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Can we restore the response to erythropoietin resistance ? Iain C Macdougall BSc, MD, FRCP

Can we restore the response to erythropoietin resistance ? Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal Unit, King’s College Hospital, London, UK. 90-95% of patients respond well to ESAs. 14. 12.

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Can we restore the response to erythropoietin resistance ? Iain C Macdougall BSc, MD, FRCP

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  1. Can we restore the response to erythropoietin resistance ? Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal Unit, King’s College Hospital, London, UK

  2. 90-95% of patients respond well to ESAs 14 12 Hb (g/dl) 10 8 6 0 2 4 6 8 10 12 Time on therapy (months)

  3. Type 1 poor response to ESAs 14 12 Hb (g/dl) 10 8 6 0 2 4 6 8 10 12 Time on therapy (months)

  4. Type 2 poor response to ESAs 14 12 Hb (g/dl) 10 8 6 0 2 4 6 8 10 12 Time on therapy (months)

  5. Poor response to ESAs - causes MajorMinor Iron deficiency Blood loss Infection / inflammation Hyperparathyroidism Underdialysis Aluminium toxicity B12 / folate deficiency Haemolysis Marrow disorders, e.g. MDS Haemoglobinopathies ACE inhibitors Carnitine deficiency Anti-EPO antibodies

  6. Factors influencing response to ESAs A A T T B B l l o o o o d d l l o o s s s s e s D D i i a a l l y y s s i i s s a a d d e e q q u u a a c c y y I I n n f f e e c c t t i i o o n n , , I I n n f f l l a a m m m m a a t t i i o o n n I I r r o o n n s s u u p p p p l l e e m m e e n n t t a a t t i i o o n n AT = Adjuvant therapy

  7. Haemoglobin Epoetin dose 175 14 150 12 125 10 Mean (IU/kg/week) Mean (g/dl) 8 100 6 75 4 50 2 25 0 0 1 2 3 4 5 6 1 2 3 45 6 CRP50 mg/l on 3 or more months (n=201) CRP<50 mg/l on 4 or more months (n=3,014) Epoetin dose and Hb levels in patients with chronic infection/inflammation (ESAM) Month Month Hörl W et al., NDT 2000;15(Suppl 4): 45–45.

  8. Inflammatory response and EPO doseSitter et al NDT 15:1207,2000.

  9. Influence of CRP concentration on EPO dose 30–50% of CKD patients have serological evidence ofan activated inflammatory response (CRP > 8–10 mg/l). 180 160 140 120 100 80 60 40 20 0 138.7 34% difference in EPO dose EPO dose [IU/kg/week] 92 P<0.01 Group I: CRP > 10 mg/l Group II: CRP < 10 mg/l Stenvinkel P, NDT 2002;17 Suppl 5:32–37. Nitta K, Acta Haematol 2002;108;168–170.

  10. What do you do about the patient who is responding poorly to ESAs in the absence of any obvious cause ?

  11. The explanation ? Uraemia Chronic inflammation (c.f. anaemia of chronic disease, e.g. RA, malignancy) IL-1 IL-6 TNF- IFN- Suppression of erythropoiesis

  12. Factors affecting erythropoiesis Erythroid progenitor cell +ve EPO -ve Pro-inflammatory cytokines BFU-E Bone Marrow CFU-E Erythroblast Red blood cells

  13. Where do cytokines come from ? IFN- Th1 Th0 CD4 IL-4 IL-10 Th2 T-cell IL-2 CD8 IL-2 TNF- CD8+ T-cell IL-6 IL-12 TNF- Monocyte

  14. Aim • To examine whether HD patients responding poorly to EPO have altered T cell and monocyte activation states compared with: • Patients responding well to EPO • Normal controls

  15. 3 groups of subjects: 1 -HD patients not responding to EPO(Hb < 10g/dl, EPO dose > 250 IU/kg/wk) 2 - HD patients responding well to EPO(Hb > 11g/dl, EPO dose < 200 IU/kg/wk) 3 - Normal healthy controls

  16. Demographic and haematological characteristics of subjects (mean±SD)

  17. Hb levels and EPO dose requirements 18 Controls Good responders 16 Poor responders Hb (g/dl) 14 12 10 8 6 4 0 100 200 300 400 500 600 EPO dose (IU/kg/wk)

  18. Plasma cytokines

  19. Intracellular cytokines

  20. Intracellular cytokine methodology Whole blood Peripheral blood mononuclear cells Culture for 48h @ 37°C, 5% CO2 PMA/ionomycin Brefeldin A Surface stain cells with fluorescent mabs to CD3 & CD8 Permeabilize cells and stain for intracellular cytokines 3 colour flow cytometric analysis

  21. CD4+ T-cell expression of IFNstimulated by PMA/ionomycin P <0.005 30 30 ns P <0.005 20 20 CD4+ T cells expressing IFNg (%) 10 10 0 0 Normal controls Good responders Poor responders Normal controls Good responders Poor responders

  22. CD8+ T-cell expression of IFNstimulated by PMA/ionomycin P <0.005 100 100 ns ns 75 75 CD8+ T cells expressing IFNg (%) 50 50 25 25 0 0 Normal controls Good responders Poor responders Normal controls Good responders Poor responders

  23. CD4+ T-cell expression of TNF stimulated by PMA/ionomycin P <0.05 80 80 ns P <0.01 60 60 CD4+ T cells expressing TNFa (%) 40 40 20 20 0 0 Normal controls Good responders Poor responders Normal controls Good responders Poor responders

  24. CD8+ T-cell expression of TNF stimulated by PMA/ionomycin P <0.001 80 80 ns ns 60 60 CD8+ T cells expressing TNFa (%) 40 40 20 20 0 0 Normal controls Good responders Poor responders Normal controls Good responders Poor responders

  25. CD4+ T cell expression of IL-10 stimulated by PMA/ionomycin P <0.05 3 3.0 ns ns 2.5 2 2.0 CD4+ T cells expressing IL-10 (%) 1.5 1 1.0 0.5 0 0.0 Normal controls Good responders Poor responders Normal controls Good responders Poor responders

  26. CD8+ T cell expression of IL-10 stimulated by PMA/ionomycin P <0.001 4 4 P <0.02 P <0.05 3 3 CD8+ T cells expressing IL-10 (%) 2 2 1 1 0 0 Good responders Poor responders Normal controls Good responders Poor responders Normal controls

  27. Summary of intracellular cytokine staining study a g T N F I FN I L - 1 0 C D 4 i n c re a s e d i n c re a s e d t r e nd f o r i n c re a s e C D 8 t r e nd f o r t r e nd f o r i n c re a s e d i n c re a s e i n c re a s e

  28. Kaplan Meyer survival curve for poor responders versus good responders over 24 months 100 Good responders * Poor responders Percent survival 5 0 0 0 5 1 0 1 5 2 0 2 5 Time (months) * P < 0.05 poor responders versus good responders Cooper et al, Nephrol Dial Transplant (2003)

  29. Conclusions • Poor response to EPO is associated with: • Increased capacity to generate IFN and TNF from CD4+ and CD8+ T cells • In the absence of any other cause, poor response to ESAs may result from enhanced T cell activation

  30. Uraemia (± other inflammatory conditions) Immune activation CD4+T cell CD8+T cell –ve TNFa –ve IL-10 +ve EPO –ve IL-13 anti-apoptotic –ve IFNg Cytokine-mediated inhibition of erythropoiesis • Proposed model of inhibition in poor responders to EPO therapy Erythroidprogenitorcellproliferation pro-apoptotic Cooper et al JASN 2003

  31. Blocking cytokine production • Increase dialysis prescription • Drugs • Pentoxifylline • Thalidomide • Anti-cytokine antibodies • Anti-lymphocyte therapy

  32. Pentoxifylline • Phosphodiesterase inhibitor • Useful in peripheral vascular disease: • Anti-platelet effect • Effect on erythrocyte deformability • Anti-TNF effect • Anti-IFN effect • Anti-IL-10 • Anti-oxidant effect • Anti-apoptotic effect

  33. Pentoxifylline trials • IBD • Improved disease activity index • Correction of inflammatory markers (Blam et al, 2001) • Dilated cardiomyopathy • Improved exercise tolerance • Improved ejection fraction (Skudicky et al, 2001) • Septic shock • Improved GFR • Correction of coagulopathy (Jaimes et al, 2001) • Membranous nephropathy • Reduction of proteinuria (Duclox et al, 2001)

  34. Effect of Pentoxifylline treatment on TNF production in a patient with poor response to erythropoietin therapy 60% 9% CD3 TNF TNF After treatment (6 weeks) Before treatment

  35. Effect of Pentoxifylline treatment on IFN production in a patient with poor response to erythropoietin therapy 24% 6% CD3 IFN IFN After treatment (6 weeks) Before treatment

  36. Pentoxifylline study Protocol • At recruitment • blood sample taken for T cell cytokines • patients given 400 mg pentoxifylline od • Hb monitored monthly • 6-8 weeks blood sample taken for T cell cytokines

  37. Pentoxifylline study 16 patients were recruited 12 patients completed the study 2 patients were non-compliant 1 patient developed nausea 1 patient developed confusion unrelated to therapy

  38. p=0.0007 p=0.0002 IFNg(%) 50 40 30 20 10 0 Before treatment After treatment (6–8 weeks) Effect of pentoxifylline treatment on ex vivo cytokine production by CD3+ T cells TNF (%) 75 50 25 0 Before treatment After treatment (6–8 weeks)

  39. Effect of pentoxifylline treatment on Hb level (n=12) P = 0.0001 1 4 1 2 1 0 Hb (g/dl) 8 6 4 pentoxifylline 2 0 -6 -5 -4 -3 -2 -1 0 1 2 3 4 Pentoxifylline therapy (months)

  40. Conclusions • Pro-inflammatory cytokines in renal failure may be an important cause of a poor response to ESAs • Pentoxifylline may be a useful adjuvant therapy in patients who respond poorly to ESAs

  41. What can we do to restore the response to erythropoietin resistance ? • Ensure compliance if self-administering • Ensure adequate iron status ? trial of IV iron • Exclude / treat other deficiencies e.g. B12/folate/thyroxine • ? parathyroidectomy if severe hyperparathyroidism • Treat any infection/inflammatory cause aggressively ? transplant nephrectomy • Increase dialysis prescription • ? consider pentoxifylline if “inflammation” present and other causes excluded • Pro-inflammatory cytokines in renal failure may be an important cause of resistance to ESAs

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