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

Discussion

Hemoglobin

In a recent study of almost 160,000 HD patients who had Medicare as their primary payer both highly variable and persistently and transiently low Hb levels (< 110 g/L) in the first 6 months of 2004 were associated with increased risk of death in the second six months of the same year, whereas transiently and persistently high Hb levels (> 125 g/L or > 120 g/L) were not.[21]

Taking confounding factors and other significant predictors of survival into account, our long-term observations showed clearly that patient survival was better the higher the Hb, and that survival was best with a Hb level > 120 g/L. The 50% survival estimates for Hb > 120, 110–120, 100–110, and ≤ 100 g/L were, respectively, 1198, 1144, 751, and 534 days.

Recent controlled clinical trials that reported adverse effects of a high Hb level in CKD patients[2,3] are the basis for warnings about adverse effects of raising Hb above 120 g/L. The trials were of short duration, without reference to the iron status of the patients or the known iron deficiency of CKD patients,[6,7,8,9] and were designed to increase the Hb concentration by manipulating the ESA dose. Moreover, supplementary iron was not provided to patients whose relatively dormant bone marrow would have been stimulated by the ESA, thereby depleting iron stores available for metabolic functions other than Hb production.[2,3,9,10]

The development of thrombocytosis is one possible mechanism for adverse effects of ESAs in the presence of depleted iron stores. An inverse relationship between TSAT and platelet counts and platelet volume has been demonstrated in women with iron deficiency anemia.[22] Evidence has recently been presented suggesting that, in HD patients given high doses of EPO to achieve Hb ^ 130 g/L, iron depletion and the associated relative thrombocytosis might play a role in the reported increased mortality.[23]

Studies on cytokines in chronic HD patients point to another possible mechanism for adverse effects on morbidity and mortality of EPO administration in iron deficient or marginally iron sufficient patients. The pro-inflammatory cytokine TNF-α was reported to be about 6 times higher in HD patient plasma than in controls (5.6 ± 0.9 versus 0.9 ± 0.1 pg/ml).[24] In another study, plasma concentrations of TNF-α, the anti-inflammatory cytokine IL-4, and total peroxide concentrations were measured in a 90-day randomized controlled trial in patients receiving EPO without or in combination with IV iron.[25] Patients receiving both IV iron and EPO had lower pro-inflammatory cytokine TNFa and higher anti-inflammatory cytokine IL-4 levels, as well as lower levels of total peroxide a marker of free radical concentration.

These observations suggest a possible role for these cytokines in relation to the adverse effect of iron deficiency on morbidity and mortality in EPO treated CKD and HD patients in whom there was inattention to the iron status.

Non-hematological Effects of Iron Deficiency

The renal literature refers rarely to non-hematological consequences of iron deficiency. Iron is a key component of many cellular enzymes, including oxidases, catalases, peroxidases, aconitases, and nitric oxide synthetases.[26,27,28] Iron deficiency adversely affects metabolic processes that include electron transport, catecholamine metabolism, DNA synthesis, and several enzyme systems.[4] Iron is an integral part of the requirement of mitochondrial enzymes of the electron transport chain, and of cytochromes and iron-sulfur proteins required for oxidative phosphorylation of ADP to ATP, and iron deficiency in rats leads to oxidant-induced mitochondrial damage.[29] Iron deficiency results in decreased exercise performance in rats, corrected rapidly by iron but not by blood transfusion.[30,31] In HD patients iron deficiency without evidence of iron deficiency anemia has been reported, and IV iron repletion was associated with positive effects on serum albumin, muscle mass, hospitalization, and blood pressure.[32] Low serum iron (< 8.1 μmol/L) and low TSAT levels were shown to be associated with increased mortality.[33] In the present study survival was worst with very low levels of serum iron (≤ 5.4 μmol/L), TSAT (≤ 20%), and serum ferritin (≤ 100 μg/L), and in those who received no IV iron.

When ESAs are administered to patients deficient or marginally sufficient in iron, the demands for iron for Hb production are likely to further deplete iron available for other essential metabolic processes The rise in plasma TNF-α and decrease in IL-4 levels may also be important as noted above. We conclude that close attention to iron repletion and iron sufficiency is essential for HD patient well-being.

Seeking an Optimal Dose of IV Iron for Hemodialysis Patients

Widely publicized clinical guidelines caution about administering IV iron to HD patients with serum ferritin levels above thresholds varying from 500 to 800 μg/L,[14,15,16,34] but recent reviews have concluded that an evidence based guideline for an upper limit of serum ferritin is not available.[35,36] Ferritin levels up to 1200 μg/L were not associated, in a large study, with an increase in all cause mortality.[37] The present study confirms this by demonstrating clearly that serum ferritin levels of between 600 and 1,000 and > 1,000 μg/L were not associated with adverse effects on survival in univariate and multivariate analysis. There is no clear evidence for the association of infection with high serum ferritin levels in dialysis patients.[38,39,40] We found that whereas malnutrition and infections are, not surprisingly, associated with patient deaths, neither a serum ferritin level > 600 μg/L nor a high dose of iron (> 455 mg/month) was significantly associated with either infection or malnutrition (Table 9). That the best survival was observed in patients with a serum iron level > 10.7 μmol/L and with a TSAT level > 25% also confirms the report of Kalantar-Zadeh and colleagues.[37]

Survival decreases sharply as serum iron and TSAT levels decrease in both univariate and multivariate analyses: this strongly suggests that serum iron > 10.7 μmol/L and TSAT > 25% are reasonable targets to assess iron sufficiency in HD patients. When the needed amount of IV iron is considered in relation to these targets and survival our data showed that amounts up to 455 mg per month were associated with improved survival. On the other hand, amounts > 455 mg per month, close to the reported cut-off point of 400 mg per month reported by Kalantar-Zadeh and colleagues,[37] were associated with worsened survival.

In this study we summarized hematological parameters and rates of administration of EPO and IV iron for each patient to assess the effects of these parameters and treatments on survival. Assessing effects of temporal changes in treatments or hematological parameters on patient's survival is also important and is subject of future investigation.

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