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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Liver Transpl. Author manuscript; available in PMC 2016 July 5.
Published in final edited form as:
PMCID: PMC4933521
NIHMSID: NIHMS789144

CIRCULATING LEVELS OF SOLUBLE RAGE AND RAGE-LIGANDS IN PATIENTS WITH ACUTE LIVER FAILURE

Giuseppina Basta,* Serena Del Turco,* Teresa Navarra,* William M Lee,° and the Acute Liver Failure Study Group

Abstract

Animal studies suggest that receptor for advanced glycation end-product (RAGE)-dependent mechanisms contribute to acetaminophen-induced liver damage. We examined whether circulating levels of soluble RAGE (sRAGE) or RAGE ligands including extracellular newly identified RAGE binding protein (EN-RAGE), High-Mobility Group Box 1 (HMGB1) and Nepsilon-(Carboxymethyl) lysine-adducts (CML), could aid prognostication following acetaminophen overdose.

Sixty well-characterized acetaminophen-related acute liver failure (ALF) patients (30 spontaneous survivors and 30 transplanted and/or died) enrolled in the NIH-sponsored Acute Liver Failure Study Group, matched for age and meeting standard criteria of encephalopathy and INR > 1.5, were retrospectively studied. HMGB1, EN-RAGE, CML and sRAGE were detected by ELISA methods in sera from ALF patients as well as in 30 healthy controls.

Levels of sRAGE, EN-RAGE and HMGB1, but not CML, were significantly greater (p < 0.0001) in ALF patients than normal controls. The levels of sRAGE, HMGB1 and EN-RAGE were significantly higher (p = 0.029, p = 0.083, p = 0.033) in patients with systemic inflammatory response syndrome score (SIRS) > 2 than in patients with SIRS ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who were transplanted and/or died than in spontaneous survivors (p = 0.0005) and were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified the encephalopathy grade > 2 as independent predictors of adverse outcome on admission (odds ratio = 13, 95% CI 2.3–73, p = 0.00038).

The RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research.

Keywords: soluble Receptor for Advanced Glycation End-product, High-Mobility Group Box 1, Extracellular Newly identified RAGE binding protein, Acute Liver Failure, Acetaminophen

INTRODUCTION

Acute liver failure (ALF) is a rare but serious condition occurring in individuals without pre-existing liver disease and characterized by sudden severe liver dysfunction associated with coagulopathy and hepatic encephalopathy (1, 2). Acetaminophen overdoses are the number one cause of ALF in the United States; they account for ~50% of all cases of ALF and carry a 30% mortality (2, 3). Whilst the majority of patients recover spontaneously following acetaminophen overdose, many, develop severe ALF. In spite of significant advances in medicinal therapy, the only effective treatment for severe ALF due to acetaminophen remains emergency liver transplantation (LT) (46). The decision to transplant is complex, particularly in this patient population. Accurate and early identification of those patients who survive spontaneously is therefore vital to utilize LT effectively and prevent needless transplantation. Therefore, prognostication in ALF patients remains extremely interesting to investigate. Current models such as King’s College Hospital Criteria (7) are not satisfactory, and improved strategies for predicting outcomes in ALF continue to be needed (8, 9).

Spontaneous recovery from ALF depends, in part, on the capacity of the liver to regenerate following acute injury (10) and that amplification of pro-inflammatory mediators in the regenerating tissue is also recognized to play an important role in limiting liver regeneration (11). A key pathway in this process appears to involve the receptor for advanced glycation end-products (RAGE) (1214), a cell-surface multi-ligand pattern recognition receptor linked with amplification of the innate inflammatory response to cell death (15). Engagement of membrane-bound RAGE with ligands such as high-mobility group box 1 (HMGB1) protein, extracellular newly identified RAGE binding protein (EN-RAGE) or Nepsilon – (Carboxymethyl) lysine – adducts (CML) sustains inflammatory responses and promotes apoptosis in the hepatic remnant following massive hepatectomy (15). Blockade of this pathway with soluble RAGE (sRAGE), the extracellular ligand binding domain of the receptor, interrupting ligand-RAGE signalling markedly reduced hepatic necrosis in animals with acetaminophen-induced liver injury (14). In human plasma, there are also circulating isoforms of RAGE, called collectively sRAGE, which have the same ligand-binding specificity as membrane-RAGE. The sRAGE isoform consists of a heterogeneous population, with at least two different isoforms: (1) the extracellular RAGE formed by ectodomain shedding of the membrane-associated receptor by the action of membrane-associated metalloproteinases (MMPs) (16); (2) an endogenous secreted form, generated by alternative RNA splicing (17). Spanning the ligand-binding domain, sRAGE probably acts as a decoy for ligands, thus competitively inhibiting the engagement of cell-surface RAGE (17). Circulating levels of sRAGE are elevated in patients with decreased renal function, which may be due to increased levels of MMPs (18), while they are reduced in chronic diseases including coronary artery disease, essential hypertension, chronic obstructive lung disease and heart failure (17). Therefore, the balance of RAGE ligands, circulating sRAGE and cell surface-RAGE expression is a complex, dynamic system, with important pathophysiological implications.

In patients with acetaminophen-induced ALF, enrolled in the NIH-sponsored ALF Study Group, we explored whether circulating levels of sRAGE and RAGE- ligands (EN-RAGE, HMGB1 and CML), were involved and could aid prognostication in this group of patients.

MATERIALS AND METHODS

Patient selection

The US Acute Liver Failure Study Group was established in 1998 as a consortium of liver centers interested in better defining the causes and outcomes of ALF. To date, more than 2,500 subjects have been enrolled prospectively at 23 tertiary centers within the US, all of which have liver transplantation programs. All enrolled subjects met standard criteria for ALF: presence of coagulopathy (prothrombin time >15 seconds or INR ≥1.5) and any degree of hepatic encephalopathy (HE), occurring within 26 weeks of the onset of first symptoms in a patient without previous underlying liver disease (19, 20). Since the subjects were encephalopathic by definition, written informed consent was obtained from their legal next of kin. Detailed demographic, clinical, laboratory and outcome data as well as daily sera for 7 days were collected prospectively. All centers were in compliance with their local institutional review board requirements. A Certificate of Confidentiality was obtained from the National Institutes for Mental Health for the entire study.

The cohort of 60 well-characterized acetaminophen-related ALF patients from the registry were selected as consecutive patients meeting the above criteria, balanced to obtain roughly an equal number of survivors and patients who either died or underwent transplantation. Within this cohort, 30 spontaneous survivors and 30 transplanted and/or died (of which three were transplanted), of similar age, were selected. Patients in the ALFSG registry are enrolled at or near admission to the study site hospital, and are managed according to a relatively uniform protocol (21); however, decisions concerning listing and transplantation are, of necessity, individual site decisions. In general, patients meeting usual criteria are listed as UNOS Status 1, and are assumed to have a high 7-day mortality. Decision to transplant depends on subsequent organ availability and the decision is made at the time an organ becomes available.

In addition, 30 age-matched healthy controls were included. Serum samples were tested for RAGE ligands as well as circulating sRAGE. The Institutional Ethics Committee of the University Hospital of Pisa (Italy) approved the study (approval number: 3653).

Laboratory analysis

Blood sample collection

Serum samples obtained usually on day 1 of admission to study were centrifuged at 4 °C and stored at −80 °C until analysis. All laboratory tests were performed in blinded fashion with respect to the identity of the samples. Routine biochemical analyses were determined by standard laboratory methods.

The Model for End-Stage Liver Disease (MELD) score, and the bilirubin, lactate, and etiology (BiLE) score were derived as indicated elsewhere (22) and (23).

Determination of serum sRAGE levels

Serum sRAGE levels were determined using a double-sandwich ELISA kit (DuoSet ELISA development kit; R&D Systems, Minneapolis, MN, USA) as previously described (24). Intra-assay and inter-assay coefficients of variation was 5.9% and 8.2%, respectively. The lower limit of detection of sRAGE was 21.5 pg/mL.

Determination of serum CML levels

Serum CML levels were measured by an in-house competitive ELISA using the mouse F(ab’)2 fragment anti-AGE monoclonal antibody (clone 6D12) (ICN Biochemical Division, Aurora, OH, USA), as previously described (25). Intra-assay and inter-assay coefficients of variation were 3.2% and 8.7% respectively. The lower limit of detection of CML was 0.5μg/mL.

Determination of serum HMGB1 levels

Serum HMGB1 levels were determined using the double-sandwich ELISA Kit II (IBL International, Hamburg, Germany) according to the manufacturers’ description. Intra-assay and inter-assay coefficients of variation were < 8 % and 10 % respectively. The lower limit of detection of HMGB1 was 0.1 ng/mL.

Determination of serum EN-RAGE levels

EN-RAGE concentration was measured by an in-house competitive ELISA assay, as previously described (26). The intra-assay and inter-assay coefficients of variation were less than 7.9% and less than 8.0%, respectively. The lower limit of detection of EN-RAGE was 0.05 ng/mL.

Statistical analysis

Data with a normal distribution are given as mean ± SD. Variables with a skewed distribution are expressed as median and interquartile range. Variables with a non-normal distribution were logarithmically transformed before each analysis. Chi-square tests and Student’s t-tests were used to compare categorical variables or continuous variables, respectively. A Pearson correlation analysis was performed to examine the relationship between sRAGE and the study’s variables. Variables that were statistically significant (p < 0.01) in Table 2 formed a pool of potential independent predictors of which was assessed the sensitivity, specificity, diagnostic accuracy and area under the receiver operating characteristic curve (AUROC) (Table 3). These predictors were then entered into a backward elimination variable selection procedure by multivariate logistic regression analysis. The predictors with a P value less than 0.05 were retained. For all analyses, a two-tailed P value <0.05 was considered significant. Statistical analysis was performed by SPSS software for Windows (version 10.0; SPSS, Chicago, IL).

Table 2
Univariate analysis of variables on admission in spontaneous survivors and in patients who died or were transplanted for ALF
Table 3
AUROC and diagnostic accuracy for prediction of poor outcome in ALF patients

RESULTS

Serum levels of RAGE-ligands and sRAGE were measured in 30 controls of healthy subjects, as well as in 60 age-matched acetaminophen-related ALF patients. Circulating levels of sRAGE, EN-RAGE and HMGB1 were found to be significantly higher (p < 0.0001) in ALF patients than normal controls while CML values did not differ between two groups (Table 1). The values of sRAGE were significantly higher in transplanted and/or died group than spontaneous survivor group (P = 0.0005). EN-RAGE levels tended to be higher in non-surviving patients than in spontaneous survivors (P = 0.055), while HMGB1 and CML levels did not differ between two groups (Table 2). Between the two groups, there were significant differences in plasma levels of prothrombin time, creatinine, aspartate aminotransferase (AST) and pH (Table 2). Further, they differed significantly for encephalopathy grade (COMA) and MELD score as well as significant differences in the BiLE score, a novel predictor of poor outcome in ALF patients (23) (Table 2).

Table 1
Comparison of sRAGE, EN-RAGE, HMGB1 and CML values between ALF patients and normal controls

The Pearson correlation analysis highlighted that in all patients sRAGE levels were positively associated with MELD score (r = 0.39, p = 0.002), BiLE score (r = 0.48, p = 0.004), COMA grade (r = 0.28, p = 0.03) and SIRS score (r = 0.33, p = 0.01). Further, sRAGE was positively associated with conventional markers of disease severity: AST (r = 0.30, p = 0.02), creatinine (r = 0.48, p < 0.0001), prothrombin time (r = 0.26, p = 0.04), as well as EN-RAGE (r = 0.41, p = 0.001), and HMGB1 levels (r = 0.25, p = 0.05). We also found significant higher levels of sRAGE, HMGB1 and EN-RAGE in patients with SIRS > 2 (3 and 4 grades) than in patients with SIRS ≤ 2 (Fig. 1).

Figure 1
Serum levels of sRAGE, HMGB1 and EN-RAGE in relationship with the SIRS severity

Variables that were statistically significant (with a p < 0.01) in Table 2 formed a pool of potential independent predictors of outcome. As shown in the Table 3, creatinine >1.9 mg/dL displayed the best diagnostic accuracy (84%) while both COMA grade > 2 and sRAGE > 3021 pg/mL had the major diagnostic sensitivity (87% and 83% respectively). Finally, a multivariate logistic regression analysis with these predictors was then assessed. The COMA grade > 2, with an odds ratio of 13 (CI, 2.3–73, p = 00038), was the best predictor of outcome selected in this model.

In order to improve the prognostication of ALF patients, we emulated the study of Bechmann et al. (27) in which a modified MELD score using levels of the cell death marker cytokeratin 18/M65 substituted for bilirubin, better predicted prognosis of ALF patients. Thus, we modified the MELD score with sRAGE in place of bilirubin, (which in our ALF patients had no prognostic value), while retaining all other factors: modified MELD = 10*(0.957*Ln Creatinine [mg/dL]+ 0.378*Ln sRAGE[pg/mL] + 1.12*Ln INR + 0.643). The sRAGE-modified MELD scores had a somewhat higher diagnostic accuracy (84% vs 80%) than unmodified- MELD scores, but there was no effect on outcome in the multivariate logistic analysis.

DISCUSSION

In this study, we examined the levels and prognostic significance of sRAGE and RAGE-ligands on admission in a carefully studied cohort of patients with acetaminophen-related ALF and compared these novel markers with other indicators of ALF prognosis. RAGE and RAGE-ligands appear to be involved in the pathogenesis of severe liver injury in humans exposed to excessive acetaminophen. We measured three RAGE ligands as well as sRAGE in the same cohort of patients to explore their interrelationship. EN-RAGE, HMGB1 and sRAGE, were all markedly elevated in this setting from 3 to 10 times control values, while CML levels were not increased. We focused attention on sRAGE because it was the most increased in ALF patients. The reasons for these elevated levels might be secondary to decreased renal function or possibly up-regulation of sRAGE that would provide “protection” against possible toxic effects of RAGE-ligands. The close association we found between sRAGE and creatinine levels indeed support the first hypothesis. The relationship between sRAGE and compromised renal function has been noted previously by Kalousova et al. (18) and in a recent study on trauma patients in which the release of sRAGE in the bloodstream was associated with coagulation abnormalities and acute renal failure (28). These findings notwithstanding, higher levels of sRAGE in ALF patients, particularly in those died and/or transplanted patients may still reflect increased tissue expression and release, consequent to the development of an inflammatory response and coagulopathy. The positive correlation between sRAGE levels and SIRS severity in our study suggests that sRAGE may be implicated in inflammatory responses occurring in ALF patients. In support of our results, it has been shown that high admission plasma levels of sRAGE in non-survivors of sepsis than in survivors were associated with worse outcome (29) suggesting that circulating sRAGE levels may reflect tissue RAGE expression and may be elevated in parallel with serum RAGE ligands as a counter-system against ligand-elicited tissue damage. Since RAGE is a cell surface receptor that belongs to the immunoglobulin superfamily such as intercellular adhesion molecule 1, which values at admission were also more elevated in non-survivor septic patients (30) as well as in non-survivor ALF patients (31) than in survivors, sRAGE might represent a marker of cellular damage. In this study, we have no serial data on sRAGE levels during recovery or with deterioration to allow us to more firmly establish an association between improving levels in the survivors and outcome. However, we recently found (32) that in patients with chronic liver disease undergoing LT, serum levels of sRAGE decreased by day 7, showing that the levels of this protein were not stable but changed after surgery.

Since bilirubin levels had no prognostic value in ALF patients, we emulated the study of Bechmann et al (27), modifying the MELD score through the substitution of bilirubin with sRAGE in the formula. This modification improved the diagnostic accuracy of MELD score but not its predictive value for outcome. Although sRAGE levels alone or in combination with MELD scores were not independent predictors of mortality, high levels of sRAGE in ALF patients who died are an important signal of the severity of damage to the liver and presumably spontaneous survival in ALF patients.

Among RAGE ligands, the most remarkable indicator of liver impairment is HMGB1 protein, which has been shown to play a role in experimental models of both acetaminophen-induced hepatotoxicity (3335) and ischaemia-reperfusion injury (36, 37). In our patients there was a positive correlation between HMGB1 and SIRS severity, that is in line with the literature showing highest levels of HMGB1 in patients with sepsis, especially in those with a poor prognosis (38). In agreement with Craig et al. (39), our data confirmed that admission HMGB1 levels were significantly higher in ALF patients than healthy control subjects, but did not significantly differ between non-survivor patients compared with spontaneous survivors. Given the crucial role attributed to HMGB1 in many experimental models of acute injury and sepsis, it is perhaps surprising that circulating HMGB1 levels did not predict outcome in ALF patients. A plausible explanation is that HMGB1 is not sufficient to cause the systemic dysfunction, since recombinant HMGB1fails to stimulate strong pro-inflammatory reactions (40). Rather, it seems that HMGB1 forms complexes with other inflammatory mediators amplifying the downstream effects of these mediators through interaction with a variety of receptors including the RAGE (41).

In addition to this ligand, we found a good correlation between SIRS severity with the RAGE-ligand EN-RAGE but no value of EN-RAGE in prediction of outcome. Similarly to HMGB1, the admission EN-RAGE levels were found up regulated in patients with SIRS features, compared with healthy subjects (42).

Of interest, the third ligand studied – the CML adduct – did not differ between ALF patients and healthy subjects, not unexpected for us. CML adducts form and accumulate in diverse settings including in inflammatory milieu through the myeloperoxidase pathway (43). Nevertheless, their accumulation in plasma is not an immediate process and more time might be required for them to become detectable.

In order to bring out the global picture of these interrelationships and to highlight the mechanisms by which sRAGE may increase in this pathological context, we have schematically shown these possible dynamics in the Fig. 2. Thus, we suppose that sRAGE may be released to counter the toxic effect of its ligands, as a beneficial response to the inflammatory milieu of ALF and, in addition, its circulating levels increase in the presence of decreased renal function (Fig. 2).

Figure 2
Schematic diagram of the RAGE-ligands release, inflammatory responses and feedback mechanism in RAGE ligands/RAGE/sRAGE system after injury induced by acetaminophen overdose

The chief limitation of this study is its retrospective nature. It is necessary a prospective evaluation in a larger patient set to draw unequivocal conclusions. However, it provides proof of concept that the RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research.

Acknowledgments

The serum specimens from the Acute Liver Failure Study reported here were supplied by the NIDDK Central Repositories.

We also acknowledge the Acute Liver Failure Study Group Investigators:


University of Texas Southwestern Medical CenterWilliam M. Lee, M.D.

University of WashingtonIris Liou, M.D.

Washington University (closed)Jeffrey Crippin, M.D.

University of California, San FranciscoOren Fix, M.D.

Mount Sinai (closed)Lawrence Liu, M.D.

University of Nebraska (closed)Timothy M. McCashland, M.D.

Mayo Clinic, Rochester (closed)J. Eileen Hay, M.D.

Baylor University Medical Center (closed)Natalie Murray, M.D.

University of Pittsburgh (closed)Obaid Shakil Shaikh, M.D.

Northwestern UniversityDaniel R. Ganger, M.D.

Oregon Health Sciences Center (closed)Atif Zaman, M.D.

University of California, Los AngelesSteven Han, M.D.

University of Miami (closed)Eugene Schiff, M.D.

University of MichiganRobert Fontana, M.D.

Yale UniversityMichael Schilsky, M.D.Cary A. Caldwell M.D

University of Alabama, BirminghamBrendan McGuire, M.D.

Massachusetts General Hospital (closed)Raymond T. Chung, M.D.

Duke University (closed)Don C. Rockey, M.D.

Columbia-Presbyterian (closed)Robert Brown, MD

Mayo Clinic, Scottsdale (closed)M. Edwyn Harrison, MD

Medical University of South CarolinaAdrian Reuben, M.B.B.S.

Albert Einstein Medical Center (closed)Santiago J. Munoz, M.D.

University of PennsylvaniaK.Rajender Reddy, M.D.

Virginia Commonwealth UniversityTodd Stravitz, M.D.

University of California, Davis (closed)Lorenzo Rossaro, MD

Mayo Clinic, Jacksonville, Jacksonville, FL (closed)Raj Satyanarayana, M.D.

University of California, San Diego (closed)Tarek Hassanein, M.D.

California Pacific Medical Center, San Francisco, CA (closed)Timothy Davern, M.D.

The Ohio State University, Columbus, OhioA. James Hanje, M.D.

University of Kansas Medical Center, Kansas City, KSJody C. Olson, M.D.

Emory University, Atlanta, GARam Subramanian, M.D.

University of Alberta, Edmonton, CanadaConstantine J. Karvellas, M.D.

Financial support

The project was supported by NIDDK U01-DK-58369.

List of abbreviations

ALF
Acute Liver Failure
RAGE
Receptor for Advanced Glycation End-products
sRAGE
soluble RAGE
HMGB1
High-Mobility Group Box 1
EN-RAGE
Extracellular Newly identified RAGE binding protein
CML
Nepsilon-(Carboxymethyl)Lysine-adducts
MELD
Model for End-Stage Liver Disease
BiLE
Bilirubin Lactate, and Etiology
SIRS
Systemic Inflammatory Response Syndrome
COMA
Encephalopathy grade
AUROC
Area Under the Receiver Operating Characteristic curve

Footnotes

Potential conflict of interest

The authors have no conflicts of interest to disclose.

Authors ‘contributions

Giuseppina Basta, principal investigator, participated in the design of the study, in the statistical plan and drafted this manuscript.

Serena Del Turco was involved in data analysis and writing the article.

Teresa Navarra participated in performing the experiments.

William M Lee participated in the design and coordination of the study and supervised all aspects of the study.

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