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Professor of Clinical Medicine
Department of Medicine
Indiana University School of Medicine
Chief Medical Officer for Outpatient Dialysis
Division of Nephrology
Indiana University Health
Jay Wish, MD: consultant/advisor/speaker: Akebia, Amgen, AstraZeneca, CSL Behring, FibroGen, Otsuka, Rockwell Medical, Vifor Pharma; independent contractor: GlaxoSmithKline.
There are more than 5 million patients with chronic kidney disease (CKD) in the United States who meet the World Health Organization definition of anemia. Men are considered anemic when their hemoglobin (Hb) is <13 g/dL and women are anemic when their Hb is <12 g/dL. Although many patients with CKD can have mild anemia, significant numbers of patients have more severe anemia, defined as Hb <10.5 g/dL. Severe anemia is associated with adverse outcomes such as a 5-fold increase in mortality and progression to end-stage kidney disease and a 2-fold increase in hospitalization for cardiovascular events than their nonanemic counterparts with CKD. Many patients with CKD and more severe anemia do not complain of symptoms that trigger an anemia evaluation. This is often because their symptoms are attributed to other comorbidities such as the CKD itself or because the progression of symptoms, particularly fatigue, is insidious and minimized by the patient.
Screening and Testing Recommendations
Because of the frequency of anemia in stage ≥3 CKD, the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines recommend at least annual screening for anemia in patients with stage 3 CKD and at least twice yearly in nondialysis patients with stage 4/5 CKD. To assess the effectiveness of treatment for anemia, laboratory testing should be done every 3 months in patients with CKD diagnosed with anemia and should include a complete blood count, absolute reticulocyte count, ferritin, transferrin saturation, and in some cases, vitamin B12 and folic acid. Most patients with stage 3 CKD are not treated by nephrologists; they are treated by primary care physicians, endocrinologists, and cardiologists who may be unfamiliar with these anemia screening recommendations. Unfortunately, only approximately 60% of incident dialysis patients are seen by a nephrologist within 2 years before dialysis initiation, so the remaining 40% of patients with advanced kidney disease, more than 50% of whom have anemia, are likely not being adequately screened or treated for anemia by other providers or have no healthcare providers at all.
Erythropoiesis-Stimulating Agents in CKD
In addition to the increased risk for adverse outcomes among anemic patients with CKD is the increased risk for blood transfusion. Blood transfusions increase allosensitization or the formation of antibodies against human antigens, which means longer waits for transplantable organs and higher risks of organ rejection. Due to the underappreciation of the anemia and the treatment burden, almost 40% of anemic nondialysis patients with CKD receive no treatment at all for their anemia. According to the most recent data from 2014, 40% of incident dialysis patients aged 67 years and older received a blood transfusion during the 2 years before dialysis initiation, only 35% received erythropoiesis-stimulating agents (ESAs), and only approximately 12% received an oral or IV iron supplement. The low rate of iron utilization is due to underdiagnosis of iron deficiency, poor patient tolerance of oral iron agents, and the logistical challenges of IV iron infusions. The low rate of ESA utilization is also related to logistical challenges with parenteral administration that many prescription drug plans, including Medicare, require must occur in a healthcare facility. Even if the patient is allowed and is able to self-administer ESAs at home, these agents require cold storage and special handling, which many economically disadvantaged patients do not have the resources to provide.
ESAs have a black box warning regarding risks of cardiovascular and thromboembolic events, but nephrologists have been comfortable prescribing these agents for more than 3 decades and generally accept the risks that were demonstrated in clinical trials using much higher Hb targets (13-14 g/dL) than the 9.5-11.0 g/dL range currently used. The KDIGO anemia guidelines recommend the use of ESAs in iron-replete patients with CKD and Hb <10 g/dL after evaluation for the presence of anemia symptoms, the risk of transfusion, and the risks related to ESA therapy. The product information for ESAs has similar language. Even the TREAT study assessing an ESA in patients with diabetes, CKD, and moderate anemia had a Hb floor of 9 g/dL among placebo-treated patients, below which ESA rescue was administered because it is the standard of care. Nonetheless, because of the safety warnings, the requirement for parenteral administration in an infusion center, and the logistical challenges to the patient, most nonnephrologists and nonhematologists are reluctant to prescribe ESAs, leading to undertreatment among many patients who would benefit from their use both for symptom and transfusion reduction.
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