Mayo Clinic Proceedings Home

Biomedical System Dynamics to Improve Anemia Control With Darbepoetin Alfa in Long-Term Hemodialysis Patients



      To determine the value of a biomedical system dynamics (BMSD) approach for optimization of anemia management in long-term hemodialysis patients because elevated hemoglobin levels and high doses of erythropoiesis-stimulating agents (ESAs) may negatively affect survival in this population.

      Patients and Methods

      A model of erythropoiesis and its response to ESAs on the basis of a BMSD method (Mayo Clinic Anemia Management System [MCAMS]) was developed. Thereafter, an open-label, prospective, nonrandomized practice quality improvement project was performed with retrospective analysis in 8 community-based outpatient hemodialysis facilities. All prevalent hemodialysis patients seen from January 1, 2007, through December 31, 2010 (300-342 patients per month), were included with darbepoetin as the ESA. The primary outcome was the percentage of patients who attained the desired hemoglobin level. Secondary outcome measures included the percentage of patients with hemoglobin values above the desired range and mean dose of darbepoetin used.


      The 3 treatment periods were (1) standard ESA protocol in 2007, (2) transition to the MCAMS (2008 to June 2009), and (3) stability period with the MCAMS used in all hemodialysis facilities (2009 to 2010). In the first 6 months of 2007, 69% of patients were in the desired range and 26% were above the range. In comparison, during the first 5 months of 2010, 83% were in and 6% were above the range (P<.001). The mean monthly darbepoetin dose per patient decreased from 304 μg in 2007 to 173 μg by the second half of 2009 (P<.001).


      With the introduction of the MCAMS, more patients had hemoglobin levels in the desired range and fewer patients exceeded the target range, with a concomitant 40% reduction in darbepoetin use.

      Abbreviations and Acronyms:

      BMSD (biomedical system dynamics), ESA (erythropoiesis-stimulating agent), MCAMS (Mayo Clinic Anemia Management System), MCDS (Mayo Clinic Dialysis System)
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Mayo Clinic Proceedings
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Eschbach J.W.
        • Abdulhadi M.H.
        • Browne J.K.
        • et al.
        Recombinant human erythropoietin in anemic patients with end-stage renal disease: results of a phase III multicenter clinical trial.
        Ann Intern Med. 1989; 111: 992-1000
        • Evans R.W.
        • Rader B.
        • Manninen D.L.
        • Cooperative Multicenter EPO Clinical Trial Group
        The quality of life of hemodialysis recipients treated with recombinant human erythropoietin.
        JAMA. 1990; 263: 825-830
        • Beusterien K.M.
        • Nissenson A.R.
        • Port F.K.
        • Kelly M.
        • Steinwald B.
        • Ware Jr., J.E.
        The effects of recombinant human erythropoietin on functional health and well-being in chronic dialysis patients.
        J Am Soc Nephrol. 1996; 7: 763-773
        • Cannella G.
        • La Canna G.
        • Sandrini M.
        • et al.
        Reversal of left ventricular hypertrophy following recombinant human erythropoietin treatment of anaemic dialysed uraemic patients.
        Nephrol Dial Transplant. 1991; 6: 31-37
        • Besarab A.
        • Bolton W.K.
        • Browne J.K.
        • 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. 1998; 339: 584-590
        • Besarab A.
        • Goodkin D.A.
        • Nissenson A.R.
        The normal hematocrit study: follow-up.
        N Engl J Med. 2008; 358: 433-434
        • Drueke T.B.
        • 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
        • Singh A.K.
        • Szczech L.
        • Tang K.L.
        • et al.
        Correction of anemia with epoetin alfa in chronic kidney disease.
        N Engl J Med. 2006; 355: 2085-2098
        • Levin A.
        • Djurdjev O.
        • Thompson C.
        • et al.
        Canadian randomized trial of hemoglobin maintenance to prevent or delay left ventricular mass growth in patients with CKD.
        Am J Kidney Dis. 2005; 46: 799-811
        • Rossert J.
        • Levin A.
        • Roger S.D.
        • et al.
        Effect of early correction of anemia on the progression of CKD.
        Am J Kidney Dis. 2006; 47: 738-750
        • Furuland H.
        • Linde T.
        • Ahlmen J.
        • Christensson A.
        • Strombom U.
        • Danielson B.G.
        A randomized controlled trial of haemoglobin normalization with epoetin alfa in pre-dialysis and dialysis patients.
        Nephrol Dial Transplant. 2003; 18: 353-361
        • KDOQI
        KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update on hemoglobin target.
        Am J Kidney Dis. 2007; 50: 471-530
        • Locatelli F.
        • Nissenson A.R.
        • Barrett B.J.
        • et al.
        Clinical practice guidelines for anemia in chronic kidney disease: problems and solutions: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO).
        Kidney Int. 2008; 74: 1237-1240
        • Singh A.K.
        • Fishbane S.
        The optimal hemoglobin in dialysis patients: a critical review.
        Semin Dial. 2008; 21: 1-6
      1. Food and Drug Administration. Erythropoiesis-Stimulating Agents (ESAs) in Chronic Kidney Disease: Drug Safety Communication - Modified Dosing Recommendations. Accessed August 10, 2013.

        • Fishbane S.
        • Berns J.S.
        Hemoglobin cycling in hemodialysis patients treated with recombinant human erythropoietin.
        Kidney Int. 2005; 68: 1337-1343
        • Ebben J.P.
        • Gilbertson D.T.
        • Foley R.N.
        • Collins A.J.
        Hemoglobin level variability: associations with comorbidity, intercurrent events, and hospitalizations.
        Clin J Am Soc Nephrol. 2006; 1: 1205-1210
        • Yang W.
        • Israni R.K.
        • Brunelli S.M.
        • Joffe M.M.
        • Fishbane S.
        • Feldman H.I.
        Hemoglobin variability and mortality in ESRD.
        J Am Soc Nephrol. 2007; 18: 3164-3170
        • Gilbertson D.T.
        • Ebben J.P.
        • Foley R.N.
        • Weinhandl E.D.
        • Bradbury B.D.
        • Collins A.J.
        Hemoglobin level variability: associations with mortality.
        Clin J Am Soc Nephrol. 2008; 3: 133-138
        • Brunelli S.M.
        • Lynch K.E.
        • Ankers E.D.
        • et al.
        Association of hemoglobin variability and mortality among contemporary incident hemodialysis patients.
        Clin J Am Soc Nephrol. 2008; 3: 1733-1740
        • Gallaher E.J.
        Biological System Dynamics: from personal discovery to universal application.
        Simulation. 1996; 66: 243-257
        • Gallaher E.J.
        • Macovsky L.M.
        • Wakeland W.W.
        The need for system dynamics in biological education: examples from pharmacodynamics.
        in: Hargrove J.L. Berdanier C.D. Mathematical Modeling in Nutrition and Toxicology. Mathematical Biology Press, Athens, GA2005
        • Wakeland W.W.
        • Gallaher E.J.
        • Macovsky L.M.
        • Aktipis C.A.
        Comparison of system dynamics and agent-based simulation applied to the study of cellular receptor dynamics.
        in: Proceedings of the 37th Annual Hawaii International Conference on Systems Dynamics (HICSS'04) - Track 3. 3. Institute of Electrical and Electronics Engineers, New York, NY2004 (30086.30082)
        • Rogers J.
        • Gallaher E.J.
        • Hocum C.
        • et al.
        Individualized medicine and biophysical system dynamics: an example from clinical practice in end stage renal disease.
        in: 29th International Conference of the System Dynamics Society. System Dynamics Society, Washington, DC2011
      2. IV. NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: update 2000.
        Am J Kidney Dis. 2001; 37: S182-S238
        • Foley R.N.
        • Parfrey P.S.
        • Morgan J.
        • et al.
        Effect of hemoglobin levels in hemodialysis patients with asymptomatic cardiomyopathy.
        Kidney Int. 2000; 58: 1325-1335
        • Parfrey P.S.
        • Foley R.N.
        • Wittreich B.H.
        • Sullivan D.J.
        • Zagari M.J.
        • Frei D.
        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
      3. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease.
        Am J Kidney Dis. 2006; 47: S11-S145
        • Brier M.E.
        • Gaweda A.E.
        • Dailey A.
        • Aronoff G.R.
        • Jacobs A.A.
        Randomized trial of model predictive control for improved anemia management.
        Clin J Am Soc Nephrol. 2010; 5: 814-820
        • Doshi S.
        • Chow A.
        • Perez Ruixo J.J.
        Exposure-response modeling of darbepoetin alfa in anemic patients with chronic kidney disease not receiving dialysis.
        J Clin Pharmacol. 2010; 50: 75S-90S
        • Gabutti L.
        • Nobile F.
        • Forni V.
        • Rigamonti F.
        • Weibel N.
        • Burnier M.
        Development of an erythropoietin prescription simulator to improve abilities for the prescription of erythropoietin stimulating agents: is it feasible?.
        BMC Nephrol. 2011; 12: 11
        • Ait-Oudhia S.
        • Vermeulen A.
        • Krzyzanski W.
        Non-linear mixed effect modeling of the time-variant disposition of erythropoietin in anemic cancer patients.
        Biopharm Drug Dispos. 2011; 32: 1-15
        • Gaweda A.E.
        • Jacobs A.A.
        • Aronoff G.R.
        • Brier M.E.
        Model predictive control of erythropoietin administration in the anemia of ESRD.
        Am J Kidney Dis. 2008; 51: 71-79
        • Robinson B.M.
        • Fuller D.S.
        • Bieber B.A.
        • Turenne M.N.
        • Pisoni R.L.
        The DOPPS Practice Monitor for US dialysis care: trends through April 2011.
        Am J Kidney Dis. 2012; 59: 309-312
      4. Ann Arbor Research Collaborative for Health. Dialysis Outcomes and Practice Patterns Study (DOPPS) Practice Monitor. 2013. Accessed August 10, 2013.

        • Brunelli S.M.
        • Monda K.L.
        • Burkart J.M.
        • et al.
        Early trends from the Study to Evaluate the Prospective Payment System Impact on Small Dialysis Organizations (STEPPS).
        Am J Kidney Dis. 2013; 61: 947-956