Baseline characteristics
The mean age of the patients was 63.53 ± 14.19 years, and 61.90% of them were male. The mortality rates at 28 days and 90 days were 496 and 583, respectively. The mean times to death at 28 days and 90 days were 18.35 ± 11.62 days and 30.04 ± 37.48 days, respectively. There were no significant differences in age, K, P, aCCI, BMI, SBP, DBP, MAP, WBC, BUN, Cr, GFR, UO, SOFA score, CRRT dose (total effluent volume), sex, Indications for CRRT, and AKIN stage among patients in the ALB tertile groups. Compared with the patients in the T1 group, the rest had significantly longer survival times, higher HCO3 and HGB, and lower MV percentage, CRP, and APACHE-II score. The baseline characteristics of the patients are shown in Table 1.
Table 1. Baseline characteristics of the patients
ALB tertiles
|
TI group
(0.00-2.20g/dl)
|
T2 group
(2.30-2.70g/dl)
|
T3 group
(2.80-5.90g/dl)
|
P value
|
N (794)
|
218
|
286
|
290
|
|
ALB
|
1.92 ± 0.32
|
2.50 ± 0.14
|
3.17 ± 0.39
|
<0.001
|
Time to death=28 days
|
28.00 (3.00–28.00)
|
28.00 (4.00–28.00)
|
28.00 (7.00–28.00)
|
0.024
|
Time to death=90 days
|
3.00 (1.00–29.69)
|
5.80 (1.00–58.96)
|
14.40 (1.00–90.00)
|
<0.001
|
Age (years)
|
65.00 ± 12.85
|
63.72 ± 14.49
|
62.49 ± 14.59
|
0.137
|
K (mmol/L)
|
4.76 ± 1.15
|
4.59 ± 0.99
|
4.77 ± 1.12
|
0.098
|
HCO3 (mmol/L)
|
15.71 ± 5.18
|
17.10 ± 5.67
|
17.73 ± 5.76
|
<0.001
|
P (mg/dL)
|
5.53 ± 2.26
|
5.47 ± 2.15
|
5.90 ± 2.45
|
0.067
|
aCCI score
|
2.00 (1.00–5.00)
|
3.00 (2.00–5.00)
|
3.00 (1.25–4.00)
|
0.155
|
BMI (kg/m2)
|
23.36 ± 4.48
|
23.39 ± 4.34
|
23.89 ± 4.54
|
0.309
|
SBP (mmHg)
|
110.44 ± 20.62
|
112.21 ± 21.71
|
111.71 ± 20.50
|
0.632
|
DBP (mmHg)
|
61.00 ± 13.91
|
61.05 ± 14.70
|
60.28 ± 13.79
|
0.774
|
MAP (mmHg)
|
77.42 ± 14.02
|
77.76 ± 15.58
|
77.23 ± 14.62
|
0.909
|
WBC (uL)
|
10690.00 (5130.00–18960.00)
|
11070.00 (6355.00–18285.00)
|
12060.00 (8170.00–18740.00)
|
0.171
|
HGB (g/dL)
|
9.23 ± 2.06
|
9.73 ± 1.98
|
10.03 ± 2.37
|
<0.001
|
BUN (mg/dL)
|
55.00 (36.00–78.00)
|
49.00 (35.00–74.00)
|
48.00 (34.00–71.00)
|
0.162
|
Cr (mg/dL)
|
2.26 (1.59–3.16)
|
2.42 (1.67–3.39)
|
2.34 (1.66–3.36)
|
0.358
|
CRP (mg/L)
|
89.60 (20.10–199.50)
|
73.25 (20.55–176.70)
|
46.90 (15.00–133.50)
|
0.011
|
GFR (ml/min/1.73 m2)
|
27.05 (18.27–39.55)
|
26.45 (17.62–38.98)
|
26.30 (16.17–38.60)
|
0.547
|
UO (mL)
|
25.00 (4.25–100.00)
|
30.00 (5.00–96.25)
|
40.00 (10.00–100.00)
|
0.139
|
APACHE-II score
|
28.37 ± 7.63
|
27.46 ± 7.64
|
26.60 ± 8.48
|
0.047
|
SOFA score
|
12.26 ± 3.38
|
12.16 ± 3.45
|
11.64 ± 3.73
|
0.09
|
CRRT dose (mL/kg)
|
36.99 ± 5.01
|
36.62 ± 4.85
|
36.57 ± 4.39
|
0.579
|
Sex
|
|
|
|
0.187
|
Male
|
132 (60.55%)
|
189 (66.08%)
|
171 (58.97%)
|
|
Female
|
86 (39.45%)
|
97 (33.92%)
|
119 (41.03%)
|
|
MV
|
|
|
|
0.049
|
No
|
36 (16.51%)
|
57 (19.93%)
|
73 (25.26%)
|
|
Yes
|
182 (83.49%)
|
229 (80.07%)
|
216 (74.74%)
|
|
Indications for CRRT
|
|
|
|
0.326
|
Volume overload
|
22 (10.09%)
|
35 (12.24%)
|
45 (15.52%)
|
|
metabolic acidosis
|
49 (22.48%)
|
73 (25.52%)
|
61 (21.03%)
|
|
hyperkalemia
|
14 (6.42%)
|
8 (2.80%)
|
17 (5.86%)
|
|
uremia
|
23 (10.55%)
|
33 (11.54%)
|
25 (8.62%)
|
|
oliguria
|
53 (24.31%)
|
77 (26.92%)
|
75 (25.86%)
|
|
others
|
57 (26.15%)
|
60 (20.98%)
|
67 (23.10%)
|
|
AKIN stage
|
|
|
|
0.983
|
stage Ⅱ
|
59 (27.06%)
|
76 (26.57%)
|
79 (27.24%)
|
|
stage Ⅲ
|
159 (72.94%)
|
210 (73.43%)
|
211 (72.76%)
|
|
Univariate analysis between ALB levels and the endpoints
The results of the univariate analyses are presented in Table S1. P, aCCI, BMI, SBP, DBP, MAP, MV, Cr, ALB levels, UO, APACHE-II score, SOFA score, and CRRT were associated with death at both 28 and 90 days (P < 0.05). GFR was only correlated with death at 90 days (P < 0.05).
Kaplan–Meier curves of survival probability
The K–M curves of the survival probabilities of the ALB tertiles are shown in Fig. 2. From the chart, we clearly see that the survival probabilities among ALB tertiles at 28 days and 90 days were significantly different (log-rank test P = 0.00012 for 28 days and P < 0.0001 for 90 days, respectively).
Multivariate analysis between ALB levels and the endpoints
We displayed four models, including non-adjusted, multivariate adjusted (adjusted I and adjusted II), and fully adjusted models (Table 2).
Table 2. Results of the multivariate analysis between ALB and the endpoints
N (death at 28 days)
|
794
|
757
|
581
|
482
|
Models
|
Non-adjusted HR (95% CI) P value
|
Adjusted I HR (95% CI) P value
|
Adjusted II HR (95% CI) P value
|
Fully adjusted HR (95% CI) P value
|
ALB (g/dL)
|
0.71 (0.61–0.82) <0.0001
|
0.74 (0.63–0.88) 0.0004
|
0.75 (0.62–0.90) 0.0024
|
0.72 (0.58–0.90) 0.0039
|
ALB tertiles
|
|
|
|
|
Low (0.00-2.20g/dl)
|
Ref
|
Ref
|
Ref
|
Ref
|
Middle (2.30-2.70g/dl)
|
0.87 (0.71–1.08) 0.2042
|
0.86 (0.69–1.08) 0.1944
|
0.75 (0.57–0.98) 0.0332
|
0.81 (0.60–1.09) 0.1700
|
Middle (2.80-5.90g/dl)
|
0.63 (0.51–0.79) <0.0001
|
0.67 (0.53–0.85) 0.0008
|
0.64 (0.49–0.85) 0.0019
|
0.65 (0.47–0.89) 0.0069
|
P for trend
|
<0.0001
|
0.0006
|
0.0022
|
0.0069
|
N (death at 90 days)
|
794
|
790
|
731
|
482
|
Models
|
Non-adjusted HR (95% CI) P value
|
Adjusted I HR (95% CI) P value
|
Adjusted II HR (95% CI) P value
|
Fully adjusted HR (95% CI) P value
|
ALB (g/dL)
|
0.70 (0.61–0.80) <0.0001
|
0.75 (0.65–0.87) 0.0001
|
0.73 (0.63–0.86) <0.0001
|
0.68 (0.55–0.85) 0.0005
|
ALB tertiles
|
|
|
|
|
low
|
Ref
|
Ref
|
Ref
|
Ref
|
middle
|
0.83 (0.68–1.02) 0.0713
|
0.83 (0.68–1.02) 0.0762
|
0.81 (0.65–1.00) 0.0547
|
0.72 (0.55–0.96) 0.0253
|
high
|
0.62 (0.50–0.76) <0.0001
|
0.67 (0.54–0.82) 0.0002
|
0.63 (0.50–0.79) <0.0001
|
0.60 (0.45–0.80) 0.0005
|
P for trend
|
<0.0001
|
0.0001
|
<0.0001
|
0.0006
|
Non-adjusted model adjusted for: None
Adjusted I model (death at 28 days) adjusted for: age, sex, P, BUN, Cr, UO, SOFA score, and Indications for CRRT.
Adjusted I model (death at 90 days) adjusted for: age, sex, BUN, Cr, and SOFA scores.
Adjusted II model (death at 28 days) adjusted for: age, sex, K, HCO3, P, aCCI, BMI, SBP, DBP, MAP, MV, WBC, HGB, BUN, Cr, CRP, UO, APACHE-II score, SOFA score, Indications for CRRT, CRRT dose, and AKIN.
Adjusted II model (death at 90 days) adjusted for: age, sex, K, HCO3, P, aCCI, BMI, SBP, DBP, MAP, MV, WBC, HGB, BUN, Cr, GFR, UO, APACHE-II score, SOFA score, Indications for CRRT, CRRT dose, and AKIN.
Fully adjusted model adjusted for: all variables except ALB and the endpoints.
In the crude model, the ALB level was negatively correlated with death at 28 days and 90 days (HR = 0.71, 95% CI: 0.61–0.82, P < 0.0001 for 28 days; HR = 0.70, 95% CI: 0.61–0.80, P < 0.0001 for 90 days). In the adjusted I and II models, the HRs of the negative association were listed as follows: HR = 0.74, 95% CI: 0.63–0.88, P = 0.0004 and HR = 0.75, 95% CI: 0.62–0.90, P < 0.0001, respectively for death at 28 days; HR = 0.75, 95% CI: 0.65–0.87, P = 0.0001 and HR = 0.73, 95% CI: 0.63–0.86, P < 0.0001, respectively for death at 90 days. In the fully adjusted model, the ALB level was also negatively related with the endpoints (HR = 0.72, 95% CI: 0.58–0.90, P = 0.0039 for death at 28 days; HR = 0.68, 95% CI: 0.55–0.85, P = 0.0005 for death at 90 days). In the sensitivity analysis, we also viewed the ALB level as a categorical variable (tertile), and the same trends were detected in the four models (P for trend < 0.05). We found that some variables for K, HCO3, P, BMI, SBP, DBP, MV, WBC, HGB, BUN, Cr, CRP, GFR, UO, APACHE II score, and SOFA score were missing in the raw data, with the numbers of patients with missing variables being 5, 110, 30, 16, 2, 2, 1, 5, 1, 2, 1, 166, 2, 5, 12, and 3, respectively. Thus, we created five replications based on MI and conducted multivariate Cox regression analysis of the four models using imputed data. Thereafter, the HRs, 95% CIs, and P values of multivariable Cox analysis of the five replications were combined based on Rubin’s rule (Table S2). The results of the MI indicated that between the raw data and combined imputed data, there was only a slight difference in HR. In other words, we concluded that the data were missing at random, which would not significantly affect the results of the analysis in the four models.
Linearity or non-linearity of the correlation between ALB levels and the endpoints
Analysis of nonlinear correlation was indispensable because ALB levels were continuous variables. Through the application of smooth curve fitting, we determined that the associations between the ALB levels and death at 28 days and 90 days were nonlinear after adjusting for variables in the adjusted I and II models (Fig S1). By calculation and bootstrap resampling, the inflection points for death at 28 days were found to be 2.20 g/dl (95% CI: 2.10–2.24) and 2.10 g/dl (95% CI: 1.80–2.21) after adjusting variables in adjusted I and adjusted II models, respectively. For death at 90 days, the thresholds were 1.84 g/dl (95% CI: 1.79–2.01) and 1.80 g/dl (95% CI: 1.71–2.04) after adjusting variables in two models. However, the log-likelihood ratio test indicated that P values were less than 0.05 for death at both 28 days and 90 days (Table S3). As a result, the correlation between the ALB levels and the endpoints was linear.
The results of subgroup analysis and test for interaction
The subgroup analyses and tests for the interaction of the correlations between ALB levels and death at 28 days and 90 days are presented in Table S4. The negative correlations between ALB levels and the endpoints were stable in nearly all subgroups. The interaction analysis revealed that HCO3 and CRP played an interactive role in the association between ALB levels and mortality (Fig. 3). The patients with HCO3 ≥ 22 mmol/L had lower HRs (HR = 0.11, 95% CI: 0.04–0.29 for death at 28 days; HR = 0.33, 95% CI: 0.18–0.60 for death at 90 days) than those with HCO3 < 22 mmol/L (HR = 0.79, 95% CI: 0.63–0.99, P for interaction = 0.0020 for death at 28 days; HR = 0.75, 95% CI: 0.62–0.92, P for interaction = 0.0235 for death at 90 days). In addition, the HR between ALB levels and death at 90 days was significantly higher in patients with high CRP (low CRP group: HR = 1.04, 95% CI: 0.75–1.43; middle CRP group: HR = 0.70, 95% CI: 0.50–0.97; high CRP group: HR = 0.64, 95% CI: 0.38–0.77; P for interaction = 0.0195). The same trend was also found between ALB levels and death at 28 days among the CRP subgroups, but the difference was not statistically significant (P for interaction = 0.1465).