Ajay K. Singh, MBBS, MBA, is Chair of the Nephrology Times Editorial Board, Senior Nephrologist at Brigham and Women's Hospital, and Associate Professor of Medicine at Harvard Medical School, as well as a co-author of the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT). Dr. Singh disclosed that he has received consulting income from Amgen, Johnson & Johnson, and FibroGen, and research grants from Amgen, Johnson & Johnson, and Watson.
Reducing the dose of erythropoiesis-stimulating agent (ESA) used to manage the anemia of chronic kidney disease (CKD) makes scientific and economic sense.
The recently published Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT),1 as well as the randomized controlled trials preceding it, such as the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) trial2 and the Normal Hematocrit Study,3 have demonstrated that targeting a higher hemoglobin concentration is associated with increased risk. Observational studies and secondary analyses of the clinical trials have suggested that exposure to high ESA doses is a plausible explanation for the risk.4
In this article, my goal is to evaluate “ESA-sparing strategies” that clinicians might consider in the management of patients with CKD anemia. Reducing ESA dose will require clinicians to use a variety of approaches. My focus will be on hemodialysis patients.
Iron: Replete and Available
The single most important ESA-sparing strategy is making sure that iron stores are fully replete and that iron is available for erythropoiesis.
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) strongly recommends using intravenous iron in dialysis patients and aiming for a serum ferritin greater than 200 ng/mL and a transferrin saturation (TSAT) greater than 20%.5
Although the clinical practice guidelines from KDOQI also state that there is insufficient evidence to recommend the routine administration of IV iron for serum ferritin levels above 500 ng/mL, recent data from the randomized controlled Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) study indicates that in fact these patients do respond to iron.6 In a six-week follow-up to DRIVE (DRIVE II), treatment with intravenous iron reduced epoetin doses (P=0.017).7
While some have raised concerns about the safety of iron,8 the data published so far is reassuring.9 Still, long-term safety studies are needed.
Maintaining hemodialysis patients on regular iron replacement therapy should prevent the development of iron deficiency and obviate the need to increase ESA dose.
While precipitating iron overload is a concern with aggressive iron therapy, the risk is low as long as the TSAT remains below 40% and there are no clinical parameters suggestive of iron overload.
Hepcidin, which is synthesized by the liver, is now recognized as critical for iron homeostasis.10 The protein regulates the movement of iron through intestinal cells and macrophages by binding to and inhibiting ferroportin.
Hepcidin levels are influenced by a variety of stimuli, including the proinflammatory cytokine interleukin-6. Thus, inflammation can upset iron homeostasis, which in turn affects production of healthy red blood cells.
Modulating inflammation, then, by removing an inflammatory focus (such as a failed kidney allograft11) or treating an indolent infection in a tunneled line12 can lead to reduced ESA dose.
Drug therapy also has been effective in reducing inflammation. In a study by Cooper et al, pentoxifylline inhibited the proinflammatory cytokines tumor necrosis factor-alpha and interferon-gamma, resulting in greater ESA responsiveness (as measured by a higher hemoglobin level on a stable ESA dose).13
Ultrapure dialysate, biocompatible dialysis membranes, statins, and vitamin E supplementation also have been used to influence the inflammatory response and improve ESA hyporesponsiveness.14
And ascorbic acid, which mobilizes iron, has been tested as an ESA-sparing therapy in patients on dialysis. In a recent systematic review by Deved et al15 of six studies, ascorbic acid was associated with a statistically significant decrease in ESA dose and an improvement in TSAT. Information on the safety of ascorbic acid in the dialysis patient population is quite limited, however.
Switching to Subcutaneous Epoetin
Another powerful ESA-sparing strategy is switching the patient from intravenous to subcutaneous epoetin. The KDOQI clinical practice guidelines state that, in the Work Group's opinion, convenience favors intravenous ESA administration in patients on hemodialysis.5
In a trial by Kaufman et al, though, subcutaneous epoetin given three times a week maintained the same level of hematocrit at a one-third lower dose compared with intravenous epoetin.16 In fact, in almost all published studies, subcutaneous administration is associated with a 25% to 50% lower epoetin dose.
Subcutaneously delivered epoetin is the preferred modality at Kaiser Permanente dialysis facilities in California and in the Veterans Affairs system. Survey data from the American Association of Kidney Patients indicates that patients are willing to accept subcutaneously injected epoetin if it is for safety reasons.17
Folic Acid, Dialysis Regimen
Optimization of metabolic parameters results in reduced ESA utilization. Evidence demonstrates that folic acid deficiency can lead to ESA hyporesponsiveness, especially in elderly hemodialysis patients with poor dietary folate intake who are not receiving regular oral supplementation.18 Folic acid deficiency can be easily detected if macrocytosis is present or if folate levels are measured.
A modification in dialysis regimen could also be in order. Optimizing dialysis adequacy19 and/or switching to nocturnal dialysis20 or peritoneal dialysis21 is effective in lowering ESA utilization.
There is also good evidence that hyperparathyroidism is an important factor in ESA hyporesponsiveness.22 In addition, L-carnitine therapy may lower ESA utilization. However, its use in dialysis patients remains controversial.23
While ensuring that iron stores are replete and that iron is available for erythropoiesis is the most important ESA-sparing strategy, there are several approaches that can be employed to reduce ESA dose. Most of these strategies are inexpensive and easy to implement.
1. Pfeffer MA, Burdmann EA, Chen CY, et al, for the TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N Engl J Med
2. Singh AK, Szczech L, Tang KL, et al, for the CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med
3. Besarab A, Bolton WK, Browne JK, et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med
4. Singh AK. Resolved: Targeting a higher hemoglobin is associated with greater risk in patients with CKD anemia: pro. J Am Soc Nephrol
5. National Kidney Foundation Kidney Disease Outcomes Quality Initiative. Clinical practice guidelines and clinical practice recommendations for anemia in chronic kidney disease in adults. Am J Kidney Dis
2006; 47(suppl 3):S16-S85.
6. Coyne DW, Kapoian T, Suki W, et al, for the DRIVE Study Group. Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results of the Dialysis Patients’ Response to IV Iron with Elevated Ferritin (DRIVE) Study. J Am Soc Nephrol
7. Kapoian T, O'Mara NB, Singh AK, et al. Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin.J Am Soc Nephrol
8. Bishu K, Agarwal R. Acute injury with intravenous iron and concerns regarding long-term safety. Clin J Am Soc Nephrol
9. Feldman HI, Joffe M, Robinson B, et al. Administration of parenteral iron and mortality among hemodialysis patients. J Am Soc Nephrol
10. de Francisco AL, Stenvinkel P, Vaulont S. Inflammation and its impact on anemia in chronic kidney disease: from hemoglobin variability to hyporesponsiveness. NDT Plus
11. López-Gómez JM, Pérez-Flores I, Jofré R, et al. Presence of a failed kidney transplant in patients who are on hemodialysis is associated with chronic inflammatory state and erythropoietin resistance. J Am Soc Nephrol
12. Hung AM, Ikizler TA. Hemodialysis central venous catheters as a source of inflammation and its implications. Semin Dial
13. Cooper A, Mikhail A, Lethbridge MW, Kemeny DM, Macdougall IC. Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol
14. Johnson DW, Pollock CA, Macdougall IC. Erythropoiesis-stimulating agent hyporesponsiveness. Nephrology
(Carlton) 2007; 12:321–330.
15. Deved V, Poyah P, James MT, et al, for the Alberta Kidney Disease Network. Ascorbic acid for anemia management in hemodialysis patients: a systematic review and meta-analysis. Am J Kidney Dis
16. Kaufman JS, Reda DJ, Fye CL, et al. Subcutaneous compared with intravenous epoetin in patients receiving hemodialysis. Department of Veterans Affairs Cooperative Study Group on Erythropoietin in Hemodialysis Patients. N Engl J Med
17. Patel TV, Robinson K, Singh AK. Is it time to reconsider subcutaneous administration of epoetin? Nephrol News Issues
18. Schiffl H, Lang SM. Folic acid deficiency modifies the hematopoietic response to recombinant human erythropoietin in maintenance dialysis patients. Nephrol Dial Transplantation
19. Ayli D, Ayli M, Azak A, et al. The effect of high-flux hemodialysis on renal anemia. J Nephrol
20. Schwartz DI, Pierratos A, Richardson RM, Fenton SS, Chan CT. Impact of nocturnal home hemodialysis on anemia management in patients with end-stage renal disease. Clin Nephrol
21. Coronel F, Herrero JA, Montenegro J, et al. Erythropoietin requirements: a comparative multicenter study between peritoneal dialysis and hemodialysis. J Nephro
22. Drüeke TB, Eckardt KU. Role of secondary hyperparathyroidism in erythropoietin resistance of chronic renal failure patients. Nephrol Dial Transplantation
23. Hedayati SS. Dialysis-related carnitine disorder. Semin Dial