Clinical and Biological Predictors of Plasma Levels of Soluble RAGE in Critically Ill Patients: Secondary Analysis of a Prospective Multicenter Observational Study

Thibaut Pranal, Bruno Pereira, Pauline Berthelin, Laurence Roszyk, Thomas Godet, Russell Chabanne, Nathanael Eisenmann, Alexandre Lautrette, Corinne Belville, Raiko Blondonnet, Sophie Cayot, Thierry Gillart, Yvan Skrzypczak, Bertrand Souweine, Damien Bouvier, Loic Blanchon, Vincent Sapin, Jean-Michel Constantin, Matthieu Jabaudon, Thibaut Pranal, Bruno Pereira, Pauline Berthelin, Laurence Roszyk, Thomas Godet, Russell Chabanne, Nathanael Eisenmann, Alexandre Lautrette, Corinne Belville, Raiko Blondonnet, Sophie Cayot, Thierry Gillart, Yvan Skrzypczak, Bertrand Souweine, Damien Bouvier, Loic Blanchon, Vincent Sapin, Jean-Michel Constantin, Matthieu Jabaudon

Abstract

Rationale: Although soluble forms of the receptor for advanced glycation end products (RAGE) have been recently proposed as biomarkers in multiple acute or chronic diseases, few studies evaluated the influence of usual clinical and biological parameters, or of patient characteristics and comorbidities, on circulating levels of soluble RAGE in the intensive care unit (ICU) setting.

Objectives: To determine, among clinical and biological parameters that are usually recorded upon ICU admission, which variables, if any, could be associated with plasma levels of soluble RAGE.

Methods: Data for this ancillary study were prospectively obtained from adult patients with at least one ARDS risk factor upon ICU admission enrolled in a large multicenter observational study. At ICU admission, plasma levels of total soluble RAGE (sRAGE) and endogenous secretory (es)RAGE were measured by duplicate ELISA and baseline patient characteristics, comorbidities, and usual clinical and biological indices were recorded. After univariate analyses, significant variables were used in multivariate, multidimensional analyses.

Measurements and main results: 294 patients were included in this ancillary study, among whom 62% were admitted for medical reasons, including septic shock (11%), coma (11%), and pneumonia (6%). Although some variables were associated with plasma levels of RAGE soluble forms in univariate analysis, multidimensional analyses showed no significant association between admission parameters and baseline plasma sRAGE or esRAGE.

Conclusions: We found no obvious association between circulating levels of soluble RAGE and clinical and biological indices that are usually recorded upon ICU admission. This trial is registered with NCT02070536.

Figures

Figure 1
Figure 1
Spearman rho coefficients of the correlation between quantitative variables and plasma sRAGE at ICU admission. Dark bars represent positive correlations; grey bars represent negative correlations. The body mass index (BMI) is the weight in kilograms divided by the square of the height in meters. LIPS: lung injury prediction score; SAPS II: simplified acute physiology score II; MAP: mean arterial pressure; GCS: Glasgow coma scale; Vt: tidal volume; PEEP: positive end-expiratory pressure; Pplat: inspiratory plateau pressure; FiO2: fraction of inspired oxygen; PaO2: arterial partial pressure of oxygen; PaCO2: arterial partial pressure of carbon dioxide; P/F ratio: PaO2/FiO2; CRP: C-reactive protein; PINI: prognostic nutritional and inflammatory index; ICU: intensive care unit; sRAGE: soluble form of the receptor for advanced glycation end products.
Figure 2
Figure 2
Spearman rho coefficients of correlation between quantitative variables and plasma esRAGE at ICU admission. Dark bars represent positive correlations; grey bars represent negative correlations. The body mass index (BMI) is the weight in kilograms divided by the square of the height in meters. LIPS: lung injury prediction score; SAPS II: simplified acute physiology score II; MAP: mean arterial pressure; GCS: Glasgow coma scale; Vt: tidal volume; PEEP: positive end-expiratory pressure; Pplat: inspiratory plateau pressure; FiO2: fraction of inspired oxygen; PaO2: arterial partial pressure of oxygen; PaCO2: arterial partial pressure of carbon dioxide; P/F ratio: PaO2/FiO2; CRP: C-reactive protein; PINI: prognostic nutritional and inflammatory index; ICU: intensive care unit; ICU: intensive care unit; esRAGE: endogenous secretory form of the receptor for advanced glycation end products.
Figure 3
Figure 3
Size effect coefficient (Cohen's d coefficient), with upper standard deviation (SD) for baseline qualitative variables tested against plasma sRAGE at ICU admission. Dark bars represent positive values for size effect, grey bars represent negative values, and stars represent coefficient values with 95% confidence intervals that exclude 0, i.e. statistical significance. sRAGE: soluble form of the receptor for advanced glycation end products. ICU: intensive care unit. COPD: chronic obstructive pulmonary disease.
Figure 4
Figure 4
Size effect coefficient (Cohen's d coefficient), with upper standard deviation (SD) for baseline qualitative variables tested against plasma esRAGE at ICU admission. Dark bars represent positive values for size effect, grey bars represent negative values, and stars represent coefficient values with 95% confidence intervals that exclude 0, that is, statistical significance. esRAGE: endogenous secretory form of the receptor for advanced glycation end products; ICU: intensive care unit; COPD: chronic obstructive pulmonary disease.
Figure 5
Figure 5
Multidimensional analyses. (a) Principal component analysis (PCA) of clinical and biological variables (significant in univariate analysis) against log-transformed plasma sRAGE. The first two axes of PCA were chosen, as they represent 31% of total inertia and because including other axes did not influence the results (data not shown). PCA suggests an absence of correlation between plasma sRAGE and selected variables. (b) Multiple correspondence analysis (MCA) with mixed quantitative and qualitative variables against plasma sRAGE as subdivided into quartiles. No significant association between quartiles of sRAGE and selected variables was found. [1], [2], [3], and [4] represent the 1st, 2nd, 3rd, and 4th quartiles, respectively. sRAGE: soluble form of the receptor for advanced glycation end products.
Figure 6
Figure 6
Multidimensional analyses. (a) Principal component analysis (PCA) of clinical and biological variables (significant in univariate analysis) against log-transformed plasma esRAGE. The first two axes of PCA were chosen as they represent 26% of total inertia, and because including other axes did not influence the results (data not shown). PCA suggests an absence of correlation between plasma esRAGE and selected variables. (b) Multiple correspondence analysis (MCA) with mixed quantitative and qualitative variables against plasma esRAGE as subdivided into quartiles. No significant association between quartiles of esRAGE and selected variables was found. [1], [2], [3], and [4] represent the 1st, 2nd, 3rd, and 4th quartiles, respectively. esRAGE: endogenous secretory form of the receptor for advanced glycation end products.

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