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Observational Study
. 2019 Sep 13;14(9):e0222547.
doi: 10.1371/journal.pone.0222547. eCollection 2019.

Endothelial dysfunction and low-grade inflammation in the transition to renal replacement therapy

April C E van Gennip  1 , Natascha J H Broers  1   2 , Karlien J Ter Meulen  1 , Bernard Canaud  3   4 , Maarten H L Christiaans  1 , Tom Cornelis  5 , Mariëlle A C J Gelens  1 , Marc M H Hermans  6 , Constantijn J A M Konings  7 , Jeroen B van der Net  1 , Frank M van der Sande  1 , Casper G Schalkwijk  8   9 , Frank Stifft  10 , Joris J J M Wirtz  11 , Jeroen P Kooman  1   2 , Remy J H Martens  1   9
Affiliations
Observational Study

Endothelial dysfunction and low-grade inflammation in the transition to renal replacement therapy

April C E van Gennip et al. PLoS One. .

Abstract

Introduction: End-stage renal disease (ESRD) strongly associates with cardiovascular disease (CVD) risk. This risk is not completely mitigated by renal replacement therapy. Endothelial dysfunction (ED) and low-grade inflammation (LGI) may contribute to the increased CVD risk. However, data on serum biomarkers of ED and LGI during the transition to renal replacement therapy (dialysis and kidney transplantation) are scarce.

Methods: We compared serum biomarkers of ED and LGI between 36 controls, 43 participants with chronic kidney disease (CKD) stage 5 non-dialysis (CKD5-ND), 20 participants with CKD stage 5 hemodialysis (CKD5-HD) and 14 participants with CKD stage 5 peritoneal dialysis (CKD5-PD). Further, in 34 and 15 participants repeated measurements were available during the first six months following dialysis initiation and kidney transplantation, respectively. Serum biomarkers of ED (sVCAM-1, E-selectin, P-selectin, thrombomodulin, sICAM-1, sICAM-3) and LGI (hs-CRP, SAA, IL-6, IL-8, TNF-α) were measured with a single- or multiplex array detection system based on electro-chemiluminescence technology.

Results: In linear regression analyses adjusted for potential confounders, participants with ESRD had higher levels of most serum biomarkers of ED and LGI than controls. In addition, in CKD5-HD levels of serum biomarkers of ED and LGI were largely similar to those in CKD5-ND. In contrast, in CKD5-PD levels of biomarkers of ED were higher than in CKD5-ND and CKD5-HD. Similarly, in linear mixed model analyses sVCAM-1, thrombomodulin, sICAM-1 and sICAM-3 increased after PD initiation. In contrast, incident HD patients showed an increase in sVCAM-1, P-selectin and TNF-α, but a decline of hs-CRP, SAA and IL-6. Further, following kidney transplantation sVCAM-1, thrombomodulin, sICAM-3 and TNF-α were lower at three months post-transplantation and remained stable in the three months thereafter.

Conclusions: Levels of serum biomarkers of ED and LGI were higher in ESRD as compared with controls. In addition, PD initiation and, less convincingly, HD initiation may increase levels of selected serum biomarkers of ED and LGI on top of uremia per se. In contrast to dialysis, several serum biomarkers of ED and LGI markedly declined following kidney transplantation.

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Conflict of interest statement

The studies included in this article were supported by an unrestricted grant from Fresenius Medical Care Deutschland GmbH (study NL33129.068.10 and NL43381.068.13), a Baxter International extramural grant (study NL35039.068.10; grant reference number 11CECHHDEU1004) and the Dutch Kidney Foundation (study NL35039.068.10; grant reference number SB166). BC and AG, who are employees of Fresenius Medical Care and hold shares in the company, reviewed the manuscript. However, the funding sources had no role in the preparation or analysis of data, and the decision to publish. In addition, RJHM, NJHB and JPK are supported by an (un)restricted grant from Fresenius Medical Care. RJHM and NJHB received lectures fees from Fresenius Medical Care. MHC reports Astellas Travel support grants to visit the international conferences ESOT 2017 and TTS 2018. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Figures

Fig 1
Fig 1. Boxplots of serum biomarkers of endothelial dysfunction and low-grade inflammation stratified according to participant group.
Abbreviations: hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; IL-8, interleukin 8; NA, not applicable; SAA, serum amyloid A; sICAM-1, soluble intercellular adhesion molecule 1; sICAM-3, soluble intercellular adhesion molecule 3; sVCAM-1, soluble vascular cell adhesion molecule 1; TNF-α, tumor necrosis factor alpha. Please note that in the boxplot of IL-8 levels in controls, one extreme outlier with an IL-8 level of 2469.8 ng/L was removed to improve the clarity of the graph. † P value < 0.05 vs. controls; ‡ P value < 0.05 vs. CKD5-ND; P value < 0.05 vs. CKD5-HD based on unadjusted linear regression analyses of natural log transformed serum biomarkers.
Fig 2
Fig 2. Boxplots and individual trajectories of serum biomarkers of endothelial dysfunction and low-grade inflammation over time in incident hemodialysis patients.
Abbreviations: hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; IL-8, interleukin 8; NA, not applicable; SAA, serum amyloid A; sICAM-1, soluble intercellular adhesion molecule 1; sICAM-3, soluble intercellular adhesion molecule 3; sVCAM-1, soluble vascular cell adhesion molecule 1; TNF-α, tumor necrosis factor alpha. † P value < 0.05 vs. baseline based on linear mixed model analyses with a random intercept.
Fig 3
Fig 3. Boxplots and individual trajectories of serum biomarkers of endothelial dysfunction and low-grade inflammation over time in incident peritoneal dialysis patients.
Abbreviations: hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; IL-8, interleukin 8; NA, not applicable; SAA, serum amyloid A; sICAM-1, soluble intercellular adhesion molecule 1; sICAM-3, soluble intercellular adhesion molecule 3; sVCAM-1, soluble vascular cell adhesion molecule 1; TNF-α, tumor necrosis factor alpha. † P value < 0.05 vs. baseline based on linear mixed model analyses with a random intercept.
Fig 4
Fig 4. Boxplots and individual trajectories of serum biomarkers of endothelial dysfunction and low-grade inflammation over time in kidney transplant recipients.
Abbreviations: hs-CRP, high-sensitivity C-reactive protein; IL-6, interleukin 6; IL-8, interleukin 8; NA, not applicable; SAA, serum amyloid A; sICAM-1, soluble intercellular adhesion molecule 1; sICAM-3, soluble intercellular adhesion molecule 3; sVCAM-1, soluble vascular cell adhesion molecule 1; TNF-α, tumor necrosis factor alpha. † P value < 0.05 vs. baseline based on linear mixed model analyses with a random intercept.
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