The role of humoral rejection in acute and chronic rejection of human renal allografts other than in hyperacute rejection has not been well established, but humoral rejection probably affects approximately 5% of transplant recipients [1]. Recently, a specific histologic pattern of antibody-mediated rejection has been recognized in renal allografts [2-4]. The antigens targeted by this mode of rejection are not well defined but are likely located on the endothelium of small vessels (arterioles, and glomerular and peritubular capillaries) [5]. The microvasculature of transplanted organs, including the kidney, appears to be a main target of injury in both cellular and humoral rejection [6-11]. Antibody-mediated rejection (also called atypical or delayed hyperacute rejection) may be seen in a pure form or associated with cellular rejection, and is characterized histologically early on by glomerular solidification, fibrin thrombi in glomerular capillaries, accumulation of neutrophils in glomerular and peritubular capillaries, and interstitial edema [2-4]. In contrast, the histological features of "classical" rejection (or cellular-mediated rejection) are tubulitis, arteritis, and interstitial inflammatory infiltrate with blasts. We further describe the light microscopic findings of antibody-mediated rejection, over a period of up to 8 months, in 5 highly sensitized patients with a diagnosis of "pure" antibody-mediated rejection [12], with an emphasis on the ultrastructural findings of the peritubular capillaries (PTCs).
One week post-transplantation:
Light microscopy (LM): In the early post-transplantation
period, glomerular involvement is reflected by glomerular capillary
thrombi and endothelial cell swelling (glomerular solidification),
associated with a variable number of intracapillary neutrophils.
Acute tubular ischemic damage is a constant finding. At this early
stage, there are no marked alterations of PTCs in most biopsies.
Focal PTC congestion and margination of neutrophils are seen in
some cases.
Electron microscopy (EM): In contrast
to the subtle light microscopic changes, PTCs examined ultrastructurally
demonstrate focal endothelial cell cytoplasmic swelling and detachment
of endothelial cell from the basement membrane with expansion
of the subendothelial zone by electron-lucent "fluffy"
material. Interstitial edema and red blood cell extravasation
are additional features. Platelet-fibrin thrombi are seen rarely.
Two weeks post-transplantation:
LM: At two weeks, there is persistent
ischemic tubular damage now associated with increasing interstitial
edema. PTCs exhibit more congestion and contain an increased number
of intraluminal inflammatory cells, predominantly neutrophils
(Fig.1).
EM: Neutrophils are found both within
the lumen of PTC and in the interstitium. There is marked microscopic
interstitial hemorrhage around PTCs that show endothelial cell
swelling. Increased vascular permeability is reflected by accumulation
of "fluff" and red blood cells in the subendothelial
space. There is an increasing number of mononuclear cells adhering
to PTC endothelial cells. There is marked endothelial cell damage
and accumulation of platelets in some capillaries (Fig. 2).
 |
Figure 1. Two weeks post-transplantation. Dilated peritubular capillaries contain numerous marginated neutrophils. There is also ischemic tubular damage (not illustrated here). |
 |
Figure 2. Two weeks post-transplantation. Peritubular capillary lined by swollen and focally necrotic endothelial cells. A platelet thrombus is present. |
Two to three months post-transplantation:
LM: Tubular atrophy and interstitial
fibrosis increase in severity. Subtle thickening of basement membranes
around PTCs is seen on PAS stain. PTCs are distorted, dilated
and have small abnormal lumina. Neutrophils are present in PTCs.
EM: In addition to the acute changes
described in the earlier biopsies, some capillaries are in the
process of being completely destroyed with fragmentation and disappearance
of endothelial cell lining. The remaining capillaries are abnormally
shaped and have thickened reduplicated basal lamina (Fig. 3).
 |
Figure 3. Two to three months post-transplantation. Misshapen and dilated peritubular capillary with abnormal lumen formation. |
 |
Figure 4. Eight months post-transplantation. Disintegrated peritubular capillary poorly delineated by endothelial cell cytoplasmic fragments and residual basement membrane contour. |
In summary, antibody-mediated rejection in renal allografts presents with specific light and electron microscopic features. By a detailed ultrastructural examination, we have demonstrated that the endothelium of PTCs, and to a lesser extent that of glomerular capillaries, are main targets of injury. Sustained immune injury to the microvasculature of allografts probably contributes to chronic, progressive and irreversible damage. The contribution of antibody-mediated rejection to chronic rejection of renal allografts however remains to be established. The potential contribution of antibody-mediated rejection to acute and chronic rejection of renal allografts needs to be explored further if new avenues of therapy are to be developed.
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