The determinants, biomarkers, and consequences of microvascular injury in kidney transplant recipients

Abstract

Independent of the initial cause of kidney disease, microvascular injury to the peritubular capillary network appears to play a central role in the development of interstitial fibrosis in both native and transplanted kidney disease. This association is explained by mechanisms such as the upregulation of profibrotic genes and epigenetic changes induced by hypoxia, capillary leakage, endothelial and pericyte transition to interstitial fibroblasts, as well as modifications in the secretome of endothelial cells. Alloimmune injury due to antibody-mediated rejection and ischemia-reperfusion injury are the two main etiologies of microvascular damage in kidney transplant recipients. The presence of circulating donor-specific anti-human leukocyte antigen (HLA) antibodies, histological findings, such as diffuse C4d staining in peritubular capillaries, and the extent and severity of peritubular capillaritis, are commonly used clinically to provide both diagnostic and prognostic information. Complement-dependent assays, circulating non-HLA antibodies, or evaluation of the microvasculature with novel imaging techniques are the subject of ongoing studies.

Extracellular vesicles beyond biomarkers: Effectors of antibody-mediated rejection

“…These results are in line with a predominant role for endothelial injury in the pathophysiology of AMR. 2 It is likely, although not specifically tested in this publication, that EVs found in AMR patients are derived from injured or dying endothelial cells from the kidney microvasculature. Indeed, antibody-mediated endothelial injury is one of the main etiologies of microvascular damage in kidney transplant recipients.…”

“…It is likely, although not specifically tested in this publication, that EVs found in AMR patients are derived from injured or dying endothelial cells from the kidney microvasculature. Indeed, antibody‐mediated endothelial injury is one of the main etiologies of microvascular damage in kidney transplant recipients 2 . The presence of donor‐specific anti‐human leukocyte antigen (HLA) antibodies or non‐HLA autoantibodies have been implicated in in complement activation with diffuse C4d staining in peritubular capillaries, leading to endothelial stress and death and peritubular capillaritis.…”

Magnetic Resonance Elastography-derived Stiffness Predicts Renal Function Loss and Is Associated With Microvascular Inflammation in Kidney Transplant Recipients

“…3-6 In particular, microvascular inflammation, whether meeting criteria for antibody-mediated rejection or not, is an important cause of allograft damage, 7-11 that can cause capillary leak, tissue edema, and consequent organ stiffening. 12-14…”

“…[3][4][5][6] In particular, microvascular inflammation, whether meeting criteria for antibodymediated rejection or not, is an important cause of allograft damage, [7][8][9][10][11] that can cause capillary leak, tissue edema, and consequent organ stiffening. [12][13][14] Magnetic resonance elastography (MRE) is a functional MRI technique that can be used to image organ stiffness. 15 In this technique, an oscillatory pressure source transmits small vibrations through the allograft, whereas synchronized MRI images are used to measure the induced microscopic tissue motion.…”

IL-10 Mediated Immunomodulation Limits Subepithelial Fibrosis and Repairs Airway Epithelium in Rejecting Airway Allografts

“…Microvascular injury and associated tissue remodeling during acute rejection are caused by a massive microvascular infiltration of CD4 + T cells and antibody-mediated complement activation on vascular endothelial cells [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 ], and there are no ongoing immunosuppressive regimens that sufficiently preserve functional microvasculature [ 3 , 9 , 10 ]. This leads to the progression of chronic lung rejection/bronchiolitis obliterans syndrome (BOS) as seen in clinical settings [ 7 , 11 ].…”