Treating Patients with IV Iron Therapy: Special Considerations
ANNA CE Satellite Symposium, April 21, 2005


Anemia Management in Pediatric Patients on Chronic Dialysis



Bradley A. Warady, MD
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This offering for 2.1 contact hours is being provided by the American Nephrology Nurses Association (ANNA), which is accredited as a provider and approver of continuing education in nursing by the American Nurses Credentialing Center-Commission on Accreditation (ANCCCOA). This educational activity is approved by most states and specialty organizations that recognize the ANCC-COA accreditation process. ANNA is an approved provider of continuing education in nursing by the California Board of Registered Nursing, BRN Provider No. 00910.
Date of Original Release: August 12, 2005
CE Credit Eligible Through: May 1, 2007
CE Credit Hours/Completion Time: 2.1
Target Audience: Nephrology nurses and technicians.
Method of participation: Listen to the talk, read the PubMed abstracts of linked slides and references, take the post-test, and complete the evaluation form.
 
LEARNING OBJECTIVES:
After participating in this program, the learner should be able to:
  1. Define serum ferritin and the current understanding of it in terms of safety and efficacy Describe special concerns that exist in treating anemia in pediatric patients on dialysis
  2. Discuss dosing guidelines for administering IV iron in pediatric patients
  3. Evaluate the safety and efficacy of IV iron therapy
SPEAKER DISCLOSURE STATEMENT:
Dr. Warady has received grant/research support from Watson Pharma, Inc. and is a member of the Advisory Board and Speakers Bureau for Watson Pharma, Inc.


SPONSORSHIP / SUPPORT :
This ANNA Satellite symposium was developed in conjunction with Fallon Medica and ANNA, and sponsored by a restricted educational grant from Watson Pharma, Inc.

ANNA AND HDCN CE POLICY STATEMENTS:
The CE policy and disclosure statements of ANNA are given in detail on the Symposium Home Page. The CE policy statements of HDCN are listed on this page.

00:01



Introduction:
It is my pleasure, at this point, to introduce our second speaker today. Dr. Bradley Warady is the chief of the section of Pediatric Nephrology, and the director of dialysis and transplantation at the Children's Mercy Hospital in Kansas City, Missouri. Brad, it is a pleasure to have you here today. It is an honor to be here and I am absolutely amazed that all of you got here at 6:45 in the morning.

00:43



Anemia management in children on dialysis
What I am going to do, as Steve mentioned is talk to you about anemia management in children on dialysis and give you some background information as well as about the success of anemia management.

01:06



Speed limit
Now, as a pediatric nephrologist, I usually like to show pictures of children as I give my presentations, and today is no different. My first slide, this slide here, this is probably what you are thinking about. You are going to go back home to work tomorrow or today, and your agreed upon speed limit at work is about 35 miles per hour but the doctors are telling you to go at 99. Do not worry about this. Just take it easy this morning. Have a good breakfast, and just learn a little bit about children on dialysis.

01:38



Group at Camp Chimer
This is the group we are going to talk about. This is a slide of our camp, Camp Chimer in Kansas City. These are kids on dialysis. While the numbers of children on dialysis pale in comparison to the adult experience, these kids require great attention to their care if they are to be provided optimal care.

02:00



Optimal care
When we look at optimal care for children on dialysis, it is truly multifaceted and somewhat different than in the adult population. We have to focus on the cognitive development of the children. We certainly have to focus on their growth. We have to look at ways to prevent infection. More recent data have emphasized the fact that we have to be alert to the development of cardiovascular disease in children on dialysis. We must control their bone disease. We must provide them adequate nutrition because these things affect their overall quality of life.

02:34



Anemia management
This morning again, we are going to focus on the anemia in management of these kids. Anemia clearly can have significant impact on their outcomes.

02:44



Am J Kidney Dis 2001 Aug;38(2):442.
K/DOQI guidelines
The entire presentation will be based upon this concept that Steve already mentioned, that of the K/DOQI guidelines and the K/DOQI targets. Again, the current guideline states that the target hemoglobin should be 11 to 12 g/dL, and this is based upon evidence, predominantly evidence that has been generated in the adult population, but we still utilize this target for the children that are cared for on dialysis.

03:13



Hemoglobin value at dialysis initiation - 2002
Let us now look at some of the data on the pediatric dialysis population. This is data from the United States Renal Data System that looks at the hemoglobin value of children at dialysis initiation. This reflects their management during the period of chronic renal insufficiency and this is data from 2002. If you look at the left side of the slide, you look at the males and the right side, the females, and you can see on the bottom of the slide there, we look at all pediatric patients and the different pediatric age groups. If you focus first on the male population, you can see that the mean population or the mean hemoglobin for those male patients that are starting hemodialysis was only 9.2 g/dL. If you focus on the males who are starting peritoneal dialysis, somewhat better at 9.8 g/dL but certainly much below the K/DOQI target of 11 g/dL. We can then turn our attention to the female patients, again, the same age groups. When we look at all pediatric patients, females, who are starting hemodialysis, note that their mean hemoglobin value is only 8.7 g/dL and for those starting PD, 9.4 g/dL. This data from 2002 certainly suggests that the anemia management of the CKD population in pediatrics is less than optimal.

04:41



Mean hemoglobin at dialysis initiation - 2004
This is more recent data on mean hemoglobin at dialysis initiation from the 2004 USRDS report. On the left side of the slide again, we are looking at all pediatric patients, their mean hemoglobin value, and if you look at that yellow bar, we see that the mean hemoglobin value is only 9.4 g/dL with the black population having even a lower mean value. Children with secondary glomerulonephritis have the worst data in terms of the hemoglobin at dialysis initiation. It certainly suggests that we need to be more aggressive in the management of anemia for these pediatric patients.

05:21



Impact of anemia on progression
What is the impact of anemia on the CKD population? This is data from the North American Pediatric Renal Transplant Cooperative Study, or NAPRTCS, and NAPRTCS is the largest pediatric renal database in the world. We have 3 registries that make up the NAPRTCS. There is a CRI registry, there is a dialysis registry, and there is a transplant registry. Here, we are looking at the CRI registry, and correlating the percent of patients that progress to end-stage kidney disease, correlated to their hematocrit level, differentiating those that are anemic as reflected by a hematocrit of less than 33% to those who are not anemic as reflected by a hematocrit of greater than or equal to 33%. It should be very clear to you that those patients who are anemic had a greater percentage of patients who progressed to end-stage kidney disease over a 48-month period of time, so this suggests that significant morbidity is associated with the presence of anemia during the period of CKD.

06:26



Morbidity and mortality in children with anemia
One year ago, I reviewed the NAPRTCS database to look at the correlation between anemia at the onset of dialysis and morbidity and mortality in our patient population.

06:40



Warady BA et al. Pediatr Nephrol. 2003 Oct;18(10):1055-62.
Reflection of morbidity
To reflect morbidity, we looked at the probability of being hospitalized for more than 30 days within the first year post dialysis initiation. We divided the patients again by modality, PD versus hemodialysis, and divided them by hematocrits. Between those again, we got a hematocrit of less than 33% to those who had a hematocrit of more than 33%, and what you can see in both the PD and the HD populations, the presence of anemia was significantly associated with an increased risk of morbidity or increased risk for prolonged hospitalization.

07:18



Warady BA et al. Pediatr Nephrol. 2003 Oct;18(10):1055-62.
Relative risk of all-cause death
Maybe most important is this data. The data looks at the relative risk of all-cause death in children associated with the presence of anemia. If you compare those patients who had a hematocrit of greater than or equal to 33% to those who had a hematocrit of less than 33%, you will note that the relative risk of death increased by 52%. If you look at those patients whose hematocrit was less than 30%, their risk of death increased by 80%. This is the very first and very important data that correlates the anemia in children with CKD with the presence of increased risk of mortality.

07:58



Adolescent population
What about the adolescent population, the prevalent dialysis population? Is there any impact of anemia on their overall care, on their quality of life, and on their outcomes?

08:10



Gerson A et al. Am J Kidney Dis. 2004 Dec;44(6):1017-23.
Quality of life of adolescent patients with chronic renal failure
This is recently published data from Johns Hopkins that looks at the quality of life of adolescent patients with chronic renal failure who are on dialysis, and what Dr. Gerson, who was the first author in this paper did, was to look at the correlation between a number of different quality-of-life domains and the presence or absence of anemia. Anemia in this study was defined as a hematocrit of less than 36%. Here, we are looking at 2 different domains. Role-physical is the domain that looks at the ability of children to engage in peer-related activities and physical function looks at overall physical functioning of these children. What you can see is that the presence of anemia, again a hematocrit of less than 36%, in each case was correlated with a poor outcome in terms of role-physical or physical functioning. In other words, the presence of anemia had a negative effect on the quality of life in these prevalent patients.

09:11



Cardiovascular disease in children on dialysis
This is USRDS data that looks at cardiovascular disease in children on dialysis, both incident patients and prevalent patients. You note, at the bottom of the slide, different hemoglobin levels, with pink representing a hemoglobin more than 11 g/dL, green 10 to 11, and red less than 10. We are looking at atherosclerotic heart disease, congestive heart failure, other cardiovascular diseases, such as arrhythmias or cardiomyopathies and CVAs or TIAs. Those individuals who had the lowest hemoglobin levels had the greatest risk for having cardiovascular disease during the pediatric period of time.

09:56



Hemoglobin and EPO dose in prevalence patients
The impact of these studies has led us to this change. This is USRDS data from the most recent report, looking at the change in hemoglobin in the yellow line and the change in EPO dose in the gold line over time, between 1991 and 2003 in prevalent pediatric dialysis patients. The good news is as you can see there has indeed been a gradual rise in both the mean hemoglobin value and the mean EPO dose between 1991 and 2003.

10:30



Mean hemoglobin values with different groupings
This is another way to look at the same data. Here we are looking at the mean hemoglobin values of pediatric dialysis patients with different groupings. The green grouping, a hemoglobin of more than 12 g/dL; the orange, 11 to 12 g/dL; and so on. Let us turn our attention to 1993, 10 years before the end of this observation period. You can see in 1993, only about 10% of children who were on dialysis did in fact achieve the K/DOQI target of mean hemoglobin value of more than 11 g/dL. We then turn our attention to 2003. You can see that we have much improvement with a significantly greater percentage of children achieving the K/DOQI target, but even in 2003, nearly 40% of children who are receiving hemodialysis have a mean hemoglobin value below 11 g/dL. They are indeed anemic.

11:25



Am J Kidney Dis. 2004 Aug;44(2 Suppl 2):A5-6, S1-92.
Hemoglobin in hemodialysis patients
Let us look closer at one of the populations, the population of children on hemodialysis, and this is as yet unpublished data from the most recent CPM report, and this reflects data from all children in this country who are receiving hemodialysis and this looks at the spectrum of mean hemoglobin levels for this population of patients. Indeed a significant percentage of these children have now achieved the K/DOQI target, again of more than 11 g/dL, but you will note the significant percentage of children, some 30%, that continues to have a mean hemoglobin value of less than that K/DOQI target, and in fact, 21% of children receiving hemodialysis have a mean hemoglobin value of less than 10 g/dL despite the evidence of morbidity and mortality associated with anemia.

12:17



Am J Kidney Dis. 2004 Aug;44(2 Suppl 2):A5-6, S1-92.
Data in adolescent age groups - age 12 and 18
We can break down this data into different age groups. Let us look at the adolescent population first. These are children between 12 and 18 years of age, all on hemodialysis, and here we are looking at the CPM data at 5 different points in time, snapshots between October and December of 1999 through 2003. We are looking at the percent of patients who have a mean hemoglobin value of more than 11 g/dL. Clearly, we have seen improvement. In 1999, only 55% of this population had a mean hemoglobin value of more than 11, but you will note in October through December 2003, still 30% of this population continues to have a hemoglobin value that is suboptimal.

13:07



Am J Kidney Dis. 2004 Aug;44(2 Suppl 2):A5-6, S1-92.
Data in younger age groups - age 0 to less than 12
The data is even less encouraging with the younger population. Again, these are all children between 0 and 12 years of age in this country on hemodialysis, and here we are looking at 3 points in time, 2001 through 2003 and you will note no improvement over that period of time. In 2003, just over 50% of children between 0 and 12 years of age on hemodialysis have a hemoglobin of more than 11 g/dL.

13:38



Percent of erythropoietin use by dialysis modality
If you look at the reasons for this persistence of anemia in these children, it certainly is not for lack of erythropoietin. This is data from the NAPRTCS again, looking at our dialysis registry, and here we are looking at EPO utilization at 4 different points in time, 6, 12, 24, and 36 months post initiation of dialysis, looking at the percent of patients that are receiving erythropoietin, and you can see that virtually all children on hemodialysis in this registry do in fact receive erythropoietin.

14:12



Reasons for EPO resistance
We now need to turn our attention to reasons for EPO resistance, and, as Steve mentioned to you earlier, iron deficiency is clearly the primary obstacle to the achievement of the target hemoglobin for those patients that are receiving erythropoietin. Indeed, there are other causes. Again, as is already mentioned to you, we must concern ourselves even in children with chronic inflammation. We must rule out causes of infection. We have to look at malignancy and uncontrolled bone disease or secondary hyperparathyroidism. We have to look for sources of bleeding in children, and I think we have to become again alert to the nutritional issues, folic acid deficiency, B12 deficiency, and even copper deficiency, which is something that more and more pediatric units are seeing in our patient population. We also have to keep in mind that children can be carnitine deficient and very few children are evaluated for this deficiency, and this is another well-recognized cause of EPO resistance. But clearly, iron deficiency is the major obstacle to the achievement of the target hemoglobin for those children on hemodialysis receiving EPO.

15:24



Body iron distribution and pathways - average adult
Steve already mentioned to you the reasons for iron loss in normal situations in terms of total body iron. This just gives you some quantitation to his explanation. You can see in the average adult there is about 1 mg/day loss of iron and thus only 1 mg is required to be absorbed to maintain iron balance with two thirds of iron being stored in the red blood cells and about one third of iron being stored in the reticuloendothelial system.

15:54



Body iron distribution and pathways - hemodialysis patient
This is the data on the hemodialysis patients. As already mentioned, these patients bleed in their GI tract. You phlebotomize these patients, red cells are left in their dialysis tubing. Overall, they have a net loss of 4.5 mg per day, and they also have decreased absorption of only 0.5 mg per day. If we extrapolate this to children, children lose approximately 1.6 g for 1.73 m. sq. of iron on a yearly basis, so substantial iron losses and decreased absorption.

16:29



Hepcidin
Hepcidin is a new peptide that you will be hearing more and more about because hepcidin may be at the root of much of the iron deficiency we see. Hepcidin is a peptide that is released from the liver as a result of inflammation that many of our patients experience, and as a result of infection that again many of our patients have to deal with. Hepcidin has 2 important functions that impact on iron status. Hepcidin decreases absorption of iron across the GI tract and hepcidin decreases the release of iron from the reticuloendothelial system. It clearly has a negative impact on the overall iron status of our patients and can help predispose to iron deficiency in children and adults as well.

17:18



Iron depletion
The end result, as Steve already mentioned to you, can be iron depletion. Functional iron deficiency, again per the current K/DOQI guidelines, is reflected by a serum ferritin value of more than 100 ng/mL and a TSAT of less than 20%. An absolute iron deficiency is defined by a serum ferritin of less than 100 and a TSAT of less than 20%. Most importantly, in the hemodialysis patient, both of these scenarios can be successfully addressed by the use of intravenous iron.

17:51



Am J Kidney Dis 2001 Aug;38(2):442.
K/DOQI administration of supplemental iron
It is for that reason that K/DOQI has this guideline, guideline #8 that says to achieve and maintain a hemoglobin of 11 to 12 g/dL, most hemodialysis patients, children and adults, will require intravenous iron on a regular basis. This is the optimal approach to the care for these patients.

18:14



Peritoneal dialysis vs. HD in kids
You may say to me, well, you are a pediatric nephrologist and you should know that most children receive peritoneal dialysis and this is one of our patients who is on peritoneal dialysis. Many of our kids indeed are on PD. I want to get rid of the myth that children do not receive hemodialysis. In fact, many patients in the pediatric age range do receive hemodialysis, and this is 2 of our kids in our unit, the child on the right knowing he was having a picture that was going to be shown to 1000 nurses, and there he is. Clearly, there is some differentiation in terms of the patient population that receives hemodialysis in pediatrics based upon the age of the patient, and this is NAPRTCS data correlating the percent of patients on PD versus hemo by the age of the patient. You will note that the youngest children, those between 0 and 1 year of age, who are on dialysis, the vast majority of them do in fact receive peritoneal dialysis because of clear difficulties with vascular access, but if one looks at the NAPRTCS data in the adolescent population, you note that there is a near-even split between those who receive PD and those who receive hemodialysis.

19:38



Prevalent dialysis patients by age and modality
This is very interesting data from the USRDS that looks at the 2004 information on the distribution of dialysis modality in the pediatric population around the world. The yellow bars represent those pediatric patients on in-center hemodialysis, the green bars those on home hemodialysis, and the red bars represent peritoneal dialysis. If you look at the US, you will note that in 2003, 60% of children that are on dialysis do in fact receive in-center hemodialysis, a marked change over the past decade. A small percentage receives home hemodialysis - this is an area that will increase in the coming years - and about 38% of children are on PD. The pediatric population is now a predominantly hemodialysis population, and thus we must address the hemodialysis needs of these kids like you do in the adult population.

20:44



Chavers BM et al. Kidney Int. 2004 Jan;65(1):266-73.
IV iron utilization
Let us now look at IV iron utilization in children that are on hemodialysis. This is data from the USRDS looking at the experience with intravenous iron in percent patient years with IV iron, between 1996 and 2000, again per USRDS. We are looking again at different age groups, 0 to 4 shown in the yellow bars, 5 to 9 in the green bars, 10- to 14-year olds in red, and 15- to 19-year olds in pink. If you look at the hemodialysis population, you will note that the youngest children, those between 0 and 4 years of age have little exposure to intravenous iron despite receiving chronic hemodialysis. The experience is somewhat better in the older children between 5 and 14 years of age and even in the adolescent population, but the exposure to intravenous iron is still suboptimal when compared to the adult experience when over 80% of the patients were receiving intravenous iron. Obviously, a small minority of the PD population in children receive IV iron.

21:50



Iron utilization in 12 months
Here, we are looking at the NAPRTCS data, and we are looking at data at 12 months after initiation of dialysis, looking at those patients who received oral iron versus those who received intravenous iron. The PD population is in gold. The hemo population is in red. If you focus our attention on the hemodialysis population, you will note that about 40% of children on hemodialysis are receiving oral iron therapy despite the evidence, at least in the adult experience, of its ineffective success rate in terms of approaching the target hemoglobin value. If you look at the IV iron usage, you can see that less than 50% of children in this registry are receiving intravenous iron despite receiving hemodialysis.

22:39



Am J Kidney Dis. 2004 Aug;44(2 Suppl 2):A5-6, S1-92.
Iron management
Here is the most recent data, again from the CPM project reports looking at iron management in children, adolescent children between 12 and 18 years of age, receiving hemodialysis, 5 different points in time, 1999 through 2003. What you see, again if you look at left side of the slide, is the patients prescribed IV iron in terms of percent of patients. Indeed in 1999, only 53% of children in the adolescent age group on hemo were receiving any intravenous iron. There has been improvement through the year of 2003, but keep in mind that we still see 30% of children on hemodialysis who are not receiving intravenous iron. That 30% figure should be familiar to you if you remember that 30% of this population does not achieve the K/DOQI target of 11 g/dL. In large part, those adolescents that are receiving hemodialysis but do not receive intravenous iron do not achieve a hemoglobin of more than 11 g/dL.

23:44



Previous studies
Why is that? Well, I think that the pediatric population has been somewhat anxious about the use of iron dextran in large part because of concerns about anaphylaxis and anaphylactoid reactions, but I think the other reason is that there have been very few studies of this population in the pediatric literature. This is the total extent of the literature on the use of intravenous iron in children on hemodialysis - a total of only 9 papers. That first paper by Flores et al is a retrospective study of 50 patients based upon a review of the medical records. The remainder of the studies, you can see, have very few patients involved. Some of them are maintenance studies as reflected by the letter M, others are replacement studies as reflected by the letter R, and they used different iron preparations, iron dextran, ferric gluconate, and iron sucrose. The third from the bottom study that we published in 2004 is the only study that has actually compared in a randomized fashion the use of oral iron therapy to intravenous iron therapy in children on hemodialysis.

24:50



Warady BA et al. Pediatr Nephrol. 2004 Jun;19(6):655-61.
Iron therapy in pediatric hemodialysis: Serum ferritin
Two slides that show you some information from that study. Here, we are looking at the serum ferritin value comparing the baseline data to 18-week data. The iron therapy was given for 16 weeks and then the evaluation was conducted 2 weeks later. You can see that there were 17 patients randomized to intravenous iron in gold and 18 patients randomized to oral iron in red, and you will note at 18 weeks, a significant increase in serum ferritin was only experienced by that patient population who received intravenous iron therapy.

25:27



Warady BA et al. Pediatr Nephrol. 2004 Jun;19(6):655-61.
Iron therapy in pediatric hemodialysis: EPO dosage
This is data, like that which has been shown to you in the adult population, that looks at the change in the erythropoietin dosage, again, comparing baseline data to 18-week data. Once again, only those children on hemodialysis who received intravenous iron experienced a significant fall in their EPO dosage. This data is the first data that truly emphasizes the importance and the superiority of intravenous iron to oral iron in children on hemodialysis.

25:57



NAPRTCS: IV iron and Hct
This is NAPRTCS data looking at the correlation between intravenous iron usage and the percent of patients who have a hematocrit of more than 35%. You see the gold bars represent those patients who have ever received intravenous iron while receiving hemodialysis and the red bars those patients who have never received intravenous iron. Clearly, a greater percentage of children who have received intravenous iron do in fact achieve a hematocrit of more than 35%. This data certainly suggests to us that there is certainly need for the use of intravenous iron in an aggressive manner in children who are receiving hemodialysis if we hope to achieve our target hemoglobins, but clearly we needed to study the newer agents to decide what was the best approach in the pediatric population.

26:47



Three different iron preparations
This is what we are left with, 3 different iron preparations to choose from. Iron dextran, ferric gluconate, and iron sucrose. You have already heard about the issues of anaphylactic and anaphylactoid reactions with iron dextran. Clearly this was not the agent that we wanted to study in pediatrics. Then we were left with looking at 2 different agents, ferric gluconate and iron sucrose, but based upon the very superior and very safe results with ferric gluconate in the adult population, we decided to study that agent for pediatric patients on hemodialysis.

27:22



Sodium ferric gluconate study
I want to show you the results of a study that will soon be published in the Journal of Pediatric Nephrology on the use of sodium ferric gluconate complex therapy in the treatment of iron deficiency in children receiving hemodialysis.

27:37



Study design
There are 2 purposes of this study. Number one is to compare the effectiveness of 2 different doses of ferric gluconate in increasing hemoglobin and the iron indices in children on hemodialysis and then clearly to look at the safety of this agent in our pediatric population. This was a prospective, randomized, multicenter trial where the children received 8 consecutive doses of ferric gluconate during 8 consecutive hemodialysis sessions, randomized to 1.5 mg/kg/dose or 3 mg/kg/dose, at no time exceeding 125 mg.

28:15



Inclusion/exclusion criteria
These were indeed pediatric patients between 2 and 15 years of age per protocol, and they were iron depleted as reflected by TSAT of less than 20% and/or serum ferritin of less than 100 ng/mL as characterized by the K/DOQI guidelines, and all of them had to have a have a stable EPO dosing regimen, meaning that there was no more than a 25% change in EPO dose during the 4-week screening period prior to the initiation of the trial, and clearly these patients could not be receiving any other iron preparations prior to the initiation of the study.

28:54



Results of study
These are the results of our study. Sixty-six patients were studied. This is the largest prospective study of intravenous iron in children on hemodialysis. There were 32 children who received the low-dose therapy and 34 who received the high-dose therapy. You will note their mean age was comparable about 12 years, the gender distribution was similar, the majority of the patients were Caucasian and the majority of the children were between 6 and 12 years of age.

29:21



Serum ferritin response to ferric gluconate
The next 4 slides will all be in the same format with the low-dose ferric gluconate being in the gold bars, the high dose or 3 mg/kg being in the red bars. The stars represent significant difference from baseline when we compare the results 2 weeks after the last iron infusion and 4 weeks after the last iron infusion, and the crosses represent significant differences between the 2 groups. I should mention that at the end of that last infusion, no further iron was given to these children for a 4-week period of time. If you look here first, it is serum ferritin. You can see that in both groups, both the 1.5 mg/kg and the 3 mg/kg, both groups enjoyed a significant increase in serum ferritin when compared to baseline at 2 weeks and 4 weeks after the last infusion, but as you might except, that patient population that received the high-dose therapy had a significantly greater increase in serum ferritin than those patients who received the low-dose therapy.

30:21



Change in TSAT
Here, we are looking at the change in the transferrin saturation. Once again, at 2 weeks and 4 weeks following the last infusion, significant increases in TSAT were experienced by both patient groups but in contrast to serum ferritin, there was no difference in the 2 groups - comparable changes when compared to baseline in the low-dose and high-dose therapies.

30:44



Hemoglobin response to ferric gluconate
We looked at the hemoglobin response in much the same data. Significant increases in hemoglobin as a result of intravenous iron therapy 2 weeks and 4 weeks following the last infusion in both the low-dose and the high-dose groups but like with the TSAT, no difference in the hemoglobin change between the 2 groups.

31:05



CHr response to ferric gluconate
Finally, Steve mentioned to you the reticulocyte hemoglobin content, or CHr, as a potentially valuable means of looking at the iron status of patients. We also looked at that and once again found a significant increase in the CHr when compared to baseline in both groups but no difference between the 2 patient groups.

31:27



Safety issues
The safety issue was important to the pediatric patient and there were 4 treatment-related adverse events reported in 2 patients. One patient in the low-dose group experienced one occurrence each of nausea, diarrhea, and vomiting, and one patient in the high-dose group had one occurrence of persistence of severe anemia. In neither case did this preclude the further use of ferric gluconate. There were a number of hypotensive events in association with this protocol but in all cases, investigators felt that this was secondary to ultrafiltration and not secondary to the medication itself. Most important to the safety of these kids, there were no occurrences of either anaphylactic allergic reactions or nonallergic anaphylactoid reactions in association with the use of ferric gluconate.

32:18



Study conclusion
The conclusions to this study are two. Number one, that the use of the intravenous infusion of ferric gluconate, whether one uses a dose of 1.5 mg/kg or 3 mg/kg is a safe and effective approach to iron-repletion therapy in children receiving hemodialysis and erythropoietin, and given the equivalent efficacy in terms of TSAT, hemoglobin, and reticulocyte hemoglobin content, we are recommending an initial dosing regimen of 1.5 mg/kg/dose for 8 consecutive doses with no dose to exceed 125 mg. Clearly on an individual patient basis, one then has to monitor the iron status of that patient. Some patients may require more iron, others less iron, but for the vast majority of children, the provision of this dose of Ferrlecit or ferric gluconate will indeed lead to an excellent iron-repleted state.

33:14



A happy red blood cell
All of this leads to this picture. This is an electron micrograph of a red cell. One of my colleagues says, "Well, how do you know this is a happy red cell?" "Well, there is a smile on the red cell, so of course it is happy." So iron repletion does lead to a happy red cell, but we also want to again lead to a happy patient on dialysis.

33:32



Iron-repleted state
How do we again treat this patient and have him, again, be happy in terms of his iron-repleted state.

33:40



Iron administration
I think, in pediatrics as well as adults, we have to follow treatment algorithms, and I know all nurses like algorithms. This allows us to treat our patients in a very rapid, efficient, and effective manner. Here you can see an algorithm that we put together for pediatrics that focuses on all the issues that Dr. Fishbane mentioned, looking at TSAT, looking at ferritin, looking at issues of inflammatory block, and deciding on those patients who have TSAT less than 100 or hemoglobin values that are suboptimal with very high EPO doses, that may be those patients do in fact require and deserve a trial of intravenous iron.

34:19



Maintenance EPO therapy
Associated with the iron algorithm, obviously we have an EPO algorithm that also helps us optimize the care of the pediatric patient on hemodialysis.

34:31



Patterson P et al. Am J Kidney Dis. 1998 Oct;32(4):635-41.
Impact of treatment
The impact to treatment algorithms can be nicely seen in this study from Alabama. Here, these individuals looked at the percentage of patients that have achieved a target hematocrit of more than 31% at baseline and 6 months after initiating a treatment algorithm, and you can see that a significantly increased percentage of patients did in fact achieve that target hematocrit with the use of the algorithms. These are very, very beneficial tools that we should all be using because they clearly will benefit our patients.

35:01



Conclusions
In conclusion, I hope I have shown to you that anemia management is a clearly important component of optimal care to provide it to children on dialysis, and iron deficiency is a key factor in the persistence of anemia, especially in our patients that are on hemodialysis. Based upon the study we have conducted, we can tell you for sure that IV iron therapy with ferric gluconate is a safe and effective approach to repletion iron therapy in the pediatric hemodialysis population, and I think with the use of intravenous iron and other tools that we have now, we can provide aggressive and optimal care to our patients that will clearly benefit them in their outcomes and their long-term care.

References
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  2. Warady BA, Ho M. Morbidity and mortality in children with anemia at initiation of dialysis. Pediatr Nephrol. 2003 Oct;18(10):1055-62.

  3. Gerson A, Hwang W, Fiorenza J, Barth K, Kaskel F, Weiss L, Zelikovsky N, Fivush B, Furth S. Anemia and health-related quality of life in adolescents with chronic kidney disease. Am J Kidney Dis. 2004 Dec;44(6):1017-23.

  4. 2003 annual report: ESRD clinical performance measures project. Am J Kidney Dis. 2004 Aug;44(2 Suppl 2):A5-6, S1-92.

  5. Chavers BM, Roberts TL, Herzog CA, Collins AJ, St Peter WL. Prevalence of anemia in erythropoietin-treated pediatric as compared to adult chronic dialysis patients Kidney Int. 2004 Jan;65(1):266-73.

  6. Warady BA, Kausz A, Lerner G, Brewer ED, Chadha V, Brugnara C, Dahl NV, Watkins SL. Iron therapy in the pediatric hemodialysis population. Pediatr Nephrol. 2004 Jun;19(6):655-61.

  7. Patterson P, Allon M. Prospective evaluation of an anemia treatment algorithm in hemodialysis patients. Am J Kidney Dis. 1998 Oct;32(4):635-41.


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