Time of occurrence of kidney acute antibody-mediated allograft rejection/acute cellular rejection and cell senescence: implications for function outcome.
BACKGROUND
Late versus early acute antibody-mediated rejection (AAMR) or acute cellular rejection (ACR) episodes are associated with poorer kidney function and graft survival. We explored whether cell senescence upon detection of AAMR ± ACR contributes to these results.


METHODS
We reviewed the renal transplant database of 2 Institutions. Biopsies performed for acute graft dysfunction from January 2000 to March 2007 were analyzed for morphological criteria of AAMR with or without ACR (n = 17 from 17 patients). Immunoperoxidase staining for p16(INK4B) was performed on the remaining paraffin-embedded tissue in 9 of 17 cases. The average number of positive cells/high power field (HPF) was calculated in every case. Cases with rejection were grouped according to the time of presentation: early (<3 months n = 8) versus late (>3 months; n = 9). Graft function was obtained using the Modification of Diet in Renal Disease (mDRD) glomerular filtration rate estimate (eGFR) before, during rejection, and at the last visit, to calculate ΔeGFR.


RESULTS
Nuclear expression of p16(INK4B) was 12.2 ± 11.3 cells/HPF in 4 of 8 biopsies performed at a median of 23 (range = 4-80) days (early AAMR ± ACR), and 59.8 ± 51.3 cells/HPF in 5 of 9 biopsies performed at a median of 1171 (range = 279-3210) days (late AAMR ± ACR). eGFR before rejection was 48.5 ± 7.6 mL/min, and 43.7 ± 4.3 mL/min for early and late rejection episodes, respectively (P = not significant [NS]). ΔeGFR of 12.5 ± 25.9 mL/min (early rejection), and -13.7 ± -12.3 mL/min (late rejection), versus last follow-up visit (P = .02) occurred at a median of 143.9 ± 94.1 and 69.6 ± 35.1 weeks after the rejection episodes, respectively.


CONCLUSIONS
Even though the number of biopsies analyzed for p16(INK4a) was small, it was evident that the number of cells expressing this marker of senescence was higher among biopsy specimens obtained with late rejection episodes. This finding suggests the presence of injuries prior to the rejection episode. The significantly lower eGFR at last follow-up in the late rejection group may translate to a reduced capacity of the repair process to sustain nephron function.
Arvizu-Hernández
M
M
Departamento de Trasplantes, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, D.F. Mexico.
Morales-Buenrostro
L E
LE
Vilatoba-Chapa
M
M
Mancilla-Urrea
E
E
Uribe-Uribe
N
N
Avila-Casado
M C
MC
de Leo
C
C
Arvizu
A
A
Gonzalez
J L
JL
Torres
J
J
Gabilondo
B
B
Correa-Rotter
R
R
Alberú
J
J
D000208:Acute Disease; D000328:Adult; D002102:Cadaver; D016922:Cellular Senescence / Q000502:physiology; D050762:Cyclin-Dependent Kinase Inhibitor p15 / Q000235:genetics; D005260:Female; D005919:Glomerular Filtration Rate; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D007518:Isoantibodies / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D014019:Tissue Donors
D050762:Cyclin-Dependent Kinase Inhibitor p15; D007166:Immunosuppressive Agents; D007518:Isoantibodies