Use Of Plasma Exchange Research Articles

Long-term follow-up of patients with severe ANCA-associated vasculitis comparing plasma exchange to intravenous methylprednisolone treatment is unclear

Patients with antineutrophil cytoplasm antibody-associated vasculitis (AAV) requiring dialysis at diagnosis are at risk for developing end-stage renal disease (ESRD) or dying. Short-term results of a trial comparing plasma exchange (PLEX) to intravenous methylprednisolone (IV MeP) suggested PLEX improved renal recovery. Here we conducted long-term follow-up to see if this trend persisted. A total of 137 patients with newly diagnosed AAV and a serum creatinine over 500 μmol/l or requiring dialysis were randomized such that 69 received PLEX and 68 received IV MeP in addition to cyclophosphamide and oral glucocorticoids. The patients were followed for a median of 3.95 years. In each group there were 35 deaths, while 23 PLEX and 33 IV MeP patients developed ESRD. The hazard ratio for PLEX compared to IV MeP for the primary composite outcome of death or ESRD was 0.81 (95% confidence interval 0.53-1.23). The hazard ratio for all-cause death was 1.08 with a subhazard ratio for ESRD of 0.64 (95% confidence interval 0.40-1.05). Thus, although short-term results with PLEX are encouraging, the long-term benefits remain unclear. Further research is required to determine the role of PLEX in AAV. Given the poor outcomes of patients with severe AAV, improved treatment is urgently needed.

Therapeutic plasma exchange for the treatment of pediatric renal diseases in 2013

Therapeutic plasma exchange is an extracorporeal treatment modality that removes systemic circulating pathologic factors or replaces absent plasma components and plays a role in many nephrologic conditions. It presents a number of technical challenges in the pediatric population but has become an increasingly common practice in pediatric nephrology over the past several decades. While prospective evidence is often lacking, our increased understanding of the molecular pathogenesis underlying many pediatric renal diseases provides sound reasoning for the use of plasma exchange in treating these conditions. This review will present the currently accepted indications for plasma exchange in children, the technical aspects of the procedure and its potential complications.

Kidney-limited thrombotic microangiopathy in patients with SLE treated with romiplostim

We present the case of a 19 year-old Caucasian female with history of systemic lupus erythematosus (SLE) and normal baseline kidney function who developed severe acute renal failure following treatment of thrombocytopenia with the thrombopoietic agent romiplostim. Percutaneous kidney biopsy revealed thrombotic microangiopathy (TMA) without immune complex lupus glomerulonephritis. We discuss pathogenesis and differential diagnosis of TMA in patients with SLE and raise concerns regarding the use of thrombopoietic agents in such patients. Based on favorable long-term outcome in our case aggressive treatment and in particular prolonged use of plasma exchange in these patients are advocated.

Immunoadsorption in steroid-refractory multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disorder, with involvement of both the humoral and cellular components of the immune system. The use of plasma exchange (PE) in steroid-refractory relapses has become an integral part of national and international guidelines for the treatment of steroid-resistant relapses of MS with an efficacy of 40–70%. So far, 6 studies of immunoadsorption (IA) treatment in different forms of MS have been published, 4 of them in steroid-refractory MS relapses. These 4 studies revealed a significant clinical improvement in 73–85% of patients with steroid-refractory MS relapses. However in MS patients with non-active relapsing–remitting or secondary progressive course, there was no clinical improvement. Despite the limited number of patients and studies, these data suggest a reasonably similar efficacy of IA in the treatment of steroid-refractory MS relapses compared to PE. More prospective trials are needed to confirm and extend these results.

Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines

AbstractPlasma exchange is a therapeutic procedure used to treat a variety of diseases through the bulk removal of plasma. To apply this treatment to patients appropriately, it is essential to understand the methods to remove plasma, its effects on normal plasma constituents, the role of replacement fluids in the treatment, and the risks associated with the procedure. To facilitate the appropriate evidence-based use of plasma exchange and to encourage research, the American Society for Apheresis has published guidelines providing practical guidance and information to those responsible for ordering or providing this treatment.

Plasma exchange: concepts, mechanisms, and an overview of the American Society for Apheresis guidelines.

Plasma exchange is a therapeutic procedure used to treat a variety of diseases through the bulk removal of plasma. To apply this treatment to patients appropriately, it is essential to understand the methods to remove plasma, its effects on normal plasma constituents, the role of replacement fluids in the treatment, and the risks associated with the procedure. To facilitate the appropriate evidence-based use of plasma exchange and to encourage research, the American Society for Apheresis has published guidelines providing practical guidance and information to those responsible for ordering or providing this treatment.

Successful Use of Plasma Exchange to Prevent Recurrence of C3 Glomerulonephritis after Kidney Transplantation: A Case Report

Background: Complement-mediated glomerulonephritis relapses in about 80% of patients with a history of disease recurrence in a previous graft. There is so far no efficient treatment to prevent recurrence. Methods: Case report on the use of intermittent plasma exchange to prevent recurrence of C3 glomerulonephritis (C3GN) in a second kidney transplant, after loss of a previous graft due to disease recurrence. Results: Our 26 year-old patient was initially diagnosed with type 1 membranoproliferative glomerulonephritis with isolated C3 deposits. She developed end stage renal disease and received a first kidney transplant in 2007. The post-transplant course was complicated by an early graft loss due to biopsy proven recurrence of C3GN (after 9 months). Persistent activation of the alternative complement pathway (low C3, high C3d and normal C4) was noted before, during and after transplantation. Thus far no underlying pathogenic mechanism has been found despite extensive evaluation of the complement pathway. Because of specific anti-HLA antibodies against more than 85% of the donor panel the patient was admitted to the Eurotransplant Acceptable Mismatch program. A second kidney transplantation was performed in January 2011. We combined standard triple immunosuppression with plasma exchange (40mL/kg body weight per treatment) at decreasing frequency, with a maintenance schedule of 1 exchange every two weeks after the first month. One year after transplantation no rejection has occurred and the patient maintains good graft function (creatinine 1.3 mg/dL) without signs of complement activation, microscopic hematuria and proteinuria. A protocol biopsy 3 months after transplantation showed no signs of disease recurrence on immunofluorescence and electron microscopy. Conclusion: Prophylactic plasma exchange might correct the underlying pathogenic mechanism in patients with C3 glomerulonephritis, thereby preventing uncontrolled complement activation and recurrence of disease after kidney transplantation. Plasma exchange could be a cost-effective and widely available alternative to the recently developed C5 inhibitor Eculizimab in this indication.

Role of Plasma Exchange in ABO-incompatible Kidney Transplantation

BackgroundIn the past, ABO incompatibility was an absolute contraindication for solid organ transplantation. However, multiple recent trials have suggested strategies for overcoming the reactions between graft antigens and recipient antibodies that cause graft rejection. In this study, we determined the usefulness of plasma exchange (PE) for removing anti-A/B antibodies that cause hyperacute/acute humoral graft rejection in patients undergoing ABO-incompatible kidney transplantation.MethodsIn our study, 12 patients underwent ABO-incompatible kidney transplantation. All recipients received pre-transplantation conditioning by PE or intravenous immunoglobulin (IVIG) administration. After pre-transplantation conditioning, anti-A/B antibody titers were evaluated, and transplantation was performed when the titer was below 1:8. To assess the transplantation outcome, anti-A/B antibody titers, creatinine level, estimated glomerular filtration rate (eGFR), and proteinuria levels were measured.ResultsAnti-A/B antibody titers were below 1:8 in all patients at the time of transplantation. eGFR measured on post-transplant day 14 showed that 10 patients had immediate recovery of graft function, while 2 patients had slow recovery of graft function. Short-term outcomes of ABO-incompatible kidney transplantation (measured as creatinine levels) after reducing anti-A/B antibody titers were similar to those of ABO-compatible kidney transplantation. After transplantation, the anti-A/B antibody titers were below 1:8 in 7 patients, but the remaining 5 patients required post-transplantation PE and IVIG treatment to prevent antigen-antibody reactions.ConclusionsWith the increasing demand for kidney donations, interest in overcoming the ABO incompatibility barrier has increased. PE may be an important breakthrough in increasing the availability of kidneys for transplantation.

Therapeutic plasma exchange in systemic vasculitis

Therapeutic plasma exchange has been long proposed as a potentially useful modality to treat several systemic vasculitis conditions. This review summarizes the available evidence for the effectiveness of plasma exchange in systemic vasculitis. Therapy with plasma exchange, most often combined with immunosuppressive agents, has been found effective for antiglomerular basement membrane disease, antineutrophil cytoplasmic antibody-associated vasculitis (AAV), Henoch-Schönlein purpura, cryoglobulinemic vasculitis, hepatitis B virus-associated polyarteritis nodosa and Kawasaki disease. The most common indications are life-threatening or organ function-threatening manifestations, particularly advanced renal dysfunction and disease refractory to traditional therapy. Thus, most of the available evidence favoring plasma exchange in these circumstances is from small observational studies or expert consensus. Recent advances in findings include results strengthening the notion of a small beneficial effect on preserving renal function with adjunct plasma exchange therapy in AAV with renal failure and observational data suggesting plasma exchange as a promising effective salvage option for children with Kawasaki disease not responding to standard therapy with intravenous immunoglobulins. Evidence from case reports and case series and a few randomized controlled trials continues to support plasma exchange as a major rescue-treatment modality for several systemic vasculitis diseases. These studies offer some guidance for use of plasma exchange in systemic vasculitis, but additional data from controlled trials are needed for more accurate assessment of the indications, practical modalities, benefits and shortcomings of this treatment approach.

Antibodies Directed Against AB Blood Antigens or Human Leukocyte Antigen Molecules Activate Different Intracellular Pathways Explaining Their Differential Effects Toward Accommodation

The limited availability of organs for transplantation has driven the search for new strategies, such as the use of ABO and human leukocyte antigen (HLA) incompatible donor grafts for which antidonor antibodies (Abs) preexist in the recipient. The control of T-cell alloresponses has considerably improved over the last two decades thanks to the discovery of novel anti-T-cell molecules, dramatically reducing the incidence of acute cellular rejection. On the other hand, control of the humoral response remains a considerable challenge. Nevertheless, recent strategies, such as the use of plasma exchange, intravenous immune globulin, rituximab, bortezomib, or anti-C5 mAb (eculizumab), have helped to improve the success rate for so-called incompatible transplants. However, ABO and HLA incompatibility seems to be different. In fact, ABO-incompatible transplantation has improved considerably, with results now comparable with ABO-compatible transplants. On the contrary, HLA-incompatible transplantation with donor-specific Abs poses a higher risk of Ab-mediated rejection (ABMR), with a significant negative impact on graft survival. Graft survival despite the presence of antigraft Abs is known as “accommodation,” a phenomenon first described in the context of successful ABO-incompatible liver transplantation performed for acute liver failure (1). The first graft tissue with which antidonor Abs come into contact is the endothelium, whose response seems to be Ab-dependent. For example, endothelial cells (EC) seem to be particularly resistant to anti-A/B Abs in the context of accommodation, which is not the case for anti-HLA Abs, suggesting that differential EC pathways are involved in defining response to antidonor Abs. The study by Iwasaki et al. (2) aimed to compare the in vitro signal transduction pathways triggered in EC upon binding of anti-A/B and anti-HLA Abs, particularly in the context of accommodation. They showed that in resistance to complement-dependant cytotoxicity (CDC), the effect of EC preincubation with high-titer anti-A/B Abs was comparable with that of low-titer anti-HLA class I Abs. They additionally showed that a 1-hr incubation of EC with high-titer anti-A/B Abs up-regulated CD55 and CD59 by means of ERK1/2 pathway inactivation. However, a 1-hr incubation of EC with low-titer anti-HLA Abs resulted in reduced CDC, associated with an AKT pathway-dependent increase in mRNA expression of the cytoprotective proteins HO-1 and ferritin H. Given that CDC is the major (but not unique) mechanism by which Abs acutely aggress graft tissue, complement staining in graft biopsies, particularly C4d (or C3c/C3d), is considered as a good indicator of ABMR, especially in the context of donor-specific Abs. On the contrary, in ABO-incompatible transplantation, C4d or C3d staining is found in graft biopsies of stable nonrejected grafts without any correlation with poor outcome (3). The up-regulation of CD55 and CD59 shown by Iwasaki et al. (2) could explain the endothelial resistance to A/B Abs despite deposition of C4d and C3d, because the complement activation pathway is blocked at this step and cannot progress to full activation. In fact, the complement regulatory molecules CD55 and CD59 exert their inhibitory roles at multiple levels of the complement cascade: dissociation of C3 convertases by CD55 and prevention of membrane attack complex assembly by CD59. These roles are acted out locally at the site of Ab binding to EC, and a correlation exists between their up-regulated expression and the efficacy of CDC blockade. Their action is so efficient locally that in the field of xenotransplantation, this has spurred the generation of human CD55 or CD59 transgenic pigs expressing high levels of the human molecules on their EC, thereby preventing hyperacute ABMR in primate models. On another hand, the finding of reduced CDC through activation of the PI3K/AKT pathway and expression of cytoprotective genes upon EC preincubation with low-titer anti-HLA Abs well confirms the work of Reed et al. (4). The latter authors also reported on an induction of the antiapoptotic genes A20, Bcl-2, and Bcl-xL, driving EC to an accommodated profile. The identification of specific signaling pathways that could render EC resistant to Ab-mediated cytotoxicity would be of great value in transplantation, because it would help to understand how the status of accommodation may be acquired. Two parameters are obviously critical in this phenomenon referred here: Ab preincubation and Ab titer. So far, encouraging data such as these have only been observed in vitro and their confirmation in whole organs could justify strategies such as ex vivo preconditioning of donor organs with high-titer A/B Abs before A/B-incompatible transplantation or low-titer recipient anti-HLA Abs. Such strategies would aim to induce these particular protective pathways before transplantation in the context of prepared recipients (plasma exchange and immunosuppression) in an attempt to obtain accommodation in the context of HLA incompatibility.

Plasma exchange for renal disease: Evidence and use 2011

Over the past 37 year the role of plasma exchange in the treatment of patients with renal disease has undergone several changes. The majority of the changes for the use of plasma exchange relied on randomized control trials and delineations of mechanisms that potentially would benefit from the use of plasma exchange. Over the past 11 years plasma exchange indications for renal disease, the absolute numbers have been relatively unchanged but the indications are quite different. The Canadian Apheresis Group indicated in 2010 that TTP/HUS is still the number 1 indication at 63% of the total plasma exchange activity for renal disease but P and C ANCA Vasculitis had risen to 14% followed by renal transplant at 10%, Goodpasture's Syndrome at 6% and transplant FSGS at 5% with Cryoglobulinemia 2% and Myeloma Nephropathy had dropped dramatically to less than 1% with no cases of SLE reported. This report describes the most common indications for plasma exchange in patient's with renal disease and the evidence that supports it's use in 2011.

Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: what is the treatment?

IntroductionHyperferritinemia is associated with increased mortality in pediatric sepsis, multiple organ dysfunction syndrome (MODS), and critical illness. The International Histiocyte Society has recommended that children with hyperferritinemia and secondary hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS) should be treated with the same immunosuppressant/cytotoxic therapies used to treat primary HLH. We hypothesized that patients with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS can be successfully treated with a less immunosuppressant approach than is recommended for primary HLH.MethodsWe conducted a multi-center cohort study of children in Turkish Pediatric Intensive Care units with hyperferritinemia associated secondary HLH/sepsis/MODS/MAS treated with less immunosuppression (plasma exchange and intravenous immunoglobulin or methyl prednisolone) or with the primary HLH protocol (plasma exchange and dexamethasone or cyclosporine A and/or etoposide). The primary outcome assessed was hospital survival.ResultsTwenty-three children with hyperferritinemia and secondary HLH/sepsis/MODS/MAS were enrolled (median ferritin = 6341 μg/dL, median number of organ failures = 5). Univariate and multivariate analyses demonstrated that use of plasma exchange and methyl prednisolone or intravenous immunoglobulin (n = 17, survival 100%) was associated with improved survival compared to plasma exchange and dexamethasone and/or cyclosporine and/or etoposide (n = 6, survival 50%) (P = 0.002).ConclusionsChildren with hyperferritinemia and secondary HLH/sepsis/MODS/MAS can be successfully treated with plasma exchange, intravenous immunoglobulin, and methylprednisone. Randomized trials are required to evaluate if the HLH-94 protocol is helpful or harmful compared to this less immune suppressive and cytotoxic approach in this specific population.

Tandem plasma-exchange and haemodialysis in a paediatric dialysis unit

The simultaneous use of plasma-exchange (PE) and haemodialysis (HD), known as tandem PE and HD (TPH), may be an additional resource for treating patients who need both therapies at the same time. However, little experience is reported in the paediatric setting. We retrospectively reviewed the TPH sessions performed in the last 5 years in our unit. Thirty-nine TPH treatments in eight pediatric patients were traced. The median age of the patients was 10.5 (range 5.1-19.2) years, and median weight was 27.6 (range 14.7-66.2) kg. Indications for TPH were atypical haemolytic uremic syndrome due to factor H or factor I dysregulation, or to a not yet defined abnormality, in most of the sessions (34/39 sessions). The remaining five sessions were performed for vasculitis, focal segmental glomerulosclerosis and hyperimmunization in a patient waiting for kidney transplant. In all treatments, TPH was completed and reached the desired ultrafiltration and substitution volumes; the duration of PE was shorter than that of HD. No significant adverse events were observed. In those rare patients who require both PE and HD, TPH can improve their quality of life by reducing the time spent in extracorporeal circulation. This tandem treatment is safe and well-tolerated, even in subjects of relatively small body size.

Encefalopatía aguda en un paciente tratado con inmunoglobulina endovenosa por un síndrome de Guillain-Barré

Adverse reactions to intravenous immunoglobulin (ivIg) therapy, such as anaphylaxis, acute encephalopathy, aseptic meningitis, or thrombotic phenomena are uncommon. We report a 58-year-old man with hypertension presenting with muscle weakness which led to paraparesia and respiratory failure. With the diagnosis of Guillain-Barré syndrome (GBS), he was treated with ivIg. He developed an acute encephalopathy few hours after the administration of ivIg, with a decreased level of consciousness and agitation. A CT scan revealed moderate and diffuse brain edema. Encephalopathy resolved 96 hours after ivIg withdrawal and use of plasma exchange. A CT scan performed seven days after showed the resolution of brain edema.

HELLP Syndrome and Its Relationship with Antiphospholipid Syndrome and Antiphospholipid Antibodies

To perform a systematic review of the association between antiphospholipid antibodies, antiphospholipid syndrome (APS), and HELLP syndrome (Hemolysis; Elevated Liver enzymes; Low Platelet count), describing clinical features, outcome, pathophysiological findings, and treatment. We performed a literature search in PubMed using the following MeSH entry terms: HELLP syndrome, anticardiolipin antibodies, lupus anticoagulant, antiphospholipid antibodies, and antiphospholipid syndrome. We limited our search to articles published in the English literature from 1994 to 2010. We identified 29 case reports/studies including a total of 51 pregnancies with HELLP syndrome in 50 patients. The majority of the cases occurred during the 28 to 36 weeks of pregnancy. Nausea, vomiting, epigastric, or right upper quadrant pain was the most frequently reported symptoms at disease onset. Elevated liver enzymes and low platelet count were reported in all studies. Concomitant hypertension and proteinuria were reported in 2/3 of the patients. Hepatic infarctions were observed in 33.3% pregnancies. However, thrombosis was also reported in the central nervous system, deep or superficial vein thrombosis, skin, intestine, bone, spleen, and adrenal glands. Treatment is still a matter of debate in HELLP syndrome. Aspirin, subcutaneous, intravenous, and oral anticoagulation, and prednisone have been used. In addition to the use of plasma exchange and fresh frozen plasma administration, intravenous immunoglobulins and plasmapheresis have been described. The incidence of obstetric events in patients with APS is a matter of great interest among rheumatology and gynecology and obstetrics professionals. The current knowledge that antiphospholipid antibodies/APS is not only a thrombotic disease, but also associated with microangiopathic features, can explain the greater prevalence of HELLP syndrome in these patients.

Immune-mediated hemolytic anemia in children after liver and small bowel transplantation

Four children who underwent ABO-compatible combined liver and small bowel transplantation developed severe immune-mediated hemolytic anemia. The main management strategies were early and aggressive treatment with steroids, the introduction of rituximab (an anti-CD20 monoclonal antibody), and the use of plasma exchange together with compatible but minimal blood transfusions. Three of the 4 children developed thrombi in the major vessels. In small bowel transplant patients, the early recognition of hemolytic anemia and intensified management with anticoagulation are necessary for the prevention of this complication.

Use of plasma exchange in patients with heparin‐induced thrombocytopenia: A report of two cases and a review of the literature

Heparin-induced thrombocytopenia (HIT), which is characterized by thrombocytopenia and potentially serious thromboses, may develop in patients exposed to heparin anticoagulation. HIT is caused by antibodies to the heparin/platelet factor 4 (PF4) complex. Management of HIT involves discontinuation of heparin and anticoagulation with a nonheparin alternative such as a direct thrombin inhibitor (DTI). This poses a challenge in the management of patients who need to undergo cardiopulmonary bypass surgery (CPB), because CPB requires anticoagulation with heparin and standardized protocols for use of DTIs are not widely available. We report two patients with HIT who underwent successful CPB with heparin anticoagulation following plasma exchange (PE) to reduce heparin/PF4 antibody titers. Case 1 is a 46-year-old male with cardiac amyloidosis who needed urgent placement of a left ventricular assist device. Case 2 is a 34-year-old woman with acute myocarditis who needed placement of a biventricular assist device. Both patients had positive enzyme-linked immunosorbent assay assays for heparin/PF4 antibodies and clinical evidence of HIT before PE. Following PE and subsequent CPB, neither patient had clinical or laboratory evidence of HIT. The literature regarding the use of PE for the treatment of complications of HIT and as prophylaxis before CPB is reviewed.

Plasma exchange in the treatment of Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and renal limited vasculitis

The article reviews the use of plasma exchange (PLEX) in the management of the antineutrophil cytoplasm antibody-associated vasculitides (AAV). Early mortality and end-stage renal disease (ESRD) remain frequent outcomes for AAV patients. Demonstration of the pathogenic potential of anti-neutrophil cytoplasm antibody (ANCA) has provided a rationale for antibody removal by PLEX in vasculitis therapy; however, other mechanisms may contribute to the therapeutic effect. Clinical studies have focused on the use of PLEX to rescue organ function in rapidly progressive glomerulonephritis and lung haemorrhage; other indications, including immunomodulatory actions, have received little attention. Randomized controlled trials of PLEX in renal vasculitis suggest a reduction in the risk of development of ESRD with adjunctive PLEX, although the data are not sufficiently strong to make firm recommendations and there are no controlled trials in alveolar haemorrhage. It is unclear at what severity of renal failure PLEX is beneficial, the optimal PLEX dosing and type and dosing of concomitant medications. These subjects are the focus of an ongoing study (PEXIVAS). PLEX remains a nonselective, expensive therapy with common adverse events. Selective apheresis techniques (cytapheresis, immunoadsorption) offer theoretical advantages but their use is limited by incomplete understanding of the mechanism of PLEX in AAV and expense.

Progressive multifocal leukoencephalopathy and other forms of JC virus disease

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the JC virus (JCV). PML usually occurs via reactivation of JCV when an immune system becomes compromised. A diagnosis of PML is normally made on the basis of distinguishing neurological features at presentation, characteristic brain MRI changes and the presence of JCV DNA in cerebrospinal fluid. PML has a 3 month mortality rate of 20-50%, so prompt intervention is essential. Currently, reconstitution of the immune system affords the best prognosis for this condition. When PML is first suspected, and where possible, immunosuppressant or immunomodulatory therapy should be suspended or reduced. If PML is associated with a protein therapy that has a long half-life the use of plasma exchange to accelerate the removal of the drug from the circulation may aid the restoration of immune system function. Rapid improvements in immune function, however, might lead to transient worsening of the disease. In this Review, we critically appraise the controversies surrounding JCV infection, and provide practical management guidelines for PML.

Liver Dialysis: A Review

Liver dialysis, like kidney dialysis for end-stage kidney disease, refers to the use of extracorporeal devices for temporary support when the liver fails. Unlike the toxemia of kidney failure, the toxins that are retained in the blood when the function of the liver becomes severely deranged, including many protein bound as well as water soluble toxins. These include small molecular weight toxins (ammonia, phenol, false neurotransmitters, free bile acids, etc.) also mediators of inflammation (e.g. cytokines, chemokines) vasoactive substances, cell growth inhibitors (e.g. TGFβ1) and endotoxin.1 Their exact role in causing neurological and other organ impairment and in aggravating injury to the liver, remains undetermined. The beneficial effects, clinically, of clearing the blood of such toxins were shown very early in the history of temporary liver support when exchange transfusion was tried in patients with fulminant hepatic failure and shown to be followed by temporary improvements in encephalopathy. A similar application was returned 10 years later with the use of plasma exchange.2 This approach was taken further in 1994, by Fin Larsen of the Copenhagen Liver Unit. The technique that he developed was of high volume plasmapheresis where 16% of the body weight is exchanged with FFP daily.3 The controlled clinical trial that he set up in patients with acute liver failure (ALF) closed in 2009, with 182 patients entered. According to a personal communication from him, around 20% survival benefit was in the group of patients who were not transplanted. The two pathways of development in liver support devices, namely artificial and bioartificial, are based on different premises (Box 1). Whether there is a need to provide supplementary metabolic and synthetic functions in addition to efficient removal of toxic substances in improving survival, is of fundamental importance. The findings to date with respect to the provision of greater synthetic and metabolic function are, in the writer’s opinion, unconvincing. This is possibly because many of the cell lines are used in the biological modules whether porcine, primary human, tumor cell subclones or immortalized human hepatocyte preparations have limitations in terms of functional capacity. The first major controlled clinical trial of a bioartificial device which was carried out by Demetriou, a pioneer in this field, gave disappointing results in patients with fulminant hepatic failure or primary graft failure without a statistically significant improvement in overall survival (Box 2). The study also illustrated the profound impact of transplantation on survival in ALF, which makes analysis of a possible beneficial effect from the device extraordinarily difficult.4 More encouraging results with respect to survival were reported in a recently conducted trial of extracorporeal liver assist device (ELADTM) based on a tumor cell clone which has been greatly improved over the years.5 This was carried out in China (Box 3) and led the manufacturers – Vital Therapies Inc, San Diego Ca, to set up a multicenter controlled clinical trial initially in the USA. Early findings from this (Box 4), on the safety and efficacy of the device were reported at Key Functions of Liver Devices