Non-iron pharmacologic adjuvants to erythropoiesis-stimulating agent therapy in dialysis patients
- Jeffrey S Berns, MD
Jeffrey S Berns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Dialysis
- Professor of Medicine
- Perelman School of Medicine at the University of Pennsylvania
Treatment with recombinant human erythropoietin (rHuEPO; epoetin) or darbepoetin alfa is effective in treating anemia in the vast majority of patients on dialysis. However, some patients are relatively resistant or "hyporesponsive" to epoetin. This may be defined as the failure to reach target hemoglobin (Hgb) or hematocrit (Hct) levels despite epoetin doses greater than 300 to 450 international units/kg/week in the absence of iron deficiency (and equivalent darbepoetin) [1,2]. Iron deficiency, either absolute or functional, and inflammation are the most common causes of an inadequate response to epoetin therapy. (See "Erythropoietin for the anemia of chronic kidney disease among predialysis and peritoneal dialysis patients" and "Erythropoietin for treatment of the anemia of chronic kidney disease in hemodialysis patients" and "Inflammation in renal insufficiency".)
In patients with chronic kidney disease (CKD), absolute iron deficiency is characterized by a serum ferritin concentration <100 ng/mL and transferrin saturation (TSAT) <20 percent. Functional iron deficiency is characterized by ferritin levels that are generally >500 ng/mL but with TSAT that is often <20 percent. (See "Diagnosis of iron deficiency in chronic kidney disease" and "Iron balance in nondialysis, peritoneal dialysis, and home hemodialysis patients" and "Use of iron preparations in hemodialysis patients".)
Similar iron indices (elevated serum ferritin with a low TSAT) are often also seen in patients with inflammatory processes associated with epoetin hyporesponsiveness. In such patients, other laboratory markers associated with the acute phase response that may be clinically useful include low (or falling) serum albumin levels and elevated level of C-reactive protein (CRP). While a CRP level diagnostic of inflammation-related epoetin hyporesponsiveness in dialysis patients has not been established, a level >20 mg/L would be very suggestive of an active, underlying inflammatory process [3,4]. (See "Inflammation in renal insufficiency" and "Anemia of chronic disease/inflammation".)
This topic review will address pharmacologic therapies other than iron that have been investigated as adjuvants to erythropoiesis-stimulating agent (ESA) therapy to either address epoetin hyporesponsiveness or otherwise enhance the response to epoetin and reduce its economic impact. The effect of dialysis adequacy, hemodialysis membrane composition, and different dialysis modalities will not be discussed herein.
A number of non-iron pharmacologic agents have been evaluated as adjuvants to ESAs. Although some have been suggested for use in patients who are "hyporesponsive" to epoetin, these agents have not been studied in hyporesponsive patients for the most part. These agents include L-carnitine, ascorbic acid, androgens, pentoxifylline, statins, and others.
- SECTION IV. Failure to respond to treatment. Nephrol Dial Transplant 2004; 19:II32.
- IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000. Am J Kidney Dis 2001; 37:S182.
- Kalantar-Zadeh K, McAllister CJ, Lehn RS, et al. Effect of malnutrition-inflammation complex syndrome on EPO hyporesponsiveness in maintenance hemodialysis patients. Am J Kidney Dis 2003; 42:761.
- Gunnell J, Yeun JY, Depner TA, Kaysen GA. Acute-phase response predicts erythropoietin resistance in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis 1999; 33:63.
- Hothi DK, Geary DF, Fisher L, Chan CT. Short-term effects of nocturnal haemodialysis on carnitine metabolism. Nephrol Dial Transplant 2006; 21:2637.
- Kitamura Y, Satoh K, Satoh T, et al. Effect of L-carnitine on erythroid colony formation in mouse bone marrow cells. Nephrol Dial Transplant 2005; 20:981.
- Golper TA, Goral S, Becker BN, Langman CB. L-carnitine treatment of anemia. Am J Kidney Dis 2003; 41:S27.
- Hurot JM, Cucherat M, Haugh M, Fouque D. Effects of L-carnitine supplementation in maintenance hemodialysis patients: a systematic review. J Am Soc Nephrol 2002; 13:708.
- Labonia WD. L-carnitine effects on anemia in hemodialyzed patients treated with erythropoietin. Am J Kidney Dis 1995; 26:757.
- Caruso U, Leone L, Cravotto E, Nava D. Effects of L-carnitine on anemia in aged hemodialysis patients treated with recombinant human erythropoietin: a pilot study. Dial Transplant 1998; 27:498.
- Kletzmayr J, Mayer G, Legenstein E, et al. Anemia and carnitine supplementation in hemodialyzed patients. Kidney Int Suppl 1999; 69:S93.
- Mercadal L, Coudert M, Vassault A, et al. L-carnitine treatment in incident hemodialysis patients: the multicenter, randomized, double-blinded, placebo-controlled CARNIDIAL trial. Clin J Am Soc Nephrol 2012; 7:1836.
- Vaux EC, Taylor DJ, Altmann P, et al. Effects of carnitine supplementation on muscle metabolism by the use of magnetic resonance spectroscopy and near-infrared spectroscopy in end-stage renal disease. Nephron Clin Pract 2004; 97:c41.
- Semeniuk J, Shalansky KF, Taylor N, et al. Evaluation of the effect of intravenous l-carnitine on quality of life in chronic hemodialysis patients. Clin Nephrol 2000; 54:470.
- Yang SK, Xiao L, Song PA, et al. Effect of L-carnitine therapy on patients in maintenance hemodialysis: a systematic review and meta-analysis. J Nephrol 2014; 27:317.
- Evans A. Dialysis-related carnitine disorder and levocarnitine pharmacology. Am J Kidney Dis 2003; 41:S13.
- Bain MA, Faull R, Milne RW, Evans AM. Oral L-carnitine: metabolite formation and hemodialysis. Curr Drug Metab 2006; 7:811.
- Trovato GM, Iannetti E, Murgo AM, et al. Body composition and long-term levo-carnitine supplementation. Clin Ter 1998; 149:209.
- Verrina E, Caruso U, Calevo MG, et al. Effect of carnitine supplementation on lipid profile and anemia in children on chronic dialysis. Pediatr Nephrol 2007; 22:727.
- SECTION III. Treatment of renal anaemia. Nephrol Dial Transplant 2004; 19:ii16.
- Eknoyan G, Latos DL, Lindberg J, National Kidney Foundation Carnitine Consensus Conference. Practice recommendations for the use of L-carnitine in dialysis-related carnitine disorder. National Kidney Foundation Carnitine Consensus Conference. Am J Kidney Dis 2003; 41:868.
- Golper TA, Ahmad S. L-carnitine administration to hemodialysis patients: has its time come? Semin Dial 1992; 5:94.
- Steinman TI, Nissenson AR, Glassock RJ, et al. L-carnitine use in dialysis patients: is national coverage for supplementation justified? What were CMS regulators thinking--or were they? Nephrol News Issues 2003; 17:28.
- KDOQI, National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 2006; 47:S11.
- Wasserstein AG. L-carnitine supplementation in dialysis: treatment in quest of disease. Semin Dial 2013; 26:11.
- Descombes E, Hanck AB, Fellay G. Water soluble vitamins in chronic hemodialysis patients and need for supplementation. Kidney Int 1993; 43:1319.
- Bridges KR, Hoffman KE. The effects of ascorbic acid on the intracellular metabolism of iron and ferritin. J Biol Chem 1986; 261:14273.
- Lipschitz DA, Bothwell TH, Seftel HC, et al. The role of ascorbic acid in the metabolism of storage iron. Br J Haematol 1971; 20:155.
- GOLDBERG A. The enzymic formation of haem by the incorporation of iron into protoporphyrin; importance of ascorbic acid, ergothioneine and glutathione. Br J Haematol 1959; 5:150.
- Deicher R, Ziai F, Habicht A, et al. Vitamin C plasma level and response to erythropoietin in patients on maintenance haemodialysis. Nephrol Dial Transplant 2004; 19:2319.
- Tarng DC, Wei YH, Huang TP, et al. Intravenous ascorbic acid as an adjuvant therapy for recombinant erythropoietin in hemodialysis patients with hyperferritinemia. Kidney Int 1999; 55:2477.
- Sirover WD, Siddiqui AA, Benz RL. Beneficial hematologic effects of daily oral ascorbic acid therapy in ESRD patients with anemia and abnormal iron homeostasis: a preliminary study. Ren Fail 2008; 30:884.
- Keven K, Kutlay S, Nergizoglu G, Ertürk S. Randomized, crossover study of the effect of vitamin C on EPO response in hemodialysis patients. Am J Kidney Dis 2003; 41:1233.
- Taji Y, Morimoto T, Okada K, et al. Effects of intravenous ascorbic acid on erythropoiesis and quality of life in unselected hemodialysis patients. J Nephrol 2004; 17:537.
- Deira J, Diego J, Martínez R, et al. Comparative study of intravenous ascorbic acid versus low-dose desferroxamine in patients on hemodialysis with hyperferritinemia. J Nephrol 2003; 16:703.
- Giancaspro V, Nuzziello M, Pallotta G, et al. Intravenous ascorbic acid in hemodialysis patients with functional iron deficiency: a clinical trial. J Nephrol 2000; 13:444.
- Attallah N, Osman-Malik Y, Frinak S, Besarab A. Effect of intravenous ascorbic acid in hemodialysis patients with EPO-hyporesponsive anemia and hyperferritinemia. Am J Kidney Dis 2006; 47:644.
- Kang DW, Ahn CY, Ryu BK, et al. The effect of intravenous ascorbic acid in hemodialysis patients with normoferritinemic anemia. Kidney Res Clin Pract 2012; 31:48.
- Deved V, Poyah P, James MT, et al. Ascorbic acid for anemia management in hemodialysis patients: a systematic review and meta-analysis. Am J Kidney Dis 2009; 54:1089.
- Einerson B, Chaiyakunapruk N, Kitiyakara C, et al. The efficacy of ascorbic acid in suboptimal responsive anemic hemodialysis patients receiving erythropoietin: a meta-analysis. J Med Assoc Thai 2011; 94 Suppl 1:S134.
- Badve SV, Beller EM, Cass A, et al. Interventions for erythropoietin-resistant anaemia in dialysis patients. Cochrane Database Syst Rev 2013; :CD006861.
- Sedighi O, Makhlough A, Janbabai G, Neemi M. Comparative study of intravenous iron versus intravenous ascorbic Acid for treatment of functional iron deficiency in patients under hemodialysis: a randomized clinical trial. Nephrourol Mon 2013; 5:913.
- Balcke P, Schmidt P, Zazgornik J, et al. Ascorbic acid aggravates secondary hyperoxalemia in patients on chronic hemodialysis. Ann Intern Med 1984; 101:344.
- Pru C, Eaton J, Kjellstrand C. Vitamin C intoxication and hyperoxalemia in chronic hemodialysis patients. Nephron 1985; 39:112.
- Eiselt J, Racek J, Trefil L, Opatrný K Jr. Effects of a vitamin E-modified dialysis membrane and vitamin C infusion on oxidative stress in hemodialysis patients. Artif Organs 2001; 25:430.
- Canavese C, Petrarulo M, Massarenti P, et al. Long-term, low-dose, intravenous vitamin C leads to plasma calcium oxalate supersaturation in hemodialysis patients. Am J Kidney Dis 2005; 45:540.
- Chen WT, Lin YF, Yu FC, et al. Effect of ascorbic acid administration in hemodialysis patients on in vitro oxidative stress parameters: influence of serum ferritin levels. Am J Kidney Dis 2003; 42:158.
- Teruel JL, Marcen R, Navarro-Antolin J, et al. Androgen versus erythropoietin for the treatment of anemia in hemodialyzed patients: a prospective study. J Am Soc Nephrol 1996; 7:140.
- Gascón A, Belvis JJ, Berisa F, et al. Nandrolone decanoate is a good alternative for the treatment of anemia in elderly male patients on hemodialysis. Geriatr Nephrol Urol 1999; 9:67.
- Navarro JF, Mora-Fernández C, Rivero A, et al. Androgens for the treatment of anemia in peritoneal dialysis patients. Adv Perit Dial 1998; 14:232.
- Navarro JF, Mora C, Macía M, García J. Randomized prospective comparison between erythropoietin and androgens in CAPD patients. Kidney Int 2002; 61:1537.
- Ballal SH, Domoto DT, Polack DC, et al. Androgens potentiate the effects of erythropoietin in the treatment of anemia of end-stage renal disease. Am J Kidney Dis 1991; 17:29.
- Berns JS, Rudnick MR, Cohen RM. A controlled trial of recombinant human erythropoietin and nandrolone decanoate in the treatment of anemia in patients on chronic hemodialysis. Clin Nephrol 1992; 37:264.
- Gaughan WJ, Liss KA, Dunn SR, et al. A 6-month study of low-dose recombinant human erythropoietin alone and in combination with androgens for the treatment of anemia in chronic hemodialysis patients. Am J Kidney Dis 1997; 30:495.
- Sheashaa H, Abdel-Razek W, El-Husseini A, et al. Use of nandrolone decanoate as an adjuvant for erythropoietin dose reduction in treating anemia in patients on hemodialysis. Nephron Clin Pract 2005; 99:c102.
- Carrero JJ, Bárány P, Yilmaz MI, et al. Testosterone deficiency is a cause of anaemia and reduced responsiveness to erythropoiesis-stimulating agents in men with chronic kidney disease. Nephrol Dial Transplant 2012; 27:709.
- Benbernou N, Esnault S, Potron G, Guenounou M. Regulatory effects of pentoxifylline on T-helper cell-derived cytokine production in human blood cells. J Cardiovasc Pharmacol 1995; 25 Suppl 2:S75.
- Bienvenu J, Doche C, Gutowski MC, et al. Production of proinflammatory cytokines and cytokines involved in the TH1/TH2 balance is modulated by pentoxifylline. J Cardiovasc Pharmacol 1995; 25 Suppl 2:S80.
- Navarro JF, Mora C, García J, et al. Effects of pentoxifylline on the haematologic status in anaemic patients with advanced renal failure. Scand J Urol Nephrol 1999; 33:121.
- Cooper A, Mikhail A, Lethbridge MW, et al. Pentoxifylline improves hemoglobin levels in patients with erythropoietin-resistant anemia in renal failure. J Am Soc Nephrol 2004; 15:1877.
- Johnson DW, Pascoe EM, Badve SV, et al. A randomized, placebo-controlled trial of pentoxifylline on erythropoiesis-stimulating agent hyporesponsiveness in anemic patients with CKD: the Handling Erythropoietin Resistance With Oxpentifylline (HERO) trial. Am J Kidney Dis 2015; 65:49.
- Mora-Gutiérrez JM, Ferrer-Nadal A, García-Fernández N. Effect of pentoxifylline on anaemia control in haemodialysis patients: retrospective observational case-control study. Nefrologia 2013; 33:524.
- Mortazavi M, Seyrafian S, Taheri S, et al. Role of pentoxifylline in treatment of anemic patients suffering chronic hemodialysis: a randomized clinical trial. Med Arh 2012; 66:84.
- Koc M, Dogan C, Arinsoy T, et al. Statin use is associated with lower inflammation and erythropoietin responsiveness index in hemodialysis patients. Hemodial Int 2011; 15:366.
- Sirken G, Kung SC, Raja R. Decreased erythropoietin requirements in maintenance hemodialysis patients with statin therapy. ASAIO J 2003; 49:422.
- Tsouchnikas I, Dounousi E, Papakonstantinou S, et al. Beneficial effect of atorvastatin on erythropoietin responsiveness in maintenance haemodialysis patients. Nephrology (Carlton) 2009; 14:560.
- Chiang CK, Yang SY, Peng YS, et al. Atorvastatin increases erythropoietin-stimulating agent hyporesponsiveness in maintenance hemodialysis patients: role of anti-inflammation effects. Am J Nephrol 2009; 29:392.
- Hutchinson FN, Jones WJ. A cost-effectiveness analysis of anemia screening before erythropoietin in patients with end-stage renal disease. Am J Kidney Dis 1997; 29:651.
- Pronai W, Riegler-Keil M, Silberbauer K, Stockenhuber F. Folic acid supplementation improves erythropoietin response. Nephron 1995; 71:395.
- Ono K, Hisasue Y. Is folate supplementation necessary in hemodialysis patients on erythropoietin therapy. Clin Nephrol 1992; 38:290.
- Bostom AG, Shemin D, Lapane KL, et al. High dose-B-vitamin treatment of hyperhomocysteinemia in dialysis patients. Kidney Int 1996; 49:147.
- Cristol JP, Bosc JY, Badiou S, et al. Erythropoietin and oxidative stress in haemodialysis: beneficial effects of vitamin E supplementation. Nephrol Dial Transplant 1997; 12:2312.
- Németh I, Túri S, Haszon I, Bereczki C. Vitamin E alleviates the oxidative stress of erythropoietin in uremic children on hemodialysis. Pediatr Nephrol 2000; 14:13.
- El-Nakib GA, Mostafa TM, Abbas TM, et al. Role of alpha-lipoic acid in the management of anemia in patients with chronic renal failure undergoing hemodialysis. Int J Nephrol Renovasc Dis 2013; 6:161.
- Kumar VA, Kujubu DA, Sim JJ, et al. Vitamin D supplementation and recombinant human erythropoietin utilization in vitamin D-deficient hemodialysis patients. J Nephrol 2011; 24:98.
- Miskulin DC, Majchrzak K, Tighiouart H, et al. Ergocalciferol Supplementation in Hemodialysis Patients With Vitamin D Deficiency: A Randomized Clinical Trial. J Am Soc Nephrol 2016; 27:1801.