Serum Iron Markers Are Inadequate for Guiding Iron Repletion in Chronic Kidney Disease

Abstract

Summary Background and objectives Iron (Fe) overload may complicate parenteral Fe therapy used to enhance the efficacy of erythropoietic-stimulating agents in the treatment of anemia of chronic kidney disease. However, serum Fe markers are influenced by inflammation or malignancy and may not accurately reflect the amount of body Fe. Design, setting, participants, & measurements We studied the relationship between parenteral Fe therapy, conventional serum Fe markers, and liver iron concentration (LIC) measured using magnetic resonance R2 relaxometry (FerriScan) in 25 Fe-deficient predialysis chronic kidney disease patients before and 2 and 12 weeks after single high-dose intravenous Fe and in 15 chronic hemodialysis patients with elevated serum ferritin (>500 μg/L). Results In predialysis patients, there was strong dose dependency between the administered Fe dose and changes in LIC at weeks 2 and 12; however, no dose dependency between Fe dose and changes in ferritin or transferrin saturation (TSAT) were observed. In hemodialysis patients, LIC correlated with the cumulative Fe dose and duration of dialysis but not with current ferritin or TSAT. The cumulative Fe dose remained a significant independent predictor of LIC in a multiple regression model. Two dialysis patients who received >6 g parenteral Fe had substantially elevated LIC >130 μmol/g, which is associated with hemochromatosis. Conclusions In Fe-deficient predialysis patients, intravenous Fe therapy is associated with increases in LIC unrelated to changes in conventional Fe markers. In hemodialysis patients, TSAT and ferritin are poor indicators of body Fe load, and some patients have LICs similar to those found in hemochromatosis.

New Options for Iron Supplementation in Maintenance Hemodialysis Patients

“…As described in a recent review, 9 use of IV iron preparations can increase the risk for infection, 10,11 cause oxidative stress, [12][13][14][15][16][17][18][19] promote cardiovascular disease, 11,[20][21][22][23][24] and lead to iron overload. [25][26][27][28] In addition, some IV iron preparations cause life-threatening anaphylactic reactions in susceptible individuals.…”

Safety Issues in Iron Treatment in CKD

“…They further showed that serum ferritin values exceeding 340 µg/L were associated with iron overload. Similarly Ferrari et al 72 and Rostoker et al 73 recently showed a dramatic increase of liver iron contents approaching those found in hemochromatosis with routine administration of IV iron preparations in hemodialysis patients. It thus is clear that iron overload commonly occurs in ESRD patients treated with ESAs and IV iron according to the currently accepted guidelines.…”

Iatrogenic iron overload and its potential consequences in patients on hemodialysis

“…Of note, no cardiac iron deposits were observed by T2* in either study [61,62]. Thus, most hemodialysis patients receiving ESA and IV iron supplementation according to current guidelines appear to have hepatic iron overload in these recent LIC imaging studies [8,11,[59][60][61][62]. Whereas the potential iron overload toxicity is now one of the most controversial topics in the management of anemia in hemodialysis patients, data on this topic are lacking in peritoneal dialysis patients.…”

“…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].…”

“…Major changes in the approach to iron therapy have occurred recently. First, the 2013 European Renal Best Practice position statement on anemia management warned against excessive use of IV iron products and the potential risk of iatrogenic iron overload, beside other potential toxicities, based on studies published in 2011 and 2012 and analysing LIC in dialysis patients by MRI [8,59,60] and a SQUID study published in 2004 [11,81]. This ERBP-2013 position statement did not fully endorse the 2012 KDIGO guideline on iron therapy, because of the potential risk of iron toxicities, and advocated a more conservative and safer upper limit of ferritin at 300 ng/mL instead of 500 ng/mL for starting iron therapy [81].…”