In this cohort study, only ADIAD patients undergoing triple-branched stent implantation surgery were included, and patients with aortic intramural hematoma with relatively lower inflammatory response were excluded. Although the plasma RIP3 levels were associated with hypotension and higher sCr levels, there was no difference in the incidence of the fore-mentioned preoperative complications as well as malperfusion syndrome among the three groups. Thus the patients were relatively homogeneous in the three groups.
The preoperative plasma RIP3 levels in renal malperfusion group was higher, but with no statistical significance, which might be associated with only unilateral renal malperfusion and the renal function was compensated by the other renal. The plasma RIP3 level was higher than control groups, and postoperative RIP3 level was higher than preoperative levels. This could be explained by a secondary inflammatory blow. On the other hand, no difference was found in preoperative plasma RIP3 levels among the different AKI stage groups, but the postoperative and elevated RIP3 levels were significantly different among the three groups and showed positive linear trends across the AKI stage. Additionally, the postoperative plasma RIP3 levels were significantly elevated in all three groups. Besides, the preoperative and postoperative RIP3 levels were positively correlated with sCr, and the comparison of ROC curves of this two biomakers further showed that the plasma RIP3 levels was similar to sCr in diagnosing postoperative AKI in ADIAD. All these might indicate that the surgery and extracorporeal circulation promoted the necroptosis in kidney, and the postoperative plasma RIP3 levels might originate from the injured kidney. Hence the postoperative plasma RIP3 levels might show as a new biomaker in postoperative AKI in ADIAD.
Our study also indicated that the postoperative and elevated plasma RIP3 levels and ACCT were independent risk factors for postoperative AKI in ADIAD, and the postoperative RIP3 levels were significantly positively correlated with the ACCT. This is consistent with the research review  indicating that ACCT is an independent risk factor for postoperative AKI in ADIAD. The longer the ACCT was, the longer the times of surgery, extracorporeal circulation and myocardial ischemia were. These effects could lead to more severe systemic inflammation, a necroptosis process that affects the recovery of postoperative cardiac function, malperfusion of visceral organs and more severe postoperative AKI. So necroptosis may participate in the occurrence and development of postoperative AKI in ADIAD during surgery and extracorporeal circulation. Additionally, our study also showed that the preoperative hypotension were associated with higher plasma RIP3 levels. This could also be explained by the fact that the cardiac function could affect renal perfusion.
In addition, our study showed that the plasma RIP3 levels were significantly positively correlated with postoperative inflammatory cytokines such as PCT and IL-6, a finding that was consistent with a study showing a positive correlation between the plasma RIP3 and PCT levels in sepsis patients . Both PCT and IL-6 are acute reactive proteins with increased expression in the body under stress, and they are also increased in patients with AD [24, 25]. The correlation between the plasma RIP3 levels and inflammatory cytokines also reflected the correlation between necroptosis and necroinflammation. A self-amplifying positive feedback cycle exists between necroptosis and necroinflammation, and RIP3 has a proinflammatory effect independent of the function of necroptosis [26, 27]. Inhibition of RIP3 can inhibit necroptosis and necroinflammation . The significant positive correlation between the plasma RIP3 levels and PCT and IL-6 showed that all three could serve as human hematology markers of necroptosis and necroinflammation . Additionally, necroinflammation caused by necroptosis may further aggravate the occurrence and development of postoperative AKI in ADIAD, as well as prolong the postoperative mechanical ventilation time and ICU stay time, affecting the survival rate of patients. This finding was consistent with the results that the plasma RIP3 levels were correlated with the critical condition and prognosis in patients with coronary heart disease and heart failure [20, 21]. Therefore, inhibiting necroptosis and controlling inflammation could be therapeutic targets for postoperative AKI in ADIAD, and the effect of controlling inflammation might be better and faster than that of inhibiting necroptosis pathways .
Notably, some plasma samples were collected when the patients had undergone CRRT or extracorporeal membrane oxygenation (ECMO), during which the patient's blood was in direct contact with the surface of abiotic materials, significantly activating the inflammatory reaction of the body [30, 31]. However, CRRT and ECMO can lead to blood dilution and pipeline adsorption of cytokines, and CRRT can filter some of the inflammatory cytokines ; thus, these factors may exert certain effects on the levels of RIP3 and inflammatory cytokines. However, in our study, the levels of inflammatory cytokines in patients who had undergone CRRT or ECMO were still very high, possibly because the plasma collection time was relatively early after surgery, and the severity of the inflammatory reaction in patients was significantly stronger than that of filtrating inflammatory cytokines, blood dilution and pipeline adsorption by CRRT.
The strengths of this study: The prospective cohort study and the included relatively homogeneous patients reduce the confounding bias. The limitations of this study: (1) The sample size was small. (2) Postoperative RIP3 was detected at only one time point without dynamic detection. (3) The urine RIP3 levels did not be detected. (4) Although there was a correlation between RIP3 levels and postoperative AKI stage in our study, no gold standard exists currently to detect necroptosis in humans. The elevated RIP3 levels cannot prove causally that necroptosis directly leads to the occurrence and development of postoperative AKI in ADIAD; further animal studies are warranted.