Assessment of Iron Deposition in Major Organs of Hemodialysis Patients

Assessment of Iron Deposition in Major Organs of Hemodialysis Patients, Using T2*MRI and Novel Biomarkers of Free Iron Species

The purpose of the present study is to evaluate in hemodialysis patients, who have elevated serum ferritin ( >2000ng/ml) and transferrin saturation (TSAT) >30%, iron deposition in the heart, pancreas, liver and spleen using the T2* MRI technique.

In addition, we will also measure the free iron forms in the plasma and LPI, LCI in red blood cells, platelets and PMN, in addition to serum hepcidin, TSAT, serum ferritin, CRP and oxidative stress parameters (ROS,GSH, and malonyldialdehyde (MDA).

Despite the foregoing advances in the management of anemia associated with chronic kidney disease by the use of erythropoiesis stimulating agents and intravenous iron, assessment of iron status in these patients remains an unresolved issue.

It is estimated that following administration of erythropoietin together with intravenous iron, nearly 50% of all hemodialysis patients in the United states have a serum ferritin >500ng/ml (1). However, in many patients high serum ferritin levels (>2000ng/ml) have been documented. These levels are indicative of iron overload, also defined as hemosiderosis (2).

The risk of using IV iron in spite of serum ferritin levels of >2000ng/ml can result in accumulation of excess iron in tissues, such as the heart, liver, and pancreas similar to findings in patients with hemochromatosis (3) with possible deleterious effects. Accordingly, a recent study indicated a mathematically significant correlation between serum ferritin and liver iron stores using the indirect imaging known as SQUID (4).

Recently, T2*MRI (magnetic resonance imaging) became a non-invasive modality for evaluating tissue iron stores (5). Since high iron content shortens the T2* relaxation, decreased T2* values have been advocated as an early marker of iron deposition in target organs, related to the paramagnetic properties of hemosiderosis (5). This method is commonly used to evaluate and monitor iron deposition in major organs in thalassemia major and myelodysplastic syndrome (MDS) who are multitransfused.

In the former diseases, one of the consequences of iron overload is the presence of labile iron forms, which are redox active and therefore are associated with the propensity to catalyze the generation of reactive oxygen species (ROS) by the Haber Weiss reaction .Two forms of labile iron have been identified, one in the plasma (Labile plasma iron-LPI) and the other is found in the cells (labile cellular iron -LCI)(6,7 ).

In iron overload syndromes such as hemochromatosis, thalassemia or MDS these labile iron forms are increased, causing increased generation of oxidative stress with subsequent damage to membrane, cytoplasmatic and nuclear components.

An important master regulator of iron hemostasis is hepcidin, which is liver derived acute phase protein, and its synthesis is regulated by cytokines and iron status in the body (8).

It has been suggested that increased hepcidin levels may also contribute significantly to the severity of anemia of CKD.

Inclusion Criteria:

• patients for study are > 50 years of age,
• on chronic hemodialysis for at least one year,
• with serum ferritin levels > 2000 ng/ml and TSAT > 30%.

Exclusion Criteria:

• malignancies,
• any active infection requiring systemic antibiotic therapy, and
• hospitalization within the two weeks before screening.