Narrative Review of Hyperferritinemia, Iron Deficiency, and the Challenges of Managing Anemia in Aboriginal and Torres Strait Islander Australians With CKD

Abstract

Aboriginal and Torres Strait Islander Australians (Indigenous Australians) suffer some of the highest rates of chronic kidney disease (CKD) in the world. Among Indigenous Australians in remote areas of the Northern Territory, prevalence rates for renal replacement therapy (RRT) are up to 30 times higher than national prevalence. Anemia among patients with CKD is a common complication. Iron deficiency is one of the major causes. Iron deficiency is also one of the key causes of poor response to the mainstay of anemia therapy with erythropoiesis-stimulating agents (ESAs). Therefore, the effective management of anemia in people with CKD is largely dependent on effective identification and correction of iron deficiency. The current identification of iron deficiency in routine clinical practice is dependent on 2 surrogate markers of iron status: serum ferritin concentration and transferrin saturation (TSAT). However, questions exist regarding the use of serum ferritin concentration in people with CKD because it is an acute-phase reactant that can be raised in the context of acute and chronic inflammation. Serum ferritin concentration among Indigenous Australians receiving RRT is often markedly elevated and falls outside reference ranges within most national and international guidelines for iron therapy for people with CKD. This review explores published data on the challenges of managing anemia in Indigenous people with CKD and the need for future research on the efficacy and safety of treatment of anemia of CKD in patients with high ferritin and evidence iron deficiency.

INFERR-Iron infusion in haemodialysis study: INtravenous iron polymaltose for First Nations Australian patients with high FERRitin levels on haemodialysis—a protocol for a prospective open-label blinded endpoint randomised controlled trial

“…Findings of studies that we conducted in the NT [ 6 , 16 , 23 ] and evidence from other international studies demonstrate a need to use serum ferritin levels and TSAT in conjunction with other markers of iron status, particularly in patients with a high serum ferritin concentration. A report from the United Kingdom National Institute for Health and Care Excellence (NICE) has discouraged the use of either measure alone due to significant problems with lack of accuracy in determining the correct treatment [ 14 ].…”

“…Anaemia is a major complication of ESKD [ 3 ]. Prevalence rates of anaemia are also high among First Nations Australians [ 4 – 6 ]. Anaemia is associated with reduced quality of life, increased risk of cardiovascular disease, hospitalisations, cognitive impairment, and mortality [ 7 , 8 ].…”

“…Ferritin is an intracellular protein which stores excess iron, and low serum ferritin is a marker of iron deficiency. However, ferritin is also an acute phase protein, and increased serum ferritin concentration, along with increases in other acute phase reactants such as C-reactive protein (CRP), is observed in patients who have inflammation [ 6 , 16 ]. There is also growing evidence that high serum ferritin concentration is independently associated with high rates of hospitalisations, cardiovascular disease and mortality [ 6 , 17 , 18 ].…”

“…Monitoring liver fibrosis (using FibroScan®) and cirrhosis is also crucial [ 31 , 38 – 40 ]. Considering the high prevalence of diabetes mellitus and metabolic syndrome in the First Nations Australian population, it may be hypothesised that a high prevalence of hepatic steatosis and fibrosis exists as encountered in dialysis patients more and more frequently in developed countries as well as the dysmetabolic iron overload [ 6 ]. There is a need to identify those patients with these underlying liver diseases, to adapt iron dosage and to monitor the safety of IV iron in this setting.…”

“…There is a need to identify those patients with these underlying liver diseases, to adapt iron dosage and to monitor the safety of IV iron in this setting. This peculiar safety issue seems particularly relevant since indiscriminate IV iron has recently been shown to either trigger or aggravate non-alcoholic fatty liver disease / non-alcoholic steatohepatitis in dialysis patients suggesting a double-edged iron sword [ 6 ].…”