Prevention of Cardiac Surgery–Associated Acute Kidney Injury by Implementing the KDIGO Guidelines in High-Risk Patients Identified by Biomarkers

The PrevAKI-Multicenter Randomized Controlled Trial

Alexander Zarbock, MD; Mira Küllmar, MD; Marlies Ostermann, MD; Gianluca Lucchese, MD; Kamran Baig, MD; Armando Cennamo, MD; Ronak Rajani, MD; Stuart McCorkell, MD; Christian Arndt, MD; Hinnerk Wulf, MD; Marc Irqsusi, MD; Fabrizio Monaco, MD; Ambra Licia Di Prima, MD; Mercedes García Alvarez, MD; Stefano Italiano, MD; Jordi Miralles Bagan, MD; Gudrun Kunst, MD; Shrijit Nair, MD; Camilla L'Acqua, MD; Eric Hoste, MD; Wim Vandenberghe, MD; Patrick M. Honore, MD; John A. Kellum, MD; Lui G. Forni, MD; Philippe Grieshaber, MD; Christina Massoth, MD; Raphael Weiss, MD; Joachim Gerss, PhD; Carola Wempe, PhD; Melanie Meersch, MD

Disclosures

Anesth Analg. 2021;133(2):292-302. 

In This Article

Discussion

In this multicenter, randomized controlled clinical trial of cardiac surgery patients at high risk for AKI, we demonstrated that the adherence to a protocol consisting of a bundle of supportive measures is feasible in a multinational setting. Additionally, we showed that the adherence to the KDIGO recommendations was low (<5%) for patients in the standard of care arm. Moreover, the occurrence of moderate to severe AKI (stages 2 and 3) was significantly lower in the intervention group compared to controls.

At present, based on international consensus, AKI is defined by a change of the functional biomarkers serum creatinine and urine output. These 2 functional biomarkers cannot be reliably used for early detection of AKI. In contrast, TIMP-2 and IGFBP7 may increase earlier following renal stress and allow the implementation of preventive measures well before clinical AKI becomes manifest.[10,16] In other specialties, biomarkers are used for an early initiation of a therapy as well as the commencement of molecular-targeted therapies.[17–19] Based on data in this study and in our previous single-center trial, it is reasonable to implement treatment strategies in high-risk patients to prevent AKI. As [TIMP-2]•[IGFBP7] has very good performance in predicting AKI[7,8] and the biomarkers were used in 2 previous studies with a personalized approach, we used these biomarkers to identify cardiac surgery patients at high risk for CSA-AKI.

Although it has been shown that the adherence to guidelines is associated with better patient outcomes,[20] the adherence to guidelines is generally very low. It tends to be lower if multiple bundles have to be used at the same time.[21,22] Importantly, compliance rate is not influenced by the complexity of the implemented measures. This was highlighted by an observational study showing that only one-third of septic patients received the multifaceted sepsis bundle and a similar proportion of acute respiratory distress syndrome (ARDS) patients was exposed to low tidal volume ventilation.[21] In line with these data, we recently reported the results of an observational study and showed that compliance with all elements of the KDIGO bundle was low in routine clinical practice in patients undergoing cardiac surgery with CPB.[22] In patients randomized to standard care, all 6 aspects of the bundle were applied to only 5.3% of patients, and in 37.9% of patients, only 3 elements were applied. Furthermore, there was no difference in adherence with the KDIGO bundle between patients with and without AKI after cardiac surgery. These results were replicated in the control arm of our study in which only 4.2% of patients received the bundle despite being high risk as defined by [TIMP-2]•[IGFBP7] >0.3. In contrast to the sepsis bundle which is recommended for patients with established sepsis, the KDIGO bundle is recommended only for patients at high risk for AKI, but not all patients in general. The rationale behind this recommendation is that the implementation of some of the measures might be associated with potential adverse events, including increased risk of thrombosis, hypoglycemia, arrhythmias, and ischemia.[23,24] In addition, due to the interaction with other guidelines, time, and financial costs, it is not feasible to implement the KDIGO recommendations in all patients.

The pathophysiology of AKI after cardiac surgery is very complex and clinical trials using pharmacological and nonpharmacological strategies to prevent the development of AKI have failed,[25,26] although some nonpharmacological treatments may be effective in high-risk patients.[9] Based on the complex pathophysiology of CSA-AKI, we implemented the KDIGO bundle as a multifactorial approach that may reduce inflammation, improve renal perfusion, and decrease oxidative stress.[4] Here, we showed that the implementation of the KDIGO guidelines resulted in an increased use of dobutamine and crystalloids, resulting in a significantly higher blood pressure at different time points and a shift toward less severe AKI (from KDIGO stage 2 to stage 1). It is possible that the frequent use of dobutamine in the intervention group had an effect on the development or progression of AKI. During CPB, blood is redistributed away from the kidneys which might lead to focal ischemia in some areas within the kidneys. Increasing blood flow in the perioperative period with dobutamine might lead to more homogeneous perfusion of the kidneys and reduce local ischemia. The results of our trial are in contrast to the findings of a recently published study by Osawa et al[27] which showed that goal-directed therapy did not affect the incidence of AKI. However, the study included patients who were not at high risk for AKI, whereas our trial only randomized patients at high risk for AKI. Our results are in line with other studies, demonstrating that the implementation of a supportive bundle can reduce the occurrence of AKI.[11,12,28]

AKI is a heterogeneous condition consisting of distinct phenotypes based on its etiology, prognosis, and molecular pathways, and that may potentially require different therapies. Serum creatinine (SCr)-based AKI definitions provide no information on these AKI phenotypes. However, biomarkers can identify different phenotypes.[29] We have recently shown that elevated renin levels could be used to identify high-risk patients for cardiovascular instability and AKI who would benefit from timely intervention that could improve their outcomes.[30] Combining renin with TIMP-2•IGFBP7 identified the group with the highest risk to develop a moderate or severe AKI after cardiac surgery, suggesting that the combination of both biomarkers identify another AKI phenotype.[30]

AKI after cardiac surgery is associated with increased morbidity and mortality[31] and any reduction in the AKI rate should have an impact on patient outcomes. Although we showed in this multicenter trial that implementing the KDIGO bundle significantly reduced the occurrence of moderate to severe CSA-AKI, this intervention had no impact on the secondary outcomes for several reasons. First, in contrast to our single-center trial,[11] but similar to a trial in abdominal surgery,[12] we did not impact on the rates of "any stage" AKI. Indeed, we increased the rates of stage 1 AKI but reduced those in stage 2. While it would have been desirable to reduce all AKI, stage 2 AKI is associated with significant greater short- and long-term complications compared to stage 1.[2] Second, the complication rate was low but this trial was not powered to demonstrate differences of rare events. This might be the reason for the lack of association between AKI and prolonged renal dysfunction demonstrated in other studies. Finally, a follow-up duration of 90 days might be too short, especially since other studies demonstrated that even milder forms of AKI, including isolated stage 1 oliguria, are associated with adverse long-term consequences.[2]

The strengths of this study include a personalized treatment approach through the use of a commercially available biomarker, the easy adoption of our study based on the limited numbers of exclusion criteria and the fact that the study was conducted multinationally.

The study is not without limitations. First, although we demonstrated a reduced occurrence of moderate to severe AKI in the intervention group, we could not detect a difference in major adverse kidney events at day 90. The protective effect on AKI might be by chance. However, the findings are in accordance with already published results from single-center studies and likely reflect the beneficial effect of the bundle.[11] The latter may be explained by the fact that the study was not powered to detect a difference in major adverse kidney events at day 90. Second, although randomized to the intervention group, a certain proportion of patients did not receive the bundles. This demonstrates that even under study conditions, it is difficult to successfully implement the bundle in every patient and underlines the importance of the findings to sensitize clinicians. Third, it remains unclear whether all components of the bundle are necessary to prevent AKI or whether some of the measures are more effective than others.

In conclusion, adherence to a bundle of supportive measures recommended by the KDIGO guidelines in patients at high risk identified by biomarkers is feasible in a multicenter and multinational setting, a finding that will underpin a definitive trial. In addition, in the intervention group (bundle of supportive measures), a reduced occurrence of moderate to severe AKI could be observed.

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