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

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.