**10. Future directions**

In the 33 patients with iron overload, iron stores fell significantly after iron withdrawal or after a major reduction in the iron dose (first MRI: 220 µmol/g (CI: 60-340); last MRI: 50 µmol/g (CI: 5-210); p< 0.0001, Wilcoxon's paired test)(figure 4)[6]. The slope of the decline in hepatic iron was not significantly different after iron withdrawal (17.9 µmol/g dry weight/month), iron dose reduction (12.8 µmol/g dry weight/month), and renal transplantation (11.9 µmol/g dry weight/month)(p>0.05, Kruskal-Wallis test) [6]. Thus, the frequency of iron overload appears to be markedly underestimated in hemodialysis patients receiving both erythropoeisisstimulating agents and parenteral iron [6,7]. We concluded that most hemodialysis patients receiving ESA and intravenous iron supplementation likely have hepatic iron overload on MRI and called for a revision of guidelines on iron therapy in this setting, especially regarding the amount of iron infused and the use of non invasive methods for monitoring iron stores [6,7].

The classical (although rare) clinical picture of hemodialysis-associated hemosiderosis in the pre-ESA era (pigmented skin, cirrhosis and cardiac failure associated with multiple endocrine disorders) has totally disappeared from dialysis centers for at least 3 decades [5]. It is also noteworthy that genetic hemochromatosis and secondary hemosiderosis related to hemato‐ logical disorders are now diagnosed very early, long before any organ dysfunction is detected [37,40]. Therefore, iron overload in dialysis patients in the ESA era is more likely to silently increase the burden of complications of dialysed CKD than to have obvious clinical effects.

Three recent epidemiological studies convergently show that excessive IV iron administra‐ tion can adversely affect the prognosis of hemodialysis patients by increasing mortality and cardiovascular events [52-54]. In a prospective cohort study conducted in Taiwan, 1239 hemodialysis patients were followed for one year: 583 patients not receiving iron therapy were compared to 656 patients treated with IV ferric chloride hexahydrate, the latter patients being divided into 3 subgroups according the cumulative dose of IV iron: 40-800 mg/6 months, 840-1600 mg/6 months and 1640-2400 mg/6 month [52]. Patients in the 2 subgroups with the largest cumulative iron dose had higher adjusted mortality (Hazard ratio (HR) 3.1 and 3.7) and more cardiovascular events (HR 3.5 and 5.1) than those not receiving IV iron and those having received less than 820 mg/6 months (136 mg/month) [52]. Similarly, Kuragano and coworkers prospectively followed 1086 Japanese hemodialysis patients during 2 years and compared 4 subgroups of patients: an oral iron group, an oral iron+very low IV iron group, a low IV iron group (< 200 mg/month), and a high IV iron group (> 200 mg/month) [53]. They observed more acute cardiocerebralvasculardisease (hazardratio 6.02) andhospitalizations (hazardratio 2.77) in the high IV iron group, whereas both low (hazard ratio 1.78) and high (hazard ratio 5.22) IV ironregimens increasedthe frequencyofinfectionsbut atdifferentrates [53].Highferritinlevels (consistently above 100 µg/L) were associated with an increase risk of acute cardiocerebral vascular disease (hazard ratio 2.22), infections (hazard ratio 1.76) and death (hazard ratio 2.28) [53]. Similarly, a jump in the ferritin level from low to high (from less to more than 100 µg/L) was associated with an increased risk of acute cardiocerebral vascular disease (hazard ratio 1.59) and death (hazard ratio 6.18) [53]. More recently, the DOPPS study, using Cox regres‐ sion models with multiple adjustments, analyzed associations between IV iron and outcomes

**9. Detrimental effects of iron overload in dialysis patients**

68 Updates in Hemodialysis

Iron overload in hemodialysis patients may be favored by reimbursement policies in the USA and many other developed countries, which have led to a dramatic increase in the use of intravenous iron preparations in order to offset the cost of ESA therapy; the situation may also be aggravated by excessive advocated doses of intravenous iron and erroneous iron biomarker targets aimed at "repleting exaggerately" iron stores [6,7]. A new pharmacometric and economic approach to iron therapy has recently been advocated [6,7,26,58]. Moreover, the KDIGO Controversies Conference on Iron Management in Chronic Kidney Disease, which took place in San Francisco on March 27-30, 2014 and was attended by nephrologists, hema‐ tologists, hepatologists and specialists in iron metabolism, recognized the entity of iron overload in hemodialysis patients and called for an agenda of research on this topic, especially by means of MRI [63]. Analysis of liver iron content in dialysis patients by means of quanti‐ tative MRI, a new research tool that overcomes a major hypothetical limitation in hemodialysis patients, namely bone marrow iron depletion despite severe hepatosplenic siderosis, and allows safe non aggressive iterative "radiological liver biopsy" might, in combination with data-mining statistical methods and classical statistical methods such as AUC determination and logistic regression, allow nephrologists to determine both a non toxic dose of infused iron and relevant target values for biological markers of iron metabolism, thereby improving the safety of parenteral iron products in dialysis patients [6,7,26,58, 63]. Finally, specific MRI protocols need to be established in radiology and nephrology divisions for each pharmaceut‐ ical iron product, in order to avoid spurious results [47].
