To the best of our knowledge, this study exploited the largest cohort of elderly patients to estimate the postoperative AKI risk following liver resection surgery. Comprehensive information from consecutive 850 patients with hepatic resection over the past eight years was thoroughly reviewed and analyzed. The results provided previously unexplored insights for exploring the potential therapeutic strategies for renal function protection in adults, especially elder subjects, in peri- and postoperative conditions.
Summary of key findings
The present study summarized the incidence rates, predictors, and mortality impact of AKI in an elderly population following liver resection surgery. Our findings indicated that the prevalence of postoperative AKI was high (18%) among older populations with any of the three different categories of liver resection, and associated with six-fold increased mortality rates compared with no occurrence of AKI, corroborating results from previous studies by Lim et al. [3] and Slankamenac et al. [17]. Furthermore, a predictive nomogram for postoperative AKI was established and subsequently validated with seven predictors readily available in clinical situations. A simple risk score scale was also developed based on the seven predictors, which predicted AKI as accurately as the nomogram and was more easily accessible in clinical use. Depending on this approach, we can speculate that the nomogram together with risk score assessment can help optimize decision-making in predicting and preventing postoperative renal dysfunction.
Predictors for postoperative AKI
Several prediction models for postoperative AKI have been developed in noncardiac surgeries [4, 17, 26]. Although AKI occurred in about 20% of patients following liver surgeries, the prediction of AKI in this subgroup population had been rarely concerned. Slankamenac et al. [17] have developed and validated a prediction score system for postoperative AKI in adult patients scheduled for liver resection. However, the model obtained from preoperative factors alone was subject to debate for accurately predicting postoperative AKI. Since postoperative AKI prediction can be affected by multiple factors resulting from the interactions between surgery, anesthesia procedure, and intensive care, therefore, therapeutic options to prevent and treat AKI following liver resection should involve pre-, intra-, and postoperative approaches. Considering these facts, Slankamenac et al. have updated their risk prediction models, including three additional intraoperative variables: blood transfusions, hepaticojejunostomy, and oliguria [4]. The updated risk scoring system was superior in identifying patients who would benefit from a special care unit stay in case of AKI onset, compared to the preoperative prediction score.
Based on the previous studies, here we explored the risk factors in elderly patients. Predictors identified in the present study included age, CKD, NSAIDs medication, direct bilirubin count, intraoperative hepatic inflow occlusion, the volume of blood loss, and transfusion. Thus, optimization of controllable factors such as preoperative renal dysfunction, NSAIDs usage, and blood transfusion due to substantial surgical bleeding may benefit patient’s survival outcomes. Surgical variables such as intraoperative hepatic occlusion and blood loss remained significant predictors of postoperative AKI. A possible explanation could be the complexity of the procedures needed for hepatic inflow occlusion, the requirement of extensive hepatic excision, and severe blood loss [27, 28].
In this context, minimization of surgical trauma and bleeding were fundamental protective strategies for renal conservation and also equally crucial to restore liver function and minimize resection extent. Inflammatory responses to surgical stress and trauma lead to tubular injury and subsequent development of AKI, potentially due to microcirculatory dysfunction, oxidative stress, and endothelial cell injury [29]. This group of patients should be given special attention because of their exceptionally high-risk exposure to perioperative procedures. Reducing the duration of hepatic occlusion has been shown to be favorable to control trauma and alleviate ischemia-reperfusion injury [30], which might contribute to the risk of renal injury mediated by inflammatory mediators and microcirculatory dysfunction [31].
Low CVP was required during the hepatectomy to reduce bleeding complications and mortality. Hughes et al. [32] have consolidated reduced blood loss and transfusion requirement by maintaining CVP below 5 mmHg, by intravenous fluid restriction, and by applying diuretics. At the same time, the resultant hypovolemia and oliguria may increase the risks of renal impairment, as demonstrated by Myles et al. [5] in a study comparing restrictive and liberal fluid administration. Historically, whether restrictive or liberal fluid therapy benefits outcomes remained controversial. Surgeons expect a very low CVP, while anesthesiologists argue against the low fluid load. The prolonged fluid restriction may lead to possible renal hypoperfusion with resultant oliguria. Vasopressors to correct hypovolaemia could further aggravate oliguria. Therefore, the urine output criterion may result in an overestimation of AKI [33]. It has been suggested that intraoperative urine output of 0.3 ml/kg/h was the optimal threshold for oliguria, nevertheless a moderate association and poor predictive value for postoperative AKI [34-36]. In the present study, we found that postoperative AKI was associated with high urine output and more employment of diuretics. Numerous studies have established the negative bearing of diuretics usage in AKI in major abdominal surgeries [37]. However, the relationship between the predictive value of diuretics and urine output in AKI remained to discuss, and further studies are needed to confirm the associations.
Preoperative CKD is the most important patient-related risk factor. It was not a new finding regarding the associations between CKD and postoperative AKI and death. While Chaudery et al. [8] has illustrated that in patients with a history of previous CKD, low estimated GFR does not markedly increase the mortality in the absence of AKI, highlighting AKI is likely to be a pivotal event connecting preoperative CKD and survival outcomes.
Several studies have implied a higher risk resulting from disrupted renal autoregulation due to NSAIDs usage during the perioperative period [38, 39]. NSAIDs inhibit cyclooxygenase activity and reduce prostaglandin secretion, resulting in tubular toxicity, renal vasoconstriction, decreasing renal blood flow, and low GFR. A systemic review conducted by Lee et al. [40] has demonstrated that NSAIDs may cause a clinically transient reduction in renal function in the early postoperative period in patients with normal preoperative renal function. Therefore, it is reasonable to minimize the nephrotoxic NSAIDs exposure in elderly patients concerning postoperative renal function, especially in the case of those with persistent renal dysfunction.
Implications for research priorities
Previous studies have indicated that preoperative hepatic dysfunction predisposes a patient to more medical complications such as renal insufficiency [3, 17]. Despite the multiple potential mechanisms necessitating further investigation, no effective treatment is available so far for this syndrome, apart from prophylactic measures. More importantly, it is critical to introduce close surveillance to raise early alarms for renal deterioration.
The application of novel biomarkers as clinical approaches for detecting early renal injury has been a matter of intense research. Though several biomarkers have been found promising in predicting postoperative AKI, the evidence has been controversial [41, 42]. For example, neutrophil gelatinase-associated lipocalin (NGAL) is not present in normal urine and plasma, and can be detected in urine during ischemic renal injury. Mishra et al. [43] have observed elevated NGAL in cardiac surgery-associated AKI within 2 hours and sustained high levels up to 24 hours. Inconsistent with these findings, subsequent studies in non-cardiac surgical cases have failed to correlate an association between NGAL and AKI onset [44, 45]. Urinary tissue inhibitor of metalloproteinases-2 and insulin-like growth factor-binding protein 7 (TIMP2•IGFBP7) ratio has been proved to accurately detect high-risk surgical patients and enhance clinical prediction for imminent AKI [46]. These findings were further confirmed by Gocze et al. [47] in a randomized clinical trial evaluating the biomarker-triggered implementation of the KDIGO care bundle to prevent AKI. The study suggests that urinary TIMP2•IGFBP7 > 0.3 successfully allows for early initiation of renal protective interventions. Before these biomarkers are available in clinical settings, intense research is needed to explore the combined biomarker panels with agreeable predictive sensitivity and specificity.
It is of interest to develop target strategies for close monitoring of renal function. Previous studies have suggested that persistent intra- and postoperative low regional oxygen saturation (rSO2) can be associated with postoperative renal dysfunction [48]. Unlike biomarkers, renal oxygenation measured by near-infrared spectroscopy (NIRS) enables noninvasive and real-time monitoring of renal function, indicating earlier alarms of renal injury than biomarkers such as NGAL. These potential targets are capable of implementing effective interventions to optimize renal function. Whether intraoperative renal desaturation predicts AKI and survival in noncardiac surgery remains to be investigated in our future studies.
Strengths of the study
The present nomogram and risk score assessment approach a landmark toward identifying strategies to reduce the prevalence of AKI following liver resection surgery. The general overview of the main highlights of this study is as follows. Firstly, we reviewed all relevant and eligible cases, acquired a few missing pieces of information. The large sample cohort allowed us the development and validation of a predictive model. Secondly, the estimated GFR was selected as a better predictor of outcome to define preexisting renal dysfunction instead of serum creatinine level. Thirdly, advanced statistical techniques such as the stepwise regression method increased the accuracy and applicability of the model. Finally, the simple summary risk score could be used to rapidly identify patients at high risk of developing AKI at the bedside without complex computation.
The prediction model was superior to the previous models, owing to the introduction of intraoperative variables. Notably, a patient assessed as the moderate risk of AKI preoperatively could still experience severe renal dysfunction mediated by the surgical insults (such as extended procedures and massive blood loss), which remained paramount in influencing renal function. Thus, it is considered to integrate risk scores with pre- and intraoperative parameters available throughout the entire perioperative process to precisely evaluate the risk of postoperative AKI.
Our findings shed light on a particular challenge faced by medical staff, including surgeons, anesthesiologists, and intensive care providers, which signify growing concerns that: (1) the incidence and prevalence of postoperative AKI is increasing as the number of the elderly population undergoing surgical procedures increases due to the aging population, proposing socio-economic and public health burdens; (2) early identification of AKI high-risk patients cannot be overemphasized to reduce the burden of postoperative complications and eventually the risk of death; (3) development of continuous surveillance (early identification) for renal dysfunction should be strengthened so that effective interventions could be started early rather than delayed.
Therefore, our attempts sought to provide a novel understanding of the disease to establish preventive strategies in perioperative patients, and promote potential targets for optimizing renal function in prospective clinical trials.