Relationship Between Serum Indirect Bilirubin Levels and Cardiovascular Events and All-Cause Mortality in Maintenance Hemodialysis Patients

Figures & data

Figure 1 Study flow.

Table 1 Baseline Characteristics of Chronic Hemodialysis Patients Classified by the Serum Indirect Bilirubin Median Value

Characteristics of Patients	All Participants	Serum Indirect Bilirubin Concentration		P-value
		I1: <3 μmol/L	I2: ≥3 μmol/L
N	284	139	145	-
Men, n(%)	162(57.0%)	84(60.4%)	77(53.8%)	0.259
Age (yr)	59.82±13.93	58.79±13.83	60.80±14.01	0.222
HD vintage(months)	62(40–101)	58(38–94)	71(43–111)	0.019
Hypertension	163(57.4%)	78(56.1%)	85(58.6%)	0.669
Diabetes mellitus	82(28.9%)	44(31.7%)	38(26.2%)	0.595
Previous coronary artery disease	23(8.1%)	11(7.9%)	12(8.3%)	0.911
Previous cerebrovascular disease	31(10.9%)	12(8.6%)	19(13.1%)	0.228
Previous congestive heart failure	43(15.1%)	25(18.0%)	18(12.4%)	0.191
Systolic BP (mmHg)	140.1±18.6	140.8±18.07	139.5±19.2	0.545
Diastolic BP (mmHg)	83.4±11.9	84.1±11.7	82.7±12.1	0.317
SpKt/V	1.26±0.22	1.27±0.22	1.24±0.21	0.338
Laboratory values
Hemoglobin (g/L)	85(70–100)	83(65–99)	86(71.5–101)	0.132
Albumin (g/dL)	36.2(32. 2–40.3)	34.9(31.4–38.6)	37.7(33.6–41.3)	0.001
Creatinine (μmol/L)	769(626–1009)	755 (618–968)	774 (628–1019)	0.647
Uric acid(μmol/L)	475(376–577)	476(379–599)	474(366–568)	0.324
Total cholesterol (mg/dL)	3.92 (3.31–4.78)	3.93(3.22–4.66)	3.90(3.37–4.82)	0.330
LDL-C (mg/dL)	2.30(1.72–2.93)	2.32(1.68–2.99)	2.26(1.81–2.89)	0.660
HsCRP (mg/dL)	3.4 (1–17)	4.9(1–24)	3(1–14)	0.326
Calcium(mmol/L)	2.04(1.85–2.20)	2.02(1.82–2.15)	2.10(1.86–2.25)	0.035
Phosphorus(mmol/L)	1.83(1.48–2.29)	1.90(1.52–2.30)	1.74(1.43–2.28)	0.127
Magnesium (mmol/L)	0.87(1.00–1.15)	1.00(0.87–1.13)	1.00(0.87–1.16)	0.678
TBIL(μmol/L)	5.4 (1.9–7.0)	3.9(3.1–4.8)	6.9(5.6–8.3)	<0.001
DBIL(μmol/L)	2.2 (1.6–3.0)	2.0(1.5–2.7)	2.3(1.8–3.1)	0.029
IBIL(μmol/L)	3.0 (1.9–4.2)	1.9(1.3–2.4)	4.0(3.4–5.7)	<0.001
ALT (U/L)	11(7–18)	11(7–18)	11(7–18.8)	0.503
AST (U/L)	15(11–20)	15(11–21)	15(11–19)	0.714
Parathyroid hormone(pg/mL)	92.4(30.4–228)	82.9(29.7–222)	93.3(31–228)	0.759
Medication, n(%)
CCB	88(31%)	41(30%)	47(32%)	0.595
ARB or ACEi	159(56%)	74(53%)	85(59%)	0.361
β-receptor blocker	123(43%)	59(42%)	64(44%)	0.774
Aspirin	107(37%)	57(41%)	50(35%)	0.257
Statins	94(33%)	49(35%)	45(31%)	0.450
Clinical outcomes
CVD event	96(33.8%)	59(42.4%)	37(25.5%)	0.003
All-cause death	134(47.2%)	64 (46.0%)	70(48.3%)	0.706

Note: Values expressed as mean ± standard deviation, median, percentage or median (interquartile range).

Abbreviations: SpKt/V, single-pool Kt/V; LDL-C, low-density lipoprotein-cholesterol; HsCRP, hypersensitive C reactive protein; TBIL, total bilirubin; DBIL, direct bilirubin; IBIL, indirect bilirubin; ALT, alanine amino-transferase; AST, aspartate amino-transferase; CCB, calcium-channel blocker; ARB, angiotensin II type 1 receptor blocker; ACEi, angiotensin-converting enzyme inhibitor; CVD, cardiovascular diseases.

Figure 2 Kaplan–Meier analysis curves for cardiovascular events in two groups (I1 group with serum IBIL<3.0 μmol/L, I2 group with serum IBIL≥3.0 μmol/L. The Log rank test showed a significant difference between the two groups (P < 0.001). Symbols are: I1 ̶̶̶; I2 ̶̶̶.

Figure 3 Kaplan–Meier analysis curves for all-cause mortality in two groups (I1 group with serum IBIL<3.0 μmol/L, I2 group with serum IBIL≥3.0 μmol/L. The Log rank test showed no significant difference between the two groups (P =0.428). Symbols are: I1 ̶̶̶; I2 ̶̶̶.

Table 2 Risk Factors for Cardiovascular Events by the Cox Proportional Hazards Analysis in Maintenance Hemodialysis Patients

Covariate	Univariate			Multiple
	HRs	95% CI	P-value	HRs	95% CI	P-value
Age	1.041	1.021–1.061	<0.001	1.038	1.016–1.061	0.001
Male	1.202	0.751–1.924	0.442	1.531	0.872–2.687	0.138
Hypertension	0.849	0.457–1.578	0.605	0.975	0.447–2.125	0.950
Diabetes	1.468	0.358–6.028	0.594	2.705	0.528–13.851	0.232
Previous coronary artery disease	4.341	2.443–7.714	<0.001	3.839	1.832–8.044	<0.001
Previous cerebrovascular disease	1.715	0.850–3.460	0.132	1.018	0.424–2.444	0.969
Previous congestive heart failure	1.405	1.446–4.001	0.001	1.941	1.021–3.692	0.043
Systolic Blood pressure	1.003	0.991–1.016	0.608
Diastolic Blood pressure	1.006	0.987–1.025	0.549
SpKt/V	0.490	0.156–1.533	0.220	0.495	0.138–1.772	0.280
Albumin	0.974	0.939–1.010	0.159	1.022	0.975–1.070	0.363
Hemoglobin	1.000	0.988–1.013	0.945	0.998	0.983–1.014	0.834
Uric acid	1.001	1.000–1.003	0.127	1.001	0.999–1.003	0.317
HsCRP	0.493	0.164–1.481	0.207	0.439	0.095–2.029	0.292
Alanine amino-transferase	1.002	1.001–1.004	0.004	0.989	0.964–1.014	0.381
Aspartate amino-transferase	1.002	1.001–1.003	0.007	1.012	0.990–1.034	0.296
Total bilirubin	0.942	0.859–1.035	0.213
Direct bilirubin	1.117	0.977–1.278	0.106
Indirect bilirubin	0.852	0.751–0.966	0.012	0.773	0.660–0.906	0.001
Total cholesterol	1.010	0.826–1.233	0.926	1.059	0.860–1.304	0.591
LDL-C	1.038	0.824–1.308	0.752
Calcium	0.733	0.356–1.508	0.399
Phosphorus	1.142	0.799–1.633	0.465	0.857	0.541–1.359	0.513
Parathyroid hormone	1.000	0.998–1.001	0.628

Abbreviations: HRs, hazard ratios; 95% CI, 95% confidence interval; SpKt/V, single-pool Kt/V; HsCRP, hypersensitive C reactive protein; LDL-C, low-density lipoprotein-cholesterol.

Table 3 The Relationship Between Cardiovascular Events and the Baseline Serum Indirect Bilirubin by Multiple Cox Analysis

	Binary Variable			Tertile Variable
	HRs	95% CI	P-value	HRs	95% CI	P-value
Unadjusted	0.617	0.383–0.993	0.047	0.710	0.535–0.943	0.018
Model 1^a	0.543	0.334–0.882	0.014	0.643	0.480–0.863	0.003
Model 2^b	0.489	0.296–0.806	0.005	0.617	0.458–0.832	0.002
Model 3^c	0.495	0.291–0.840	0.009	0.594	0.427–0.827	0.002
Model 4^d	0.484	0.278–0.844	0.010	0.578	0.410–0.815	0.002

Notes: ^aAdjusted for age, sex; ^bAdjusted for model 1 covariates and hemoglobin, HsCRP, serum albumin, SpKt/V; ^cAdjusted for model 2 covariates and serum uric acid, serum total cholesterol, serum phosphorus, alanine amino-transferase, aspartate amino-transferase. ^dAdjusted for model 3 covariates and hypertension, diabetes, coronary artery disease, congestive heart failure, congestive heart failure.

Abbreviations: CI, confidence interval; HRs, hazard ratios.