Evidence for tissue iron overload in long‐term hemodialysis patients and the impact of withdrawing parenteral iron

Abstract

Background/aims Erythropoiesis in long‐term hemodialyzed (LTH) patients is supported by erythropoietin (rHuEpo) and intravenous (IV) iron. This treatment may end up in iron overload (IO) in major organs. We studied such patients for the parameters of IO in the serum and in major organs. Methods Patients were treated with rHuEpo (6–8 x 103 units × 1–3/wk) and IV 100 mg ferric saccharate. Results Of 115 patients, 21 had serum ferritin (SF) > 1000 ng/mL. This group was further analyzed. Their SF and transferrin saturation (TSAT) were 2688 ± 1489 ng/mL and 54.2 ± 32.7%, respectively (vs. 125–360 ng/mL and 20–50% in normal controls). Serum hepcidin was 60.1 ± 29.5 nm (vs. 10.61 ± 6.44 nm in controls) (P < 0.001). Nineteen patients had increased malonyldialdehyde, a product of lipid peroxidation, indicating oxidative stress. T2* MRI disclosed in 19 of 21 patients moderate to severe IO in the liver and spleen, in three of eight patients in the pancreas, but in no patient in the heart. After stopping IV iron for a mean of 12 months, while continuing rHuEpo, the mean SF decreased in 11 patients to 1682 ng/mL and the mean TSAT decreased to 28%, whereas hemoglobin did not change indicating that tissue iron was utilized. Conclusion High SF correlates with IO in the liver and spleen, but not in the heart.

Considerations and Challenges in Defining Optimal Iron Utilization in Hemodialysis

“…Most hemodialysis patients receiving ESA and IVI supplementation have excessive hepatic iron on magnetic resonance imaging. 44,45 In a study that closely followed guidelines for ESA administration and iron supplementation, 80% of the patients had excessive iron in the liver on magnetic resonance imaging and 30% had severe liver iron overload. 45 A 2009 study including 96 hemodialysis patients using bone marrow biopsy showed that most patients with ferritin levels of .500 ng/ml had higher levels of C-reactive protein and an increased content of bone marrow iron.…”

“…80 To our knowledge, the long-term effect of IVI administration to patients with elevated baseline serum ferritin levels upon surrogate markers of atherosclerosis, immune function, inflammation, and vascular reactivity also remain unstudied. However, a recent study in which 19 of 21 (90.5%) long-term dialysis patients with serum ferritin .1000 ng/ml had evidence of increased oxidative stress as well as splenic and hepatic tissue iron overload 44 suggests caution.…”

Hepcidin levels in chronic hemodialysis patients: a critical evaluation

“…During the same period in which we performed the last large study on CHD [24], we also analyzed in our laboratory CHD samples from another dialysis center using a different policy as regards to intravenous iron supplementation. In this particular setting, including selected CHD patients with MR-ascertained iron overload and serum ferritin levels > 1000 μ g/L [18], we observed serum hepcidin levels substantially higher than controls even after careful matching using the same criteria outlined above for the patients enrolled in Milan [24]. In agreement with the view that iron status rather than uremia per se appears as the major determinant of hepcidin in CHD, serum ferritin was the major predictor of hormone level in nearly all the studies published so far, which also included CRP as covariate (Table 1).…”

Iatrogenic iron overload and its potential consequences in patients on hemodialysis

“…These studies also strongly suggest a link between the IV iron dose and the risk of iron overload in this setting, challenging current guidelines with respect to the influence on LIC of IV iron products at high repeated doses [4,8,17,18,59,60], as well as the reliability of iron biomarker cutoffs, and methods for monitoring iron stores in dialysis patients [8,9,15,16]. Two recent MRI studies have focused on iron overload in hemodialysis patients with serum ferritin levels far above 500 mg/L [60]. Pancreatic involvement was sought in only 8 most overloaded patients and was found in 3 cases (37%) [60].…”

“…Radiologists and nephrologists should realize that there are marked differences in the pharmacokinetics of IV iron products, and that these can interfere with MRI (tables II and III) [57]. The required time interval between the last IV iron infusion and MRI should range from one week (iron sucrose, iron gluconate, iron carboxymaltose) to one month (low-molecularweight iron dextran and iron isomaltoside), 3 months (highmolecular-weight iron dextran) or even 6 months (ferumoxytol) if spurious results due to magnetic interference are to be avoided ( Iron overload in dialysis patients in the ESA era Studies using superconducting quantum interference device (SQUID) thirteen years ago [11] and more recent studies employing quantitative MRI [8,59,60] to estimate LIC in hemodialysis patients, have provided new information on iron metabolism in ESRD and have underlined the risk of hemosiderosis. These studies also strongly suggest a link between the IV iron dose and the risk of iron overload in this setting, challenging current guidelines with respect to the influence on LIC of IV iron products at high repeated doses [4,8,17,18,59,60], as well as the reliability of iron biomarker cutoffs, and methods for monitoring iron stores in dialysis patients [8,9,15,16].…”