Concepts of Blood Purification

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Blood purification within the body is performed by different organs - carbon dioxide is removed by the lungs; excess water and products arising from the dietary breakdown of ingested protein and cellular metabolism are removed by the kidney. The liver has a wide range of functions, including detoxification, protein synthesis and production of biochemicals necessary for digestion. Extracorporeal circulatory procedures may be used as a technique to replace or augment a number of these functions. Such techniques rely upon the removal of compounds from the blood by diffusion, convection or adsorption. The most commonly used extracorporeal circulatory process is the replacement or augmentation of kidney function, with around 20,000 patients in the United Kingdom being treated currently. In the United States in 2004 (the most recent year for which complete data are available), 104,364 patients (approximately 0.03% of the US population) began renal replacement therapy; however, considerable inequalities in the number of patients treated are known to exist, in both emerging economies and Western countries [1, 2].

The primary function of the kidney is to maintain homeostasis in the body. It does so by removing excess fluid, and metabolites resulting from metabolic activity and the intake of food, by a complex process involving filtration, selective reabsorption and excretion. In addition, it has a number of metabolic functions related to the control of blood pressure, red cell production and the conversion of vitamin D. Damage or injury to the kidney necessitates augmentation or replacement of function by artificial means. Such augmentation or replacement focuses on fluid and metabolite removal but does not at present involve any augmentation of the metabolic functions of the organ. The augmentation or replacement of kidney function is generally initiated when a substantial or total loss of the ability of the human kidneys to remove water, excrete metabolic waste products or maintain body homeostasis occurs. The most commonly used augmentation or replacement method is known as haemodialysis, and involves continuous passage of patient's blood through an artificial kidney or a haemodialyser containing a semipermeable membrane and returning it back to the patient. Blood flows on one side of the membrane while a dilute electrolyte solution (dialysis fluid) flows on the other side of the membrane. The processes that occur within the haemodialyser can be summarised as follows:

• Equilibration of the electrolyte composition of blood and dialysis fluid.

• Elimination of metabolites elevated as a consequence of renal insufficiency by diffusion into the dialysis fluid. Some convective mass transport due to ultrafiltration or fluid removal also takes place and contributes to the overall solute removal.

• In both reversible and end-stage renal disease, there is a need to remove fluid from the body, and this removal is via a process known as ultrafiltration, which is governed by the hydrostatic pressure difference between the blood and the dialysis fluid. The hydrostatic pressure gradient is generally supplemented by an osmotic pressure gradient induced by the inclusion of glucose in the dialysis fluid.

Haemodialysis is the most widely used procedure for the treatment of end-stage renal disease. The process of haemodialysis can be divided further into low and high flux dialysis. Low flux dialysis utilises membranes with a low hydraulic permeability, blood and dialysis fluid flow rates of 250 and 500 ml/min, respectively, and a treatment duration of 4 hours or more. If the dialyser surface area is increased and the blood and dialysis fluid rates are increased up to 400 and 800 ml/min, respectively, the treatment is termed high flux dialysis.

Haemodialysis is a process in which the solute transport from the blood to the dialysis fluid occurs by diffusion. This tends to favour the removal of low-molecular-weight solutes. To eliminate high-molecular-weight compounds whose presence in nonphysiological levels is associated with long-term complications in dialysis patients, such as p2-microglobulin (~11 kDa), which aggregates into amyloid fibres that deposit in joint spaces, resulting in dialysis-related amyloidosis, recent approaches to the treatment of kidney disease by extracorporeal circulatory approaches have focused on the use of high flux membranes and a combination of convection and diffusion or convection alone to enhance the range of metabolites retained that have to be removed [3].

As the clinical requirements for the treatment of acute or reversible kidney failure differ, the treatments used are primarily those in which transmembrane transport of metabolites occurs by convection.

Irreversible renal failure is treated intermittently. Historically, this was because of problems of gaining access to the circulation as well as the complexity of the equipment used. Currently, the accepted standard for the treatment of irreversible or end-stage renal disease is three times a week treatment. Since such treatment is uneven in its spacing, there is considerable interest in moving to more frequent schedules to avoid the large changes in patient biochemistry that are associated with the traditional approach [4].

Acute or reversible renal failure arising from an injury or damage to the kidney is treated continuously over a period of several days. Furthermore, as acute renal failure may frequently be associated with sepsis, the dialytic process in such instances needs to be supplemented by extracorporeal adsorption techniques to remove endotoxins. Such removal can be attained by the use of cellulose-coated microspheres, as they demonstrate a high adsorptive capacity for endotoxins [5, 6]. When ingested, poisons, with or without renal failure, can also be similarly removed [7].

End-stage liver disease is generally treated by liver transplantation. However, transplantation is often delayed due to the unavailability of a donor organ, and temporary liver support may be used in this interim period. Such temporary support is by the use of bioartificial liver systems, which function as bridging devices. Such devices utilise liver cells or hepatocytes derived from human liver tumours, such as the hepatoma cell line HepG2, or in vitro immortalised cell lines, such as the NKNT-3 cell line. Tumour-derived cell lines such as HepG2 and C3A express a variety of liver functions, but some specific liver functions, such as ammonia detoxification and ureagenesis, are poorly expressed and are insufficient to sustain life. More recently, a novel, clonal, immortalised human fetal liver cell line, cBAL111, that displays hepatocyte-specific functions has been described in the literature [8].

There is considerable interest in the use of alternative approaches such as the use of livers of transgenic pigs; however, in such an approach, the possibility exists that porcine endogenous retrovirus may infect human tissues, and clinical application of this approach remains in abeyance.

Culture-based extracorporeal liver assist devices may be simple hollow fibre devices in which the area around the fibres is used to grow cells to a high density with the culture remaining stable for an extended period. In such devices, the blood from the patient flows through the lumen of the fibres and is separated from the liver cells by the membrane wall. Early approaches used a cellulose acetate membrane whose nominal molecular cut-off was 70 kDa thereby permitting the diffusion of not only small-molecular metabolites but also low-molecular-weight proteins. This type of approach was used clinically by Sussman and co-workers [9].

Current culture-based extracorporeal liver assist devices use synthetic membranes and are more complex in their design. Poyck and co-workers in their recent studies used a device that externally retained the structure of a hollow fibre dialyser, but differed internally. It contained a three-dimensional nonwoven hydrophilic polyester matrix for high-density hepatocyte culture. The matrix was circularly wound around a polycarbonate core, and hydrophobic polypropylene gas capillaries situated between the matrix layers in a parallel fashion supplied oxygen and removed CO2. This combination of the polyester matrix and the oxygenation capillaries creates a third compartment used to perfuse the plasma or medium through the bioreactor. Within this design, the plasma or medium has direct access to the hepatocytes in the polyester fabric. Plasma is perfused through the bioreactor via the side ports. The integrated oxygenation capillaries are embedded in polyurethane resin and fitted with gas inlet and outlet caps. The homogeneous distribution of the oxygenation capillaries throughout the bioreactor compartment ensures that every hepatocyte has an oxygen source within its immediate surroundings [8].

Liver failure following ingestion of poisons may also be treated using such an approach, but more frequently, hybrid systems, which combine dialytic concepts with approaches intended to remove protein-bound metabolites, are used such as the molecular adsorbents recirculation system [10], single-pass albumin dialysis [11] and the Prometheus system [12].

Other blood purification methods include plasmapheresis, a therapeutic treatment of blood in which the cellular component is separated from the plasma and which is used primarily in the treatment of immune-mediated diseases such as Guillain-Barre syndrome, lupus and thrombotic thrombocytopenic purpura. There are four main types of membrane plasmapheresis: plasma exchange (PE), double-filtration plasmapheresis (DFPP), plasma adsorption and immunoadsorption (IA). In PE, plasma separated with a plasma separator is discarded and replaced with the same volume of fresh frozen plasma or albumin solution. In DFPP, plasma separated with a plasma separator is allowed to pass through the plasma component separator with a small pore size. High-molecular-weight proteins are discarded and low-molecular-weight substances including valuable albumin are returned to the patient. A small amount of substitution fluid such as albumin may be added. A variant of this technique is rheopheresis, which is used to treat microcirculatory disorders or impaired microcirculation; in this process, fibrinogen and high-molecular-weight substances responsible for microcirculatory disorders (e.g., age-related macular degeneration) are removed. In plasma adsorption, plasma separated with a plasma separator is allowed to flow into a plasma adsorption column. Pathogenic substances are adsorbed and removed due to affinity between ligands and pathogenic substances. In contrast to the above approaches, no substitution fluid is used. IA is a subcategory of plasma adsorption in which the adsorption column selectively adsorbs immune complexes and autoantibodies. Current clinical practice relies on the use of hollow fibres for PE and DFPP; however, the membranes used (cellulose acetate or synthetic polymers) have a larger pore size (0.1-0.5 pm).

Haemoperfusion, used for removing drugs or poisons from the blood in emergency situations, is a technique that involves passing the patient's blood over an adsorbent substance and then returning it back to the circulation. The adsorbent substances most commonly used are resins or activated carbon. When activated carbon is used, to minimise the shedding of microparticles during use and to eliminate damage to blood cells, it is encapsulated in cellulose acetate [13].

For many years, the clinical application of haemoperfusion was limited to treatment of acute poisoning. Since the 1990s, interest in the use of adsorbents in extracorporeal medical devices has been increasing and a number of new sorbent materials have become available [14, 15].

Hollow fibre devices may also be used for the removal of viruses from the blood and are primarily used for the enhancement of safety in the production of biotherapeutic drug products such as biopharmaceuticals and plasma derivatives. Historically, cuprammonium rayon was used for this application, but today it has been replaced by a hydrophilised polyvinylidene fluoride membrane.

Lung function can also be replaced or augmented by artificial means. Oxygen and carbon dioxide transfer can be accomplished by diffusion through semipermeable membranes interposed between the blood and gas phases without the injurious effects of the direct blood-oxygen interface, which characterised the earlier forms of oxygenators. Early forms of this approach used ethyl cellulose and cellophane membranes [16]. Such membranes were subsequently replaced by synthetic materials, which offered a markedly improved gas transport. Today, in addition to forming part of the heart-lung machine used in cardiopulmonary bypass operations, to take over the function of the heart and lungs and to maintain the circulation of blood and the oxygen content of the body during surgery, extracorporeal membrane oxygenation is used to provide respiratory support to patients whose heart and lungs are severely diseased or damaged. The technique is most commonly used in neonatal intensive care units, for newborns in pulmonary distress, but can also be used for adults. One of the recent uses of this approach has been the treatment of adults and children with respiratory distress following infection by the H1N1 flu virus [17].

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