Patient and Care Partner Burden in CKD Patients With and Without Anemia: A US-Based Survey.

Rationale & Objective: Chronic kidney disease (CKD) has a far-reaching impact on both patients and care partners, which can be further compounded by frequent complications such as anemia. This study assessed the burden experienced by patients with CKD and the care partners of patients with CKD, with and without anemia. Study Design: Online survey. Setting & Participants: Adult patients with CKD and the care partners of adult patients with CKD living in the United States were recruited through the American Association of Kidney Patients and a third-party online panel (January 9, 2020-March 12, 2020). Outcomes: Patient and care partner characteristics, care received or provided; health-related quality of life, and work productivity. Analytical Approach: Descriptive statistics were reported separately based on the presence or absence of anemia. Results: In total, 410 patients (anemia: n=190, no anemia: n=220) and 258 care partners (anemia: n=110, no anemia: n=148) completed the survey. Most patients reported receiving paid or unpaid care because of their health condition (anemia: 58.9%, no anemia: 50.9%), with an overall average of 14.2 and 11.3 h/wk among the anemia and no anemia patients, respectively. The care partners also reported providing numerous hours of care (anemia: 33.6 h/wk, no anemia: 38.0 h/wk), especially care partners living with their care recipient (anemia: 52.6 h/wk, no anemia: 42.8 h/wk). Among the patients, those with anemia reported a numerically lower average health-related quality of life (Functional Assessment of Cancer Therapy-Anemia score, anemia: 110.1; no anemia: 121.6). Most care partners reported a severe or very severe burden (Burden Scale for Family Caregivers-Short Version score≥15, anemia: 69.1%; no anemia: 58.8%). The work productivity impairment was substantial among employed patients (anemia: 44.9%, no anemia: 35.4%) and employed care partners (anemia: 47.9%, no anemia: 40.7%). Limitations: The survey results may have been subject to selection and recall biases; moreover, the observational nature of the study does not allow for causal inferences. Conclusions: Patients with CKD and the care partners of patients with CKD experience a considerable burden, especially when anemia is present.

Recent and Emerging Therapies for Iron Deficiency in Anemia of CKD: A Review.

Iron deficiency commonly contributes to the anemia affecting individuals with chronic kidney disease. This review describes diagnostic criteria for iron deficiency in chronic kidney disease, as well as mechanisms of functional and absolute iron deficiency and general treatment principles as delineated in the KDIGO (Kidney Disease: Improving Global Outcomes) guideline. Repletion of absolute iron deficits has progressed over time with the addition of better tolerated, more effective oral agents, including ferric citrate, ferric maltol, and sucrosomial iron. This article examines the structural characteristics and trial data enabling regulatory approval of these novel oral agents. Newer intravenous iron therapies, including ferric carboxymaltose and ferric derisomaltose, allow for fewer infusions and decreased risk of serious hypersensitivity reactions. Concerns about adverse effects such as cardiovascular events and infections are discussed. The potential risk of 6H syndrome (high FGF-23, hypophosphatemia, hyperphosphaturia, hypovitaminosis D, hypocalcemia, and secondary hyperparathyroidism) due to these intravenous agents is emphasized. The proposed pathophysiology of 6H syndrome and hypophosphatemia is described. Ferric pyrophosphate citrate enables administration of iron for repletion through dialysate. Relative merits, costs, and risks of various iron agents such as hypersensitivity and 6H syndrome/hypophosphatemia are summarized.

Iron Deficiency in CKD Without Concomitant Anemia.

The physiological role of iron extends well beyond hematopoiesis. Likewise, the pathophysiological effects of iron deficiency (ID) extend beyond anemia. Although inextricably interrelated, ID and anemia of chronic kidney disease (CKD) are distinct clinical entities. For more than 3 decades, however, nephrologists have focused primarily on the correction of anemia. The achievement of target hemoglobin (Hgb) concentrations is prioritized over repletion of iron stores, and iron status is generally a secondary consideration only assessed in those patients with anemia. Historically, the correction of ID independent of anemia has not been a primary focus in the management of CKD. In contrast, ID is a key therapeutic target in the setting of heart failure (HF) with reduced ejection fraction (HFrEF); correction of ID in this population improves functional status and quality of life and may improve cardiovascular (CV) outcomes. Given the strong interrelationships between HF and CKD, it is reasonable to consider whether iron therapy alone may benefit those with CKD and evidence of ID irrespective of Hgb concentration. In this review, we differentiate anemia from ID by considering both epidemiologic and pathophysiological perspectives and by reviewing the evidence linking correction of ID to outcomes in patients with HF and/or CKD. Furthermore, we discuss existing gaps in evidence and provide proposals for future research and practical considerations for clinicians.

Strategies to Reduce Rehospitalization in Patients with CKD and Kidney Failure.

Readmissions in patients with nondialysis-dependent CKD and kidney failure are common and are associated with significant morbidity, mortality, and economic consequences. In 2013, the Centers for Medicare and Medicaid Services implemented the Hospital Readmissions Reduction Program in an attempt to reduce high hospitalization-associated costs. Up to 50% of all readmissions are deemed avoidable and present an opportunity for intervention. We describe factors that are specific to the patient, the index hospitalization, and underlying conditions that help identify the "high-risk" patient. Early follow-up care, developing volume management strategies, optimizing nutrition, obtaining palliative care consultations for seriously ill patients during hospitalization and conducting goals-of-care discussions with them, instituting systematic advance care planning during outpatient visits to avoid unwanted hospitalizations and intensive treatment at the end of life, and developing protocols for patients with incident or prevalent cardiovascular conditions may help prevent avoidable readmissions in patients with kidney disease.

Iron Administration, Infection, and Anemia Management in CKD: Untangling the Effects of Intravenous Iron Therapy on Immunity and Infection Risk.

Patients with chronic kidney disease (CKD) are at increased risk for infection, attributable to immune dysfunction, increased exposure to infectious agents, loss of cutaneous barriers, comorbid conditions, and treatment-related factors (eg, hemodialysis and immunosuppressant therapy). Because iron plays a vital role in pathogen reproduction and host immunity, it is biologically plausible that intravenous iron therapy and/or iron deficiency influence infection risk in CKD. Available data from preclinical experiments, observational studies, and randomized controlled trials are summarized to explore the interplay between intravenous iron and infection risk among patients with CKD, particularly those receiving maintenance hemodialysis. The current evidence base, including data from a recent randomized controlled trial, suggests that proactive judicious use of intravenous iron (in a manner that minimizes the accumulation of non-transferrin-bound iron) beneficially replaces iron stores while avoiding a clinically relevant effect on infection risk. In the absence of an urgent clinical need, intravenous iron therapy should be avoided in patients with active infection. Although serum ferritin concentration and transferrin saturation can help guide clinical decision making about intravenous iron therapy, definition of an optimal iron status and its precise determination in individual patients remain clinically challenging in CKD and warrant additional study.

The Evolution of Target Hemoglobin Levels in Anemia of Chronic Kidney Disease.

Since the introduction of erythropoiesis-stimulating agents (ESAs) into clinical practice in 1989, considerable effort has been put forth toward identifying the optimal treatment strategy for managing anemia of CKD. After initial treatment of only the most severely anemic patients, therapy was subsequently expanded to include most patients on dialysis and many nondialysis CKD patients. Many nephrology societies and regulatory agencies have sought to identify the most appropriate hemoglobin levels to which ESA therapy should be targeted. As increasing evidence became available about the impacts of ESAs on varying endpoints including morbidity, mortality, and quality of life, the guidelines put forth by such agencies evolved over time. We review the literature impacting these determinations through the past 3 decades and comment on how this informs the application of this knowledge to the care of patients today.

Erythropoietin mimetic peptides and erythropoietin fusion proteins for treating anemia of chronic kidney disease.

PURPOSE OF REVIEW: First generation erythropoiesis stimulating agents (ESAs) have short duration of action which requires administration once weekly or greater. Second generation ESAs were developed which have longer duration of action and can be administered one to two times monthly. Erythropoietin (EPO) mimetic peptides (EMPs) activate the EPO receptor but have no structural analogy to EPO, offering the potential for lower cost as they are not biologic drugs. The first approved EMP, peginesatide, was withdrawn from the market within a year of its approval because of fatal anaphylactic reactions. In this review, we summarize recent progress regarding the development of newer, possibly less toxic, EMPs. We also summarize the development of EPO fusion proteins which fuse EPO with a portion of an immunoglobulin molecule or another EPO molecule, achieving a longer duration of action and less frequent dosing. RECENT FINDINGS: AGEM400(hydroxyethyl starch) and pegolsihematide are EMPs in phase II clinical trials. Three EPO fusion proteins are under development, two in phase I and one in phase II. SUMMARY: The future success of EMPs is limited by the prior experience with peginesatide and EPO fusion proteins do not offer cost savings or longer duration of action than currently available ESAs.

Positive Iron Balance in Chronic Kidney Disease: How Much is Too Much and How to Tell?

BACKGROUND: Regulation of body iron occurs at cellular, tissue, and systemic levels. In healthy individuals, iron absorption and losses are minimal, creating a virtually closed system. In the setting of chronic kidney disease and hemodialysis (HD), increased iron losses, reduced iron absorption, and limited iron availability lead to iron deficiency. Intravenous (IV) iron therapy is frequently prescribed to replace lost iron, but determining an individual's iron balance and stores can be challenging and imprecise, contributing to uncertainty about the long-term safety of IV iron therapy. SUMMARY: Patients on HD receiving judicious doses of IV iron are likely to be in a state of positive iron balance, yet this does not appear to confer an overt risk for clinically relevant iron toxicity. The concomitant use of iron with erythropoiesis-stimulating agents, the use of maintenance iron dosing regimens, and the reticuloendothelial distribution of hepatic iron deposition likely minimize the potential for iron toxicity in patients on HD. Key Messages: Because no single diagnostic test can, at present, accurately assess iron status and risk for toxicity, clinicians need to take an integrative approach to avoid iron doses that impose excessive exposure while ensuring sufficient replenishment of iron stores capable of overcoming hepcidin blockade and allowing for effective erythropoiesis.

Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitors: A Potential New Treatment for Anemia in Patients With CKD.

Erythropoiesis-stimulating agents (ESAs) increase hemoglobin levels, reduce transfusion requirements, and have been the standard of treatment for anemia in patients with chronic kidney disease (CKD) since 1989. Many safety concerns have emerged regarding the use of ESAs, including an increased occurrence of cardiovascular events and vascular access thrombosis. Hypoxia-inducible factor (HIF) prolyl hydroxylase (PH) enzyme inhibitors are a new class of agents for the treatment of anemia in CKD. These agents work by stabilizing the HIF complex and stimulating endogenous erythropoietin production even in patients with end-stage kidney disease. HIF-PH inhibitors improve iron mobilization to the bone marrow. They are administered orally, which may be a more favorable route for patients not undergoing hemodialysis. By inducing considerably lower but more consistent blood erythropoietin levels than ESAs, HIF-PH inhibitors may be associated with fewer adverse cardiovascular effects at comparable hemoglobin levels, although this has yet to be proved in long-term clinical trials. One significant concern regarding the long-term use of these agents is their possible effect on tumor growth. There are 4 such agents undergoing phase 2 and 3 clinical trials in the United States; this report provides a focused review of HIF-PH inhibitors and their potential clinical utility in the management of anemia of CKD.

New Options for Iron Supplementation in Maintenance Hemodialysis Patients.

End-stage renal disease results in anemia caused by shortened erythrocyte survival, erythropoietin deficiency, hepcidin-mediated impairment of intestinal absorption and iron release, recurrent blood loss, and impaired responsiveness to erythropoiesis-stimulating agents (ESAs). Iron malabsorption renders oral iron products generally ineffective, and intravenous (IV) iron supplementation is required in most patients receiving maintenance hemodialysis (HD). IV iron is administered at doses far exceeding normal intestinal iron absorption. Moreover, by bypassing physiologic safeguards, indiscriminate use of IV iron overwhelms transferrin, imposing stress on the reticuloendothelial system that can have long-term adverse consequences. Unlike conventional oral iron preparations, ferric citrate has recently been shown to be effective in increasing serum ferritin, hemoglobin, and transferrin saturation values while significantly reducing IV iron and ESA requirements in patients treated with HD. Ferric pyrophosphate citrate is a novel iron salt delivered by dialysate; by directly reaching transferrin, its obviates the need for storing administered iron and increases transferrin saturation without increasing serum ferritin levels. Ferric pyrophosphate citrate trials have demonstrated effective iron delivery and stable hemoglobin levels with significant reductions in ESA and IV iron requirements. To date, the long-term safety of using these routes of iron administration in patients receiving HD has not been compared to IV iron and therefore awaits future investigations.

The approval process for biosimilar erythropoiesis-stimulating agents.

A biosimilar drug or follow-on biologic drug is defined by the Public Health Service Act as a product that is "highly similar to the reference product notwithstanding minor differences in clinically active components and there are no clinically meaningful differences between the biologic product and the reference product in terms of the safety, purity and potency of the product." The advantage of biosimilar drugs is that they are significantly less expensive than the reference products, allowing for increased accessibility and cost savings. Recognizing these advantages, the US Congress passed the Biologics Price Competition and Innovation Act in 2009 as part of health care reform. The Biologics Price Competition and Innovation Act allows sponsors of biosimilar agents to seek approval by showing structural and functional similarity to the reference agent, with the extent of required clinical studies to be determined on the basis of the degree of biosimilarity with the reference product. The goal is to bring biosimilar agents to the market more efficiently while still protecting the safety of the public. The European Union has had such a process in place for a number of years. Two biosimilar epoetin agents have been approved in the European Union since 2007, and their companies are conducting trials to seek approval in the United States, because Amgen's patent protection for epoetin alfa expires in 2014. Trials completed for European Union approval of both agents showed similar efficacy and safety to the reference epoetin alfa. As with all biologics, immunogenicity concerns may persist because of the fragility of the manufacturing process and the worldwide experience with pure red cell aplasia as a result of epoetin therapy. The uptake of biosimilar epoetins after approval in the United States will depend on the balance of cost advantage against safety concerns. Competition in the marketplace will likely decrease the cost of the reference agent as well.

A physician's perseverance uncovers problems in a key nephrology study.

The Normal Hematocrit Cardiac Trial, published in 1998, was a foundational study testing erythropoietin analog treatment to normal hematocrit targets. It served as a warning that erythropoietin replacement was not a panacea. Its large size gave it disproportionate weighting in evidence reviews and guideline development and thereby impacted treatment decisions. Coyne shows that the published results did not completely and clearly represent the study's actual results. We discuss the implications and make recommendations to prevent such occurrences.