Abstract
Ischemia reperfusion injury (IRI) is linked with inflammation in kidney transplantation (ktx). The chemokine CXCL13, also known as B lymphocyte chemoattractant, mediates recruitment of B cells within follicles of lymphoid tissues and has recently been identified as a biomarker for acute kidney allograft rejection. The goal of this study was to explore whether IRI contributes to the up-regulation of CXCL13 levels in ktx. It is demonstrated that systemic levels of CXCL13 were increased in mouse models of uni- and bilateral renal IRI, which correlated with the duration of IRI. Moreover, in unilateral renal IRI CXCL13 expression in ischemic kidneys was up-regulated. Immunohistochemical studies revealed infiltration of CD22+ B-cells and, single-cell RNA sequencing analysis a higher number of cells expressing the CXCL13 receptor CXCR5, in ischemic kidneys 7 days post IRI, respectively. The potential relevance of these findings was also evaluated in a mouse model of ktx. Increased levels of serum CXCL13 correlated with the lengths of cold ischemia times and were further enhanced in allogenic compared to isogenic kidney transplants. Taken together, these findings indicate that IRI is associated with increased systemic levels of CXCL13 in renal IRI and ktx.
Highlights
Ischemia reperfusion injury (IRI) in kidney transplantation is linked with inflammation and leukocyte recruitment [1]
A 15 min ischemia time causes subclinical IRI without elevation of creatinine and blood urea nitrogen (BUN), whereas a 30 min IRI induced these clinical parameters of acute kidney injury (AKI) (Supplementary Figure 1)
A pronounced increase of CXCL13 levels in serum was observed in animals that received 30 min compared to 15 min of bilateral IRI (Figure 1A)
Summary
Ischemia reperfusion injury (IRI) in kidney transplantation (ktx) is linked with inflammation and leukocyte recruitment [1]. In deceased donor renal transplants, median cold ischemia time (CIT) in Germany can be up to 14 to 16 h. B-cell inhibitors are only used for pretreatment of IRI ktx CXCL13 recipients in ABO-incompatible living donor ktx to reduce or eliminate blood group antibodies prior to transplantation. Despite these interventions, acute rejection occurs shortly after ktx in 6–12% of deceased allograft recipients and some of these patients have signs of antibody-mediated rejection donor-specific antibodies are not detectable. We demonstrate that renal IRI causes increased levels of systemic CXCL13 with subsequent infiltration of CXCR5+ leukocytes in kidneys in models of IRI, and in that of allogenic ktx
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