Anemia As a Risk Factor for All-Cause Mortality: Obscure Synergic Effect of Chronic Kidney

Anemia as a risk factor for all-cause mortality: Obscure synergic effect of chronic kidney disease

Yuji Sato MD, PhD, Shouichi Fujimoto MD, PhD, Tsuneo Konta MD, PhD, Kunitoshi Iseki MD, PhD, Toshiki Moriyama MD, PhD, Kunihiro Yamagata MD, PhD, Kazuhiko Tsuruya MD, PhD, Ichiei Narita MD, PhD, Masahide Kondo, MD, PhD, Masato Kasahara, MD, PhD, Yugo Shibagaki MD, PhD, Koichi Asahi MD, PhD, , and Tsuyoshi Watanabe MD, PhD

Supplementary Materials

Table S1. Comparison of characteristicsofthose with and without anemia in each eGFR level

Table S2. Hazard ratios and 95% confidence intervals of covariates

Table S3. Comparison of number of participants divided by presence of anemia and mortality in propensity score quintile

Table S4. Comparison of characteristics ofincluded and excluded participants

Fig. S1.Flow chart of participant enrollment

Fig.S2. Kaplan–Meier survival curve in participants witheGFR≥60 mL/min/1.73m2

Fig.S3. Kaplan–Meier survival curve in participants with45≤eGFR <60 mL/min/1.73m2

Fig.S4. Kaplan–Meier survival curve in participants witheGFR<45 mL/min/1.73m2

Table S1. Comparison of characteristicsofthose with and without anemia in each eGFR level

eGFR≥60 level (Group A) / 45≤eGFR<60 level (Group B) / eGFR<45 level (Group C) / Total
(-) Anemia / (+) Anemia / P-value / (-) Anemia / (+) Anemia / P-value / (-) Anemia / (+) Anemia / P-value / Total
n / 47323 / 6152 / 7365 / 1078 / 658 / 355 / 62931
Age, years / 63.5 (8.0) / 62.7 (9.7) / 0.67 / 66.9 (5.6) / 68.3 (5.6) / <0.01 / 68.2 (5.4) / 69.0 (5.1) / 0.02 / 64.0 (8.0)
Sex, male (%) / 38.2% / 24.3% / <0.01 / 50.2% / 38.9% / <0.01 / 55.5% / 48.5% / 0.04 / 38.5%
BMI / 23.2 (3.2) / 22.0 (23.6) / <0.01 / 23.6 (3.1) / 22.4 (3.0) / <0.01 / 24.1 (3.4) / 23.0 (3.5) / <0.01 / 23.1 (3.2)
eGFR / 77.5 (13.1) / 80.0 (15.8) / <0.01 / 54.4 (3.5) / 53.4 (3.7) / <0.01 / 38.6 (7.1) / 32.4 (10.2) / <0.01 / 73.9 (15.6)
Hemoglobin
Men / 14.8 (1.0) / 12.1 (1.0) / <0.01 / 14.8 (1.1) / 12.1 (0.9) / <0.01 / 14.6 (1.1) / 11.6 (1.3) / <0.01 / 14.6 (1.3)
Women / 13.3 (0.8) / 11.1 (1.0) / <0.01 / 13.3 (0.8) / 11.3 (0.6) / <0.01 / 13.0 (0.8) / 10.8 (1.0) / <0.01 / 13.0 (1.1)
Serum creatinine
Men / 0.79 (0.10) / 0.78 (0.10) / <0.01 / 1.05 (0.07) / 1.06 (0.72) / 0.02 / 1.58 (1.04) / 2.16 (1.74) / <0.01 / 0.86 (0.28)
Women / 0.61 (0.08) / 0.60 (0.09) / <0.01 / 0.82 (0.04) / 0.83 (0.05) / <0.01 / 1.25 (1.12) / 1.45 (0.68) / <0.01 / 0.64 (0.17)
Systolic BP / 129 (17) / 124 (18) / <0.01 / 131 (17) / 128 (18) / <0.01 / 134 (17) / 132 (19) / 0.38 / 128 (18)
HDL-C / 61.7 (15.6) / 62.4 (15.5) / <0.01 / 59.0 (15.5) / 59.1 (16.1) / 0.96 / 55.5 (14.6) / 56.9 (16.2) / 0.29 / 61.3 (15.6)
A1c / 5.4 (0.7) / 5.4 (0.6) / 0.01 / 5.4 (0.6) / 5.4 (0.7) / 0.41 / 5.5 (0.7) / 5.5 (0.8) / 0.54 / 5.4 (0.7)
Diabetes mellitus (%) / 8.6 / 7.5 / <0.01 / 9.2 / 12.2 / <0.01 / 16.7 / 22.8 / 0.02 / 8.8
Dipstick proteinuria / 0.50 / 0.13 / <0.01
- / 90.9% / 90.6% / 86.1% / 83.6% / 65.8% / 50.4% / 89.7%
+/- / 5.5% / 5.7% / 6.9% / 8.3% / 10.0% / 7.9% / 5.8%
1+ / 2.6% / 2.5% / 4.7% / 5.0% / 10.6% / 17.5% / 3.1%
2+ / 0.7% / 0.8% / 1.7% / 2.1% / 10.2% / 16.6% / 1.0%
3+ / 0.4% / 0.4% / 0.5% / 0.9% / 3.3% / 7.6% / 0.5%
CVD history, % / 8.50% / 8.10% / 0.25 / 13.70% / 17.50% / 0.01 / 23.60% / 23.40% / 1.00 / 9.50%
Drug user, %
hypertension / 26.0% / 21.7% / <0.01 / 36.5% / 40.1% / 0.02 / 58.8% / 69.9% / 0.01 / 27.6%
diabetes / 4.5% / 5.0% / 0.045 / 5.4% / 8.7% / <0.01 / 12.0% / 18.0% / 0.01 / 4.9%
dyslipidemia / 14.2% / 11.7% / <0.01 / 18.6% / 19.7% / 0.40 / 29.0% / 29.9% / 0.83 / 14.8%
Current smoking, % / 14.0% / 8.3% / <0.01 / 10.9% / 6.5% / <0.01 / 12.6% / 9.9% / 0.22 / 12.9%
Total death, n (%) / 517 (1.1%) / 129 (2.1%) / <0.01 / 120 (1.6%) / 23 (2.1%) / 0.25 / 13 (2.0%) / 26 (7.3%) / <0.01 / 828 (1.3%)
malignancy / 290 (0.6%) / 83 (1.3%) / 0.02 / 60 (0.8%) / 14 (1.3%) / 0.31 / 4 (0.6%) / 11 (3.1%) / 0.71 / 462 (0.7%)
CVD / 92 (0.2%) / 10 (0.2%) / 34 (0.5%) / 3 (0.3%) / 5 (0.8%) / 7 (2.0%) / 151 (0.2%)
others and unknown / 135 (0.3%) / 36 (0.6%) / 26 (0.4%) / 6 (0.6%) / 4 (0.6%) / 8 (2.3%) / 215 (0.3%)

Data given as mean (standard deviation) unless otherwise specified. p-values refer to differences between anemic and non-anemic cohorts.

Abbreviations: ABSI, a body shape index; BMI, body mass index; eGFR, estimated glomerular filtration rate: SBP, systolic blood pressure; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin: CVD, cardiovascular disease.

Table S2.Hazard ratios and 95% confidence intervalsof covariates

Covariates / HR (95% CI) / P-value
Age (+1 SD), year / 1.58 (1.44 - 1.74) / <0.01
Sex, men vs. women / 2.49 (2.12 - 2.91) / <0.01
BMI (+1 SD), kg/m2 / 0.91 (084 -0.98) / 0.01
SBP (+1 SD), mmHg / 1.08 (1.01 - 1.16) / 0.04
HDL-C (+1 SD), mg/dL / 0.96 (0.89 - 1.03) / 0.27
A1c (+1 SD), % / 1.10 (1.04 - 1.17) / <0.01
Proteinuria, ≧1+ / 1.68 (1.33 - 2.12) / <0.01
anti-hypertensive drug use / 1.06 (0.90 - 1.24) / 0.50
anti-diabetes drug use / 1.39 (1.08 - 1.79) / 0.01
anti-hyperlipidemic drug use / 0.68 (0.54 - 0.85) / <0.01
CVD history / 1.24 (1.02 - 1.52) / 0.03
Current smoking / 1.62 (1.37 - 1.93) / <0.01

Abbreviations: BMI, body mass index; SBP, systolic blood pressure; HDL-C, high-density lipoprotein cholesterol; HbA1c, glycated hemoglobin;CVD, cardiovascular disease; CI, confidence interval; SD, standard deviation.

Table S3. Comparison of number of participants divided by presence of anemia and mortality in propensity score quintile

mortality / (-) anemia / (+) anemia
Quintile 1 / none / 13576 / 769
yes / 214 / 33
Quintile 2 / none / 12591 / 1219
yes / 157 / 27
Quintile 3 / none / 10542 / 1457
yes / 123 / 32
Quintile 4 / none / 9890 / 1773
yes / 84 / 35
Quintile 5 / none / 8097 / 2189
yes / 72 / 51

Table S4. Comparison of characteristics ofincluded and excluded participants

Included / Excluded / Total / P-value
n / 62931 / 232366 / 295297
Age, years / 64.0 (8.0) / 63.4 (8.5) / 63.6 (8.4) / <0.01
Sex, male (%) / 38.5% / 41.1% / 40.6% / <0.01
Drug user, %
hypertension / 27.6% / 28.1% / 28.0% / 0.01
diabetes / 4.9% / 4.8% / 4.8% / 0.40
dyslipidemia / 14.8% / 14.2% / 14.3% / <0.01
Current smoking, % / 12.9% / 13.8% / 13.6% / <0.01
All-cause mortality, n (%) / 828 (1.3%) / 2,936 (1.3%) / 3,764 (1.3%) / 0.30
Malignancy, n (%) / 462 (0.73%) / 1446 (0.62%) / 1908 (0.65%) / 0.04
Cardiovascular disease, n (%) / 153 (0.24%) / 615 (0.26%) / 768 (0.26%)
Others or unknown, n (%) / 213 (0.34%) / 875 (0.38%) / 1088 (0.37%)

Fig. S1. Flow chart of participant enrollment

Of the 295,297 individuals registered in the Specific Health Checkup program, 231,842 were excluded because of missing data. Ultimately, 62,931 individuals were included in our analysis. Abbreviations: BMI, body mass index; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; SBP, systolic blood pressure; WC, waist circumference.

Fig.S2. Kaplan–Meier survival curve in participants witheGFR≥60 mL/min/1.73m2

Survival curveis shown by Kaplan–Meier method. p-value was calculated by log-rank test.

Blue line indicates participants without anemia. Green line indicates participants with anemia.

Fig.S3. Kaplan–Meier survival curve in participants with45≤eGFR <60 mL/min/1.73m2

Survival curveis shown by Kaplan–Meier method. p-value was calculated by log-rank test.

Blue line indicates participants without anemia. Green line indicates participants with anemia.

Fig.S4. Kaplan–Meier survival curve in participants witheGFR<45 mL/min/1.73m2

Survival curveis shown by Kaplan–Meier method. p-value was calculated by log-rank test.

Blue line indicates participants without anemia. Green line indicates participants with anemia.