Individualizing Hb targets in dialysis patients with anemia

Anemia, a condition characterized by decreased levels of red blood cells or hemoglobin, is a complex health issue that affects individuals across various medical contexts.¹ One such context where anemia has significant implications is in chronic kidney disease (CKD).² For individuals suffering from CKD, anemia adds an extra layer of complexity to their already challenging medical condition.² It is not merely a stand-alone concern but rather an intertwined factor that contributes to increased morbidity and mortality while simultaneously diminishing the overall quality of life.^2–4. In this blog, we will talk about the interconnection between anemia and chronic kidney disease, delving into the far-reaching consequences of this dual challenge and discussing the evolving strategies to manage it effectively.

Erythropoiesis-stimulating agents (ESAs) have proven their effectiveness in enhancing and maintaining hemoglobin (Hb) levels, leading to a reduced reliance on red-cell transfusions.⁵ As a result, they have emerged as gold standard for managing anemia in renal patients.^6,7

Since the inception of the first ESA in 1989, there have been significant strides in treatment aimed at addressing the needs of both patients and healthcare providers. These advancements include the development of longer-acting ESAs and implementation of various dosing strategies.⁸

Darbepoetin Alfa, classified as a second-generation long-acting recombinant erythropoietin formulation, possesses notable attributes such as an extended half-life in the bloodstream and enhanced in vivo biological effectiveness.^9,10

Extensive clinical research has demonstrated that Darbepoetin Alfa, administered at reduced dosing intervals (either weekly or biweekly) for managing anemia in patients with CKD, delivers comparable efficacy and safety outcomes when compared to Epoetin Alfa.^11,12 This not only benefits patients but also eases the burden on healthcare professionals.¹³

As our understanding of managing renal anemia with ESAs has grown, it has brought forth new clinical complexities. Early observational studies, involving both dialysis and non-dialysis CKD populations, revealed connections between decreased hemoglobin (Hb) levels and increased risks of mortality and morbidity.^3,14

Additionally, both observational and certain prospective studies indicated that achieving higher or normalized Hb levels in CKD patients did not correlate with elevated risks of adverse outcomes.^15,16 In fact, it was suggested that such achievements could potentially enhance mortality and morbidity outcomes, especially in terms of cardiovascular health and overall quality of life.^14,17

These significant observations spurred a series of randomized controlled trials, initially conducted among dialysis patients. The primary goal was to assess the effectiveness and safety of targeting higher Hb levels using ESAs. While there was a hypothesis that maintaining high Hb levels might yield advantages in terms of reduced morbidity and mortality,¹⁸ the consistent outcome of these trials revealed that intervening with ESAs to achieve high Hb target did not confer any clinical benefits compared to control treatments.^19,20

In order to provide precise patient care, guidelines for the management of renal anemia were established. These guidelines not only suggest target Hb levels but also emphasize the importance of customizing treatment for each individual patient. The European Best Practice Guidelines (EBPGs) for renal anemia in 2004 initially recommended a target Hb level of >11 g/dL for most patients.²¹ However, they emphasized that the precise Hb target should be determined based on various individual factors, including the patient's gender, age, ethnicity, activity level, comorbid conditions, and disease state.²¹ Subsequently, in 2009 and 2010, the European Renal Best Practice Working Group (formerly EBPG) recommended that all CKD patients should aim for a target Hb range between 11 and 12 g/dL. However, there were exceptions for patients with type-2 diabetes mellitus (T2DM) and a history of stroke, where the recommended target was set at 10–12 g/dL.^22,23 The Working Group acknowledged that Hb levels might naturally fluctuate outside this narrow target during treatment but cautioned against intentionally exceeding levels beyond 13 g/dL.²² Furthermore, they advised against targeting Hb levels above 12 g/dL in patients with T2DM.²³ Similar adjustments were made to the Kidney Disease Outcomes Quality Initiative Guidelines in 2007.²⁴

As per KDIGO guidelines, for adult CKD patients undergoing dialysis, the initiation of erythropoiesis-stimulating agent (ESA) therapy is recommended when the hemoglobin concentration falls within the range of 9g/dL and 10 g/dL, with the aim of preventing it from dropping below 9g/dL.⁷

As our understanding continues to evolve, the objectives of managing renal anemia in patients will undergo further adjustments. However, the disparities between real-world observations and clinical trial outcomes, coupled with the significant revisions to guidelines, present considerable challenges for both healthcare providers and patients.⁸ This challenge becomes particularly pronounced when considering the recommendation to treat all CKD patients according to a closely defined Hb target. The CKD population is notably diverse, encompassing variations in disease severity, age, medical history, healthcare behaviors, and other contributing factors.⁸

Nevertheless, it is through ongoing research and collaboration that we aim to bridge these gaps and enhance the care provided to CKD patients, ushering in a new era of improved outcomes and tailored treatments.

References

1. Chaparro CM, Suchdev PS. Anemia epidemiology, pathophysiology, and etiology in low- and middle-income countries. Ann N Y Acad Sci. 2019 Aug;1450(1):15-31.
2. Mikhail A, Brown C, Williams JA, et al. Renal association clinical practice guideline on Anaemia of Chronic Kidney Disease. BMC Nephrol. 2017;18(1):345.
3. Pisoni RL, Bragg-Gresham JL, Young EW, et al. Anemia management and outcomes from 12 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis. 2004;44:94–111. 
4. Leaf DE, Goldfarb DS. Interpretation and review of health-related quality of life data in CKD patients receiving treatment for anemia. Kidney Int. 2009;75:15–24.
5. Cody J, Daly C, Campbell M, et al. Recombinant human erythropoietin for chronic renal failure anaemia in pre-dialysis patients. Cochrane Database Syst Rev. 2005;(3):CD003266.
6. Locatelli F, Aljama P, Barany P, et al. Revised European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19:ii16–ii31.
7. KDIGO clinical practice guideline for Anemia in chronic kidney disease. Kidney Int Suppl. 2012;2(4):279–335.
8. de Francisco AL. Individualizing anaemia therapy. NDT Plus. 2010 Dec;3(6):519–526.
9. Al Raisi F, Al Salmi I, Kamble P, et al. Initiation of darbepoetin for management of anemia in non‐dialysis‐dependent patients with chronic kidney disease. Saudi J Kidney Dis Transpl. 2016;27(6):1182–1187.
10. Chen N, Xing C, Niu J, et al. Darbepoetin alfa injection versus epoetin alfa injection for treating anemia of Chinese hemodialysis patients with chronic kidney failure: A randomized, open-label, parallel-group, non-inferiority Phase III trail. Chronic Dis Transl Med. 2022;8(1):59–70.
11. Carrera F, Burnier M. Use of darbepoetin alfa in the treatment of anaemia of chronic kidney disease: clinical and pharmacoeconomic considerations. NDT Plus. 2009;2(Suppl_1):i9–i17.
12. Locatelli F, Canaud B, Giacardy F, et al. Treatment of anaemia in dialysis patients with unit dosing of darbepoetin alfa at a reduced dose frequency relative to recombinant human erythropoietin (rHuEpo). Nephrol Dial Transplant. 2003;18:362–369
13. Sinha SD, Bandi VK, Bheemareddy BR, et al. Efficacy, tolerability and safety of darbepoetin alfa injection for the treatment of anemia associated with chronic kidney disease (CKD) undergoing dialysis: a randomized, phase‐III trial. BMC Nephrol. 2019;20(1):90
14. Xue JL, St Peter WL, Ebben JP, et al. Anemia treatment in the pre-ESRD period and associated mortality in elderly patients. Am J Kidney Dis. 2002;40:1153–1161.
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16. Furuland H, Linde T, Ahlmen J, et al. A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients. Nephrol Dial Transplant. 2003;18:353–361. 
17. McMahon LP, Mason K, Skinner SL, et al. Effects of haemoglobin normalization on quality of life and cardiovascular parameters in end-stage renal failure. Nephrol Dial Transplant. 2000;15:1425–1430.
18. Strippoli GF, Navaneethan SD, Craig JC. Haemoglobin and haematocrit targets for the anaemia of chronic kidney disease. Cochrane Database Syst Rev. 2006 CD003967.
19. Drueke TB, Locatelli F, Clyne N, et al. Normalization of hemoglobin level in patients with chronic kidney disease and anemia. N Engl J Med. 2006;355:2071–2084. 
20. Parfrey PS, Foley RN, Wittreich BH, et al. Double-blind comparison of full and partial anemia correction in incident hemodialysis patients without symptomatic heart disease. J Am Soc Nephrol. 2005;16:2180–2189.
21. Locatelli F, Aljama P, Barany P, et al. Revised European Best Practice Guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant. 2004;19:ii6–ii15.
22. Locatelli F, Covic A, Eckardt KU, et al. Anaemia management in patients with chronic kidney disease: a position statement by the Anaemia Working Group of European Renal Best Practice (ERBP) Nephrol Dial Transplant. 2009;24:348–354. 
23. Locatelli F, Aljama P, Canaud B, et al. Target haemoglobin to aim for with erythropoiesis-stimulating agents: a position statement by ERBP following publication of the Trial to Reduce Cardiovascular Events with Aranesp(R) Therapy (TREAT) Study. Nephrol Dial Transplant. 2010;25:2846–2850. 
24. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007;50:471–530.

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