Erythropoietin for the anemia of chronic kidney disease among predialysis and peritoneal 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
The anemia of chronic kidney disease (CKD) is, in most patients, normocytic and normochromic. It is principally due to reduced renal erythropoietin production and, to a lesser degree, to shortened red cell survival and decreased responsiveness to the hormone.
Anemia can develop well before the onset of uremic symptoms due to end-stage renal disease (ESRD). Although anemia due to renal dysfunction generally develops when the glomerular filtration rate (GFR) declines to <30 mL/min, it can also be observed in those with markedly higher GFRs (such as 60 mL/min) and tends to occur at higher levels of GFR in African Americans than whites.
If left untreated, the anemia of CKD is associated with several abnormalities. These include deterioration in cardiac function, decreased cognition and mental acuity, fatigue, and other signs and symptoms. There are also associations with an increased risk of morbidity and mortality, principally due to cardiac disease and stroke.
The primary therapeutic options for the anemia of CKD include red blood cell transfusions, erythropoiesis-stimulating agents (ESAs), and, to a much lesser degree, androgens.
The use of erythropoietin in the treatment of anemia of CKD in predialysis patients with CKD is discussed in this topic review. A discussion of its use in hemodialysis and peritoneal dialysis patient is presented separately. (See "Erythropoietin for the anemia of chronic kidney disease in hemodialysis patients" and "Erythropoietin: Subcutaneous administration", section on 'Peritoneal dialysis patients'.)
- Hsu CY. Epidemiology of anemia associated with chronic renal insufficiency. Curr Opin Nephrol Hypertens 2002; 11:337.
- Hsu CY, McCulloch CE, Curhan GC. Epidemiology of anemia associated with chronic renal insufficiency among adults in the United States: results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2002; 13:504.
- Astor BC, Muntner P, Levin A, et al. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med 2002; 162:1401.
- KDIGO clinical practice guidelines for anemia in chronic kidney disease. Kidney Int Suppl 2012; 2:288.
- Lim VS, DeGowin RL, Zavala D, et al. Recombinant human erythropoietin treatment in pre-dialysis patients. A double-blind placebo-controlled trial. Ann Intern Med 1989; 110:108.
- Roth D, Smith RD, Schulman G, et al. Effects of recombinant human erythropoietin on renal function in chronic renal failure predialysis patients. Am J Kidney Dis 1994; 24:777.
- Revicki DA, Brown RE, Feeny DH, et al. Health-related quality of life associated with recombinant human erythropoietin therapy for predialysis chronic renal disease patients. Am J Kidney Dis 1995; 25:548.
- Portolés J, Torralbo A, Martin P, et al. Cardiovascular effects of recombinant human erythropoietin in predialysis patients. Am J Kidney Dis 1997; 29:541.
- Fink J, Blahut S, Reddy M, Light P. Use of erythropoietin before the initiation of dialysis and its impact on mortality. Am J Kidney Dis 2001; 37:348.
- Li S, Collins AJ. Association of hematocrit value with cardiovascular morbidity and mortality in incident hemodialysis patients. Kidney Int 2004; 65:626.
- Jones M, Ibels L, Schenkel B, Zagari M. Impact of epoetin alfa on clinical end points in patients with chronic renal failure: a meta-analysis. Kidney Int 2004; 65:757.
- 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.
- Mohanram A, Zhang Z, Shahinfar S, et al. Anemia and end-stage renal disease in patients with type 2 diabetes and nephropathy. Kidney Int 2004; 66:1131.
- Chatterjee PK. Pleiotropic renal actions of erythropoietin. Lancet 2005; 365:1890.
- Chung SD, Huang KH, Liao CH, et al. Acute heart failure with elevated cardiac enzymes. Kidney Int 2007; 72:521.
- Jungers P, Choukroun G, Oualim Z, et al. Beneficial influence of recombinant human erythropoietin therapy on the rate of progression of chronic renal failure in predialysis patients. Nephrol Dial Transplant 2001; 16:307.
- Gouva C, Nikolopoulos P, Ioannidis JP, Siamopoulos KC. Treating anemia early in renal failure patients slows the decline of renal function: a randomized controlled trial. Kidney Int 2004; 66:753.
- Rossert J, Levin A, Roger SD, et al. Effect of early correction of anemia on the progression of CKD. Am J Kidney Dis 2006; 47:738.
- Drüeke 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.
- Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085.
- Minutolo R, Conte G, Cianciaruso B, et al. Hyporesponsiveness to erythropoiesis-stimulating agents and renal survival in non-dialysis CKD patients. Nephrol Dial Transplant 2012; 27:2880.
- Provenzano R, Garcia-Mayol L, Suchinda P, et al. Once-weekly epoetin alfa for treating the anemia of chronic kidney disease. Clin Nephrol 2004; 61:392.
- Piccoli A, Malagoli A, Komninos G, Pastori G. Subcutaneous epoetin-alpha every one, two, and three weeks in renal anemia. J Nephrol 2002; 15:565.
- Provenzano R, Bhaduri S, Singh AK, PROMPT Study Group. Extended epoetin alfa dosing as maintenance treatment for the anemia of chronic kidney disease: the PROMPT study. Clin Nephrol 2005; 64:113.
- Benz R, Schmidt R, Kelly K, Wolfson M. Epoetin alfa once every 2 weeks is effective for initiation of treatment of anemia of chronic kidney disease. Clin J Am Soc Nephrol 2007; 2:215.
- McGowan T, Vaccaro NM, Beaver JS, et al. Pharmacokinetic and pharmacodynamic profiles of extended dosing of epoetin alfa in anemic patients who have chronic kidney disease and are not on dialysis. Clin J Am Soc Nephrol 2008; 3:1006.
- Pergola PE, Gartenberg G, Fu M, et al. A randomized controlled study comparing once-weekly to every-2-week and every-4-week dosing of epoetin alfa in CKD patients with anemia. Clin J Am Soc Nephrol 2010; 5:598.
- Spinowitz B, Germain M, Benz R, et al. A randomized study of extended dosing regimens for initiation of epoetin alfa treatment for anemia of chronic kidney disease. Clin J Am Soc Nephrol 2008; 3:1015.
- Lacson E Jr, Diaz-Buxo JA. The treatment of anemia in peritoneal dialysis patients. Clin Nephrol 2001; 56:415.
- Muirhead N. Erythropoietic agents in peritoneal dialysis. Perit Dial Int 2005; 25:547.
- Flanigan MJ, Rocco MV, Prowant B, et al. Clinical performance measures: the changing status of peritoneal dialysis. Kidney Int 2001; 60:2377.
- Obrador GT, Roberts T, St Peter WL, et al. Trends in anemia at initiation of dialysis in the United States. Kidney Int 2001; 60:1875.
- Wright DG, Wright EC, Narva AS, et al. Association of Erythropoietin Dose and Route of Administration with Clinical Outcomes for Patients on Hemodialysis in the United States. Clin J Am Soc Nephrol 2015; 10:1822.
- Navarro JF, Mora C, Macía M, García J. Randomized prospective comparison between erythropoietin and androgens in CAPD patients. Kidney Int 2002; 61:1537.
- Locatelli F, Aljama P, Bárány P, et al. Revised European best practice guidelines for the management of anaemia in patients with chronic renal failure. Nephrol Dial Transplant 2004; 19 Suppl 2:ii1.
- Vadas O, Hartley O, Rose K. Characterization of new multimeric erythropoietin receptor agonists. Biopolymers 2008; 90:496.
- Wrighton NC, Farrell FX, Chang R, et al. Small peptides as potent mimetics of the protein hormone erythropoietin. Science 1996; 273:458.
- Macdougall IC. Hematide, a novel peptide-based erythropoiesis-stimulating agent for the treatment of anemia. Curr Opin Investig Drugs 2008; 9:1034.
- Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol 2006; 34:1303.
- Woodburn KW, Fan Q, Winslow S, et al. Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia model. Exp Hematol 2007; 35:1201.
- Johnson DL, Jolliffe LK. Erythropoietin mimetic peptides and the future. Nephrol Dial Transplant 2000; 15:1274.
- Sulowicz W, Locatelli F, Ryckelynck JP, et al. Once-monthly subcutaneous C.E.R.A. maintains stable hemoglobin control in patients with chronic kidney disease on dialysis and converted directly from epoetin one to three times weekly. Clin J Am Soc Nephrol 2007; 2:637.
- Levin NW, Fishbane S, Cañedo FV, et al. Intravenous methoxy polyethylene glycol-epoetin beta for haemoglobin control in patients with chronic kidney disease who are on dialysis: a randomised non-inferiority trial (MAXIMA). Lancet 2007; 370:1415.
- Klinger M, Arias M, Vargemezis V, et al. Efficacy of intravenous methoxy polyethylene glycol-epoetin beta administered every 2 weeks compared with epoetin administered 3 times weekly in patients treated by hemodialysis or peritoneal dialysis: a randomized trial. Am J Kidney Dis 2007; 50:989.
- Macdougall IC, Walker R, Provenzano R, et al. C.E.R.A. corrects anemia in patients with chronic kidney disease not on dialysis: results of a randomized clinical trial. Clin J Am Soc Nephrol 2008; 3:337.
- González MT, Ramos R, Vera M, et al. Monthly CERA treatment maintains stable hemoglobin levels in routine clinical practice of peritoneal dialysis patients. Ren Fail 2013; 35:314.
- OVERVIEW OF TREATMENT OPTIONS
- USE IN PREDIALYSIS PATIENTS WITH CHRONIC KIDNEY DISEASE
- Efficacy and benefits
- - Progression of renal failure
- Iron issues
- Whom to treat and target hemoglobin level
- Adverse effects
- USE IN PERITONEAL DIALYSIS PATIENTS
- Iron issues and exclusion of nonrenal anemia
- Erythropoietin efficacy and dosing
- FUTURE DIRECTIONS
- Continuous Erythropoiesis Receptor Activator
- SUMMARY AND RECOMMENDATIONS