The initially controversial contention that the presence or absence of circulating antibodies [donor-specific antibody (DSA)] determines to a large extent renal graft outcomes is now widely accepted (1). The association between anti-human leukocyte antigen (HLA) DSA and antibody-mediated allograft rejection (AMR) has been substantiated by the identification of a predictable constellation of morphologic, clinical, and molecular features that define this process (2–10).
Current guidelines for the diagnosis of renal AMR rest on the identification of (a) DSA, (b) immunohistochemical demonstration of C4d deposition in peritubular capillaries (PTC), and (c) morphologic evidence of tissue injury (e.g., acute tubular necrosis-like changes, capillary inflammation, glomerular inflammation, capillary thrombosis, necrotizing arteritis, glomerular basement membrane [GBM] double contours, multilayering of PTC basal laminae, interstitial fibrosis/tubular atrophy, and fibrous intimal arterial thickening) (8). Some of these morphologic features are not sensitive or specific (e.g., interstitial fibrosis/tubular atrophy, fibrous intimal arterial thickening, acute tubular necrosis-like changes). In contrast, microvascular inflammation and repair (glomerulitis, capillaritis, and GBM remodeling) have been consistently associated with AMR (3–5, 7, 9–14). The current diagnostic guidelines have provided the framework for a better understanding of AMR, but their full applicability is challenged by its bewildering heterogeneity (15). In particular, C4d staining is strongly associated with early AMR in presensitized patients (4, 16–18) but is inconstantly present in the protracted forms of AMR (3, 7, 19–21) and can be also found independently of AMR (22).
Experience with highly sensitized patients has helped delineate the features of early-acute AMR. This is a fairly predictable form of AMR that occurs in a proportion of presensitized patients early after transplantation. (19, 23–25). In contrast, late-chronic AMR, which is common in both highly sensitized and conventional renal transplant recipients, has defied a stereotypical definition. Two broad categories of late-chronic AMR can be identified: (a) chronic microvascular injury developing in a proportion of highly sensitized patients with or without history of early-acute AMR (3, 4, 9, 15, 19, 26–31) and (b) chronic microvascular injury developing in a proportion of nonsensitized patients who develop de novo DSA (7, 19, 21, 26, 29, 31–33). In both settings, most patients experience eventual progression to graft failure, but the rate of progression and the histologic manifestations vary considerably from one patient to another and in serial biopsies from the same patient (19, 21, 34). In addition, the relationship of DSA/AMR with T-cell–mediated rejection (21, 35), the potential association with treatment noncompliance, and the occasional ultra-late, cases further complicate the clinicopathologic picture of late-chronic AMR (19, 36).
Features attributed to late-chronic AMR (i.e., GBM remodeling) can already be identified within the first weeks of ongoing early-acute AMR (9, 27). Conversely, features typically attributed to early-acute AMR (i.e., capillary thrombosis and thrombotic microangiopathy) can be found at any point during the course of late-chronic AMR (7, 37). The morphologic features of AMR are difficult to categorize (e.g., acute vs. chronic) because they follow an unpredictable course that is in part dependent on bouts of disease activity (i.e., episodic increase in antibody production), partial or complete responses to treatment, and complex interactions with other components of the immune system (7, 10, 38–40).
The most specific histologic features of AMR result from DSA-related endothelial cell (EC) injury in the microvasculature (26). The pathogenesis of AMR at the EC level can explain the capricious heterogeneity of the microvascular lesions in AMR.
Quiescent EC have a well-organized cytoskeleton with a peripheral actin cytoplasmic ring that supports cell-cell and cell-matrix adherence, helps maintain a stable monolayer organization, and sustains the EC barrier/filter function (41). In addition, complex intercellular EC junctions prevent leakage of intravascular components and exposure of the basal lamina to procoagulant factors (42, 43).
Away from the mesangial stalks, where the bulbous EC nucleus lies, the glomerular capillaries are lined by an extremely thin, fenestrated EC lining (Fig. 1A). The fenestrations measure 70 to 100 nm in diameter and are easily appreciated on routine electron microscopic studies. The extensive network of PTC is similarly lined by thin fenestrated endothelium (Fig. 1B). Endothelial injury can be readily appreciated in both the glomerular and the PTC compartments with electron microscopy, but in general, the changes are more easily identified in the glomerular endothelium because the morphology of the PTC lining tends to be less uniform (42, 43). The intact endothelium is free of any surface disruption and is covered by negatively charged proteins that repel coagulation factors and avoids platelet aggregation (44, 45). The normal EC also express inhibitors of coagulation (e.g., thrombomodulin and tissue factor inhibitor) (46).
LYTIC EC LESION
High levels of DSA acutely interacting with the EC lead to EC lysis/death. Lysis due to HLA DSA has been well characterized. Anti-HLA antibodies targeted against major histocompatibility complex components expressed by the graft endothelium bind to EC, usually in conjunction with complement (10, 47). Full activation of the complement cascade leads to the formation of numerous membrane attack complexes (MAC; transmembrane pores). EC can eliminate MAC up to a point, but if the number of MAC exceeds the cell’s capacity for elimination, osmotic death is unavoidable. Metabolic exhaustion due to ATP metabolite loss also plays a role in complement-mediated cell death (48). In addition to lysis (necrosis), MAC can induce EC apoptosis, but this appears to be rare in acute AMR (49). EC disruption, cytoplasmic retraction, and cell loss lead to leakage of intravascular fluids and expose the underlying matrix with resulting activation of the coagulation cascade and aggregation of platelets. All of these changes lead to mesangiolysis in the glomeruli and microthrombi throughout the microvasculature (50, 51). Complement activation with production of chemotactic factors also leads to margination of inflammatory cells, most commonly neutrophils, within the capillary lumina (31, 52, 53).
Glomerular or PTC EC lysis is dramatically appreciated on electron microscopic studies, which characteristically demonstrate narrowing or disappearance of the microvascular lumen due to marked EC swelling, fragmentation, and dissolution, with accumulation of cellular debris, fibrin, platelet clusters, and irregular collections of inflammatory cells (Fig. 1C) (53). Microvascular necrosis with rupture of the glomerular or PTC basement membranes is not uncommon (Fig. 1D) (43).
Light Microscopic Features
Hyperacute rejection is the most characteristic example of generalized EC lysis leading to diffuse vascular thrombosis and necrosis. Substantially milder EC lysis characterizes early-acute AMR, which typically appears with localized microvascular thrombotic lesions (15, 17, 19, 51).
The severity of histologic changes in acute-early AMR correlates with DSA levels (23). Mild cases present with subtle EC swelling, bland glomerular microthrombi, and mild neutrophilic capillaritis (Fig. 1E). In severe acute AMR, there are multifocal microthrombi, frank thrombotic microangiopathy, global glomerular necrosis, and foci of interstitial hemorrhage (14, 19, 24, 52) (Fig. 1F).
Early-acute AMR appears to be often associated with type I anti-HLA DSA and is commonly associated with diffuse C4d positivity in PTCs (4, 8, 19). Isolated C4d positivity preceding for a few days frank acute AMR (23) likely relates to sampling variations with the absence of the diagnostic morphologic lesions in the biopsy at earlier times.
Overlap Between Lytic and Sublytic lesions
Early-acute AMR has been best studied in highly sensitized patients receiving positive cross-matched transplants after desensitization treatments. Increasing DSA levels after transplantation are more likely associated with early-acute AMR, which usually responds to treatment or it may resolve spontaneously. Unfortunately, up to 40% of the highly sensitized patients develop features of chronic AMR (15, 17, 23). From the clinical and morphologic points of view, chronic DSA-related injury in highly sensitized patients is indistinguishable from late-chronic AMR occurring in patients with conventional transplants and development of de novo DSA (21, 29).
Although the essential components in both processes remain the same (i.e., DSA, complement, and microvascular injury), the protracted forms of AMR undoubtedly have a different pathogenesis from that of early-acute AMR. The difference likely relates to modified interactions between DSA and EC. Specifically, continual exposure to DSA and complement results in decreased immediate susceptibility to injury by modifying EC functions (4, 20, 26, 38, 49, 54, 55).
Experimental studies demonstrate that EC exposure to sublytic amounts of MAC stimulates their elimination from the EC membrane through endocytosis (internalization) or shedding (49, 56). Chronic EC exposure to DSA and complement also triggers multiple defense and repair mechanisms resulting in cellular changes known as EC activation (50). Molecular studies in patients with AMR confirm EC activation (20).
SUBLYTIC EC LESIONS
EC Shape Changes and Proliferative-Reparative Functions
Sublytic exposure to DSA and complement leads to cytoskeletal conformational changes in the EC. Specifically, reorganization of the peripheral actin ring with the formation of transcellular stress fibers changes the cellular shape from polygonal and flat to contracted and protruding above the level of the monolayer. These changes lead to the formation of intercellular gaps and disruption in the endothelial barrier. Complement-induced intercellular gap formation is reversible, and repair is partly mediated by the complement cascade itself (i.e., completion of the complement reaction and formation of more MAC) (41, 57, 58).
EC repair is further modulated by cell and matrix adhesion molecules and junctional-complex molecules. The nature of the matrix influences the shape and growth of the EC via integrins that mediate matrix-cytoskeletal connections. In comparison with stable endothelium, the repairing endothelium rests on modified matrix proteoglycans, resulting in disorganized EC growth (59). EC exposure to terminal complement complexes also results in the release of heparan sulfate as well as basic fibroblast growth factor (which increases the secretion of matrix degrading proteins) and platelet-derived growth factors. Mitogenic and proliferative effects of these growth factors at least in part explain the extensive reparative chronic changes seen in the renal microvasculature, including mesangial matrix expansion, duplication of the GBMs, and multilayering of the PTC basal lamina (58, 60).
Ultrastructural studies demonstrate that EC shape abnormalities and associated matrix changes characterize evolving AMR. EC swelling, blebbing, loss of fenestrations, expansion of the subendothelial space, and subendothelial accumulation of amorphous or linear dense material representing incipient basement membrane duplication can be observed after a few weeks in the course of acute AMR (9, 27) (Fig. 2). Late-chronic AMR similarly evolves with extensive disarray of the glomerular architecture due to accumulation of extracellular matrix, expansion of the subendothelial space, and variable degrees of basement membrane duplication. EC shape abnormalities and reparative changes of variable severity coexist within the same biopsy and within the same glomerulus (5, 9, 19, 27). Extensive remodeling in PTCs leads to multilayering of their basal lamina as well (61) (Fig. 2F).
Light Microscopic Features
EC activation manifesting with cytoplasmic swelling and nuclear enlargement leading to narrowing of the glomerular capillary lumina is an integral component of the definition of glomerulitis (Figs. 2 and 3) (62). Morphometric studies have shown that glomerular EC enlargement correlates with C4d staining in PTCs, further substantiating its relationship to AMR (63).
Only the advanced stages of remodeling leading to reduplication of the GBMs (transplant glomerulopathy) can be appreciated by light microscopy (Figs. 2 and 3) (65).
EC Procoagulant Changes
Exposure of EC to sublytic concentrations of MAC leads to a strong procoagulant status through a variety of pathways including increased expression of tissue factor (65), proinflammatory molecules (i.e., P-selectin), and integrins (i.e., intercellular and vascular adhesion molecules) leading to increased adhesion of platelets. Exocytosis of Weibel–Palade bodies that contain P-selectin and von Willebrand factor also contribute to platelet aggregation (66). In addition, platelets have complement receptors that localize them to the areas of complement activation. Furthermore, any disruption of EC integrity with exposure of platelet receptors in the underlying matrix results in enhanced thrombogenesis (67). Decrease in blood flow due to EC damage and microthrombi enhances full EC activation through interleukin (IL)-1α (46).
In late-chronic AMR, ultrastructural evaluation commonly demonstrates an increased number of platelets within the glomerular capillary lumina. In fact, platelet aggregates can be commonly demonstrated by electron microscopy in cases that do not show thrombotic microangiopathy on light microscopy (68) (Fig. 3C).
Light Microscopic Features
The association between thrombotic microangiopathy and early-acute AMR is well recognized (19, 26, 51). The importance of a thrombogenic milieu should not be under-estimated in late-chronic AMR (7, 37, 69), which, in addition to full-blown thrombotic microangiopathy, displays more subtle changes including small intracapillary thrombi, mesangiolysis, or incipient platelet aggregations (Fig. 3).
EC Proinflammatory Changes
Exposure of EC to sublytic concentrations of MAC results in dose- and time-dependent expression of adhesion molecules (ELAM-1, ICAM-1, and VCAM-1) (65). Furthermore, terminal complement complexes have proinflammatory activity by inducing the secretion of IL-8 and monocyte chemotactic protein (MCP)-1 (70). Exposure to antibodies alone can cause EC production of cytokines (IL-6 and MCP-1), which are further increased by the activation of macrophages through their Fc receptor. Macrophages are also activated by complement split products (71).
Linking the procoagulant (see above) and proinflammatory changes, there is evidence that ongoing platelet adherence and degranulation on the EC surface results in the release of inflammatory mediators (i.e., thromboxane and RANTES), which attract inflammatory cells (66, 67). The expression of P-selectin on platelets costimulates monocytes to produce inflammatory mediators, including MCP-1 and tumor necrosis factor. In addition, platelets produce CD154, which is a ligand for B lymphocytes, macrophages, dendritic cells, and ECs (47).
It has been recently shown that, in response to EC injury, glomerular capillary and PTC overexpress T-bet (a transcription factor regulating Th1 lineage commitment), which correlates with CD4, CD8, and CD68 microvascular infiltration and capillary dilatation (72).
Ultrastructural evaluation of samples with late-chronic AMR readily demonstrates increase in inflammatory cells in the microvascular lumina as well as infiltration of inflammatory cells within the excessive extracellular matrix. Monocytoid cells with features compatible with macrophages often adhere to swollen ECs (Fig. 3), and inflammatory cells may be present also within the duplicated basement membranes (Fig. 2D, E). Comparable changes are also commonly observed in PTCs (61) (Fig. 4).
Light Microscopic Features
The contribution of cellular infiltrates to the process of AMR was recognized in the earliest description of this entity (14). Subsequent studies have shown that microvascular inflammation, particularly macrophages, are a constant component of AMR (3, 7, 11, 12). Whereas similar changes can be found in a minority of biopsies with acute T-cell–mediated rejection, most investigators agree that microvascular inflammation strongly correlates with AMR (3, 4, 7, 12, 14, 15, 23, 31, 63, 73, 74). Routine light microscopy easily demonstrates glomerulitis and capillaritis, which often coexist but which may be identified independently likely due to sampling variations (74). Subtle EC swelling and minimal inflammatory infiltrates characterize early glomerulitis, whereas glomerular tuft obliteration by large numbers of inflammatory cells is more typical of progression to transplant glomerulopathy (Fig. 4A, B) (7). Biopsies with late-chronic AMR may also show an overall increase in interstitial inflammation even in the absence of tubulitis or other features characteristic of acute T-cell–mediated rejection.
Clinical studies have shown that macrophages are the most predominant component in AMR-related microvascular inflammatory accumulations and that this type of cell predominates in the late-chronic forms of AMR (7, 31, 74); however, transplant glomerulopathy presents with a lesser but significant component of infiltrating T-lymphocytes as well (7).
The routine use of C4d staining has changed our understanding of the main mechanisms of allograft rejection by pointing to the widespread occurrence of AMR in solid organ transplants (75). Although the C4d stain is routinely used for diagnostic purposes and for determination of therapeutic maneuvers, there is now generalized recognition of “C4d-negative AMR”. This is more commonly observed in the context of late-chronic AMR (5, 7, 16) and in AMR due to non-HLA DSA (76). Also, significant variability with respect to C4d staining is found in multiple biopsies from the same patients (77).
The pathogenetic basis for the presence or absence of C4d staining in individual biopsies with AMR is not yet understood. C4d deposits at various cellular locations and in extracellular sites have been demonstrated by ultrastructural immunolocalization (77). It can be speculated that heterogeneity related to EC injury and repair may contribute to the variability in C4d staining. Similarly, various types of DSA may engage complement differently (78). Interestingly, a recent study demonstrated that the renal microvasculature could by itself produce complement components (79).
AMR and Transplant Vasculopathy
EC lining in larger vessels is also injured by exposure to anti-HLA DSA. Complement complexes C5b-7 and MAC cause EC disruption with leakage into the extravascular space. In this proinflammatory environment, the underlying smooth muscle cells acquire a synthetic phenotype with production of cytokines and extracellular matrix leading to vascular remodeling and sclerosis (5, 26, 47, 80). In the context of a procoagulant EC phenotype, platelet aggregation also contributes to proliferation of EC and smooth muscle cells by secretion of growth factors, such as platelet-derived growth factor, endothelial growth factor, and fibroblast growth factor (47). DSA may also lead to vascular sclerosis due to microvascular injury to the vasa vasorum (71).
The presence of DSA with C4d deposition but no evidence of microvascular tissue injury or graft dysfunction, as well as experimental evidence of EC adaptation, suggests the possibility of graft accommodation to chronic DSA. Specifically, up-regulation of complement modifiers such as CD55 (decay accelerating factor) and CD59 (membrane inhibitor of lysis), which increase cell resistance to complement-mediated injury, as well as up-regulation of Bcl-2 and related proteins that decrease EC apoptosis, have been identified experimentally (5, 26, 28, 71). The vast array of EC changes secondary to exposure to DSA certainly indicates that there is a physiologic attempt for accommodation (54, 81–84). In most patients, however, these mechanisms fall short of preventing accelerated graft loss typically associated with DSA.
AMR is highly prevalent in kidney allografts and remains the most serious obstacle to long-term graft function due to limited therapeutic options (85). Criteria for diagnosis of AMR are evolving particularly regarding the development of more sensitive and specific techniques for antibody detection and with respect to histopathologic assessments (15). It has become clear that both C4d staining and demonstration of DSA have diagnostic limitations (16, 24, 76).
Current therapies, including DSA removal (i.e., plasma exchange) and modulation (i.e., intravenous immunoglobulin), as well as early complement component antagonists (i.e., eculizumab), have been relatively successful to treat early-acute AMR (15, 23, 86). In contrast, chronic progression in AMR has proven to be intractable (19).
DSA±complement EC injury is at the core of AMR-related graft loss, and as in most biological systems, the vast array of EC responses triggered by the initial injury is not unidirectional. The multifaceted and versatile self-protective EC responses that may be initially beneficial eventually lead to irreversible graft injury.
From the pathogenetic point of view, the main processes of microvascular injury and progression in AMR can be broadly classified as procoagulant, proinflammatory, and proliferative/reparative as described above. Although these processes typically coexist, one mechanism of injury may predominate in an individual patient, also determining a particular clinical course (i.e., ongoing thrombotic microangiopathy leading to more rapid graft loss vs. slowly evolving, paucicellular transplant glomerulopathy; Fig. 5).
The mechanisms of graft injury extensively studied in anti-HLA–related AMR appear to be remarkably similar to those operating in non-HLA–related AMR. In particular, recent studies of AMR due to angiotensin type 1 receptor antibody highlight similar proinflammatory and procoagulant responses of injured EC leading to the characteristic allograft pathology (87).
In all types of AMR, the contribution of the “cellular lesions” should be better understood (7, 11), particularly in view of recent studies emphasizing that chronic injury in positive cross-matched renal transplants is strongly associated with expression of genes related to inflammation and cellular inflammatory infiltrates (39). Therapeutic interventions targeting macrophages, which appear to represent an integral component of late-chronic AMR, are not routinely available. Therapies directed to minimize the procoagulant aspects of AMR (i.e., against platelet specific mediators) are being developed (66).
Other factors that can modify the DSA±complement EC responses should be also studied, including drug interactions (i.e., inhibitors of membrane lipid turnover, such as cyclosporine, which may decrease the rate of MAC elimination) (88).
EC integrity including preservation of the fenestrations is dependent on VEGF (vascular endothelial growth factor) (89). This mediator, essential for EC proliferation and repair, also has tight interactions with a variety of cellular pathways, which are likely to play a very important role in the development of transplant glomerulopathy. Specific studies in this area are currently lacking.
Complete understanding of the evolving and heterogeneous processes underlying the histopathologic features of AMR will be also necessary to better determine treatment endpoints in AMR, specifically with respect to potential reversibility of lesions (2).
The constellation of EC changes in AMR is characteristic but not unique to this process. Ischemia-reperfusion injury can resemble ultrastructurally early-acute AMR (43), and there are remarkable morphologic similarities among transplant glomerulopathy, hepatitis C–related membranoproliferative glomerulonephritis, and “idiopathic” thrombotic microangiopathy. Systematic studies to determine the potential association between these processes are very limited (90, 91).
In summary, a mounting collection of clinical and experimental data points to an extremely complex relationship between DSA, EC, complement, innate immunity elements, coagulation system, and intercellular matrix, ranging from immediate and overwhelming microvascular destruction to varying levels of functional adjustment. These interactions overlap to a degree that makes distinction between acute injury and chronic injury to a large extent irrelevant. A deeper understanding of these processes can allow for a better recognition of the morphologic lesions and a potential discovery of more targeted therapeutic interventions.
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