DAMAGE TO PERITUBULAR CAPILLARIES IN ACUTE HUMORAL REJECTION OF RENAL ALLOGRAFTS: AN ULTRASTRUCTURAL STUDY
P. Liptak,a E. Kemeny,a Z. Morvay,b E. Szederkenyi,c P. Szenohradszky, c F. Marofka,c J. Toldid , H. Regele,e M. Exnere and B. Ivanyia
Departments of aPathology, bRadiology and cSurgery, University of Szeged, Szeged, Hungary; dRegional Transfusion Centre of the NBTS, Szeged, Hungary; Clinical Institute of Pathology and Department of Laboratory Medicine, University of Vienna, Vienna, Austria
Background. The main target of the alloimune response in the acute humoral rejection (AHR) of renal allografts is the vascular endothelium. Recently, a link between alloantibodies and graft cell apoptosis was recently proposed and investigated in vitro. In the present study, lesions to peritubular capillaries (PTCs) were evaluated by electron microscopy in renal biopsies from allograft recipients with AHR. The presence of apoptosis and other inflammatory phenomena in PTCs was searched for.
Materials and methods. Biopsies from 8 patients with AHR were examined by light microscopy, immunofluorescence (IgG, IgA, IgM, C3, C1q, C4d and fibrinogen) and electron microscopy. The graft dysfunction started on postTx day 0-119 (median: day 5), and biopsies were obtained on day 11-120 (median: day 11). The grafts were ultimately removed from all 8 recipients. The diagnosis of AHR was established with regard to the suggestive histological features and the demonstration of C4d deposition in the PTCs. A panel reactive antibody titer increase of ≥20% was detected in all patients. Apoptosis of PTC endothelial cells was identified in 10 consecutive PTC profiles complete with endothelial cell nuclei in every case. PTCs from 9 kidney allografts with acute ischemic damage (C4d: negative) were used as controls.
Results. An increased occurrence of PTC endothelial cell apoptosis was observed (p=0.032 vs. controls). Swelling, focal lytic injury to PTCs, and denudation of basement membrane were occasionally encountered. There was a luminal accumulation of monocytes and neutrophils, and they exhibited an increased adherence to PTC endothelial cells. The intraluminal inflammatory cells were frequently degranulated, and at times, the monocytes were transformed into macrophages. Focal fragmentation of PTCs was observed in the vicinity of capillary wall-localized mononuclears. Marked endothelial hypertrophy was not a feature of AHR.
Conclusions. In AHR, different types of damage to PTC endothelial cells develop: apoptosis, lysis, and fragmentation. Alloantibody-mediated cytotoxicity, parenchymal ischemia, and activated leukocyte-induced fragmentation of PTCs play a role in the evolution of PTC injury. The different pathways of PTC endothelial cell damage act in concert, culminating in destruction of the PTCs.