Date of publication: May 19, 2016

News & Views

Unravelling the Controversies in IV Iron (Part 1): Iron Overload and Oxidative Stress

The use of iron in treating patients with chronic kidney disease (CKD) has evolved in line with new medications and understanding. The increasing use of IV iron in recent years led to the ‘Kidney Disease: Improving Global Outcomes’ (KDIGO) Controversies Conference to discuss potential safety concerns. The panel of experts assessed evidence for the risks and benefits of parenteral iron in relation to the potential for iron overload, oxidative stress, infections and hypersensitivity reactions. The conclusions of this meeting have recently been published in Kidney International.[1]* This article summarizes the Conference’s conclusions on iron overload and oxidative stress, with two further topics covered in our next article.

Achieving the right balance: iron deficiency vs. iron overload

Patients with CKD are prone to iron deficiency for a variety of reasons, including:

  • blood loss during hemodialysis and/or routine tests
  • blood loss from the gastrointestinal (GI) tract
  • reduced iron absorption
  • reduced iron availability, and
  • increased demand for iron due to use of erythropoiesis-stimulating agents (ESAs).

While a patient may be iron deficient, assessing the actual iron loss of an individual in order to calculate the precise dose for effective iron replacement is not straightforward, and can lead to a risk of positive iron balance, particularly if IV iron doses of >3g/yr are given.

Assessing iron requirements is multifactorial – and iron overload is also not a simple matter of ‘too much iron’. Any impact of increased body iron content depends on its distribution among parenchymal cells and cells of the reticuloendothelial system, duration of the excess and the presence of comorbidities. Any iron accumulation in CKD patients may not be enough to see the organ toxicity present in hemochromatosis.

The use of serum ferritin as a marker for iron accumulation is limited as elevated ferritin levels do not always correlate with increased liver iron content, and hyperferritinemia does not reliably indicate a positive iron balance or the location of the stored iron. MRI scans are being investigated as a tool to estimate body iron content and calculate iron therapy, but current evidence is insufficient to recommend use in clinical practice with CKD patients.

Given the evidence available, the panel concluded that, while end-organ damage as a result of IV iron use in CKD patients has not been unequivocally proven, the potential for iron toxicity from repeated, high-dose IV iron cannot be excluded.

Research recommendations

  • Develop more precise estimates of iron loss via the gut in a range of populations
  • Develop a methodology to determine body iron stores and tissue distribution
  • Clarify whether the thresholds used to indicate risk of organ damage in HFE-hereditary hemochromatosis patients are applicable to CKD patients (TSAT >45%, ferritin >1000 µg/l).

Oxidative stress

Oxidative stress is present in CKD patients and is often associated with inflammation and a poor prognosis. Although there are markers for oxidative stress, these are not widely used in the clinical setting due to a lack of established reference ranges, variable analytical techniques and poor understanding of the relationship between the markers of oxidative stress, kidney function and comorbidities.

Clinical studies have shown a link between IV iron administration and oxidative damage to peripheral blood lymphocyte DNA, protein oxidation and lipid peroxidation, but these do not necessarily translate into negative cardiovascular outcomes. Mouse models and patient studies looking at iron-mediated oxidative stress and cardiovascular risk remain inconclusive, and the observational nature of the studies means that firm conclusions regarding IV iron dose and cardiovascular risk cannot be made.

A proatherogenic role of hepcidin has been suggested, and one study links serum hepcidin-25 with cardiovascular events, although the evidence is limited. Like hepcidin, ferritin is upregulated during the acute phase response, and can reflect inflammation rather than an iron-replete state. Hyperferritinemia as a marker of cardiovascular risk, or a risk factor itself, is still unclear.

Investigations into the potential benefits of antioxidants highlight the complicated interplay of factors on the impact of IV iron. One study showed that IV iron with vitamin C actually increased production of reactive oxygen species, while a six-month RCT of antioxidative therapy in hemodialysis patients reported no impact on inflammation or oxidative stress.

Research recommendations

  • Investigate potential benefits of iron treatment in CKD patients beyond stimulation of erythropoiesis, as reported in patients with chronic heart failure, pulmonary arterial hypertension, restless leg syndrome and premenopausal women with low ferritin
  • Clarify the role of hepcidin as a predictor of anemia and cardiovascular events in non-dialysis patients
  • Study the oxidative impact of specific IV formulations, due to their pharmacokinetic differences
  • Conduct prospective controlled trials to examine whether iron promotes atherosclerosis and accelerates cardiovascular mortality, particularly in CKD patients with diabetes and/or persistent inflammation
PIVOTAL study

The KDIGO panel recognised the importance of the ongoing PIVOTAL study in answering many of their questions. 2,080 HD patients from across the UK will be randomised to high vs low-dose IV iron with at least 2 years follow-up. Endpoints include death, myocardial infarction, stroke, heart failure and infections.[2]

 

* The studies mentioned in this article are referenced to the KDIGO Conference paper (unless otherwise stated) as they represent those reviewed by the panel.

References

  1. Macdougall IC, Bircher AJ, Eckardt K-U, et al. Iron management in chronic kidney disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2016;89:28-39. doi:10.1016/j.kint.2015.10.002.
  2. Macdougall IC. Proactive IV irOn therapy for HaemodiALysis patients (PIVOTAL).; 2013. Available at: https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-002267-25/GB.

 

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