Division of Transplant Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Harvard Medical School, Boston, Massachusetts 02115, USA.
Nat Commun. 2017 Jan 10;8:13899. doi: 10.1038/ncomms13899.
Ischaemic acute kidney injury (AKI), an inflammatory disease process, often progresses to chronic kidney disease (CKD), with no available effective prophylaxis. This is in part due to lack of clinically relevant CKD models in non-human primates. Here we demonstrate that inhibition of the archetypal innate immune receptor CD11b/CD18 prevents progression of AKI to CKD in cynomolgus monkeys. Severe ischaemia-reperfusion injury of the right kidney, with subsequent periods of the left ureter ligation, causes irreversible right kidney failure 3, 6 or 9 months after AKI. Moreover, prophylactic inactivation of CD11b/CD18, using the orthosteric CD11b/CD18 inhibitor mAb107, improves microvascular perfusion and histopathology, reduces intrarenal pro-inflammatory mediators and salvages kidney function long term. These studies reveal an important early role of CD11b leukocytes in post-ischaemic kidney fibrosis and failure, and suggest a potential early therapeutic intervention to mitigate progression of ischaemic AKI to CKD in humans.
缺血性急性肾损伤 (AKI) 是一种炎症性疾病过程，常进展为慢性肾脏病 (CKD)，目前尚无有效的预防措施。部分原因是非灵长类动物中缺乏临床相关的 CKD 模型。在这里，我们证明了抑制典型的先天免疫受体 CD11b/CD18 可预防食蟹猴 AKI 进展为 CKD。右侧肾脏的严重缺血再灌注损伤，随后左侧输尿管结扎，会导致 AKI 后 3、6 或 9 个月右肾不可逆衰竭。此外，使用正位 CD11b/CD18 抑制剂 mAb107 对 CD11b/CD18 进行预防性失活，可改善微血管灌注和组织病理学，减少肾内促炎介质，并长期挽救肾功能。这些研究揭示了 CD11b 白细胞在缺血后肾脏纤维化和衰竭中的重要早期作用，并提示可能存在早期治疗干预措施，以减轻人类缺血性 AKI 向 CKD 的进展。
