Identification of Iron Agglomerates by T2* MRI In Major Organs of Patients with End-Stage Renal Disease Who Receive Regularly Erythropoietin with Intravenous Iron

The anemia of patients with end-stage renal disease (ESRD) undergoing hemodialysis is significantly improved following treatment with recombinant human erythropoietin (rHuEpo). However, the optimal response is determined by the availability of iron for erythropoiesis, particularly when it is administered intravenously (iv). Consequently, the use of iv iron in conjunction with rHuEpo has become standard practice in most hemodialysis programs worldwide to increase Hb levels >11gm/dl. Currently, the used parameters for judicious determination of iron supplementation and body iron status still rely on measurements of serum ferritin (SF) and percent transferrin saturation (TSAT). These measurements might be misleading since SF is an acute phase reactant, increased by inflammation, which is frequent in ESRD patients, while TSAT levels are subject to diurnal fluctuations. Moreover, following administration of iv iron, the values of TSAT are artificially increased since standard clinical assays assume all plasma iron is bound to transferrin, including iron forms administrated with iv supplements. While in plasma, these forms transiently generate labile plasma iron (LPI), which is redox active and prone to generate oxidative damage of plasma components, as previously demonstrated following iv iron saccharate administration in ESRD patients. The kinetics of utilization of iron supplements indicate that at any given time a major fraction of the iron is withdrawn from plasma into the reticuloendothelial system (spleen and liver) and that the dwelling time of the iron in tissue might expose those organs to deleterious effects mainly in chronic conditions. Iron processing might be further delayed due to blockage of iron export evoked by hepcidin-mediated repression of ferroportin. As T2* MRI sequence has been validated as a reliable, reproducible methodology for non-invasive assessment of iron agglomerates, it has been used for assessing pathological iron accumulation in organs of iron overloaded (IO) patients.

The present study measured by T2* MRI the organ distribution of iron agglomerates in 12 ESRD patients (7 males and 5 females, mean age 61.5 years; mean Hb level of 9.0g/dl) undergoing dialysis for at least 1 year (range 1–12) treated with rHuEpo and 100mg of iron saccharate (Venofer) given iv once a week. Serum samples were collected 7 days after iv iron. The median SF level was 2883 ng/ml (range 1756–6820) and mean TSAT was 70.5% (range 41–122). The patients are nearly 10% from a group of 140 dialyzed patients treated in a single hemodialysis facility, characterized by chronic inflammatory state with refractory anemia to rHuEpo without regular iron supplementation.

MRI (1.5T, GE MRI system) sequences included: steady-state free precession (SSFP) for left ventricular ejection fraction (LVEF) evaluation; breath-hold T2* multi echo gradient for iron load quantification, sampled across regions of interest in the left ventricular septum, liver, spleen and pancreatic parenchyma.

The results showed major iron deposition in the liver, (median 1.95ms, range 1–15) and spleen (median 2.8ms, range 1–15) while cardiac function was normal and no iron deposition in the heart (median 36ms, range 29–42) (table 1). Pancreas T2* measurements (normal values 41±7ms) were obtained only in 4/11 patients due to their inability to sustain sufficient breath holds. In 2/4 of the patients the median T2* of 8.5ms, (range 8–9) in pancreas was indicative of major iron accumulation. LPI levels were detected in 4/11 patients (range 0.2–0.7μM) with SF levels >3000ng/ml.

These results indicate that in dialyzed ESRD patients (1-12 years) with chronic inflammation with mean SF levels of 2883 ng/ml and mean TSAT of 70.5% that received weekly iv iron, major iron deposition was demonstrated in liver and spleen but none in the heart. Implementation of T2* MR imaging was able to detect iron agglomerates which might reflect transitory iron-saccharate particles in the process of solubilization or residual particles accumulating due to inability of the system to process them. However, they might also reflect a more persistent state of regional IO with deleterious implications that need further exploration.

No relevant conflicts of interest to declare.