Influence of contrast media on renal function and outcomes in patients with sepsis-associated acute kidney injury: a propensity-matched cohort study

Contrast media (CM) have long been regarded as a potential risk for nephropathy. Multiple risk factors, including diabetes, sepsis, anemia, hypotension, circulatory insufficiency, and nephrotoxic agents, can increase the risk of contrast-associated acute kidney injury (CA-AKI) [1‐5]. However, the majority of evidence for contrast nephrotoxicity is from cardiology procedures, such as coronary angiography and/or intervention. Performing a controlled study in this situation is difficult because the procedures always require CM. In the critical care setting, several studies have reported that CA-AKI occurs in 11–23% [1‐3, 6‐8] of patients who undergo a radiological examination and is associated with a worse outcome. However, those studies only examined patients who were exposed to CM and did not exclude potential causes other than CM.

Recently, the evidence for CA-AKI has been challenged in several studies, including a meta-analysis, which compared critically ill patients who were scanned with or without radiocontrast enhancement. In these studies, CM exposure was not associated with decreased renal function or an increased incidence of nephropathy in critically ill patients [9‐11]. However, the effects of CM in septic patients, especially those who already have AKI, remain unknown. Patients with AKI are often considered vulnerable to CM nephrotoxicity. Determining whether CM induces further deterioration of renal function is clinically important because physicians often face the dilemma between reliable diagnosis of the infectious source and exacerbation of septic AKI when considering contrast-enhanced examinations. Additionally, whether AKI is the same as chronic kidney disease as a risk factor for contrast nephropathy is undetermined. AKI is a disorder of the proximal tubules, and chronic kidney disease is histologically different from AKI, with nephron injury and fibrosis. Therefore, the risk of AKI for development of CM toxicity for renal function needs to be determined.

The present study aimed to examine the effect of CM on renal function in patients with sepsis who already had AKI. We hypothesize that CM exposure is not associated with deterioration of renal function (DRF) upon sepsis-associated AKI, which was defined as an elevation of serum creatinine (Cr) levels or induction of renal replacement therapy (RRT). We conducted a propensity-matched historical cohort study to investigate the additional DRF and mortality in septic patients with AKI depending on CM exposure.

Of 5857 patients who were admitted to our ICU during the study period, 822 were diagnosed with sepsis, while 483 were excluded according to our exclusion criteria. The remaining 339 patients were included in our study. Of these, 136 (40.1%) patients received CM on the day of admission or within 24 h before admission (Fig. 1). All administration of CM was used for CT scan imaging. No patients used CM for intervention. The characteristics of the unadjusted and propensity score-matched patients are shown in Table 1. Before propensity score matching, patients in the C group had more abdominal or neck infection (62.1% versus 45.9%, P < 0.01, and 9.1% versus 0.5%, P < 0.01, respectively), less thoracic and urinary tract infection (10.6% versus 26.1%, P < 0.01, and 1.5% versus 8.2%, P = 0.01, respectively), and a lower renal Sequential Organ Failure Assessment score (1 (0–1) versus 1 (1–2), P < 0.01) compared with the NC group. Patients in the C group also had lower serum levels of Cr (1.38 mg/dL versus 1.91 mg/dL, P < 0.01), blood urea nitrogen (31.0 mg/dL versus 44.0 mg/dL, P < 0.01), urinary acid (5.4 mg/dL versus 6.4 mg/dL, P = 0.01), and cystatin C (1.58 mg/dL versus 2.01 mg/dL, P < 0.01) and higher hemoglobin (10.5 g/dL versus 9.5 g/dL, P < 0.01) before matching. After propensity score matching, 100 pairs of patients were selected, and almost all significant differences in the patients’ characteristics and laboratory data between the two groups were eliminated.

In the present study, we investigated the influence of CM administration on the outcomes in septic patients with AKI in the ICU. We found that there was no significant further DRF and no additional increase in the induction of RRT in patients with AKI who received CM compared with those who did not receive CM. Further, these results were robust, even in the subgroup of patients with severe renal impairment (AKI stages 2 and 3).

Several recent studies examined the relationship between CM and development of renal impairment in critically ill patients and suggested that the incidence of CM-induced nephropathy was low [4, 19, 20]. Cely et al. [4] reported that decreased renal function was common following contrast-enhanced CT scanning, but that the changes were mostly caused by factors other than contrast exposure itself. Further, in a meta-analysis, Ehrmann et al. [11] found no evidence for the development of AKI attributable to CM in critically ill patients. Our results are relatively similar to these findings, although these previous studies enrolled patients with stable renal function at baseline, while our study patients had already developed AKI before CM exposure. Additionally, we focused on septic patients, who are considered as high risk for decreased renal function. The proportion of patients with sepsis in a recent large study was approximately 30%, which may be insufficient to examine the effect of CM administration in septic patients [10]. Our results provide further support for low CM toxicity in septic patients with AKI. This suggests that withholding CM-enhanced imaging studies may not be necessary when an accurate diagnosis is required, even in patients with decreasing renal function.

There are two main reasons why CM administration was not associated with decreased renal function or a poor prognosis in patients with sepsis-associated AKI. First, the specific additional toxicity of CM may be low [11, 21]. Second, septic AKI has a high recovery rate of renal function. Although septic AKI is strongly associated with worse outcomes, complete recovery of renal function occurs in > 90% of septic patients with AKI, with a mean time for recovery of approximately 10 days [22]. Indeed, 98.0% of patients in the NC group and 100% in the C group were free from chronic hemodialysis at hospital discharge in our study.

The primary outcome of our study was the rate of DRF. We defined DRF as elevated Cr levels and induction of RRT. Because there is no widely accepted definition for the Cr threshold that indicates DRF, we defined the threshold on the basis of the KDIGO criteria [16]. We also analyzed the same data using the Barrett and Parfrey criteria [18] and found no differences in Cr elevation with either diagnostic criteria (data not shown). There was no difference in the RRT induction rate between the two groups in the present study. The rate of RRT introduction in septic AKI was reported as 24–89% [23, 24]. Further, the rate of induction of hemodialysis in the NC group was 26% in the present study, which is similar to that previously reported [23, 24], and suggests no additional effect of the use of CM. We also investigated the short-term and long-term mortality rates as secondary outcomes. Although there were no significant differences in short-term and long-term mortality rates between the two groups, the mortality rates at 28 and 90 days were higher in the NC group compared with the C group.

In clinical practice, physicians are often faced with the difficult decision on whether to use CM for enhanced imaging to evaluate the infectious source in septic patients with severe renal dysfunction. We found no significant effects of CM on major outcomes in a subgroup of patients with AKI stages 2 and 3. These results contrast with the findings of McDonald et al., who found that an increased risk of dialysis was observed in the contrast group patients with an estimated GFR < 45 mL/min/1.73 m² [10]. However, in their study, there was no significant difference in the rate of AKI development between the contrast and non-contrast groups, although the non-contrast group had a greater decrease in serum Cr levels after an unenhanced CT scan. Additionally, our study focused on patients who already had AKI. Therefore, the effects of CM on the changes in Cr levels or induction of RRT would be different between patients with AKI and patients with chronic kidney disease. Future large multicenter studies are required to evaluate this higher risk population with renal insufficiency.

Our study has several limitations. First, because our study was retrospective from a single ICU, the population size was relatively small. There may have been selection bias, and our results may not be generalizable. Nevertheless, prospective studies on the use of CM are ethically difficult [9, 10]. Further multicenter studies on the effect of CM administration in septic patients with AKI may be warranted. Second, propensity score adjustment can only account for measured or known confounders. While our model included 16 clinical covariates, unmeasured confounders may still remain in our study that could affect the patient outcomes. Third, patients in the NC group did not always receive a CT examination. Patients requiring CT may be sicker than other patients [20]. Furthermore, the reasons why CM was not used in patients in the NC group are unknown, although this may relate to confounding factors that were not identified, which may have affected our results. Fourth, our AKI phase data are missing, although we targeted patients with impaired renal function at entry. Therefore, whether AKI was in the recovery or deterioration period is unknown. However, considering that the patients’ background and severity between the two groups were consistent with the propensity score, the phase of AKI was unlikely to be significantly different between the two groups. Fifth, all administration of CM was used for CT scan imaging. No patients received CM for intervention. Our results cannot be adopted for the use of CM for interventional purposes in septic patients with AKI. Additionally, the dose of CM per patient was not available in this study. The use of > 100 mL of contrast is associated with an increased risk of kidney injury [25]. The effect of contrast-enhanced CT using a large amount of CM is unknown. Sixth, we did not have sufficient information on other drugs that may affect renal function, except for vancomycin and aminoglycoside. Finally, because CM administration was mainly performed for examining the infectious source, the prognosis may have been affected by earlier diagnosis in patients with CM. However, the comparison between the groups that used propensity score matching showed no correlation with a poor prognosis in the C group. The reason for withholding the use of CM for accurate diagnosis in our patients remains unclear.

A single administration of CM for a CT scan was not associated with further deterioration of renal function in patients with sepsis-associated AKI. Further, even in patients with a high-risk subset, there was no evidence of adverse effects on renal function or short-term and long-term mortality. Our results suggest that contrast-enhanced imaging should not be avoided in clinical practice if required to evaluate the source of infection.