Background: The ischemia–reperfusion (IR) environment during deep hypothermic circulatory arrest (DHCA) cardiovascular surgery is a major cause of acute kidney injury (AKI), which lacks preventive measure and treatment. It was reported that cold inducible RNA-binding protein (CIRP) can be induced under hypoxic and hypothermic stress and may have a protective effect on multiple organs. The purpose of this study was to investigate whether CIRP could exert renoprotective effect during hypothermic IR and the potential mechanisms. Methods: Utilizing RNA-sequencing, we compared the differences in gene expression between Cirp knockout rats and wild-type rats after DHCA and screened the possible mechanisms. Then, we established the hypothermic oxygen–glucose deprivation (OGD) model using HK-2 cells transfected with siRNA to verify the downstream pathways and explore potential pharmacological approach. The effects of CIRP and enarodustat (JTZ-951) on renal IR injury (IRI) were investigated in vivo and in vitro using multiple levels of pathological and molecular biological experiments. Results: We discovered that Cirp knockout significantly upregulated rat Phd3 expression, which is the key regulator of HIF-1α, thereby inhibiting HIF-1α after DHCA. In addition, deletion of Cirp in rat model promoted apoptosis and aggravated renal injury by reactive oxygen species (ROS) accumulation and significant activation of the TGF-β1/p38 MAPK inflammatory pathway. Then, based on the HK-2 cell model of hypothermic OGD, we found that CIRP silencing significantly stimulated the expression of the TGF-β1/p38 MAPK inflammatory pathway by activating the PHD3/HIF-1α axis, and induced more severe apoptosis through the mitochondrial cytochrome c-Apaf-1-caspase 9 and FADD-caspase 8 death receptor pathways compared with untransfected cells. However, silencing PHD3 remarkably activated the expression of HIF-1α and alleviated the apoptosis of HK-2 cells in hypothermic OGD. On this basis, by pretreating HK-2 and rats with enarodustat, a novel HIF-1α stabilizer, we found that enarodustat significantly mitigated renal cellular apoptosis under hypothermic IR and reversed the aggravated IRI induced by CIRP defect, both in vitro and in vivo. Conclusion: Our findings indicated that CIRP may confer renoprotection against hypothermic IRI by suppressing PHD3/HIF-1α-mediated apoptosis. PHD3 inhibitors and HIF-1α stabilizers may have clinical value in renal IRI.

Objective Cardiac surgery associated-acute kidney injury (CS-AKI) occurs in 40–55% of patients undergoing surgery for repair of acute type A aortic dissection (ATAAD). Few studies have investigated the association of postoperative AKI with kidney dysfunction seen long-term in patients after surgical repair for ATAAD. The aim of our study was to identify the risk factors of developing post-ATAAD repair chronic kidney disease (CKD) at 6 months.Methods We retrospectively reviewed a contemporary cohort of all patients who underwent surgery for ATAAD repair from January 1, 2020 to December 31, 2021 at Xiamen Cardiovascular Hospital affiliated with Xiamen University.Results Of the 255 included patients, frequency of ATAAD AKI was 112/255 (56.1%). Renal malperfusion (OR 2.175, p = 0.00591), intraoperative urine output (OR 0.75/ 1 ml/kg/h, p < 0.001) and intraoperative RBC transfusion (OR 1.27(/ 1 U, p = 0.00613) were significantly associated with early post ATAAD repair AKI. AKI was independently associated with postoperative adverse composite outcome(OR 3.496, 95% CI 1.955 ~ 6.379). CKD data was non-missing for 87% of participants, among the 232 patients included, 40 of 232 (17.2%) had post-operative CKD. The independent predictors of CKD at 6 mouths were body mass index (OR = 0.827, 95% CI: 0.723 ~ 0.931), cardiac tamponade (OR = 5.344, 95% CI:1.65 ~ 17.958), eGFR baseline < 60mL/min/BSA (OR = 12.629, 95% CI:5.003 ~ 35.373), time to peak SCr > 3 days after surgical repair (OR = 7.566, 95% CI: 2.799 ~ 22.731), and a graded effect of AKI [stage 1 (OR = 4.418, 95% CI: 1.339 ~ 15.361), stage 2 (OR = 8.345, 95% CI: 1.762 ~ 40.499) and stage 3 (OR = 9.463, 95% CI: 2.602 ~ 37.693)].Conclusions The peri-operative period has a major impact on CKD incidence. Both duration and severity of AKI provide prognostic value to predict the development of CKD.