Extracorporeal therapies for post-liver transplant recipient: The road less traveled

Table 1 Principal mechanism of extracorporeal therapies.

Modality	Mechanism
PMX hemoperfusion	Endotoxin, a cell wall component of gram-negative bacilli, is primary reason for generating inflammatory mediators, the emergence of septic shock, and multiple organ failure
	PMX, a polycationic antibiotic, attaches to lipid A (part of endotoxin), thus neutralizing it
	Toraymyxin® (Toray Medical Co., Ltd., Japan) is a PMX-immobilized fiber blood-purification column
	PMX is immobilized covalently on the surface of polystyrene-derived, polypropylene-reinforced conjugated carrier fiber for selective endotoxin adsorption from the blood
Cytokine adsorption (Cytosorb®)	Cytokine storms are caused by a high number of circulating cytokines and immune cell hyperactivation
	One of the most difficult problems in liver transplantation is adverse immunological reactions mediated by cytokines against the allograft, which can cause early malfunction, severe rejection, and chronic damage
	Hemoperfusion cartridge containing polymer beads to adsorb proinflammatory and anti-inflammatory cytokines but not endotoxins
Oxiris® hemofilter (cytokine + endotoxin removal)	During manufacture, 4500 UI/m2 heparin is pregrafted onto the oXiris® membrane
	A layer of PEI, a positively charged molecule that promotes greater biocompatibility, constitutes the membrane surface treatment
	PEI grafting has the capacity to adsorb large negatively charged molecules, such as endotoxins, due to its higher concentration of free amino groups, which carry a positive charge
	As a result, the oXiris® membrane is composed of three distinct layers
	Thanks to this innovative design, one device may perform four functions: Renal support; cytokine removal; endotoxin removal; and local anticoagulant treatment
Therapeutic plasma exchange	Elimination of large molecules from the blood, such as albumin-bound and water-soluble toxins, followed by replacement with plasma and/or albumin
	Toxins removed include cytokines, endotoxins, bilirubin, bile acids, ammonia, and aromatic amino acids
Molecular adsorbent recirculation system	The system utilizes a dialysate enriched with albumin to aid in the removal of albumin-bound toxins
	It consists of three separate fluid compartments: A blood circuit, a circuit with 600 mL of 20% human albumin that includes a charcoal column and an anion exchange resin column, and a dialysate circuit
DPMAS	Uses ion exchange resin and neutral macroporous resin to create a new artificial liver model, which may have a better adsorption effect on inflammatory mediators and bilirubin
	It also reduces the risk of allergic reactions and transmitted diseases, among other risks by avoiding any replacement with plasma or albumin
	DPMAS also has drawbacks, like the inability to supplement albumin and coagulation factors
DIALIVE	DIALIVE uses a dual filtration system coupled in series with a renal dialysis machine (Prismaflex, Baxter)
	The first filter is made up of a membrane that enables albumin and cytokines to be ultrafiltered (Septex, Baxter, United States); the second filter, called oXiris® (Baxter, United States), adsorbs damage-associated molecular patterns and pathogen-associated molecular patterns
	20% bottled albumin is added in equal amounts to replace the lost albumin
Prometheus	The Prometheus system operates based on the principle of plasma separation using a filter that allows albumin, clotting factors, and fibrinogen to pass through
	It requires an albumin filter (AlbuFlow® AF 01), a neutral resin adsorber (prometh® 01), an adsorber for anion exchange (prometh® 02), and a polysulfone® high-flux dialyzer with the corresponding tubing system
	Endogenous albumin is passed through the circuit using an Albuflow filter
	Albumin is reactivated in prometh 01 and 02 adsorbers and returned to circulation
	Blood then passes through the polysulfone filter, where it is treated by conventional high flux hemodialysis, eventually returning blood to the patient
ECMO	In veno-venous ECMO, deoxygenated blood is drawn from the venous catheter and pumped into an oxygenator
	This device functions like a synthetic lung, facilitating the exchange of gases by removing carbon dioxide and adding oxygen
	Inside the oxygenator, air and oxygen circulate through small, hollow fibers
	As blood flows through these fibers, oxygen is transferred into the red blood cells, while carbon dioxide is expelled into the fibers
	The carbon dioxide is then eliminated through the exhaust, and the oxygenated blood is returned to the patient via the catheter
	In veno-arterial ECMO, blood is drained from the venous side and pumped into the arterial side, bypassing the heart

DPMAS: Double plasma molecular adsorption system; ECMO: Extracorporeal membrane oxygenation; PEI: Polyethyleneimine; PMX: polymyxin B.

Table 2 Advantages and disadvantages of extracorporeal therapies in post-liver transplant care

Modality	Advantages	Disadvantages
Polymyxin B hemoperfusion	Reduced endotoxemia and potentially improved hemodynamic stability and organ function. Demonstrated positive effects on septic shock caused by gram-negative infections. Can stabilize inflammatory and hemodynamic responses in transplant recipients. Some studies suggest improved survival in specific patient populations	Limited evidence in large, well-designed trials. No consistent reduction in mortality across all trials. Uncertainty around optimal timing for initiation of therapy. High cost and logistical challenges of administering multiple sessions. Not effective for all cases of sepsis, especially when endotoxin levels are low
Cytokine adsorption (Cytosorb®)	Removed a broad spectrum of proinflammatory cytokines, potentially preventing or mitigating cytokine storms and graft rejection. Demonstrated high clearance rates of cytokines (> 90%-95%) in vitro. Can be combined with other therapeutic approaches such as continuous renal replacement therapy. May improve hemodynamics and blood lactate levels in some patients	Clinical evidence is limited and inconsistent, with no definitive survival benefit. Primarily used in case reports or small case series, so generalizability is uncertain. Does not target endotoxins, limiting its effectiveness in endotoxin-driven sepsis. Expensive and may require extended treatment (e.g., 6 h per day). No specific cutoff value of interleukin-6 to initiate cytokine adsorption
oXiris® hemofilter (cytokine + endotoxin removal)	Multitasking device capable of removing endotoxins and cytokines and providing renal support. It showed promise in managing septic shock and liver dysfunction post-transplant. Can provide anticoagulation during treatment, reducing the need for additional medications	Clinical outcomes are not consistently improved in large trials. Data from case reports and small studies did not establish clear benefits in post-transplant care. More research is needed to confirm its clinical efficacy and safety in the liver transplant population
Molecular adsorbent recirculation system	Effectively removed toxins and promoted liver function in cases of liver failure. Showed benefits in early allograft dysfunction and primary allograft nonfunction. Decreased serum bilirubin levels, bile acids, serum creatinine, and ammonia levels	Expensive and resource intensive. Long treatment sessions are required (several hours). Evidence for significant survival benefit remains limited. Not universally available, limiting its application in all settings
Therapeutic plasma exchange	Can remove circulating immune complexes, toxins, and cytokines, potentially improving graft survival and reducing inflammation. Established role in managing autoimmune liver diseases, which could benefit patients after transplant. Some studies suggest improvement in post-transplant liver function	Does not directly address the underlying cause of inflammation; only removes circulating mediators. Limited evidence for efficacy in the specific post-transplant setting. Requires multiple sessions, potentially leading to increased costs and complications like transfusion-related acute lung injury, transfusion-associated circulatory overload, etc.
Extracorporeal membrane oxygenation	Provides respiratory and circulatory support in patients with hepatopulmonary syndrome, portopulmonary syndrome, and/or respiratory failure. Can improve oxygenation and hemodynamics in critical patients, reducing the need for mechanical ventilation. Acts as a bridge to recovery	High risk of complications, including bleeding, infection, and organ dysfunction. High resource utilization and intensive monitoring required. Does not address liver dysfunction directly; only provides supportive care