Baseline characteristics
A total of 2224 incident PD patients were enrolled in the present study, of whom ten patients younger than 18 years, 84 patients on PD <3 months, 35 with current drinking, 279 with a history of CVD, 134 with chronic liver disease, 77 without baseline AST/ALT ratio, and 26 with AST or ALT values ≥two times higher than normal values were excluded. The remaining 1579 patients with baseline AST/ALT ratio were eligible for the present analysis (Figure 1). Of 1579 patients with CCI of 3.87±1.66, the mean age was 49.3±14.6 years, 55.4% were male sex, 18.1% had diabetes, 64.2% had hypertension, and 16.2% had hyperlipidemia.
In ROC curve analysis (supplement), the AST/ALT ratio (area under curve = 0.75, 95% CI 0.72-0.77; p < 0.001) was found to be a significant predictor of CVD mortality with a sensitivity (79.4%) and specificity (75.8%). The cut-off of the AST/ALT ratio for CVD mortality was 1.0 in the cohort population. A total of 1210 (76.6%) patients were in the high group and 369 (23.4%) patients in the normal group. The baseline characteristics of the study population are shown in Table 1. Patients with high AST/ALT ratio were older (P<0.001), likely to be female sex (P<0.001), had higher frequency of hyperlipidemia (P=0.029) and statin use (P=0.037), had higher CCI (P<0.001) and LDL (P=0.038), and had a lower ALT values (P<0.001) as compared to their counterparts.
Table 1. Baseline characteristics of patients stratified by baseline AST/ALT ratio.
Variables
|
cohort (n=1579)
|
Normal group (n=369)
|
High group (n=1210)
|
P value
|
Age (years)
|
49.3±14.6
|
45.8±13.7
|
50.3±14.7
|
<0.001
|
Male (%)
|
874 (55.4)
|
276 (74.8)
|
598 (49.4)
|
<0.001
|
CCI
|
3.87±1.66
|
3.59±1.58
|
3.95±1.68
|
<0.001
|
Diabetes (%)
|
286 (18.1)
|
64 (17.3)
|
222 (18.3)
|
0.700
|
Hypertension (%)
|
1014 (64.2)
|
244 (66.1)
|
770 (63.6)
|
0.420
|
Hyperlipidemia (%)
|
256 (16.2)
|
46 (12.5)
|
210 (17.4)
|
0.029
|
Gastrointestinal bleeding (%)
|
41 (2.6)
|
10 (2.7)
|
31 (2.6)
|
0.853
|
Current smoking (%)
|
47 (3.0)
|
6 (1.6)
|
41 (3.4)
|
0.113
|
ACEI/ARB use (%)
|
518 (32.8)
|
114 (30.9)
|
404 (33.4)
|
0.410
|
Calcium antagonist use (%)
|
1141 (72.3)
|
272 (73.7)
|
869 (1.8)
|
0.507
|
β-blocker use (%)
|
505 (32.0)
|
122 (33.1)
|
383 (31.7)
|
0.611
|
Diuretic use (%)
|
94 (6.0)
|
20 (5.4)
|
74 (6.1)
|
0.707
|
Statin use (%)
|
157 (9.9)
|
26 (7.0)
|
131 (10.8)
|
0.037
|
BMI (kg/m2)
|
22.1±3.6
|
22.3±4.5
|
22.0±3.3
|
0.305
|
Ejection fraction (%)
|
60.0±5.9
|
59.8±6.6
|
60.0±5.7
|
0.820
|
eGFR (ml/min/1.73 m2)
|
5.63 (4.38–8.47)
|
5.81 (4.31–8.93)
|
5.50 (4.01–8.64)
|
0.367
|
Hemoglobin (g/dL)
|
8.6±2.0
|
8.6±2.1
|
8.6±2.0
|
0.873
|
Albumin (g/dL)
|
3.5±0.5
|
3.5±0.5
|
3.4±0.5
|
0.059
|
AST (IU/L)
|
18 (14-23)
|
19 (13-25)
|
18 (14-23)
|
0.086
|
ALT (IU/L)
|
13 (8-20)
|
36 (27-56)
|
8 (5-11)
|
<0.001
|
Bilirubin (mg/dL)
|
0.30 (0.22-0.41)
|
0.33 (0.27-0.40)
|
0.30 (0.21-0.41)
|
0.565
|
Cholesterol (mg/dL)
|
159±60
|
156±55
|
160±61
|
0.361
|
Triglyceride (mg/dL)
|
132±97
|
126±90
|
133±98
|
0.198
|
HDL (mg/dL)
|
45.4±16.3
|
44.7±17.1
|
45.6±16.1
|
0.432
|
LDL (mg/dL)
|
99.0±38.8
|
95.1±37.0
|
100.2±39.3
|
0.038
|
hs-CRP (mg/L)
|
4.03 (1.97-11.04)
|
2.25 (0.85-19.5)
|
4.25 (2.04-14.20)
|
0.209
|
NT-pro-BNP (pg/mL)
|
2017 (800-6545)
|
771 (412-4835)
|
2375 (840-5760)
|
0.824
|
24-hr urine output (mL)
|
851±534
|
890±589
|
839±527
|
0.131
|
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CCI, Charlson comorbidity index; ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; BMI, body mass index; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; high-sensitivity C-reactive protein (hs-CRP); NT-pro-BNP, N-terminal -prohormone BNP.
The high AST/ALT ratio
The prevalence of the high AST/ALT ratio was 76.6% (74.5%-78.7%) in the cohort population (Figure 2). Multivariate Logistic analysis showed that older age [increased pre one year, HR=1.02, 95% confidence interval (CI) 1.01-1.03, P<0.001] and female (HR=2.94, 95%CI 2.30-3.77, P<0.001), statin using (HR=1.66, 95%CI 1.22-2.44, P=0.011), and lower bilirubin (HR=0.54, 95%CI 0.33-0.90, P=0.018)were independently associated with the high AST/ALT ratio (Table 2).
Table 2. Predictors for high AST/ALT ratio by Logistic regression
Variables
|
Multivariate Logistic regression
|
HR (95%CI)
|
P value
|
Age (increased pre 1 years)
|
1.02 (1.01-1.03)
|
<0.001
|
Female (yes/no)
|
2.94 (2.30-3.77)
|
<0.001
|
Current smoking (yes/no)
|
-
|
-
|
CCI (increased per 1 score)
|
-
|
-
|
Hypertension (yes/no)
|
-
|
-
|
Hyperlipidemia (yes/no)
|
-
|
-
|
Statin use (yes/no)
|
1.66 (1.12-2.44)
|
0.011
|
Bilirubin (increased per 1 mg/dL)
|
0.54 (0.33-0.90)
|
0.018
|
Variables clinically considered to be associated with high AST/ALT ratio were picked into a multivariate-adjusted Logistic regression model. AST/ALT, aspartate aminotransferase/alanine aminotransferase; CCI, Charlson comorbidity index; LDL, low-density lipoprotein.
Baseline AST/ALT ratio and endpoints
The total follow-up period was 4659.6 patient-years. By the end of this study, 316 (20.0%) patients had died, 106 (6.7%) patients had undergone renal transplantation, 247 (15.6%) patients had transferred to hemodialysis, 18 (1.1%) patients had transferred to other PD centers, and 60 (3.8%) patients had been lost to follow-up; the remaining 832 (52.7%) patients were still followed at these PD centers. Of 316 deaths, 193 (61.1%) deaths were caused by CVD episodes. The Kaplan-Meier estimates showed that the cumulative CVD and all-cause mortality incidence were significantly different between two AST/ALT ratio groups (HR=1.50, 95%CI 1.09-2.07, and HR=1.53, 95%CI 1.16-1.93, Figure 3 A and Figure 4 A). At the end of 1, 3, and 5 years in this study, the incidence of CVD mortality was 8.1%, 15.8%, and 24.5% in the high group, and 6.1%, 10.2%, and 15.2% in the normal group, respectively. The incidence of all-cause mortality was 12.7%, 26.7%, and 32.6% in the normal group, and 9.8%, 17.8%, and 20.7% in the high group, respectively.
The association between the baseline AST/ALT ratio and CVD and all-cause mortality is shown in Table 3. Crude Cox model analysis showed that a high AST/ALT ratio was associated with an increased risk of CVD and all-cause mortality (HR=1.63, 95% CI 1.13-2.27; HR=1.58, 95%CI 1.18-2.10, Model 1). Multivariate Cox model analysis found that patients with a high AST/ALT ratio carried a higher risk of CVD and all-cause mortality (HR=1.43, 95% CI 1.08-2.41, and HR=1.45, 95% CI 1.13-2.37, Model 3), even after adjusting for confounding factors. In addition, the association between quartiles of AST/ALT ratio and CVD mortality were shown in Table 4.
Table 3. Adjusted hazards ratio for CVD and all-cause mortality using Cox regression models
|
Model 1
|
Model 2
|
Model 3
|
HR (95%)
|
HR (95%)
|
HR (95%)
|
CVD mortality
|
1.63 (1.13-2.27)
|
1.55 (1.10-2.36)
|
1.43 (1.08-2.41)
|
All-cause mortality
|
1.58 (1.18-2.10)
|
1.48 (1.16-2.24)
|
1.45 (1.13-2.37)
|
Hazards ratio: high AST/ALT ratio vs. normal AST/ALT ratio. Model 1: unadjusted. Model 2: adjusted for age, sex, CCI, smoking, and medication use. Model 3: model 2 adjusted for BMI, eGFR, hemoglobin, albumin, bilirubin, cholesterol, triglycerides, hs-CRP, and 24-hr urine output.
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CVD, cardiovascular disease; CCI, Charlson comorbidity index; BMI, body mass index; eGFR, estimated glomerular filtration rate; high-sensitivity C-reactive protein (hs-CRP).
Table 4. The association between quartiles of AST/ALT ratio and CVD mortality
|
Model 1
|
Model 2
|
Model 3
|
HR (95%)
|
HR (95%)
|
HR (95%)
|
Quartiles 1
|
Reference
|
Quartiles 2
|
1.77 (1.24-2.51)
|
1.40 (0.96-2.05)
|
1.39 (0.96-2.03)
|
Quartiles 3
|
1.73 (1.20-2.50)
|
1.70 (1.20-2.41)
|
1.71 (1.21-2.43)
|
Quartiles 4
|
1.67 (1.16-2.41)
|
1.58 (1.10-2.27)
|
1.49 (1.20-2.18)
|
Model 1: unadjusted. Model 2: adjusted for age, sex, CCI, smoking, and medication use. Model 3: model 2 adjusted for BMI, eGFR, hemoglobin, albumin, bilirubin, cholesterol, triglycerides, hs-CRP, and 24-hr urine output.
AST/ALT, aspartate aminotransferase/alanine aminotransferase; CVD, cardiovascular disease; CCI, Charlson comorbidity index; BMI, body mass index; eGFR, estimated glomerular filtration rate; high-sensitivity C-reactive protein (hs-CRP).
Subgroup analyses
The prevalence of high AST/ALT ratio ranged from 68.4% (95%CI 65.3%-71.5%) to 86.9% (95%CI 84.3%-89.3%) among all subgroups (Figure 2). Survival analysis showed that the cumulative CVD mortality incidence between high and normal groups was a significant difference in the male and non-hyperlipidemia subgroups (Figure 3 B and C). The cumulative all-cause mortality incidence between high and normal groups was a significant difference in the non-diabetes, hypertension, and non-hyperlipidemia subgroups (Figure 4 B, C, and D). Adjusted HRs for CVD mortality were conducted in the male and non-hyperlipidemia subgroups, and for all-cause mortality in the non-diabetes, hypertension, and non-hyperlipidemia subgroups by the Cox regression models (Figure 5).