Day 1 of ASN Kidney Week. November 12, 2014 Thursday.

On March 2014, a KDIGO Controversies Conference on Iron Management in Chronic Kidney Disease was conducted in San Francisco, CA, co-chaired by Drs. Glenn M Chertow (Stanford University School of Medicine, USA) and Iain C Macdougall (King’s College Hospital, UK).

There has been recognition of a pattern of increase in utilization of IV iron formulations in recent years, and one of the postulates for this is the decrease in use of ESAs (also discussed in a previous blog post of mine) because of attendant safety concerns with achieving normalization of Hgb (with ESA usage).

Similarly, the US DOPPS Practice Monitor reported that that “the ferritin threshold at which IV iron administration is discontinued exceeds 800 ng/mL in over 80% of facilities” and that “25% of surveyed facilities have serum ferritin levels exceeding 800 ng/mL in at least two thirds of their patients.”

Although it has been recognized that iron plays an important role in management of anemia, there has been some concern regarding potential confounding toxicities that may arise from its use namely:

1. Iron Overload
2. Inflammation and Oxidative Stress
3. Iron and Infections, and
4. Iron and hypersensitivity reactions

Dr. Macdougall gave a nice summary of what were discussed and addressed in these meetings.

Iron Deficiency and Overload

1. Iron deficiency (in the presence of anemia) was associated with poor prognosis, lower quality of life and exercise capacity, particularly in patients with CHF, e.g., Cardiorenal Syndrome.
2. No test has been identified to be diagnostic of iron overload.
3. The iron overload that occurs with IV iron administration is particularly distinct from hemochromatosis, in terms of its effects on organ systems, e.g., liver, heart, pancreas, kidneys.

Inflammation and Oxidative Stress

1. There are several laboratory tests that are available that can be used to measure oxidative stress, e.g., MDA, F2-Isoprostanes, lipid hyperoxides, ADMA, 8-oxodG, protein carbonyl, AOPP, glutathione-related activity, GSH/GSSG.
2. There is experimental evidence alluding to IV iron’s capacity to promote oxidative stress, inflammation, and atherogenesis. However, most clinical trials supporting this theory, are primarily ‘observational’ in nature.
3. At present, there is insufficient evidence to recommend that 1 IV iron formulation is superior over another as far as their ability to induce oxidative stress is concerned.

Iron and Infections

1. There is experimental evidence that suggest that iron can modulate host immune function, e.g., monocytes, neutrophils, BUT the results of various studies seem to be conflicting.
2. Regarding whether cumulative doses of iron actually correlate with increasing risks of infections, most of the support for this come from observational epidemiological studies.

Iron and Hypersensitivity reactions

1. All IV iron formulations can potentially cause hypersensitivity reactions BUT the risk of life-threatening events remain rare.
2. First dose should be given in a set-up whereby resuscitative staff and equipment are readily available. Furthermore, there is “no physiological basis for the 30-minute post-infusion observation window.” This because “IV iron delivery should not be associated with a ‘severe delayed reaction’ as seen with subcutaneous antigen presentation or in vaccination or allergen immune therapy.”

Dr. Macdougall added further, that based on current available literature, the benefit/risk ratio of IV iron remains the same, and the WG felt that there was not enough information to justify updating the current KDIGO Anemia Management Guideline. The WG recognizes that need for greater evidence-based RCTs on this topic cannot be underscored.

In conclusion, he mentioned about an upcoming trial called PIVOTAL (Proactive IV irOn Therapy in hemodiALysis patients) which is a UK multi-centered prospective open-label 2-arm randomized controlled trial of IV iron therapy in incident hemodialysis patients. This will hopefully shed some light on some of the issues previously discussed.

Post by Dr. Edgar Lerma, eAJKD Advisory Board member. 

Check out more of eAJKD’s coverage of Kidney Week 2014! Also, follow @eAJKD on Twitter for live updates!