Microvasculature and Renal Transplant Rejection

Endothelium of the allograft vasculature is the interface between an allograft and the recipient's immune system. In this boundary position, endothelial cells may play important roles in the afferent and efferent phases of allograft rejection. The expression by endothelial cells of granule membrane protein-140 (GMP-140/P-selectin) and endothelial leukocyte adhesion molecule-1 (ELAM-1/E-Selectin) increases tissue factor activity, augments secretion of plas-minogen activator inhibitor, and decreases thrombomodulin, contributing to hyperacute rejection. Similarly, endothelial cells may actively participate in acute cellular rejection and in the development of transplant-associated arteriopathy as a result of induction of antigen-presenting function (i.e., MHC class 2 expression), upregulation of adhesion molecules for lymphocytes and monocytes, and release of platelet-derived growth factors. Therefore, endothelial cell functions, which are important for normal inflammatory responses and vessel behavior, may be pathogenic in the allograft [2].

Microvascular Injury in Hyperacute and Accelerated Kidney Transplant Rejection

Hyperacute rejection occurs within minutes to hours after the vascular clamps to the transplanted organ are released. This dramatic event is caused by preexisting cytotoxic, anti-HLA class 1 (IgG) or anti-ABO blood group antibodies (IgM) in the recipient. The antibodies bind to the endothe-lial surface of the arterioles on the graft, activate complement, and lead to severe microvascular injury including thrombosis and obliteration of the graft vasculature. The endothelial cells are stimulated to secrete von Willebrand factor (vWF), which mediates platelet adhesion and aggregation. Complement activation initiates coagulation cascade and the generation of multiple inflammatory mediators. Eventually, transplanted tissue suffers irreversible ischemic damage. Hyperacute rejection is mediated by antibodies against alloantigens that have appeared in response to previous exposure to these antigens through blood transfusion, prior transplantation, or multiple pregnancies. Pathologic findings show fibrin thrombus formation, margination of neutrophils, and ultimately fibrinoid necrosis of the vessel walls. The transplant may become flaccid or cyanotic and hard and may rupture.

Accelerated acute rejection taking place within 1 to 4 days after transplantation occurs when the recipient has been sensitized by prior interaction with graft antigen, gen erally by prior transplantations but also by transfusions, and is thought to represent an immunologic memory response to prior sensitization. This type of rejection may represent a combination of cellular and antibody-mediated injury, but the cellular infiltration may not be as intensive as with acute rejection.

Renal Microvasculature and Acute Transplant Rejection

Acute renal graft rejection is able to activate human endothelial cells leading to upregulation of mRNAs coding for VCAM-1 and ICAM-1 and plays a direct role in the pathogenesis of acute rejection [3]. Endothelial deposition of the complement split product C4d is an established marker of antibody-mediated acute renal allograft rejection. Cells of the monocyte/macrophage system have active contribution to acute allograft destruction. Monocytes are recovered from both the central and the marginal blood pool by perfusing either the recipient's circulation or the allograft vasculature. During allograft rejection MHC class 2 molecules, CD161 (NKR-P1A), CD62L, and CD8, are upregulated, while CD4 and CD43 are down-modulated. Activated monocytes participate in the kidney allograft destruction by directly damaging endothelial cells and by promoting intravascular coagulation.

Recruitment of leukocytes during immune responses requires the coordinate expression of adhesion molecules in concert with chemokines and their receptors. The Duffy antigen receptor for chemokines (DARC) binds multiple chemokines and is expressed on postcapillary venules in the normal kidney. The chemokine receptor CCR5, which shares the ligand regulated upon activation, normal T-cell expressed and secreted (RANTES) with DARC, is expressed by infiltrating T cells in the renal interstitium. DARC is involved in the attraction of CCR5-positive cells. Therefore, the increased number of DARC-positive venules in areas of interstitial injury and the co-localization with CCR5-positive infiltrating leukocytes indicate a role for endothelial DARC expression during leukocyte adhesion and interstitial infiltration [4]. Histopathology of the allo-grafts reveals edema and interstitial cellular infiltration as well as tubulitis, and necrosis and hemorrhage in severe cases. Destruction PTCs and tubules accompanied by disruption of basement membrane (BM) occurred with capil-laritis or tubulitis in areas with a severe cellular infiltrate. Glomerular changes notably included swelling of the tufts due to hypercellularity, which is consistent with transplant glomerulitis. The intrarenal arteries exhibit intimal or in severe cases transmural mononuclear cell inflammation with or without fibrinoid necrosis of vessel wall (the latter often with antibody mediated rejection) [5].

Microvasculopathy during Chronic Kidney Transplant Rejection

Chronic rejection is associated with the development of interstitial fibrosis and PTC, endothelial cell, and tubular

Figure 3 Chronic rejection. Lymphocyte (L) infiltration and fibrosis of intima (F). There is perivascular sclerosis and edema (S). Endothelial cells are swollen and some are pyknotic (E) (Mallory, original magnification 400x). (see color insert)

epithelial cell death associated with CD3+ cell infiltration (Figure 3). During the development of chronic rejection, capillaritis of PTCs and tubulitis are maintained by persistent T-cell infiltration, and the remaining PTCs and tubules exhibit progressive atrophy with thickening and/or lamination of BM. Then identifiable PTCs and tubules are lost in areas of interstitial fibrosis. Proliferating myofibroblasts accumulate around PTCs and tubules and in interstitium, and there is widespread interstitial fibrosis. The contribution of alloantibody-dependent immune reactions to chronic rejection is being increasingly appreciated.

Influence of Ischemic Reperfusion Injury on Renal Graft Function and Kidney Microvasculature

All allografts undergo some degree of ischemic reperfusion injury (IRI) during transplantation. IRI causes renal vascular endothelial damage and plays an important role in kidney transplant pathophysiology. IRI induces allograft endothelial cell swelling, alters endothelial cell-cell connection, and alters endothelial cell-basement membrane attachment. Functional consequences of these morphological changes include altered vascular reactivity, increased leukocyte adherence and extravasation, altered coagulation due to loss of normal endothelial function and/or barrier, and increased interstitial edema. Increased levels of gene transcripts involved in cellular adhesion, chemotaxis, apoptosis, and monocyte recruitment and activation dominate the immediate postreperfusion state. T cells are a fundamental link between IRI injury and alloimmunity. This phenomenon is highlighted by data demonstrating that T-cell depletion can improve the course of experimental renal IRI [6]. Damage during IRI predisposes to acute and chronic rejection.

Microvascular Injury Caused by Immunosuppressive Therapy

Calcineurin inhibitors such as cyclosporine A (CyA) and tacrolimus (FK506) drastically enhance the survival of organ transplants and recipients. But they themselves can affect endothelial function in renal transplant patients, as administration of these immunosuppressants is correlated with a high incidence of transplant arteriolopathy. The endothelium-dependent and -independent vasodilation of the patients on FK506 is better preserved than in patients on CsA therapy. Vascular endothelial cells naturally express a death factor, Fas ligand, that inhibits detrimental leukocyte infiltration. It has been shown that CyA and FK506 down-regulate Fas ligand expression on endothelial cells with accompanying decrease in the cytotoxicity toward Fas-bearing cells. These data suggest a mechanism by which immunosuppressive treatment contributes to atherogenesis [7]. Development of thrombotic microangiopathy has been associated with CyA and FK506 toxicity.


Allograft: A transplant of an organ or tissue that is donated either by a genetically matched relative of the patient or by an unrelated (but genetically similar) donor.

Cytokines: Nonantibody proteins secreted by inflammatory leukocytes, and some nonleukocytic cells, that act as intercellular mediators. They differ from classical hormones in that they are produced by a number of tissue or cell types rather than by specialized glands. They generally act locally in a paracrine or autocrine rather than endocrine manner.

Endothelium: The layer of epithelial cells that lines the cavities of the heart and of the blood and lymph vessels, originating from the mesoderm.

Lymphokines: Soluble protein factors generated by activated lymphocytes that affect other cells, primarily those involved in cellular immunity.

Rejection: Any immune process leading to the destruction or detachment of a graft or other specified structure.


1. Complete sequence and gene map of a human major histocompatibility complex The MHC sequencing consortium. Nature (1999). 28, 921-923.

2. Sedmak, D. D., and Orosz, C. G. (1991). The role of vascular endothelial cells in transplantation. Arch. Pathol. Lab. Med. 115(3), 260-265.

3. Lucchiari, N., Panajotopoulos, N., Xu, C., Rodrigues, H., Ianhez, L. E., Kalil, J., and Glotz, D. (2000). Antibodies eluted from acutely rejected renal allografts bind to and activate human endothelial cells. Hum. Immunol. 61(5), 518-527.

4. Segerer, S., Regele, H., MacK, M., Kain, R., Cartron, J. P., Colin, Y., Kerjaschki, D., and Schlondorff, D. (2000). The Duffy antigen receptor for chemokines is up-regulated during acute renal transplant rejection and crescentic glomerulonephritis. Kidney Int. 58(4), 1546-1556.

5. Haishima, A., Kawakami, Y., Mizuno, S., Kageyama, T., Muto, M., Suzuki, T., Inoue, K., and Shirota, K. (2002) Acute vascular and interstitial rejection following renal allograft transplantation in dogs. J. Vet. Med. Sci. 64(12), 1137-1140.

6. Yokota, N., Daniels, F., Crosson, J., and Rabb, H. (2002). Protective effect of T cell depletion in murine renal ischemia-reperfusion injury. Transplantation 74(6), 759-763.

7. Sata, M., and Walsh, K. (1999). Cyclosporine downregulates Fas ligand expression on vascular endothelial cells: implication for accelerated vas-culopathy by immunosuppressive therapy. Biochem. Biophys. Res. Commun. 263(2), 430-432.

Further Reading

Inston, N., and Cockwell, P. (2002). The evolving role of chemokines and their receptors in acute allograft rejection. Nephrol. Dial. Transplantation 17, 1374—1379. The article is concentrated on the expression of chemokine receptors that direct the trafficking of alloactivated T cells into the graft in response to local production of chemokines, initially by resident cells. There is now deep interest in this area that reflects the recent identification of restricted chemokine—receptor interactions as key functional events in T-cell recruitment and potential therapeutic targets for the prophylaxis of acute allograft rejection.

Shimizu, A., Colvin, R. B., and Yamanaka, N. (2000). Rejection of peritubular capillaries in renal allo- and xeno-graft. Clin. Transplantation 14, 6-14. The review shows that microvasculature plays an important role in the pathogenesis of humoral- and cell-mediated renal allograft rejection. PTC endothelium expresses the MHC antigens in the resting phase, as does the glomerular capillary endothelium.

Thiru, S., and Waldmann, H. (eds.) (2001). Pathology and Immunology of Transplantation and Rejection. Boston: Blackwell Science. This textbook offers a good insight into various aspects of organ transplantation.

Capsule Biography

Vladimir Savransky, M.D., Ph.D., received his medical school and surgical training in St. Petersburg, Russia. He is currently a Postdoctoral Research Fellow in the Division of Nephrology, Johns Hopkins University School of Medicine.

Mark Haas, M.D., Ph.D., received his medical school training at Duke University and specialization in kidney pathology at Yale. He is currently Professor in the Department of Pathology, Johns Hopkins University School of Medicine.

Hamid Rabb, M.D., received his medical school training at McGill University and specialization in kidney diseases at Harvard. He is currently Director, Transplant Nephrology and Associate Professor of Medicine, Johns Hopkins University School of Medicine.

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