|Year : 2000 | Volume
| Issue : 3 | Page : 315-324
|Plasmapheresis: Indications and Techniques
Department of Nephrology and Rheumatology, Heinrich-Heine-University, Duesseldorf, Germany
Click here for correspondence address and email
|How to cite this article:|
Schneider M. Plasmapheresis: Indications and Techniques. Saudi J Kidney Dis Transpl 2000;11:315-24
In 1976, Lockwood et al and Jones et al first described the therapeutic use of plasmapheresis in systemic lupus erythematosus (SLE) and other autoimmune diseases. , Aimed at eliminating circulating immunecomplexes (IC), plasmapheresis was one of the first pathophysiologically based concepts.
Since that time, numerous studies have been published documenting the benefit of plasmapheresis in acute situations of systemic autoimmune diseases and a number of other diseases. With more than 20 years experience, plasmapheresis and other extracorporeal therapies, e.g. immunoadsorption and leukapheresis, are now fairly old therapeutic options, but the discussion about their value is still ongoing. The reasons are multiple; one major obstacle is that important pathogens and therapeutic targets have been defined in only a small number of disorders. Also, the general therapeutic options of autoimmune diseases have improved and only few indications seem to be open for extracorporeal treatments.
Randomized, prospective, controlled trials are considered as the gold standard to verify the efficacy of any therapy. If this is the threshold to be overcome by plasmapheresis, the conclusion would be, as stated by Lewis in 1992 for SLE, that plasmapheresis is ineffective.  In his randomized, controlled, unblinded trial, 84 patients with severe lupus nephritis were treated either with a standard regime of prednisone and cyclophosphamide alone or in combination with plasmapheresis. At a mean follow-up of 136 weeks, no siginificant difference could be detected between the two groups for the outcome parameters namely, renal failure and survival. This result is in good agreement with earlier controlled trials using plasmapheresis in SLE. We found no clinical efficacy of plasmapheresis in mild SLE,  and the French study group reported little benefit in the first two years of observation.  Wallace analyzed from his data that only patients who underwent plasmapheresis came to remission,  but with only 17 patients in the controlled trial, the number was too small for statistical analysis. In addition, the not yet completely published LPSG study using synchronization of cyclophosphamide bolus with or without plasmapheresis in severe lupus found no difference between the two groups. 
The conclusion of these studies has to be that there is no need to treat SLE patients with plasmapheresis, since it provides no significant effect and is a rather high-risk, and expensive method. The long list of case reports and uncontrolled trials with good responses fails to give convincing evidence of the value of plasmapheresis, although the approximately 70% responder rate in lupus nephritis and acute flares suggests quite a good overall effect.
Although controlled trials in other autoimmune diseases came to similar conclusions,  extracorporeal treatments offer some major advantages that should be used at the proper time and for appropriate indications. The rationale for use of plasmapheresis and immunoadsorption is given by the basic principles of extracorporeal treatments, which are most intensively investigated in SLE, the prototype of human diseases mediated principally by IC. Depending on their composition, IC are formed in circulation or in situ. Under physiological conditions, they will be cleared by the reticuloendothelial system (RES). In SLE, an impaired RES function and/or the hyperproduction of antibodies may lead to their accumulation and cause organic damage.
Plasma contains the circulating type of IC, other immunoglobulins, complement, autoantibodies, cytokines and soluble adhesion molecules. With plasmapheresis, these proinflammatory substances can be removed from the intravascular space [Figure 1]. This effect is exemplified even in the Lewis study.  Plasmapheresis was performed three times weekly for four weeks, with three or four liters of plasma being exchanged each time. By six weeks, both anti ds-DNA antibodies and whole IgG serum concentrations were more distinctly reduced in the plasmapheresis group than in the standard group. Accompanied by immunosuppressive therapy as in this study, three weeks after completing plasmapheresis, IgG concentrations increased to values found in the standard group, indicating some regulatory events after plasmapheresis. These consequences were already described in early studies by Jones, who showed that plasmapheresis is more effective in combination with immunosuppression and that relapse of disease activity will occur in every SLE patient without such treatment. 
The increase in serum antibody concentration after plasmapheresis is, at least in part, caused by de novo synthesis of antibodies, because cellular components of the immune system are not directly affected by plasmapheresis. Other regulatory mechanisms include redistribution from tissue into the vascular space and the effect of plasmapheresis on IC clearance by the RES [Figure 1]. From very early studies using plasma-pheresis, it is known that in some cases the reduction of the serum autoantibody concentration was higher than expected from the volume exchanged. In addition to the direct effect of antibody removal, a nonspecific deblockade of the RES by plasmapheresis was supposed.
Low and colleagues confirmed this nonspecific clearance of the RES in patients with clinical improvement only.  This indirect effect of plasmapheresis may contribute to the efficacy of this focus of treatment.
The benefit of plasmapheresis is also influenced by the substitution fluid. Plasma-pheresis is unselective removal of all plasma proteins. Only very few of the removed substances are pathogenic, and something benefical that counteracts the process of immunologically mediated tissue injury, e.g. complement, may also be removed. This was exemplified by the deterioration caused by plasmapheresis of a patient with C 2 deficiency, described by Parry in 1981.  It may also be concluded from better results obtained with plasmapheresis using fresh frozen plasma instead of albumin as substitution. Also, clinical responses lasted longer when fresh frozen plasma was used.
Thus, there are at least two effects of plasmapheresis; but how can antibody removal and enhanced RES clearance be used to help patients? To answer this question, one has to look at the regulatory events induced by plasmapheresis, at the indications of extracorporal methods and, at side effects.
The list of possible side effects is long. They may be related to the substitution fluid, e.g. the risk of virus infections from fresh frozen plasma; to technical problems, e.g. venous access; and to intercurrent diseases. Only 3% of patients treated with plasmapheresis will develop serious complications.  Pohl reported in the 86 patients of the Lewis study, no increased risk of infection in the plasmapheresis group.  Hamblin described 11 patients treated up to 309 times during up to 75 months without severe side effects.  Singer observed that bacteremia occurred only in patients that were also under immunosuppression.  The negative experiences of the Vienna group are unique.  Most of the retrospectively evaluated negative effects in patients treated with plasmapheresis are not timerelated to the treatment and may only document the severe illness of those patients. In general, plasmapheresis is safe, specially in compa-rison with immunosuppressive drugs used in systemic autoimmune diseases.
With plasmapheresis, some of the best results are found in patients with immune thrombocytopenic purpura (ITP). In our own studies,  we observed the same response of hemocytopenias in SLE patients. This may be due to the direct effect of plasmapheresis on the intravascular space, where these antibodies are pathogenic. Another reason for this effect on thrombocytes and other blood cells is that these cells are continuously replicated, as are skin cells and mucosal cells. Therefore, whenever anti-thrombocytic antibodies are removed, a favorable response will be induced. In addition, the obvious clinical signs of ITP, purpura and probably bleeding, will force us to treat very early in the course of the disease, whereas in SLE and vasculitis, other internal organ manifestations, such as nephritis, are the usual indications for extracorporeal treatment. It is not rare for involvement of these organs to have lasted some months before it is clinically manifest. In contrast to blood cells, glomerular cells are non-replicating cells. Therefore, chronic damage is related to poor outcome as known from histological evaluation of kidney biopsies in lupus nephritis. The best predictor of poor outcome is a chronicity index greater than one.
The patients in the Lewis study  were stated to have had severe nephritis at entry, with the criterion for "severe" denoted by a mean serum creatinine level of >180 µmol/L. The accompanying editorial claimed that this is precisely the group that clinicians consider treating with plasmapheresis.  But this is precisely the group where non-responsiveness can be predicted, because the patients in this study had "chronic", rather than "severe" nephritis. In the plasmapheresis group, the mean duration of nephritis was 16 months at study entry; in 71 patients from the whole group the chronicity index was already two and higher.  But, as expected in such a group of patients, even if plasmapheresis did reduce locally deposited immune complexes, most of the cells were already damaged.
So, if plasmapheresis is used in organic manifestations like nephritis, patients have to be treated very early to prevent organ failure. This, in my opinion, is a must, but there are only few studies to confirm this hypothesis. In 1986, Fossela and colleagues described four patients with diffuse proliferative lupus nephritis treated with plasmapheresis. The best responder was the patient with the shortest duration of nephritis. Despite the fact that this patient was not given any immunosuppressive drugs in addition to plasmapharesis, her kidney function normalized; whereas, the other three patients with a duration of diseases of at least six months showed only slight improvement. We observed the same in six patients subjected to immuno-adsorption. 
It is obvious that plasmapheresis is most effective in diseases with more intravascular circulating IC and with a limited amount of continuously synthesized antibodies. However, there are examples suggesting that the efficacy of plasmapheresis is not restricted to the intravascular space. The best results are obtained in diseases with a temporally limited antibody production, e.g. in Guillan-Barre syndrome and Goodpasture syndrome. Pusey and colleagues listed a great number of patients with the anti-glomerular basement membrane (GBM) induced disease,  in whom plasmapheresis is a generally accepted therapeutic option. They divided the patients into three groups depending on their kidney function at onset of therapy. In 75% of patients not needing dialysis at that point, the kidney function could be preserved by plasmapheresis. In contrast, in 85% of patients who were under dialysis at therapy onset, no benefit from plasmapheresis could be detected.
These data may indicate that the actual kidney function is the predictor of efficacy when plasmapheresis is used in cases of glomerulonephritis. But the same group also published the results of treating patients with rapidly progressive glomerulo-nephritis with plasmapheresis, and in this group the response to plasmapheresis was independent of the kidney function at therapy onset.  These results first indicate that plasmapheresis is of some benefit in glomerulonephritis, but the benefit is not directly and exclusively dependent on the kidney function at therapy onset. There must be other parameters that determine the efficacy of plasmapheresis, e.g. avidity and affinity of the autoantibodies causing tissue damage. In SLE, for example, we have five different forms of nephritis and only one antibody known to be pathogenically important. So we are really moving in a black box and the effect of plasmapheresis on injury-inducing high affinity ds-DNA antibodies is uncertain.
Experiments performed with radioimmuno-imaging of malignant tumors may give some idea of the influence of antibody removal from plasma on the antibody concentration in tissues. Noorgren used a nude rat model to calculate the adsorbed dose of a monoclonal antibody after simulated extracorporeal immunoadsorption.  The used antibody was specific for a surface glycoprotein of human melanoma cells, which is found only in trace amounts in normal tissue. The immunoadsorption removed 90-95% of the antibody in the blood. For heart, liver and lung, this resulted in an increased outflow of radioactivity, while for the tumor and for the lymph nodes, activity decreased only moderately. Transferring these data to our in vivo situation, where we reduce the plasma concentration to only 40% by plasmapheresis, the real reduction rate of antigen bound high avid autoantibodies might be down to 5%.
This mild reduction might, on the other hand, induce the so-called rebound phenomenon. Beginning with the first experiences with plasmapheresis, the rebound phenomenon is omnipresent. It might be induced by re-exposition of antigens induced by antibody removal, by an antigen excess in IC or by an activation of B-cells through withdrawal of anti-idiotypes.
Terman and colleagues studied the antibody rebound in dogs actively immunized to bovine (BSA) and human serum albumin.  Using a BSA collodion charcoal, they reduced the BSA antibody titer to about 25%. The post immunoadsorption antibody response, a rise of up to 100% in about eight days, was described as antibody rebound. The control antibody was unchanged during this period, and antibody rebound could be suppressed by various immunosuppressive drugs. In this system, immunoresponse was antigen driven, which is not clear in systemic autoimmune diseases, and a circulating antibody was reduced. From the data given, it can be concluded that there is no redistribution from tissues in this experiment. From response time and from reduction by immunosuppression it is clear that the socalled rebound depends at least in part on biosynthesis of antibodies, which is obviously induced by removal. Another effect of antibody reduction is a delayed catabolic clearance of IgG. 
Treating SLE patients with immunoadsorption and monitoring anti ds-DNA antibodies gives another situation in Terman's model, which was documented by Suzuki and colleagues.  They reduced more than 50% of antibodies from four liters of plasma without any significant reduction of antibody titer in serum. This is an outcome of the desirable redistribution of antibodies from tissues. These nearly unchanged serum and, as discussed above, tissue concentrations will not induce a rebound phenomenon. To induce a B-cell reponse, the antibody level has to be decreased to below a level at which antibody/antigen complexes dissociate and the antigen is available. Rebound phenomenon is only one kind of response to antibody removal. If only a small portion of an antibody is reduced, the response will not exceed the titers before treatment and, if no antigen is present, the result of plasmapheresis will be a clear reduction of antibody titer.
In SLE, both active and inactive, B cells are already stimulated.  There is no further reponse to pokeweed mitogen *(PWM) stimulation in vitro on the number of plaque forming cells (PFC). After plasmapheresis the number of spontaneously activated PFC decreases to normal values and are found to have a good response to PWM stimulation. These data are in contrast to the situation that was expected in the so-called Kiel protocol.  The results of the original B protocol using high volume plasmapheresis and high dose cyclophosphamide are really excellent. A high number of patients treated with this protocol were in no need of further therapy after six months, although their illness was life-threatening at study entry. But in the multicenter trial, this protocol had to be stopped because of severe side effects. In the A protocol, intravenous (i.v.) cyclophosphamide was used with or without plasmapheresis in severe lupus with no significant difference.  However, it seems difficult to document a benefit of plasmapheresis in an indication where cyclophasphamide is already effective in more than 80% of patients. 
In general, extracorporeal therapies are too resource-intensive to be used just instead of a proven medication. But because plasmapheresis and immunoadsorption are safe treatments, they may be performed especially in young patients to prevent the need for drugs like cyclophosphamide and are helpful in situations in which immunosuppressive drugs are not tolerated or are contraindicated, e.g. with severe infections. In addition, extracorporeal treatments may be indicated to reduce application of long-term highdose steroids to avoid late morbidity. Use of immunoadsorption instead of plasmapheresis will further increase the safety of the intervention. Except in situations where the therapeutically important step is plasma exchange and substitution, e.g., in thrombotic thrombocytopenic purpura, immunoadsorption is no real alternative to plasmapheresis.
The great advantage of immunoadsorption is the more selective removal of pathogenic agents like antibodies, which allows more intensive perfusion and thus, a more significant reduction of the pathogen. This opportunity is especially given with regenerable colums, e.g., Ig-Therasorb® and Protein A. The specificity of immunoadsorbers implies that not every pathogen is bound by any one adsorber [Figure 1]. This is especially problematic if the pathogenic substance that should be removed is not known with certainty, which is the situation in most systemic autoimmune diseases.
This disadvantage is overcome by using adsorbers that bind all antibodies. [Table - 1] lists known binding profiles of available colums; their importance in the removal of cytokines and adhesion molecules is not yet clarified but is an important question for further investigations.
Because of their anti-DNA antibody binding capacity, Dextran Sulfate (DS) columns are mostly used in SLE patients. , In one patient with the anti-phospholipid syndrome, DS immunoadsorption was used during pregnancy. In lupus, synchronization with i.v. cyclophosphamide offered no advantage during a short follow-up despite a more rapid decrease of anti-DNA antibody.  For long-term outcome of lupus patients, the LDL-binding effect of DS adsorbers may also be important.
We have more experience with IMPH-350 columns in the treatment of SLE. A total of 39 out of 50 SLE patients who were treated three times with IMPH-350 showed a significant clinical improvement which was maintained for up to six months.  In lupus nephritis, only six out of 11 patients showed a significant clinical improvement which was significantly related to the duration of nephritis. Because of its hydrophobic interaction with IC, IMPH-350 may be helpful in certain situations such as hepatitis associated systemic manifestations. 
Protein-A immunoadsorption has been described in case reports as being successful, in combination with a complex therapy with cyclophosphamide and steroids, in SLE.  Some positive results with Protein-A immuno-adsorption in primary vasculitis patients demand more controlled investigations. , In eight out of nine patients, ANCA levels decreased to normal values followed by a clinical response as well as biopsy-proven inactivation of glomerulonephritis. More extensive removal by higher volume immuno-adsorption should further improve outcome in anti-GBM antibody syndrome because of the pathogenic importance of anti-GBM antibody. But this is not confirmed by some preliminary results. With Immunosorba Protein-A® , two patients showed an unchanged anti-GBM antibody titer despite a marked reduction in whole IgG, whereas another patient improved significantly after unsuccessful plasmapheresis. , The clinical value of real specific binding columns of antibodies against NC1 fragment of collagen type IV has to be tested.
The importance of the controlled trial using Prosorba® columns in rheumatoid arthritis is not yet clear because of the early interruption of the prospective study due to superiority of the verum arm. With IgTherasorb® , a first controlled trial of immuno-adsorbers was performed on 20 SLE patients. 
Only one patient failed to respond; antiDNA-antibody titer was reduced by about 40% after the first, and by 50-60% after the third treatment. Perfusion of higher volumes (60-80 liters) in five other patients revealed no higher susceptibility to infections but allowed a more pronounced reduction of specific antibodies. In two patients with pANCA-antibody associated vasculitis, IgTherasorb® perfusion led to the expected antibody reduction and to some clinical improvement [unpublished data]. Very recent data indicate that both Ig-binding columns are helpful in treating relapsing nephrotic syndrome after kidney transplantation. 
In conclusion, less than 3% of patients suffering from severe systemic autoimmune diseases today are treated with extracorporeal therapies in Japan.  In other countries, the frequency will be even lower. However, the rate of use of these forms of therapy has been increasing since the early 90s.  Nevertheless, more than 30 years of use in clincal practice has failed to answer most questions concerning indications and efficacy of extracorporeal therapy in patients with systemic autoimmune diseases. This is because extracorporeal therapy is often performed in addition to immunosuppression in life-threatening situations, an indication that can never be evaluated in controlled trials.
The best response to extracorporeal treatment may be expected in diseases with circulating antibodies causing damage to a frequently regenerated target, e.g. ITP, where immunoadsorption is less expensive and more effective than initial treatment with splenectomy.  The same situation is found in inhibitor-associated hemophilia A and B.  In other situations, efficacy is influenced by the ability to remove organ bound pathogens and by the degree of already induced irreversible damage. The nature of kidney involvement in various diseases are the best examples of the variability of the responses. As known from histological investigations of lupus nephritis, chronicity is the best predictor of a poor outcome, and data recorded by Lewis and by ourselves confirm that extracorporeal therapy may not influence a late situation. A similar course is found in anti-GBM syndrome where dialysis dependency cannot be overcome by plasma exchange. But plasmapheresis and immunoadsorption are helpful in rapidly progressive glomerulonephritis (RPGN) by shortening the time of pathogenic action and the need for high steroid dosages.
These results demand an early intervention with extracorporeal therapy in such situations. Data documented in compensated RPGN probably indicate that plasma exchange or immunoadsorption may offer an opportunity to reduce the cumulative dosage of cyclophosphamide or even better, to avoid it. Because the outcome of patients with systemic autoimmune diseases is mainly influenced today, by the short-term (e.g. infections) and long-term side-effects (e.g. carcinogenic potential) of immunosuppressive drugs, the use of extracorporeal therapies may further improve the outcome and quality of life in these patients. This hypothesis invites long-term follow-ups, though these are complicated by the small numbers of patients with very heterogenous disease expression.
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Department of Nephrology and Rheumatology, Heinrich-Heine-University Duesseldorf, Moorenstr. 5, D - 40225 Duesseldorf
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