis stems from the fact that in their studies, no correlation between the magnitude of leucopenia and the degree of complement activation was observed Our own, as yet unpubiished, experiments studies using routine immunochernical and functional techniques, have failed to demonstrate significant changes in complement activity during haemodialysis, despite the presence of leucopenia This inability to demonstrate changes may be due to the fact that concentrations of the various complement components being measured are in a state of dynamic equilibrium. Furthermore, functional haemolytic assays are the subject of wide interassay variations due to the use of animal cells in

the technique, while immunochemical techniques using antigen antibody reactions, particularly for C3, suffer from non-specificity, since they detect not only native C3 but also the split products such as C3c and C3d. When the more recently developed radi~immunoassay techniques used for the measurement of complement fractions are performed then a correlation between leucopenia and complement activation may be demonst~ted more readily”.

THE RELATIONSHIP BETWEEN LEUCOPENI~ COMPLEMENT ACTIVATION AND HYPOXIA Craddock in his studies demonstrated that leucopenia was associated with changes in pulmonary function manifested by a rise in intrapulmonary arterial pressure, and an increase in lymph effluent from the lungs, a consequence of endothelial leakage when cellophane incubated with plasma was injected into animals. In patients they observed a fall in pulmonary diffusing capacity at 15 min, coinciding with the nadir of leucocyte fall; this fall was followed by a gradual return to normal. Based on these findings, they concluded that the most probable sequence of events was complement activation leading to neutrophil aggregation in the lungs, which results in impaired oxygen transport across the lungs and leads to hypoxia; Craf i5 and Mahajan4 supported Craddock’s hypothesis. However, there are a number of factors against this hypothesis. Firstly, the absence of any correlation between the intensity of complement activation leucopenia and the magnitude of hypoxia Reuse of haemodialysers modifies leucopenia but there is no evidence that it influences hypoxia Separation of ultrafiltration in dialysis during conventional haemodialysis modifies hypoxia but fails to influence leucopenia16. Consequently, a number of alternate hypotheses have been suggested. In the early 1970’s B&hell7 proposed that rnicroemboli resulting from the cellular debris deposited on the membrane may be’responsible. Subsequent studies by Aurigemmais who used filters smaller than the microemboli, failed to eliminate hypoxia During haemodialysis there is an increase in blood pH. Two mechanisms have been suggested whereby this alteration may affect Pao,. First, by decreasing the oxygen delivery to the tissues (Bohr Effect) and secondly the correction of acidosis induced hyperventilation might lead to a fall in is the fact that acidosis PdO*. Against this suggestion may worsen initially during dialysis and may rapidly be corrected by bicarbonate dialysis. The loss of CO* into the dialystate has been suggested as being responsible by Sherlockig; this has been supported by other published work’6*za. However, there is disagreement as to whether this

is the sole cause of hypoxia since Hakim and Lowrie2’, and more recently Hune2, demonstrated hypoxemia even when using bicarbonate, a finding that our own studies have confirmed.

9 .Z

.E

In the course of routine dialysis there is an uptake of acetate from the dialysate, the metabolism of which increases oxygen consumption and decreases CO, production; the resultant change in respiratory quotient is accompanied by hypoventilation, which, together with the increased oxygen consumption, results in hypoxia This may partially explain the observations with bicarbonate dialysis, since bicarbonate-based dialysate contains some (4-lOmEq/l) acetate.

6 #

EO-

;B =

60-

I = % .=

40-

f -

20 -

I Pre cl

I

I

30

80

I

/f ”

I

120

180

Duration of dialysis fmin)

It would therefore appear that leucopenia and lung sequestration can be followed by hypoxia, but the major causes of hypoxia during haemodialysis are multiple, with two mechanisms predominating: first, the loss of CO, through the dialyser, and, second, the increased oxygen consumption and decreased CO, production resulting from the metabolism of acetate. The inability to eliminate hvpoxia totally in the case of bicarbonate containing dialysate, may be the consequence of acetate contained in such dialysates while the role of leucocyte mediated pulmonary dysfunction, as a contributory factor, cannot be excluded. THE

ROLE

OF THE

DIALYSER

Figure 1 Haetnodialysis Irucopenia type (cellulose and tnodified cettutost 0, Cuprophan (6); 0, Ccllulate (6); -k. P < 0.05

-- influence of’ tnernbratt< tnctnbranes). A, SCE ($1; *, P < 0.001;

120-

MEMBRANE

Haemodialysis membranes in current clinical use can be divided into two categories: membranes based on cellulose and the more recent synthetic alternatives (Table I). Within the first category Cuprophan manufactured by the Cuoxam process remains the most widely used membrane. Membranes produced hy the viscose process, together with membranes produced by modification of these processes have become available. The second category of membranes includes the more recent synthetic polymer membranes that have seen a limited clinical application and include polyacrylonitrile (AN69, PAN 15), polysulphone, polyethylene vinyl alcohol (EVAL), polymethylmethacrylate (PMMA) and polvcarbonate.

O1

Pre D

I

I

30

,I

60

”

I

1

120

180

Duration of dialysis (mins) Figure 2 Haemodialvsis leucopcnia - influence of metnbrane type (cellulose and syithetic tnetnbranes). 0, Cuprophan (20); 0, PMMA (6); A, PCM (6)

Leucopenia Our results for leucopenia observed for cellulose and modified cellulose membranes are shown in z Z E

:: :

ii’ ,

PR 1530 dialysis

I

t

60

1

120 Duration

of dialysis

180 (min)

Figure 3 Haemodialvsis leucopenia influelw~ ot tncwbrartc tvpc (cellulose and svnthrtic tnetnbrat~c.s]. n , Potvsutphone; I, PAN 15; 0. Cuphphan; data shown as tnt‘atl k s.t‘.tn.

Figure I while those for synthetic membranes are shown in Fzgures 2, 3. These results demonstrate a profound leucopenia with cellulose based

I 240

possible that the differences between cellulose and synthetic membranes may lie in the surface layering or adsorption of proteins at the blood membrane interface, since studies relating to reuse of haemodialysers have demonstrated modifications on haemodialyser x-use (E~ure d), a factor which may also influence complement activation and will be discussed below.

120E z I .= .c % ap z E

loo-

ao-

60-

membranes, associated with a fall in white cells to 20% of pre-dialysis value. The magnitude of the observed changes is, however, influenced by the chemical derivative of the cellulose. Synthetic membranes, on the other hand, are associated with more modest changes in white cell counts (70-90% of pre-dialysis value).

Complement activation Studies relating to complement activation of haemodialysis membranes may be divided into two categories. Firstly, studies in which the total complement activity was studied (CH50) and secondly, studies in which complement components such as Factor B, C3, C4 and C5 levels were studied. More recently, interest has focussed on the measurement of split products, notab!y of C3 by the use of recently developed radio-immunoassay techniques. In the studies correlating the different ability of membranes to induce leucopenia with complement activation the results are conflicting - some demonstrating changes but others failing to do SO~~,‘~,*~. Our own studies have failed to differentiate between cellulose based and synthetic membranes in terms of complement levels measured by immunochemical and functional techniques. When using the more sensitive radioimmunoassays, the results obtained confirm published findings” and demonstrate major differences between cellulose and synthetic membranes (Tables 2-4).

The reason for these consistently observed differences is not clear. They may be due to a variety of factors which include the membrane’s affinity for water, its surface change, the method of sterilisation and hydraulic permeability. It is also

In parallel with the observations for leucopenia on re-use, Chenoweth et al24 demonstrated a diminishing C3a antigen formation indicating an abatement of this phenomena by repeated blood exposure.

z 7I 0 z 5

40-

20-

OL I

I

I,

t

30

Pre. D

60

I

I

180

120

”

Duration of dialysis (min) Figure 4 Haemodialysis leucopenia - influence of membrane treatment on reuse when using reverse osmosis (RO) water wash. 0, First use (20); A, third use j12); 0, sixth use (5); a:;. P< 0.001

Table

2

Normalised

values

for cellulosic

membranes

routine

immunochemical

assays

Mrnlhranc

7

CH50

Cuprophdn (61

15 60 240

83.8 + 18.3 94.1 + 13.9 104.9 f 15.1

94.1 + 14.0 96.5 f 32.4 95.8 f 25.6

82.9 + 6.4 92.5 f 14.2 92.5 k 8.3

SCE (61

15 60 240

93.1 f 14.0 97.4 * 11.1 101.8 + 15.3

106.1 f 15.2 102.4 IL 15.2 99.3 f 14.1

77.0 + 15.9 105.7 f 57.6 110.7 + 81.2

All data pwsrrned

Table

3

Membrane

as % of prr-dialys

Normalized

values 1.

valur

Alternatr

and rxpresscd

for synthetic

membranes

Pathway

as rncan and standard

routine

C3

Altcrnatr

B

77.0 + 99.5 + 96.7 +

8.7 25.0 14.9

79.4 + 18.4 116.4 z!z 83.9 123.0 t 110.2

deviation

immunochemical

CH50

Factor

Pathway

assays c3

Factor B

AN69 16)

15 60 240

139 f 9.5 100.9 f 5.5 94.8 f 7.8

91.0 f 12.0 87.9 f 16.6 106.3 f 24.3

86.6 + 28.5 79.1 + 13.2 78.1 f 6.2

86.2 k 31.2 76.8 + 12.7 76.3 + 8.8

PCM 161

15 60

87.1 f 9.5 96.8 f 5.5

120.1 * 27.9 115.8 IJZ44.9

89.2 f 9.3 99.4 f 16.1

83.7 + 6.1 102.9 + 10.2

PMMA (4)

15 60

87.9 k 9.6 93.5 + 5.5

110.1 f 30.6 99.4 f 21.1

86.2 k 21.8 93.3 + 10.8

87.4 f 23.0 92.5 f 14.0

Figuws in parentheses rrfer t
6 J. Bionwd.

Eng. 1986, Vol. 8, January

as nwan

and standard

deviation

CLINICAL IMPLICATIONS OF LEUCOPENIA COMPLEMENT ACTIVATION AND HYPOXIA

Op2~~ I Pre dialysis

I 15

L

30

I

I

I

60

120

I

180

240

Duration of dialysis IminI

Hypoxia The effect of membrane type of hypoxia has received little attention. Hakim and LowriP’ studied the changes in PO2 for Cuprophan, polvacrvlonitrile and polymethylmethacrylate; they obs>rvhd no statistical difference between the fall for non-cellulosic membranes which were diminished compared to cellulose acetate; Jacob et alz3 failed to distinguish between the hypoxia caused by synthetic and cellulose based membranes. Our own studies of PaOi changes for Cuprophan and two synthetic membranes PAN15 (Asahi Medical), and polysuphone ( Fresenius Ag) are shown in Figure 5. When using Cuprophan patients experienced a rapid fall during the first 15 min and the value of Pao2 remained below predialvsis level at 60 min. With PAN15, PdO? was d&eased only at 15 min, while polysulphone membrane failed to produce significant changes at any of the sampling times compared to pre-dialysis value. 111addition to the measurement of hypoxia induced bv different membranes, interest has also focussed 011 the measurement of changes in lung function induced by treatment. The parameter studied has been carbon monoxide diffusing capacity (11, CO) an indicator of the gaseous exchange across the alveolar membrane. The magnitude of changes in this parameter during haemodialysis are shown in Figure 6, and show impairment of carbon monoxide diffusing capacity even with more bio-compatible (or less neutropenic) membranes.

The clinical implications of these phenomena and their long term consequences are far from clear. Leucopenia is associated with functional changes in ncutrophils, such as chemotaxis, phagocytic abilitv, decreased random mobilitv and an increased adhcrencP5~28. The clinical implications of complement activation observed during haemodialysis have received little attention. However, in a recent publication by Hakim and colleagueP9 in which they studied complement activation in patients with and without ‘first use’ syndrome in Cuprophan containing haemodialysers they demonstrated an association between the level of complement activation as measured by C3a and adverse allergic reactions experienced during treatment. Hvpoxia during haernodialysis may be ameliorated bi the use of a more biocompatiblc membrane or bL the use of cellulose based membranes in c&njunction with bicarbonate based dialvsate or by the use of prostacyclin 3o. Long term lunff pathology related to the effects of dialysis in chronic renal failure has been the subject of two sludies by Let rt aPI and Wolf et af’* who demonstrated that the lung function of patients undergoing dialysis for chronic renal failure are abnormal in two major respects. Firstly, they often show restrictive ventilatory changes due to the possible fibrotic

f B .+ 2 H B h

o-

-20

Cuprophan (n = 8)

Biocompatibdity of Haemodialysis

membranes: N.A. Hoenich

changes within the lung, and secondly, there is a general decrease in the carbon monoxide diffusing capacity of the lung which is attributed partly to anaemia and to an increase in the resistance of the alveolar membrane to gaseous diffusion. Whether these changes are a consequence of the repeated exposure to complement activated leucocytes has yet to be established.

11

12

13

In conclusion, although cellulose based membranes have been in clinical use for well over twenty years and there are surviving patients who have received over 3000 dialyses and in turn have been exposed to leucopenia and hypoxia on each occasion without apparent ill-effects, the clinical significance of the phenomena have yet to be more fully understood and should receive further study. At the present time, however, there is still a considerable cost difference between synthetic and cellulose based membranes and in view of this, it would seem unreasonable to suggest a changeover for the majority of patients on the basis of the differences in biocompatibility. However, in deciding treatment regimes for specific groups of dialysis patients such as the elderly, patients who have experienced hypersensitivity or allergic reactions to cellulose based membranes as well as those with co-existing cardio-vascular or pulmonary complications the factor of biocompatibility should be given serious consideration.

20

ACKNOWLEDGEMENTS

21

We should like to thank the Scientific Research Committee of the Newcastle Health Authority for financial support.

14

15

16

17

18

19

22 23

REFERENCES Kaplow, L.S. and Goffinet, J.A. Profound neutropenia during the early phase of haemodialysis. J.A.M.A. 1968, 203, (13). 133 2 Town, M., Coffinet, J.A., Kaplow, LS. Pulmonary bed sequestration of neutrophils during haemodialysis. Blood 1970,3, 337 3 Dodd, N.J., Gordge, M.P., Tarrant, J., Parsons, V., Weston, M.J. A demonstration of neutrophil accumulation in the pulmonary vasculature during haemodialysis. Proc. Eur. Dial Transplant Assoc. 1983, 20, 186 4 Mahajan, S., Gardiner, H. De Tar, B. Desai, S., Muller, B., Johnson, N., Briggs, W., McDonald, F. Relationship between pulmonary functions and haemodialysis induced leukopenia. Trans. Am Sot. Artij Intern Organs, 1977. 23, 411 5 Dumler, F., Levin, N. W. Leukopenia and Hypoxemia Arch Int. Med 1979, 139, 1103 6 Savdie, E., Bruce, L, Vincent, P.C. Modified neutropenic response to reused dialyzers in patients with chronic renal failure. Clin Nephrol 1977, 8 (4), 422 7 Novello, A. C., Port, F. K. Haemodialysis eosinophilia Int J. Artif Orgns. 1982, 5 (1). 5 8 Marshall, C., Pearson, F., Segona, M., Lee, W.. Dolovich, J. Reactions during haemodialysis due to allergy to ethylene oxide gas sterilization. Unpublished observations. 9 Craddock P.R., Hammerschmidt. D., White, J, G., Dalmasso, A. P., Jacob, H.S. Complement (C5a)-induced granulocyte aggregation in vitro. J. Clin Inust. 1977, 60, 260 10 Vaziri, N. D. Dialysis-induced hypoxemia In/. J Artif Organs. 1982, 5 (l), 8 1

85 Bionled. Eng. 1986, Vol. 8. January

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Chenoweth, D. E., Cheung, A.K., Henderson, L.W. Anaphylatoxin formation during haemodialysis: Comparison of Cuprophan with polyacrylonitrile membranes. Kidney Int 1983, 24, 764 Aljama, P., Bird, P.A.E., Ward, M.K., Feest, T.G., Walker, W., Tanboga. H., Sussman, M., Kerr, D.N.S. Haemodialysis-induced leucopenia and activation of complement Effects of different membranes. BOG. Eur Dial Transplant Assoc 1978, 15, 144 Jones, R.H., Broadfield, J.B., Parsons, V. Arterial hypoxemia during haemodialysis for acute renal failure in mechanically ventilated patients: observations and mechanisms. Clin Nephrol 1980, 14 (l), 18 De Vinuesa, S.G., Resano, M., Luno, J., Gonzalez, C., Barril, G.. Junco, E., Valderrabano, F. Leucopenia, hypoxia and complement activation in haemodialysis, three unrelated phenomena hoc. Eur. Dial Transplant Assoc. 1982, 19, 159 Graf, H., Stummvoil, H.K., Haber, P., Kovarik, J. Pathophysiology of dialysis related hypoxaemia Proc. Eur. Dial Transplant. Assoc. 1980, 17, 155 Kraut. J., Gafter, U., Brautbar, N., Miller, J., Shinabergei, J. Prevention of hypoxemia during dialysis by the use of sequential isolated ultrafiltration-diffusion dialysis with bicarbonate dialyzate. Chn Nephrol 1981, 15 (4), 181 Bischel, M.D., Orrell, F.L. Stoles, B.C., Mohler, J.G., Barbour, B. H. Effects of microemboli blood filtration during haemodialysis. Trans. Am Sec. Art@. Intern Organ 1973, 19, 492 Aurigemma, N.M., Feldman, N.T., Gottlieb, M., Ingram, R H., Lazarus, J. M., Lowrie, E.G. Arterial oxygenation during haemodialysis. N. Engl J Med 1977, 297 (16), 871 Sherlock_ J. E., Ledwith, J.E., Letteri, J.M. Hypoxemia during dialysis. N. Engl J. M ed 1977, 297 (lo), 558 Nissenson, A. R Prevention of dialysis-induced hypoxemia by bicarbonate dialysis. Trans Am Sot. Art$ Intern Organs. 1980, 26, 339 Hakim, R M., Lowrie, E.G. Haemodialysis-associated neutropenia and hypoxemia: The effect of dialyzer membrane materials. Nephron, 1982, 32, 32 Hunt, J.M., Chappell, T.R., Henrich, W.L, Rubin, LJ. Gas exchange during dialysis. Amer. J. Med 1984, 77, 255 Jacob, A.]., Gavellas, G., Zarco, R., Perez, G., Borgoignie, J.J. Leukopenia, hypoxia and complement function with different haemodialysis membranes. Kidney Int. 1980, 18, 505 Chenoweth, D.E., Cheung, A.K., Ward, D.M., Henderson, L W. Anaphylatoxin formation during haemodialysis: Comparison of new and re-used dialyzers. Kidney Int. 1983, 24, 770 Lespier-Dexter, LE., Guerra, C., Ojeda, W., MartinezMaldonado, M. Granulocyte adherence in uremia and haemodialysis. Nephron. 1979, 24, 64 MacGregor, RR. Granulocyte adherence.changes induced by haemodialysis, endotoxin, epinephrine and glucocorticoids. Ann Intern. Med 1977, 86, 35 Ringoir, S., Van Looy, L, Van de Heyning, P., LerouxRoels, G. Impairment of phagocytic activity of macrophages as studied by the skin window test in patients on regular haemodialysis treatment. C/in Nephrol 1975, 4 (6). 234 Bjorksten, B., Mauer, S.M., Mills, E.L, Quie, P.G. The effect of haemodialysis on neutrophil chemotactic responsiveness. Acta Med Scard 1978, 203, 67 Hakim, RM., Breillatt, J., Lazarus, J.M., Port, F. K. Complement activation and hypersensitivity reactions to dialysis membranes. N. Engl J Med 1984, 311 (14), 878 De Broe, M.E., De Backer, W.A., Verpooten, G.A., Vermeire, P.A, Van Waelegham, J. P., Herman, A. G. Leucopenia and hypoxemia during haemodialysis with different membranes: Effect of prostacyclin. Contr Nephrol 1983, 36, 26 Lee, H.Y., Stretton, T. B., Barnes, AM. The lungs in renal failure. Thorax, 1975, 30, 46 Wolf, A., Kummer, F., Dorda, W. et al. Renal failure and carbon monoxide diffusing capacity of the lung. Wzen Olin Wochenschr 1979, 91, (6). 189