# Effects of intermittent hemodialysis on plasmatic levels of endocan.

Maxence Hureau, Julien Poissy, Daniel Mathieu, Sylvain Dubucquoi, Alexandre Gaudet

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Maxence Hureau, Julien Poissy, Daniel Mathieu, Sylvain Dubucquoi, Alexandre Gaudet. Effects of intermittent hemodialysis on plasmatic levels of endocan.. Critical Care, 2021, Critical Care, 25, pp.412. 10.1186/s13054-021-03829-6 . hal-04481940

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# Effects of intermittent hemodialysis on plasmatic levels of endocan

Maxence Hureau¹,²,³,<fnref n="4" />, Julien Poissy<fnref n="4" />,⁵, Daniel Mathieu¹,²,³,<fnref n="4" />, Sylvain Dubucquoi⁶ and Alexandre Gaudet¹,²,³,<fnref n="4" />*

To the editor,

Endocan is a prognostic biomarker of pulmonary and systemic inflammatory states [1], such as acute respiratory distress syndrome or sepsis, with substantial proportion of subjects requiring RRT [2]. In previous correspondences, Honoré et al. raised the question of the actual impact of hemodialysis on plasmatic levels of endocan in critically ill subjects [3, 4].

To address this question, we retrospectively collected serial measurements of endocan performed for routine care in EDTA plasma from 11 patients undergoing intermittent hemodialysis in a 50-bed ICU in Lille, France. Hemodialysis was performed using either ELISIO

(Nipro, France), a polyethersulfone membrane with very low adsorptive capacities or EVODIAL (Baxter, USA), a heparin-grafted AN 69 ST membrane with higher adsorptive properties. Patients' characteristics on ICU admission and on day of hemodialysis were collected retrospectively.

We categorized measurements of plasma endocan according to timing of blood collection relatively to hemodialysis, as following: T0, within 1 h before start of hemodialysis; T1, 30 min to 60 min after start of hemodialysis; T2, 90 min to 120 min after start of hemodialysis, T3, 180 min to 240 min after start of hemodialysis; T4: 90 min to 120 min after end of hemodialysis.

<table><caption>**Table 1** Characteristics of patients</caption><tr><td>Sex, male</td><td>6 (55%)</td></tr><tr><td>Age, years</td><td>66 (59–69)</td></tr><tr><td>Body weight on ICU admission, kg</td><td>80 (72–96)</td></tr><tr><td>SAPS II on ICU admission</td><td>48 (41–72)</td></tr><tr><td>Disorder category</td><td></td></tr><tr><td>Medical</td><td>8 (73%)</td></tr><tr><td>Surgical</td><td>3 (27%)</td></tr><tr><td>Preexisting conditions</td><td></td></tr><tr><td>Chronic kidney failure</td><td>5 (45%)</td></tr><tr><td>Chronic heart failure</td><td>3 (27%)</td></tr><tr><td>Cirrhosis</td><td>1 (9%)</td></tr><tr><td>Diabetes mellitus</td><td>4 (36%)</td></tr><tr><td>Diagnosis on ICU admission</td><td></td></tr><tr><td>Soft tissues infection</td><td>3 (27%)</td></tr></table>

<table><tr><td>Pneumonia</td><td>3 (27%)</td></tr><tr><td>Carbon monoxide poisoning</td><td>1 (9%)</td></tr><tr><td>Decompensated cirrhosis</td><td>1 (9%)</td></tr><tr><td>Cardiogenic shock</td><td>1 (9%)</td></tr><tr><td>Hemorrhagic shock</td><td>1 (9%)</td></tr><tr><td>Gas embolism</td><td>1 (9%)</td></tr><tr><td>Inflammation biomarkers on day of hemodialysis</td><td></td></tr><tr><td>CRP, mg/l</td><td>66 (41–154)</td></tr><tr><td>Procalcitonin, ng/ml</td><td>2 (1.4–2.8)</td></tr><tr><td>Characteristics of hemodialysis</td><td></td></tr><tr><td>Residual volume of diuresis (ml/24 h)</td><td>100 (25–450)</td></tr><tr><td>Systemic anticoagulation</td><td>8 (72%)</td></tr><tr><td>Daily UFH dose, IU/24 h</td><td>10000 (0; 12000)</td></tr><tr><td>Heparin-coated membrane (EVODIAL)</td><td>3 (27%)</td></tr><tr><td>Duration of hemodialysis, hrs</td><td>5 (4.5–6)</td></tr></table>

<figure><img src="image_2.png" /></figure>

<footnote>*Correspondence: alexandre.gaudet@chru-lille.fr</footnote>

<footnote n="4">⁴ CHU Lille, Pôle de Médecine Intensive – Réanimation, Hôpital Roger Salengro, 59000 Lille, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
<figure><img src="image_2.png" /></figure>

# Effects of intermittent hemodialysis on plasmatic levels of endocan

Maxence Hureau¹,²,³,<fnref n="4" />, Julien Poissy<fnref n="4" />,⁵, Daniel Mathieu¹,²,³,<fnref n="4" />, Sylvain Dubucquoi⁶ and Alexandre Gaudet¹,²,³,<fnref n="4" />*

To the editor,

Endocan is a prognostic biomarker of pulmonary and systemic inflammatory states [1], such as acute respiratory distress syndrome or sepsis, with substantial proportion of subjects requiring RRT [2]. In previous correspondences, Honoré et al. raised the question of the actual impact of hemodialysis on plasmatic levels of endocan in critically ill subjects [3, 4].

To address this question, we retrospectively collected serial measurements of endocan performed for routine care in EDTA plasma from 11 patients undergoing intermittent hemodialysis in a 50-bed ICU in Lille, France. Hemodialysis was performed using either ELISIO

(Nipro, France), a polyethersulfone membrane with very low adsorptive capacities or EVODIAL (Baxter, USA), a heparin-grafted AN 69 ST membrane with higher adsorptive properties. Patients' characteristics on ICU admission and on day of hemodialysis were collected retrospectively.

We categorized measurements of plasma endocan according to timing of blood collection relatively to hemodialysis, as following: T0, within 1 h before start of hemodialysis; T1, 30 min to 60 min after start of hemodialysis; T2, 90 min to 120 min after start of hemodialysis, T3, 180 min to 240 min after start of hemodialysis; T4: 90 min to 120 min after end of hemodialysis.

<table><caption>**Table 1** Characteristics of patients</caption><tbody><tr><td>Sex, male</td><td>6 (55%)</td></tr><tr><td>Age, years</td><td>66 (59–69)</td></tr><tr><td>Body weight on ICU admission, kg</td><td>80 (72–96)</td></tr><tr><td>SAPS II on ICU admission</td><td>48 (41–72)</td></tr><tr><td>Disorder category</td><td></td></tr><tr><td>Medical</td><td>8 (73%)</td></tr><tr><td>Surgical</td><td>3 (27%)</td></tr><tr><td>Preexisting conditions</td><td></td></tr><tr><td>Chronic kidney failure</td><td>5 (45%)</td></tr><tr><td>Chronic heart failure</td><td>3 (27%)</td></tr><tr><td>Cirrhosis</td><td>1 (9%)</td></tr><tr><td>Diabetes mellitus</td><td>4 (36%)</td></tr><tr><td>Diagnosis on ICU admission</td><td></td></tr><tr><td>Soft tissues infection</td><td>3 (27%)</td></tr></tbody></table>

<table><tbody><tr><td>Pneumonia</td><td>3 (27%)</td></tr><tr><td>Carbon monoxide poisoning</td><td>1 (9%)</td></tr><tr><td>Decompensated cirrhosis</td><td>1 (9%)</td></tr><tr><td>Cardiogenic shock</td><td>1 (9%)</td></tr><tr><td>Hemorrhagic shock</td><td>1 (9%)</td></tr><tr><td>Gas embolism</td><td>1 (9%)</td></tr><tr><td>Inflammation biomarkers on day of hemodialysis</td><td></td></tr><tr><td>CRP, mg/l</td><td>66 (41–154)</td></tr><tr><td>Procalcitonin, ng/ml</td><td>2 (1.4–2.8)</td></tr><tr><td>Characteristics of hemodialysis</td><td></td></tr><tr><td>Residual volume of diuresis (ml/24 h)</td><td>100 (25–450)</td></tr><tr><td>Systemic anticoagulation</td><td>8 (72%)</td></tr><tr><td>Daily UFH dose, IU/24 h</td><td>10000 (0; 12000)</td></tr><tr><td>Heparin-coated membrane (EVODIAL)</td><td>3 (27%)</td></tr><tr><td>Duration of hemodialysis, hrs</td><td>5 (4.5–6)</td></tr></tbody></table>

<footnote>*Correspondence: alexandre.gaudet@chru-lille.fr</footnote>

<footnote n="4">⁴ CHU Lille, Pôle de Médecine Intensive – Réanimation, Hôpital Roger Salengro, 59000 Lille, France</footnote>

<footnote>Full list of author information is available at the end of the article</footnote>
<table><caption>**Table 1** (continued)</caption><tr><td>Blood flow rate, ml/min</td><td>250 (250–250)</td></tr><tr><td>Dialysate flow rate, ml/min</td><td>500 (500–500)</td></tr><tr><td>Ultrafiltration volume, ml</td><td>2000 (860–2500)</td></tr><tr><td>Ultrafiltration rate, ml/h</td><td>333 (240–500)</td></tr></table>

Anticoagulation of the extracorporeal circuit with unfractioned heparin 5000 IU was performed for all patients. Data are presented as number (%) or median (IQR)

SAPS, Simplified Acute Physiology Score; ICU, Intensive Care Unit; IU, International Unit; UFH, unfractioned heparin

We are reporting characteristics of patients and of hemodialysis in Table 1 and kinetics of plasma endocan during hemodialysis in Fig. 1. We find a significant variation of endocan during the time course of hemodialysis, with median [IQR] values measured at 10.9 [4.3; 14.9] ng/ml at T0, 15.4 [5; 19.4] ng/ml at T1, 14.9 [5.4; 18.8] ng/ml at T2, 12.4 [6.1; 20] ng/ml at T3, 10.1 [4.2; 16.1] ng/ml at T4 (p = 0.025). In addition, relatively to values observed at T0, we found significant increases of median [IQR]

<figure><img src="image_3.png" /><figcaption>**Fig. 1** a Box plots of plasma endocan values during hemodialysis. Box plots show median, 1st and 3rd quartiles, and whiskers at 1.5-time interquartile range. Comparisons between paired values were performed using Friedman test. b Variations of plasma endocan relatively to values measured at T0. Comparisons between values at each time point with T0 value were performed using Wilcoxon-signed ranks test. c Values of endocan expressed in ng/ml at each time point. Patients are shown in yellow rows in case of hemodialysis with EVODIAL membranes and blue rows in case of ELISIO membranes. We used a linear mixed model with type of membrane set as fix effect and timing of blood collection set as random effect to assess the effect of the type of membrane on variations of endocan during hemodialysis. Plasma endocan was measured at the Immunology Institute of Lille Teaching Hospital, France, using the ENDOMARK H1 ELISA kit (Biothelis, France). T0: sampling within 1 h before start of hemodialysis. T1: sampling 30–60 min after start of hemodialysis. T2: sampling 90–120 min after start of hemodialysis. T3: sampling 180–240 min after start of hemodialysis. T4: sampling 90–120 min after end of hemodialysis. All statistical tests were two-tailed, and *p* values < 0.05 were considered statistically significant. All data analyses were performed using R, version 3.6 (R Foundation for Statistical Computing, Austria). *p* < 0.05.</figcaption></figure>

<footnote>**p** < 0.01. ns: non-significant</footnote>
<table><caption>**Table 1** (continued)</caption><tr><td>Blood flow rate, ml/min</td><td>250 (250–250)</td></tr><tr><td>Dialysate flow rate, ml/min</td><td>500 (500–500)</td></tr><tr><td>Ultrafiltration volume, ml</td><td>2000 (860–2500)</td></tr><tr><td>Ultrafiltration rate, ml/h</td><td>333 (240–500)</td></tr></table>

Anticoagulation of the extracorporeal circuit with unfractioned heparin 5000 IU was performed for all patients. Data are presented as number (%) or median (IQR)

SAPS, Simplified Acute Physiology Score; ICU, Intensive Care Unit; IU, International Unit; UFH, unfractioned heparin

We are reporting characteristics of patients and of hemodialysis in Table 1 and kinetics of plasma endocan during hemodialysis in Fig. 1. We find a significant variation of endocan during the time course of hemodialysis, with median [IQR] values measured at 10.9 [4.3; 14.9] ng/ml at T0, 15.4 [5; 19.4] ng/ml at T1, 14.9 [5.4; 18.8] ng/ml at T2, 12.4 [6.1; 20] ng/ml at T3, 10.1 [4.2; 16.1] ng/ml at T4 (p = 0.025). In addition, relatively to values observed at T0, we found significant increases of median [IQR]

<figure><img src="image_3.png" /></figure>

**Fig. 1** a Box plots of plasma endocan values during hemodialysis. Box plots show median, 1st and 3rd quartiles, and whiskers at 1.5-time interquartile range. Comparisons between paired values were performed using Friedman test. b Variations of plasma endocan relatively to values measured at T0. Comparisons between values at each time point with T0 value were performed using Wilcoxon-signed ranks test. c Values of endocan expressed in ng/ml at each time point. Patients are shown in yellow rows in case of hemodialysis with EVODIAL membranes and blue rows in case of ELISIO membranes. We used a linear mixed model with type of membrane set as fix effect and timing of blood collection set as random effect to assess the effect of the type of membrane on variations of endocan during hemodialysis. Plasma endocan was measured at the Immunology Institute of Lille Teaching Hospital, France, using the ENDOMARK H1 ELISA kit (Biothelis, France). T0: sampling within 1 h before start of hemodialysis. T1: sampling 30–60 min after start of hemodialysis. T2: sampling 90–120 min after start of hemodialysis. T3: sampling 180–240 min after start of hemodialysis. T4: sampling 90–120 min after end of hemodialysis. All statistical tests were two-tailed, and *p* values < 0.05 were considered statistically significant. All data analyses were performed using R, version 3.6 (R Foundation for Statistical Computing, Austria). *p* < 0.05.

<footnote>**p** < 0.01. ns: non-significant</footnote>
plasma endocan variations at T1 (+22% [+12%; +72%], p=0.006), T2 (+34% [-4%; +68%], p=0.019), and T3 (+27% [+5%; +56%], p=0.014), but not at T4 (+34% [-8%; +57%], p=0.053). Noteworthy, our analyses suggest that the variations of endocan depend on the type of membrane, with lower increases in the EVODIAL group (p=0.009 by linear mixed model). This lower increase in endocan blood levels seems consistent with greater adsorption properties of EVODIAL membranes. However, because of the limited number of patients in the EVODIAL group, this result should be interpreted with caution.

Our results suggest an increase in levels of plasma endocan at the initial phase of hemodialysis. This may be explained by the response to vascular stress, resulting in an increase in secretion of endocan [1], or by hemoconcentration, which may occur during hemodialysis. Interestingly, the quick raise in endocan blood levels is consistent with previous data from a human LPS-induced endothelial stress model [5]. Additionally, our data tend to show a progressive decrease of plasma endocan during the time course of hemodialysis, possibly related to alleviation of endothelial stress or actual elimination of endocan. Adsorption on the membrane may explain this progressive decrease in blood levels of endocan, as suggested by the likely influence of adsorptive properties of the membranes on the variations of endocan. Conversely, the possibility that this decrease could be explained by diffusion mechanisms seems unlikely, given the 50 kDa molecular weight of endocan, exceeding the diffusion properties expected with our hemodialysis settings [6]. Similar mechanisms should be observed during continuous renal replacement therapy (CRRT), potentially resulting in greater removal of plasma endocan, because of longer RRT durations in CRRT.

Hence, these results suggest major interference of hemodialysis with blood concentrations of endocan, especially when highly adsorptive membranes are used, making it unreliable as a prognostic biomarker of pulmonary and systemic inflammation in critically ill patients undergoing hemodialysis.

**Acknowledgements**

Not applicable.

**Authors' contributions**

MH, JP, DM, and AG designed the whole study, conducted data analyses, and drafted the manuscript. SD performed the biological measurements. All authors read and approved the final manuscript.

**Funding**

None.

**Availability of data and materials**

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

**Declarations**

**Ethics approval and consent to participate:**

In accordance with the French law, and because of the retrospective observational design, written informed consent was not required for this study. Data collection for this study was declared to and approved by the Commission Nationale de l'Informatique et des Libertés (CNIL/Declaration Number DEC19-450). Accordingly, patients included in this study received an information letter, as required by the French law.

**Consent for publication**

Not applicable.

**Competing interests**

The authors have disclosed that they do not have any conflicts of interest.

**Author details**

¹Univ. Lille, U1019 – UMR 9017 – CIL – Center for Infection and Immunity of Lille, 59000 Lille, France. ²CNRS, UMR 9017, 59000 Lille, France. ³INSERM, U1019, 59000 Lille, France. ⁴CHU Lille, Pôle de Médecine Intensive – Réanimation, Hôpital Roger Salengro, 59000 Lille, France. ⁵Univ. Lille, Inserm U1285, CHU Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structuale et Fonctionnelle, 59000 Lille, France. ⁶Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE - Institute for Translational Research in Inflammation, 59000 Lille, France.

Received: 15 September 2021 Accepted: 17 November 2021

Published online: 29 November 2021

**References**

1. De Freitas CN, Gaudet A, Portier L, Tsicopoulos A, Mathieu D, Lassalle P. Endocan, sepsis, pneumonia, and acute respiratory distress syndrome. Crit Care Lond Engl. 2018;22:280.

2. Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from The Intensive Care Over Nations audit. Crit Care Lond Engl. 2018;22:188.

3. Honore PM, De Bels D, Attou R, Redant S, Gallerani A, Kashani K. Endocan removal during continuous renal replacement therapy: does it affect the reliability of this biomarker? Crit Care Lond Engl. 2019;23:184.

4. Honore PM, Redant S, De Bels D. Reliability of biomarkers of sepsis during extracorporeal therapies: the clinician needs to know what is eliminated and what is not. Crit Care Lond Engl. 2020;24:553.

5. Cox LAE, van Eijk LT, Ramakers BPC, Dorresteijn MJ, Gerretsen J, Kox M, et al. Inflammation-induced increases in plasma endocan levels are associated with endothelial dysfunction in humans in vivo. Shock Augusta Ga. 2015;43:322–6.

6. Pino CJ, Humes HD. Chapter 83—Renal replacement devices. In: Orlando G, Remuzzi G, Williams DF, editors. Kidney Transplant Bioeng Regen. Academic Press; 2017 [cited 2021 Nov 6]. p. 1135–49. https://www.sciencedirect.com/science/article/pii/B9780128017340000837

**Publisher's Note**

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
plasma endocan variations at T1 (+22% [+12%; +72%], *p*=0.006), T2 (+34% [-4%; +68%], *p*=0.019), and T3 (+27% [+5%; +56%], *p*=0.014), but not at T4 (+34% [-8%; +57%], *p*=0.053). Noteworthy, our analyses suggest that the variations of endocan depend on the type of membrane, with lower increases in the EVODIAL group (*p*=0.009 by linear mixed model). This lower increase in endocan blood levels seems consistent with greater adsorption properties of EVODIAL membranes. However, because of the limited number of patients in the EVODIAL group, this result should be interpreted with caution.

Our results suggest an increase in levels of plasma endocan at the initial phase of hemodialysis. This may be explained by the response to vascular stress, resulting in an increase in secretion of endocan [1], or by hemoconcentration, which may occur during hemodialysis. Interestingly, the quick raise in endocan blood levels is consistent with previous data from a human LPS-induced endothelial stress model [5]. Additionally, our data tend to show a progressive decrease of plasma endocan during the time course of hemodialysis, possibly related to alleviation of endothelial stress or actual elimination of endocan. Adsorption on the membrane may explain this progressive decrease in blood levels of endocan, as suggested by the likely influence of adsorptive properties of the membranes on the variations of endocan. Conversely, the possibility that this decrease could be explained by diffusion mechanisms seems unlikely, given the 50 kDa molecular weight of endocan, exceeding the diffusion properties expected with our hemodialysis settings [6]. Similar mechanisms should be observed during continuous renal replacement therapy (CRRT), potentially resulting in greater removal of plasma endocan, because of longer RRT durations in CRRT.

Hence, these results suggest major interference of hemodialysis with blood concentrations of endocan, especially when highly adsorptive membranes are used, making it unreliable as a prognostic biomarker of pulmonary and systemic inflammation in critically ill patients undergoing hemodialysis.

**Acknowledgements**

Not applicable.

**Authors' contributions**

MH, JP, DM, and AG designed the whole study, conducted data analyses, and drafted the manuscript. SD performed the biological measurements. All authors read and approved the final manuscript.

**Funding**

None.

**Availability of data and materials**

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

**Declarations**

**Ethics approval and consent to participate:**

In accordance with the French law, and because of the retrospective observational design, written informed consent was not required for this study. Data collection for this study was declared to and approved by the Commission Nationale de l'Informatique et des Libertés (CNIL/Declaration Number DEC19-450). Accordingly, patients included in this study received an information letter, as required by the French law.

**Consent for publication**

Not applicable.

**Competing interests**

The authors have disclosed that they do not have any conflicts of interest.

**Author details**

¹Univ. Lille, U1019 – UMR 9017 – CIL – Center for Infection and Immunity of Lille, 59000 Lille, France. ²CNRS, UMR 9017, 59000 Lille, France. ³INSERM, U1019, 59000 Lille, France. ⁴CHU Lille, Pôle de Médecine Intensive – Réanimation, Hôpital Roger Salengro, 59000 Lille, France. ⁵Univ. Lille, Inserm U1285, CHU Lille, CNRS, UMR 8576, UGSF, Unité de Glycobiologie Structuale et Fonctionnelle, 59000 Lille, France. ⁶Univ. Lille, Inserm, CHU Lille, U1286 – INFINITE - Institute for Translational Research in Inflammation, 59000 Lille, France.

Received: 15 September 2021 Accepted: 17 November 2021

Published online: 29 November 2021

**References**

1. De Freitas CN, Gaudet A, Portier L, Tsicopoulos A, Mathieu D, Lassalle P. Endocan, sepsis, pneumonia, and acute respiratory distress syndrome. Crit Care Lond Engl. 2018;22:280.

2. Peters E, Antonelli M, Wittebole X, Nanchal R, François B, Sakr Y, et al. A worldwide multicentre evaluation of the influence of deterioration or improvement of acute kidney injury on clinical outcome in critically ill patients with and without sepsis at ICU admission: results from The Intensive Care Over Nations audit. Crit Care Lond Engl. 2018;22:188.

3. Honore PM, De Bels D, Attou R, Redant S, Gallerani A, Kashani K. Endocan removal during continuous renal replacement therapy: does it affect the reliability of this biomarker? Crit Care Lond Engl. 2019;23:184.

4. Honore PM, Redant S, De Bels D. Reliability of biomarkers of sepsis during extracorporeal therapies: the clinician needs to know what is eliminated and what is not. Crit Care Lond Engl. 2020;24:553.

5. Cox LAE, van Eijk LT, Ramakers BPC, Dorresteijn MJ, Gerretsen J, Kox M, et al. Inflammation-induced increases in plasma endocan levels are associated with endothelial dysfunction in humans in vivo. Shock Augusta Ga. 2015;43:322–6.

6. Pino CJ, Humes HD. Chapter 83—Renal replacement devices. In: Orlando G, Remuzzi G, Williams DF, editors. Kidney Transplant Bioeng Regen. Academic Press; 2017 [cited 2021 Nov 6]. p. 1135–49. https://www.sciencedirect.com/science/article/pii/B9780128017340000837

**Publisher's Note**

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.