Prolonged cold ischemia promote the progression of chronic allograft nephropathy by chemokine C-C ligand 2 induced macrophage recruitment

Background Prolonged cold ischemia (pCI) is a well-established risk factor for both acute kidney injury and chronic allograft nephropathy (CAN). The chemokine C-C motif ligand 2 (CCL2) plays a pivotal role in sustaining chronic inflammation. This study aimed to elucidate the effect of pCI on functional role of CCL2 in the pathogenesis CAN in a rat model of renal transplantation. Method Isogenic (Lewis to Lewis) and allogenic (Fisher 344 to Lewis) kidney transplants (KTx) were performed, with donor kidneys subjected to cold storage for either 2 h or 12 h. Animals were thus divided into four groups: iso-2 h, iso-12 h, allo-2 h, and allo-12 h. In the allo-12 h group, a subset of recipients received the CCL2 inhibitor cenicriviroc (CVC) as the allo12h + CVC group. Recipients were monitored for up to 90 days post-transplantation. Results At day 90 post-implantation, allografts exhibited significant fibrosis and markedly impaired renal function in the animaols with pCI, as indicated by higher total Banff scores and lower creatinine clearance rates ( P  < 0.05). In contrast, these changes were not evident in isografts with pCI. The levels of of macrophages and M1 activation in the Allo-12 h group were increased, as demonstrated by elevated expression levels of CD68 and inducible nitric oxide synthase (iNOS); which were significantly mitigated by CVC treatment. Furthermore, during the acute phase (day 7 post-surgery), pCI caused severe acute kidney injury and induced a higher infiltration of CD3 + lymphocytes in the allografts compared to the isografts ( P  < 0.05). Additionally, the CCL2 receptor CCR2 positive cells showed a substantial increase in the Allo-12 h group, concomitant with upregulation of CCL2 expression in allografts compared to isografts. Conclusion Our study demonstrates that chemokine CCL2 involves in the development of CAN, through recruitment of inflammatory cells during the acute phase following surgery.