Anemia of Inflammation with An Emphasis on Chronic Kidney Disease

Abstract

Iron is vital for a vast variety of cellular processes and its homeostasis is strictly controlled and regulated. Nevertheless, disorders of iron metabolism are diverse and can be caused by insufficiency, overload or iron mal-distribution in tissues. Iron deficiency (ID) progresses to iron-deficiency anemia (IDA) after iron stores are depleted. Inflammation is of diverse etiology in anemia of chronic disease (ACD). It results in serum hypoferremia and tissue hyperferritinemia, which are caused by elevated serum hepcidin levels, and this underlies the onset of functional iron-deficiency anemia. Inflammation is also inhibitory to erythropoietin function and may directly increase hepcidin level, which influences iron metabolism. Consequently, immune responses orchestrate iron metabolism, aggravate iron sequestration and, ultimately, impair the processes of erythropoiesis. Hence, functional iron-deficiency anemia is a risk factor for several ailments, disorders and diseases. Therefore, therapeutic strategies depend on the symptoms, severity, comorbidities and the associated risk factors of anemia. Oral iron supplements can be employed to treat ID and mild anemia particularly, when gastrointestinal intolerance is minimal. Intravenous (IV) iron is the option in moderate and severe anemic conditions, for patients with compromised intestinal integrity, or when oral iron is refractory. Erythropoietin (EPO) is used to treat functional iron deficiency, and blood transfusion is restricted to refractory patients or in life-threatening emergency situations. Despite these interventions, many patients remain anemic and do not respond to conventional treatment approaches. However, various novel therapies are being developed to treat persistent anemia in patients.

The Influence of Inflammation on Anemia in CKD Patients

“…Anemia treatment in CKD patients should be based on drugs that enhance the synthesis of erythrocytes and provide adequate levels of iron for hemoglobin formation [75,76]. According to National Institute for Health and Care Excellence (NICE) the treatment of anemia in CKD patients requires the use of either iron or erythropoiesis-stimulating agents, their combination in order to address both absolute and functional iron deficiency [77,78].…”

“…The inflammatory state observed in CKD hinders erythropoiesis and reduces iron availability by the production of hepcidin [98,99]. Due to the fact that CKD patients also suffer from greater blood loss and diminished intestinal absorption of dietary iron, the supplementation of this compound is important to prevent absolute iron deficiency [76].…”

“…New therapies targeted at inhibiting hepcidin production are being investigated as potential anemia treatment [76]. Studies are performed to assess the efficacy and safety of anti-IL-6 antibodies such as Tocilizumab and IL-6 monoclonal antibodies such as sultuximab.…”

Jian-Pi-Yi-Shen Regulates EPO and Iron Recycling Protein Expressions in Anemic Rats with Chronic Kidney Disease: Accumulation of Hypoxia Inducible Factor-2α via ERK Signaling

“…In line with this notion, previous studies showed that JPYS could suppress pro-inflammatory cytokines production in 5/6 nephrectomized rats [38]. The hepcidin expression in the liver can be induced by the up-regulation of cytokines, most notably IL-6 and LPS [29], whereas increased systemic hepcidin level can act on macrophages, preventing the release of iron recovered from senescent red blood cells into plasma [39]. This could also explain the expression of iron recycling proteins in macrophages of liver and spleen of CKD rats.…”

“…Unlike anemia of iron deficiency, anemic patients with CKD suffer from various factors such as EPO resistance, functional iron deficiency and chronic inflammation [25]. In consideration of the safety of recombinant EPO and iron treatment, some novel therapies such as HIF stabilizers, prolyl hydroxylase domain (PHD) inhibitors and hepcidin antagonists have emerged in recent years [26][27][28][29]. All these treatments are targeting HIF signaling that are associated with EPO expression and iron metabolism.…”