Hemodialysis patients with endstage

Insights into Achieving Target Hemoglobin Levels: Increasing the Serum Ferritin Parameter Scott Bralow, DO Dr. Scott Bralow is the Medical Director of the Renal Center of Philadelphia. Evidence suggests that higher serum ferritin levels may not be an accurate refl ection of iron stores or predict a patient s response to intravenous (IV) iron. Therefore, our dialysis unit revised its IV iron and anemia management protocol, from initially holding IV iron at a lower limit of serum ferritin to now continuing IV iron therapy at higher serum ferritin levels. This article describes our facility s experiences with IV iron administration at higher serum ferritin levels and the resulting improvements in patient outcomes as measured by an improved erythropoietic response. Hemodialysis patients with endstage renal disease (ESRD) frequently suffer from anemia due to impaired erythropoiesis and ongoing blood and iron losses occurring during the dialysis procedure. 1 This patient population can lose up to 3 g of iron annually, making iron deficiency a significant concern. 2 The dynamics of erythropoiesis dictates that an adequate supply of iron needs to be available for healthy red blood cell (RBC) production. Red blood cell development is a 25-day process that initiates in the bone marrow as hematopoietic stem cells proliferate and differentiate into erythroid precursor cells. Iron is essential on approximately day 20, as transferrin receptors are at a maximum on the cell surface and iron is taken up by the cells and incorporated into hemoglobin (Hgb). Insufficient iron supplies at this stage will eventually result in microcytic hypochromic RBCs. 3 Over the past decade the nephrology community has recognized the importance of intravenous (IV) iron therapy, in conjunction with erythropoiesis-stimulating agents (ESAs), in the routine management of iron-deficiency anemia. Data from the ESRD Clinical Performance Measures Project reported that 70% of the adult in-center hemodialysis sample population was prescribed IV iron therapy between October and December 2006, up from 59% during this period in 1998. 4 Accordingly, from 1998 to 2006 the percentage of hemodialysis patients with serum ferritin levels 100 ng/ml increased from 83% to 95% and the percentage of those with serum ferritin levels >800 ng/ml increased from 16% to 22% indicating an environment of more effective anemia management. These accomplishments are consistent with an increase in the percentage of hemodialysis patients who achieved a mean target Hgb level 11 g/dl, from 59% in 1998 to 84% in 2006. A total of 95% of patients in this analysis were also receiving ESA therapy, demonstrating the importance of a balanced approach to ESA and IV iron therapy. Although serum ferritin is a commonly used measure of iron in the body and some clinicians hold iron at a specific serum ferritin value, increasing evidence suggests that higher serum ferritin levels do not accurately reflect iron stores 5 or predict a patient s response to IV iron. 6 A recent study has demonstrated that anemic hemodialysis patients with iron-restricted erythropoiesis, characterized by high serum ferritin levels (ie, 500 1,200 ng/ml) and low transferrin saturation (TSAT) levels (ie, 25%), can benefit from IV iron therapy while receiving adequate ESA doses. 7 Our dialysis facility changed its IV iron and anemia management protocol, initially holding iron at a lower serum ferritin level and then allowing for the continuation of IV iron therapy at higher serum ferritin levels. This article describes our experience and the resulting improvements in patient outcomes as measured by an improved erythropoietic response, as well as other relevant issues involving the serum ferritin marker. Consequences of Reducing the Serum Ferritin Upper Limit In 2006, the National Kidney Foundation revised the Kidney Disease Outcomes Quality Initiative (KDOQI) recommendation on administering IV iron therapy to achieve a specific serum ferritin level. According to the KDOQI recommendations, there is insufficient evidence to recommend routine administration of IV iron if serum ferritin is >500 ng/ml. 1 Furthermore, KDOQI states that when serum ferritin is >500 ng/ml, decisions on IV iron administration should weigh several factors, including the patient s clinical status, ESA responsiveness, Hgb level, and Disclosure: Dr. Bralow is on the Watson Nephrology speakers bureau. The author acknowledges the assistance of Barbara Ciano in preparation of this manuscript. Writing assistance was provided with support from Watson Nephrology. œ May 2009 Dialysis & Transplantation 1

Increasing the Serum Ferritin Parameter TABLE I. Comparison of the IV iron dosing protocols. Serum Ferritin 500 ng/ml Protocol Serum Ferritin 1,000 ng/ml Protocol Serum Ferritin 1,200 ng/ml Protocol Step 1 Ferritin 200 ng/ml Ignore TSAT and Hgb Ferritin 300 ng/ml Ignore TSAT and Hgb Step 2 TSAT <20% Evaluate Hgb and ferritin TSAT <20% TSAT <20% Step 3 TSAT 20% 30% Evaluate Hgb and ferritin Ferrlecit 125 mg IVP q wk TSAT 20% 40% Give 500 mg iron in divided doses treatment 4 doses) TSAT 20% 40% Give 500 mg iron in divided doses treatment 4 doses) Step 4 TSAT 30% 40% TSAT 40% Ferrlecit 62.5 mg IVP q other wk TSAT 40% Step 5 Ferritin >500 ng/ml Hold continuous dose Ferritin >1,000 ng/ml Notify nephrologist for further instruction Iron dosing per nephrologist Ferritin >1,200 ng/ml Iron dosing per MD order Hgb, hemoglobin; IVP, intravenous push; TSAT, transferrin saturation TSAT level. Although KDOQI does not support an upper limit of serum ferritin at which to withhold IV iron, some clinicians interpret the new recommendation to indicate that patients with serum ferritin levels >500 ng/ml do not require IV iron therapy. Our team at the Renal Center of Philadelphia, a dialysis center affiliated with the larger Renal Ventures Management dialysis network, revised our IV iron protocol in response to the new KDOQI statements. We reduced our serum ferritin upper limit from 800 to 500 ng/ml. Following the strict withholding of IV iron in patients with serum ferritin levels >500 ng/ml, we observed a downward trend in Hgb levels and a marked increase in ESA dosing requirements. Our center fell to a lower tier of quality indicators identified by the larger dialysis network. Our quality team, which consisted of a medical director, clinic manager, nurse anemia manager/administrator, patient care technician, social worker, and staff nurse, recognized that patients were responding poorly to the new serum ferritin cut off of 500 ng/ml and decided to abandon 2 Dialysis & Transplantation May 2009

FIGURE 1. Distribution of hemoglobin by serum ferritin protocol. the withholding of IV iron at this level. Our team hypothesized that a more intelligent use of IV iron therapy could result in improved outcomes. After consultation between physicians and the nurse anemia manager, we determined that a higher proportion of patients could achieve target Hb values if the IV iron protocol allowed for a more liberal serum ferritin upper limit. Also, the nurse anemia manager who was working at an affiliated dialysis unit had experienced improved patient outcomes with a serum ferritin cut off of 1,200 ng/ml and suggested a similar pilot program for our dialysis unit. Increasing the Serum Ferritin Upper Limit to Improve Outcomes The new protocol directed clinicians to individually assess patients who exceeded a serum ferritin level of 1,000 ng/ml. Another important change to the protocol was to allow for IV iron (sodium ferric gluconate) repletion dosing of 500 mg in divided doses for patients with TSAT levels between 20% and 40%, followed by continuous IV iron dosing of 62.5 mg per week. This is in contrast to our earlier protocol which allowed continuous iron dosing alone for patients with TSAT levels >30%. Our quality team convened each month to assess our individual unit outcomes, compare our standing to those of other affiliated dialysis units, and analyze our patient outlier population. Our dialysis unit s census is approximately 80 patients, and approximately 10% to 15% of them may be outliers. Our quality team was required to examine outliers for all sources of inflammation, including infection, hospitalizations, and comorbid conditions such as cancer, which could explain the presence of an elevated serum ferritin level. An action plan was established for these patients and follow-up occurred each month. The attending physician made the final decision on whether to continue the administration of IV iron or withhold iron until the next month s follow-up. Of the outlying cases, 1 patient reached a serum ferritin level of 1,500 ng/ml. The new IV iron protocol resulted in more patients receiving IV iron therapy, the relatively immediate improvement of Hb levels, and a substantial decrease in ESA usage. In reviewing the data for 65 patients in our dialysis unit who followed both protocols, we found that increasing the serum ferritin cut off from 500 to 1,000 ng/ml enabled patients to maintain Hb targets between 11 and 12 g/dl while ESA dosing decreased from approximately 5,600 to 4,400 units per treatment per week. Serum ferritin values were clinically unchanged from an average of 765 to 833 ng/ml. Based on these results, our center s quality indicators increased to the top tier of the dialysis network. These observations are consistent with the clinical trial, Dialysis Patients Response to IV Iron With Elevated Ferritin (DRIVE), in hemodialysis patients who had serum ferritin levels of 500 to 1,200 ng/ml and TSAT levels 25% and were anemic despite adequate ESA therapy. 7 In consideration of our center s findings, as well as the DRIVE data, we concluded that patient outcomes improved with a higher serum ferritin upper limit (ie, 1,000 ng/ml). The medical directors and corporate quality assurance staff of our dialysis organization decided to institute a corporate change in the IV iron and anemia management protocols that reflected a further increase in the serum ferritin threshold to 1,200 ng/ml. Furthermore, the corporate protocol was changed to note that at the discretion of the attending nephrologist, IV iron therapy could be administered to patients exhibiting serum ferritin levels above this threshold. Table I compares the IV iron dosing strategies of the 3 protocols based on serum ferritin of 500, 1,000, and 1,200 ng/ml. Patient outcome data have demonstrated that the majority of patients (61%) have maintained Hgb levels in the range of 10 to 12 g/dl at a serum ferritin of 1,200 ng/ ml (Figure 1). This is in comparison to 50% of patients maintaining the same Hgb range at a serum ferritin of 1,000 ng/ml. Overcoming Challenges in Our Understanding of Anemia Treatment The initiative conducted by our dialysis facility is highly applicable in the current environment of hemodialysis care. Approximately 60% of hemodialysis patients in the United States have a serum ferritin level >500 ng/ml, and the national mean level is 576 ng/ml. In addition, hemodialysis patients often have a high serum ferritin (>800 ng/ml) in combination with low TSAT and Hgb levels, bringing about the question of how to appropriately treat these patients with IV iron therapy. 7 The clinical relevance of elevated serum ferritin levels in hemodialysis patients is an intensely debated topic, fueled by ongoing discussions on an appropriate target, whether patients with higher levels can respond to IV iron therapy, and the safety of IV iron use at these higher levels. The following discussion addresses these issues œ May 2009 Dialysis & Transplantation 3

Increasing the Serum Ferritin Parameter FIGURE 2. Change in mean hemoglobin as observed in the DRIVE trial. 7 LOCF, last observation carried forward. FIGURE 3. Reduction in erythropoiesis-stimulating agent requirements as observed in the DRIVE and DRIVE-II trials. 7,20 Adapted with permission from Kapoian et al. 20 surrounding serum ferritin and other current challenges that nephrology clinicians face when managing iron-deficiency anemia. Iron Homeostasis Is Altered in Hemodialysis Patients Multiple factors are often present in hemodialysis patients that can alter iron homeostasis and impact the amount of iron available for erythropoiesis. Hemodialysis patients suffer from decreased dietary intake of iron due to a low protein diet and impaired gastrointestinal absorption of iron due to the use of phosphate binders. 2,8 Compounding this problem, iron loss is common in hemodialysis patients because of blood loss through routine blood sampling for diagnostic purposes, gastrointestinal ulcers, dialysis site bleeding, and blood remaining in the dialysis tubing and dialyzer. 2,9 Iron deficiency can become more pronounced as the use of ESA therapy increases the demand for iron by the bone marrow to an extent that exceeds tissue iron release, driving the patient into a state of iron-restricted erythropoiesis. 10 Inflammatory conditions, which are common in hemodialysis patients, can limit iron availability for effective erythropoiesis in patients who already have a compromised iron supply. 11 Inflammatory states can occur with a wide variety of disorders, such as endotoxin transfer from dialysate, exposure to a foreign body during dialysis, arthritis, and surgery. 12 Inflammation can reduce or restrict the release of iron from the reticuloendothelial system, resulting in iron-restricted erythropoiesis and decreased RBC production. Inflammatory cytokines restrict iron availability through the upregulation of hepcidin, a protein secreted by the liver. 13 An increase in hepcidin concentration decreases ferroportin, the exporter of iron from cells. This process causes reduced intestinal absorption of dietary iron, retention of iron by macrophages, and decreased transfer of stored iron from hepatocytes. 14 In the absence of adequate levels of circulating iron, ESA resistance can develop, which is characterized by poor Hgb response despite increasing ESA doses. IV iron administered on a regular schedule will replace ongoing iron losses and overcome ESA resistance, resulting in more efficient erythropoiesis. In addition, a course of IV iron therapy corrects the imbalance of iron in the body that results in iron-restricted erythropoiesis. 7,15 Appropriate Interpretation of Serum Ferritin Levels The routine monitoring of iron status is critical in the hemodialysis population, but effectively measuring iron supply can be challenging. Although serum ferritin is widely regarded as a standard measure of iron storage, it is an indirect, imprecise measure of iron. 5,16 Serum ferritin contains little or no iron. Rather, iron binds to tissue ferritin as it enters the reticuloendothelial cell where it is stored, at which time serum ferritin is released into the circulation. In addition, serum ferritin is an acute-phase reactant, so values are elevated in a setting of inflammation and/or malnutrition. This can complicate the interpretation of higher serum ferritin levels and hinder the administration of IV iron therapy in patients who could benefit from it. It has been suggested that serum ferritin levels in the range of 200 to 2,000 ng/ml may be a marker of non iron-related factors. This is important because the prevalence of inflammation in hemodialysis patients is 40% to 60% and can occur from many underlying conditions, including infections, autoimmune disorders, and malignancies. 5,17 Current KDOQI recommendations that fall short of supporting the routine administration of IV iron in patients with 4 Dialysis & Transplantation May 2009

serum ferritin levels >500 ng/ml should be cautiously interpreted. 1 Clinicians should not mistake the 500 ng/ml threshold as a hard upper limit at which to withhold IV iron therapy. The KDOQI recommendations advise that clinicians should use clinical judgment in these circumstances, and patients whose serum ferritin level is >500 ng/ml and concurrently measured TSAT is <20% can have iron deficiency and a course of iron treatment may be required. Because the serum ferritin level is not predictive of a patient s response to IV iron, it should not be a sole clinical marker for withholding iron. 6 When interpreting serum ferritin levels, clinicians should consider many patient factors, such as clinical status, medical history, current ESA dose and response to previous dosing, and Hgb values to guide IV iron treatment decisions. Perceptions of Anemia Management Versus Clinical Studies Although there is no evidence-based recommendation to withhold IV iron in hemodialysis patients at a serum ferritin level >500 ng/ml, some clinicians believe that these patients will not respond to treatment or may have an increased risk of inflammation or infection. However, studies have shown the benefits of IV iron administration at higher levels of serum ferritin. 7,17-19 In one retrospective analysis of hemodialysis patients who received IV iron (sodium ferric gluconate) and had serum ferritin levels >800 ng/ml and TSAT levels <25% on at least 1 occasion, investigators reported that patients responded to IV iron with increased Hgb levels and decreased requirements for ESA therapy. 17 This finding is echoed in the DRIVE study which randomized 134 hemodialysis patients who had serum ferritin levels of 500 to 1,200 ng/ml and TSAT levels 25% and were anemic despite adequate ESA therapy to receive IV iron (sodium ferric gluconate administered over 8 hemodialysis sessions) or no iron (control). 7 At week 1, both groups received an ESA dose increase of 25%, which was then held constant for 6 weeks. The DRIVE findings demonstrated that the IV iron group had significantly greater increase in mean Hgb level (p 0.028) compared to the control group (Figure 2). In addition, rate of response, defined as 2 g/dl increase in Hgb, occurred faster (p 0.035) and more patients responded (p 0.041) after administration of IV iron compared to the control group. Responsiveness to IV iron was similar whether serum ferritin was 800 or >800 ng/ml, supporting that this iron measure should not be used to guide IV iron therapy. Patients in the DRIVE study were then enrolled in DRIVE-II, a 6-week followup observational study in which patients returned to routine management of ESA and IV iron therapy at the treating nephrologist s or anemia manager s discretion. Results showed that overall ESA requirements were reduced in the IV iron group (Figure 3). 20 A subsequent analysis with the DRIVE population demonstrated that neither serum ferritin nor TSAT predicted response to IV iron. 6 Without reliable predictors of response, a therapeutic trial of IV iron is reasonable. The DRIVE data showed that a course of IV iron did not increase C-reactive protein levels, a measure of inflammation, suggesting that a concern of increased infections/worsening of inflammation with IV iron use at elevated serum ferritin levels may be impractical. Also, the increase in serum ferritin and TSAT seen in the DRIVE patients following a 1-g course of IV iron was inconsistent with any serious concerns of iron overload. The DRIVE trial is not the first study to support IV iron administration in patients with serum ferritin levels approaching 1,200 ng/ml. In 1 retrospective case study analysis of 58,058 hemodialysis patients treated over a period of 2 years, certain IV iron doses and serum ferritin levels were associated with improved survival. 21 Researchers determined that patients with serum ferritin levels between 200 and 1,200 ng/ml exhibited the lowest risk of all-cause and cardiovascular mortality, after adjusting for the confounding effects of inflammation and malnutrition. Additionally, the administration of IV iron in doses of up to 400 mg per month was associated with improved survival in this population compared to those who did not receive IV iron therapy. Conclusions Speculative implications of high serum ferritin levels can set in motion practices that deny necessary treatment with IV iron to hemodialysis patients, particularly those with iron-restricted erythropoiesis due to ESA therapy or inflammation. Nevertheless, researchers have repeatedly demonstrated that serum ferritin levels do not adequately reflect iron status or predict response to IV iron therapy. The DRIVE study demonstrated that anemic hemodialysis patients receiving adequate ESA doses and who had serum ferritin levels between 500 and 1,200 ng/ml and low TSAT levels responded to sodium ferric gluconate, and treatment did not worsen existing inflammation. Outcomes improved after our dialysis facility changed its IV iron protocol to incorporate a higher serum ferritin threshold of 1,000 ng/ml and then 1,200 ng/ml. Evidence-based data have demonstrated that establishing a specific serum ferritin level at which to withhold IV iron can be problematic. D&T References 1. KDOQI. National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47(5 suppl 3):S11-145. 2. Sakiewicz P, Paganini E. The use of iron in patients on chronic dialysis: mistake and misconceptions. J Nephrol. 1998;11:5-15. 3. Brock JH, Halliday JW, Pippard MJ, Powell LW. Iron Metabolism in Health and Disease. 1994; Philadelphia, PA: WB Saunders Company. 4. Centers for Medicare & Medicaid Services. 2007 Annual Report, End Stage Renal Disease Clinical Performance Measures Project. Department of Health and Human Services, Centers for Medicare & Medicaid Services, Offi ce of Clinical Standards & Quality, Baltimore, Maryland, December 2007. 5. Kalantar-Zadeh K, Rodriguez RA, Humphreys MH. Association between serum ferritin and measures of infl ammation, nutrition and iron in haemodialysis patients. Nephrol Dial Transplant. 2004;19:141-149. 6. Singh AK, Coyne DW, Shapiro W, et al. Predictors of the response to treatment in anemic hemodialysis patients with high serum ferritin and low transferrin saturation. Kidney Int. 2007;71:1163-1171. 7. Coyne DW, Kapoian T, Suki W, et al. Ferric gluconate is highly effi cacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol. 2007;18(3):975-984. 8. Petroff S. Evaluating traditional iron measures and exploring new options for patients on hemodialysis. Nephrol Nursing J. 2005;32:65-73. 9. Kosch M, Bahner U, Bettger H, et al. A randomized, controlled parallel-group trial on effi cacy and safety of iron sucrose (Venofer) vs iron gluconate (Ferrlecit) in haemodialysis patients treated with rhuepo. Nephrol Dial Transplant. 2001;16:1239-1244. 10. Tarng DC, Huang TP, Chen TW, Yang WC. Erythropoietin hyporesponsiveness: from iron defi - ciency to iron overload. Kidney Int. 1999;69: S107-S118. May 2009 Dialysis & Transplantation 5

Increasing the Serum Ferritin Parameter 11. Kalantar-Zadeh K, McAllister CJ, Lehn RS, et al. Effect of malnutrition-infl ammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis. 2003;42:761-773. 12. Bistrian BR, Khaodhiar L. The systemic infl ammatory response and its impact on iron nutriture in endstage renal disease. Am J Kidney Dis. 1999;34(4 suppl 2):S35-S39. 13. Nemeth E, Tuttle MS, Powelson J, et al. Hepcidin regulates cellular iron effl ux by binding to ferroportin and inducing its internalization. Science. 2004;306:2090-2093. 14. Rivera S, Nemeth E, Gabayan V, et al. Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs. Blood. 2005;106:2196-2199. 15. Besarab A. Resolving the paradigm crisis in intravenous iron and erythropoietin management. Kidney Int. 2006;69:S13-S18. 16. Cavill I. Iron status as measured by serum ferritin: the marker and its limitations. Am J Kidney Dis. 1999:34:S12-S17. 17. Kopelman RC, Smith L, Peoples L, et al. Functional iron defi ciency in hemodialysis patients with high ferritin. Hemodial Int. 2007;11(2):238-246. 18. DeVita MV, Frumkin D, Mittal S, et al. Targeting higher serum ferritin concentrations with intravenous iron dextran lowers erythropoietin requirements in hemodialysis patients. Clin Nephrol. 2003;60:335-340. 19. Chang CH, Chang CC, Chiang SS. Reduction in erythropoietin doses by the use of chronic intravenous iron supplementation in iron-replete hemodialysis patients. Clin Nephrol. 2002;57:136-141. 20. Kapoian T, O Mara NB, Singh AK, et al. Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. J Am Soc Nephrol. 2008;19:372-379. 21. Kalantar-Zadeh K, Regidor DL, McAllister CJ, et al. Time-dependent associations between iron and mortality in hemodialysis patients. J Am Soc Nephrol 2005;16(10):3070-3080. 6 Dialysis & Transplantation May 2009