Predicting In-hospital Outcomes of CSA-AKI

By Integrating New Biomarkers

Zhongli Chen, State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College

This article is related to Cardiac Surgery-associated Acute Kidney Injury (CSA-AKI). After the disease diagnosis, the risk stratification for renal replacement therapy and in-hospital mortality is of great importance. The article introduces a predictive model for the in-hospital outcomes of CSA-AKI patients.

As a type unique operation-related AKI, CSA-AKI is closely bond to poor in-hospital outcomes including progressed renal dysfunction. A considerable number of patients experienced a subsequent deteriorating renal function and required Renal Replacement Therapies (RRT). For these patients, the Intensive Care Unit (ICU) length of stay and mortality was particularly high. Identifying CSA-AKI patients who are at high risk of hard in-hospital outcomes like renal replacement therapy and in-hospital mortality could potentially improve patient care or aid in the development of novel treatment strategies.

Traditional Signature: Change of Creatinine

Serum creatinine is absolutely the most commonly-used marker to access renal function. There are several guidelines for AKI diagnosis after cardiac surgery based on the elevation of serum creatinine. For example, both the AKIN and the KDIGO guidelines suggest that if the creatinine level increases by ≥0.3mg/dl (26.5µmol/l) within 48h after cardiac surgery, then the CSA-AKI can be diagnosed. So it is undeniable that creatinine change still severe as a strong clinical predictor for renal dysfunction. But defining the risk of poor in-hospital kidney outcome only by the change of creatinine was problematic. The most predominant limitation is that serum creatinine sometimes lacks sensitivity and might delay the identification of the disease process in AKI[1].Besides, the levels of creatinine can be affected by physiological processing (for example, muscle mass), drugs and specific conditions. Therefore, disease-specific biomarkers are being sought out for screening and for early diagnosis of several kidney disorders.

New Biomarkersfor CSA-AKI Identification: Closely Bound to Pathophysiological Process

When it comes to the novel biomarkers, it is essential to refer to the disease mechanism. For one, AKI has been closely bound to renal hypoperfusion, which resulted from the low-flow, low-pressure, and rapid temperature changes. If a low cardiac output state or a hypotensive state persists, renal impairment will occur. During the past decade, the cell cycle arrest biomarkers (such as Tissue Inhibitor of Metalloproteinases 2 (TIMP2) and Insulin-like Growth Factor-Binding Protein 7 (IGFBP7), Neutrophil Gelatinase-associated Lipocalin (NGAL), Kidney Injury Molecule 1 (KIM1)) that are directly associated with kidney injury have been investigated in animal models and clinical scenarios[2]. For another, the immuno-inflammatory process also played an important role from the disease initiation to the deterioration or recovery[3]. During CSA-AKI, ischemia and most notably reperfusion induce reactive oxygen species production and reactive oxygen species to induce inflammation by upregulation of pro-inflammatory transcription factors[4]. Pro-inflammatory cytokines and chemokines recruit neutrophils, macrophages, and lymphocytes into the renal parenchyma, thus amplifying cell damage and worsening organ dysfunction getting worse. Meanwhile, it has been recognized that the acute inflammatory response incorporates counter-regulatory components, anti-inflammatory cytokines are also key players for repair and regeneration[5]. Therefore, elevated plasma concentrations of pro- or anti-inflammatory cytokines at least partly represented the presence and progression of kidney injury. Over the past decades, immune-inflammatory biomarkers such as L-6, IL-4, IL-8, IL-18, IL-10, TNF-α, IFN-γ and MCP-1showed promising potential for early identification of the CSA-AKI.

What matters: After the AKI Identification.

The progress of early identification of CSA-AKI using novel biomarkers is impressive. But after the CSA-AKI diagnosis, there are still a considerable number of patients who experienced a subsequent deteriorating renal function and required RRT. Among these patients, the ICU length of stay and mortality was particularly high. Identifying CSA-AKI patients who are at high risk of poor in-hospital outcomes is also another important topic.

Although there are still limited interventions for the completely successful treatment of CSA-AKI (only supportive therapy or RRT), the intensity and time of the intervention in a more targeted population also matters. Some might think that critical care doctors will take their responsibility. However, in real clinical practice (especially in ICUs of overpopulated cities), the critical care doctors are busying dealing with different conditions of critically ill patients. The risk stratification of CSA-AKI patients is rational. Although there are unified therapeutic principles of AKI, the specific strategies and extend of supporting therapy vary between the "stable" and the "high-risk" ones. In fact, it was reported that among the CSA-AKI patients, a majority of them only underwent transient AKI or the AKI can be self-limiting, which might not affect in-hospital outcomes[6]. By contrast, some patients experienced severe renal dysfunction and require RRT. For the patients at risk of severe conditions, more attention has to be paid by the ICU doctors. If they can identify the CSA-AKI patients who were likely to develop deteriorating renal dysfunction and poor outcomes earlier, ICU doctors will apply more intensive monitor and management in these patients, thus assisting in improving the prognosis of the patients.

Although according to different changes of serum creatinine, the patients can be stratified into three stages (increase in sCr of 1.5-1.9, 2-3, >3 fold of the baseline) to imply the disease severity, such staging does not necessary means that patients will experience the poor in-hospital outcomes because it only based on the creatinine, which as mentioned before has several drawbacks. Hence, to precisely predict whether a patient will get AKI progression and require RRT or in-hospital outcome, new markers are still needed.

New Model: Integrates Traditional and New Markers for Outcome Prediction

In a recent study published in JTCVS[7]. We measured 32 plasma immuno-inflammatory cytokines at the time of AKI diagnosis in the training cohort incorporating one hundred and ninety-six patients and used the LASSO regression and Random forest algorithm to identify the key blood markers for in-hospital composite outcomes (requiring RRT or (and) suffering in-hospital death). We constructed a predictive model using the selected marker IL-16, IL-8 and change of creatinine and tested it in an external validation cohort. It’s encouraging to find the model displayed good performance with high discriminability and goodness of fit. (ROC-AUC 0.974, PR-AUC: 0.809, Brier Score 0.056, Hosmer-Lemeshow test p=0.651)

In fact, in this model IL-16 and IL-8 also give us some clues as to the significance of risk stratification. Compared with using change of the creatinine alone, addition of IL-16 and IL-8 led to a significant improvement of risk reclassification [category-free Net Reclassification Improvement(NRI) = 0.992 (0.640 - 1.345), p<0.001; Integrated Discrimination Improvement(IDI) = 0.172 (0.074 - 0.269), p<0.001].

From the pathophysiological aspect, the immune-inflammatory makers IL-8 and IL-16 were also proved to participate in acute kidney injury. IL-8 is a proinflammatory cytokine produced by monocyte, neutrophil, endothelial, and epithelial cells. The animal models also showed that AKI was characterized by elevated blood IL-8 concentrations. And it acts as a potent neutrophil activator and chemoattractant. After the ischemia-reperfusion injury, IL-8 is released by stem cells and endothelial progenitor cells into the systemic circulation, thereby increasing inflammation[8]. Also, as a T-cell chemoattractant, IL-16 significantly expressed in proximal and distal straight tubules of the kidney. It also has the potential for mediating kidney injury during the CSA-AKI. Previous researches reported that IL-16 contributed to renal ischemia-reperfusion injury in animal models and inactivation of IL-16 alleviated the kidney injury. Inactivation of IL-16 by antibody therapy prevented ischemia-reperfusion injury as shown by reduced levels of serum creatinine in animal models[9].

By integrating these immune-inflammatory markers on top of the clinically importantly factor creatinine, we have access to reclassify the CSA-AKI patients and improve the risk management. It also means if we can select the patients who were at lower risks of dialysis and mortality, we might give them other necessary medication and get them out of the ICU sooner.

A Long but Promising Way: Finding New Interventions of CSA-AKI

From previous publications to current guidelines, it seems that we can resort only to supportive therapy, or renal replacement therapy to treat CSA-AKI. However, we are also trying to succeed while admitting the previous failure. Several clinical trials, such as early or intensive management (NCT00306059, NCT01621152, NCT04005105), early initiation of RRT (NCT00806039) and cell or pharmaceutical treatments (NCT04194671, NCT03510897) are still in progress.Moreover, because of the complexity of CSA-AKI, it might be necessary to apply multifaceted interventions in targeted patients to address this difficult situation.

In an era where the usage of monoclonal antibodies against interleukins such as tocilizumab and sarilumab (an IL-6R antibody) is tried in several diseases, including cancer, arthritis, atherosclerosis and sepsis, and even the emerging COVID-19, it is compelling to look forward to antibody therapy in CSA-AKI.As an important mechanism of CSA-AKI, inflammatory cytokines such as IL-8 and IL-16 have been proven to participate in this process through preclinical models and molecular experiments.The high levels of immune-inflammatory biomarkers might also indicate specific patients that might benefit from antibodies in the future. Since the IL-8 monoclonal antibody BMS-986253 was developed, with several ongoing clinical trials[10], it is imaginable that the IL-8 antibody might also be used to treat CSA-AKI in the future. Moreover, small molecules that mimic the IL-16 antibody was developed[11], providing new opportunities for alleviating damages of AKI. Therefore IL-16 might also be a therapeutic target for AKI in clinical practice.

The deep insights of the disease mechanism, cutting-edge technology and proactive registration of standard clinical trials help us to explore promising biomarkers and therapeutics. We now have good start but needs further clinical evidence.

Reference

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Zhongli Chen

Zhongli Chen is working as a cardiovascular physician and PhD student in State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science and Peking Union Medical College in hospital in China.In cooperation with researcher and surgeon Dr Liang Chen, they focused on the clinical and translational studies of biomarkers in cardiovascular disease.

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