Presentation is loading. Please wait.

Presentation is loading. Please wait.

Anaemia treatment in CKD, ESRD, and kidney transplant recipients Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal.

Similar presentations


Presentation on theme: "Anaemia treatment in CKD, ESRD, and kidney transplant recipients Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal."— Presentation transcript:

1 Anaemia treatment in CKD, ESRD, and kidney transplant recipients Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal Unit, King’s College Hospital, London, UK

2 Outline of presentation Erythropoiesis in 2009 ESA therapy Target Hb Iron management Anaemia management in kidney transplantation The future

3 Hb (g/dL) Declining GFR (mL/min) Development of renal anaemia prior to the availability of EPO therapy Dialysis CKD stages 1–2 Stage 3 Stage 4 Stage 5 120–6059–30 29–15< 15 NHANES data

4 Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4 th ed. 2005; SCF, GM-CSF, IL-3 SCF, IL-1, IL-3, IL-6, IL-11 Pluripotent Stem Cell Burst-Forming Unit-Erythroid Cells (BFU-E) Colony-Forming Unit-Erythroid Cells (CFU-E) ReticulocytesRBCsErythro- blasts Proerythro- blasts About 8 Days Iron Erythropoietin Erythropoiesis in CKD Erythropoiesis in CKD in 2009

5 Pro-inflammatory cytokines (IL-1, TNFα, IL-6, IFNγ)  EPO production EPO + + Iron  Fas Ag Apoptosis ─ hepcidin  Fe absorption  Fe transport  Fe availability (EPO-R, Tf, TfR, Ferriportin, DMT-1) ─ Erythropoiesis in CKD in 2009

6 Papayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4 th ed. 2005; SCF, GM-CSF, IL-3 SCF, IL-1, IL-3, IL-6, IL-11 Pluripotent Stem Cell Burst-Forming Unit-Erythroid Cells (BFU-E) Colony-Forming Unit-Erythroid Cells (CFU-E) ReticulocytesRBCsErythro- blasts Proerythro- blasts About 8 Days Iron Erythropoietin Anti-Anaemic therapies in CKD

7 Outline of presentation Erythropoiesis in 2009 ESA therapy Target Hb Iron management Anaemia management in kidney transplantation The future

8 Development of recombinant human EPO human EPO isolated from 2,500 litres of urine (Miyake et al) gene for human EPO isolated and cloned (FK Lin et al) first clinical report in dialysis patients r-HuEPO licensed for use in Europe

9 Epoetin alfa (Eprex) Epoetin beta (NeoRecormon)

10 Hb (g/dL) Declining GFR (mL/min) Development of renal anaemia prior to the availability of EPO therapy Dialysis CKD stages 1–2 Stage 3 Stage 4 Stage 5 120–6059–30 29–15< 15 Winearls CG, et al. (Lancet 1986; 2: ) Eschbach JW, et al. (N Engl J Med 1987; 316:73-8) Macdougall IC, et al. (Lancet 1990; 335: )

11 Macdougall et al., Lancet 1990; 335:

12 Time (months) Hb (g/dl) EPO Macdougall et al., Lancet 1990; 335: Mean baseline Hb = 6.3g/dl Hb increment > 5g/dl

13 Strategies for treating renal anaemia Time or creatinine Prevention Dialysis Earlier start Higher target Hb (g/dl)

14 Anaemia therapy in CKD Initially, Epoetin alfa (Eprex, Erypo) – 1990 Epoetin beta (NeoRecormon) – 1990 Epoetin alfa Epoetin beta

15 Anaemia therapy in CKD Initially, Epoetin alfa (Eprex, Erypo) – 1990 Epoetin beta (NeoRecormon) – nd generation ESA:- Darbepoetin alfa (Aranesp) – 2001 Epoetin alfa Epoetin beta

16 First extra N-linked chain Second extra N-linked chain Darbepoetin alfa: a molecule with two more N-linked glycosylation chains than r-HuEPO

17 Third-generation ESAs C.E.R.A. (MIRCERA) Methoxy polyethylene glycol epoetin beta – licensed 2007

18 C.E.R.A. Continuous Erythropoietin Receptor Activator PEGylated Epoetin beta CERA EPO

19 Epoetin delta (DYNEPO TM )

20 Biosimilar EPOs First biosimilar epoetins licensed in Europe – Binocrit TM (Sandoz) – Retacrit TM (Hospira)

21 Epoetin alfa (Eprex) Epoetin beta (NeoRecormon) Darbepoetin alfa (Aranesp) C.E.R.A. (MIRCERA) Epoetin delta (Dynepo) Biosimilar Epoetin alfa (Binocrit) Biosimilar Epoetin zeta (Retacrit) Current licensed ESAs in Europe

22 IV half-lives of ESA therapy

23 days Epoetin (TIW) Plasma ESA (ng/ml) *estimated values based on 6000 IU epoetin / week Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs*

24 days Epoetin (TIW) Darbepoetin (QW) Plasma ESA (ng/ml) *estimated values based on 6000 IU epoetin / week Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs*

25 days Epoetin (TIW) Darbepoetin (QW) C.E.R.A. (QM) Plasma ESA (ng/ml) *estimated values based on 6000 IU epoetin / week Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs*

26 ESAs Short-acting Medium-acting Long-acting Dosing frequency x2 or x3 / week x1/wk or x1/2wks x1/2wks or x1/mth

27 Outline of presentation Erythropoiesis in 2009 ESA therapy Target Hb Iron management Anaemia management in kidney transplantation The future

28 Ofsthun et al, Kidney Int 2003; 63: Hb predicts survival in observational studies HD patients

29 Hb predicts survival in observational studies ND-CKD patients Levin A. et al, Nephrol Dial Transplant 2006; 21:

30 US Normal Haematocrit Trial Besarab A et al. N Engl J Med 339: , 1998.

31 Low-haematocrit group Normal-haematocrit group Probability of death or MI (%) Months after randomization US Normal Haematocrit Trial - probability of death or first non-fatal MI Besarab et al. NEJM 1998; 339:

32 CREATE CHOIR

33

34 Primary endpoint Time to first CV event (105 events) Events: 58 vs 47 HR=0.78 (0.53–1.14) Log rank test p=0.20

35

36 CHOIR Trial 125 vs 97 events; p < 0.03

37

38 Hb target ranges – the evidence Hb (g/dl) Sources:- – Lancet meta-analysis – K/DOQI Anemia Guidelines update (evidence review by Boston Tufts University Evidence Rating Group)

39 Outline of presentation Erythropoiesis in 2009 ESA therapy Target Hb Iron management Anaemia management in kidney transplantation The future

40 Why are CKD patients prone to develop iron deficiency? Occult G-I losses Peptic ulceration Blood sampling Dialyser losses Concurrent meds. – e.g. aspirin Heparin on dialysis INCREASED LOSSESREDUCED INTAKE Poor appetite Poor G-I absorption Concurrent medication – e.g. omeprazole Food interactions

41 Iron metabolism PLASMA Iron stores Ferritin Serum iron/TIBC TSAT CHr % hypochromic RBC Marrow stainable iron Serum TfR RBC ZPP

42 Minimum ranges: Serum ferritin > 100  g/l Hypochromic RBC < 10% TSAT > 20% Aim for : Serum ferritin  g/l Hypochromic RBC < 2.5% TSAT 30-40% Monitoring iron status

43 IV Iron Agents are Spheroid Particles with an Iron Core and a Carbohydrate Shell ironoxyhydroxidecore carbohydrateshell

44 DOPPS III: Type of IV Iron Prescribed in HD patients Patients (%) DOPPS III data ( ), among prevalent cross-section of HD patients using IV iron. n =(393)(396)(333)(339)(419)(304)(566)(469)(449)(334)(1327) - Sucrose Fe-Oxide Saccharate Polymaltose Dextran Chondroitin SO 4 Gluconate Cideferron Other

45 Benefits of IV iron in CKD patients  IV iron can improve the anaemia of CKD even in the absence of ESA therapy  IV iron can significantly enhance the response to ESA therapy, even in iron-replete patients

46 Short-term Anaphylactic reactions (iron dextran only; dextran Abs) “Free iron” reactions (all IV iron preparations) Potential dangers of IV iron ? Long-term Increased susceptibility to infection Increased oxidative stress Iron overload

47 Balance of benefits vs. risks of IV iron  Mortality risk Oxidative stress Infection risk Anaphylaxis Benefits of IV iron

48 Outline of presentation Erythropoiesis in 2009 ESA therapy Target Hb Iron management Anaemia management in kidney transplantation The future

49 Y Vanrenterghem et al., For TRESAM, Am J Transplantation 2003 Hb < 12 g/dl : 28.4%Hb < 12 g/dl : 22.7% Hb < 12 g/dl : 25.5% Hb < 12 g/dl : 24.4% Overall 24.5 % were anaemic n = centres, 16 countries Prevalence of anaemia in European kidney transplant recipients

50 Hb < 11 g/dl Hb < 10 g/dl Y. Vanrenterghem et al., for TRESAM, Am J Transplantation Among 8.5% patients with severe anaemia, 18% were on EPO therapy Prevalence of severe anaemia in Europe Overall 8.5% with severe anaemia

51 Post-transplantation anaemia Causes–iron deficiency –infections (CMV) –immunosuppresssive therapy –ACE-I / ARB therapy –impaired renal function (  EPO) –failing graft (pro-inflammatory cytokines)

52 ESA hyporesponsiveness in renal transplantation Iron deficiency Infection/ inflammation Underdialysis Hyperparathyroidism Aluminium toxicity Carnitine deficiency PRCA Blood loss Haemolysis B 12 /folate deficiency Marrow disorders Haemoglobinopathies ACE inhibitors Viral (CMV, EBV, Parvovirus) Malignancy (e.g. lymphoma) Immunosuppression (Aza, MMF, SRL)

53 Outline of presentation Erythropoiesis in 2009 ESA therapy Target Hb Iron management Anaemia management in kidney transplantation The future

54 Clin J Am Soc Nephrol, 2008

55 Hematide EPO-mimetic peptide, now in Phase III clinical trials Amino acid sequences completely unrelated to native EPO Shows same functional / biological properties as EPO

56 What is different about Hematide? Peptide-based (epoetin, darbepoetin, CERA – all protein-based) Not genetically-engineered in cells (unlike epoetin, darbepoetin, CERA) Manufactured by synthetic peptide chemical techniques ? More stable at room temperature ? less immunogenic Does not cross-react with antibodies against EPO – should not cause PRCA; can be used to treat Ab+PRCA First ESA to be tested de novo once-monthly in CKD patients

57 Jak2 PP PP EPO, rHuEPO EPO-mimetic peptide Darbepoetin alfa membrane C.E.R.A. Peg-rHuEPO Signal Transduction Survival, differentiation, proliferation, and maturation of RBC progenitors and precursors Gene Activation Jak2 PP PP PP PP PP PP Anti-EPO antibodies do not neutralise Hematide Anti-EPO Antibodies

58 58 Hematide in the Treatment of Antibody-Mediated Pure Red Cell Aplasia I C Macdougall et al, ASN 2007 (updated in 2008) n = (Data from three subjects were censored due to kidney transplantation) BL Study Months Percent Patients Receiving RBC Transfusions During Each Study Month Mean (SD) Hb Concentration (g/dL)

59 HIF stabilisers HIF is the hypoxic sensor that upregulates EPO gene expression HIF is broken down by a prolyl hydroxylase enzyme An inhibitor of HIF hydroxylase has been synthesised (FibroGen) It causes an increase in EPO levels, even in CKD patients Upside This enzyme inhibitor is orally-active Downside >100 other genes (e.g. VEGF) also turned on Rare development of severe liver toxicity (may be fatal)

60 New IV irons pending……. 2 new IV irons forthcoming:- – Ferumoxytol (US) – Ferric carboxymaltose – Ferinject TM (Europe) Advantages – ? safer – no need for test dose – more rapid high-dose bolus injection – main benefits in the pre-ESRD population

61 Ferric carboxymaltose (Ferinject) Licensed in Europe Stable iron complex Low immunogenic potential – dextran-free Minimal detectable and releasable free iron Ferric hydroxide molecules Ribbon-like carboxymaltose No test dose required Rapid administration – 200mg push – 500mg in 6 mins – 1000mg infusion in 15 mins

62 Ganz, 2006.

63

64 Iron transport

65 Savino R, Ciliberto G. Cell Death Differ. 2004;11 Suppl 1:S2-4. EPO: an all-purpose tissue-protective agent?

66 EPO therapy: beyond Hb Mediated via the anti-apoptotic action of EPO on non- erythroid cells Relevant for acute cardiac, renal, and cerebral ischaemia ? Therapeutic benefit in :- – Acute MI – Acute stroke – Reperfusion injury – Post-transplantation

67 Conclusions Our understanding of erythropoiesis in 2009 has advanced to include the role of hepcidin and pro-inflammatory cytokines Until further evidence is forthcoming, we should generally target an Hb of 11–12 g/dl Even in 2009, there is still a need for additional grade A level evidence in the management of anaemia in CKD Several new ESAs and IV iron preparations are appearing, and the non-erythropoietic effects of ESAs are being explored


Download ppt "Anaemia treatment in CKD, ESRD, and kidney transplant recipients Iain C Macdougall BSc, MD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Renal."

Similar presentations


Ads by Google