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. 2023 Oct 28;15(11):2166.
doi: 10.3390/v15112166.

Patterns of Circulating Cytokines and Vascular Markers' Response in the Presence of COVID-19 in Kidney Transplant Recipients Compared with Non-Transplanted Patients

Milena Karina Coló Brunialti  1 , Giuseppe G F Leite  1 , Gabriela Strafolino Eburneo  1 , Orlei Ribeiro de Araujo  2 , Paula M Peçanha-Pietrobom  1 , Paulo Roberto Abrão Ferreira  1 , Nancy C Junqueira Bellei  1 , Jaquelina Sonoe Ota Arakaki  3 , José Medina-Pestana  4   5 , Lúcio Requião-Moura  4   5 , Reinaldo Salomao  1   6
Affiliations

Patterns of Circulating Cytokines and Vascular Markers' Response in the Presence of COVID-19 in Kidney Transplant Recipients Compared with Non-Transplanted Patients

Milena Karina Coló Brunialti et al. Viruses. .

Abstract

COVID-19's severity has been associated with a possible imbalance in the cross-regulation of cytokines and vascular mediators. Since the beginning of the pandemic, kidney transplant recipients (KTRs) have been identified as patients of high vulnerability to more severe diseases. Thus, aiming to describe the patterns of cytokines and vascular mediators and to trace patients' differences according to their KTR status, this prospective study enrolled 67 COVID-19 patients (20 KTRs) and 29 non-COVID-19 controls before vaccination. A panel comprising 17 circulating cytokines and vascular mediators was run on samples collected at different time points. The cytokine and mediator patterns were investigated via principal component analysis (PCA) and correlation-based network (CBN). In both groups, compared to their respective controls, COVID-19 was associated with higher levels of cytokines and vascular mediators. Differentiating between the KTRs and non-KTRs, the number of correlations was much higher in the non-KTRs (44 vs. 14), and the node analysis showed the highest interactions of NGAL and sVCAM-1 in the non-KTRs and KTRs (9 vs. 4), respectively. In the PCA, while the non-KTRs with COVID-19 were differentiated from their controls in their IL-10, IFN-α, and TNF-α, this pattern was marked in the NGAL, sVCAM-1, and IL-8 of the KTRs.

Keywords: SARS-CoV-2; correlation-based network; cytokines; kidney transplant recipients; vascular mediators.

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Conflict of interest statement

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Figure 1
Figure 1
Study design. Patients with COVID-19 were prospectively enrolled, including KTR and non-KTR patients. Healthy volunteers and KTR patients without COVID-19 were included as control groups.
Figure 2
Figure 2
Baseline plasma biomarker levels in patients with COVID-19 stratified by kidney transplant recipient status and respective controls. To investigate potential differences in plasma biomarkers, we employed the Kruskal–Wallis test, followed by Dunn’s test, with Benjamini–Hochberg correction for multiple comparisons. Statistically significant results are denoted by the following symbols: * p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001. The outliers are showed as black dots. Abbreviations: IL-6: interleukin 6. IL-8: interleukin 8. IL-9: interleukin 9. IL-10: interleukin 10. sICAM-1: soluble intercellular adhesion molecule 1. sVCAM-1: soluble circulating vascular cell adhesion molecule 1. IFN-γ: interferon gamma. IFN-α: interferon alpha. SAA: serum amyloid A. GDF-15: growth/differentiation factor 15. MPO: myeloperoxidase. NGAL: neutrophil gelatinase-associated lipocalin. D0 (day 0): blood samples were collected at admission. KTRs: kidney transplant recipients. Non-KTRs: non-kidney transplant recipients.
Figure 3
Figure 3
Correlation-based network analysis. (A) Non-kidney transplant recipient networks and (B) kidney transplant recipient networks. The links displayed in these networks indicate statistically significant Spearman’s rank correlations (p < 0.05). Specifically, red links represent positive correlations (rho ≥ 0.20), while blue links represent negative correlations (rho ≤ 0.20). Abbreviations: IL-6: interleukin 6. IL-8: interleukin 8. IL-9: interleukin 9. IL-10: interleukin 10. G-CSF: granulocyte colony-stimulating factor. TNF-α: tumor necrosis factor alpha. IFN-α: interferon alpha. IFN-γ: interferon gamma. GDF-15: growth/differentiation factor 15. sICAM-1: soluble intercellular adhesion molecule 1. MPO: myeloperoxidase. NGAL: neutrophil gelatinase-associated lipocalin. sVCAM-1: soluble circulating vascular cell adhesion molecule 1. SAA: serum amyloid A. MYO: myoglobin. P-Sel: P-selectin. D0 (day 0): blood samples were collected at admission. KTRs: kidney transplant recipients. Non-KTRs: non-kidney transplant recipients.
Figure 4
Figure 4
Principal component analysis (PCA) of plasma biomarkers. (A) Non-kidney transplant recipient PCA: percentage of explained variance in principal components 1 and 2. (B) Contribution of variables (non-kidney transplant recipients): top 3 variables explaining variance in the data. (C) Kidney transplant recipient PCA: percentage of explained variance in principal components 1 and 2. (D) Contribution of variables (kidney transplant recipients): top 3 variables explaining variance in the data. The ellipse indicates the central 33% of the data points, representing the grouping of the samples. The arrows denote the direction (arrow orientation) and strength (arrow length) of the correlation between each biomarker and the principal components. Abbreviations: IL-10: interleukin 10. IFN-α: interferon alpha. TNF-α: tumor necrosis factor alpha. NGAL: neutrophil gelatinase-associated lipocalin. sVCAM-1: soluble circulating vascular cell adhesion molecule 1. IL-8: interleukin 8. KTRs: kidney transplant recipients. Non-KTRs: non-kidney transplant recipients. HCs: healthy controls.
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