Baseline characteristics
From June 1st, 2015, to December 1st, 2020, 250 patients were included in the study. Of these enrolled patients, 133 patients were included in the CERTAIN group, and 117 patients were included in the standard care group. Fourteen patients were excluded, 9 (6.8%) of whom were in the CERTAIN group and 5 (4.3%) of whom were in the standard care group. In the CERTAIN group, 5 (3.8%) patients withdrew consent, and 4 (3.0%) were lost to follow-up. In the standard care group, 5 (4.3%) patients were lost to follow-up. Thus, 236 patients (124 in the CERTAIN group and 112 in the standard care group) were included in the primary analysis (Fig. 1).
The baseline characteristics of patients in the CERTAIN group and standard care group are summarized in Table 1. There were no significant differences in age, sex, Acute Physiology and Chronic Health Evaluation (APACHE II) score, Sequential Organ Failure Assessment (SOFA) score, comorbidities, site of infection, or stage of AKI (P > 0.05).
Initiation of CERTAIN checklist and therapy
The volumes infused into the patients increased on day 1 in the CERTAIN group compared with the standard care group. In contrast, the volumes infused into the patients decreased on day 7 in the CERTAIN group. The urinary output was lower in the standard care group than in the CERTAIN group on day 3 and day 7. The proportion of patients with KDIGO 2/3 was higher in the standard care group than in the CERTAIN group on day 7 (56.3% vs 40.3%, 95% CI 0.564–0.941). The CERTAIN group had lower proportions of patients receiving mechanical ventilation and RRT than the standard care group (83.1% vs 92.9%; 33.9% vs 48.2%). There were marginally fewer days on ventilation among patients in the CERTAIN group than among those in the standard care group (6 vs 7, 95% CI 1.501–4.387). Patients in the CERTAINgroup had more ventilator-free days and vasoactive-free days (22 vs 17, 95% CI -9.486–5.060; 23 vs 19, 95% CI -5.538–0.075, respectively). Patients in the CERTAIN group had a shorter ICU stay than those in the standard care group (95% CI 0.951–4.512, P < 0.01). Patients in the two groups had similar durations of hospitalization. (Table 2)
Table 1
Characteristics of the participants at baseline
Characteristic
|
Standard care group
|
CERTAIN group
|
P value
|
|
(N = 112)
|
(N = 124)
|
|
Age (years), mean ± SD
|
60.8 ± 15.2
|
57.6 ± 15.9
|
0.12
|
Male sex, n (%)
|
67(59.8%)
|
73(58.9%)
|
0.88
|
Severity scores in SA-AKI patients
|
|
|
|
APACHE II, mean ± SD
|
24.2 ± 5.2
|
22.9 ± 4.7
|
0.05
|
SOFA, mean ± SD
|
10.5 ± 3.6
|
10.4 ± 2.9
|
0.67
|
Comorbidities
|
|
|
|
Coronary heart disease, n (%)
|
82(45.6)
|
98(54.4)
|
0.36
|
Hypertension, n (%)
|
83(46.4)
|
96(53.6)
|
0.65
|
COPD, n (%)
|
45(43.7)
|
58(56.3)
|
0.36
|
Diabetes mellitus, n (%)
|
67(53.2)
|
59(46.8)
|
0.07
|
Stroke, n (%)
|
37(49.3)
|
38(50.7)
|
0.78
|
Malignancy, n (%)
|
24(43.6)
|
31(56.4)
|
0.54
|
Immunosuppression, n (%)
|
50(43.1)
|
66(56.9)
|
0.2
|
Site of infection
|
|
|
0.62
|
Pulmonary, n (%)
|
45(40.2)
|
56(45.2)
|
|
Abdomen, n (%)
|
31(27.7)
|
26(21.0)
|
|
Urinary system, n (%)
|
22(19.6)
|
24(19.4)
|
|
Blood stream, n (%)
|
6(5.4)
|
11(8.9)
|
|
Skin and soft tissue, n (%)
|
8(7.1)
|
7(5.6)
|
|
AKI stage
|
|
|
0.66
|
KDIGO stage 1, n (%)
|
18(16.1)
|
15(12.1)
|
|
KDIGO stage 2, n (%)
|
56(50.0)
|
63(50.8)
|
|
KDIGO stage 3, n (%)
|
38(33.9)
|
46(37.1)
|
|
Biomarker kinetics
According to the worst AKI stage within seven days after inclusion, the level of [TIMP-2] × [IGFBP7] decreased progressively over time in patients with all stages of AKI. Patients receiving RRT had the highest levels of [TIMP-2] × [IGFBP7] at all time points. Patients with stage 1 AKI had the lowest level of [TIMP-2] × [IGFBP7] at each time point (Fig. 2a).
Next, we evaluated the outcome of SA-AKI patients on the basis of the level of [TIMP-2] × [IGFBP7] within seven days after enrolment. According to course of AKI, patients were divided into four groups [24]: 1) stable AKI 1; 2) stable AKI 2/3; 3) AKI progression (from AKI 1 to AKI 2/3); and 4) AKI recovery (from AKI 2/3 to AKI 1). The distribution of patients across these groups is shown in Fig. 3. At baseline, the [TIMP-2] × [IGFBP7] levels in patients with stable AKI 2/3, AKI progression (AKI 1 to AKI 2/3), and AKI recovery (AKI 2/3 to AKI 1) were greater than that in patients with stable AKI 1. Patients with AKI progression had an increase in the level of [TIMP-2] × [IGFBP7] from baseline to 12 hours after inclusion. Patients with stable AKI 1 had median [TIMP-2] × [IGFBP7] levels below 0.3 (ng/mL)2/1,000. The elevation of [TIMP-2] × [IGFBP7] was prolonged in patients with AKI progression (Fig. 2b).
Primary and secondary outcomes
The difference in 90-day mortality was marked (Table 3). The rates of mortality at 90 days were 45.6% and 55.4% in the CERTAIN group and standard care group, respectively (P = 0.039). In-hospital mortality was higher in the CERTAIN group, but the difference was not significant (35.5% vs 33.9%, P = 0.909). Patients in the CERTAIN group had significantly less RRT dependence at 90 days (36.3% vs 22.4%, P = 0.026). Consistent with this finding, the proportion of patients with MAKEs in the CERTAIN group was lower than that in the standard care group (55.6% vs 76.8%, P = 0.001). Patients in the CERTAIN group had a lower risk of rehospitalization (relative risk, 0.956; 95% CI, 0.673 to 1.358), but there was no difference between the two groups in the proportion of patients who were rehospitalized within 90 days (13.4% vs 13.8%, P = 0.953). The impact of the spontaneous remission of AKI, which was mainly observed in those with mild AKI (stage 1), was excluded. Among those with moderate-to-severe AKI (stages 2 and 3), the CERTAIN group had a higher proportion of patients who recovered renal function than the standard care group (54.3% vs 38.2%, P = 0.029). A Kaplan-Meier analysis of 90-day mortality showed tendency towards improved survival in the CERTAIN group, but there was no significant difference (Fig. 4).
Table 2
Measures during the evaluation period in the CERTAIN and standard care groups
Parameters
|
Standard care group
|
CERTAIN group
|
P value
|
Volume of infusion (ml), mean ± SD
|
|
|
|
Day 1
|
2660 ± 812
|
4124 ± 975
|
< 0.01
|
Day 2
|
2912 ± 1016
|
2878 ± 919
|
0.79
|
Day 3
|
3048 ± 1000
|
2278 ± 765
|
< 0.01
|
Output of urine (ml), mean ± SD
|
|
|
|
Day 1
|
1110 ± 975
|
962 ± 862
|
0.22
|
Day 2
|
1555 ± 1268
|
1611 ± 1189
|
0.73
|
Day 3
|
1764 ± 1448
|
2144 ± 1404
|
0.042
|
Day 7
|
1365 ± 894
|
1865 ± 1078
|
0.044
|
AKI stage
|
|
|
0.019
|
KDIGO stage 1, n (%)
|
49(43.8)
|
74(59.7)
|
|
KDIGO stage 2/3, n (%)
|
63(56.3)
|
50(40.3)
|
|
Median no. of ventilator-free days at 28 days (IQR)
|
17(0–23)
|
22(21–23)
|
< 0.01
|
Median no. of days free from vasoactive agents at 28 days (IQR)
|
19(0–20)
|
23(0–25)
|
0.04
|
Length of ICU stay, days
|
10(6–21)
|
10(6–13)
|
< 0.01
|
Length of hospital stay, days
|
17.5(12–22)
|
17(14–22)
|
0.76
|
Table 3
Primary and secondary outcomes
|
Standard care
|
CERTAIN
|
Relative risk
|
|
group
|
group
|
or difference (95% CI)
|
Primary outcome
|
|
|
|
Death from any cause at 90 days, n (%)
|
62/112 (55.4%)
|
52/124 (45.6%)
|
1.294 (1.009 to 1.660)
|
Secondary outcomes
|
|
|
|
RRT dependence at 90 days, n (%)a
|
37/102 (36.3%)
|
26/116 (22.4%)
|
1.618 (1.063 to 2.479)
|
MAKEs at 90 days, n (%)
|
86/112 (76.8%)
|
69/124 (55.6%)
|
1.525 (1.211 to 1.921)
|
Death from any cause, n (%)
|
|
|
|
In-hospital mortality, n (%)
|
38/112(33.9%)
|
44/124 (35.5%)
|
0.956 (0.673 to 1.358)
|
Rehospitalization at 90 days, n (%)
|
8/58 (13.8%)
|
9/67 (13.4%)
|
1.027 (0.424 to 2.488)
|
Recovery of renal function after AKIa
|
39/102 (38.2%)
|
63/116 (54.3%)
|
0.715 (0.526 to 0.959)
|
a. The number of patients with AKI progression and stable AKI 2/3 were 102 in the standard care group and 116 in the CERTAIN group. |