Kidney ischemic injury genes expressed after donor brain death are predictive for kidney transplantation outcome

Dorota Kaminska¹, Katarzyna Koscielska-Kasprzak¹, Dominika Drulis-Fajdasz¹, Agnieszka Halon², Wojciech Polak³, Pawel Chudoba³, Dariusz Janczak³, Oktawia Mazanowska¹, Dariusz Patrzalek³, Marian Klinger¹.

¹Dept. Nephrology and Transplantation Medicine; ²Dept. Pathological Anatomy; ³Dept. Vascular, General and Transplant Surgery, Wroclaw Medical University, Poland.

The result of deceased kidney transplantation is largely dependent on the extent of the organ injury induced by the brain death and transplantation procedure. In the study we analyzed the pre-procurement intragraft expression of 29 genes involved in apoptosis, tissue injury, immune cell migration and activation. We also assessed their influence on allograft function.

50 kidney core biopsies of deceased donor kidneys were obtained immediately after organ retrieval, before flushing with cold solution. 18 biopsies obtained during living donor transplantation served as a control. Gene expression was analyzed with low density arrays (Taqman).

The comparison of deceased kidneys to control organs revealed the significantly larger expression of LCN2 (8.0x, p=0.0006) and HAVCR1 (4.7x, p<0.0001). Their expression was positively correlated with serum creatinine concentration after 6 months since transplantation: LCN2, r=0.65, p<0.0001; HAVCR1, r=0.44, p=0.006. Kidneys, which further developed delayed graft function and/or acute rejection episode in the first 6 months after transplantation had higher LCN2 expression compared to event free ones (1.7x, p=0.027).

We also observed the significantly increased expression of TLR2 (5.2x), IL18 (4.6x), HMGB1 (4.1x), GUSB (2.4x), CASP3 (2.0x), FAS (1.8x) and TP53 (1.6x) in deceased kidneys compared to controls. Their expression levels were not related to clinical outcome, however they showed significant correlation with one another (r>0.6, p<0.0001). We also observed slightly lowered expression of IL10 (0.6x, p=0.004).

LCN2/lipocalin-2 is considered a biomarker of kidney epithelia ischemic injury with a renoprotective function. HAVCR1/KIM-1 is associated with acute tubular injury process. Our data suggest that the increase in LCN2 and HAVCR1 expression observed in the kidneys after donor brain death are the hallmarks of the initiated organ injury process. LCN2 expression level in the just retrieved kidney predicts the transplantation outcome.