Editorial <\/p>\n\n\n\n
October 9, 2024<\/p>\n\n\n\n
<\/a>Acute kidney injury (AKI) is a common complication in hospitalized patients, associated with significant short-term morbidity and mortality, and for which the only current therapeutic strategies are supportive. Of the common causes of AKI, cardiac surgery\u2013associated AKI has been an appealing target for novel therapeutics, in part because the timing of the surgical insult is established and therapies can be offered before, during, or after the surgical procedure. AKI occurs in up to 30% of patients undergoing cardiac surgery.1<\/a><\/sup>\u00a0A number of different mechanisms have been proposed to contribute to cardiac surgery\u2013associated AKI, including ischemia-reperfusion, inflammation, oxidative stress, and exposure to toxic mediators such as cell-free hemoglobin.1<\/a>,2<\/a><\/sup>\u00a0Numerous therapies, including steroids, statins, n-acetylcysteine, remote ischemic preconditioning, and mesenchymal stromal cell therapy, have been tested for the prevention or early treatment of cardiac surgery\u2013associated AKI, without apparent benefit.3<\/a><\/sup><\/p>\n\n\n\n One important proposed mechanism of AKI associated with cardiac surgery is that surgical trauma and cardiopulmonary bypass induce a systemic inflammatory response, which then incites direct tubular damage. To modulate this inflammatory response, several extracorporeal blood purification (EBP) devices have been developed to remove exogenous and endogenous inflammatory mediators. These devices pass blood through a hemofilter, and the mediators are adsorbed by a sorbent-containing membrane. At present, several different types of EBP devices are available that filter cytokines, endotoxin, or both. Although the major area of focus for these EBP devices has been sepsis, there has been interest in using these devices in the context of cardiac surgery\u2013associated AKI given the systemic inflammatory response that occurs during cardiopulmonary bypass, as well as the fixed timing of the cardiac surgery insult.<\/a><\/p>\n\n\n\n In this issue of JAMA<\/em>, P\u00e9rez-Fern\u00e1ndez et al4<\/a><\/sup> report the results of a double-blind, randomized trial that evaluated the effect of an EBP device on AKI in those undergoing nonemergent cardiac surgery. The SIRAKI02 trial enrolled 343 adult patients who were scheduled for nonemergent cardiac surgery with an anticipated cardiopulmonary bypass time of 90 minutes or more at 2 hospitals in Spain. Those with advanced chronic kidney disease (CKD; defined as Kidney Disease Improving Global Outcomes [KDIGO] stage 4 or 5) were excluded.<\/a><\/p>\n\n\n\n The EBP group (n\u2009=\u2009169) received treatment with the EBP device attached to a continuous kidney replacement therapy machine during cardiopulmonary bypass. This device is a nonselective membrane that absorbs both cytokines and endotoxin. Slow continuous ultrafiltration was used for fluid removal if felt to be clinically indicated. In the standard care control group (n\u2009=\u2009175), a polysulfone-based membrane was used for ultrafiltration. Although the care team involved in the surgical intervention could not be masked to treatment assignments, intensivists assessing outcomes were masked.<\/a><\/p>\n\n\n\n Baseline characteristics of the 2 study groups were relatively balanced, except patients randomized to receive EBP reported more statin and aspirin use. The primary end point of AKI was defined by KDIGO serum creatinine criteria (\u22650.3-mg\/dL increase over 48 hours or \u22651.5 times baseline) within the first 7 days and urine output criteria (<0.5 mL\/kg\/h for \u22656 hours) up to day 4 after the surgical procedure. Significantly lower rates of AKI were noted among patients in the EBP group compared with the standard care group (28.4% vs 39.4%; P<\/em>\u2009=\u2009.03). A higher percentage of patients in the EBP group had ultrafiltration (24% vs 12%; P<\/em>\u2009=\u2009.01), although the volume of fluid removed was higher in the standard care group. In theory, ultrafiltration may affect AKI parameters by changing volume status and the volume of distribution of creatinine. The difference in AKI rates remained statistically significant when those receiving ultrafiltation were excluded from the analysis (29% vs 41%; P<\/em>\u2009=\u2009.03). In subgroup analyses, those with CKD, diabetes, hypertension, heart failure, and low body mass index were more likely to benefit from the intervention.<\/a><\/p>\n\n\n\n In the overall cohort, the difference in peak serum creatinine was modest (0.13 mg\/dL). From the analyses presented, oliguria appears to be a driver of the primary end point, with a 7% difference in the incidence of oliguria between the 2 groups, in favor of EBP. The majority of AKI was transient (defined as less than 48 hours), and the impact of the intervention was on transient and not persistent AKI. There was no difference in a number of clinical secondary end points, including 90-day survival, intensive care unit and hospital length of stay, and need for vasopressors or mechanical ventilation. There were some changes in inflammatory biomarkers between the 2 groups, including reductions in interleukin 8 (IL-8) and tumor necrosis factor (TNF) \u03b1. No differences in complications, such as thrombocytopenia or blood transfusion requirements, were observed. Thus, the SIRAKI02 trial is the first trial to demonstrate a reduction in cardiac surgery\u2013associated AKI with EBP, although this impact on short-term AKI outcomes did not translate into benefit for more durable clinical outcomes, including intensive care unit or hospital length of stay.<\/a><\/p>\n\n\n\n To date, most EBP studies have focused on patients with severe sepsis and septic shock, and these studies have yielded largely mixed results.5<\/a><\/sup>,6<\/a><\/sup> The clinical efficacy of EBP in patients with sepsis has remained inconclusive, likely because of the heterogeneity of study design, interventions, and measured end points.7<\/a><\/sup> In addition, sepsis-associated AKI often occurs prior to hospital presentation, so treatment in these cases is often reactive. In comparison, the timing of cardiac surgery is known, and preventive measures may occur in a more controlled setting. The few existing trials of EBP in patients undergoing cardiac surgery have focused on cytokine removal and have not evaluated AKI as the primary outcome.8<\/a><\/sup>,9<\/a><\/sup> Only the REMOVE trial enrolled more than 200 patients and randomized patients with infectious endocarditis undergoing cardiac surgery to receive CytoSorb integration into the cardiopulmonary bypass circuit vs standard care.10<\/a><\/sup> This trial found no significant differences in the primary end point, change of Sequential Organ Failure Assessment (SOFA) score, among those randomized to receive EBP vs no EBP.<\/a><\/p>\n\n\n\n The SIRAKI02 study is, to our knowledge, the largest randomized clinical trial evaluating the efficacy of EBP in patients undergoing nonemergent cardiac surgery, and is the first to use the Oxiris filter. This trial demonstrated a significant change in cardiac surgery\u2013associated AKI rates with EBP use. However, most of the AKI episodes were early, transient, mild, and appear to be identified by urine output rather than creatinine criteria. There was no benefit on longer-term secondary outcomes, with very limited to no signal of potential benefit. The authors of the SIRAKI02 trial suggest that the lack of significant differences in secondary end points may be due to more limited power for these end points. However, this finding is reminiscent of the CORONARY trial of off-pump vs on-pump cardiac surgery, where short-term differences in AKI between the treatment groups were not associated with differences in kidney function at 1 year after the surgical procedure.11<\/a><\/sup> Similarly, the 2024 PROTECTION trial tested a preoperative intravenous amino acid infusion and demonstrated a reduction of AKI among patients undergoing cardiac surgery, but did not examine the impact of this intervention on longer-term kidney outcomes and did not demonstrate an impact on 30-day mortality.12<\/a><\/sup><\/a><\/p>\n\n\n\n Despite the proposed mechanism of EBP in modulating inflammation, few significant changes in inflammatory biomarkers were observed, although cytokines were only evaluated in 60% of the SIRAKI02 study population. Similar reductions in IL-8 and TNF-\u03b1 have been observed in a trial of another blood purification device in patients undergoing elective on-pump cardiac surgery.13<\/a><\/sup> However, the role that the reduction of these biomarkers plays in decreasing cardiac surgery\u2013associated AKI remains unknown. Patients with CKD, heart failure, hypertension, diabetes, and low body mass index seemed to benefit more from EBP than patients without these comorbidities. CKD, heart failure, hypertension, and diabetes are often considered pro-inflammatory conditions. Although additional targeting of these subgroups may yield a stronger signal of efficacy, this was not a prespecified hypothesis. More studies would be needed to draw any conclusions about potential efficacy in these subgroups; ideally, such studies would also contain inflammatory biomarker measurements if this is the proposed mechanism of efficacy.<\/a><\/p>\n\n\n\n The SIRAKI02 trial is notable as the first study to provide high-quality evidence that EBP may reduce cardiac surgery\u2013associated AKI. Given the lack of significant impact on persistent or severe AKI as well as other important clinical outcomes, including vasopressor and mechanical ventilation use, length of stay, and mortality, additional studies are needed to confirm these results and to potentially identify treatment-responsive subgroups. If the effect is in fact more transient, the risks and benefits including cost of EBP will need to be considered closely. Nonetheless, this exciting study certainly inspires promise for additional studies of therapeutics focused on the prevention of AKI among patients undergoing cardiac surgery, including further studies of EBP.<\/p>\n","protected":false},"excerpt":{"rendered":" Editorial October 9, 2024 Impact of Ads […]<\/p>\n","protected":false},"author":3,"featured_media":0,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":[],"categories":[24,23],"tags":[],"_links":{"self":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27000"}],"collection":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/users\/3"}],"replies":[{"embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=27000"}],"version-history":[{"count":1,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27000\/revisions"}],"predecessor-version":[{"id":27001,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=\/wp\/v2\/posts\/27000\/revisions\/27001"}],"wp:attachment":[{"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=27000"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=27000"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/csccm.org.cn\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=27000"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}