Ferroportin inhibition attenuates plasma iron, oxidant stress, and renal injury following red blood cell transfusion in guinea pigs

Abstract

BACKGROUND Red blood cell (RBC) transfusions result in the sequestration and metabolism of storage‐damaged RBCs within the spleen and liver. These events are followed by increased plasma iron concentrations that can contribute to oxidant stress and cellular injury. We hypothesized that administration of a ferroportin inhibitor (FPN‐INH) immediately after acute RBC exchange transfusion could attenuate posttransfusion circulatory compartment iron exposure, by retaining iron in spleen and hepatic macrophages. STUDY DESIGN AND METHODS Donor guinea pig blood was leukoreduced, and RBCs were preserved at 4°C. Recipient guinea pigs (n = 5/group) were exchange transfused with donor RBCs after refrigerator preservation and dosed intravenously with a small‐molecule FPN‐INH. Groups included transfusion with vehicle (saline), 5 mg/kg or 25 mg/kg FPN‐INH. A time course of RBC morphology, plasma non–transferrin‐bound iron (NTBI) and plasma hemoglobin (Hb) were evaluated. End‐study spleen, liver, and kidney organ iron levels, as well as renal tissue oxidation and injury, were measured acutely (24‐hr after transfusion). RESULTS RBC transfusion increased plasma NTBI, with maximal concentrations occurring 8 hours after transfusion. Posttransfusion iron accumulation resulted in tubule oxidation and acute kidney injury. FPN inhibition increased spleen and liver parenchymal/macrophage iron accumulation, but attenuated plasma NTBI, and subsequent renal tissue oxidation/injury. CONCLUSION In situations of acute RBC transfusion, minimizing circulatory NTBI exposure by FPN inhibition may attenuate organ‐specific adverse consequences of iron exposure.

Ferroportin inhibitor vamifeport ameliorates ineffective erythropoiesis in a mouse model of β-thalassemia with blood transfusions

“…Repeated blood transfusions had no effects on iron concentrations in liver or heart, but increased kidney iron levels in Hbb th3/+ mice, likely due to iron derived from transfused RBC. 11 In transfused or non-transfused Hbb th3/+ mice, vamifeport had no significant effects compared with vehicle treatment on liver and heart iron content, suggesting that vamifeport does not remove existing iron, but rather prevents further iron accumulation in cells from these tissues. 1 In contrast, vamifeport significantly reduced spleen iron content in non-transfused Hbb th3/+ mice ( Online Supplementary Figure S2 ).…”

“… 10 Moreover, these patients often show elevated transferrin saturation (TSAT) and non-transferrin-bound iron (NTBI), triggered by ferroportin-mediated iron release from macrophage recycling of damaged RBC, which can lead to oxidative stress, vascular injury and organ iron overload. 8 , 11 In addition, the accelerated recycling of RBC due to blood transfusions results in a high serum iron concentration and an increase in NTBI that correlates with the occurrence of heart disease. 12 …”

Safety and efficacy of human polymerized hemoglobin on guinea pig resuscitation from hemorrhagic shock

“…To better clarify the extent of the change in kidney function, additional experiments will be necessary to assess renal function after 48 h. Acute kidney injury (AKI) after RBC transfusion is usually associated with excess iron in the circulation and if ferritin is not present to remove the excess of iron, it can cause even worse clinical outcomes. Baek et al demonstrated that administration of a ferroportin inhibitor to switch compartmentalization of iron from the plasma to the spleen and liver, prevents post-transfusion iron accumulation, oxidative stress, and AKI 42 . Unlike the published study, we elected to use whole blood instead of RBCs, but we believe that potential iron toxicity still remains as mechanism of iron toxicity.…”

“…Baek et al . demonstrated that administration of a ferroportin inhibitor to switch compartmentalization of iron from the plasma to the spleen and liver, prevents post-transfusion iron accumulation, oxidative stress, and AKI 42 . Unlike the published study, we elected to use whole blood instead of RBCs, but we believe that potential iron toxicity still remains as mechanism of iron toxicity.…”

Differentiation of intestinal stem cells toward goblet cells under systemic iron overload stress are associated with inhibition of Notch signaling pathway and ferroptosis

“…Iron overload can occur in patients with inherited diseases, such as hereditary haemochromatosis [ 3 ] and β thalassaemia [ 4 ], or secondary to iron overload during blood transfusion and haemolysis [ 5 ]. Iron accumulation in multiple organs causes extra clinical problems and oxidative damage in the liver [ 6 ], pancreas [ 7 ] and kidney [ 8 ]. The metabolism of non-transferrin-bound iron results in reactive oxygen species, which are linked to apoptosis, necrosis, and cellular malfunction [ 9 ].…”