1. CHRONIC ACTIVE ANTIBODY-MEDIATED REJECTION PREDOMINATES AMONG CAUSES OF LATE KIDNEY ALLOGRAFT LOSS
T. N. Nikonenko, A. V. Trailin and A. S. Nikonenko
Medical Academy of Postgraduate Education, Interregional Transplantation Center, Zaporizhzhya, Ukraine
Introduction:
The causes of late kidney allograft (KAG) loss remain controversial. Herein we investigated these causes in 62 kidney recipients.
Patients and methods: 69 allograft biopsies from 62 patients were performed for evaluation of late allograft dysfunction. Seven patients lost two grafts during the study period and each instance was analyzed individually.
Paraffin sections of 3 µm were stained with H&E, PAS, Masson’s trichrome and immunoperoxidase labeling with antibodies to C4d, CD45R0 (activated T-lymphocytes) and CD68 (monocytes/macrophages). H&E, PAS and Masson stained sections were assessed according to the Banff classifications.
Additional morphological changes, potentially related to acute antibody-mediated rejection, as well as the number of T-lymphocytes and macrophages in PTC, glomeruli, arterial wall, interstitium were also scored semiquantitatively.
Image analysis was used to quantitatively evaluate interstitial T-lymphocytes and macrophages infiltration with ImageJ 1.34s software.
CsA-nephrotoxicity
Hypertensive nephropathy
Chronic pyelonephritis
Chronic glomerulonephritis
CsA-nephrotoxicity
Hypertensive nephropathy
Chronic pyelonephritis
Acute rejection
Negative impact of chronic active antibody-mediated rejection on KAG survival
Results and discussion: Chronic CsA-nephrotoxicity was diagnosed in 4 cases (5,8%), interstitial nephritis – in 13 (18,8%) cases. In 5 (7,25%) cases the histopathologic diagnoses was vascular allograft pathology (hypertensive nephropathy and atherosclerotic nephropathy). Chronic glomerulonephritis was diagnosed in 5 (7,3%) cases. Acute rejection was the primary cause of graft failure in 12 of 69 cases (17,4%). In 3 cases it was severe T-cell-mediated rejection, antibody-mediated rejection – in 2 cases, and in 7 cases there were signs of two rejection types simultaneously. In several cases graft suffered from multiple injuries.
Chronic transplant rejection (CR) was diagnosed in 30 cases (43,5%). In 24 cases (80%) of CR we diagnosed chronic active antibody-mediated rejection (CAAMR). The distinguishing morphological features of CAAMR included: IF/TA, TG, PTC basement membranes thickening and duplication, fibrous intimal thickening. 13 cases were C4d-diffuse-positive and 11 – C4d-focal-positive.
In 6 cases (20%) of CR we diagnosed chronic active T-cell-mediated rejection (CATMR). The distinguishing morphological features of CATMR included: IF/TA, fibrous intimal thickening, disruptions of the internal elastica, mononuclear in the fibrotic intima, neointima formation. All these biopsies were C4d-negative.
Interstitial hemorrhages (R=0,46), PTC basement membranes thickening and duplication (R=0,56), neutrophils number in PTC (R=0,44), CD68+ macrophages number in interstitium (R=0,43) correlated with C4d-positivity of PTC (Р < 0,05). Frequency of interstitial hemorrhages and neutrophils number in PTC significantly increased only in C4d-diffuse-positive cases.
Lifetime of KAG with C4d-diffuse-positive biopsies was significantly decreased compared to KAG with C4d-focal-positive biopsies: 22 (10-35) vs. 40 (29-41) months.
KAG survival was significantly influenced by arteritis, fibrinoid necrosis of arteries and capillaries, ТМА and infarct in biopsies, characteristic for active phase of CAAMR.
TMA-
Infarct-
C4d-focal+
TMA+
Infarct+
C4d-diffuse+
Morphological features of CAAMR
Morphological features of CATMR TG
Interstitial hemorrhages
Fibrous intimal thickening
The structure of late kidney allograft dysfunction
CsA-nephrotoxicity
Chronic
glomerulonephritis
Late acute rejection
Vascular allograft
pathology
PTC basement membranes duplication
C4d-positivity of PTC
Disruptions of the internal elastica
Chronic interstitial
nephritis
Chronic rejection
The structure of сhronic transplant rejection
Chronic active T-cell-mediated rejection
Fibrinoid necrosis of arteries
CD68+ monocytes in the PTC
CD45R0+ lymphocytes
Conclusions:
Our findings indicate that most cases of late allograft failure are attributed by specific (immunological) causes, mainly, CAAMR.
Routine staining for C4d, T-lymphocytes and macrophages with semiquantitative evaluation and/or quantitative image analysis is advisable for differential diagnostics of chronic KAG dysfunction variants. Uncovered histological and immunohistochemical features of CAAMR may help to diagnose its C4d-negative variants.
Chronic active antibody-mediated rejection