2003/2 EDTNA/ERCA Journal Club Discussion Summary

The June 2003 EDTNA/ERCA Renal Care Journal Club discussed the paper entitled
'Iron management in Renal Failure Patients – How do we achieve the best results?? by Prof. Dr. Roland SCHAEFER and M. KOSCH from the university of Münster, Germany. This paper was published in the EDTNA/ERCA Journal 2002 XXVIII n° 4, pp. 182-184.

The paper was discussed and circulated in a group of 519 JC Members within the world. Anyone interested in Renal Care can simply become a JC Member by subscribing for free at the Journal Club

The paper has been actively discussed between Prof.Dr.Stanley SHALDON (Monaco), Lizzi LINDLEY (UK), Lee FISCHBACH (USA), Frankie O´KANE (Ireland), André STRAGIER (Belgium) and Jean-Yves DE VOS (Belgium).

DISCUSSION SUMMARY

Prof.Dr. Stanley SHALDON: As the first person to use IV iron in dialysis patients in 1965, I would like to mention the possibility that colloidal iron given intravenously might act as a stimulator of erythropoietin production even in grossly overloaded iron saturated patients. The value of the ferritin test is extremely dubious. As an acute phase protein it rises especially in dialysis patients for multiple reasons, the most relevant of all being the giving of colloidal iron IV which stimulates the acute phase response and causes an acute rise in Ferritin level.
Therefore the value of ferritin limits to the stopping of IV iron can only be of value if the patient has not received IV iron during the previous 2 weeks. We always gave iron every dialysis to all patients in small doses mixed with the heparin and by continuous infusion and in over 30 years of giving it this way no untoward reactions were seen and erythropoietin consumption has been extremely low. The anecdote I account of the possibility that IV colloidal iron does not work as a replacement source of iron alone but as a possible stimulator of liver erythropoietin acting on the EPO gene in the liver has been raised on several occasions.
The discussion on the observation that I ed. to this iconoclastic use of IV colloidal iron can be followed orally at a website where I give a talk on history of dialysis: http://www.mybesthealth.com/shaldon Now that we live in an era of Pure Red Cell Aplasia (PRCA) with EPO replacement therapy, more attention needs to be given to the use of IV iron in small doses. I suggest 10 mg colloidal IV iron every dialysis indefinitely. An upper limit of 1000 has arbitrarily been set for monthly ferritin level taken after no IV iron for 2 weeks. Further clinical details of this approach can be obtained from Dr. Céline GRANOLLERAS, contractible at: celine.granolleras@wanadoo.fr

Lizzi LINDLEY: I agree that the use of IV iron is vital to the correction of renal anaemia. Our policy is to dose all haemodialysis patients with ferritin levels below 500 ng/ml with IV iron, unless they have a haemoglobin of over 15.5 g/dl. This does work well for the whole population but there are a few patients with very high ferritin levels who are denied iron and who remain anaemic despite high EPO doses. The high ferritin in these patients is probably related to inflammation, not iron overload.

Lee FISCHBACH: What came to mind when I first read this paper was something for the future: Can we administer iron from the dialysate? There is a company in the USA that is working on a water soluble iron to be put into the concentrate. The iron would then be administered to the patient during dialysis through the membrane. This in theory would delete the need to give an IV injection of iron. What I would like to know will this work for all patients? If there is a small amount of iron in the concentrate will this give a correct dose for all patients, or will it be necessary to have several concentrates for alternative use? From what Prof. Shaldon has presented it would appear that this might come close to solving all anaemia problems in dialysis. However, Dr. Lindley seems to take a more conservative approach and limits IV iron to patients with hemoglobin below 15.5 g/dl. There is also a caution for patients with high ferritin levels. Would a dialysate administered iron dose be correct for these patients? Prof. Schaefer´s paper suggests that it is necessary to test ferritin levels only after a one week stoppage of an administered dose. Would this mean that it would be necessary to stop iron dialysate for three or more treatments to get an accurate patient test if the iron was administered through the dialysate? The concept of administering the iron through the dialysate seems like a great idea. The part I am not sure about is the management of such a way of administering iron.

Frankie O´KANE: In Belfast we have 7 consultant nephrologists. Until recently each one used a different approach to iron management. We eventually got a protocol together which ensure uniformity of prescribing in our hemodialysis patients. Virtually all our patients are maintained on a dose of around 200 mg of iron saccharate per month. We measure ferritin, transferrin saturation and TIBC on a monthly basis and doses are adjusted as needed. In the non-hemodialysis patients, we still have different methods applied by each consultant. I run a non-hemodialysis intravenous iron clinic on a weekly basis with around 10 to 12 patients a week. Each patient who is found to be iron deficient, based on the above tests, is offered a course of iron saccharate, total dose 1000 mg. This is given as 200 mg bolus dose over 5 to 10 minutes on 5 separate occasions. These patients come from the pre-dialysis clinics, from peritoneal dialysis and from transplant clinics. Some are intolerant of oral preparations. Our experience has shown an average increase in hemoglobin of 1 g/dl in both EPO dependant patients and those not using EPO. In over 18 months experience of using the bolus dose method we have had no serious adverse effects, in a total of over 600 injections. We avoid the use of veins that may be used for fistula formation. By changing to the bolus dose method in October 2001 we have been able to increase the number of patients treated by avoiding 3 to 4 hour clinic visits for patients attending for iron infusion. Patients who have experienced both methods much prefer the bolus dose, mainly for the reasons of time spent at the hospital. We are embarking on a programme of home HD and are keen that patients carry out self-administration of IV iron. As anyone experiences with this?

Jean-Yves DE VOS: Indeed,GUPTA et al. (Dialysate iron therapy: Infusion of soluble ferric pyrophosphate via the dialysate during hemodialysis. Kidney Int1999;55:1891-1898 ), and maybe others, reported on a novel means of supplying soluble iron pyrophosphate to the dialysate. This mode of administration was assessed in 10 haemodialysis patients who received increasing concentrations of iron pyrophosphate up to12 microg/dl in the dialysate over a 6 month period. The requirements for IV iron were dramatically reduced in this group ( 10 to 23 mg/week ;2 out of 10 patients ) compared with a control group continuing on IV iron dextran ( 56 to 37 mg/week; 11 out of 11 patients), and no significant adverse effects were seen. It looks as being an alternative to the IV administration at each dialysis session as proposed by Prof. Shaldon. Questions are:

1. is there a real need to add iron in dialysate as small doses IV looks quite without adverse effects?
2. 120 microg of ferric pyrophosphate per liter dialysis fluid is proposed. What is cost of this? What if HDF on-line is used?
3. what is effect on dialysis equipment and membranes ( deposits?, microbiologic?, biofilm?, etc… )?

With respect to the management of iron in general (IV or via dialysis fluid), still no reliable laboratory test for indicating iron deficiency promptly is available. That is likely why so many different managing opinions are still existing on the field.
Our home hemodialysis patients are treated in a similar way as our in- hospital hemodialysis patients. They receive according to ferritin level, transferin saturation, reticulocytes, MCV (Mean Corpus volume) and Hb values, inflammation and hemolysis status, 100 mg of iron sucrose (Venofer) on a weekly, two-weekly, monthly (28 days ), two-monthly (56 days) or not basis. They inject in bolus at finishing their treatment over 5 to 10 minutes in the venous chamber without problems.
In the pre-EPO period, when single needle dialysis was still very common in Belgium ( > 80% of patients in single needle ) we often saw hidden hemolysis due to the relatively high peak flows ( QB peak of > 500 ml/min in case of effective QB of > 250 ml/min ) causing shear stress when no size adapted needles where used, resulting in increasing ferritin levels (> 1000 ng/ml). So, high ferritin levels can be next to different other factors be a result of hidden hemolysis every dialysis session. Low grade hemolysis should be excluded therefore if ferritin level is high, simply by controlling of LDH ( Lacto Dehydrogenase ) before and after a dialysis session, regularly or on indication.

André STRAGIER: I would like to join Lee Fischbach on his open questions related to iron therapy via the dialysate: is this what we all will use in the future or are there hidden drawbacks with this alternative approach?
Rockwell, a US based company specialised in dialysis concentrate dry powders, launched the idea of iron therapy by means of water-soluble iron (ferric pyrophosphate) as well in HD as PD, via the dialysate. This company states that “ferric pyrophosphate decreases the need for intravenous iron by 80% and consequently reduces the risks associated with the toxic effects of IV iron such as hypotension and anaphylactic reactions, which can be life threatening. Unlike the IV iron, ferric pyrophosphate does not require processing by the liver and thereby eliminates the liver toxicity. It is effective in treating patients who are not able to release iron from storage sites due to a co-existent inflammatory state. Phase II clinical studies also showed that ferric pyrophosphate is well tolerated by patients without any short-term or long-term side effects. Most importantly, it maintains a constant state of iron balance thereby facilitating the hematopoietic effects of EPO without overloading the tissues with iron and thereby mitigating oxidative injury. Released pyrophosphate is also an anti-oxidant, which reduces the negative impact of oxidative stress that occurs to the patient during dialysis”.
The latter could be interesting as the usually recommended IV iron therapy doses are now also considered to increase oxidative stress, contributing to early atherosclerosis of ESRF patients. Also this would reduce the workload for the nursing staff.

FOR YOUR INFORMATION: ( information received from Dr. Eric GHEUENS (Belgium))

The normal iron content of the body is about 3 to 4 g. It exists in the following forms:

• Hemoglobin in circulating red cells – about 2.5 g
• Iron containing proteins, such as myoglobin, cytochromes and catalase – 400 mg
• Bound to transferrin in plasma –3 to 7 mg
• The remainder is storage iron in the form of ferritin or hemosiderin

Only a small amount of iron enters and leaves the body on a daily basis. Most iron is recycled from the breakdown of old red blood cells by macrophages of the reticuloendothelial system ( = recycling of heme- iron).Iron homeostasis is regulated strictly at the level of intestinal absorption and this varies according to the form of iron in the diet. A Western diet contains about 15 mg of iron. Some of this is heme iron (essentially meat products), of which about 30 percent is promptly absorbed. The remaining iron, accounting for almost all of the iron in non-Western countries, is poorly absorbed, with less than 10 percent being taken into the mucosal cells.
Heme dietary sources (fish, poultry and meat ) have a higher bioavailability than have non-heme (vegetable) sources ( 30 versus 10 percent).

CLOSING WORDS by Prof.Dr.SCHAEFER.

Management of renal anaemia is an important issue in the care of patients with chronic renal insufficiency. However, iron deficiency, absolute or functional, is a common problem in epoetin-treated patients and may lead to iron-deficient erythropoiesis. Lack of available iron is a frequent cause for hypo- or unresponsiveness to epoetin. Assessing iron status and optimising iron stores are therefore essential for the effective therapy of renal anaemia. Measurements of serum ferritin, transferrin saturation and percentage of hypochromic red cells or reticulocyte hemoglobin content (CHr) allow the assessment of iron status. However, low iron resorption and dose-dependent side effects limit the effectiveness of oral iron supplementation in the setting of epoetin-stimulated erythropoiesis.
Therefore, therapy with intravenous iron is the treatment of choice particularly in haemodiaylsis patients where 2000 - 3000 mg of iron have to be substituted per year. In Europe three intravenous iron preparations are available: iron sucrose, iron gluconate and iron dextran. Among those, it is iron sucrose (Venofer) that allows for safe and reliable iron supplementation without the risk of anaphylaxis and minimal iron toxicity. In haemodialysis patients 100 mg of Venofer every other week will in most cases be sufficient to guarantee adequate iron delivery to the bone marrow. In peritoneal and predialysis patients (Venofer) can be given in single doses of up to 200 - 300 mg (diluted in 200 - 300 ml of 0.9% saline over 30- 90 min) depending on the individual iron need of the patient.

Jean-Yves DE VOS (Belgium)
EDTNA/ERCA JC Manager