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Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin

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Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin UC Irvine UC Irvine Previously Published Works Title Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin. Permalink https://escholarship.org/uc/item/7k1593dd Journal Advances in therapy, 38(1) ISSN 0741-238X Authors Hanna, Ramy M Streja, Elani Kalantar-Zadeh, Kamyar Publication Date 2021 DOI 10.1007/s12325-020-01524-6 Peer reviewed eScholarship.org Powered by the California Digital Library University of California Adv Ther (2021) 38:52–75 https://doi.org/10.1007/s12325-020-01524-6 REVIEW Burden of Anemia in Chronic Kidney Disease: Beyond Erythropoietin Ramy M. Hanna . Elani Streja . Kamyar Kalantar-Zadeh Received: June 24, 2020 / Accepted: October 3, 2020 / Published online: October 29, 2020 Ó The Author(s) 2020 ABSTRACT complications. In particular, treatment with high doses of erythropoiesis-stimulating agents has Anemia is a frequent comorbidity of chronic been associated with increased rates of hospital- kidney disease (CKD) and is associated with a ization, cardiovascular events, and mortality. considerable burden because of decreased patient Resistance to erythropoiesis-stimulating agents health-related quality of life and increased health- remains a therapeutic challenge in a subset of care resource utilization. Based on observational patients. Hypoxia-inducible factor transcription data, anemia is associated with an increased risk factors, which regulate several genes involved in of CKD progression, cardiovascular events, and erythropoiesis and iron metabolism, can be sta- all-cause mortality. The current standard of care bilizedbyanewclassofdrugsthatactas includes oral or intravenous iron supplementa- inhibitors of hypoxia-inducible factor prolyl-hy- tion, erythropoiesis-stimulating agents, and red droxylase enzymes to promote erythropoiesis and blood cell transfusion. However, each of these elevate hemoglobin levels. Here, we review the therapies has its own set of population-specific burden of anemia of chronic kidney disease, the patient concerns, including increased risk of car- shortcomings of current standard of care, and the diovascular disease, thrombosis, and mortality. potential practical advantages of hypoxia-in- Patients receiving dialysis or those who have ducible factor prolyl-hydroxylase inhibitors in the concurrent diabetes or high blood pressure may treatment of patients with anemia of CKD. be at greater risk of developing these Keywords: Anemia; Burden; Chronic kidney disease; Erythropoietin; Hypoxia-inducible factor; Iron; Nephrology R. M. Hanna Division of Nephrology, Hypertension and Kidney Transplantation, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California, Irvine School of Medicine, Orange, CA, USA E. Streja Á K. Kalantar-Zadeh (&) Division of Nephrology and Hypertension, University of California, Irvine School of Medicine, Orange, CA, USA e-mail: [email protected] Adv Ther (2021) 38:52–75 53 hemoglobin (Hb) \ 13.0 g/dl for men Key Summary Points and \ 12.0 g/dl for nonpregnant women [3]and largely results from decreased erythropoietin Anemia is common in patients with (EPO) production by the failing kidney and/or chronic kidney disease and has been altered iron homeostasis [4, 5]. The current stan- associated with increased risk of dard of care for anemia of CKD includes oral or cardiovascular morbidity and mortality in intravenous (IV) iron, erythropoiesis-stimulating observational studies as well as decreased agents (ESAs), and red blood cell (RBC) transfu- patient quality of life and increased sion, each of which has potential problems and healthcare utilization. variable effectiveness [2, 3]. The impact of anemia correction on patient health-related quality of life The current standard of care includes (HR-QOL) is unknown, and persistent safety supplemental iron, erythropoiesis- issues contribute to uncertainty regarding the stimulating agents, and red blood cell optimal target Hb. This article reviews the burden transfusions, although each has of anemia of CKD, including its impact on mor- drawbacks. tality and cardiovascular risk, HR-QOL, hospital- High doses of erythropoiesis-stimulating ization and transfusion needs, iron supple- agents have been associated with mentation needs, the conservative management increased cardiovascular complications of CKD to delay dialysis, end-stage renal disease and mortality. (ESRD) transition outcomes, anemia manage- ment at home, and anemia management in Hypoxia-inducible factor-prolyl transplant recipients. An assessment of the risk to hydroxylase inhibitors are novel the benefit profile associated with current stan- treatments for anemia of chronic kidney dard of care and discussion surrounding novel disease that prevent degradation of the agents in development based on alternative ery- transcription factor hypoxia-inducible thropoietic mechanisms are also provided. This factor, which stimulates erythropoiesis to article is based on previously conducted studies physiologic levels. and does not contain any studies with human participants or animals performed by any of the authors. DISEASE BURDEN DIGITAL FEATURES Prevalence This article is published with digital features, including a summary slide, to facilitate under- The estimated global prevalence of CKD is 11% standing of the article. To view digital features for patients with CKD stage 3 [estimated for this article go to https://doi.org/10.6084/ glomerular filtration rate (eGFR) \ 60 ml/min/ m9.figshare.13035146. 1.73 m2] to stage 5 (eGFR \ 15 ml/min/1.73 m2) and 13% for patients with CKD stage 1 (albu- INTRODUCTION min-to-creatine ratio [ 30 plus eGFR [ 90 ml/ min/1.73 m2) to stage 5 [6]. In the US, the Anemiaisacommoncomplicationofchronic prevalence of stage 1–5 CKD was 14.0% (repre- kidney disease (CKD), representing a significant senting * 31.4 million people) according to the burden to patients and healthcare systems [1, 2]. 2007–2010 data from the National Health and According to the Kidney Disease: Improving Nutrition Examination Survey (NHANES) [7]. Global Outcomes (KDIGO) clinical practice Similarly, the US Centers for Disease Control guidelines, anemia of CKD is defined as and Prevention estimated that the prevalence of 54 Adv Ther (2021) 38:52–75 CKD stage 1 to stage 4 (eGFR 15–29 ml/min/ dyslipidemia), patients with anemia in the US 1.73 m2) was 15% (*37 million people) in Atherosclerosis Risk in Communities (ARIC) 2013–2016 [8]. study had a significantly increased risk of stroke Anemia prevalence increases with CKD with comorbid CKD versus no CKD (HR 5.43, stage. In the NHANES analysis, 15.4% (*4.8 95% CI 2.04–14.41), whereas in patients without million people) had anemia of CKD, and ane- anemia, the risk of stroke with CKD was not sig- mia prevalence was 17.4%, 50.3%, and 53.4% in nificantly increased (HR 1.41, 95% CI 0.93–2.14) stages 3, 4, and 5 CKD, respectively [7]. Anemia [14]. In patients with diabetes, a pooled analysis of CKD prevalence also increases in patients of data from the ARIC, Cardiovascular Health, with comorbidities and with age, from 28.0% in Framingham Heart, and Framingham Offspring those aged 18–63 years to 50.1% in those studies found an association between anemia and aged C 66 years among US patients with non- increased risks of the individual and composite dialysis-dependent (NDD) CKD [1]. outcomes of myocardial infarction (MI), fatal coronary heart disease, stroke, or death, and all- Cardiovascular Risk and Mortality cause mortality among patients with comorbid CKD, but not in those without CKD [15]. An Anemia, fluid overload, and arteriovenous fis- association between low Hb levels and increased tulas can lead to volume overload that ulti- risks of cardiovascular and all-cause mortality was * mately results in cardiomyopathy, including also observed in a Korean study of 300,000 increased left ventricular hypertrophy (LVH), patients without cardiovascular disease [16]. Fur- and systolic and diastolic dysfunction [9, 10]. thermore, anemia was associated with increased This cardiomyopathy may present as ischemic cardiovascular risk among Japanese patients heart disease or heart failure, even when arterial undergoing treatment for hypertension [17]and vascular disease is absent [10]. Anemia has been in an Italian study of patients with diabetes [18]. associated with an increased risk of cardiovas- However, the association between anemia cular events and all-cause mortality in a number and cardiovascular morbidity and mortality in of observational studies [11–18], and the patients with CKD is primarily based on obser- American Heart Association considers anemia vational studies, and randomized interven- to be a nontraditional (non-Framingham) car- tional trials have yet to demonstrate a reduction diovascular risk factor in patients with CKD in mortality risk with correction of anemia [19]. [10]. In a US study of [ 900,000 patients with Notably, clinical trials that attempted to raise NDD-CKD, functional iron deficiency anemia Hb to high levels (13–13.5 g/dl) with darbepo- was associated with an increased risk of mor- etin alfa therapy found an increased risk of tality [hazard ratio (HR) 1.11, 95% CI 1.07–1.14] mortality or cardiovascular- or renal-related and an increased relative risk (RR) of cardio- complications compared with a near-normal or vascular hospitalization after 1 year (RR 1.21, low Hb target (11.3 g/dl; HR 1.34, 95% CI P 95% CI 1.12–1.30) and 2 years (RR 1.13, 95% CI 1.03–1.74, = 0.03) [20] and also an increased 1.07–1.21) [11]. Similarly, a Danish study of risk of fatal or non-fatal stroke compared with P \ patients with dialysis-dependent-CKD (DD- placebo (HR 1.92, 95% CI 1.38–2.68, 0.001) CKD) and NDD-CKD found that anemia was [21]. associated with increased risks of major adverse cardiovascular events (MACE), acute hospital- Health-Related Quality of Life ization, and all-cause death [12], and a Japanese study of NDD-CKD patients reported that iso- Anemia of CKD represents an independent risk lated anemia and iron deficiency anemia were factor for poor HR-QOL [22]. In patients with associated with increased risks of cardiovascu- CKD anemia, cardiovascular complications are lar-related and all-cause mortality [13].
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