Challenges to a Timely Diagnosis of Anemia
Anemia is a frequent complication of chronic kidney disease (CKD). The prevalence of the condition increases with disease stage, comorbidities, and patient age.1,2 In stage 1 CKD, anemia affects about 8% of patients, but by stage 5, 50% to 60% of patients are affected.3 Compared to patients with CKD who are not anemic, anemia in CKD is associated with decreased quality of life (QoL) and work productivity, and increased healthcare costs, risk of CKD progression, cardiovascular (CV) disease, and all-cause mortality— especially when hemoglobin (Hgb) drops below 10 g/dL.1,2,4,5 Therefore, diagnosing and treating patients in a timely manner is essential.
An accurate diagnosis of anemia requires a specific set of laboratory tests, for example, a complete blood count (CBC) including a check of the mean corpuscular volume (MCV) for red blood cell (RBC) size; an iron panel, including ferritin, iron, and total iron binding capacity (TIBC); B12 or folic level indices; and in some patients, a reticulocyte index.3,6 These laboratory measurements help characterize the anemia and determine the appropriate treatment for the patient. It is important to ensure there is not another cause of anemia for these patients, such as colorectal cancer. Thus, colonoscopy and other routine screenings need to be up to date.
The standard of care (SOC) in managing patients with anemia in CKD is to recognize and appropriately treat anemia according to the patient’s needs.3,7-9
Patients with CKD need to be screened routinely for anemia. Anemia in CKD is often detectable at stage 3b, when the eGFR is below 45 mL/min/1.73 m2, and treatment is appropriate. Starting at CKD stage 3, patients should be getting a CBC at least annually. At CKD stages 4 and 5, a CBC should be done at least every 6 months and more often if the patient is symptomatic. For patients with CKD who are on dialysis, the minimum standard for labs to assess anemia is every 3 months. Considering the likelihood of comorbidities in patients with CKD, it can be a challenge to prioritize healthcare management needs,1 and electronic health record decision aids can help ensure that patients receive appropriate therapy.
Treatment Burdens for Patients and Care Partners
Patients with CKD often have comorbidities, such as CV disease, diabetes, or hypertension. Even mild anemia is consequential for all patients with CKD because CKD already has a far-reaching impact on patients and care partners, which is then compounded by anemia.4 Patients frequently have fatigue, exercise intolerance, and difficulty concentrating.10,11 They may attribute their symptoms to age, comorbidities, or work stress and not report them to their clinicians. Care partners may be helpful in noticing and describing these effects of anemia.
Management of Anemia in CKD
In patients with CKD, current guidelines advise a target Hgb below the definition of normal and recommend balancing the potential benefits of avoiding or minimizing blood transfusions, erythropoiesis-stimulating agents (ESAs), and anemia-related symptoms against the potential risks of iron supplementation.3,7,8 Some patients can be treated with over-the-counter oral iron. A 324-mg tablet of iron sulfate, for example, taken twice a day provides enough elemental iron to raise a patient’s Hgb over a period of a few months.Clinicians shouldavoid RBC transfusions when possible because exposing patients who may be good kidney transplant candidates to other blood products increases their risk of forming antibodies.12 If the Hgb is still low after a patient’s iron is replete and their B12 has been corrected, other treatments, including ESAs, should be considered.
Pathophysiology of Anemia in CKD
An understanding of the pathophysiology of anemia in CKD, which results from decreased erythropoietin (EPO) production by the failing kidney and altered iron homeostasis, is essential for optimal patient management.3,13,14 Iron deficiency, which limits responsiveness to EPO,15 and a relative decrease in EPO production in CKD are the key mechanisms involved in anemia in CKD.16 These factors are the basis for the current management of anemia in CKD with ESAs and iron supplementation.13,17
Iron metabolism is controlled in part by the hormone hepcidin, which regulates uptake of iron from the gut and release of iron from stores in the body.18 This hormone has a unique role because it affects the way that iron is used and incorporated into blood cells. Hepcidin production is up-regulated by inflammation—which is seen in many patients with CKD and other comorbid conditions.19,20 CKD is associated with increased hepcidin levels,21 which further impairs the body’s ability to use iron and to make new RBCs. A decrease in hepcidin may allow patients with anemia in CKD to mobilize iron stores and decrease the need for iron supplementation.1 Patients with CKD may also have increased blood loss from needle sticks or gastrointestinal bleeding, which can lead to absolute loss of iron and increased risk of anemia.22
Treating Iron Deficiency in Patients with CKD
Anemia in CKD is defined as Hgb < 13.0 g/dL for men and < 12.0 g/dL for nonpregnant women.8Patients with CKD who are close to that threshold should be treated with oral iron, which is relatively innocuous and easy to take. Guidelines typically suggest considering the addition of an ESA to iron supplementation if a patient’s Hgb is < 10 mg/dL and they are symptomatic; an ESA should definitely be added if a patient’s Hgb is < 9 mg/dL.23
Parenteral iron administration may be a good option for some patients with anemia in CKD who cannot tolerate oral iron.3,24 Several parenteral iron formulations are available, and the choice of formulation may be based on safety profile, cost, and ease of administration (single versus multiple infusions).3 However, the need for multiple infusions of iron or ESAs may pose logistical, physical, psychological, or monetary challenges for patients and caregivers. Clinicians also need to consider a patient’s other medications, such as insulin injections.
ESAs reduce the risks associated with blood transfusions, but they are not as effective in improving mortality or CV outcomes. Several well-conducted studies in patients indicate that the use of ESAs to treat anemia in patients with CKD may worsen CV outcomes.3 The trials found a higher incidence of stroke and CV events and increased mortality.1 Thus, the current treatment guidelines recommend keeping the Hgb between 10 mg/dL and 11.5 mg/dL when treating patients with anemia in CKD.8
Hypoxia-Induced Factor Prolyl Hydroxylase Inhibitors
Hypoxia-induced factor prolyl hydroxylase inhibitors (HIF-PHIs) provide a novel pathway for patients with anemia in CKD.25 These oral agents, which are generally considered safe and efficacious, decrease levels of hepcidin, the inflammatory blocker of iron use.1 Compared with ESAs, HIF-PHIs significantly lower EPO levels26 through effects on hepcidin and other iron-related proteins, transferrin, and transferrin receptor expression.27,28
Roxadustat, vadadustat, and daprodustat are the 3 drugs in this class that are being studied in patients with stages 3 to 5 CKD with anemia.
The OLYMPUS trial compared roxadustat to a placebo and showed that the study drug raised patients’ Hgb to the prespecified threshold of 10 mg/dL to 11.5 mg/dL.29
The PROTECT trial compared vadadustat to the SOC, recombinant erythropoietin.30 The study drug was as efficacious as recombinant erythropoietin in the trial. However, there were some increases in CV events, which resulted in statistically significantly increased mortality, leading the US Food and Drug Administration to reject vadadustat for approval in the United States.
The ASCEND-D trials of dialysis patients (DD) and the ASCEND-ND trials of non-dialysis (NDD) patients compared daprodustat to recombinant erythropoietin to see whether the Hgb was raised to the prespecified target of 10 mg/dL to 11.5 mg/dL and to ensure that there was no increase in CV events, which was the primary endpoint for the trials.31,32 The trials did meet the prespecified target, and there was no increase in CV events compared to the SOC. However, the studies showed that daprodustat could increase malignancies, particularly of a gastrointestinal nature. Researchers are continuing to investigate this potentially serious adverse event. More long-term data are expected, with the hope that the additional evidence will support approval of the new medication.
Conclusions
Anemia is a frequent complication of CKD, which is associated with multiple patient and caregiver burdens, including effects on QoL, increased healthcare costs, increased risk of CKD progression, CV events, and all-cause mortality. Therefore, timely diagnosis and treatment are important. Diagnosis of anemia in CKD can be challenging, and accurate assessment must be based on specific laboratory tests. Supplemental oral or parenteral iron, RBC transfusions, and ESAs are the current SOC. Each of these has drawbacks, including CV safety concerns and inconvenience, and drug resistance is associated with ESAs. Guidelines recommend cautious use of ESAs and limited correction of anemia. Given these limitations and the fact that the management of CKD often includes co-management of comorbidities that can complicate treatment, novel safe and effective treatments are urgently needed. Phase 3 trials have been completed for the oral HIF-PHIs daprodustat, roxadustat, and vadadustat for US populations. Daprodustat has shown efficacy with no increased CV risk across NDD and DD study populations.
References
- Hanna RM, Streja E, Kalantar-Zadeh K. Burden of anemia in chronic kidney disease: beyond erythropoietin. Adv Ther. 2021;38(1):52-75. doi:10.1007/s12325-020-01524-6
- St Peter WL, Guo H, Kabadi S, et al. Prevalence, treatment patterns, and healthcare resource utilization in Medicare and commercially insured non-dialysis-dependent chronic kidney disease patients with and without anemia in the United States. BMC Nephrol. 2018;19(1):67. doi:10.1186/s12882-018-0861-1
- Batchelor EK, Kapitsinou P, Pergola PE, Kovesdy CP, Jalal DI. Iron deficiency in chronic kidney disease: updates on pathophysiology, diagnosis, and treatment. J Am Soc Nephrol. 2020;31(3):456-468. doi:10.1681/asn.2019020213
- Michalopoulos SN, Gauthier-Loiselle M, Aigbogun MS, et al. Patient and care partner burden in CKD patients with and without anemia: a US-based survey. Kidney Med. 2022;4(4):100439. doi:10.1016/j.xkme.2022.100439
- Awan AA, Walther CP, Richardson PA, Shah M, Winkelmayer WC, Navaneethan SD. Prevalence, correlates and outcomes of absolute and functional iron deficiency anemia in nondialysis-dependent chronic kidney disease. Nephrol Dial Transplant. 2021;36(1):129-136. doi:10.1093/ndt/gfz192
- Lopez A, Cacoub P, Macdougall IC, Peyrin-Biroulet L. Iron deficiency anaemia. Lancet. 2016;387(10021):907-916. doi:10.1016/s0140-6736(15)60865-0
- Wong MMY, Tu C, Li Y, et al. Anemia and iron deficiency among chronic kidney disease stages 3-5ND patients in the Chronic Kidney Disease Outcomes and Practice Patterns Study: often unmeasured, variably treated. Clin Kidney J. 2020;13(4):613-624. doi:10.1093/ckj/sfz091
- Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2:279-335.
- Anemia in CKD. KDIGO. Accessed September 2, 2022. https://kdigo.org/guidelines/anemia-in-ckd/
- Romagnani P, Remuzzi G, Glassock R, et al. Chronic kidney disease. Nat Rev Dis Primers. 2017;3:17088. doi:10.1038/nrdp.2017.88
- National Institute of Diabetes and Digestive and Kidney Diseases. Anemia in chronic kidney disease. Updated September 2020. Accessed April 24, 2022. https://www.niddk.nih.gov/health-information/kidney-disease/anemia
- Bynum JP, Zachary A, Ness PM, et al. Transfusion of leukoreduced blood products and risk of antibody-mediated rejection of renal allografts. Transfusion. 2018;58(8):1951-1957. doi:10.1111/trf.14800
- Babitt JL, Lin HY. Mechanisms of anemia in CKD. J Am Soc Nephrol. 2012;23(10):1631-1634. doi:10.1681/asn.2011111078
- Bonomini M, Del Vecchio L, Sirolli V, Locatelli F. New treatment approaches for the anemia of CKD. Am J Kidney Dis. 2016;67(1):133-142. doi:10.1053/j.ajkd.2015.06.030
- Yilmaz MI, Solak Y, Covic A, Goldsmith D, Kanbay M. Renal anemia of inflammation: the name is self-explanatory. Blood Purif. 2011;32(3):220-225. doi:10.1159/000328037
- Lopes MB, Tu C, Zee J, et al. A real-world longitudinal study of anemia management in non-dialysis-dependent chronic kidney disease patients: a multinational analysis of CKDopps. Sci Rep. 2021;11(1):1784. doi:10.1038/s41598-020-79254-6
- Zumbrennen-Bullough K, Babitt JL. The iron cycle in chronic kidney disease (CKD): from genetics and experimental models to CKD patients. Nephrol Dial Transplant. 2014;29(2):263-273. doi:10.1093/ndt/gft443
- Panwar B, Gutiérrez OM. Disorders of iron metabolism and anemia in chronic kidney disease. Semin Nephrol. 2016;36(4):252-261. doi:10.1016/j.semnephrol.2016.05.002
- Basseri RJ, Nemeth E, Vassilaki ME, et al. Hepcidin is a key mediator of anemia of inflammation in Crohn's disease. J Crohns Colitis. 2013;7(8):e286-e291. doi:10.1016/j.crohns.2012.10.013
- Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood. 2003;102(3):783-788. doi:10.1182/blood-2003-03-0672
- Zaritsky J, Young B, Wang HJ, et al. Hepcidin--a potential novel biomarker for iron status in chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(6):1051-1056. doi:10.2215/cjn.05931108
- Mehdi U, Toto RD. Anemia, diabetes, and chronic kidney disease. Diabetes Care. 2009;32(7):1320-1326. doi:10.2337/dc08-0779
- Portolés J, Martín L, Broseta JJ, Cases A. Anemia in chronic kidney disease: from pathophysiology and current treatments, to future agents. Front Med (Lausanne). 2021;8:642296. doi:10.3389/fmed.2021.642296
- O'Lone EL, Hodson EM, Nistor I, Bolignano D, Webster AC, Craig JC. Parenteral versus oral iron therapy for adults and children with chronic kidney disease. Cochrane Database Syst Rev. 2019;2(2):CD007857. doi:10.1002/14651858.CD007857.pub3
- Locatelli F, Fishbane S, Block GA, Macdougall IC. Targeting hypoxia-inducible factors for the treatment of anemia in chronic kidney disease patients. Am J Nephrol. 2017;45(3):187-199. doi:10.1159/000455166
- Haase VH. HIF-prolyl hydroxylases as therapeutic targets in erythropoiesis and iron metabolism. Hemodial Int. 2017;21 Suppl 1(Suppl 1):S110-S124. doi:10.1111/hdi.12567
- Kaplan JM, Sharma N, Dikdan S. Hypoxia-inducible factor and its role in the management of anemia in chronic kidney disease. Int J Mol Sci. 2018;19(2):389. doi:10.3390/ijms19020389
- Sugahara M, Tanaka T, Nangaku M. Prolyl hydroxylase domain inhibitors as a novel therapeutic approach against anemia in chronic kidney disease. Kidney Int. 2017;92(2):306-312. doi:10.1016/j.kint.2017.02.035
- Fishbane S, El-Shahawy MA, Pecoits-Filho R, et al. Roxadustat for treating anemia in patients with CKD not on dialysis: results from a randomized phase 3 study. J Am Soc Nephrol. 2021;32(3):737-755. doi:10.1681/asn.2020081150
- Chertow GM, Pergola PE, Farag YMK, et al. Vadadustat in patients with anemia and non-dialysis-dependent CKD. N Engl J Med. 2021;384(17):1589-1600. doi:10.1056/NEJMoa2035938
- Singh AK, Carroll K, McMurray JJV, et al. Daprodustat for the treatment of anemia in patients not undergoing dialysis. N Engl J Med. 2021;385(25):2313-2324. doi:10.1056/NEJMoa2113380
- Singh AK, Carroll K, Perkovic V, et al. Daprodustat for the treatment of anemia in patients undergoing dialysis. N Engl J Med. 2021;385(25):2325-2335. doi:10.1056/NEJMoa2113379
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