Intravenous Iron Requirement in Adult Hemodialysis Patients

Intravenous Iron Requirement in Adult Hemodialysis Patients Timothy V. Nguyen, PharmD The author is a clinical pharmacy specialist with Holy Name Hospital in Teaneck, New Jersey. He is also an adjunct assistant professor at the Ernest Mario School of Pharmacy, Rutgers University, Piscataway, New Jersey and Saint Peter s College, Jersey City, New Jersey. Objective. Chronic hemodialysis patients often require maintenance intravenous iron, as iron is an essential component of effective erythropoiesis. The Anemia Work Group (NKF-K/DOQI) anemia guidelines suggest a maintenance intravenous iron dose of 25 125 mg, but the optimal maintenance dose regimen remains difficult to determine. K/DOQI recommends these iron parameters: TSAT 20% and <50%, ferritin 100 and <800 ng/ml. An assessment of the maintenance dose regimen used in the present study is presented in this article. Patients and Methods. Data were collected retrospectively to evaluate clinical response in 40 adult chronic hemodialysis patients who received regular maintenance intravenous iron sucrose of 100 mg either every other week or every fourth week based on their ferritin and transferrin saturation (TSAT) levels. If ferritin level was between 100 and 500 ng/ml and TSAT level was 20% and 30%, then iron sucrose was administered every other week; if ferritin was 500 700 ng/ml or TSAT was 30% 45%, then iron sucrose was administered every fourth week. Ferritin and TSAT levels were monitored quarterly. Results. After the first quarter, 15 (38%) of the patients (n ¼ 15) remained on their original dosing regimen; 21 (53%) patients required adjustment to their regimen, either by discontinuing the regimen (n ¼ 18) or decreasing the dosing interval (n ¼ 3), 45% and 7.5% respectively; and 4 (10%) patients required additional intravenous iron supplementation. Conclusions. Iron sucrose administered at a dosage of 100 mg on a maintenance regimen either every other week or every fourth week exceeded most patients requirements. Maximum intravenous iron maintenance doses for adult chronic hemodialysis patients remain difficult to determine, and the maintenance iron requirement varies from patient to patient. Iron deficiency is common in patients undergoing hemodialysis (HD) treatment. When the kidneys fail, a patient will require either kidney transplantation or regular dialysis treatments to replace the functions normally performed by healthy kidneys. HD patients develop iron deficiency for a variety of reasons, including iron loss via dialysis-related procedures, bleeding from access sites, gastrointestinal bleeding, phlebotomies, erythropoietic therapy, and inadequate iron intake. 1 2 Because iron is essential for erythropoiesis, as iron stores deplete, anemia management of these patients becomes difficult. The Anemia Work Group of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) recommends regular maintenance intravenous (IV) iron therapy as part of anemia management of HD patients. 3 Iron deficiency is considered the most common cause of epoetin alfa resistance. Therefore, regular administration of iron is extremely important in anemia management. The K/DOQI guidelines recommend the administration of IV iron doses ranging from 25 to 125 mg and monitoring iron parameters regularly. It is also recommended that a transferrin saturation (TSAT) level of at least 20% but less than 50% and a ferritin level of 100 800 ng/ml be achieved in order to maximize epoetin alfa therapy and to maintain a target hemoglobin level of 11 12 g/dl. Optimal maintenance IV iron dosing of HD patients remains difficult to determine because the recommended ranges are broad. This article presents an assessment of the maintenance IV iron regimens for adult HD patients at the institution where the present study took place. Iron sucrose (100 mg) was administered every other week or every fourth week based on serum ferritin and transferrin saturation levels, and data were collected retrospectively to evaluate clinical responses. Patients and Methods Data were collected retrospectively during the second and third quarters of 2004 and into the first quarter of 2005. The process was approved by the institution s oversight committees, the nephrology department, the Pharmacy and Therapeutics Committee and the Medical Executive Committee. Patients receiving IV iron had to be at least 18 years old, receiving HD for SEPTEMBER 2006 DIALYSIS & TRANSPLANTATION 1

at least 1 year, receiving erythropoietic growth factor therapy to maintain target hemoglobin level (11 12 g/ dl), require IV iron supplementation, and have tolerated IV iron. The institution-approved protocol was for the administration of 100 mg of iron sucrose (Venofer, American Regent, Shirley, NY) IV push during HD treatment every other week (Group I, n ¼ 8) if ferritin was at least 100 but less than 500 ng/ml and TSAT was at least 20% but less than 30%, or every fourth week (Group II, n ¼ 32) if ferritin was 500 700 ng/ ml or TSAT was 30% 45%. All orders had to be initiated by the physician. Iron indices (ferritin, iron, total iron building capacity, and TSAT) were monitored quarterly for 3 quarters. Regimen adjustment was as follows: if the iron parameters of those in Group I increased to the levels of those in Group II, dose interval was decreased from every other week to every fourth week; if the iron parameters of those in Group II fell to the levels of those in Group I, dose interval was increased from every fourth week to every other week; if TSAT was greater than 45% or ferritin was greater than 700 ng/ml, IV iron was discontinued. Analysis Success rates for the groups were analyzed. Standard error for Group I (every other week administration) was 18% (78% CI), and standard error for Group II (every fourth week administration) was 9% (91% CI). Variation between the 2 regimens was analyzed using Fisher s exact test. Armitage and Berry mid-p value (0.228722) was greater than 5%; therefore, there was no significant difference in the results between the regimens. Results After the first quarter, 25 of the 40 patients (62%) required regimen adjustments: 18 patients (45%) had their administration of IV iron discontinued, 3 patients (7.5%) had their dosing interval decreased, and 4 patients (10%) had their dosing interval increased. The remaining 15 patients (38%) did not require a change in therapy (Figure 1). Subanalysis of the every-otherweek and every-fourth-week regimens was follows. Originally, 8 patients were receiving the everyother-week regimen (Group I). After the first quarter, 75% of these patients required adjustments to their regimen: 3 patients (38%) had their administration of IV iron discontinued, 2 (25%) had their dosing interval decreased, and 1 (12%) had it increased. The remaining 2 patients (25%) maintained the same regimen (SE 18%, 78% CI) for the next 3 quarters. Of the 2 patients who required a decreased dosing interval after the first quarter, 1 required discontinuation after the second quarter, and the other patient remained on the same regimen for the entire evaluation (Table I). Originally, 32 patients received the every-fourth-week regimen (Group II). After the first quarter, 19 patients (59%) required a regimen adjustment: 15 patients (46.9%) had their administration of IV iron discontinued, 1 patient (3.1%) had the dosing interval decreased, and 3 patients (9.4%) had the dosing interval increased; the remaining 13 patients (40.6%) maintained the same regimen (SE 9%, 91% CI). By the end of the second quarter, 11 of the 32 patients in Group II (34.4%) remained on the same regimen, and 21 patients (65.6%) required a regimen adjustment: 17 (53%) had administration of IV iron discontinued, 1 (3%) had a decrease in the dosing interval, and 3 (10%) had an increased dosing interval. By the end of the third quarter, 10 of 32 patients (31.3%) remained on the same regimen, and 22 patients (68.8%) required a regimen adjustment: 18 patients (56%) had administration of IV iron discontinued, 1 (3%) had a decrease in the dosing interval, and 3 (10%) had an increase in the dosing interval (Table I). Discussion HD patients often require IV iron supplementation to maintain iron stores and to replace iron loss. Maintenance administration of IV iron in conjunction with erythropoietic agents is well recognized as a means to maintain effective erythropoiesis and to effectively manage anemia for patients undergoing HD treatment. 2 4 However, determining the most effective dose and the frequency of administration of IV iron to these patients to replace iron loss and maintain adequate iron stores can be a challenge. Maintenance doses have been reported anywhere from a 25 mg to 125 mg administered with varied frequencies. IV administration of Figure 1. Intravenous iron dosing interval changes for the study patients (n ¼ 40). 2 DIALYSIS & TRANSPLANTATION SEPTEMBER 2006

Table I. Study period IV iron dosing interval changes during the study period for Group I (n ¼ 8) and Group II (n ¼ 32).* 1st Quarter 2nd Quarter 3rd Quarter Action Group 1 Group 2 Group 1 Group 2 Group 1 Group 2 no change 2 (25%) 13 (40.6%) 2 (25%) 11 (34.4%) 2 (25%) 10 (31.3%) discontinued 3 (37.5%) 15 (46.9%) 4 (50%) 17 (53%) 4 (50%) 18 (56%) fecreased interval 2 (25%) 1 (3%) 1 (12.5%) 1 (3%) 1 (12.5%) 1 (3%) increased interval 1 (12.5%) 3 (10%) 1 (12.5%) 3 (10%) 1 (12.5%) 3 (10%) *Group I originally received 100 mg IV iron every other week; Group II originally received 100 mg IV iron every fourth week. 100 mg of iron sucrose every other week or every fourth week achieved higher ferritin and TSAT levels than those set as goals by the Anemia Work Group. Sixty-two percent of our patients required an adjustment in their dosage, and more than 50% either discontinued therapy or required a reduction in dose after 1 quarter. This dose may represent an excess iron requirement in adult HD patients. One study estimated an average iron loss of 28 mg per week, and therefore determined the maintenance dose of IV iron gluconate to be 31.25 mg per week. The authors concluded that 31.25 mg of iron per week could not prevent the risk of iron overload. 5 Another observational study used the administration of 100 mg of iron sucrose once weekly to maintain a target ferritin level of 200 800 ng/ml, and a TSAT of 30% 45%. In this study, more than 50% of the patients achieved a ferritin level >1,100 ng/ml. 6 In the present study, 100 mg of IV iron sucrose was administered every other week or every fourth week to adult chronic HD patients to maintain ferritin levels of 100 700 ng/ml and TSAT levels of 20% 45%. This resulted in more than 50% of patients exceeding the target levels. The upper ferritin and TSAT targets were chosen to reduce the probability that the iron parameters would exceed the NKF-K/DOQI recommendations of 800 ng/ml ferritin and 50% TSAT. Administering too much iron may lead to excess iron and eventually to the development of iron overload. 7 It is important to monitor and assess iron parameters frequently in order to minimize any potential risks of iron overload. For the most part, IV iron therapy has been proven safe and effective, but the long-term risks such as its effect on the cardiovascular system and infection are still debated. A previous study suggested elevated serum ferritin levels were associated with an increased risk of myocardial infarction, and other studies raised questions about the relationship between oxidative stress and cardiovascular tissue damage. 8 9 Several previous articles pointed out the association between IV iron and infection. It was reasoned that infection was a result of IV iron stimulating bacterial growth and increasing the replication of bacteria during an infectious process. 10 11 Collins et al. reported that among Medicare recipients with higher claims, iron usage for at least 4 months was associated with increased infectionrelated deaths. 12 The amount of iron administered to HD patients to replace iron loss varies considerably, as can be seen in the results of the present study. The average reported iron loss among HD patients is about 2 g per year, but can reach approximately 3 g per year. 1,3,13 Among the 40 chronic dialysis patients in this study, 8 (20%) were receiving every-otherweek dosing, and 32 (80%) were receiving every-fourth-week dosing. After 1 quarter 75% of the patients on the every-other-week regimen and more than 50% of the patients on the every-fourth-week regimen had their regimen changed. The numbers constantly changed throughout the three quarters, and by the end of the third quarter, close to 70% of those initially on the every-fourth-week regimen had had their regimen changed, with only about 30% of the patients remaining on the original regimen. This variation is probably a result of the severity and chronic nature of the disease affecting dialysis patients. It is often difficult to predict the exact amount of iron required for the hemodialysis patient population, as many patients have multiple comorbid diseases and concurrent conditions such as gastrointestinal bleeding, infection, inflammation, variation in the amount of nutrient intake, and concurrent erythropoietic therapy. Iron sucrose (100 mg) was administered every other week to maintain ferritin levels of at least 100 ng/ ml but less than 500 ng/ml and TSAT of 20% 30% and every fourth SEPTEMBER 2006 DIALYSIS & TRANSPLANTATION 3

Rico, and the U.S. Virgin Islands, is 1 of 18 ESRD Network in the United States. Its goal is to collect data and to oversee ESRD care for all dialysis patients. It is close to impossible to have 100% of HD patients achieve the desired hemoglobin levels because their failed kidneys do not produce erythropoietin hormone, which is not present to stimulate the bone marrow to produce more red blood cells. Also making it nearly impossible for dialysis patients to achieve desired hemoglobin levels is that many are very sick, have multiple chronic conditions, have phlebotomies for blood work done on a regular basis, and lose blood every time they are dialyzed. Iron measurements were reported based solely on serum ferritin and transferrin saturation levels without consideration of other factors such as blood loss, acute illness, or other comorbid conditions. The small number of patients who required a dose increase did not affect the overwhelmingly high ferritin and TSAT levels. It is essential to establish comprehensive iron guidelines and to closely monitor iron therapy and hematologic response parameters in order to maximize the benefit of IV iron administration in this practice setting. The amount of iron administered to HD patients varies considerably. It is often difficult to predict the exact amount required for these patients, as many have multiple comorbid diseases and concurrent conditions. week to maintain ferritin levels 500 700 ng/ml or TSAT of 30% 45%. This resulted in more than 50% of all the patients in the study having adjustments made to their regimens, either discontinuation of therapy or a decrease in dosing interval after the first quarter, and up to 55% of the patients having their regimens discontinued or their dosing interval decreased by the end of the third quarter. Given that a small percentage of patients remained on the same regimen based on the predefined criteria throughout the entire evaluation (3 quarters), it was concluded that adult HD patients may not need as much IV iron as previously anticipated, reflecting the K/DOQI recommendations. As a result, the protocol at the institution where the present study took place was re-evaluated, and necessary adjustments were made. The dose of IV iron sucrose was reduced from 100 mg to 60 mg. This dose seems to be a more appropriate iron replacement that better reflects the average iron loss of dialysis patients. 5 On average, 80% of the patients maintained the target hemoglobin level of 11 12 g/dl recommended by the K/DOQI guidelines. The goal was to have as many patients as possible maintain this target. Meeting the anemia management goals of the Trans-Atlantic Renal Council Network was another objective. The goal was for 80% of pre-dialysis patients to maintain a hemoglobin level of at least 11 g/dl. 14 The Trans- Atlantic Renal Council Network, which consists of New Jersey, Puerto During the study, patients also received erythropoietic growth factor (darbepoetin alfa) to maintain target hemoglobin levels. The weekly average darbepoetin alfa dose was 55 (5) mg. To my knowledge, this is one of only a few studies that have also reported the average darbepoetin alfa dose in hemodialysis. Darbepoetin alfa is relatively newer than epoetin alfa and therefore is less extensively used or reported in the literature for this patient population. It would have been interesting to observe the trend of IV iron and its effects on darbepoetin alfa usage, but it was not the intention of this study and hence no comparison data were evaluated, although IV iron therapy has been shown to reduce erythropoietic usage and at the same time help to maintain desired hemoglobin levels. 15,16 Limitations to the present study include the lack of a control group. Conclusions Administration of supplemental IV iron to end-stage renal disease patients has been proven to be beneficial in managing anemia. With a regimen of 100 mg of iron sucrose administered intravenousely every other week or every fourth week, the iron requirements for most adult HD patients were exceeded in terms of the serum ferritin and TSAT levels suggested by the NKF-K/DOQI guidelines. This article was presented as an abstract (No. 202E) at the American College of Clinical Pharmacy Annual Meeting, San Francisco, California, October 23 26, 2005. The author acknowledges Danielle Picone, BSN, RN, CNN, and Jennifer Ash, PharmD, for reviewing the manuscript. Statistical analysis was done by Kailin Tu, director, Performance Engineering. References 1. Eschbach JW, Cook JD, Scribner BH, et al. Iron balance in hemodialysis patients. Ann Intern Med. 1977;87:710 713. 4 DIALYSIS & TRANSPLANTATION SEPTEMBER 2006

2. Fishbane S, Wagner J. Sodium ferric gluconate complex in the treatment of iron deficiency for patients on dialysis. Am J Kidney Dis. 2001;37:879 883. 3. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease. Am J Kidney Dis 2001;37(Suppl 1):S194 S206. 4. Macdougall IC, Tucker B, Thompson J, et al. A randomized controlled study of iron supplementation in patients treated with erythropoietin. Kidney Int. 1996;50: 1694 1699. 5. Canaves C, Bergamo D, Ciccone G, et al. Low-dose continuous iron therapy leads to a positive iron balance and decreased serum transferring levels in chronic hemodialysis patients. Nephrol Dial Transplant. 2004;19:1564 1570. 6. Edwards JH. Clinical review of the newer intravenous iron therapy options. Nephrol Nurs J. 2003;30(1):70 73. 7. Venofer. Package insert. Shirley, NY: American Regent Laboratories, Inc., 2000. 8. Morrison HI, Semenciw RM, Mao Y, et al. Serum iron and risk of fatal acute myocardial infarction. Epidemiology. 1994;5:243 246. 9. Besarab A, Frinak S, Yee J. An indistinct balance: the safety and efficacy of parenteral iron therapy. J Am Soc Nephrol. 1999;10:2029 2043. 10. Hoen B. Iron and infection: clinical experience. Am J Kidney Dis. 1999;34(Suppl 2):S30 S34. 11. Douvas GS, May MH, Pearson JR, et al. Hypertriglyceridemia, very low density lipoprotein and iron enhance mycobacterium avium replication in human macrophages. J Infect Dis. 1994;170: 1248 1255. 12. Collins A, Ebben J, Ma J. Frequent IV iron dosing is associated with higher infectious deaths [abstract]. J Am Soc Nephrol. 1997; 8:190A. Abstract A0884. 13. Cook JD, Eschbach JW. Iron absorption and loss in CKD. In: Iron Metabolism and Its Disorders. Excerpta Medica International Congress Series 366. New York: Elsevier, 1975:190 198. 14. Available at: http://www.tarcweb.org. Accessed April 19, 2006. 15. Chang CK, Chang CC, Chang SS. Reduction in erythropoietin doses by the use of chronic intravenous iron supplementation in iron-replete hemodialysis patients. Clin Nephrol. 2002;57:136 141. 16. Richardson D, Bartlett C, Will EJ. Optimizing erythropoietin therapy in hemodialysis patients. Am J Kid Dis. 2001;38:107 117. SEPTEMBER 2006 DIALYSIS & TRANSPLANTATION 5