Chronic kidney disease (CKD) is prevalent among people with diabetes. Many people with CKD suffer from anemia as a complication. Despite its prevalence in CKD, anemia tends to be an underrecognized and undertreated condition in this population. Since the 1980s, effective treatments to correct anemia have been available. Additionally, newer treatments are on the horizon that have the potential to provide additional therapy options to improve outcomes for patients with anemia in CKD.
This article is intended to serve as an executive summary for a series of short videos now available on the Clinical Diabetes website in which the authors, who each provide care to people with type 2 diabetes, discuss approaches to identifying and managing anemia in CKD and prescribing erythropoiesis- stimulating agents (ESAs) in the primary care setting. They also review novel emerging agents targeting hypoxia-inducible factor (HIF) that are being studied to treat anemia in CKD. The video series described below is available in its entirety at https://diabetesjournals.org/clinical/pages/anemia_in_ckd. Short biographies of the authors and links to generate continuing education credits for viewing the series are also available at this website.
Identifying and Managing Anemia in CKD (Video 1)
Anemia in people with CKD is primarily a result of decreased secretion of erythropoietin (1). As CKD progresses, anemia becomes more likely to occur. Data from the National Health and Nutrition Examination Survey 2007–2010 (2) indicate the following prevalence rates of anemia by CKD stage: stage 1, 8.4%; stage 2, 12.2%; stage 3, 17.4%; stage 4, 50.3%; and stage 5, 53.4% (2).
Patients with CKD and anemia have a reduced quality of life because of symptoms such as fatigue, reduced exercise capacity, increased ventricular mass, and higher incidence of heart failure and myocardial infarction (3). Identifying anemia in primary care is crucial because primary care practitioners (PCPs) are often the first to encounter this condition. The authors review recommendations for screening, diagnosis, and management of anemia in CKD in primary care settings.
Despite the high prevalence of anemia in CKD, it tends to be underrecognized in clinical settings because it is often asymptomatic, and attention is directed toward other comorbidities of CKD (4,5). PCPs are often hesitant to manage anemia in patients with CKD, often referring these patients to nephrology specialty care even when such a referral is unnecessary (4,5). Because PCPs are more aware of this condition and its basic management recommendations, they can help detect and treat anemia earlier.
Kidney Disease Improving Global Outcomes (KDIGO) guidelines represent the current standard of care for treating anemia in CKD (6). For patients without anemia, KDIGO recommends testing hemoglobin (Hb) at specific frequencies depending on the patient population and clinical conditions (6). Diagnosis of anemia occurs at Hb thresholds of <13.0 g/dL in men and <12.0 g/dL in women (6). The authors discuss how to apply these recommendations in primary care and review additional tests that should be ordered for initial evaluation of anemia.
After establishing a diagnosis of anemia, the next step is to rule out other causes. Treatment of anemia in CKD can be accomplished with iron replacement, use of ESAs, and/or red blood cell (RBC) transfusion (6). In selecting a treatment for anemia, PCPs should consider the patient’s severity of anemia, Hb levels, and symptoms. Key considerations for initiating and monitoring treatment of anemia in CKD are also highlighted. For all treatments, the risks and benefits to patients should be considered, and generally the lowest effective dose is recommended to correct anemia.
Although many patients with anemia in CKD can be managed in the primary care setting, some scenarios warrant referral to a nephrologist or hematologist. For patients with severe symptomatic anemia, acutely worsening CKD, or low Hb despite standard treatment, a referral to nephrology is appropriate (7). Additionally, patients with causes of anemia other than CKD who do not improve after addressing the cause should be referred to a hematologist. The authors review some patient case scenarios and discuss how to manage the patients’ anemias, including whether they should be referred to a specialist or could be managed in primary care.
How to Prescribe and Monitor ESAs for Anemia in CKD (Video 2)
ESAs have been used to improve production of erythropoietin in patients with anemia and CKD since the 1980s, with the introduction of epoetin alfa (8–10). Initially, ESAs were primarily used in patients on dialysis, but their use has expanded to other stages of CKD over time. Newer ESAs were developed over the years (darbepoetin alfa and methoxy polyethylene glycol-epoetin β) with longer durations of action and less frequent dosing requirements (11,12). In this video, the authors focus on the use of ESAs to treat anemia in CKD.
ESAs are known to increase Hb levels and correct anemia, reduce the need for RBC transfusion, and improve symptoms of anemia (13). However, ESAs also have risks—primarily cardiovascular risks related to thrombosis. Several key studies have highlighted the importance of avoiding overtreatment of anemia and have shown how Hb levels that are too high can increase the risk of cardiovascular events (14–16). The authors review key information from these studies and discuss what clinicians need to know and apply when prescribing ESAs.
Although ESAs have recognized benefits in treating anemia, clinicians must also consider their associated risks when identifying patients who are good candidates for ESA therapy. The authors discuss dosing of ESA agents as well as indications for treatment. ESAs can be initiated when Hb is <10.0 g/dL, and ESA therapy is recommended for patients on dialysis whose Hb is at risk for dropping to <9.0 g/dL (6).
Once patients are initiated on ESA therapy, it is essential to monitor their Hb levels and clinical symptoms to ensure adequate response. Dose adjustment for ESAs is based on the degree of Hb increase, current ESA dose, and clinical circumstances (6). The authors conclude this video by highlighting key considerations for Hb targets and response measures for patients treated with ESAs.
Novel Emerging Agents for Anemia in CKD (Video 3)
In recent years, researchers have focused on developing new agents to treat anemia in CKD because more than a decade has passed since the last U.S. Food and Drug Administration (FDA)-approved treatment for this complication was brought to market. The need for additional therapies is highlighted by challenges and shortcomings of current treatments (13,18). The authors discuss these challenges and the ways in which having new treatment options could benefit patients.
The new class of agents being developed for anemia in CKD works by enhancing the effects of HIF by inhibiting prolyl hydrolase (13). Thus, these agents are collectively termed hypoxia-inducible factor prolyl hydrolase inhibitors (HIF-PHIs). Enhancing the effects of HIF promotes increased production of erythropoietin and improved iron utilization through a variety of mechanisms within RBCs and bone marrow (13). If approved, these oral agents could provide treatment options that offer a more convenient dosage form to patients. The authors review these mechanisms and effects and discuss how they relate to improvement in anemia.
At present, several investigational HIF-PHIs are being studied in late-stage clinical trials for anemia in CKD (19). Daprodustat, roxadustat, and vadadustat are all currently under FDA review. Individual agents are usually studied in two different trials—one for patients with CKD and anemia who are not on dialysis and one for those who are on dialysis. The authors describe key trials for selected HIF-PHIs.
Daprodustat was studied in the ASCEND-ND and ASCEND-D trials and compared with either epoetin alfa or darbepoetin alfa, depending on the trial and subgroup (20,21). Overall, the daprodustat groups demonstrated noninferiority compared with the ESAs for mean change in Hb and incidence of major cardiovascular adverse events (MACE).
Two primary trials evaluating roxadustat, DOLOMITES and SIERRAS, studied roxadustat compared with either epoetin alfa or darbepoetin alfa (22,23). In both trials, roxadustat met noninferiority criteria compared with ESAs for mean change in Hb. Treatment-emergent adverse events were similar between roxadustat and ESAs in both trials.
The authors conclude this video by summarizing two key trials for vadadustat: PRO2TECT and INNO2VATE (24,25). Vadadustat was compared with darbepoetin alfa in both trials and demonstrated noninferiority for mean change in Hb. For MACE, vadadustat met noninferiority compared with darbepoetin alfa in INNO2VATE but not in PRO2TECT.
The production of this video series and associated materials was funded by an educational grant from GlaxoSmithKline. The authors received writing and editorial support in the preparation of this digital publication and executive summary from Austin Ulrich, PharmD, on behalf of the Primary Care Metabolic Group and Primary Care Education Consortium. The content for this article and the associated video series was produced according to the policies of the Accreditation Council for Continuing Medical Education. GlaxoSmithKline had no input into the topic, forum discussion, or any content for this article or its accompanying videos.
Duality of Interest
S.B. serves on an advisory board and/or speakers bureau for Abbott Diabetes Care, AstraZeneca, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, and Xeris. He holds stock options with Paracrine. He is also editor-in-chief of Clinical Diabetes. S.F. is a consultant and/or researcher for Akebia, AstraZeneca, Fibrogen, and GlaxoSmithKline. J.D.G. serves on an advisory board and/or speakers bureau for Abbott Diabetes Care, Amarin, Bayer, Boehringer Ingelheim, Lilly, Novo Nordisk, Sanofi, and Xeris. E.W. serves as an advisor, consultant, and/or speakers bureau member for Abbott Diabetes Care, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Lilly, and Sanofi.
S.B. and E.W. reviewed and approved the manuscript. S.F. reviewed and provided content for the manuscript. J.D.G. researched data for the manuscript. S.B. is the guarantor of this work and, as such, had full access to all the data included and takes responsibility for the integrity of the data and the accuracy of the data analysis.