Abstract
Background
Although hemoglobin (Hb) levels are affected by a change in the body fluid status, the relationship between Hb levels and mortality while taking interdialytic weight gain (IDWG) at blood sampling into account has not yet been examined in hemodialysis patients.
Study design
Cohort study.
Setting, Participants
Data from the Miyazaki Dialysis cohort study, including 1375 prevalent hemodialysis patients (median age (interquartile range), 69 (60–77) years, 42.3% female).
Predictor
Patients were divided into 5 categories according to baseline Hb levels and two groups based on the median value of IDWG rates at blood sampling at pre-HD on the first dialysis session of the week.
Outcomes
All-cause and cardiovascular mortalities during a 3-year follow-up.
Measurements
Hazard ratios were estimated using a Cox model for the relationship between Hb categories and mortality, and adjusted for potential confounders such as age, sex, dialysis duration, erythropoiesis-stimulating agent dosage, Kt/V, comorbid conditions, anti-hypertensive drug use, serum albumin, serum C-reactive protein, serum ferritin, and serum intact parathyroid hormone. Patients with Hb levels of 9–9.9 g/dL were set as our reference category.
Results
A total of 246 patients (18%) died of all-cause mortality, including 112 cardiovascular deaths. Lower Hb levels (<9.0g/dL) were associated with all-cause mortality (adjusted HRs 2.043 [95% CI, 1.347–3.009]), while Hb levels were not associated with cardiovascular mortality. When patients were divided into two groups using the median value of IDWG rates (high IDWG, ≥5.4% and low IDWG, <5.4%), the correlation between lower Hb levels and all-cause mortality disappeared in high IDWG patients, but was maintained in low IDWG patients (adjusted HRs 3.058 [95% CI,1.575–5.934]). On the other hand, higher Hb levels (≥12g/dL) were associated with cardiovascular mortality in high IDWG patients (adjusted HRs 2.724 [95% CI, 1.010–7.349]), but not in low IDWG patients.
Conclusion
In hemodialysis patients, target Hb levels may need to be selected in consideration of IDWG at blood sampling.
Introduction
Anemia is common in end-stage renal disease and is a major risk factor that contributes to mortality in patients with chronic kidney disease. The optimal hemoglobin (Hb) target in these patients remains controversial. In many observational studies on hemodialysis (HD) patients, low Hb levels have been associated with mortality [1, 2], cardiovascular events [3], and quality of life [4, 5].
On the other hand, for higher Hb levels, an appropriate Hb target has remained under debate. Previous studies showed that higher Hb levels slightly increased the risk of death [6], and elevations in Hb levels have been implicated in a higher risk of mortality and cardiovascular events [7, 8]. Higher Hb targets have been suggested to reduce the need for transfusions, and have beneficial effects on quality of life [9–11]; however, disadvantages have also been reported [12–14].
Hb levels are known to vary during HD, and significantly differ when measured before or after dialysis or in the interdialysis period depending on ultrafiltration [15–18].
Although Hb levels are affected by a change in the body fluid status, the relationship between Hb levels and mortality while taking the interdialytic weight gain (IDWG) at blood sampling into account has not yet been examined. Therefore, the aim of the present study is to evaluate the relationships between Hb levels and all-cause and cardiovascular mortalities while adjusting for the effects of IDWG.
Materials and Methods
The Miyazaki Dialysis Cohort study is a prospective observational study of maintenance HD patients from 27 dialysis centers and was initiated by the University of Miyazaki, Japan. A total of 1,375 patients were analyzed in this cohort study in December, 2009 and were followed-up for 3 years. Exclusion criteria included patients with a 3-month hemodialysis vintage, < 18 years of age, pregnant women, hospitalized patients, and patients not wishing to participate; 176 patients were excluded for missing Hb or IDWG data. Information on physical characteristics, laboratory data, basal renal diseases, comorbidities, and medications was collected by doctors in each dialysis center at the start of the study (Fig 1).
Fig 1. Flow of patients through the study.
All causes of death were checked monthly by nursing staff or medical doctors during the follow-up period using questionnaires, which were searched by Y.S. and T.T. if necessary. Check sheets were collected annually. The survival time was defined as the time from enrollment to individual outcomes, the data for which were collected longitudinally during the course of the study follow-up until December 2012.
Cardiovascular mortality was defined as death from ischemic or hemorrhagic stroke, acute MI, causes related to congestive heart failure, sudden death, or aortic aneurysm rupture. Stroke was diagnosed using typical imaging and physical findings from examinations. Acute MI was diagnosed using typical electrocardiogram findings or elevations in myocardium-derived enzymes. Cardiac disease was confirmed based on a history of ischemic heart disease and/or congestive heart failure. Ischemic heart disease was defined as prior hospitalization or medication for angina pectoris and/or MI. Congestive heart failure was confirmed using electrocardiography, chest radiography, or echocardiography together with symptoms of dyspnea or edema. Sudden death was judged as unexpected death in the first hour following the start of symptoms or when the patient was found dead and had been seen alive 24 hours earlier. Blood samples are taken in a supine position at pre-HD on the first dialysis session of the week.
We converted the darbepoetin alfa dose to an equivalent epoetin alfa dose using a dose conversion ratio of 200 units of epoetin alfa per 1 μg of darbepoetin alfa [19, 20], and the doses of epoetin alfa and beta were considered to be equivalent.
Pre-HD blood pressure was measured in the supine position. Blood pressure values were averaged from 3 consecutive HD sessions during the week of patient enrollment.
Statistical analysis
Descriptive analyses were calculated to describe variables such as patient characteristics in groups distributed according to Hb levels. All continuous variables were tested for a normal distribution, and the Student’s t-test (for a normal distribution) or Kruskal-Wallis test (for a non-normal distribution) or χ2 test was applied for comparisons of the five groups. Crude survival in a group was assessed using a Kaplan-Meier analysis with the Log-rank test. For Cox regression, our model included adjustment for age, sex, time on dialysis therapy, history of CVD, the presence of diabetes, serum albumin level. Given that previous studies found another covariates to be potential confounding factors, we also examined a model including these factors with anti-hypertension drugs, single-pool Kt/V, serum intact parathyroid hormone (iPTH), C-reactive protein and ferritin level [21–27]. All covariates were divided into categorical groups. We defined age as per 10 years, serum C-reactive protein, albumin, iPTH, ferritin, ESA dosage, time on dialysis therapy as quartile category. Patients with an Hb level of 9–9.9 g/dL were set as our reference category according to clinical guidelines [28]. All the covariates conformed to the proportional hazards model, using the Kaplan-Meier method and log–log plot. A multiple imputation approach using chained equations was used to account for missing covariates. All statistical analyses were performed with SPSS Statistics 20 (IBM Company, Chicago, USA).
Ethical Considerations
This study was conducted in accordance with the principles contained in the Declaration of Helsinki and was approved by the University of Miyazaki Research Ethics Committee (No.516). Data collection was performed in a manner that maintained patient anonymity (UMIN00000516).
Results
Study participants and baseline characteristics
Table 1 shows baseline patient characteristics according to Hb levels. Significant differences were observed in age, sex, ESA use ratios, and the median values for serum albumin, creatinine, C-reactive protein, ferritin, i-PTH, single-pool Kt/V, and ESA dosage by the Kruskal-Wallis test or Student’s t-test. Seventeen patients out of 137 with an Hb level > 12 g/dl did not use ESA. No significant differences were observed in anti-hypertension drug use including angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers.
Table 1. Baseline patient characteristics.
| Hemoglobin levels | p value* | |||||||
|---|---|---|---|---|---|---|---|---|
| Number missing | Overall | <9 g/dL | 9–9.9 g/dL | 10–10.9 g/dL | 11–11.9 g/dL | ≥12 g/dL | ||
| Number | 1375 | 111 | 319 | 435 | 373 | 137 | ||
| Age (yr) | 0 | 69 (60–77) | 75 (68–82) | 66 (60–74) | 68 (58–76) | 65 (55–74) | 65 (55–74) | 0.003 |
| Female, n (%) | 0 | 582 (42.3) | 59 (53.2) | 156 (48.9) | 187 (43.0) | 143 (38.3) | 37 (27.0) | <0.001 |
| Duration of HD (month) | 17 | 75 (33–143) | 66 (29–128) | 72 (30–138) | 79 (36–144) | 77 (34–149) | 74 (29–146) | 0.642 |
| Diabetes, n (%) | 0 | 445 (32.4) | 37 (33.3) | 109 (34.2) | 139 (32.0) | 117 (31.4) | 43 (31.4) | 0.940 |
| Pre-HD SBP (mmHg) | 63 | 155.3 (143.0–167.3) | 156.7 (145.0–166.3) | 156.7 (143.7–170.0) | 155.3 (144.0–166.0) | 154.3 (142.0–168.0) | 154.0 (136.3–164.2) | 0.150 |
| Previous history of CVD, n (%) | 0 | 377 (27.4) | 36 (32.4) | 100 (31.3) | 112 (25.7) | 95 (25.5) | 34 (24.8) | 0.226 |
| Hemoglobin (g/dL) | 0 | 10.6 (9.7–11.4) | 8.5 (7.9–8.7) | 9.6 (9.3–9.8) | 10.5 (10.2–10.7) | 11.4 (11.2–11.6) | 12.3 (12.1–12.8) | <0.001 |
| Serum albumin (g/dL) | 191 | 3.8 (3.6–4.0) | 3.6 (3.4–3.9) | 3.7 (3.5–4.0) | 3.8 (3.6–4.1) | 3.9 (3.6–4.1) | 3.9 (3.6–4.1) | <0.001 |
| Serum blood urine nitrogen (mg/dL) | 24 | 65.8 (56.0–77.5) | 64.2 (50.6–76.2) | 65.3 (55.6–78.5) | 64.3 (55.3–75.9) | 68.2 (57.8–79.2) | 66.3 (56.9–76.4) | 0.067 |
| Serum creatinine (mg/dL) | 24 | 10.6 (8.8–12.5) | 9.9 (7.9–11.4) | 10.1 (8.6–11.6) | 10.7 (9.0–12.4) | 11.1 (9.3–13.1) | 11.3 (9.1–13.7) | <0.001 |
| Serum C-reactive protein (mg/dL) | 286 | 0.20 (0.07–0.70) | 0.40 (0.10–1.48) | 0.31 (0.10–0.95) | 0.19 (0.07–0.54) | 0.13 (0.06–0.50) | 0.20 (0.06–0.67) | <0.001 |
| Transferrin saturation (%) | 682 | 27.1 (18.6–37.2) | 25.4 (14.1–36.7) | 27.8 (19.5–38.4) | 27.6 (19.0–37.8) | 26.0 (18.3–36.1) | 26.5 (17.9–35.6) | 0.331 |
| Serum Ferritin (ng/ml) | 451 | 120.0 (44.5–257.0) | 219.0 (91.8–404.5) | 193.0 (55.3–332.6) | 114.1 (45.4–227.8) | 96.0 (39.1–212.0) | 68.6 (34.3–158.8) | <0.001 |
| Serum iPTH | 556 | 150.8 (67.0–269.0) | 136.0 (50.0–246.0) | 144.0 (47.0–264.0) | 148.0 (72.0–272.0) | 149.0 (69.0–262.5) | 190.6 (69.0–262.5) | 0.033 |
| Single-pool Kt/V | 127 | 1.16 (1.03–1.32) | 1.17 (1.00–1.33) | 1.17 (1.03–1.32) | 1.18 (1.03–1.33) | 1.16 (1.04–1.31) | 1.10 (0.96–1.26) | 0.005 |
| ESA use, n (%) | 0 | 1299 (94.5) | 110 (99.1) | 308 (96.6) | 411 (94.5) | 350 (93.8) | 120 (87.6) | 0.001 |
| ESA dosage (U/week) | 542 | 3778 (2187–5705) | 6000 (4000–8000) | 4500 (3000–6000) | 3224 (2250–5102) | 3000 (2000–4486) | 2925 (1500–4500) | <0.001 |
| Anti-hypertensive drug use, n (%) | 0 | 1183 (86.0) | 88 (79.3) | 277 (86.8) | 369 (84.8) | 321 (86.1) | 118 (86.1) | 0.388 |
| -ACEI use, n (%) | 0 | 124 (10.7) | 8 (8.3) | 30 (10.8) | 32 (8.9) | 45 (14.0) | 9 (8.3) | 0.191 |
| -ARB use, n (%) | 0 | 648 (54.2) | 46 (46.9) | 155 (54.8) | 201 (54.2) | 188 (56.1) | 58 (53.2) | 0.617 |
| Interdialysis weight gain (%) | 0 | 5.4 (4.2–6.7) | 5.7 (4.0–7.5) | 5.5 (4.5–7.2) | 5.4 (4.0–6.6) | 5.7 (4.5–7.0) | 5.1 (4.4–6.5) | 0.051 |
Continuous variables are represented as a median with the interquartile range in parentheses. Abbreviations: HD—hemodialysis, SBP—systolic blood pressure, iPTH—intact parathyroid hormone, ESA—erythropoiesis-stimulating agent.
* by the Kruskal-Wallis test or χ2 test.
In the 3 years after 1 January 2010, 246 patients died of all-cause mortality, including 112 cardiovascular deaths, while 111 (8.0%) moved to other dialysis facilities, including 16 who underwent kidney transplantation.
Analysis for all-cause and cardiovascular mortalities
Fig 2 shows that the survival rate was significantly lower in patients in the Hb < 9.0% group than in those in the other groups (Kaplan–Meier analysis, Log-rank test, P < 0.001). Unadjusted and adjusted Cox’s proportional hazard models showed that the risk of all-cause mortality was significantly higher in the groups with lower Hb levels (Hb<9.0%) (unadjusted HRs 2.366 [95% CI, 1.830–3.957], adjusted HRs 2.043 [95% CI, 1.347–3.099]) (Table 2A). S1 Table shows all HRs of covariates on all-cause mortality. On the other hand, unadjusted Cox’s proportional hazard models showed that the risk of cardiovascular mortality was significantly higher in the groups with lower Hb levels (Hb<9.0%) (HRs 1.960 [95% CI, 1.008–3.809]); however, cardiovascular mortality was not correlated with the Hb level after multivariate adjustment (Table 2B).
Fig 2. Kaplan–Meier estimates for survival rates among baseline Hb levels.
The survival rate was significantly lower in patients in the Hb<9 g/dL group than in those in the other groups (Kaplan–Meier analysis, Log-rank test, P < 0.001).
Table 2. Relationship between baseline hemoglobin levels and hazard ratios of all-cause (2a) and cardiovascular (2b) mortalities.
| Hemoglobin level | ||||||
|---|---|---|---|---|---|---|
| <9 g/dL | 9–9.9 g/dL | 10–10.9 g/dL | 11–11.9 g/dL | ≥12 g/dL | ||
| 2a) | Unadjusted model | 2.366 (1.830–3.957)** | 1.000 (ref) | 0.879 (0.619–1.249) | 0.803 (0.553–1.164) | 0.970 (0.601–1.565) |
| Adjusted model* | 2.043 (1.347–3.009)** | 1.000 (ref) | 1.109 (0.766–1.607) | 1.226 (0.821–1.829) | 1.374 (0.823–2.293) | |
| 2b) | Unadjusted model | 1.960 (1.008–3.809)** | 1.000 (ref) | 1.164 (0.693–1.953) | 0.961 (0.551–1.676) | 0.985 (0.469–2.068) |
| Adjusted model* | 1.823 (0.920–3.609) | 1.000 (ref) | 1.417 (0.820–2.451) | 1.394 (0.766–2.539) | 1.266 (0.575–2.766) | |
Values shown are hazard ratios (95% confidence interval).
*Adjusted for age, sex, ESA dosage, time on dialysis therapy, diabetes, previous history of cardiovascular diseases, single pool Kt/V, serum Alb, serum ferritin, serum C-reactive protein, serum iPTH and anti-hypertensive drug.
** p value <0.05.
Effects of IDWG at blood sampling on the relationship between Hb levels and mortality
Dividing the patients into two groups using the median value of IDWG rates (high IDWG, ≥5.4% and low IDWG, <5.4%), the all-cause mortality of high IDWG group was significantly higher compared with low IDWG group (Kaplan-Meier analysis, P<0.001). However, there was no significant correlation between Hb levels and IDWG (0.040 by Pearson's correlation coefficient, p = 0.135), and these factors have no interaction on all-cause and cardiovascular mortality (S1 Fig). Baseline patient characteristics according to Hb levels were shown in Table 3. In the low IDWG group, significant differences were observed in sex, serum albumin, serum creatinine, serum C-reactive protein, serum ferritin, single-pool Kt/V, ESA use, and ESA dosage. On the other hand, in the high IDWG group, significant differences were observed in sex, age, pre-HD systolic blood pressure, serum albumin, serum blood urine nitrogen, serum creatinine, serum C-reactive protein, serum ferritin, ESA use, ESA dosage, and IDWG.
Table 3. Baseline patient characteristics stratified by the interdialytic weight gain status.
| IDWG<5.4% | IDWG>5.4% | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| <9 g/dL | 9–9.9 g/dL | 10–10.9 g/dL | 11–11.9 g/dL | ≥12 g/dL | p value* | <9 g/dL | 9–9.9 g/dL | 10–10.9 g/dL | 11–11.9 g/dL | ≥12 g/dL | p value* | |
| Number | 51 | 153 | 217 | 170 | 82 | 60 | 166 | 218 | 203 | 55 | ||
| Age (yr) | 74 (62–80) | 69 (62–78) | 68 (59–76) | 66 (59–76) | 70 (60–78) | 0.060 | 75 (65–78) | 69 (61–78) | 69 (58–77) | 67 (59–76) | 66 (55–74) | 0.026 |
| Female, n (%) | 26 (51.0) | 73 (47.7) | 91 (41.9) | 62 (36.5) | 19 (23.2) | 0.002 | 33 (55.0) | 83 (50.0) | 96 (44.0) | 81 (39.9) | 18 (32.7) | 0.049 |
| Duration of HD (month) | 68 (29–138) | 61 (27–134) | 62 (32–134) | 77 (31–152) | 55 (20–138) | 0.753 | 62 (29–128) | 81 (36–148) | 93 (44–151) | 81 (35–142) | 88 (38–165) | 0.182 |
| Diabetes, n (%) | 13 (25.5) | 50 (32.7) | 69 (31.8) | 47 (27.6) | 24 (29.3) | 0.771 | 24 (40.0) | 59 (35.5) | 70 (32.1) | 70 (34.5) | 19 (34.5) | 0.838 |
| Pre-HD SBP (mmHg) | 155.3 (143.3–166.3) | 152.0 (141.7–164.5) | 154.7 (144.5–164.0) | 152.7 (140.0–163.1) | 154.0 (135.8–164.0) | 0.679 | 157.0 (143.9–166.2) | 160.6 (150.0–173.8) | 156.2 (144.4–168.0) | 155.3 (145.7–171.3) | 154.0 (136.7–164.7) | 0.019 |
| Previous history of CVD, n (%) | 18 (35.3) | 51 (33.3) | 53 (24.4) | 38 (22.4) | 23 (28.0) | 0.112 | 18 (30.0) | 49 (29.5) | 59 (27.1) | 57 (28.1) | 11 (20.0) | 0.714 |
| Hemoglobin (g/dL) | 8.5 (7.8–8.7) | 9.6 (9.3–9.8) | 10.5 (10.2–10.7) | 11.4 (11.2–11.6) | 12.3 (12.1–12.7) | <0.001 | 8.5 (8.0–8.8) | 9.5 (9.3–9.7) | 10.5 (10.2–10.7) | 11.4 (11.2–11.7) | 12.4 (12.1–12.9) | <0.001 |
| Serum albumin (g/dL) | 3.6 (3.4–4.0) | 3.8 (3.5–4.0) | 3.8 (3.6–4.1) | 3.9 (3.7–4.1) | 3.9 (3.6–4.1) | 0.001 | 3.6 (3.3–3.8) | 3.7 (3.5–4.0) | 3.8 (3.6–4.0) | 3.9 (3.6–4.1) | 3.9 (3.6–4.1) | <0.001 |
| Serum blood urine nitrogen (mg/dL) | 64.9 (49.2–77.5) | 62.4 (50.8–73.1) | 62.7 (53.0–73.4) | 66.0 (53.1–78.1) | 64.4 (52.0–72.9) | 0.567 | 62.3 (53.1–75.1) | 69.4 (60.1–83.0) | 66.6 (57.5–78.1) | 69.4 (61.2–81.6) | 69.8 (61.6–82.3) | 0.009 |
| Serum creatinine (mg/dL) | 10.1 (7.9–11.8) | 10.1 (8.7–11.5) | 10.6 (9.0–12.2) | 11.2 (9.1–13.5) | 10.9 (8.9–13.3) | 0.002 | 9.6 (7.9–11.1) | 10.2 (8.5–11.6) | 10.8 (9.0–12.6) | 10.9 (9.3–12.8) | 12.5 (9.2–14.4) | <0.001 |
| Transferrin saturation (%) | 27.1 (12.3–34.9) | 28.5 (21.0–38.8) | 27.4 (19.9–35.1) | 26.7 (17.8–38.0) | 25.8(16.8–34.3) | 0.427 | 25.1 (16.3–37.8) | 26.0 (18.5–38.5) | 28.7 (18.9–40.3) | 25.7 (18.5–34.5) | 27.0 (18.0–37.6) | 0.435 |
| Serum C-reactive protein (mg/dL) | 0.52 (0.20–1.40) | 0.40 (0.10–1.39) | 0.17 (0.06–0.70) | 0.15 (0.06–0.70) | 0.20 (0.08–1.15) | <0.001 | 0.30 (0.10–0.98) | 0.21 (0.10–0.81) | 0.20 (0.07–0.56) | 0.10 (0.05–0.45) | 0.10 (0.04–0.40) | 0.003 |
| Serum ferritin (ng/ml) | 219.0 (70.1–378.6) | 210.6 (59.0–321.7) | 112.6 (45.9–218.8) | 92.2 (39.4–218.1) | 73.9 (37.4–148.8) | <0.001 | 227.0 (108.8–405.6) | 176.3 (51.5–344.4) | 116.3 (45.3–256.9) | 98.2 (38.9–201.2) | 66.7 (27.1–170.8) | <0.001 |
| Serum iPTH (pg/ml) | 129.0 (45.9–246.0) | 144.0 (51.0–284.0) | 147.0 (72.5–256.6) | 161.5 (67.6–287.0) | 192.3 (110.0–312.3) | 0.085 | 143.0 (60.0–250.8) | 148.0 (45.2–261.1) | 150.1 (70.1–292.7) | 142.4 (70.0–235.0) | 188.0 (102.0–293.2) | 0.344 |
| Single-pool Kt/V | 1.21 (1.03–1.33) | 1.13 (1.02–1.30) | 1.16 (1.02–1.32) | 1.16 (1.01–1.27) | 1.10 (0.95–1.25) | 0.043 | 1.12 (1.00–1.34) | 1.19 (1.04–1.32) | 1.20 (1.06–1.35) | 1.17 (1.04–1.35) | 1.11 (0.97–1.26) | 0.116 |
| ESA use, n (%) | 51 (100) | 147 (96.1) | 209 (96.3) | 157 (92.4) | 72 (87.8) | 0.008 | 59 (98.3) | 161 (97.0) | 202 (92.7) | 193 (95.1) | 48 (87.3) | 0.031 |
| ESA dosage (U/week) | 6000 (3750–8000) | 5074 (3000–6872) | 3000 (2599–4754) | 3000 (1603–4027) | 2909 (1559–4500) | <0.001 | 6000 (4500–8158) | 4182 (3000–6000) | 3251 (2000–5455) | 3000 (2000–4500) | 3000 (1339–5027) | <0.001 |
| Anti-hypertensive drug use, n (%) | 39 (76.5) | 131 (85.6) | 190 (87.6) | 145 (85.3) | 69 (84.1) | 0.386 | 49 (81.7) | 146 (88.0) | 179 (82.1) | 176 (86.7) | 49 (89.1) | 0.369 |
| Interdialysis weight gain (%) | 3.7 (2.4–4.8) | 4.4 (3.5–4.9) | 4.2 (3.3–4.8) | 4.2 (3.5–4.9) | 4.4 (3.5–4.9) | 0.161 | 6.9 (6.1–8.5) | 7.0 (6.1–7.9) | 6.6 (5.9–7.4) | 6.6 (5.9–7.9) | 6.9 (5.8–7.5) | 0.028 |
Continuous variables are represented as a median with the interquartile range in parentheses. Abbreviations: HD—hemodialysis, SBP—systolic blood pressure, CVD–cardiovascular disease, iPTH—intact parathyroid hormone, ESA—erythropoiesis-stimulating agent.
* by the Kruskal-Wallis test or χ2 test.
Table 4 shows the numbers of all-cause and cardiovascular deaths. The correlation between lower Hb levels and all-cause mortality disappeared in high IDWG patients (IDWG ≥5.4%), but was maintained in low IDWG patients (<5.4%) (adjusted HRs 3.058 [95% CI, 1.575–5.934]) (Table 5A). On the other hand, higher Hb levels (≥12g/dL) were associated with cardiovascular mortality in high IDWG patients (adjusted HRs 2.365 [95% CI, 0.087–9.9820.882–6.344]), but not in low IDWG group. (Table 5B). In higher Hb group among high IDWG group, serum ferritin levels at baseline were significantly different between the patients with or without cardiovascular death (with cardiovascular death vs. without: median (interquartile range) 232.7 (63.1–383.9) vs 56.8 (26.6–130.9), p = 0.022, Wilcoxon signed-rank test), but other covariates were not different (S2 Table).
Table 4. Number of all-cause and cardiovascular deaths and observed Hb levels stratified by the interdialytic weight gain (IDWG) status.
| IDWG<5.4% | IDWG≥5.4% | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| <9 g/dL (n = 51) | 9–9.9 g/dL (n = 153) | 10–10.9 g/dL (n = 217) | 11–11.9 g/dL (n = 170) | ≥12 g/dL (n = 82) | <9 g/dL (n = 60) | 9–9.9 g/dL (n = 166) | 10–10.9 g/dL (n = 218) | 11–11.9 g/dL (n = 203) | ≥12 g/dL (n = 55) | |
| All-cause death, n (%) | 20 (39.2) | 21 (13.7) | 29 (13.4) | 21 (12.4) | 13 (15.6) | 21 (35.0) | 35 (21.1) | 41 (18.8) | 34 (16.7) | 11 (20.0) |
| Cardiovascular death, n (%) | 9 (17.6) | 11 (7.2) | 18 (8.3) | 12 (7.1) | 3 (3.7) | 5 (8.3) | 12 (7.2) | 20 (9.2) | 15 (7.4) | 7 (12.7) |
Table 5. Relationship between baseline hemoglobin levels and adjusted hazard ratios of all-cause (5a) and cardiovascular (5b) mortalities by the category of the interdialytic weight gain status.
| Hemoglobin level | ||||||
|---|---|---|---|---|---|---|
| <9 g/dL | 9–9.9 g/dL | 10–10.9 g/dL | 11–11.9 g/dL | ≥12 g/dL | ||
| 5a) | IDWG<5.4% | 3.058 (1.575–5.934)* | 1.000 (ref) | 1.156 (0.623–2.143) | 1.504 (0.767–2.949) | 1.374 (0.622–3.003) |
| IDWG≥5.4% | 1.367 (0.760–2.461) | 1.000 (ref) | 1.061 (0.661–1.702) | 1.061 (0.640–1.758) | 1.511 (0.744–3.067) | |
| 5b) | IDWG<5.4% | 2.359 (0.895–6.221) | 1.000 (ref) | 1.025 (0.450–2.336) | 1.349 (0.543–3.353) | 0.395 (0.100–1.555) |
| IDWG≥5.4% | 1.061 (0.355–3.171) | 1.000 (ref) | 1.570 (0.744–3.314) | 1.439 (0.640–3.235) | 2.724 (1.010–7.349)* | |
Values shown are hazard ratios (95% confidence interval). Adjusted for age, sex, ESA dosage, time on dialysis therapy, diabetes, previous history of cardiovascular disease, single pool Kt/V, serum Alb, serum ferritin, serum C-reactive protein, serum iPTH and anti-hypertensive drugs.
*p value <0.05.
Discussion
In the present prospective cohort study on HD patients, lower Hb levels (<9.0 g/dL) were associated with all-cause mortality. This relationship remained largely unchanged even after adjustments for the potential confounding factors of age, sex, dialysis duration, ESA dosage, Kt/V, comorbid conditions, anti-hypertensive drug use, serum albumin, C-reactive protein, ferritin and iPTH. When patients were divided into two groups using the median value of IDWG rates (high IDWG, ≥5.4% and low IDWG, <5.4%), the correlation between lower Hb levels and all-cause mortality disappeared in high IDWG patients, but was maintained in low IDWG patients. On the other hand, higher Hb levels were associated with cardiovascular mortality in high IDWG patients, but not in low IDWG patients.
In an international comparison of Hb levels and ESA use in HD patients, despite major differences in the treatments used [29,30], several observational studies showed that severe anemia in HD patients was related to increased morbidity and mortality [31–35]. In Japan and other Asian countries, several observational studies reported similar findings [36–39]. Although the relationship between lower Hb levels and the risk of mortality is well known in HD patients, an appropriate Hb target as higher Hb levels has remained controversial in terms of cardiovascular events in addition to mortality. Three large randomized controlled trials using patients with chronic kidney disease not yet on dialysis have been completed [40–42] and found no evidence of benefits of a higher (compared with lower) Hb target on cardiovascular events or a composite outcome of death, myocardial infarction, or hospitalization for congestive heart failure and stroke, or found an increased risk of adverse events. In HD patients, the Normal Hematocrit Trial [8], a study in which more than 1200 patients with congestive heart failure or ischemic heart disease were randomized to target Hct values of 42% (normal Hct group) and 30%, had to be stopped prematurely by the Data Safety Monitoring Board because of concerns regarding increased risks of cardiovascular disease and mortality in the normal Hct arm. On the other hand, in HD patients with naturally occurring higher Hb levels, Goodkin et al. reported that Hb levels of 12 g/dl did not increase the risk of mortality in patients without ESA therapy over that in other patients [43].
ESA-sensitive patients derive survival benefits from the full correction of anemia, whereas patients with ESA resistance (which is a predictor of poor survival) may be harmed by the high doses of ESA prescribed in the attempt to increase Hb levels [44, 45]; however, this is still under debate [46]. Although higher Hb targets have been suggested to reduce the need for transfusions and have beneficial effects on the quality of life of patients [9–11], disadvantages have also been reported [12–14]. In addition to the use of ESA, several studies have shown that the survival benefit is affected by age [47], diabetes [48] and a previous history of cardiovascular disease [49].
A failure in the management of body fluid volume has a negative impact on blood pressure and the cardiovascular system [50–53]. Furthermore, there are some reports that analyzed the association between IDWG and prognosis. According to United States Renal Data System data, high IDWG (>4.8%) is associated with mortality [54]. In other studies, IDWG of more than 5.7% has been associated with a higher risk of adverse outcomes [55]. In the present study, higher IDWG (≥5.4%) was associated with all-cause mortality (Kaplan-Meier analysis, P<0.001).
Serum Hb levels have been shown to vary during HD, and Hb levels also significantly differ when measured before or after dialysis or in the interdialysis period [15–18]. Vlassopoulos et al. [15] measured Hb levels in 15 stable patients before the initiation of a HD session, and at 24, 48, and 72 hours in the interdialysis period. They observed a significant 24-h postdialysis increase in Hb levels from the predialysis level, with a gradual decrease to a non-significant level before the next HD session. Movilli et al. reported similar findings [16]. Bellizzi et al. demonstrated that interdialytic Hb increments differed in the three sessions and weight loss per 1L of ultrafiltration led to an increase in the Hb level of approximately 0.4 g/dL [17]. Castillo also reported a significant increment in Hb levels after HD. The mean percent increase in Hb levels was 6.1%, and increased to approximately 9% in patients with a body weight loss ≥ 2.5 kg/session [18]. Considering above-mentioned reports, the present study that demonstrated a correlation between cardiovascular mortality and higher Hb levels in high IDWG patients may suggest that an over-correction of Hb after HD is correlated to cardiovascular death. Higher Hb levels after HD could be reached resulting in severe hypertension and hypercoagulability or decreased perfusion to major arteries already at risk [56–58], and then be related to cardiovascular events. However, either high IDWG or high Hb levels of pre-HD are more involved in the higher Hb levels of post-HD is unknown in this study, and the definite relationship between cardiovascular death and the Hb level of post-HD remains unclear. Further studies will be needed to clarify the relationships between the post-HD Hb levels and cardiovascular events. In higher Hb group among high IDWG group, serum ferritin levels were higher in the patients with cardiovascular death than without. Recent study showed that the patients with higher serum ferritin levels were associated with higher mortality risk than those with lower ferritin levels [59]. Therefore, high serum ferritin levels may accelerate cardiovascular mortality in higher Hb group among high IDWG group.
The present study is the first prospective study to have examined the relationship between mortality and Hb levels in consideration of IDWG at blood sampling. Furthermore, multivariate analyses on mortality were performed after adjustments for some known confounding factors of all-cause and cardiovascular mortalities other than Hb levels (age, sex, dialysis duration, diabetes, Kt/V, comorbid conditions, ACEI/ARB use, serum albumin, C-reactive protein, ferritin, i-PTH, and ESA dosage) [21–27].
This study has several limitations. The present study was observational, not interventional. Furthermore, the result of this study may be limited only to the registration facility. It is necessary to examine external validity. Our cohort consisted of prevalent, but not incident chronic dialysis patients. Therefore, some patients with severe anemia control may have died before study enrollment. Moreover, a major cause of cardiovascular mortality is congestive heart failure; however, we were unable to identify the specific underlying etiologies. Thus, there may have been some valvular heart diseases in addition to ischemic heart diseases; it is unclear how Hb levels affect valvular heart diseases. Another limitation is that baseline data were used to define exposure categories in this cohort, and we were unable to examine the effects of changes from the baseline category during follow-up, although the average value of Hb and IDWG may be appropriate than single measurement. Equation between epoetin and darbepoetin [19, 20] is not established one.
Conclusions
The results of the present study demonstrated that lower Hb levels (<9.0g/dL) were associated with all-cause mortality in low IDWG patients only. Furthermore, regarding cardiovascular mortality, a correlation was observed in lower Hb levels in low IDWG patients and higher Hb levels in high IDWG patients. Although Hb levels are affected by a change in the body fluid status, the target Hb of the current guidelines [27, 60, 61] do not take into account body fluid status. The results of the present study suggest that target Hb levels may need to be selected in consideration of IDWG at blood sampling.
Supporting Information
Interaction of Hb and IDWG on all-cause mortality (a) and cardiovascular mortality (b).
(TIF)
(DOCX)
(DOCX)
Acknowledgments
The authors appreciate the help of the following attending physicians for their participation in the study by collecting data and providing useful suggestions: Y. Yamamoto, O. Wakisaka, T. Tanaka, H. Ebihara, M. Kuroki, M. Yamashita, J. Miyata, K. Aso, H. Ochiai, S. Uezono, S. Hisanaga, S. Morita, F. Iemura, T. Uchida, N. Yokota, F. Sawano, M. Kawamura, H. Washimine, T. Ishihara, N. Ueno, H. Kinoshita, F. Matsuoka, K. Yamada, K. Fukudome, H. Inagaki, K. Hidaka, M. Kuboyama, A. Baba, S. Sonoda, R. Nishizono, and F. Ebihara.
Data Availability
All relevant data are within the paper and its Supporting Information files.
Funding Statement
The authors received no specific funding for this work.
References
- 1.Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28: 53–61. [DOI] [PubMed] [Google Scholar]
- 2.Regidor DL, Kopple JD, Kovesdy CP, Kilpatrick RD, McAllister CJ, Aronovitz J, et al. Associations between changes in hemoglobin and administered erythropoiesis-stimulating agent and survival in hemodialysis patients. J Am Soc Nephrol. 2006;17: 1181–1191. 10.1681/ASN.2005090997 [DOI] [PubMed] [Google Scholar]
- 3.Pascual J, Teruel JL, Moya JL, Liano F, Jimenez-Mena M, Ortuno J. Regression of left ventricular hypertrophy after partial correction of anemia with erythropoietin in patients on hemodialysis: a prospective study. Clin Nephrol. 1991;35: 280–287. [PubMed] [Google Scholar]
- 4.Johansen KL, Finkelstein FO, Revicki DA, Evans C, Wan S, Gitlin M, et al. Systematic review of the impact of erythropoiesis-stimulating agents on fatigue in dialysis patients. Nephrol Dial Transplant. 2012;27: 2418–2425. 10.1093/ndt/gfr697 [DOI] [PubMed] [Google Scholar]
- 5.Kalantar-Zadeh K, Kopple JD, Block G, Humphreys MH. Association among SF36 quality of life measures and nutrition, hospitalization, and mortality in hemodialysis. J Am Soc Nephrol. 2001;12: 2797–2806. [DOI] [PubMed] [Google Scholar]
- 6.Akizawa T, Saito A, Gejyo F, Ohashi Y. Low hemoglobin levels and hypo-responsiveness to erythropoiesis-stimulating agent associated with poor survival in incident Japanese hemodialysis patients. Ther Apher Dial. 2014;18: 404–413. 10.1111/1744-9987.12155 [DOI] [PubMed] [Google Scholar]
- 7.Parfrey PS, Foley RN, Wittreich BH, Sullivan DJ, Zagari MJ, Frei D. Double‒blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005;16: 2180‒2189. 10.1681/ASN.2004121039 [DOI] [PubMed] [Google Scholar]
- 8.Besarab A, Bolton WK, Browne JK, Egrie JC, Nissenson AR, Okamoto DM, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med. 1998;339: 584‒590. 10.1056/NEJM199808273390903 [DOI] [PubMed] [Google Scholar]
- 9.Palmer SC, Navaneethan SD, Craig JC, Johnson DW, Tonelli M, Garg AX, et al. Meta‒analysis: erythropoiesis‒stimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010;153: 23‒33. 10.7326/0003-4819-153-1-201007060-00252 [DOI] [PubMed] [Google Scholar]
- 10.Foley RN, Curtis BM, Parfrey PS. Hemoglobin targets and blood transfusions in hemodialysis patients without symptomatic cardiac disease receiving erythropoietin therapy. Clin J Am Soc Nephrol. 2008;3: 1669‒1675. 10.2215/CJN.02100508 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Foley RN, Curtis BM, Parfrey PS. Erythropoietin therapy, hemoglobin targets, and quality of life in healthy hemodialysis patients: a randomized trial. Clin J Am Soc Nephrol. 2009;4:726‒33. 10.2215/CJN.04950908 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Johansen KL, Finkelstein FO, Revicki DA, Evans C, Wan S, Gitlin M, et al. Systematic review of the impact of erythropoiesis‒stimulating agents on fatigue in dialysis patients. Nephrol Dial Transplant. 2012;27: 2418‒25. 10.1093/ndt/gfr697 [DOI] [PubMed] [Google Scholar]
- 13.Clement FM, Klarenbach S, Tonelli M, Johnson JA, Manns BJ. The impact of selecting a high hemoglobin target level on health‒related quality of life for patients with chronic kidney disease: a systematic review and meta‒analysis. Arch Intern Med. 2009;169: 1104‒12. 10.1001/archinternmed.2009.112 [DOI] [PubMed] [Google Scholar]
- 14.Coyne DW. The health‒related quality of life was not improved by targeting higher hemoglobin in the Normal Hematocrit Trial. Kidney Int. 2012;82: 235‒241. 10.1038/ki.2012.76 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Vlassopoulos D, Sonikian M, Dardioti V, Hadjiconstantinou V. Target Haematocrit during erythropoietin treatment in dialysis patients. Which value is true-functional haematocrit? Nephrol Dial Transplant. 1999;14: 1340–1341. [DOI] [PubMed] [Google Scholar]
- 16.Movilli E, Pertica N, Cancarini G, Brunori G, Scolari F, Maiorca R. Predialysis versus postdialysis hematocrit evaluation during erythropoietin therapy. Am J Kidney Dis. 2002;39: 850–853. 10.1053/ajkd.2002.32007 [DOI] [PubMed] [Google Scholar]
- 17.Bellizzi V, Minutolo R, Terracciano V, Iodice C, Giannattasio P, De Nicola L, et al. Influence of the cyclic variation of hydration status on hemoglobin levels in hemodialysis patients. Am J Kidney Dis. 2002;40: 549–555. 10.1053/ajkd.2002.34913 [DOI] [PubMed] [Google Scholar]
- 18.Castillo N, García-García P, Rivero A, Jiménez-Sosa A, Macía M, Getino MA, et al. Should we adjust erythropoiesis-stimulating agent dosage to postdialysis hemoglobin levels? A pilot study. BMC Nephrol. 2012;13: 60 10.1186/1471-2369-13-60 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Agrawal V, Mukherjee S, Kosuri R, Dumler F. Anemia management with darbepoetin-alfa in outpatient hemodialysis patients switched from epoetin-alfa: a community hospital experience. Am J Ther. 2010;17: 469–75. 10.1097/MJT.0b013e3181b28b59 [DOI] [PubMed] [Google Scholar]
- 20.Icardi A, Sacco P, Salvatore F, Romano U. Long-term intravenous epoetin-alpha/ darbepoetin-alpha ratio in iron-replete hemodialysis patients. J Nephrol. 2007;20:73–9. [PubMed] [Google Scholar]
- 21.Saran R, Bragg-Gresham JL, Levin NW, Twardowski ZJ, Wizemann V, Saito A, et al. Longer treatment time and slower ultrafiltration in hemodialysis: associations with reduced mortality in the DOPPS. Kidney Int. 2006;69: 1222–1228. 10.1038/sj.ki.5000186 [DOI] [PubMed] [Google Scholar]
- 22.Mallick S, Rafiroiu A, Kanthety R, Iqbal S, Malik R, Rahman M. Factors predicting erythropoietin resistance among maintenance hemodialysis patients. Blood Purif. 2012;33: 238–244. 10.1159/000335256 [DOI] [PubMed] [Google Scholar]
- 23.Corwin HL, Gettinger A, Fabian TC, May A, Pearl RG, Heard S, et al. Efficacy and safety of epoetin alfa in critically ill patients. N Engl J Med. 2007;357: 965–976. 10.1056/NEJMoa071533 [DOI] [PubMed] [Google Scholar]
- 24.Hasuike Y, Nonoguchi H, Tokuyama M, Ohue M, Nagai T, Yahiro M, et al. Serum ferritin predicts prognosis in hemodialysis patients: the Nishinomiya study. Clin Exp Nephrol. 2010;14: 349–55. 10.1007/s10157-010-0288-x [DOI] [PubMed] [Google Scholar]
- 25.Kalantar-Zadeh K, Don BR, Rodriguez RA, Humphreys MH. Serum ferritin is a marker of morbidity and mortality in hemodialysis patients. Am J Kidney Dis. 2001;37: 564–72. [PubMed] [Google Scholar]
- 26.Johnson JG, Gore SM, Firth J. The effect of age, diabetes, and other comorbidity on the survival of patients on dialysis: a systematic quantitative overview of the literature. Nephrol Dial Transplant. 1999;14: 2156–2164. [DOI] [PubMed] [Google Scholar]
- 27.Rao DS, Shih M, Mohini R. Effect of serum parathyroid hormone and bone marrow fibrosis on the response to erythropoietin in uremia. N Engl J Med. 1993;328: 171–175. 10.1056/NEJM199301213280304 [DOI] [PubMed] [Google Scholar]
- 28.KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int Suppl. 2012; 2 (4): 279–335. [Google Scholar]
- 29.Pisoni RL, Bragg-Gresham JL, Young EW, Akizawa T, Asano Y, Locatelli F, et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44: 94–111. [DOI] [PubMed] [Google Scholar]
- 30.McFarlane PA, Pisoni RL, Eichleay MA, Wald R, Port FK, Mendelssohn D. International trends in erythropoietin use and hemoglobin levels in hemodialysis patients. Kidney Int. 2010;78: 215–23. 10.1038/ki.2010.108 [DOI] [PubMed] [Google Scholar]
- 31.Xia H, Ebben J, Ma JZ, Collins AJ. Hematocrit levels and hospitalization risks in hemodialysis patients. J Am Soc Nephrol. 1999;10: 1309–16. [DOI] [PubMed] [Google Scholar]
- 32.Ma JZ, Ebben J, Xia H, Collins AJ. Hematocrit level and associated mortality in hemodialysis patients. J Am Soc Nephrol. 1999;10: 610–9. [DOI] [PubMed] [Google Scholar]
- 33.Foley RN, Parfrey PS, Harnett JD, Kent GM, Murray DC, Barre PE. The impact of anemia on cardiomyopathy, morbidity, and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28: 53–61. [DOI] [PubMed] [Google Scholar]
- 34.Locatelli F, Pisoni RL, Combe C, Bommer J, Andreucci VE, Piera L, et al. Anaemia in haemodialysis patients of five European countries: association with morbidity and mortality in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant. 2004;19: 121–132. [DOI] [PubMed] [Google Scholar]
- 35.Fort J, Cuevas X, Garcia F, Perez-Garcia R, Llados F, Lozano J, et al. Mortality in incident haemodialysis patients: time-dependent haemoglobin levels and erythropoiesis-stimulating agent dose are independent predictive factors in the ANSWER study. Nephrol Dial Transplant. 2010;25: 2702–10. 10.1093/ndt/gfq073 [DOI] [PubMed] [Google Scholar]
- 36.Akizawa T, Pisoni RL, Akiba T, Saito A, Fukuhara S, Asano Y, et al. Japanese haemodialysis anaemia management practices and outcomes (1999–2006): results from the DOPPS. Nephrol Dial Transplant. 2008;23: 3643‒3653. 10.1093/ndt/gfn346 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37.Inaba M, Hayashino Y, Shoji T, Akiba T, Akizawa T, Saito A, et al. Disappearance of association in diabetic patients on hemodialysis between anemia and mortality risk: the Japan dialysis outcomes and practice pattern study. Nephron Clin Pract. 2012;120: c91–c100. 10.1159/000335979 [DOI] [PubMed] [Google Scholar]
- 38.Akizawa T, Saito A, Gejyo F, Suzuki M, Nishizawa Y, Tomino Y, et al. Low hemoglobin levels and hypo-responsiveness to erythropoiesis-stimulating agent associated with poor survival in incident Japanese hemodialysis patients. Ther Apher Dial. 2014;18: 404–13. 10.1111/1744-9987.12155 [DOI] [PubMed] [Google Scholar]
- 39.Kwon O, Jang HM, Jung HY, Kim YS, Kang SW, Yang CW, et al. ; Clinical Research Center for End-Stage Renal Disease (CRC- ESRD) Investigators. The Korean clinical research center for end-stage renal disease study validates the association of hemoglobin and erythropoiesis-stimulating agent dose with mortality in hemodialysis patients. PLoS One. 2015;10: e0140241 10.1371/journal.pone.0140241 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, et al. ; CHOIR investigators. Correction of anemia with Epoetin alfa in chronic kidney disease. N Engl J Med. 2006;355: 2085–2098. 10.1056/NEJMoa065485 [DOI] [PubMed] [Google Scholar]
- 41.Drüeke TB, Locatelli F, Clyne N, Eckardt KU, Macdougall I, Tsakiris D, et al. ; CREATE investigators: Normalization of haemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355: 2071–2084. 10.1056/NEJMoa062276 [DOI] [PubMed] [Google Scholar]
- 42.Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al. ; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med 2009; 361: 2019–2032. 10.1056/NEJMoa0907845 [DOI] [PubMed] [Google Scholar]
- 43.Goodkin DA, Fuller DS, Robinson BM, Combe C, Fluck R, Mendelssohn D, et al. Naturally Occurring Higher Hemoglobin Concentration Does Not Increase Mortality among Hemodialysis Patients. J Am Soc Nephrol. 2011;22: 358–365. 10.1681/ASN.2010020173 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Fukuma S, Yamaguchi T, Hashimoto S, Nakai S, Iseki K, Tsubakihara Y, et al. Erythropoiesis-stimulating agent responsiveness and mortality in hemodialysis patients: results from a cohort study from the dialysis registry in Japan. Am J Kidney Dis. 2012;59: 108–16. 10.1053/j.ajkd.2011.07.014 [DOI] [PubMed] [Google Scholar]
- 45.Zhang Y, Thamer M, Stefanik K, Kaufman J, Cotter DJ. Epoetin requirements predict mortality in hemodialysis patients. Am J Kidney Dis. 2004;44: 866–876. [PubMed] [Google Scholar]
- 46.Fort J, Cuevas X, Garcia F, Perez-Garcia R, Llados F, Lozano J, et al. Mortality in incident haemodialysis patients: time-dependent haemoglobin levels and erythropoiesis-stimulating agent dose are independent predictive factors in the ANSWER study. Nephrol Dial Transplant. 2010;25: 2702–2710. 10.1093/ndt/gfq073 [DOI] [PubMed] [Google Scholar]
- 47.Hanafusa N, Nomura T, Hasegawa T, Nangaku M. Age and anemia management: relationship of hemoglobin levels with mortality might differ between elderly and nonelderly hemodialysis patients. Nephrol Dial Transplant. 2014;29: 2316–2326. 10.1093/ndt/gfu272 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48.Inaba M, Hayashino Y, Shoji T, Akiba T, Akizawa T, Saito A, et al. Disappearance of association in diabetic patients on hemodialysis between anemia and mortality risk: the Japan dialysis outcomes and practice pattern study. Nephron Clinical Practice 2012;120: c91–c100. 10.1159/000335979 [DOI] [PubMed] [Google Scholar]
- 49.Maekawa K, Shoji T, Emoto M, Okuno S, Yamakawa T, Ishimura E, et al. Influence of atherosclerosis on the relationship between anaemia and mortality risk in haemodialysis patients. Nephrol Dial Transplant. 2008;23: 2329–2336. 10.1093/ndt/gfm929 [DOI] [PubMed] [Google Scholar]
- 50.Agarwal R, Nissenson AR, Batlle D, Coyne DW, Trout JR, Warnock DG. Prevalence, treatment, and control of hypertension in chronic hemodialysis patients in the United States. Am J Med. 2003;115: 291–297. [DOI] [PubMed] [Google Scholar]
- 51.Hörl MP, Hörl WH. Hemodialysis-associated hypertension: pathophysiology and therapy. Am J Kidney Dis. 2002;39: 227–244. 10.1053/ajkd.2002.30542 [DOI] [PubMed] [Google Scholar]
- 52.Wilson J, Shah T, Nissenson AR. Role of sodium and volume in the pathogenesis of hypertension in hemodialysis. Semin Dial. 2004;17: 260–264. 10.1111/j.0894-0959.2004.17323.x [DOI] [PubMed] [Google Scholar]
- 53.Rocco MV, Yan G, Heyka RJ, Benz R, Cheung AK. Risk factors for hypertension in chronic hemodialysis patients: baseline data from the HEMO study. Am J Nephrol. 2001;21: 280–288. [DOI] [PubMed] [Google Scholar]
- 54.Foley RN, Herzog CA, Collins AJ, United States Renal Data System. Blood pressure and long-term mortality in United States hemodialysis patients: USRDS Waves 3 and 4 Study. Kidney Int. 2002; 62: 1784–1790. 10.1046/j.1523-1755.2002.00636.x [DOI] [PubMed] [Google Scholar]
- 55.Leggat JE Jr, Orzol SM, Hulbert-Shearon TE, Golper TA, Jones CA, Held PJ, et al. Noncompliance in hemodialysis: predictors and survival analysis. Am J Kidney Dis. 1998;32: 139–145. [DOI] [PubMed] [Google Scholar]
- 56.van de Borne P, Tielemans C, Vanherweghem JL, Degaute JP. Effect of recombinant human erythropoietin therapy on ambulatory blood pressure and heart rate in chronic haemodialysis patients. Nehrol Dial Transplant. 1992;7: 45–49. [PubMed] [Google Scholar]
- 57.Muirhead N1, Laupacis A, Wong C. Erythropoietin for anaemia in haemodialysis patients: results of a maintenance study; the Canadian Erythropoietin Study Group. Nephrol Dial Transplant. 1992;7: 811–816. [PubMed] [Google Scholar]
- 58.Wakeen M, Zimmerman SW. Association between human recombinant EPO and peripheral vascular disease in diabetic patients receiving peritoneal dialysis. Am J Kidney Dis. 1998;32: 488–493. [DOI] [PubMed] [Google Scholar]
- 59.Kuragano T, Matsumura O, Matsuda A, Hara T, Kiyomoto H, Murata T, et al. Association between hemoglobin variability, serum ferritin levels, and adverse events/mortality in maintenance hemodialysis patients. Kidney Int. 2014;86(4):845–54. 10.1038/ki.2014.114 [DOI] [PubMed] [Google Scholar]
- 60.Tattersall J, Martin-Malo A, Pedrini L, Basci A, Canaud B, Fouque D, et al. EBPG guideline on dialysis strategies. Nephrol Dial Transplant. 2007;22 Suppl 2: ii5–21. [DOI] [PubMed] [Google Scholar]
- 61.Tsubakihara Y, Nishi S, Akiba T, Hirakata H, Iseki K, Kubota M, et al. 2008 Japanese Society for Dialysis Therapy: guidelines for renal anemia in chronic kidney disease. Ther Apher Dial. 2010;14:240–275. 10.1111/j.1744-9987.2010.00836.x [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Interaction of Hb and IDWG on all-cause mortality (a) and cardiovascular mortality (b).
(TIF)
(DOCX)
(DOCX)
Data Availability Statement
All relevant data are within the paper and its Supporting Information files.