Artificial Liver Support Systems

Abstract

Acute liver failure and acute-on-chronic liver failure, regardless of the etiology, generate an inflammatory response in the liver parenchyma and systemic inflammatory response, as well as anti-inflammatory counterregulatory mechanisms that condition a state of immunomodulation, a condition that favors sepsis and septic shock. The increase in Von Willebrand factor and the increase in cellular traffic of monocytes and macrophages in the hepatic sinusoids, altering hepatic hemodynamics, is another mechanism of damage. Artificial liver support therapy represents an alternative in the support of these patients when medical treatment does not achieve the objectives. MARS, Prometheus, and SPAD favor detoxification. Plasma exchange and DPMAS are alternatives to limit the inflammatory response, eliminate Von Willebrand factor, and improve survival. Current evidence recommends the use of plasma exchange or combined extracorporeal support therapies as an alternative to achieve organ recovery or as a bridge to liver transplantation.

1. Introduction

Liver diseases represent the tenth leading cause of death in the world and one of the leading causes of disability and years of life lost. Regardless of the etiology of liver disease, only 10% of those who require an organ get a transplant.

Acute liver failure and acute-on-chronic liver failure are serious pathologies, which despite the treatment of the cause and the associated complications, many of them require organ support through an artificial or biological system until the recovery of the liver is achieved. Liver support systems act as a bridge to liver transplantation [1].

2. Spectrum of liver diseases

Liver diseases are associated with poor outcomes and are often considered a medical emergency due to the severity and complications associated with mortality.

In the spectrum of the form of presentation, three entities are evident [2]:

1. Acute liver failure (ALF) in the context of health and normal liver function associated with a new noxa that determines the damage.

2. Acute-on-chronic liver failure (ACLF) develops on a background of chronic liver disease without cirrhosis or with underlying cirrhosis.

3. Known cirrhosis suffering from decompensation of liver function.

See Figure 1.

Figure 1.

Acute liver diseases are described: acute hepatitis, acute liver injury, and acute liver failure.

3. Acute liver failure

It represents a form of critical illness, potentially fatal, that occurs in 1 case per million, and the incidence is variable in each continent: Europe 0.62, Asia 6.2–23.8, USA 0.19 cases per 100,000 person-years [3]. The most frequent cause is paracetamol poisoning, followed by undetermined causes, drug-induced injury (DILI), and hepatitis [4].

Acute liver failure (ALF) represents severe liver damage (transaminase elevation x 3) with the development of hepatic encephalopathy preceded by jaundice. This time interval from jaundice to the presence of encephalopathy [5] allows its classification (Table 1):

Author	O’grady	AIEH
Hyperacute	1–7  days	< 10 days
Acute	8–28 days	10–30 days
Subacute	5–12 weeks	5–24 weeks
Chronic	> 26 weeks	> 24 weeks

Table 1.

Classifications of acute liver failure, which correspond to the time interval from the onset of jaundice to the development of encephalopathy.

4. Acute on chronic liver failure

The development of acute liver failure on chronic failure (ACLF) occurs at any stage of the spectrum of chronic liver disease without cirrhosis or with compensated or decompensated liver cirrhosis [6], in which there are one or several precipitating events in the liver (alcohol ingestion, DILI, hepatitis, hepatic ischemia, liver surgery) or extrahepatic (acute bacterial infection, paracentesis without albumin, major surgery), which cause the development of multiple organ failure with the increased mortality between 28 and 90 days (Figure 2) [7].

Figure 2.

In the spectrum of chronic liver disease without cirrhosis or with compensated or decompensated liver cirrhosis, the clinical condition that favors exposure to a hepatic or extrahepatic precipitant generates an inflammatory response that induces the development of multiple organ failure.

There is no universal definition, there are at least four consensuses that define it and the prevalence differs from continent to continent, in USA 10, EU 20.1, ASIA 5.1 cases per 1000 person-years [8].

The most agreed definitions of ACLF are mentioned below: (Table 2) [7],

APASL	EASL-CLIF	NACSELD	WGO
Acute liver damage manifesting as Jaundice (BT 5 mg/dl) and coagulopathy (INR > 1.5), complicated within 4 weeks with ascites and encephalopathy in a patient with diagnosed or undiagnosed chronic liver disease.	Pre-existing CLD acute deterioration, related to a precipitating event associated with multiorgan failure with high mortality at 28 and 90 days.	Syndrome characterized by acute deterioration in a patient with cirrhosis, due to an infection, developing failure of two or more extrahepatic organs.	Syndrome in CLD with or without previously diagnosed cirrhosis is characterized by acute hepatic decompensation, resulting in liver failure (jaundice and prolonged INR) and failure of one or more extrahepatic organs with high mortality at 28 and 90 days.

Table 2.

Characteristics of definitions of ACLF developed by four different consortia.

Asian Pacific Association for the Study of the Liver (APASL), European Association for the Study of Chronic Liver Failure (EASL-Clif), North American Consortium for the Study of End-Stage Liver Disease’s definition of acute-on-chronic liver failure, and World Gastroenterology Organization (WGO).

The severity of ACLF is measured by the degree of organic dysfunction through the CLIF-SOFA score in different cohorts of three subjects (CANONIC, PREDICT, KACLIF, COSSH, MAHMUD, HERNAEZ) showing us that the analytical alteration is significant insofar as to the presence of leukocytosis, PCR, increases in TNF alpha, and IL-8 in statistically significant values in patients with ACLF when compared with decompensated or compensated cirrhosis. Likewise, it is observed that transplant-free mortality is higher in patients with ACLF [8].

5. Pathophysiology

5.1 Inflammatory response

5.1.1 Acute liver failure

Regardless of the etiology of liver damage, apoptosis and hepatocyte necrosis are generated, which allows the release of damage-associated molecular patterns (DAMPs), such as micro-RNA 122, high mobility protein 1 (HMGB1), Keratin 18, which bind to toll-like receptors (TLR4) of Kupffer cells, which induces the release of cytokines.

Activation of the Kupffer cells induces the release of cytokines, which stimulates the recruitment of monocytes and induces an intrahepatic inflammatory phenotype, with sequestration of platelets and amplifying the inflammatory response. The inflammatory process is not limited to the liver, this induces a systemic inflammatory response (SIRS), and a counterregulatory mechanism called compensatory anti-inflammatory response syndrome (CARS) is induced, the latter conditions a state of immunomodulation, which explains the high risk of infections, risk of sepsis, multi-organ failure, and worsening of encephalopathy (Figure 3) [9].

Figure 3.

A) Regardless of the etiology of the liver injury, the release of DAMPs is generated, recognized by the TLR4 of Kupffer cells. B) Activated Kupffer cells release cytokines, which stimulate monocyte migration, amplifying the inflammatory response within the liver. C) Inflammation is not limited to this organ and generates SIRS; likewise, a counterregulatory mechanism (CARS) is stimulated, which leads to a state of immunoparalysis and increases the risk of infections. D) Albumin in its oxidized form contributes to the perpetuation of the inflammatory state. E) Damage to the stellate cells of the hepatic sinusoids decreases the release of ADAMTS 13, increases the expression of VWF multimers, favors platelet aggregation that predisposes to the formation of microthrombi, and, together with the increase in monocyte and macrophage trafficking, alters hepatic circulation.

Neopterin formed by macrophages, monocytes, and activated dendritic cells has been described; it is considered a marker of inflammation in ALF due to acetaminophen. It is evident that the increase in neopterin and sCD163 correlates with SIRS, greater clinical severity measured by SOFA score, and with the requirement of liver transplantation [10]. The aforementioned supports the increase in mononuclear cell activity and the increase in the inflammatory response in ALF.

Acute liver failure has great potential to develop multi-organ complications (cerebral, respiratory, metabolic, hematological, hemodynamic, infectious, and renal) despite supportive management, many of them do not stabilize and lead to an increase in mortality. In this critical condition, extracorporeal liver support therapies are used until the recovery of liver function, which, in some series, reaches 60% of acute patients and without reaching transplantation [11].

5.1.2 Acute chronic liver failure

It represents the spectrum of chronic liver disease without cirrhosis or with compensated or decompensated cirrhosis, in which a hepatic or extrahepatic precipitating factor triggers a persistent inflammatory response that induces the development.

TNF alpha and activated stellate cells, allowing nitric oxide secretion, further damage hepatocytes and cause splanchnic vasodilation. The endothelin released from endothelial cells decreases the expression of cluster of differentiation (CD) and human leukocyte anti-DR (HLA), conditions an environment of TL reg inhibition, and lowers LTH 17 activation. This conditions a state of “Ineffective Immunity,” dysfunctional cells, decreased phagocytic activity, increased anti-inflammatory cytokines, and release of reactive oxygen species (ROS) [12].

ACLF conditions a SIRS state in the first 7 days from the onset of the symptoms and after 10–14 days, a state of immunosuppression due to anti-inflammatory cytokines (CARS) is generated, increasing the risk of sepsis, septic shock, and multiple organ failure (Figure 4) [13].

Figure 4.

A) In chronic liver disease without cirrhosis and in compensated or decompensated cirrhosis, they generate the favorable environment for the arrival of PAMPs in the enterohepatic circulation, mitochondrial stress, apoptosis, and necrosis typical of liver disease, regardless of the etiology, allowing the release of DAMPs. Both molecules bind to TRL4 receptors of Kupffer cells, which are activated and release cytokines with hepatic and systemic impact. B) The intrahepatic inflammatory response and the release of chemokines induce chemotaxis of monocyte-derived macrophages from the systemic circulation to the liver at sites of injury. C) Albumin in the oxidized form contributes to the perpetuation of the inflammatory state. D) Damage to the stellate cells of the hepatic sinusoids decreases the release of ADAMTS 13 and increases the expression of VWF multimers that favors platelet aggregation and stimulates phagocytosis of these molecules by macrophages, increasing cell size and increasing the number of cells. Cell traffic contributes to lower liver perfusion.

The severity of ACLF measured by CLIF-SOFA has a direct relationship with mortality. The measures used in the management with crystalloid solutions and human albumin, and the use of vasoactive agents are a necessity to meet the hemodynamic objectives, anti-encephalopathy measures, and anti-cerebral edema. The need for transfusion of blood products and the support of mechanical ventilation and infection control represent the supportive management of these patients. Many of them, despite the optimization of the measures implemented, require extracorporeal liver support therapy, which, as in acute liver failure, has the clear objective of limiting the inflammatory response that perpetuates cell damage, decreasing macrophage activation that conditions the permanent inflammatory response.

5.2 Oxidation of albumin

Albumin is a high molecular weight protein (MW 66.5 kD), which is a fundamental determinant since it provides 75% of the oncotic pressure, necessary to maintain fluids in the intravascular compartment, and represents 54% of the plasma proteins, with a hepatic synthesis rate of 150 m/kg/day [14]. Albumin is formed by a polypeptide chain of 585 amino acids, divided into three domains I, II and III. Each domain is subdivided in types A and B, it is composed of 35 cysteine residues, of which 34 residues form 17 disulfide bridges and leave the cysteine residue (Cys) 34 free to interact with others molecules (Table 3) [15].

Domain I	Domain II	Domain III	CYS 34
Uremic toxins; Thyroxin; Warfarin	Halotan; Propofol; Ibuprofen; Uremic toxins; Thyroxin	Bilirubin; Hemin; Doxorubicin	Nitric oxide

Table 3.

Each albumin domain allows the transport of different substances, and the CYS 34 residue has the capacity to eliminate ROS.

The important functions of albumin include being a regulator of extracellular fluids, it allows the reversible transport of endogenous products, such as fat-soluble hormones and free fatty acids, transporting unconjugated bilirubin, and exogenous products such as metals, drugs, and drugs. It also fulfills a function important in PH control, buffering non-volatile acids, and competitive binding to calcium ions. Antioxidant properties are described because it is a source of reduced sulfhydryl groups with properties to eliminate ROS, with anti-inflammatory and endothelial protection effects [14].

Albumin mostly circulates in a reduced state, called human mercaptoalbumin (HMA) with a free thiol group at residue Cys 34, to which ROS and nitrogen bind, allowing their uptake and removal of free radicals. Albumin can undergo several post-translational modifications in physiological or pathological conditions, which undergoes oxidation through disulfide bonding between Cys34 and sulfhydryl-containing compounds such as glutathione, homocysteine, and cysteine. This reversibly oxidized form of albumin is called non-mercaptoalbumin type 1 (HNA-1) and the complete and irreversible oxidation of Cys 34 albumin to sulfonic or sulfinic acid confers the name non-mercaptoalbumin type 2 (HNA-2) [16, 17]. Other forms of modified albumin are also described, such as ischemia-modified albumin (IMA), in which it undergoes a conformational change in the N-terminal portion, decreasing the metal transport capacity, and the IMA/albumin ratio is also increased in patients. with cirrhosis and ACLF, described as a marker associated with higher mortality. Other forms of cystei-nylated, glycated and truncated modified alumina are mentioned, all the described forms of oxidized albumin lose the capacity to transport molecules and detoxify, increasing the free component of many toxic substances that alter the functions of organs and systems [17].

The expression of non-mercaptoalbumin types 1 and 2 has an effect on the activation of mononuclear cells by stimulating the release of cytokines (IL 1β, IL 6, IL 8, and TNF-α), amplifying or perpetuating the inflammatory response, by which a relationship between the levels of oxidized albumin and the pro-inflammatory state exists. In a cohort study of 79 patients, non-mercaptoalbumin type 1 phosphorylated the mitogen-activated protein kinase (MAP) p38α [18] was observed, which increases the activity of the transcription factor NF-κB, induces the production of cytokines, and also increases the production of inflammatory COX2 eicosanoides such as thromboxane A 2 (TXA2), leukotriene B 4 (LTB4), and prostaglandin G2 (PG2) [18].

We see that albumin oxidation is a mechanism that by itself induces and perpetuates inflammation in patients with decompensated cirrhosis and acute-on-chronic liver failure, which opens the way for the search for other applications of extracorporeal liver support therapies.

In a randomized crossover design trial of eight patients with ACLF, who underwent alternate eight treatments with MARS and Prometheus, non-mercaptoalbumin types 1 and 2 levels were measured and found to be elevated, and there was a transient change in status redox, from non-mercaptoalbumin to mercaptoalbumin that lasted a short time, returning to the oxidized forms of albumin after 24 hours [19].

There are few studies that evaluate extracorporeal liver support techniques as an alternative for albumin detoxification or regeneration. The Molecular Adsorbent Recirculating System (MARS) was found to be useful in removing substances bound to albumin and improving hepatic encephalopathy, but in a small study of 34 MARS patients [20], it did not show benefit in improving functional capacity or regenerating capacity and normal functionality of albumin. It is possible that liver damage and inflammation lead to irreversible damage to albumin and extracorporeal liver support techniques based only on albumin recirculation with small-capacity and easily saturated adsorbents.

5.3 Von Willebrand factor and ADAMTS 13 effect on ALF and ACLF

The Von Willebrand factor (VWF) is formed by endothelial cells, megakaryocytes, and hepatocytes in the latter when the hepatic injury occurs [21]. This factor is cleared by macrophages and stored in endothelial cells, in Weibel-Palade bodies, and in the alpha granules of megariocytes.

VWF has MW 10,000 KD and is released at sites of vascular damage in response to secretion stimuli, such as thrombin, endothelial stress, vasopressin, or its synthetic analog desmopressin.

In ALF and ACLF, it generates damage to the endothelial cells of the liver sinusoids and releases VWF multimers, which bind to Domain A1, Glycoprotein IB Alpha (GPIbα), and GPIIb/IIa of platelets, and subendothelial collagen, allowing adhesion, platelet aggregation, and sequestration, giving rise to the formation of microthrombi and generating intrahepatic hemodynamic changes and liver ischemia, cell necrosis, worsening of liver function, activating innate immunity, and contributing to the development of multi-organ dysfunction [22].

Basic experimentation studies in mice with ALF by paracetamol show an increase in VWF and platelet aggregation after 48 hours after drug exposure [21, 23]. In a prospective study of patients with ACLF, increased VWF was correlated with higher MELD and SOFA scores [22].

Damage to stellate cells determines a lower release of ADAMTS 13. Under normal conditions, this disintegrin metalloproteinase cleaves the TYr 1605-Met 1606 bond of the VWF A2 domain, degrading the VWF multimers. In ALF and ACLF, low levels of ADAMTS 13 [24, 25] are identified, causing less cleavage of the VWF multimeters. These new links require further studies on the use of VWF inhibitors, ADAMTS 13 supplementation, or the use of extracorporeal liver support therapies for the removal of VWF multimers [25] and limiting liver damage.

5.4 Macrophage activation

When hepatocyte damage is generated, Kupffer cells express two phenotypes: proinflammatory where Kupffer cells release cytokines (IL-1β, tumor necrosis factor (TNF)-α and Ccl2), the chemokine Ccl2 and the activity of plasmin during liver tissue damage, stimulating the chemotaxis of monocyte-derived macrophages from the systemic circulation to the liver at sites of injury, in order to control intrahepatic trafficking, endocytosis, phagocytosis, and phenotype switching to one of repair with dedifferentiation of macrophages to fibroblasts [26].

Under healthy conditions, macrophages constitutively present CD163 and CD206 receptors. During the proinflammatory phase of ALF and ACLF, a detachment of soluble sCD163 and sCD206 is generated, and the severity of ALF, ACLF, and mortality is considered biomarkers [27], which may play a role in making early medical or transplant decisions.

Macrophages are persistently activated in the presence of VWF and these cells are located in low-pressure sinusoids, being the parking residence of activated macrophages and which, together with microthrombi, alter hepatic hemodynamics.

The lines of study in inhibitors of macrophage chemotaxis, the use of extracorporeal liver purification therapies in the elimination of cytokines and chemokines, and achieving immunomodulation that allows limiting the migration of mononuclear cells to the liver and mitigates the damage may be promising.

5.5 Extracorporeal liver support therapy

Liver support therapies have been used with the aim of trying to replace the loss of important functions of the liver, and these systems are limited to detoxification and to reduce the inflammatory response.

5.5.1 Types of extracorporeal liver support therapy

They are divided into artificial and biological [28]. In this review, the description of artificial therapies will be made (Table 4).

Artificial	Biological
MARS Fractionated plasma separation and adsorption (Prometheus) Single-pass albumin dialysis (SPAD). Hemoperfusion Plasma exchange Plasma adsorption Double plasma molecular absorption system (DPMAS)	ELAD® BiologicDT Hepa-Mate™ TEAK-BALSS/HBAL AMC-BAL HEPATASSIST SYSTEM

Table 4.

Classification of liver support systems.

The artificial liver support system allows the removal of water-soluble toxins, such as ammonium, urea, creatinine, iron, aromatic amino acids, trypophan, and also fat-soluble toxins, such as bile acids, conjugated and unconjugated bilirubin, short and medium chain fatty acids, benzoadiazepines endogenous, mercaptans, copper, nitric oxide, indoyxisulfate, and protoporphyrin [29].

We consider that the removal of the mentioned toxicants with detoxification-only approach does not generate the clear benefit due to the extensive mechanisms of perpetuation of liver damage, it is possible that the traditional MARS, Prometheus techniques are not good enough due to the smaller diameter of the beads, smaller pore diameter, smaller amount of resin, and smaller adsorbent surface in the first two and that the concentration of albumin used in MARS and SPAD is not sufficient, and these details will be reviewed in each of the techniques extracorporeal support.

5.5.2 When to start extracorporeal liver support therapy?

The most agreed recommendations for the start of extracorporeal support are the following [30]:

1. Severe acute liver injury regardless of cause.

2. Acute liver failure regardless of cause.

3. Acute on chronic liver failure.

4. Sepsis with severe liver injury.

5. Acute kidney injury with criteria for hepatorenal syndrome that does not respond to treatment with Terlipressin and albumin.

6. Primary nonfunction and delayed graft function following liver transplantation.

7. Delayed graft function in simultaneous liver kidney transplantation.

8. Post-hepatectomy liver failure.

9. Hypoxic liver injury.

10. Refractory pruritus.

5.5.3 Artificial extracorporeal liver support systems

5.5.3.1 Molecular adsorbent recirculating system (MARS)

This purification system allows the elimination of toxins bound to albumin and water-soluble toxins. The blood that is extracted by catheter circulates at a blood flow of 200 ml/min and is placed in contact with the high permeability MARS® FLUX 2.1 filter (60 kD) and 600 ml of dialysate albumin circulates counter currently with pumped 150 ml/min. This recirculated albumin is placed in contact with the diaFLUX 1.8 filter and with the conventional dialysis bath of the Prismaflex System, allowing the elimination of water-soluble molecules, and the regenerated albumin circulates through the activated carbon cartridge (diaMARS® AC250) that captures cationic toxins and then goes to a second resin cartridge (diaMARS® IE250) that captures anionic toxins. The procedure is performed with an average of 8 hours up to date, with the aim of reducing total bilirubin by more than 25% in each session, achieving a reduction in nitrogen and ammonia and reversing encephalopathy (Figure 5).

Figure 5.

Molecular adsorbent recirculating system (MARS). A) Once the patient’s blood enters the high permeability (60 kD) MARS® FLUX 2.1 filter, 600 ml of dialysate albumin circulates in a countercurrent direction with pumped 150 ml/min. B) Then, the recirculated albumin is directed to the diaFLUX 1.8 filter and with the conventional dialysis bath of the Prismaflex system, allowing the elimination of water-soluble molecules. C) Next, the regenerated albumin circulates through the activated carbon cartridge (diaMARS® AC250) that captures cationic toxins. D) It is then directed to a second resin cartridge (diaMARS® IE250).

In the FULMAR study [31], a randomized control trial (RCT), a multicenter study that included 102 ALFs on the liver transplant waiting list, of which standard medical treatment (SMT) vs. SMT and MARS were compared, in this study, it was seen that overall survival at 6 months, transplant-free survival at 6 months, and survival at 1 year were not significantly different in both groups, but transplant-free survival was better in those patients who received more than 3 MARS sessions (p = 0.001) when compared to STM. In relation to other outcomes, there was no improvement in encephalopathy between both treatment groups, but a significant decrease in bilirubin, creatinine, and lactate values ​​was achieved compared to SMT, and it is a valuable therapy in patients who are not candidates for liver transplantation.

In the RELIEF study [32], a multicenter RCT, recruited 189 patients with decompensated cirrhosis (total bilirubin > 5 mg/dl, hepatorenal syndrome or hepatic encephalopathy grade II) and compared STM vs MARS and STM treatment, there were no differences in survival at 28 and 90 days, in the survival analysis by subgroups there were no differences in survival either, without differences in the length of stay in intensive care and hospital stay, but a significant decrease in bilirubin and creatinine values was achieved in favor of therapy MARS. The lack of evidence is attributed, whether it is related to the heterogeneity in the definition of ACLF, small sample size, low dose of therapy, rapid saturation of the cartridges and albumin, or that MARS therapy does not adjust to the severity of many patients.

A meta-analysis published by Arjun Vaid et al. [33] review 10 RCT and one no RCT and use the Jadad scale to assess the quality of the studies, recruited patients, including ALF and ACLF, and receive MARS from one to 10 sessions, lasting between 6 and 8 hours. The outcomes show a significant decrease in bilirubin levels (p = < 0.001), there was also improvement in encephalopathy (p = <0.001), but MARS therapy did not reduce mortality (p = 0.62), in the analysis by subgroups when performing more than three sessions or increasing the concentration of albumin >20%, which did not influence the reduction of mortality.

Rafael Banares et al. [34], published a high-intensity MARS meta-analysis, recruited 285 patients with ACLF and called high-intensity MARS when they received more than 5 sessions. In the high intensity group, 10-day survival (p = 0.001) and 30 days (p = 0.041) is higher and there was a significant decrease in the MELD score, bilirubin, creatinine, and encephalopathy improvement, compared to the low intensity group, when the number of sessions was less than 5 MARS sessions.

One recently published DELPHI consensus of international experts [35] recommends extracorporeal albumin dialysis (ECAD) in the MARS modality should be started in the early stages of grade II encephalopathy or within 24–48 hours of refractory hepatic encephalopathy and when indications for liver transplantation are present and more than 3 sessions lasting 8 hours are recommended. The reported evidence mention improvement in survival at 21 days in ACL due to acetaminophen, but no benefit at 6–12 months. The use of ECAD is not recommended in patients in the late stages of ALF where multiple organ dysfunction is already expressed.

6. Prometheus

It is a fractionated plasma separation and adsorption system, the blood extracted through a catheter circulates through an AlbuFlow® AF01 filter, with a high screening coefficient (250 kD), which separates the albumin from the blood, the first to pass through the plasma to an adsorbent cartridge Prometh® 01 contains a neutrally charged, highly porous resin that absorbs bile acids, aromatic amino acids, and phenols. Then, the plasma and the albumin circulate through a second Prometh® 02 cartridge, which is an anion exchange resin in the form of chloride that allows the absorption of bilirubin, and following the sequence of the circuit, the blood plasma and the detoxified albumin are returned to the Fresenius® helixone high-flow filter to remove water-soluble toxins (Figure 6).

Figure 6.

Fractionated plasma separation and adsorption (Prometheus). A) The blood extracted through a catheter circulates through an AlbuFlow ® AF01 filter. B) Albumin and separated plasma pass to a Prometh® 01 adsorbent cartridge. C) Albumin then circulates through a second Prometh® 02 cartridge. D) Following the circuit sequence, blood plasma and detoxified albumin are returned to the Fresenius® helixone high-flow filter.

In the HELIOS study [36], an RCT included 145 patients with ACLF and compared SMT vs. SMT and Prometheus, in the survival outcomes at 28–90 days there were no statistical differences, the mean until death had no differences, and the severity of MELD and encephalopathy improved in the Prometheus group, in the univariate analysis there was no improvement in survival in patients with hepatorenal syndrome, the length of stay in critical care and the hospital was similar in both groups, and in the analytical the only value that improved it was the bilirubin.

7. Mars and prometheus theory combination

In a randomized crossover design study, eight patients with ACLF who underwent MARS and Prometheus on alternate days were evaluated, completing 17 sessions for each of the two artificial liver support systems. Cytokine measurements were performed in healthy controls and in patients with ACLF, evidencing elevated IL-6, IL-8, IL-10, TNF-α, and sTNF-αR1 values ​​in the latter group. This work shows that there was no significant decrease in cytokines at the end of treatment and other reviews with both artificial support systems report similar results. The low efficiency is attributed to the high rate of cytokine production due to multiple mechanisms of the perpetuation of the inflammatory response, the greater saturation of the cartridges, or less adsorbent capacity [37, 38, 39].

8. Single-pass albumin dialysis (SPAD)

This purification system that uses the physical foundation of diffusion with a dialysis bath enriched with albumin in 3–4% concentrations that act as a binder for substances bound to proteins. This technique uses a continuous renal replacement therapy (CRRT) machine in continuous venovenous hemodialysis modality, with a dialysate flow of 700–1000 ml/min. The dialysate flow with albumin will allow the capture of lipophilic molecules present in the patient’s blood that will bind to the albumin that circulates in the countercurrent direction to the blood flow through the filter, allowing the elimination of bilirubin, bile acids, and nitrogen acids (Figure 7).

Figure 7.

Single-pass albumin dialysis (SPAD). A) The technique uses a continuous renal replacement therapy (CRRT) machine in continuous venovenous hemodialysis modality, with a dialysate flow of 700–1000 ml/min, the dialysate is enriched with 3–4% albumin.

This technique does not use additional cartridges or other extracorporeal circulation machines and can be performed in low-income countries.

There is evidence that SPAD allows a significant decrease in bilirubin similar to MARS, but it failed to lower bile acid and cytokine values [40], considering that the modality used is continuous venovenous hemodialysis and due to the screening coefficient of conventional membranes does not allow clearance of cytokines [41].

In a randomized crossover trial [42], of 34 patients with ACLF, who underwent dialysis with albumin, assigning the first session randomly to MARS or SPAD modality, the second session was assigned to a different therapy. Both therapies achieve a significant decrease in bilirubin, bile acids, and a greater decrease in creatinine with MARS. The significant decrease in fibrinogen in SPAD was identified as an adverse effect, and both therapies decreased hemoglobin, hematocrit, and platelets. Both therapies are considered comparable, with the advantage of the lower costs of SPAD.

9. Plasma exchange

The plasma exchange (PE) is an extracorporeal purification technique that is carried out by centrifugation or filtration. This last technique uses a high permeability membrane with a large pore size greater than 0.3 microns, allowing the separation of plasma and the removal of medium and medium molecules with high molecular weight, such as cytokines and immunoglobulins (Figure 8).

Figure 8.

Plasma exchange (PE). The technique uses a high permeability membrane with a large pore size that allows plasma separation and replacement of the extracted volume is performed with 5% albumin or fresh frozen plasma.

Within the pathophysiological mechanisms of acute and chronic liver injury, the increase in Von Willebrand multimeters stands out due to a decrease in the release of ADAMTS 13 as a result of stellate cell damage. The increase in the Von Willebrand factor multimeters intervenes in platelet aggregation in the hepatic sinusoids and conditions the migration of macrophages for their phagocytosis, and both alterations condition a deterioration of the vascular flow of the liver and also condition a greater inflammatory response.

Klaus Stahl et al. [43], in a single-center prospective study, demonstrated in 31 patients with sepsis that plasma exchange increased ADAMTS 13 activity and decreased VWF antigen, confirming the therapeutic application of this imbalance.

The RCT described by Larsen et al. [44], through an RCT in 182 patients with ALF, evaluated SMT vs. SMT and high volume plasma exchange for 3 days (8–12 L) with replacement with fresh-frozen plasma in equivalent volume. In the consulted evidence, the primary outcome that corresponds to liver transplant-free survival during the hospital stay was higher in the group that received plasma exchange (p = 0.0083), and survival in those who did not receive a transplant and received plasma exchange was better when compared with those who were not transplanted and did not receive plasma exchange. In the group with plasma exchange, the hemodynamic variables improved, noradrenaline doses were reduced, the SOFA and Clif SOFA severity scores improved, and the analysis showed improvement in coagulation times, decreased bilirubin, alanine aminotransferase (ALT), and ammonium. When the inflammatory response is assessed, plasma exchange reduces DAMPs, TNF alpha, IL 16 at 48 hours, and IL 18, and decreases in CD 163, CD 64, and CCR7, which indicates less mononuclear cell traffic.

High-volume plasma exchange carries risks with high replacement volume and could worsen cerebral edema, Maiwall et al. [45], report a prospective open-label RCT study where 40 patients with ALF were recruited, each group was divided into 20 patients for SMT vs STM and standard plasma exchange (1–1.5 plasma volumes per PE session). The outcome of transplant-free survival at 21 days was higher in the group with plasma exchange (p 0.04). In the secondary outcomes, there is evidence of a lower inflammatory response and a smaller diameter of the optic nerve sheath with a predictor of decreased cerebral edema, hemodynamic variables, vascular resistance index improved, SOFA score decreased, there was a decrease in lactate and bilirubin values they also decreased. When inflammation data are analyzed, a decrease in innate immunity cytokines and an increase in anti-inflammatory cytokines, a significant decrease in DAMPs, endotoxins, and a decrease in VWF are evident in the group that received exchange plasma.

In a retrospective study [46] of 50 patients with alcohol-related acute on chronic liver failure (A-ACLF), low-dose corticosteroid treatment was compared with low-volume plasma exchange (LVPE) (0.5–1 plasma volumes per PE session) vs. SMT, Kaplan-Meier survival analysis shows better survival in the first year (P = 0.03) and there were lower levels of VWF in the plasma exchange group. Further large randomized control trials are needed to evaluate the efficacy of LVPE in ACLF.

In a systematic review and meta-analysis [47] of 16 RCTs that included 1670 patients with ALF, the efficiency of each therapy was compared to SMT, ELAD, MARS, Prometheus, and plasma exchange. It is shown that the probability of having greater overall survival at the first and third month as well as transplant-free survival at 3 months was better with exchange plasma.

The European Association for the Study of the Liver [11], in the guidelines for the management of acute liver failure, recommends plasma exchange improves transplant-free survival and modulates immune dysfunction with evidence level I, grade of recommendation 1. and recommends early onset and in those who will not undergo liver transplantation with evidence level I, grade of recommendation 2.

One DELPHI consensus of international experts [35] recently published, in relation to PEHV, is recommended due to the greater transplant-free and in-hospital survival. The PLAS score [48] uses two derivation and validation cohorts of patients with ACLF, whose predictive value for 3-month mortality when the score was greater than 6 points (AUC 0.80 derivation cohort and 0.78 validation cohort) has better performance when it is compared with the model for end-stage liver disease (MELD) and also with other mortality scores. The variables taken into account for stratification are liver cirrhosis total bilirubin, PT-INR, infection, and hepatic encephalopathy. The score goes from a minimum of 0 to a maximum of 9, it is called grade I: score of 0–2, grade II: 3–5, grade III: 6–9 (Table 5).

Points	Liver cirrhosis	Total bilirubin (μmol/L)	PT-INR	Infection	Hepatic encephalopathy
0	No	< 425	< 2.0	Non-spontaneous bacterial peritonitis (SBP)	No
1	And it is	425–650	2.0–2.5	Yes SBP	I–II
2	And it is	≥ 650	≥ 2.5	SBP plus other site infection	III–IV

Table 5.

PALS score predictive score of short-term prognosis for patients treated with plasma exchange.

Extracorporeal liver support therapy is not recommended in patients who develop platelet counts <40,000/mm3, INR > 2.5, and fibrinogen <1 g/L, which would increase the risk of bleeding [35].

10. Plasma adsorption perfusion

Plasma adsorption perfusion (PAP) uses a CRRT or intermittent hemodialysis machine. Once the blood comes out through the catheter with a blood pump flow at 150 ml/min, it allows the blood to enter the plasma exchange filter where it allows the separation of the plasma by filtration. The obtained plasma is mobilized by a second pump at 25–50 ml/min and enters a cartridge made of styrene-divinylbenzene copolymer, with the capacity to adsorb bilirubin, bile acids, and cytokines. This technique has some advantages over the other techniques mentioned, such as it does not require the use of exogenous plasma or albumin infusion, it does not eliminate coagulation factors, and it is less expensive than MARS (Figure 9).

Figure 9.

Plasma adsorption perfusion (PAP). A) The blood exits through the catheter with a blood pump flow at 150 ml/min, it allows the blood to enter the plasma exchange filter where it allows the separation of the plasma by filtration. B) The obtained plasma is mobilized by a second pump at 25–50 ml/min and enters a cartridge made of the styrene-divinylbenzene copolymer.

A single-center retrospective study [49] evaluated the performance of three therapies (MARS, PAP, and PE) and recruited 103 patients with hyperbilirubinemia due to ALF and ACLF, and extracorporeal liver support therapy was started when the total plasma bilirubin level > 20 mg/dl, or an increase in bilirubin level of more than 2 mg/dl per day for 4 days. When total bilirubin removal is assessed in these therapies, a 25% decrease is considered the optimal value. A greater decrease in bilirubin was seen with PE (35 ± 13%) followed by PAP (30 ± 12%) and the lowest percentage with MARS (24 ± 14%), and the values of transaminases and coagulation tests were not different between the three techniques. In this review, the costs per treatment are mentioned, being the most economical PE, followed by PAP and the most expensive MARS due to equipment and the long time the therapy takes. It is important to mention that an advantage of MARS over the other techniques mentioned is its application in acute kidney injury (AKI) that requires renal support therapy.

11. Double plasma molecular adsorption system

The double plasma molecular adsorption system (DPMAS) modality has the particularity of using a CRRT or intermittent hemodialysis machine with second roller pumps. Once the blood is drawn through the catheter with a blood pump flow of 150 ml/min, the blood passes through a high permeability filter to separate the plasma and then, the separated plasma is driven by a second roller pump at 25–50 ml/min, which enters a first BS330-JAFRON styrene-divinylbenzene cartridge with anion-exchange resin and later the plasma goes through a second HA330 II-JAFRON cartridge with neutral macroporous resin, to then be reconstituted by the plasma in the blood that returns to the patient’s catheter (Figure 10).

Figure 10.

Double plasma molecular adsorption system (DPMAS). A) The blood extracted through the catheter enters a high permeability filter to separate the plasma. B) The separated plasma is driven by a second roller pump that drives the plasma into a first BS330-JAFRON cartridge made of styrene-divinylbenzene with anion-exchange resin. C) Subsequently, the plasma passes through a second cartridge HA330 II-JAFRON with neutral macroporous resin.

The evidence consulted reports an RCT from China [50], which includes patients with ALF and ACLF. They are randomized into two groups, 20 patients in the SMT and PE group vs. 27 in the SMT and DPMAS group. The result in the primary outcome shows a survival at 4–12 months is similar in both groups (p = 0.887), in the secondary outcomes measurements of bilirubin and CRP are performed, which decrease more significantly with PE (p = 0.002), and the decrease in procalcitonin was similar in both groups, greater hypoalbuminemia in the PE group. The increase in IL-6 is strikingly evident in both groups and is attributed to being a stimulatory factor in liver regeneration.

During a meta-analysis [51] of 11 articles on ACLF due to hepatitis B, where the values of total bilirubin and albumin did not differ in both groups, ALT decreased more in DPMAS+PE than, with PE alone, the levels of I international standardized ratio (INR) and blood platelet (PT) were prolonged, but there were no significant differences between the two groups. In this study, there was a lot of heretogenicity in study quality which could lead to bias.

In another meta-analysis [52] of 11 RCT studies, including 1087 hepatitis B patients with ACLF, comparing two treatment groups with DPMAS + plasma exchange vs. plasma exchange alone, 90-day survival was higher with DPMAS + plasma exchange (P = < 0.00001), and bilirubin and alanine aminotransferase values ​​after treatment were lower with DPMAS + PE (P = < 0.00001) and (P = 0.02), respectively. There was no statistical significance in prothrombin activity (PTA), PT, platelets (PLT), INR, and hemoglobin (HB).

In a retrospective controlled study [53] with DPMAS where 131 with ACLF for hepatitis B were recruited, they were assigned to the plasma exchange group vs. DPMAS + plasma exchange. Low-volume exchange plasma (2–2.4 L) was performed with fresh-frozen plasma in the DPMAS group first and then with exchange plasma. In the DPMAS + plasma exchange group, bilirubin decreases after the procedure, at 24 and 72 hours (P = < 0.05), and survival at 28 days was better (P = 0.043). Prospective studies are needed to assess long-term survival.

12. Coupled plasma filtration with adsorption

Coupled plasma filtration with adsorption (CPFA) is a technique, which requires a CRRT machine (Amplya), especially designed to combine the separation of plasma from blood by a high-permeability polyethersulfone filter. Then, the separated plasma circulates through a styrene cartridge-divinylbenzene copolymer and the purified plasma is reconstituted with the blood, which is finally returned to a CRRT polyphenylene hemofilter to remove water-soluble molecules (Figure 11).

Figure 11.

Coupled plasma filtration with adsorption (CPFA). A) Requires the separation of plasma from blood by a high-permeability polyethersulfone filter. B) The separated plasma is circulated through a styrene-divinylbenzene copolymer cartrige. C) The purified plasma is reconstituted with the blood, which is finally returned to a CRRT polyphenylene hemofilter.

The Hercole trail [54], a non-randomized observational study that included 12 patients, 4 with ALF and 8 with ACLF, started APFC with total bilirubin values ​​ > 20 mg/dl and MELD >20 that did not improve with SMT. It is observed that CPFA did not modify the SOFA and MELD score, the decrease in bilirubin (p = 0.0006) and bile acids (p = 0.047) decreased significantly, but after the third hour, the filter was saturated. Water-soluble molecules, such as water-soluble toxins, urea, and creatinine, did not change significantly before or after PAFC, attributed to low convective volumes, INR and aPTT values ​​were prolonged, but bleeding was not reported. It is important to mention that bilirubin rebound is expected to occur after the first session and ranges from 10 to 40% and is characteristic of the multicompartmental model of bilirubin kinetics, which occurs in any of the aforementioned therapies. It is a promising therapy, which requires further evidence with randomized controlled trials.

13. Hemoperfusion

There are many reports of the use of hemoperfusion in liver failure since the 70s and 80s.

Hemoperfusion is an extracorporeal therapy technique, which allows the passage of blood through a filter with the adsorption capacity of molecules with molecular weights from 5 to 50 kD, and the cartridges are classified according to a) composition in natural compounds (carbons) and synthetics (divinylbenzene), b) surface and volume, c) size, and d) selectivity.

The adsorption mechanisms attract solutes through different forces (hydrophobic interactions, ionic attraction, hydrogen bonding, and Van der Waals interactions), which allow the uptake of PAPMs, DAMPs, cytokines, chemokines, and multiple toxic substances (drugs, poisons).

The cartridges can be mounted in CRRT or in an intermittent hemodialysis (IH) machine, and it can be coupled to CRRT, prolonged intermittent renal replacement therapy (PIRRT), or IH modalities, to simultaneously perform both therapies (Figure 12).

Figure 12.

Hemoperfusion. It is an adsorptive therapy that uses activated carbon cartridges or divinylbenzene resins.

In a retrospective study [55], the use of charcoal hemoperfusion in 13 patients with refractory pruritus in cholestatic, managed to reduce pruritus in 69% of patients and in a numerical pruritus score performed before the start of therapy with a score of 9/10, decreased to 4/10, with an average of 5 sessions.

Stanje J et al. [56], in an in vitro two-compartment model established for the comparison of MARS vs. Cytosorb, water-soluble toxicants, such as creatinine, decreased significantly with MARS (p = < 0.04), and the decrease in ammonia was more significant with Cytosorb (p = < 0.05). Regarding the toxins bound to albumin, Cytosorb managed to decrease the values of total and indirect bilirubin in statistically significant values (p = < 0.03) and the elimination of bile acids was comparable. The decrease in cytokines, such as IL-6 and TNF-α with 6 hours of therapy, was significant with Cytosorb. More controlled studies are required to support the results reported in experimental studies and case series.

14. Hepatorenal syndrome

Patients with advanced cirrhosis frequently show some degree of renal dysfunction, and there is a strong relationship between the severity of cirrhosis and renal dysfunction. It has been estimated that more than 20% of patients hospitalized for acute decompensation of cirrhosis develop acute kidney injury. Cirrhotic patients can develop any type of renal failure, that is, prerenal (41.7%), intrarenal (38%), and postrenal (0.3%) types [57, 58].

Hepatorenal syndrome (HRS) is a peculiar type of functional AKI described in advanced liver disease with ascites and is characterized by vasoconstriction that does not improve with volume replacement. Hepatorenal syndrome accounts for 20% of AKI in patients with cirrhosis. The incidence of HRS in the natural history of cirrhosis is 18% after 1 year and 39% after 5 years [59].

AKI in the cirrhosis spectrum is defined using the KDIGO criteria, and the international ascites club introduces this definition of serum creatinine increase of ≥0.3 mg/dL within 48 hours in hospitalized patients or an increase of ≥50% in 7 days [60].

The multiple mechanisms that condition this pathology, and the following mechanisms are mentioned:

• Intrahepatic hemodynamics: Alterations in hepatic architecture conditioned by regeneration, fibrosis, and thrombosis nodules, together with functional alterations due to an imbalance between the greater production of vasoconstrictors (endothelin, leukotriene B4, thromboxane A2, and Angiotensin II) and less formation of local vasodilators (nitric oxide, cannabinoids) determine the development of portal hypertension and splanchnic vasodilation, which allows the sequestration of blood in this territory [61].

• Hepatorenal reflex: The presence of sensors in intrahepatic sinusoids that are stimulated based on changes in portal pressure and flow is mentioned. The increase in pressure would condition the sending of a signal by the afferent sympathetic nerve in the direction of the brain and the efferent sympathetic response at the renal level. It causes vasoconstriction of the efferent arteriole [62].

• Systemic hemodynamics: It is mentioned that a determining factor is the increase in systemic vasodilators, such as nitric oxide, among others, and the sequestration of blood in the splanchnic territory generates an effective decrease in blood volume that stimulates an increase in cardiac output, in order to restore effective arterial blood volume. When the liver disease progresses, severe portal hypertension develops and, together with bacterial translocation that mediates the release of PAMPs into the circulation, increases the inflammatory response that facilitates greater splanchnic vasodilation, causing a lower effective arterial blood volume and the consequent activation of the renin-angiotensin-aldosterone system, which facilitates the reabsorption of sodium and water, likewise this neurohumoral mechanism favors renal vasoconstriction. It is important to mention that relative hypotension stimulates the non-osmotic release of ADH, favoring the reabsorption of water in the collecting ducts [63].

• Cirrhotic cardiomyopathy: It is described in an experimental model [64] that in cirrhotic rats a severe blockage of the contractile capacity is generated by the α-adrenergic agonist isoproterenol and the limited capacity to generate the cAMP that stimulates the second messenger. The β-adrenergic receptor is the main determinant of ventricular contractility and experimental studies show a lower density and function of these receptors in patients with cirrhosis. It has been shown that NO inhibits β-adrenergic receptors, altering cardiac stimulation and decreasing cardiac contractility [65]. Endocannabinoids are also increased in patients with cirrhosis, and they can exert a negative inotropic effect in humans. It is described that the cardiac index <1.5 L and MAP <80 mmHg (p = < 0.05) are the predictors of hepatorenal syndrome in a 12-month follow-up [66].

• Inflammatory response: In cirrhosis, damaged hepatocytes release DAMPs such as high-mobility group box-1 (HMGB1), histones, and activate Kuppfer cells, leading to the production of proinflammatory mediators such as TNF-α, IL-1α, and IL. -6. These proinflammatory signals are detected by the intestinal immune system, and DAMPs bind to TLRs, intestinal Paneth cells, and dendritic cells. The inflammatory response is not limited to the liver; proinflammatory cytokines leak out and bind to TLR 2–4 in tubular cells, generating a damaging effect at the tubular level [67].

• Relative adrenal insufficiency: It is attributed by hormonal depletion in the hypothalamic-pituitary axis, adrenal, inflammatory, or ischemic damage, which is present in 80% of patients with cirrhosis with HRS compared to 30% with normal renal function, and this suggests a hormonal role in the HRS development [62].

• Intra-abdominal pressure–intra-abdominal hypertension: An experimental study in mice shows that intra-abdominal pressure from 10 to 20 mmHg is associated with higher levels of urea nitrogen and creatinine and the histological findings found report of tubular obstruction due to casts and inflammation and interstitial edema [62].

See Figure 13.

Figure 13.

Pathophysiological mechanisms of hepatorenal syndrome. A) The greater production of vasoconstrictors and less formation of local vasodilators determine the development of portal hypertension and splanchnic vasodilation, which allows the sequestration of blood in this territory. Splanchnic vasodilation generates an effective decrease in blood volume that stimulates an increase in cardiac output, in order to restore effective arterial blood volume. When the liver disease progresses, severe portal hypertension develops and, together with the bacterial translocation that mediates the release of PAMPs into the circulation, increases the inflammatory response that facilitates greater splanchnic vasodilation, causing a lower effective arterial blood volume and the consequent activation of the sympathetic and renin-angiotensin-aldosterone system, which facilitates the reabsorption of sodium and water, B) cirrhotic cardiomyopathy, there are multiple mechanisms that allow its development and condition a decrease in cardiac output, which conditions a decrease in mean arterial pressure, being a predictor of the development of hepatorenal syndrome. C) Bacterial overgrowth and bacterial translocation allow PMAPs to reach the enterohepatic circulation and precipitating factors and the progression of liver damage from the underlying disease allows the release of DAMPS, and both molecular patterns are presented to both Kupffer cells generating an intrahepatic inflammatory response and the presentation of these molecular patterns to dendritic cells and macrophages facilitates SIRS, the arrival of PAMPs and DAMPs to the kidneys allows them to filter and be captured by TLR2-4 of tubular cells, generating a damaging effect. D) Relative adrenal insufficiency that determines hemodynamic changes. E) Increased intra-abdominal pressure due to ascites, associated with changes in intrarenal hemodynamics such as renal venous congestion.

14.1 Diagnosis

The diagnosis of hepatorenal syndrome is difficult and is made by ruling out since there is no laboratory or imaging study to confirm it with certainty.

Within the International Ascites Club criteria, defines AKI as increases in serum creatinine of ≥ 0.3 mg/dL within 48 hours or 50% increase within 7 days in hospitalized patients with no response after 2 days consecutive with the use of albumin (1 g/kg of body weight), in the absence of shock, without the use of nephrotoxic drugs, absence of proteinuria (> 500 mg/day), absence of microhematuria (> 50 red blood cells per high-power field), and normal findings on renal ultrasound [60].

The aforementioned criteria should be reviewed because many patients with cirrhosis usually present hypotension without being in septic shock, and the presence of hematuria and proteinuria may be present secondary to IgA nephropathy or membranoproliferative glomerulonephritis due to C virus, and it should be considered that they are also exposed to use of antibiotics and analgesics. I believe that many of them have overlapping causes within the spectrum of hepatorenal syndrome [68].

In the analysis, there is no pathognomonic marker. In the past, it was reported that FENA <1% was an indicator of this disease; currently, the cutoff value seems to be lower <0.2% [69], in the advent of biomarkers the urinary NGAL <400 μg/L correlates with hepatorenal syndrome, and urinary NAGAL values >400 μg/L occur in acute tubular necrosis (ATN) [70].

14.2 Treatment

The initial treatment of AKI in the spectrum of cirrhosis is the use of albumin (1 g/kg of body weight) for 48 hours. Velez et. al [71] describe AKI phenotypes in cirrhosis based on the diameter of the inferior vena cava (IVC) evaluated by ultrasound, in the aforementioned work three groups are described: group with IVC diameter <1.3 cm, which is subdivided According to CVI collapse, it can be > 40%, which corresponds to the fluid depleted phenotype and this group would benefit from albumin replacement; in those with <40% collapse, it corresponds to the intra-abdominal hypertension phenotype and would benefit from paracentesis. In the second group with IVC 1.3-2 cm corresponds to the fluid repleted phenotype, which would benefit from vasoconstrictors and in the third group corresponds to those with IVC > 2 cm and which is subdivided based on collapse >40% indicating a state of euvolemia, the use of vasoconstrictors would be a good therapeutic option and those with collapsibility <40% correspond to the fluid expanded phenotype where diuretics are indicated.

If after expansion with albumin the decrease in creatinine is not achieved, albumin should be maintained at 20–40 g and add Terlipressin 0.5–1 mg/4–6 hours, titrating the dose with 2-mg increment every day until reaching a maximum dose of 12 mg, an adequate response is defined when a 25% drop in initial creatinine is achieved, and in case of no response, Terlipressin can be administered for 14 days. It is recommended that infusion is better when compared with boluses every 6 hours. The predictive factors of poor response to Terlipressin are elevated total bilirubin values >10 mg/dl, lack of MAP increase of 5 mmHg on day 3, as well as NGAL >728 μg/L. (61.63).

The evidence on Terlipressin, norepinephrine, octreotide, and midodrine is extensive and exceeds the scope of the review.

15. Renal support therapies in hepatorenal syndrome

The use of renal supportive therapy is indicated when patients with hepatorenal syndrome develop absolute indications for renal supportive therapy (RST) (severe metabolic acidosis, severe hyperkalemia, fluid overload, encephalopathy, and uremia) in nonresponders to the use of Terlipressin with albumin.

AKI, due to HRS and ATN, has a poor prognosis because 40% require RST and 60% die within 90 days [72]. In a retrospective cohort of 472 patients with diagnoses of HRS and ATN, 341 of these did not enter the waiting list and 131 were included on the waiting list. It was evident that those who developed HRS presented higher SOFA and MELD scores and patients with ATN presented sepsis and required vasopressors and mechanical ventilation. The 6-month survival for those who were not placed on the waiting list with HRS (84%) and ATN (85%) was similar. The RST start is controversial in patients who are not candidates for liver transplantation because it does not modify the prognosis.

At this point, three scenarios are proposed [73]:

1. The patient is included in the waiting list and the need for RST becomes a bridge until the transplant, in this case, there is no doubt of the benefit.

2. The second scenario is a patient in the evaluation phase for liver transplantation, where the need for RST will be until the inclusion on the list is clear.

3. In those who are not included on the waiting list for liver transplantation, can receive RST temporarily or until the experts in palliative care, the patient and the family decide they will limit efforts in a terminal illness.

16. Conclusions

ALF and ACLF represent very complex pathophysiological diseases that encompass multiple inflammation mechanisms that perpetuate liver damage and medical treatment is not successful in limiting the damage. The use of albumin-based extracorporeal support therapies has not been shown to have an impact on survival and we see plasma exchange therapies or therapies combined with hemoperfusion show better survival than the traditional ones, although more randomized controlled trials with a greater number of patients are needed of patients to have a stronger recommendation.

Hepatorenal syndrome is a renal complication in patients with advanced liver cirrhosis and is triggered by multiple mechanisms. There is no gold standard for diagnosis, which is by exclusion, albumin and Terlipressin therapy is the recommended treatment in response to treatment with higher mortality, which is not modified by the use of renal support therapies.