Microcirculation endothelial cell cycling is selectively increased in antibodymediated rejection of kidney transplants, but not in other diseases
S Osasan1,2, D de Freitas 2,J Sellares2, J Chang2, L Hidalgo1,2,
M Mengel1,2, P F Halloran2, B Sis1,2
1 Department
of Laboratory Medicine and Pathology, 2Alberta Transplant Applied
Genomics Centre, University of Alberta, Edmonton, AB, Canada.
Background: Antibody-mediated rejection (ABMR) is dominated by microcirculation
inflammation and endothelial injury, caused by donor specific antibodies.
Objective: We hypothesized that ABMR is associated with a greater endothelial repair
response compared to other diseases operating in kidney transplants.
Method: We related microcirculation endothelial cell cycling to histopathology lesions,
diagnoses, and whole-genome microarrays in 100 kidney transplant biopsies and 40
normal implantation biopsies. We performed double immunostaining for Ki-67 and CD31
to identify capillaries with cycling endothelial cells. We quantified the microcirculation
endothelial cell cycling by counting number of Ki-67+CD31+ glomerular and peritubular
capillaries in the entire cortical area of the biopsies.
Results: The transplant biopsies showed higher numbers of capillaries with cycling
endothelial cells in comparison to normal controls (p=0.003). The mean microcirculation
endothelial cell cycling was highest in ABMR compared to other diseases. (figure1)
Increased microcirculation endothelial cell cycling correlated with donor specific HLA
antibody (p=0.003), microcirculation lesions (glomerulitis, capillaritis, transplant
glomerulopathy), and C4d staining (p<0.05). Furthermore, transcript sets representing
the molecular burden of active ABMR (endothelial cell, NK-cell, and macrophageassociated transcripts as well as interferon gamma regulated transcripts) correlated with
increased microcirculation endothelial cell cycling (p<0.05). Within the ABMR biopsies,
increased microcirculation endothelial cell cycling correlated with higher grades of
glomerulitis (p=0.01) and peritubular capillaritis (p=0.08). Interestingly, cycling was not
increased in TCMR, suggesting that T cells cross the microcirculation in TCMR without
damaging the capillaries.
Conclusion: We conclude that endothelial repair response is selectively increased in
kidneys with ABMR, reflecting the burden of active microcirculation injury.
p=0.001
p=0.021
Microcirculation endothelial cell cycling
p=0.017
p=0.004
3
2
1
0
n
Controls
n = 40
ABMR
n = 25
TCMR
n = 11
Borderline
n = 18
GN
n = 12
Transplant biopsies
=
=
=
TCMR =
GN
=
Controls =
Mixed ABMR & TCMR
C4d+ ABMR
C4d- ABMR
T Cell-Mediated Rejection
Glomerulonephritis
20 living and 20 deceased donor implant biopsies
OTHER
n = 34