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Therapeutic Apheresis: Why?

2015; Wiley; Volume: 19; Issue: 5 Linguagem: Inglês

10.1111/1744-9987.12353

1744-9987

Paul S. Malchesky,

Dialysis and Renal Disease Management

My attendances at the European Society for Artificial Organs in Rome, Italy in 2014 and more recently at the International Society for Apheresis Congress in Cancún, Mexico in May 2015 and the American Society for Artificial Internal Organs in Chicago in June 2015 have indicated to me that “much is new but nothing is new”. By this I mean that in science and particularly in clinical medicine, progress is made in small incremental steps and at times it is difficult to see the “newness”. In looking back over the past 30–40 years in therapeutic apheresis, this is particularly true. In 1980 my group at the Cleveland Clinic presented on and published the paper “Macromolecule Removal from Blood” 1. In this paper we made the case for the presence for macromolecules in various diseases that if they could be removed from the blood, the symptomology and signs of the disease could lessen with the hope that a cure could be effected. The knowledge accumulated for over 70 years in the use of dialysis for the treatment of renal failure has proven contrary to what most would have expected. A simple technology, hemodialysis with membranes permeable to molecules typically less than 10 000 Daltons and more so less than about 5000 Daltons, has proven to be lifesaving for some patients for decades. Dialysis is not perfect, far from it, as patients on dialysis live a non-ideal life with treatment required several times weekly and they continue to have various organ system issues. In renal failure various chemistries are abnormally present including the presence of toxins, as metabolic by-products, electrolytes, and the buildup of fluid that cannot be removed in the absence of kidney function. Dialysis was chosen to treat this condition because it is the most practical means despite its various limitations. Research continues today to improve on the process of removing the molecules believed to be related to the signs and symptoms of the disease such as evaluating more permeable membranes and assessing processes that are better representations of the actual detoxification process of the natural kidneys, but still without providing the other physiological functions that the natural kidneys perform. Should the rationale of solute removal from blood apply to other disease states? What abnormally high values of blood chemistries exist in other disease states? Are the excess solutes causative of their signs and symptoms? Could the removal of these solutes improve the symptomology of the disease state and possibly effect a cure? How can one remove these solutes? By the late 1970s a number of disease states with elevated blood solutes were already being treated by plasma exchange 1 including those in neurology, rheumatology, nephrology, hyperlipidemias/cardiology, oncology, hematology, gastroenterology, toxicology and others. For some diseases the specific plasma solutes causative of the disease symptomology were not even known despite clinical improvements. For other diseases therapeutic plasma exchange appeared to be non-scientific to some and did not gather much support. Some clinicians persisted and for a small number of disease states the benefits were shown. In general, evidence-based studies have shown for select disease states that apheresis is beneficial or medically necessary. However, for a larger number of disease states definitive studies are not yet supportive. As with medical technologies that are invasive and costly, they are used only as a last resort and therapeutic apheresis falls into this category. Recently I have reviewed various publications and constructed Table 1, which outlines immunologic and metabolic diseases, some common symptoms, and most probable causative agents in these diseases. I do not believe this table is complete but it is very striking that so many disease states exhibit the presence of abnormal levels of macromolecules. For some of these disease states, clinical studies have shown the benefits of removing these solutes and/or cells. For some, apheresis has been shown to be lifesaving and cost effective. In the United States and various European and Asian countries, governments have approved reimbursement of therapeutic apheresis for select diseases. For example, in the United States Medicare has approved payment for a group of 18 disease states 2. Private insurance programs 3, 4, at least in the United States, approve a broader range of disease states that they recognize as medically necessary, likely because of the cost-effectiveness that therapeutic apheresis can provide. Cell and plasma separation from whole blood are the first line approaches in therapeutic apheresis therapy. Centrifugal technologies for cell and plasma separation and later (late 70s to early 80s) membrane technology for plasma separation was recognized as applicable. Plasma separation requires replacement of the essential and important plasma proteins and other plasma solutes. The disincentives for plasma exchange include the requirement for plasma products for infusion, availability of plasma products, possible contamination of infusion solutions as by viruses and prions or reactions thereof, possible adverse effects to the infusion of foreign biological proteins, loss of plasma solutes and cells, and the potential loss of essential plasma constituents. These disincentives have pushed researchers and companies to develop technologies to substitute for cell and plasma replacement products. It is most notable that in the late 1970s, the Europeans and Japanese in particular focused on the development of alternatives to simply discarding the blood components. This was for the practical reason that biological product replacements, in particular plasma and its constituents, were either unavailable or very costly. The researchers and industries embarked on the development of technologies as plasma fractionation membranes and sorbents for the more selective or specific removal of plasma solutes and select cell removal. Reconsider the use of hemodialysis for solute removal in renal failure. The history of use shows that the non-selective approach of not targeting the removal of a single or specific class of solutes, although imperfect, has proven to be life sustaining. Researchers for decades have argued over topics such as the toxicity of small molecules as urea, the importance of removing “middle molecules”, the imperfect permeability of dialysis membranes for solute removal, and other related issues. It can be argued that if the solutes in blood exist at abnormal concentrations then the normalization of their values are beneficial. The application of dialysis for renal failure where multiple chemistries are abnormal has proven to be effective. This author's own studies and review of the literature in specific cases also suggest that a non-selective approach would be preferred in most situations. Of course, the removal of all solutes as in plasma exchange is the most non-selective approach, but the limitations as noted above need to be considered. A further commercial consideration is if a technology is designed too specifically it will be more expensive to produce and the market will be limited. In select disease states (Table 1) investigators have identified multiple solutes that may preclude the use of a very selective technology. Table 2 outlines various commercial technologies for treating disease states in a more selective way. This listing is likely not comprehensive and some technologies may be missing. This table does not include those technologies that are no longer available or technologies studied but without a commercial offering at present. In particular, most technologies for online treatment are not available in the United States 2, 5 making me note on numerous occasions over the past years that in the United States we are “product-poor”. For new medical technologies there is the reluctance to apply it without extensive clinical trials, and where possible the trials should be double blinded. That has been the case for apheresis. The spread of the applications has been possible because for some disease states and patient conditions there are no other alternatives. In many cases standard drug therapies have failed and the plasma and cell abnormalities are multiple. As in the case of immunologically related disease states, immunosuppressive drugs are prescribed to decrease the production of antibodies, but even with drug therapy there are a percentage of the patients in whom pharmaceutical therapies are not sufficient. Apheresis allows the rapid normalization of the plasma factors and in the case of diseases with macromolecule pathologic solutes these molecules have very long generation times so with their removal pharmaceutical support can then be very beneficial. Studies have also shown that cellular functions may normalize with solute removal. In patients treated for rheumatoid arthritis (plasma treated by cryofiltration) and biliary cirrhosis (plasma treated by activated charcoal and an anion exchange resin) lymphocyte transformation reactivity improved, and increases in lymphocyte populations, and changes in phagocytic polymorphonuclear leukocytes were shown 6. In a subset of rheumatoid arthritis patients studied it was shown that cryogel had a suppressive effect on normal lymphocyte proliferation 7. In investigations on the solute kinetics of macromolecules found in rheumatoid arthritis 8 and hyperlipidemia patients 9, a single pool model provided very good estimates of post-treatment concentrations that can be predicted. Net generation for immunoglobulins as well as rheumatoid factor and circulating immune complexes was shown to be highly individual and related to intertreatment durations and concomitant drug therapy 10. In trials with a jaundiced dog model with plasma treatment by an anion exchange sorbent, it was shown that treated or non-jaundiced plasmas were less suppressive for normal lymphocytes and plasma perfusion over the adsorbent in jaundice was effective in improving the deteriorated lymphocyte functions 11. In the initial stages of applications of plasma exchange there were thoughts that since it may be applicable to so many disease states, might it be the fountain of youth? In fact this concept is very old, for as long ago as the mid-19th century parabiosis was investigated by physiologist Paul Bert. Parabiosis in medical physiology is when two living organisms have a shared physiology, such as a shared circulatory system via blood or plasma exchange 12. In aging, the oligodendrocytes are reduced in efficiency resulting in decreased myelination and influence on the central nervous system (CNS). By conjoining young with older mice, factors from the younger mice reversed CNS demyelination in older mice by revitalizing the oligodendrocytes and reversing the effects of age on the myelination cells 13. More recently, efforts have begun in Alzheimer's patients to giving young blood to older patients 14 and the company Alkahest has designed a randomized, double-blind, placebo-controlled, cross-over trial 15. Other investigators have identified the presence of specific antibodies, namely alpha 1 adrenergic receptor antibodies (Ab), associated with blood vessel damage in the brain 16. Grifols International S.A. is working on a trial of therapeutic plasma exchange and therapeutic albumin and immunoglobulin infusion 17. This trial is the Alzheimer Management by Albumin Replacement (AMBAR, 18). It is known that in various disease states there are factors that are stimulating to organ recovery, but can removal alone of plasma factors be sufficient to improve organ function? Using the analogy of a fire obscured by smoke, given that “smoke” is the abnormal plasma constituents and the “fire” is the organ system failure agent, might the removal of the “smoke” alone make it possible for the natural biological/physiological processes to put the “fire” out? One has to question the reasons for the buildup of pathologic molecules in the disease state. Scientific studies have shown for some diseases there is a genetic predisposition to certain diseases states. Also, environmental effects and bacterial and viral contaminations have been shown to “precipitate” or “turn on” disease states. In turn, the body responds as it can by producing “factors” to address the insults. These “factors” accumulate and become a part of the pathologic process leading to various organ or organ system failures. In the case of autoimmune diseases they strike women on average three times more than men, showing the genetic predisposition. It is also noteworthy that cryoglobulins accumulate in various autoimmune disorders (19). Cryoglobulins are a group of serum proteins that could form a reversible precipitate or gel in the cold. In addition to immunoglobulins, which are cryoprecipitable, other cold-precipitable plasma proteins include cryofibrinogen, C-reactive protein-albumin complexes, a heparin-precipitable protein related to fibrinogen, a nonclotting component of Cohn fraction I-1 from pooled normal serum and cold insoluble Bence Jones proteins. While the occurrence of cryoglobulins is not as unusual as is commonly thought, measurements in patients is rarely done as related to the difficulty of its assay (19). Differences in solubility between cryo- and non-cryoimmunoglobulins relate to differences in their amino acid sequences that alter their electrostatic interactions, structure, and solubility at low temperatures (19). The detection of a wide variety of immune reactants, including immune complexes, and complement in cryoproteins suggests the presence of pre-existing disease. They are associated with many disease states and have relatively very low concentrations in normal states and can deposit in vascular tissues. Their association with various infections also suggests they are produced in response to antigen challenges. Likely when their concentrations become very high the normal clearing processes are deficient. I am reminded of the excitement some years back when data were presented on the use of dialysis to treat schizophrenia 20. Other studies for 21 and against 22 treatment were published. Noteworthy was the hypothesis proposed 20 for any possible effect. As Dr. Kolff pointed out then that the normal kidney does not distinguish between bromide and chloride, whereas the dialysis process removes these solutes based on their gradient. In the particular case of schizophrenia, the implicated toxin, leucine5 endorphin, was hypothesized to be reabsorbed by the normal kidney 20. A common feature of senescent cells is the accumulation of abnormal or damaged proteins, including oxidatively modified forms 23, in their cytosol that leads to cellular impairment. Protein accumulation results in part from impaired protein degradation with age. Also with aging, misfolding of proteins may occur leading to aggregation, nonfunction, and associated diseases. In some cases misfolded proteins can interact with other proteins to induce their misfolding. Investigations in the field of epigenetics indicate that genome changes occur over a lifetime, perhaps as a result of the environment, diet, and even genetic design 24. With gene changes, specific proteins are produced that in turn effect cell function. With age and disease onset the body losses its ability to clear damaged and aggregated proteins. Researchers at the Max Planck Institute have reported on changes of proteins in worms. They have noted that about one third of the quantified proteins significantly change in abundance and this shift overwhelms the machinery of protein quality control and impairs the functionality of proteins and is reflected in the widespread aggregation of surplus proteins ultimately contributing to death 25. For the longer surviving worms, as a mechanism for survival they deposited the surplus and harmful proteins as insoluble aggregates and these deposits were enriched with helper proteins, molecular chaperones, which can apparently prevent the toxic effects normally exerted by aggregates 25. One approach is to remove the degraded and aggregated proteins where the normal bodily removal processes are not adequate. Disease states, transplantation, aging, and infections lead to biological processes that can address the damage and restore homeostasis. But at times these processes cannot keep the pace and pharmaceuticals have their limitations. Apheresis can fill this role by removing toxins, improving cellular functions, and stimulating the biological processes. Economic analyses on the costs of dialysis, heart mechanical support, transplantation, joint replacements, etc. worldwide show that the costs are unsustainable even for the wealthier countries further requiring their selective use. Even still, the issues of the quality of life and morbidity remain. The prevention of chronic renal failure and the need for dialysis or transplantation can save tens of thousands of dollars per year per patient. Every effort should be made to delay the progression of chronic diseases. Therapeutic apheresis is clearly an important tool in treatment of many complex conditions now and in the future. Therapeutic apheresis: Why not?