Date Published: 
Friday, 28 February, 2014

Iron therapy in Nephrology

Professor Iain Macdougall is Consultant Nephrologist and Professor of Clinical Nephrology at King’s College Hospital, London, UK. He has been involved in numerous advisory boards in renal anaemia management worldwide, including the Working Parties responsible for both the 1999 and the 2004 versions of the European Best Practice Guidelines, along with the Working Group that produced the US National Kidney Foundation Kidney Disease Outcomes Quality Initiative (KDOQI) Guidelines on Renal Anaemia Management, and the 2012 Kidney Disease Improving Global Outcomes (KDIGO) CKD Anemia guideline. He has authored 18 book chapters and over 200 journal publications.

Why did you become interested in iron deficiency?

“I first became interested in anaemia in patients with chronic kidney disease whilst conducting research on the biological effects of erythropoietin therapy in this population in the late 1980s; in these days, erythropoietin was a brand new therapy for treating anaemia. It soon became apparent that iron deficiency was a huge problem contributing to anaemia in chronic kidney disease. Patients on erythropoietin therapy developed a condition, which hadn’t previously been reported, called functional iron deficiency. This was the concept that when you provide the bone marrow with erythropoietin for red blood cell production, it sometimes runs out of the main ‘ingredient’ – namely iron – causing patients to have a slower response to the erythropoietin therapy. The nature of my research at that time was to improve the anaemia of chronic kidney disease, but iron deficiency was clearly a big part of the problem.”

Why is iron important in chronic kidney disease?

“The lack of iron availability in the bone marrow of patients with chronic kidney disease exacerbates the anaemia associated with this condition. They are then likely to develop the symptoms associated with anaemia in this population, which include fatigue, shortness of breath, immune and cognitive impairment, and gastrointestinal disturbances. Severe anaemia in this patient group is also associated with an increased risk of mortality, cardiovascular complications, and a significant reduction in quality of life.

Why do patients with chronic kidney disease become iron deficient?

Why these patients become iron deficient is partly because they have poor diets with low dietary iron intake and, in addition, they do not absorb iron well. Hepcidin, which is greatly increased in patients undergoing haemodialysis, also affects iron status, and other therapies may interact with iron, such as phosphate binders or anti-indigestion drugs such as omeprazole, which reduce iron absorption. These patients also lose iron through blood sampling, anticoagulation during haemodialysis, prophylactic aspirin consumption (which can induce bleeding), and gastrointestinal inflammation.”

How common is iron deficiency in patients with chronic kidney disease?

“The prevalence of iron deficiency is difficult to determine as there are several ways in which to define this condition. But the bottom line is that iron deficiency is very common and in the range of 30–60%. Studies that look at the prevalence of iron deficiency are the European Survey of Anaemia Management1 and, more recently, the study by Fishbane and colleagues2.”

How do you define iron deficiency in this patient population?

“A ferritin level <100 ng/ml or a ferritin level >100–300 and a TSAT <20% are the common definitions of iron deficiency. These are used to identify iron deficiency in patients with chronic kidney disease and chronic heart failure. They are not used in the general population or in pregnancy. To unequivocally determine whether a patient is iron deficient their ferritin level must be <20 ng/ml but the trouble is that very few patients have ferritin levels <20 ng/ml, but they are still iron deficient. There are a lot of iron deficient patients with very ample levels of ferritin in the chronic kidney disease population.”

How well is the importance of iron deficiency known in the nephrology community?

“Iron deficiency is now quite well known and certainly a lot better than it was 20 years ago. Today, most nephrologists would recognise that a patient is iron deficient and that those undergoing haemodialysis require intravenous iron therapy. Awareness of iron deficiency is also starting to increase in other areas, such as cardiology, gastroenterology and gynaecology. I think nephrologists have paved the way in terms of recognising iron deficiency and learning more about the condition, but more can still be done, and there are still many nephrologists who underestimate the problem.”

Are there still unmet needs in iron deficiency and chronic kidney disease?

“Absolutely. We still don’t know the best way of treating iron deficiency. We know that haemodialysis patients do not absorb oral iron therapy well because of inflammation and high hepcidin levels so they frequently require intravenous iron therapy in order to correct iron deficiency. Non-dialysis patients with chronic kidney disease have less inflammation and thus some of them can effectively absorb oral iron. However, we still don’t know the best way of treating this population – should they try oral iron first or are they are better off receiving intravenous iron first? What is the long-term safety of receiving regular relatively large amounts of intravenous iron? We’ve gathered data in the last few years about ESAs and the possible harm that they may cause in patients with CKD but we have no data on the optimal administration of intravenous iron. Many clinics across the globe administer intravenous iron therapy very liberally to haemodialysis patients to correct functional iron deficiency but with no data to say that this is the appropriate treatment in terms of safety.”

What are you currently focusing on in your research and why is this area of particular interest?

“We are trying to find out the optimum treatment for iron deficiency in haemodialysis patients – should patients have a large quantity of intravenous iron therapy or just the bare minimum required to correct the iron deficiency? We are performing a large randomised controlled study called PIVOTAL in over 2000 haemodialysis patients from more than 40 sites in the UK, randomising patients to two different dosing regimens of intravenous iron to try to determine what the appropriate level of iron therapy should be in these patients.”

What do you think will have the greatest impact on iron deficiency management in the future?

“There are several large, multicentre, randomised studies ongoing which are not just investigating iron deficiency within the nephrology arena but also in the fields of heart failure and other therapeutic areas. I think that over the next few years we will gather much more information on the best way of replacing iron in patients. The outcome of these large, multicentre trials will be key for the treatment of iron deficiency in many different therapeutic areas.”

How is the Iron Therapy website of value to you and other nephrologists?

“The Iron Therapy website is an essential education tool that encompasses all of the latest scientific developments and clinical publications on the theme of iron deficiency – the website captures anything new in this area. I think it is a huge source of information for people who don’t know the field particularly well – this one website encompasses all the different therapeutic areas. It is specialty-specific allowing each type of specialist to view their own area – gynaecologists can look at the gynaecology section and nephrologists can navigate their way through the nephrology section. In many areas there is still a lack of information, and the website offers learning from each specialty. I think that the best way of getting information in the 21st century is through the internet and gives a very global and comprehensive overview of the field.”

For further information on how to treat iron deficiency in patients with chronic kidney disease please click here. The Iron Therapy website is updated on a regular basis with all of the latest news on iron therapy in nephrology.