The Importance of Iron in Long-Term Survival of Maintenance Hemodialysis Patients Treated With Epoetin-Alpha and Intravenous Iron: Analysis of 9.5 Years of Prospectively Collected Data

Victor E. Pollak; Jonathan A. Lorch; Rakesh Shukla; Supriya Satwah

Disclosures

BMC Nephrology 

In This Article

Results

Patients

The patient characteristics are summarized in Table 1. Mean age at study start was 59 years, 53% were male, 43% White, and 36% Black; 18% were Hispanic. The primary disease leading to renal failure was glomerulonephritis in 15%, hypertension in 24%, and diabetes mellitus Types I and II in 4% and 32% respectively. Co-morbid conditions were: arteriosclerotic heart disease in 23%. cerebral vascular disease in 8%, peripheral vascular disease in 12%, malignant disease in 9%, AIDS in 4.2%, diabetes mellitus Types I and II in 4.6 and 38% respectively, and peptic ulcer in 2.1%; 649 patients (36.6%) had none of these co-morbid conditions.

Survival duration and EPO and IV iron administered are summarized in Table 2. Median survival was 789 days (interquartile range 354 and 1489). The median EPO and IV iron administered were, respectively, 18.16 (IQR 12.10 and 27.74) 103 units/week and 301.2 (IQR 201.6 and 454.7) mg/month.

Laboratory test results were analyzed for each patient for the duration that the patient was in the study, i.e., until censoring or death. Median, mean, and standard deviations are displayed in Table 3. Median Hb was 116.1 g/L, MCH 30.7 pg, MCHC 322.8 g/L, serum iron 17.34 μmol/L, TSAT 29.76%, and serum ferritin 526.2 μg/L. Median Kt/V was 1.63, and median serum albumin 39.1 g/L. Median serum calcium was 2.35 mmol/l, serum phosphorus 1.76 mmol/L, calcium × phosphorus product 4.11 mmol2/L2, and intact PTH 301.4 ng/L.

Univariate Analysis

Survival curves were calculated for the patient group as a whole (Figure 1), for mean EPO per week and for mean IV iron per month of patient follow up. Patients were categorized into three groups (low, medium, high) based on the dose of each drug administered. In the case of IV Iron, patients who did not receive IV iron (No-IV) were also included along with the three other groups. Cut-offs for the various groups were based purely on the results of the statistical analysis (Table 2). For EPO, survival was relatively worse in the high dose group (> 27.74 103 units per week), and relatively best in the low dose group (≤ 12.10 103 units per week) (Figure 2). For IV iron, survival was worst in those who received no IV iron at all (Figure 3), and was almost as bad in the high dose group (≥ 455 mg/month). It was relatively best in patients receiving a relatively low dose (1–202 mg per month), slightly worse in those receiving a relatively higher dose (202.1–455 mg per month).

Figure 1.

Estimated proportion of patients surviving.

Figure 2.

Estimated proportion of patients surviving by levels of EPO administration.
Although the differences were small, survival was best in those receiving a low dose of EPO (L = ≤ 12.1 103 units per week), slightly worse with a medium dose (M = 12.1–27.7 103 units per week), and worst in those receiving a high dose (H = > 27.7 103 units per week).

Figure 3.

Estimated proportion of patients surviving by levels of IV iron administration.
Survival was best in those receiving a low dose of IV iron (L = 1–202 mg per month), and slightly worse in those receiving a moderate dose (M = 202–455 mg per month). Survival was much worse in those who received a high dose (H = > 455 mg per month) and in those who did not receive IV iron (Ø = NO IV).

All hematological parameters measured were quantitative but, to facilitate clinical interpretation, survival curves were obtained for selected clinically relevant categorizations of these parameter values. For Hb, survival was relatively the worst in those with an overall mean ≤ 100 g/L, and was progressively better with mean Hb levels of 100.1–110, 110.1–120, best in those with mean values > 120 g/L (Figure 4). For serum iron, survival was worst with a median serum iron level ≤ 5.4 μmol/L, best with a level 10.7–19.7 μmol/L (Figure 5). For TSAT, survival was worst with a mean TSAT ≤ 16%, and progressively better with mean TSAT levels 16.1–20, 20.1–25, and > 25% (Figure 6). No explicit relationship was observed between TSAT level and IV iron administered. For example, 17% of patients with TSAT levels ≤ 20% had received no IV iron, but 50% had received > 455 mg/month (Table 4). For serum ferritin survival was worst with mean serum ferritin ≤ 100 μg/L, slightly better with levels between 100 and 300 μg/L (Figure 7). No explicit relationship was observed between serum ferritin level and IV iron administered. For example, 40% of patients with serum ferritin levels > 600 μg/L had received IV iron > 455 mg/month but 18% had received no IV iron (Table 5). The best survival was in the three groups with mean serum ferritin levels between 300 and 600, 600 and 1000, and > 1000 μg/L, which differed little from each other. For Kt/V survival was worst with mean Kt/V ≤ 1.2, successively better with Kt/V 1.21–1.4, 1.41–1.6, and best with Kt/V > 1.6. For serum albumin, median survival was worst with a mean value ≤ 35 g/L, best with a mean value > 40 g/L.

Figure 4.

Estimated proportion of patients surviving by four levels of hemoglobin.

Figure 5.

Estimated proportion of patients surviving by four levels of serum iron.

Figure 6.

Estimated proportion of patients surviving by four levels of TSAT.
The number of patients who received various levels of IV iron over the time at risk in each of the four TSAT levels is shown in Table 4.

Figure 7.

Estimated proportion of patients surviving by five levels of serum ferritin.
The number of patients who received various levels of IV iron over the time at risk in each of the five serum ferritin levels is shown in Table 5.

Multivariate Analysis

Survival duration was first analyzed using data for all years 1998–2006 for all patients in all 3 dialysis units. Included in the model were age at treatment start, race, gender, presence or absence of co-morbid conditions, EPO administration in 3 ranks (0–12.1, 12.11–27.7, and > 27.7 103 units per week), IV iron administration in 4 ranks (0, 1–202, 202–455, and > 405 mg per month), and median values for all laboratory test results. Race, gender, dialysis center, time of entry into the study, serum iron, TIBC, MCV, MCH, serum calcium, and serum phosphorus were eliminated from the model in backward elimination as they failed to reach the level of significance (P < 0.05). The results, summarized in part in Table 6, demonstrate the powerful independent positive effect on survival of intravenous iron administered in low (≤ 202 mg/month) and medium (202–455 mg/month) doses. TSAT levels > 25% and serum ferritin levels > 300 μg/L were also independently associated with a positive effect on survival. Serum albumin > 40 g/L and Kt/V > 1.6, a measure of dialysis adequacy, were associated with a positive effect on survival, as has long been recognized.[20] TIBC, MCHC, calcium × phosphorus product, and PTH were factors that also independently affected survival.

Analysis of the EPO IV Iron Interaction Effect on Patient Survival

This analysis was done with a model in which only IV iron administered and EPO administered were included as interactions along with all the other significant predictors of survival. The results are summarized in Table 7. Estimated survival curves are displayed in Figure 8. For IV iron, survival was uniformly worst for those who received no IV iron, best with 1–202 mg/month, and slightly worse with 202–455 mg/month. For those who received IV iron > 455 mg/month, survival was only slightly better than in the no IV iron group. The effect of EPO on survival was weak but had statistically significant interaction with IV iron. In particular, EPO without IV iron did not seem to have any beneficial impact on survival, whereas with IV iron EPO did have some beneficial effect on survival, albeit small.

Figure 8.

Estimated proportion of patients surviving by combinations of levels of IV iron and of EPO administration.
Low (L), medium (M) and high (H) levels of iron and EPO administered are indicated in the boxes by the appropriate symbol, and those who received no iron by the symbol ∅. The worst survival estimates were in patients who received no iron (Fe ∅). Survival estimates were slightly, but little better in those in the high iron group (Fe H). the best survival estimates were in the low iron group (Fe L), and they were slightly worse in the medium iron group (Fe M). For each of the four levels of IV iron administered, survival was best in the low EPO Group (EPO L), and worst in the high EPO group (EPO H), but the differences were very small.

Analysis of the TSAT EPO Interaction Effect on Patient Survival

This analysis was done with a model in which only TSAT and EPO administered were included as interactions along with other significant predictors of survival. As compared with patients with a mean TSAT > 25%, the hazard ratios for those with TSAT ≤ 16% was 6.62, for TSAT 16.01–20 it was 2.59, and for TSAT 20.01–25 it was 1.95. As compared with patients who received EPO > 27.7 103 units/week the hazard ratios for those who received 0–12.1 and 12.1–27.7 103 units/week were, respectively, 0.61 and 0.81. An interaction of TSAT and EPO administration on survival was not significant. The estimated survival curves (Figure 9), demonstrate the powerful effect of low TSAT levels on survival even after controlling for other significant predictors of survival.

Figure 9.

Estimated proportion of patients surviving by combinations of four levels of TSAT and three of EPO administration.
TSAT levels are shown in the boxes and low (L), medium (M) and high (H) levels of EPO administered are indicated by the appropriate symbol. The 3 worst survival estimates were in patients with TSAT ≤ 16%; of the three, the best estimate was for the low EPO (L) group. The three best survival estimates were in patients with TSAT > 25%; of the three, the best was for the low EPO (L) group. Estimates for intermediate levels of each variable are shown but not identified specifically. Survival in patients with TSAT 16.01–20% was better than that of those with TSAT ≤ 16%; in those with TSAT 20.01–25% it was better than in those with TSAT 16.01–20%, and worse than in those with TSAT > 25%. For each of these two TSAT levels, as well as for the two other TSAT levels, survival was best in the low EPO (L) group, and worst in those in the high (H) EPO group.

Analysis of the Serum Ferritin EPO Interaction Effect on Patient Survival

This analysis was done with a model in which only serum ferritin and EPO administered were included as interaction along with other significant predictors of survival. The results are summarized in Table 8. There was a significant adverse effect on survival of a serum ferritin level ≤ 100 μg/L at all three levels of EPO administration (0–12.1, 12.11–27.7 103 units/week), i.e, interactions A, F, and K; the hazard ratios were, respectively, 7.37, 5.93, and 3.39. The adverse effect on survival was still apparent but less marked when serum ferritin levels between 100 and 300 μg/L were considered (interactions B, G, and L). When higher serum ferritin levels were considered (between 300 and 600, 600 and 1000 and > 1000 μg/L), with a single exception (Interaction M) no statistically adverse effects on survival were observed.

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