Endotoxemia-Induced Release of Pro-inflammatory Mediators Are Associated With Increased Glomerular Filtration Rate in Humans in vivo

Remi Beunders; Maren J Schütz; Roger van Groenendael; Guus P Leijte; Matthijs Kox; Lucas T van Eijk; Peter Pickkers

doi:10.3389/fmed.2020.559671

Endotoxemia-Induced Release of Pro-inflammatory Mediators Are Associated With Increased Glomerular Filtration Rate in Humans in vivo

Front Med (Lausanne). 2020 Nov 5:7:559671. doi: 10.3389/fmed.2020.559671. eCollection 2020.

Authors

Remi Beunders^{1

2

3}, Maren J Schütz¹, Roger van Groenendael^{2

3

4}, Guus P Leijte^{1

2

3}, Matthijs Kox^{1

2

3}, Lucas T van Eijk^{2

3

4}, Peter Pickkers^{1

2

3}

Affiliations

¹ Department of Intensive Care Medicine, Radboud University Medical Center, Nijmegen, Netherlands.
² Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands.
³ Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
⁴ Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

Abstract

Introduction: Sepsis is the most prevalent cause of Acute Kidney Injury (AKI). Conversely, in some septic patients the glomerular filtration rate (GFR) is augmented. The role of the inflammatory response and blood pressure to induce this increased GFR is unknown. Herein, we relate inflammatory mediators and blood pressure to the iohexol clearance-derived "true" GFR and kidney injury markers during systemic inflammation in healthy volunteers. Methods: Twelve healthy subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli-derived lipopolysaccharide, LPS). As a gold-standard to determine the GFR, iohexol plasma clearance (GFR_iohexol) was calculated during a 6-h period on the day before (baseline) as well as 2 and 24 h after LPS administration. Intra-arterial blood pressure was recorded continuously using a radial artery catheter. Circulating inflammatory mediators and urinary excretion of kidney injury markers were serially measured. Results: Experimental endotoxemia profoundly increased plasma concentrations of inflammatory mediators, including [mean ± SD or median [IQR] peak values (pg/mL) of tumor necrosis factor (TNF)-α: 92 ± 40, interleukin (IL)-6: 1,246 ± 605, IL-8: 374 ± 120, IL-10: 222 ± 119, IL-1 receptor antagonist (RA): 8,955 ± 2,429, macrophage chemoattractant protein (MCP)-1: 2,885 [2,706 - 3,765], vascular adhesion molecule (VCAM)-1: 296,105 ± 34,822, intercellular adhesion molecule (ICAM)-1: 25,0170 ± 41,764]. Mean arterial pressure decreased with 13 ± 11 mmHg (p < 0.0001). No significant increase in the urinary excretion of tubular injury markers was observed following LPS administration. GFR_iohexol increased from 97 ± 6 at baseline to 118 ± 10 mL/min/1.73m² (p < 0.0001) post-LPS administration and returned to baseline levels at 24 h post-LPS (99 ± 9 mL/min/1.73m²). Peak plasma concentrations of IL-6 (R ² = 0.66, p = 0.001) and IL-8 (R ² = 0.51, p = 0.009), MCP-1 (R ² = 0.38, p = 0.03) and VCAM-1 levels (R ² = 0.37, p = 0.04) correlated with the increase in GFR_iohexol, whereas a trend was observed for TNF-α (R ² = 0.33, p = 0.0509) and IL-1RA (R ² = 0.28, p = 0.08). None of the kidney injury markers or changes in blood pressure were associated with GFR_iohexol. In multiple linear regression analysis, both peak IL-6 (p = 0.002) and IL-8 (p = 0.01) concentrations remained significantly correlated with GFR_iohexol, without collinearity. Discussion: Concentrations of pro-inflammatory cytokines, but not blood pressure, are correlated with the endotoxemia-induced increase in GFR in healthy volunteers. These findings may indicate that inflammatory mediators orchestrate the augmented GFR observed in a subgroup of sepsis patients.

Keywords: acute kidney injury; augmented renal clearance; endogenous creatinine clearance; glomerular filtration rate; iohexol plasma clearance; sepsis; systemic inflammation.