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, 3 (7), e174
eCollection

Acute Rejection After Kidney Transplantation Associates With Circulating MicroRNAs and Vascular Injury

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Acute Rejection After Kidney Transplantation Associates With Circulating MicroRNAs and Vascular Injury

Roel Bijkerk et al. Transplant Direct.

Abstract

Background: Acute rejection (AR) of kidney transplants is associated with the loss of endothelial integrity, microvascular rarefaction and, ultimately, graft dysfunction. Circulating angiogenic microRNAs (miRNAs) may serve as markers for microvascular injury. Here, we investigated the short- and long-term effects of AR after kidney transplantation on systemic vascular injury and the associated circulating miRNA profile.

Methods: Systemic vascular injury was determined by measuring capillary tortuosity and density within the oral mucosa as well as by assessing circulating levels of angiopoietin-2/angiopoietin-1 ratio, vascular endothelial growth factor and soluble thrombomodulin. After a pilot study, we selected 48 miRNAs to assess the AR- and microvascular injury associated circulating miRNAs.

Results: In stable transplant recipients (n = 25) and patients with AR (n = 13), which were also studied longitudinally (1, 6, and 12 months post-AR), we found an AR-associated increase in markers of systemic vascular injury, of which vascular endothelial growth factor and soluble thrombomodulin normalized within 1 year after AR. Of the 48 selected miRNAs, 8 were either decreased (miR-135a, miR-199a-3p, and miR-15a) or increased (miR-17, miR-140-3p, miR-130b, miR-122 and miR-192) in AR. Of these, miR-130b, miR-199a, and miR-192 associated with markers of vascular injury, whereas miR-140-3p, miR-130b, miR-122, and miR-192 normalized within 1 year after AR.

Conclusions: AR after kidney transplantation is characterized by systemic microvascular injury and associates with specific circulating miRNA levels.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Increase in markers of vascular injury in AR. A, SDF images of the oral mucosa visualizing the microvascular capillaries of a representative patient in stable and AR group. Black arrow: capillary loops. B, Mean tortuosity index of microvascular capillaries in the stable (n = 25) and AR (n = 13) group. C-E, Ang-2/Ang-1 ratio (C), VEGF-A (D) and sTM (E) serum levels (pg/mL) in stable and AR group. Data shown are mean ± SEM. *P < 0.05 compared to stable group.
FIGURE 2
FIGURE 2
Differential miRNA levels in AR. MiRNAs that show statistically significant differences between stable and AR group (*P < 0.05, **P < 0.001). Means are relative expression levels, and can also be compared among miRNAs. Stable group, n = 13; AR, n = 13. Data shown are mean ± SEM, and adjusted for sex and age as possible confounders.
FIGURE 3
FIGURE 3
Normalization of VEGF and sTM, but not of Ang-2/Ang-1 ratio and microvascular tortuosity, within 1 year after AR. A, Sidestream dark field images of the oral mucosa visualizing the microvascular capillaries of a representative stable kidney transplant patient, 1 (M1), 6 (M6), and 12 (M12) months after rejection in the longitudinal rejection study. Black arrows: capillary loops. B, Longitudinal course of the mean tortuosity index of microvascular capillaries in the stable group (n = 25), AR group (n = 13) and at 1 (M1, n = 13), 6 (M6, n = 13) and 12 (M12, n = 11) months after rejection. C-E, Longitudinal course of serum Ang-2/Ang-1 ratio (C), VEGF-A (D) and sTM (E) levels at 1, 6 and 12 months after rejection. Data are shown as mean ± SEM. *P < 0.05.
FIGURE 4
FIGURE 4
Circulating miRNA levels in patients with AR, followed up for 1 year. A-B, Longitudinal course of the circulating miRNA levels in the stable group, AR group and at 1 (M1), 6 (M6), and 12 (M12) months after rejection. A, miRNAs that show (a trend towards) normalization within 12 months after AR. B, miRNAs that do not normalize within 12 months after AR. *P < 0.05, statistically significant. Means are relative expression levels, and can also be compared among miRNAs. Stable group, n = 13; AR D0, n = 13; AR M1, n = 8; AR M6, n = 9; AR m12, n = 11. Data shown are mean ± SEM.
FIGURE 5
FIGURE 5
Correlation of circulating miRNAs with markers of (micro)vascular injury. MiRNAs that were different) between stable and AR group correlate with markers of systemic vascular injury.

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