Distinct patterns of serum and urine macrophage migration inhibitory factor kinetics predict death in sepsis: a prospective, observational clinical study

Abstract

Macrophage migration inhibitory factor (MIF) has been considered as a biomarker in sepsis, however the predictive value of the pattern of its kinetics in the serum and in the urine has remained unclarified. It is also unclear whether the kinetics of MIF are different between males and females. We conducted a single-center prospective, observational study with repeated measurements of MIF in serum and urine on days 0, 2, and 4 from admission to the intensive care unit (ICU) in 50 adult septic patients. We found that in patients who died within 90 days, there was an increase in serum MIF level from day 0 to 4, whereas in the survivors there was rather a decrease (p = 0.018). The kinetics were sex-dependent as the same difference in the pattern was present in males (p = 0.014), but not in females (p = 0.418). We also found that urine MIF was markedly lower in patients who died than in survivors of sepsis (p < 0.050). Urine MIF levels did not show temporal changes: there was no meaningful difference between day 0 and 4. These results suggest that kinetics of serum MIF during the initial days from ICU admission can predict death, especially in male patients. Additionally, lower urine MIF levels can also indicate death without showing meaningful temporal kinetics.

Figure 1

Flow diagram of the study.

Figure 2

The serum and urine levels of macrophage migration inhibitory factor (MIF) in septic patients on days 0, 2, and 4 from admission to the intensive care unit (ICU). The MIF levels are shown in (A) all patients and in patient subgroups of (B) females and males, (C) at least 65 years old and younger than 65 years, and (D) deceased and survived. Here, and in Fig. 6A, the horizontal line within each box represents the median, the bottom and the top of the box marks the lower and the upper quartile, respectively, which limit the interquartile range (IQR). The vertical line below and above the box shows the minimum and maximum levels, respectively. Outliers are shown with dots. The numbers below the boxes indicate the number of patients in each group. Note that on day 0, serum MIF level could not be determined in 4 patients and urine MIF level in 6 patients due to technical issues. *p < 0.05.

Figure 3

The individual pattern of serum macrophage migration inhibitory factor (MIF) kinetics in each patient who had at least 2 measurements between day 0 and 4 at the intensive care unit (ICU). Red line indicates an increase, while gray line shows no increase in serum MIF level in deceased and survived patients based on data obtained from (A) both sexes, (B) females, and (C) males. The number of patients (n) is indicated in the figure in each group.

Figure 4

The kinetics of serum macrophage migration inhibitory factor (MIF) levels in septic patients at the intensive care unit (ICU). (A) The mean absolute serum levels of MIF in all, deceased, and survived septic patients on day 0 and 4 from admission to the ICU. (B) The mean daily changes of serum MIF levels in deceased and survived patients based on data obtained from both sexes (top), males (middle), and females (bottom). The number of patients (n) is indicated in the figure in each group. *p < 0.05.

Figure 5

The kinetics of urine macrophage migration inhibitory factor (MIF) levels in septic patients at the intensive care unit (ICU). (A) The mean absolute urine levels of MIF in all, deceased, and survived septic patients on day 0 and 4 from admission to the ICU. (B) The mean daily changes of urine MIF levels in deceased and survived patients. (C) The correlation between urine MIF levels measured on day 0 and on day 4 from the admission to the ICU. The number of patients (n) is indicated in the figure in each group.

Figure 6

The kinetics of urine macrophage migration inhibitory factor (MIF) levels in septic patients with and without renal dysfunction at the intensive care unit (ICU). (A) Box plot of urine levels of MIF in septic patients with and without renal dysfunction on day 0, 2, and 4 from admission to the ICU (for explanation of symbols, see Fig. 2). (B) The mean absolute urine levels of MIF in septic patients with and without renal dysfunction on day 0 and 4 from admission to the ICU. (C) The mean daily changes of urine MIF levels in septic patients with and without renal dysfunction. The number of patients is indicated in the figure in each group.