CSA-AKI is a severe complication in adult patients undergoing cardiac surgery with CPB, resulting in prolonged ICU stay and increased short-term and long-term morbidity. Several processes to reduce CSA-AKI incidence have been established, and the efficacy of ulinastatin has been examined in recent years[3, 9]. In the present study, we found that ulinastatin significantly reduced the incidence of CSA-AKI diagnosed according to the KDIGO criteria. In our study, the incidences of AKI were 20.00% in the ulinastatin group and 32.40% in the control group, consistent with the findings in recent studies. Nakanishi et al. demonstrated that ulinastatin administered before CPB could decrease postoperative elevation of IL-6 and IL-8 in patients undergoing cardiac surgery with CPB, while Song et al. found that ulinastatin has no effect on attenuation of IL-6, TNF-α, and improvements in renal function. Wang et al. . Indicated that ulinastatin could reduce inflammation and dose dependently attenuate CPB-induced kidney injury in infant piglets. Wan et al. performed a propensity score-matched study and showed that administration of ulinastatin during CPB is associated with a lower incidence of CSA-AKI. Other studies have indicated that ulinastatin can inhibit polymorphonuclear neutrophils, which is helpful to reduce the risk of bleeding and the requirement for blood transfusion after surgery[14, 15]. Although AKI is a complex pathophysiological process rather than a specific syndrome, especially following cardiac surgery, SIRS arising after cardiac surgery plays a pivotal role in AKI development[17, 18]. The pathogenesis of SIRS is associated with multiple factors, including surgical trauma, transfusion, hypothermia, blood loss, ischemia-reperfusion injury, immune system activation, and endotoxemia. Ulinastatin has anti-inflammatory properties by inhibiting the activation of various inflammatory pathways[14, 20, 21]. Thus, serum IL-6 levels were evaluated in this study and found to be significantly lower in the ulinastatin group compared with the control group (p=0.001; Figure 2c). The effect of ulinastatin on reducing CSA-AKI is considered to involve the inhibition of inflammation.
Evidence suggests that the KDIGO criteria are superior to other criteria, but have less sensitivity to detect early-stage tubular damage. The KDIGO criteria are based on the SCr level for diagnosis of AKI, and changes in SCr often occur 48 hours to 7 days after the original damage. Furthermore, SCr levels are affected by many related factors, and rescue interventions may be too late to prevent early perioperative AKI. These limitations drive us to search for new biomarkers that reflect early AKI. In addition to the KDIGO criteria, pNGAL, a newly discovered biomarker, was tested to predict kidney injury and prove previous findings. NGAL plays a role in the early detection of AKI and can be upregulated at an earlier stage than elevation of SCr to meet the KDIGO criteria. NGAL in plasma and urine is upregulated when acute tubular damage occurs, but pNGAL is detectable earlier than uNGAL when tubular damage occurs. In a previous study, pNGAL was used to predict AKI based on the CSA NGAL Score, and the results were proven to be similar to those based on the KDIGO Score. According to the KDIGO criteria and CSA-NGAL Score criteria, the incidences of CSA-AKI were similar in the present study. However, according to the CSA-NGAL Score criteria, 48 (35.60%) patients in the ulinastatin group and 77 (27.70%) patients in the control group were in the region of possible tubular damage, so-called subclinical AKI that is a separate entity and provides a warning to trigger awareness and appropriate clinical therapeutic modifications.
Respiratory failure in the present study was defined as prolonged ventilation support for more than 48 hours. The findings demonstrated that ulinastatin could reduce the incidence of respiratory failure, consistent with previous studies. Xu et al. suggested that ulinastatin inhibits the release of proinflammatory cytokines and PMNE, reduces pulmonary injury, and improves pulmonary function after CPB, thereby shortening the intubation time and length of ICU stay. The lung-protective effect of ulinastatin is dose dependent and a lower-than-effective dose could lead to negative results.
The survival rate after ten years of follow-up did not differ significantly between the two groups. According to previous studies, the effect of ulinastatin may be diminished depending on the duration of administration, which is ascribed to the fact that ulinastatin is administered through a bolus injection rather than a continuous infusion. Another reason is that the half-life of ulinastatin is about 40 minutes in healthy adults, while the duration of CPB is often longer than 40 minutes and the peak of IL-6 occurs at 4–6 hours postoperatively. A meta-analysis showed that ulinastatin could reduce inflammatory cytokines but does not affect hospital mortality.
There are some limitations to the present study. First, the study was designed as a single-center prospective cohort design with less power than a randomized controlled trial. The rationale lay in the sparse evidence concerning the effect of ulinastatin on renal outcomes and the nature of a pilot study. It was in accordance with ethical considerations to conduct an observational study rather than an interventional study. Second, there were relatively high rates of loss to follow-up, comprising 14.20% (19/134) in the ulinastatin group and 14.10% (39/277) in the control group. It was a great challenge to achieve follow-up for as long as ten years. Nevertheless, the rates of loss to follow-up were comparable between the two groups and associated with less bias. Third, only SCr was evaluated for the AKI criteria in the present study. The urine output in the KDIGO criteria requires a state of oliguria or anuria lasting for more than 6, 12, or 24 hours, which was infeasible in postoperative ICU settings. For ethical considerations, oliguria and anuria would not be observed for such a long period and should be treated according to the institutional protocol promptly. Furthermore, assessment of AKI by SCr alone has been widely accepted in studies such as the BART study and the ATACAS study.
In the present study, the SCr, pNGAL, and serum IL-6 were detected, and CSA-AKI incidences according to the KDIGO criteria and CSA-NGAL Score criteria were analyzed, of which differed significantly between the two groups, except for SCr. Meanwhile, respiratory failure in the ulinastatin group was considerably lower than that in the control group. In summary, ulinastatin can significantly reduce the incidence of early postoperative AKI during cardiac surgery with CPB without affecting the long-term survival rate.