Liver replacement therapy with extracorporeal blood purification techniques current knowledge and future directions

Table 1 Comparison of basic characteristics of artificial liver support systems

System	Detoxification methods	Cost	Complexity	Applicability	Detoxification capacity/range	Impaction OS/TFS	Main characteristics
Continuous renal replacement therapy	Diffusion, convection	Low	Low	Broad (all ICUs, HDUs)	Restricted (water-soluble, low and medium molecular weight substances, mainly ammonia, cytokines)	Few data, no RCTs	Simple, no removal of albumin-bound toxins
High-volume hemofiltration	Convection	Low	Low	Broad (all ICUs, HDUs)	Restricted (water-soluble, low and medium molecular weight substances, mainly ammonia, cytokines), but more effectively than CRRT	Few data, no RCTs	Simple, better removal of low and medium sized molecules and cytokines than low-volume. No significant removal of albumin-bound toxins, loss of albumin, nutrients
High cut-off membranes	Diffusion, convection	Low	Low	Broad (all ICUs, HDUs)	Middle molecules up to 60 kDa, protein-bound uremic toxins, cytokines (IL-8, IL-6, and TNF-α)	Few data, no RCTs	Simple, removal of protein-bound-medium sized uremic toxins cytokines. No removal of other albumin bound toxins, loss of albumin
Direct hemoperfusion (Cytosorb)	Adsorption	Medium to high	Medium	Medium (ICUs, HDUs with experience)	Molecules up to 55 kDa, bilirubin, ammonia, bile acids, IL-6, CRP	Few data, no RCTs	Simple, removal of albumin bound toxins, bilirubin, bile acids, cytokines. Needs more literature
Double plasma molecular absorption system	Plasma separation, adsorption	Medium	Medium	Medium (ICUs, HDUs with experience)	Macromolecules, medium-sized plasma protein bound molecules and toxins, bilirubin, inflammatory molecules	Few data, no RCTs	Simple, removal of albumin bound toxins, bilirubin, bile acids, cytokines; needs more literature
Molecular adsorbent recirculating system	Albumin dialysis-diffusion, adsorption, convection	High	High	Limited (special centers)	Albumin-bound molecules < 50 kDa, water-soluble substances, Cytokines (TNF-α, IL-6, IL-1β, and IL-10)	Not found/not found	With available literature, removal of albumin-bound toxins; complex, expensive, limited access, uses exogenous albumin
Fractionated plasma separation and Adsorption-PROMETHE-US	Plasma separation, albumin dialysis-diffusion, adsorption, convection	High	High	Limited (special centres)	Broad (albumin-bound toxins, water-soluble substances of a wide range of molecular weight, cytokines)	Not found/not found	With available literature, removal of albumin-bound toxin; complex, expensive, limited access
Single-pass albumin dialysis	Albumin dialysis-diffusion, convection	Medium	Low	Broad (all ICUs, HDUs)	Albumin-bound substances (bilirubin, bile acids), small-sized (< 500 Da) water-soluble toxins	Few data, no RCTs	Simple, removal of albumin-bound substances, water soluble toxins; high cost of exogenous albumin, metabolic disarrangements
Coupled plasma filtration adsorption	Plasma separation, adsorption, convection	Medium	Medium	Medium (ICUs, HDUs with experience)	Albumin-bound molecules and toxins (bilirubin, tryptophan, phenols, bile acids), cytokines, water soluble toxins	Few data, no RCTs	Simple, removal of albumin-bound toxins, bilirubin, bile acids, cytokines; needs more literature
Plasma exchange	Separation of plasma substances, replacement with FFP	Medium to high, mainly due to the FFP	Medium	Medium (ICUs, HDUs with experience)	Broad (removal of cytokines, albumin-bound and water-soluble toxins, antibodies, immune complexes, lipoproteins)	Beneficial (RCTs and guidelines)	Effective with available literature from RCTs, replaces plasma proteins, clotting factors; expensive, need, cost and complications of blood products

OS: Overall survival; TFS: Transplant-free survival; ICUs: Intensive care units; HDUs: High dependency units; RCTs: Randomized controlled trials; FFP: Fresh frozen plasma; TNF-α: Tumor necrosis factor-alpha; IL: Interleukin; kDa: Kilodalton; CRP: C-reactive protein.

Table 2 Selected data from available guidelines, systematic reviews, meta-analyses or clinical studies included in this review

Ref.	Type of study	Modality-ies studied	Summary of key points of each study
[2]	Systematic review/meta-analysis	LRT systems	Liver failure pathophysiology involves immune system over-activation and overproduction of proinflammatory cytokines, resulting in multiple-organ failure; reducing cytokine levels and thus correcting the dysregulation of the immune system is the pathophysiologic base of the application of LRT systems
		Plasma exchange	The best currently available LRT system in ACLF regarding 3-mo OS
[9]	Review	Continuous renal replacement therapy	It has indication for initiation of when ammonia is more than × 3 the uln, or more than 200 µmoles/L or when severe encephalopathy occurs
[10]	Review	Continuous renal replacement therapy	It has a role in the maintenance of circulatory, acid-base, and electrolyte balance during the pro-, peri-, and post-LT periods. It facilitates control of fluid balance and avoidance of volume overload/of peripheral edemas-ascites in patients with ALF and ACLF
[11]	Guidelines	Plasma exchange	It improves transplant-free survival in ALF, and modulates immune dysregulation; patients with early treatment initiation that will not undergo LT may benefit most
[19]	Review	Adsorption therapies	They are delivered either by direct hemoperfusion or by plasma separation and subsequent plasma perfusion
		Direct hemoperfusion (Cytosorb)	It reduces levels of plasma bilirubin, ammonia, bile acids, and C-reactive protein and alters the immune response by absorbing proinflammatory cytokines; IL-6 has been identified as one of its main therapeutic targets; it presents high safety profile and easy application; indications, endpoints, effect on mortality and detection of which patients receive benefit from its use remain to be elucidated
[24]	Review	Single-pass albumin dialysis	Dialysate’s ideal albumin concentration and flow rate are not standardized while there are no commercially available albumin-containing Continuous renal replacement therapy fluids. Metabolic disarrangements and loss of antibiotics have been observed
[30]	Clinical study	High-volume hemofiltration	An inexpensive and effective method that can be performed in every ICU or HDU, requiring no special equipment. Increased ultrafiltration rates enhance the elimination of ammonia
[35]	Clinical study	High Cut-off membranes	Cytokine and toxin removal by these membranes may represent a promising intervention in ALF and ACLF
[36]	Review	Adsorption therapies	They are delivered either as stand-alone or in combination with other extracorporeal modalities; the evidence to support their routine use is still conflicting and insufficient. May be of utmost benefit when applied early in the course, for an adequate duration, and frequently repeated until hemodynamic stability is achieved; they require carefully monitoring of drug levels, supplemented with additional doses as needed
[38]	Review	Adsorption therapies	They have been used with positive effects in chronic dialysis and chronic liver disease
		Direct hemoperfusion (Cytosorb)	Ιt removes molecules up to 55 kDa
[43]	Systematic review/meta-analysis	Double plasma molecular absorption system	It combines two resins that remove macromolecules, medium-sized molecules, and toxins bound to plasma proteins, bilirubin, bile acids, ammonia, phenol, mercaptan, and inflammatory molecules
[44]	Clinical study	Double plasma molecular absorption system	It is frequently combined with Plasma exchange therapy, to overcome loss of for albumin and coagulation factors, with promising results on survival rates
[48]	Randomized controlled study	Molecular adsorbent recirculating system	It removes albumin-bound molecules and decreases the plasma concentrations of bilirubin, ammonia, creatinine, urea, and cytokines. It has good safety profile
[49]	Review	Molecular adsorbent recirculating system	Recirculation of albumin dialysate restricts albumin loss; under certain circumstances and indications, it has been associated with hemodynamic and clinical improvement at patients with liver disease; dose adjustments and therapeutic drug monitoring, especially for low protein-bound antibiotics, is required
[50]	Clinical study	Molecular adsorbent recirculating system	Expensive method, application in selected centers, but when compared to standard medical therapy alone it was found more cost-effective
[52,57]	Review, Clinical study	PROMETHEUS	It performs albumin dialysis. It removes bilirubin, ammonia, creatinine, bile acids, amino acids, cytokines and is associated with a small reduction in plasma concentration of albumin; it was associated with improvement in HE
[54]	Randomized controlled study	PROMETHEUS	It presents good safety profile and good hemodynamic tolerance
[67]	Randomized controlled study	PROMETHEUS	Favorable effect on patients’ subgroups such as those with more severe liver disease (MELD score > 30) and with type 1 HRS
[69]	Randomized controlled study	Single-pass albumin dialysis	It is inexpensive, apart from the cost of albumin, and requires no special center for its application; it performs albumin dialysis and removes bilirubin, bile acids, urea and creatinine
[76]	Review	Coupled plasma filtration adsorption	It combines plasma separation, adsorption and convection, with no loss of albumin or coagulation factors; it can effectively remove bilirubin, tryptophan, phenols, bile acids, cytokines
[77]	Randomized controlled study	Coupled plasma filtration adsorption	It cannot be performed in patients with septic shock
[87]	Review	Plasma exchange	It improves 1- and 3-mo survival in nontransplanted patients. More pronounced effect and high level of evidence for high volume plasma exchange
[93]	Review	Plasma exchange	It removes cytokines and albumin-bound toxins, and replaces plasma proteins; it effectively suppresses the inflammatory cascade of liver failure, while substituting clotting factors and correcting coagulation disorders; relatively expensive, it presents transfusion related side effects and cost

LRT: Liver replacement therapy; OS: Overall survival; ALF: Acute liver failure; ACLF: Acute-on-chronic liver failure; uln: Upper limit of normal; LT: Liver transplantation; IL: interleukin; ICU: Intensive care unit; HDU: High Dependency Unit; kDa: Kilodalton; MELD: Model for end-stage liver disease; HRS: Hepatorenal syndrome; HE: Hepatic encephalopathy.

Table 3 Advantages, disadvantages, side effects, complications and contraindications, with intended population to treat, for each liver support system (adapted with modifications from[99])

Method	Advantages	Disadvantages-side effects- complications-contraindications	Intended population
Plasma exchange	Easy operation, broad-spectrum rapid, and efficient removal of various toxins, supplementation of fresh frozen plasma, shorter treatment time, acceptable patient tolerance	Higher treatment cost, poor clearance of water-soluble toxins, aggravation of hepatic encephalopathy, plasma allergy, risk of infection associated with blood products, water and sodium retention after treatment	Patients with hepatic failure, hyperbilirubinemia, cryoglobulinemia, Guillain-Barré syndrome, thrombotic thrombocytopenic purpura, myasthenia gravis
Continuous renal replacement therapy	Hemodynamic stability in critically ill patients, maintenance of cerebral homeostasis, inexpensive and widely available	Unable to remove albumin-bound molecules	Critically ill patients, patients with refractory hepatorenal syndrome
High-volume hemofiltration	More effective removal of medium-sized and water-soluble molecules and cytokines; enhances the elimination of ammonia	Undesirable loss of molecules and substances with functional or beneficial properties, including albumin, nutrients, and antibiotics	Patients with ALF and ACLF, inborn urea cycle disorders, in children and adults with liver failure and hyperammonemia
High cut-off membranes	Removal of uremic toxins	Loss of albumin	Patients with ALF and ACLF
Direct hemoperfusion (Cytosorb)	Reduces the levels of plasma bilirubin, ammonia, bile acids, and C-reactive protein, high safety profile and ease of use	Higher treatment cost Removal of beneficial substances, such as anti-inflammatory cytokines or medications, and thrombocytopenia	Patients with liver failure, drug-induced cholestasis, and acute alcoholic hepatitis; bridge to transplantation in patients with ALF or ACLF
Double plasma molecular absorption system	Rapid removal of bilirubin, inflammatory mediators without requiring exogenous plasma	Inability to replenish coagulation factors; hypotension is likely to occur during the initial treatment period	Patients with liver failure, hyperbilirubinemia, hepatic encephalopathy, perioperative treatment of liver transplantation
Molecular adsorbent recirculating system	Effective removal of protein-bound and water-soluble toxins, excellent biocompatibility, relatively safe	Markedly expensive and complex, cannot supplement coagulation factors	Patients with acute severe liver injury or liver failure
Fractionated plasma separation and Adsorption-PROMETHEUS	Elimination of both water-soluble and albumin-bound toxins and drugs, good safety profile and good hemodynamic tolerance	Markedly expensive and complex, lack of efficient clearance of ammonia and creatinine	Patients with hepatic encephalopathy, hepatorenal syndrome
Single-pass albumin dialysis	Inexpensive, widely available, simple technique, effectively removes bilirubin, bile acids, and other albumin-bound toxins	Significant loss of albumin, metabolic disarrangements and loss of antibiotics	Patients with ALF, Wilson’s disease, acute hepatitis A, liver failure, hepatic encephalopathy, hepatorenal syndrome
Coupled plasma filtration adsorption	Removes medium and small molecular weight water-soluble toxins and is capable of volume regulation and renal support	Higher equipment requirements, higher treatment cost	Patients with liver failure, renal insufficiency, hyperammonemia, rhabdomyolysis, burns, severe autoimmune diseases, poisoning

LSS: Liver support system; ALF: Acute liver failure; ACLF: Acute-on-chronic liver failure.