A novel risk factor of contrast associated acute kidney injury in patients after enhanced computed tomography: a retrospective study

Introduction

The application of contrast agents has remarkably increased the sensitivity of medical imaging, however, the intrinsic toxicity of contrast agents can also results in a series of adverse effects, including contrast associated acute kidney injury (CA-AKI). CA-AKI refers to a pathological condition that commonly occurs 48 h after iodine-based contrast exposure, an increase in the level of serum creatinine (SCr) of more than 44.2 umol/l or 25%, compared to the baseline SCr level (Kellum et al., 2012). With the broad application of iodine contrast agent in the field of radiation diagnosis and interventional therapy, the incidence of CA-AKI is still high and did not decrease with time (Lun et al., 2021). Currently, CA-AKI has become the third leading cause of acute renal failure in hospitals after insufficient renal blood perfusion and nephrotoxic drug treatment (Katzberg & Haller, 2006) and became one of the leading causes of iatrogenic renal insufficiency (Nash, Hafeez & Hou, 2002). Quoted rates of CA-AKI vary from 0% to 90% depending on the presence or absence of risk factors such as preexisting renal insufficiency, hypovolemia, the dose and type of radiographic contrast media used, diabetes mellitus, hypertension, advanced age, and concurrent intake of potentially nephrotoxic drugs (Song et al., 2014; Moos et al., 2013; Baker & Baker, 2001). In a meta-analysis of 15,582 patients who received contrast medium, the incidence of CA-AKI was 6.4% (McDonald et al., 2013).

Apart from periprocedural hydration, which seems to reduce but not completely prevent the risk of renal injury following radiographic contrast media (RCM) administration (Jurado-Roman et al., 2015; Solomon et al., 1994; Eisenberg, Bank & Hedgock, 1981), the results of other agents such as dopamine, mannitol, N-acetylcysteine, captoopril and statins are equivocal (Dabare et al., 2013; Weisbord & Palevsky, 2010; Verdoodt et al., 2018). Since there is no available treatment and even a mild 0.3 mg/dl increase of serum creatinine also associated with a 4.3-fold increase in the odds of death, it is urgent to find the valuable risk factors (Chertow et al., 2005). Risk assessment is traditionally based on the calculation of estimated glomerular filtration rate (eGFR), but it is not precise in the range beyond 60 ml/min. Hence, eGFR is unable to detect mild tubular injury.

The red blood cell distribution width (RDW) is calculated from the ratio of average red blood cell volume to its standard deviation, reflecting the variation degree of red blood cell volume. It is mainly used for differential diagnosis of different types of anemia (Lin et al., 1992). Recent studies have shown that increased RDW correlates with an increased death risk from sepsis, chronic heart failure, coronary heart disease, stroke and many other diseases (Kim et al., 2013; Felker et al., 2007; Tonelli et al., 2008; Ani & Ovbiagele, 2009). Some recent studies have indicated that RDW is an independent predictor (Zbierska-Rubinkiewicz et al., 2017; Mizuno et al., 2015) of acute kidney injury (AKI) after the percutaneous coronary intervention (PCI), but there is no report about the relationship between RDW and CA-AKI after enhanced CT. Hence, the aim of this study was to explore the novel risk factors for CA-AKI after enhanced computed tomography (CT) and analyze whether RDW can be used as an early predictive factor of CA-AKI after enhanced CT.

Materials & Methods

Results

The value of RDW in predicting CA-AKI after enhanced CT

ROC curve showed that the area under the curve (AUC) for RDW predicting CA-AKI after enhanced CT examination was 0.803, and with 13.85% as the cut-off point, the sensitivity and specificity of RDW in predicting CA-AKI after enhanced CT examination were 72.00% and 75.80%, respectively (Fig. 1). However, RDW improved the prediction of CA-AKI over eGFR with an AUC of 0.765 (95% CI [0.70–0.83] (Fig. S1).

Discussion

Enhanced computed tomography is a scanning method by injecting an iodine contrast medium into the body quickly, which can show the scope and characteristics of lesions more clearly to improve the accuracy of imaging diagnosis. There are few studies on CA-AKI after enhanced CT examination. Fukushima et al. (2017) found that cardiac dysfunction and ICU admission may be risk factors for CA-AKI in patients with preexisting renal dysfunction. When the serum creatinine increased to ≥ 44 µmol/L or increased by >25% in two days, or the creatinine clearance decreased by >25% compared with that before using the contrast medium, it was considered CA-AKI, with an incidence of 22.1%. In this study, 632 patients undergoing enhanced CT examinations were included, 25 of which suffered from CA-AKI, with an incidence of 3.96%. It is acceptable based on the following reasons: (1) patients in various age groups were included. (2) nonionic low-osmolar contrast was used in all the patients undergoing enhanced CT, and most of them had a normal renal function. (3) The subjects were hospitalized patients, and it was relatively easy to evaluate renal function before the examination; therefore, CA-AKI was largely avoided.

CA-AKI is one of the leading causes of acute renal failure in hospitals. Although during the administration of isotonic contrast medium, the evaluation of renal function before enhanced CT and the implementation of preventive measures, such as adequate hydration, can reduce the incidence of CA-AKI after enhanced CT, it is still a significant complication after enhanced CT examinations. Hence, it is imperative to determine the predictive factors of CA-AKI. In this study, the median RDW value of the CA-AKI group was 15.10%, which was significantly higher than that of the non-CA-AKI group (13.40%). The reference range of RDW in this hospital is 0–15%. Multivariate analysis revealed that baseline RDW was positively correlated with the development of CA-AKI after enhanced CT examination, in line with findings of previous studies (Zbierska-Rubinkiewicz et al., 2017; Yamazoe et al., 2016). In this study, the ROC curve was employed to further evaluate the predictive ability of RDW for CA-AKI after enhanced CT. The results showed that AUC was 0.803. When 13.85% was considered the cut-off point, the sensitivity and specificity for CA-AKI prediction were 72.00% and 75.80%, respectively, indicating that RDW could better predict the development of CA-AKI after enhanced CT, consistent with the results reported by Akin et al. (2015).

The etiology of CA-AKI is complex. Some studies have reported that the cause is the direct toxic effect of the iodine contrast medium. The medium can aggravate the existing renal dysfunction; therefore, chronic renal insufficiency is an independent risk factor of CA-AKI, with eGFR <60 mL⋅ min-1⋅ (1.73 m²)⁻¹ as the risk threshold for CA-AKI. Kim et al. (2010) followed up the patients with CA-AKI after CT examinations in CKD (chronic kidney disease) stages 3 to 5 and found that the proportion of renal replacement therapy in patients with CA-AKI increased in the subgroup with eGFR <30 mL⋅ min-1⋅ (1.73 m²)⁻¹. Therefore, it was considered that eGFR <30 mL⋅ min-1⋅ (1.73 m²)⁻¹ was a predictive factor of renal replacement therapy after CA-AKI. Multivariate logistic regression analysis showed that the baseline eGFR was negatively correlated with CA-AKI after enhanced CT examination, while the correlation between baseline serum creatinine and CA-AKI was not statistically significant. Currently, eGFR is the most commonly used indicator of renal function in clinical practice. Therefore, eGFR should be used to evaluate renal function before enhanced CT examinations. After PSM of baseline data, the results showed that baseline RDW was positively correlated with CA-AKI after enhanced CT.

Some other studies suggest that the pathogenesis of CA-AKI is related to inflammatory reactions, immune responses, and oxidative stress mediated by the iodine contrast medium. Inflammatory reactions and oxidative stress play an essential role in the development of CA-AKI (Mehran et al., 2004; Shaker, El-Shehaby & El-Khatib, 2010; Huang et al., 2021).

Systemic inflammation increases kidney vulnerability to the local inflammatory processes that are elicited by contrast medium reabsorption. Contrast medium causes the damage of renal endothelial and tubular epithelial cells, triggers the generation of various cytokines and chemokines, then induces the recruiting of inflammatory cells into the kidney (Akcay, Nguyen & Edelstein, 2009). In recent years, some studies have shown that RDW is correlated with inflammatory reaction indexes (C-reactive protein and erythrocyte sedimentation rate) (Lippi et al., 2009), and pro-inflammatory factors, such as tumor necrosis factor- α (TNF-α) and interleukin-6 are positively correlated with RDW (Semba et al., 2010). The mechanism for an increase in RDW caused by inflammatory reactions might be related to the functions of inflammatory factors in reducing the sensitivity of bone marrow erythroid stem cells to erythropoietin stimulation, inhibiting their anti-apoptosis and promoting maturation (Patel et al., 2009). Inflammatory cytokines inhibit the maturation of red blood cells, resulting in the migration of immature red blood cells into the circulation, different sizes of red blood cells, and increased RDW. This study is retrospective and does not include inflammatory reaction indexes such as high-sensitivity C-reactive protein, erythrocyte sedimentation rate, and interleukin-6. To further explore the mechanism for the development of CA-AKI after enhanced CT, it is necessary to expand the sample size and detect the corresponding inflammatory factors. Second, some studies have shown that CA-AKI is due to oxidative stresses, which can increase the fragility of red blood cells (Tozzi-Ciancarelli et al., 1989), reduce their maturation rate (Marinkovic et al., 2007), shorten their survival time, and increased RDW. Therefore, an increase in RDW might indicate oxidative stress. Furthermore, the RDW value can reflect the nutritional status of patients. The results of this study showed that the RDW value of the CA-AKI group was higher, and its albumin level was lower. The binary logistic regression analysis showed that albumin level was negatively correlated with the development of CA-AKI after enhanced CT examinations because severe hypoproteinemia can lead to insufficient effective renal perfusion pressure and further result in CA-AKI.

There are some limitations in our study. First, the study was a single-center retrospective study with a small sample size, so multi-center investigations with larger sample sizes of enhanced CT cases need to be performed in the future. Second, further studies are needed to explore the association between RDW and hypoproteinemia. Third, relevant inflammatory factors should also be detected to further explore the mechanism for CA-AKI after enhanced CT examinations.

Conclusion

In conclusion, we found that higher RDW could be independently associated with the risk of CA-AKI in patients undergoing enhanced CT examinations. This finding suggests that RDW presents a good predictive value and can be used as an early warning marker for CA-AKI after enhanced CT examination.

Supplemental Information