This article is part of a special supplement published by Nephrology News & Issues in the February 2014 issue entitled, “Iron therapy and a quarter century of ESAs: What have we learned?”

Anemia due to the lack of erythropoietin and the associated multifactorial iron deficiency is a well-established comorbid condition in all stages of chronic kidney disease. Iron deficiency is primarily due to increased iron loss through dialysis therapy, frequent blood draws and gastrointestinal blood loss, poor iron absorption, elevated hepcidin levels (which decreases iron absorption and hinders iron mobilization from iron stores), and increased requirements during erythropoietin therapy for effective erythropoiesis to occur.

A PubMed search on “anemia in ESRD” alone reveals more than 6,000 publications dating back to the research on kinetics of erythrocyte lifespan in the 1960s to different types of iron therapies in the more recent literature. About 10% of these papers focus on iron deficiency anemia in patients with end-stage renal disease, primarily the efficacy and safety of various iron products and the ever-changing targets of the imperfect parameters routinely used to monitor iron requirements. The literature reflects the well-intertwined efforts of the renal community at large to solve this clinical problem but also the obvious gaps after more than two decades of erythropoietin therapy.1-3 The fact that several iterations of anemia practice guidelines have been published during this time emphasizes that these guidelines are mainly opinion based and reached by compromise among thought leaders, clinicians, and scientists in the presence of sparse hard data.4,5

Setting standards for treatment

Anemia is just one of our patients’ problems—undoubtedly a critical one—that needs to be addressed in the context of multiple comorbid conditions. When addressed proactively and coordinated by the interdisciplinary clinical team, these conditions will most likely lead to improved outcomes. With the ever-increasing demands in the delivery of ESRD care, driven by an increasingly older and multi-morbid patient population, regulatory mandates, and efforts to improve outcomes by focusing on comorbid conditions, it makes sense to simplify and standardize anemia management.

Standardizing an anemia protocol—with flexibility

At Satellite Healthcare, a standardized but varying anemia protocol, combining erythropoiesis-stimulating agent administration with intravenous iron maintenance administration, has been in place since 2004. The goal of this effort was primarily to introduce a reliable protocol that would ensure standardized therapy to achieve hemoglobin and iron parameter targets in our patients. Continuous monitoring of outcomes enables interventions based on the protocol and limits the “guess work” when outcome targets are not achieved by outlining a step-by-step algorithm for both incident and prevalent patients. The standardized approach allows for individualized anemia management in patients with acute intercurrent illness or comorbidity per nephrologist order.

The protocol is distributed to all referring physicians and accessible at any time. When a new patient is admitted to a center for dialysis therapy, the nephrologist decides if anemia management for this patient will be done by protocol or not. The protocol is a policy and procedure that allows the nursing staff to act upon the protocol orders without notifying the physician. Thereby, the anemia protocol simplifies one of many aspects of kidney disease care. If the nephrologist has decided to follow the anemia protocol for a patient, blood work and adjustment to medications are done per protocol. However, the protocol mandates a call to the nephrologist when an assessment of the clinical needs of the patient by the physician is required as a safeguard. This is outlined in Table 1.

Multiple revisions have been made since the initial anemia protocol was implemented, the most recent made in August 2011 in response to the U.S. Food and Drug Administration black box warning.6 The original development and subsequent revisions of the protocol were based on data review and discussion with the leadership physician team at Satellite Healthcare. The Medical Policy Committee, a 12 to 14-member panel consisting of six to eight medical directors in the community and medical and operations leadership at Satellite, meets quarterly to discuss and review clinical issues and quality outcomes, including decisions on protocols. The protocol is aligned with the FDA dosing recommendation, package insert, and black box warning, as well as experience contributed by all clinicians. Newly published evidence and internal analyses of outcomes are reviewed as part of the process to arrive at the best protocol.

When hard data are lacking, the group works to find a compromise with the patients’ safety and effective treatment in mind. Table 2 details the main reasons for changes made to the protocol over the long and winding road of anemia management during the past 10+ years. With the introduction of each new protocol, there are multiple practical consequences on the provider side for all stakeholders involved, including staff, nephrologists, and patients. The logistic responsibilities are driven by education for all, including regulatory tasks linked to signing off on protocol changes by the referring physicians.

Influence of new trials

Several of the protocol changes were driven by new evidence from landmark trials, such as CHOIR, CREATE, and TREAT and also subsequent FDA rulings concerning hemoglobin targets and safety updates for ESAs.6-9 Throughout all the controversy in anemia management, a widely accepted concept has emerged of utilizing the minimum amount of ESA necessary to ensure the patient is not suffering from symptoms of anemia while undergoing dialysis. To all of us, this translates into avoiding the need for transfusions. However, opinions diverge on the topic of further optimizing anemia symptoms, such as fatigue, shortness of breath, inability to concentrate, and dizziness due to the difficulty of distinguishing them from the underlying ESRD symptoms.

Iron therapy’s role in anemia management

It would be unwise to underappreciate the role iron therapy has and is playing in the complex ongoing discussion of anemia management in ESRD patients. Very little in the iron therapy decision-making process is black and white based on evidence. In fact, iron management is complicated by numerous uncertainties, summarized in Table 3. The lack of consensus among the scientific and clinical thought leaders in this field makes developing a standardized iron protocol challenging.1,3,10 Agreement to replace iron losses is a rational starting point for the discussion around an effective and safe iron replacement therapy protocol.

The foundation of the current iron replacement protocol is the quarterly monitoring of iron status in both hemodialysis and peritoneal dialysis patients through the testing of both iron saturation (TSAT) and ferritin. These quarterly results then direct the indication and dosing of IV iron replacement therapy with the intention of maintaining iron stores and thus allowing for the minimum amount of ESA necessary to avoid anemia symptoms or reach the target hemoglobin or both. Most controversy arises on the topic of safe administration of IV iron dependent on the level of ferritin. The fact that the upper limit of ferritin has oscillated over the past few protocols from as high as 1200 ng/mL to 800 ng/mL to 500 ng/mL, with a current target goal of 500 to 800 ng/mL, reflects the strong but diverse sentiments among physicians and a paucity of data to answer the question.

Reaction with antibiotics

The protocol also addresses the concerns regarding IV iron in the presence of acute infection and inflammatory states, a frequent conundrum in patients with end-stage renal disease. By transferring the decision for IV iron dosing in patients with either IV or intraperitoneal (IP) administration of antibiotic therapy into the hands of the nephrologist, an individualized approach per physicians’ orders within the framework of the protocol is secured. In addition, iron overload, potentially induced by a liberal approach of iron loading dose consisting of 5 x 200 mg of Venofer according to the protocol, is addressed by limiting it once per quarter until further iron measurements are available. At any time, however, the physician is at liberty to order additional IV iron per his or her assessment. The current protocol allows for adjustments without additional order from the nephrologist whenever hemoglobin values in the range of 9 to 11.4 g/dL are achieved and iron parameters are within defined ranges dependent on hemoglobin results. Physicians are contacted for iron orders when ferritin is ≥ 1200 ng/mL and hemoglobin is < 11.5 g/dL to make an individual decision weighing risk of iron overload versus benefit of ESA dose-sparing effect.


Overall this protocol—reached by consensus—has resulted in excellent adoption among referring physicians. As iron and ESA therapy are linked in the protocol, there is no option to opt out of only one of them. Opting out translates into the physician taking over anemia management for both iron and ESA dosing. Taking a patient off the protocol for a period of time is always a possibility and encouraged to ensure that individualized therapy is delivered to patients according to their clinical circumstances.


It is important to emphasize that the goal of implementing protocols is never to interfere in the physicians’ treating of the patients but rather to furnish standardization to define what works based on numerous data points and to facilitate care. Judging by our experience over the past 8+ years, this is achieved with the anemia protocol as the vast majority of patients in any given month are treated by protocol and quality outcomes are achieved. Hesitance to adopt the protocol is more often seen in the PD population where several nephrologists prefer to maximize oral iron therapy before transition to IV therapy, mostly in incident patients. In general, the utilization of IV iron in home dialysis patients, both PD and home hemodialysis, is more controversial and more difficult due to logistics. There is no consensus on how much iron should be given in a patient undergoing PD, and published data in this population are limited.

It is interesting that despite several changes in the iron portion of the anemia protocol over the past several years, both the average IV utilization as well as the average serum ferritin levels have stayed rather stable. On average, a patient undergoing in-center HD received between 2.4 to 2.8 g/year over the last five years, during which various protocols and iron formulations were utilized. The average amount given to home dialysis patients (mostly PD) during this time was 0.8 to 1.1 g/year. At the same time, the average ferritin value achieved ranged from 650 to 700 ng/mL in in-center HD patients and 560 to 630 ng/mL in PD patients. The introduction of any new iron product required a protocol change or revision. Physicians had and continue to have the choice of several IV irons for their patients. Although a primary product on formulary is the backbone of the protocol and utilized in all but a small percentage of patients, nephrologists are free to prescribe an alternative product as needed by their patients.



The primary reasons for the implementation of any protocol at the provider level are to allow for implementation of standard of care, as outlined by guidelines and published data, and to allow for standardization and appropriate interventions as needed. The treatment of patients is in the hands of the physicians who may opt in or out of protocols. This allows for an appropriate balance of standardization and individualized interventions as assessed by the nephrologist through clinical follow-up and review of laboratory results. This approach enables a close collaboration between provider and nephrologist in the best interest of the patients by aligning efforts to achieve quality care. While searching for the “holy grail of quality of life for patients requiring renal replacement therapy,” protocols are meant to support and simplify the achievement of defined quality metrics. This allows physicians and caregivers in the dialysis centers to focus on the multiple concerns of patients, including the “unmeasured, nonautomated, less defined part” of optimal ESRD care.
Read more from the iron management series


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