Eveline P van Poelgeest1, Marlous R Dillingh2, Marieke de Kam3, Karen E Malone4, Marleen Kemper5, Erik S G Stroes6, Jacobus Burggraaf7, Matthijs Moerland8. 1. Centre for Human Drug Research, Zernikedreef 8, 2333, CL, Leiden, The Netherlands. Electronic address: evpoelgeest@chdr.nl. 2. Centre for Human Drug Research, Zernikedreef 8, 2333, CL, Leiden, The Netherlands. Electronic address: mdillingh@chdr.nl. 3. Centre for Human Drug Research, Zernikedreef 8, 2333, CL, Leiden, The Netherlands. Electronic address: mdekam@chdr.nl. 4. Good Biomarker Sciences, Zernikedreef 8, 2333, CL, Leiden, The Netherlands. Electronic address: kmalon1@its.jnj.com. 5. Academic Medical Center, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. Electronic address: e.m.kemper@amc.uva.nl. 6. Academic Medical Center, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands. Electronic address: e.s.stroes@amc.uva.nl. 7. Centre for Human Drug Research, Zernikedreef 8, 2333, CL, Leiden, The Netherlands. Electronic address: kb@chdr.nl. 8. Centre for Human Drug Research, Zernikedreef 8, 2333, CL, Leiden, The Netherlands. Electronic address: MMoerland@chdr.nl.
Abstract
INTRODUCTION: Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endotoxemia on the kidneys is lacking. A study was performed to assess the effects of low- to moderate dose (0.5, 1 or 2ng/kg) endotoxemia on the endothelium and kidneys as measured by a panel of novel highly sensitive kidney injury markers. METHODS: This was a randomized, double-blind, placebo-controlled study with single ascending doses of LPS (0.5, 1 or 2ng/kg) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS:placebo 6:2). Endothelial measures included selectins, cell adhesion molecules, and thrombomodulin. Renal measures included novel, sensitive and specific biomarkers of acute kidney injury. RESULTS:Endotoxin exposure resulted in consistent LPS dose-dependent responses in inflammatory markers, E- and P- Selectin, VCAM1, ICAM1, and thrombomodulin. The observed biological responses were transient, reaching a level of significance of at least <0.01 in the highest dose group and with an effect size which was dependent on the administered LPS dose. LPS-induced inflammatory and endothelial effects did not translate into a change in renal damage biomarkers, although at 2ng/kg LPS, subtle and transient biomarker changes were observed that may relate to (subclinical) tubular damage. DISCUSSION: We demonstrated that administration of a single LPS dose of 2ng/kg to healthy volunteers results in significant inflammatory and endothelial responses, without inducing clinically relevant signs of kidney injury. These findings support the application of the human endotoxemia model in future clinical pharmacology studies.
RCT Entities:
INTRODUCTION: Although the effects of relatively high concentrations of endotoxin on endothelial activation/dysfunction and kidney markers has been described in literature, detailed insight in the LPS concentration-effect relationship, the magnitude, variability and timing of the response, and potential effects of endotoxemia on the kidneys is lacking. A study was performed to assess the effects of low- to moderate dose (0.5, 1 or 2ng/kg) endotoxemia on the endothelium and kidneys as measured by a panel of novel highly sensitive kidney injury markers. METHODS: This was a randomized, double-blind, placebo-controlled study with single ascending doses of LPS (0.5, 1 or 2ng/kg) administered to healthy male volunteers (3 cohorts of 8 subjects, LPS:placebo 6:2). Endothelial measures included selectins, cell adhesion molecules, and thrombomodulin. Renal measures included novel, sensitive and specific biomarkers of acute kidney injury. RESULTS: Endotoxin exposure resulted in consistent LPS dose-dependent responses in inflammatory markers, E- and P- Selectin, VCAM1, ICAM1, and thrombomodulin. The observed biological responses were transient, reaching a level of significance of at least <0.01 in the highest dose group and with an effect size which was dependent on the administered LPS dose. LPS-induced inflammatory and endothelial effects did not translate into a change in renal damage biomarkers, although at 2ng/kg LPS, subtle and transient biomarker changes were observed that may relate to (subclinical) tubular damage. DISCUSSION: We demonstrated that administration of a single LPS dose of 2ng/kg to healthy volunteers results in significant inflammatory and endothelial responses, without inducing clinically relevant signs of kidney injury. These findings support the application of the humanendotoxemia model in future clinical pharmacology studies.
Authors: David A C Messerer; Rebecca Halbgebauer; Bo Nilsson; Hermann Pavenstädt; Peter Radermacher; Markus Huber-Lang Journal: Nat Rev Nephrol Date: 2020-09-21 Impact factor: 28.314
Authors: Thomas P Buters; Pieter W Hameeteman; Iris M E Jansen; Floris C van Hindevoort; Wouter Ten Voorde; Hendrika W Grievink; Mascha Schoonakker; Marieke L de Kam; Derek W Gilroy; Gary Feiss; Robert Rissmann; Manon A A Jansen; Jacobus Burggraaf; Matthijs Moerland Journal: Clin Pharmacol Ther Date: 2022-01-06 Impact factor: 6.903
Authors: Jules A A C Heuberger; Jelle J Posthuma; Dimitrios Ziagkos; Joris I Rotmans; Johannes M A Daniels; Pim Gal; Frederik E Stuurman; Henri M H Spronk; Hugo Ten Cate; Jacobus Burggraaf; Matthijs Moerland; Adam F Cohen Journal: Eur J Appl Physiol Date: 2020-06-14 Impact factor: 3.078