A Systematic Review on Acute Kidney Injury Following Cardiac Surgery: Clinical Outcomes with Preventive Strategies Over the Decades

Introduction: Acute kidney injury (AKI) is a common complication following cardiac surgery, contributing to increased morbidity and mortality. This systematic review aims to comprehensively evaluate the incidence, risk factors, and clinical outcomes associated with AKI post-cardiac surgery.

Methods: A systematic search of electronic databases was conducted to identify relevant studies published. Studies reporting on AKI incidence, risk factors, and clinical outcomes in adult patients undergoing cardiac surgery were included. Data were extracted and synthesized following PRISMA guidelines.

Results: A total of 23 studies were included in the review. AKI was associated with increased short and long-term morbidity and mortality, prolonged hospital stays, and higher healthcare costs. Encouraging outcomes were noted when dexmedetomidine, a highly selective α2-adrenergic receptor agonist, was administered during surgery. Two promising non-pharmacological strategies to reduce CSA-AKI are the use of a revolutionary renal guard (RG) system and the introduction of a KDIGO-based treatment bundle. Teprasiran, a new P2Y12 receptor antagonist, was found to significantly reduce the frequency and severity of AKI. The results of this review further highlight the significance of customized preventative measures and risk stratification.

Conclusion: Acute kidney injury is a significant complication following cardiac surgery, with considerable variability in its incidence and associated risk factors. Implementation of preventive strategies is crucial in mitigating AKI-related morbidity and mortality. Further research is warranted to optimize patient outcomes and healthcare resource utilization in this population.

Acute Kidney Injury (AKI) is a prevalent and frequently encountered complication following cardiac surgery, presenting a significant challenge to patient recovery and prognosis owing to its association with amplified morbidity, mortality, and prolonged hospital stays. CSA-AKI is characterized by an abrupt worsening in kidney function following cardiac surgery as demonstrated by a reduction in the glomerular filtration rate. These patients often have risk factors for kidney disease, such as diabetes, hypertension, and hypercholesterolemia. In addition, cardiac surgery is a major surgical procedure which may contribute to an increased risk for AKI. Susantitaphong et al reported that CBP-associated AKI was associated with an 8-fold increase in mortality in a subgroup analysis within a global incidence study of AKI, based on results from 23 studies [1]. A recent meta-analysis reported that irrespective of the diverse criteria used to define AKI, its occurrence following cardiac surgery is consistently correlates with a 2-4 times higher likelihood of early mortality among patients [2]. The RIFLE criteria defined AKI by a 25% reduction in GFR (this was equated with a 50% increase in creatinine level or low urine output [3]. The AKIN definition reserved the urine output criterion of the RIFLE definition, dropped the change in GFR per se, and altered the creatinine definition such that a small increase of 0.3 mg/dL also could diagnose AKI. The AKIN definition also reduced the time over which AKI was to be diagnosed from 7 days to 48 hours [4]. The KDIGO definition united RIFLE and AKIN by allowing the relative change of 50% in creatinine level to be over 7 days, whereas absolute change is restricted to 48 hours [5].

The intricate interplay of multifactorial mechanisms, including reduced cardiac output, ischemia-reperfusion injury, renal vasoconstriction, nephrotoxic results like Cardiopulmonary bypass-induced systemic inflammatory response leading to interstitial inflammation and coagulopathy, and patient specific risk factors, contributes to the development of AKI in this setting [6]. Despite advancements in surgical techniques and perioperative care, the incidence of AKI following cardiac procedures remains substantial, impacting patient outcomes, length of hospital stays, and healthcare costs. Studies have reported the risk factors for AKI, for example, female gender, reduced left ventricular function, the presence of congestive heart failure, diabetes, chronic obstructive pulmonary disease, and elevated preoperative serum creatinine [7]. A meta-analysis of 307 studies involving 1200 patients, reported that plasma NGAL (pNGAL) can be considered to be a sensitive and specific early marker of AKI and can be detected up to 48 h before a diagnostic rise in serum creatinine [8]. Greenwood et al reported that pulse wave velocity, a non-invasive measurement tool to assess arterial stiffness, has been shown to predict kidney disease progression, and cardiovascular and all-cause mortality in patients with chronic kidney disease [9].

CSA-AKI increases the risk of death during admission, which can increase to 50% when there is a need for RRT. In 2017, Legouis D et al. studied a cohort of 4,791 patients and found that the risk of CKD was higher in patients who had experienced CSA-AKI than in the AKI-free population [10]. In the absence of precise biomarkers, it seems that even a mild instance of AKI can lead to a poorer prognosis concerning the likelihood of developing CKD and long-term survival in patients. Therefore, it might be more beneficial to prevent, and detect AKI risks rather than focusing solely on a cure. This becomes especially crucial when taking into account the 2009 NCEPOD, which reported that 30% of cases of AKI were preventable and identified a deficiency of care in 50% of cases [11]. Despite published studies detailing the link of CBP-associated AKI and unfavorable outcomes, there have been few attempts to systematically summarize the prognostic consequences of AKI. This review aims to explore the multifactorial etiology, risk factors, and preventive strategies associated with AKI post-cardiac surgery. Understanding these intricate facets is vital in developing targeted interventions to mitigate the incidence of AKI, ultimately benefitting patient care and reducing the load on healthcare systems.

This Comparative study was performed in accordance with published guidelines for systematic review, analysis, and reporting for meta-analysis of Observational studies.

Literature Search Strategy

A comprehensive search was done by the investigators in PubMed, Google Scholar and Scopus using appropriate subject headings and keywords. After an extensive search process, studies from all over the world focusing on Preventive Strategies of AKI and their outcomes were selected. The reference lists of included studies and relevant reviews were manually searched to avoid missing relevant studies. All identified articles were systematically assessed using the inclusion and exclusion criteria. All the selected studies were carefully reviewed once again individually by the team of investigators and then 23 studies matching inclusion criteria were shortlisted for the final comparison. Investigators independently reviewed the retrieved articles and evaluated the quality assessment. All data regarding the articles retrieved were entered into Excel software.

Inclusion and Exclusion Criteria

Various articles related to Acute Kidney Injury following Cardiac Surgery were searched through PubMed, Google Scholar, and Scopus. Studies concentrating on preventive strategies of Acute Kidney Injury (AKI) were shortlisted.

The following articles were excluded from the study: 1) Abstracts 2) Studies in non-English Language Literature 3) Animal studies 4) Studies published before 2000.  All other standard studies in English Literature dated from 2000 to 2023 were included. All analyses were based on previously published studies; thus, no ethical approval and patient consent are required. The reviewers performed independent manual screening of all the articles by firstly the titles/abstracts and secondly the full texts. Besides, other relevant literature and references of the included studies were also manually screened.

Data Extraction

Four independent review authors extracted relevant study characteristics and outcomes from the 23 included studies using a standardized and piloted data extraction form. The information collected from each study included: Name of the Study, Author details, Citation, year of Publication, Study design, Methodology used, Results, Preventive strategy used, Conclusion and Limitations of the study. The collected data were thoroughly reviewed again, and the information was cross verified again to prevent any mistakes during data processing. All the collected data were pooled together and the preventive strategies of AKI from all the studies were analyzed and reviewed.

Quality Assessment

Two independent reviewers assessed study quality according to criteria outlined by Downs and Black using the 27-point checklist included within 5 main sections.

The five sections include questions about:

1. Reporting (10 items);

2. External validity (3 items);

3. In- ternal validity/Bias (7 items);

4. Confounding (selection bias) (6 items);

5. Power of the study (1 item).

Studies were graded as excellent quality if their score was between 24-28 points, good if between 19-23 points, fair if between 14-28 points and poor if less than 14 points.

Outcome Measures

The primary outcome measure for this systematic review is the incidence of acute kidney injury (AKI) following cardiac surgery, categorized according to severity stages outlined in the kidney disease: Improving Global Outcomes (KDIGO) guidelines. Secondary outcome measures include evaluating risk factors associated with AKI, assessing preventive strategies' efficacy, analyzing short and long-term clinical outcomes post-AKI, exploring the utility of biomarkers, assessing healthcare resource utilization, documenting adverse events, and performing subgroup analyses to identify potential sources of heterogeneity.

Screening

Of 1849 potential studies, 1338 were excluded because they did not assess patients or had titles and abstracts that were not related to the purpose of this review, 82 were excluded because they were duplicates and 33 records were marked as ineligible by automation tools. After careful screening of the remaining 396 articles, 363 were excluded since they fail to meet the inclusion criteria. The 23 retrieved studies were assessed for eligibility. This review is based on the remaining 23 studies that fully met the inclusion criteria.

Table 1: Characteristics of The Studies Included in The Systematic Review.

The Overall risk of the included studies was found to be low. Table 2 shows the RoB assessments of individual studies. The mean RoB score was calculated to be 18.29. The mean difference of each study was calculated. Osterholt [10] was found to have the lowest mean difference of -3.7 and the highest RoB score of 22.

Table 2: ROB Using ROBIS Tool.

Tabulation of mean difference and confidence intervals.

Acute kidney injury (AKI) remains a significant and frequently encountered complication following cardiac surgery, presenting a formidable challenge to patient recovery and prognosis. This systematic review underscores the substantial burden of cardiac surgery-associated AKI (CSA-AKI), with reported incidence rates ranging from 14% to 50percentage across the included studies [8,13,19]. This variability likely arises from the heterogeneity in patient characteristics, surgical procedures, and diagnostic criteria employed. Nonetheless, these findings align with previous meta-analyses and large-scale observational studies, collectively highlighting the pervasive nature of this complication and the urgent need for effective preventive and therapeutic interventions [1,2]. Finding targeted treatments for CSA-AKI is extremely difficult due to its complex etiology, which includes ischemia-reperfusion injury, inflammation, oxidative stress, and hemodynamic disturbances. With varying degrees of success, a number of pharmacological treatments targeted at reducing these underlying mechanisms were assessed. Vitamin C, aminophylline [1], N-acetylcysteine, selenium [18], and vitamin C were among the agents that did not show a discernible decrease in the incidence or severity of AKI. These results are in line with earlier systematic reviews and meta-analyses [3,4], indicating that these medications might not be able to sufficiently address the intricate pathophysiological mechanisms driving CSA-AKI. On the other hand, encouraging outcomes were noted when dexmedetomidine, a highly selective α2-adrenergic receptor agonist, was administered during surgery [8]. According to Cho et al.'s study, the dexmedetomidine group had reduced incidence and severity of AKI, which may have been caused by the drug's pleiotropic effects, which include anti-inflammatory, anti-apoptotic, and Reno protective qualities [5]. Reno protective properties of dexmedetomidine are demonstrated by its ability to reduce ischemia-reperfusion injury and inflammatory cascades related to heart surgery.

Two promising non-pharmacological strategies to reduce CSA-AKI are the use of a revolutionary renal guard (RG) system [15] and the introduction of a KDIGO-based treatment bundle [11]. Moderate to severe AKI patients were significantly reduced as a result of the treatment bundle, which included strategies like avoiding nephrotoxic substances, optimizing fluid management, and initiating renal replacement therapy as soon as possible. This result emphasizes how crucial it is to implement multidisciplinary care protocols and evidence-based standards in order to improve renal outcomes. Comparably, the RG system showed a decreased incidence of AKI and enhanced urine production. The RG system was created to lessen the hemodynamic and inflammatory insults associated with cardiopulmonary bypass (CPB). Larger, multicenter trials should be conducted to confirm the clinical value and cost-effectiveness of this innovative technology, as these encouraging results demand for. Teprasiran, a new P2Y12 receptor antagonist, was found to significantly reduce the frequency and severity of AKI [20]. This is a noteworthy finding from the review. When adenosine diphosphate (ADP) activates the P2Y12 receptor, which is present on platelets and different types of vascular cells, it plays a crucial part in thrombosis and inflammation [7]. Teprasiran may have Reno protective effects by blocking this receptor, which would lessen the inflammatory cascade and microvascular dysfunction linked to CPB. These results underline the possibility of targeted therapeutics regulating this system and are consistent with the increasing understanding of the role of purinergic signaling in AKI development.

Because novel biomarkers like urine NGAL, plasma NGAL (pNGAL), and the urinary [TIMP-2] × [IGFBP7] product are predictively beneficial in identifying people at risk, there is hope for early intervention and prevention of CSA-AKI [8,9,22,23]. These indicators have demonstrated improved diagnostic efficacy when compared to traditional markers such serum creatinine, enabling the early detection of renal disease. By identifying high-risk individuals early on, appropriate preventive interventions and tighter monitoring can be put in place, potentially delaying the onset and severity of AKI. Meersch et al.'s work [23] further highlighted the potential clinical utility of urine [TIMP-2] × [IGFBP7], as it showed the ability to predict both the development of AKI and renal recovery. The results of this review further highlight the significance of customized preventative measures and risk stratification. Wetz et al.'s study [6] showed that sodium bicarbonate therapy is effective in lowering the incidence of AKI, especially in low-risk patients after heart surgery. On the other hand, patients who are more likely to develop AKI may benefit more from short-term calorie restriction, according to research by Grundmann et al. [9]. These results are consistent with the increasing awareness that, considering the variety of risk profiles and underlying comorbidities of patients undergoing heart surgery, a "one-size-fits-all" strategy may not be the most effective in reducing CSA-AKI. Customizing preventative measures according to personal risk evaluations could improve their efficiency and best use of available resources. There is ample evidence of the negative effects of CSA-AKI, such as higher mortality, longer hospital admissions, and higher healthcare expenditures; yet, one major obstacle continues to be the lack of consistently effective therapies. This gap emphasizes the necessity of investigating new therapeutic targets and strategies in addition to gaining a better knowledge of the intricate pathophysiological mechanisms underlying the development of AKI in the setting of cardiac surgery.

Future studies could examine targeted therapeutics that modulate particular pathways implicated in the pathophysiology of CSA-AKI, such as the purinergic signaling system that Teprasiran targets. Furthermore, more research is necessary to fully understand the significance of cutting-edge therapeutic approaches including gene therapy and cell-based therapies in the prevention and treatment of CSA-AKI. Although the administration of allogeneic mesenchymal stem cells was not shown to be effective in the trial by Swaminathan et al. [4], it does show that cell-based therapies have the capacity to modulate the inflammatory and regenerative processes involved in AKI. Moreover, the incorporation of innovative biomarkers and risk assessment instruments into clinical decision-making algorithms could expedite the execution of customized preventive and therapeutic approaches. Early identification of high-risk patients and customized interventions based on individual risk profiles may enhance treatment outcomes and the efficacy of preventive measures. The research conducted by Gocze et al. [22] and Meersch et al. [23] offers valuable perspectives on the possible use of the urinary [TIMP-2] × [IGFBP7] biomarker in risk assessment and renal recuperation tracking, respectively. Finally, this systematic review offers a thorough summary of the state of CSA-AKI today, emphasizing the problems that still need to be solved and possible directions for further investigation. The lack of consistently effective medicines highlights the need for ongoing research efforts, even if a number of interventions and methods, like the injection of dexmedetomidine, KDIGO-based treatment bundles, novel biomarkers, and targeted medications like Teprasiran, have showed promise. To reduce the significant burden connected with this consequence and enhance patient outcomes, it is imperative to clarify the intricate pathophysiological mechanisms underlying CSA-AKI and create tailored, focused preventative and therapy strategies.

Variability in study designs, patient populations, and interventions across included studies may contribute to heterogeneity. Despite quality assessment, the variability in methodological quality among included studies introduce bias and affect the robustness of the findings. The findings of the systematic review may not be fully generalizable to all patient populations or healthcare settings. The availability of high-quality interventional studies targeting AKI prevention or management post-cardiac surgery were limited, potentially restricting the ability to make firm recommendations for clinical practice.

In conclusion, this systematic review sheds light on the significant burden of acute kidney injury (AKI) following cardiac surgery, emphasizing its detrimental impact on patient outcomes and healthcare systems. Despite advancements in surgical techniques and perioperative care, the incidence of AKI remains substantial, necessitating targeted interventions to mitigate its occurrence. While pharmacological agents such as aminophylline, vitamin C, and selenium did not demonstrate significant efficacy in reducing AKI, promising results were observed with dexmedetomidine administration, the use of renal guard systems, and implementation of KDIGO-based treatment bundles. Furthermore, novel therapeutics like Teprasiran show potential in reducing the frequency and severity of AKI, providing hope for targeted interventions to alleviate the inflammatory cascades and microvascular dysfunction associated with cardiac surgery. Additionally, the identification of early biomarkers such as urinary NGAL and [TIMP-2] × [IGFBP7] offers opportunities for early intervention and preventive strategies, enabling clinicians to identify high-risk individuals and initiate timely interventions. Overall, this review underscores the complexity of AKI pathophysiology, the need for multidisciplinary approaches, and the importance of evidence-based standards in improving renal outcomes post-cardiac surgery. Future research should focus on conducting larger, multicenter trials to validate the efficacy and cost-effectiveness of innovative technologies and therapeutic interventions, ultimately enhancing patient care and reducing the burden of AKI on healthcare systems.