Presentation on theme: "Anaemia treatment in CKD, ESRD, and kidney transplant recipients"— Presentation transcript:
1Anaemia treatment in CKD, ESRD, and kidney transplant recipients Iain C Macdougall BSc, MD, FRCPConsultant Nephrologist and Honorary Senior LecturerRenal Unit, King’s College Hospital, London, UK
2Outline of presentation Erythropoiesis in 2009ESA therapyTarget HbIron managementAnaemia management in kidney transplantationThe future
3Development of renal anaemia prior to the availability of EPO therapy 15Hb (g/dL)10Dialysis5CKD stages 1–2Stage345120–6059–3029–15< 15Declining GFR (mL/min)NHANES data
4Erythropoiesis in CKD Erythropoiesis in CKD in 2009 ErythropoietinIronSCF, GM-CSF,IL-3SCF, IL-1, IL-3,IL-6, IL-11About 8 DaysPluripotent Stem CellBurst-Forming Unit-Erythroid Cells (BFU-E)Colony-Forming Unit-Erythroid Cells (CFU-E)Proerythro- blastsErythro- blastsReticulocytesRBCsPapayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4th ed. 2005;
5Erythropoiesis in CKD in 2009 EPO+ Fas AgApoptosis─+Iron Fe absorption Fe transport Fe availability(EPO-R, Tf, TfR, Ferriportin, DMT-1)─ EPO productionPro-inflammatorycytokines(IL-1, TNFα, IL-6, IFNγ)hepcidin
6Anti-Anaemic therapies in CKD ErythropoietinIronSCF, GM-CSF,IL-3SCF, IL-1, IL-3,IL-6, IL-11About 8 DaysPluripotent Stem CellBurst-Forming Unit-Erythroid Cells (BFU-E)Colony-Forming Unit-Erythroid Cells (CFU-E)Proerythro- blastsErythro- blastsReticulocytesRBCsPapayannopoulou T, et al. In: Hoffman R, et al., ed. Hematology: Basic Principles and Practice. 4th ed. 2005;
7Outline of presentation Erythropoiesis in 2009ESA therapyTarget HbIron managementAnaemia management in kidney transplantationThe future
8Development 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 patientsr-HuEPO licensed for use in Europe
10Development of renal anaemia prior to the availability of EPO therapy 15EPOHb (g/dL)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: )10Dialysis5CKD stages 1–2Stage345120–6059–3029–15< 15Declining GFR (mL/min)
16Darbepoetin alfa: a molecule with two more N-linked glycosylation chains than r-HuEPO Second extraN-linkedchainFirst extraN-linkedchainFive amino acids on the rHuEPO polypeptide backbone were changed to introduce two new N-linked carbohydrate recognition sites, resulting in Aranesp®.Aranesp® is about 51% carbohydrate by weight, and its two extra carbohydrate side chains attach precisely in the region where the amino acid sequence has been altered. Although space-filling models of Aranesp® based on crystallographic data do not show us the carbohydrate side chains, the extra glycosylation sites of Aranesp® tend to be covered by two tetraantennary glycans. These are the largest of the three kinds of carbohydrate chain (bi-, tri- and tetraantennary), and contribute to the maximal biological activity of Aranesp®.
17Third-generation ESAs C.E.R.A. (MIRCERA)Methoxy polyethylene glycol epoetin beta– licensed 2007
20Biosimilar EPOsFirst biosimilar epoetins licensed in Europe – BinocritTM (Sandoz)– RetacritTM (Hospira)
21Current licensed ESAs in Europe 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)A comprehensive clinical candidate development program was undertaken to identify a new agent to improve anemia management.A variety of options were explored, including hyperglycosylated variants of epoetin, dimers of epoetin, peptides and other small molecules, synthetic proteins, gene therapy, and integration of polymers such as polyethylene glycol.The integration of specific polyethylene glycol moieties was selected for further exploration.
23Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs* Epoetin (TIW)Plasma ESA (ng/ml)1001010.10.01days*estimated values based on 6000 IU epoetin / week
24Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs* Epoetin (TIW)Darbepoetin (QW)Plasma ESA (ng/ml)1001010.10.01days*estimated values based on 6000 IU epoetin / week
25Simulation of EPO kinetics for short-acting ESAs vs longer-acting ESAs* Epoetin (TIW)Darbepoetin (QW)C.E.R.A. (QM)Plasma ESA (ng/ml)1001010.10.01days*estimated values based on 6000 IU epoetin / week
26ESAs Dosing frequency x2 or x3 / week x1/wk or x1/2wks Short-actingx2 or x3 / weekMedium-actingx1/wk or x1/2wksLong-actingx1/2wks or x1/mth
27Outline of presentation Erythropoiesis in 2009ESA therapyTarget HbIron managementAnaemia management in kidney transplantationThe future
28Hb predicts survival in observational studies HD patientsOfsthun et al, Kidney Int 2003; 63:
29Hb predicts survival in observational studies ND-CKD patientsLevin A. et al, Nephrol Dial Transplant 2006; 21:
30US Normal Haematocrit Trial Besarab A et al. N Engl J Med 339: , 1998.
31US Normal Haematocrit Trial - probability of death or first non-fatal MI 60Normal-haematocrit group5040Low-haematocrit groupProbability of death or MI (%)302010Months after randomizationBesarab et al. NEJM 1998; 339:
38Hb target ranges – the evidence Sources:-– Lancet meta-analysis– K/DOQI Anemia Guidelines update(evidence review by Boston Tufts University Evidence Rating Group)151413Hb (g/dl)Key messageCKD patients have a higher risk for poor outcomescompared to those with normal eGFR.Data was accumulated from four community-based longitudinal cohort studies carried out in the USA between 1987 and 1993: Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study (CHS), the Framingham Heart Study (FHS) and the Framingham Offspring Study (Offspring).Analyses from 22,634 patients were included with a mean follow-up time of months. CV events refers to myocardial infarction or fatal coronary heart disease.1211109Weiner et al., Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality:a pooled analysis of community-based studies J Am Soc Nephrol 2004; 15:
39Outline of presentation Erythropoiesis in 2009ESA therapyTarget HbIron managementAnaemia management in kidney transplantationThe future
40Why are CKD patients prone to develop iron deficiency? REDUCED INTAKEPoor appetitePoor G-I absorptionConcurrent medication – e.g. omeprazoleFood interactionsOccult G-I lossesPeptic ulcerationBlood samplingDialyser lossesConcurrent meds. – e.g. aspirinHeparin on dialysisINCREASED LOSSES
42Monitoring iron status Minimum ranges:Serum ferritin > 100 g/lHypochromic RBC < 10%TSAT > 20%Aim for :Serum ferritin g/lHypochromic RBC < 2.5%TSAT 30-40%
43IV Iron Agents are Spheroid Particles with an Iron Core and a Carbohydrate Shell oxyhydroxidecorecarbohydrateshell
44DOPPS III: Type of IV Iron Prescribed in HD patients Fe-Oxide SaccharatePolymaltoseOtherDextranCideferronGluconatePatients (%)- Sucrosen =(393)(396)(333)(339)(419)(304)(566)(469)(449)(334)(1327)Chondroitin SO4DOPPS III data ( ), among prevalent cross-section of HD patients using IV iron.
45Benefits 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
46Potential dangers of IV iron ? Short-termAnaphylactic reactions (iron dextran only; dextran Abs)“Free iron” reactions (all IV iron preparations)Long-termIncreased susceptibility to infectionIncreased oxidative stressIron overload
47Balance of benefits vs. risks of IV iron Mortality riskOxidative stressInfection riskAnaphylaxisBenefits of IV iron
48Outline of presentation Erythropoiesis in 2009ESA therapyTarget HbIron managementAnaemia management in kidney transplantationThe future
49Prevalence of anaemia in European kidney transplant recipients Hb < 12 g/dl : 28.4%Hb < 12 g/dl : 22.7%Overall 24.5 % were anaemicHb < 12 g/dl : 25.5%Hb < 12 g/dl : 24.4%n = centres, 16 countriesY Vanrenterghem et al., For TRESAM, Am J Transplantation 2003
50Prevalence of severe anaemia in Europe Overall 8.5% with severe anaemiaHb < 11 g/dlHb < 10 g/dlAmong 8.5% patients with severe anaemia, 18% were on EPO therapyY. Vanrenterghem et al., for TRESAM, Am J Transplantation 2003.
55Hematide EPO-mimetic peptide, now in Phase III clinical trials Amino acid sequences completely unrelated to native EPOShows same functional / biological properties as EPO2
56What 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 immunogenicDoes not cross-react with antibodies against EPO – should not cause PRCA; can be used to treat Ab+PRCAFirst ESA to be tested de novo once-monthly in CKD patients
57Anti-EPO antibodies do not neutralise Hematide EPO, rHuEPODarbepoetin alfaC.E.R.A.Peg-rHuEPOEPO-mimetic peptideJak2PJak2PJak2PJak2PmembraneSignal TransductionGene ActivationSurvival, differentiation, proliferation, and maturation of RBC progenitors and precursors
58Hematide in the Treatment of Antibody-Mediated Pure Red Cell Aplasia 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)102030405060BL1234567891112131415161718192122232425262728293132Study MonthsPercent Patients Receiving RBC TransfusionsDuring Each Study Month8.09.010.011.012.013.014.0Mean (SD) Hb Concentration (g/dL)5858
59HIF stabilisers Upside Downside HIF is the hypoxic sensor that upregulates EPO gene expressionHIF is broken down by a prolyl hydroxylase enzymeAn inhibitor of HIF hydroxylase has been synthesised (FibroGen)It causes an increase in EPO levels, even in CKD patientsUpsideThis enzyme inhibitor is orally-activeDownside>100 other genes (e.g. VEGF) also turned onRare development of severe liver toxicity (may be fatal)2
60New IV irons pending…….2 new IV irons forthcoming: – Ferumoxytol (US) – Ferric carboxymaltose – FerinjectTM (Europe)Advantages – ? safer – no need for test dose – more rapid high-dose bolus injection – main benefits in the pre-ESRD population
61Ferric carboxymaltose (Ferinject) Ferric hydroxide molecules Ribbon-like carboxymaltoseLicensed in EuropeStable iron complexLow immunogenic potential – dextran-freeMinimal detectable and releasable free ironNo test dose requiredRapid administration – 200mg push – 500mg in 6 mins – 1000mg infusion in 15 mins
65EPO: an all-purpose tissue-protective agent? Savino R, Ciliberto G. Cell Death Differ. 2004;11 Suppl 1:S2-4.
66EPO therapy: beyond HbMediated via the anti-apoptotic action of EPO on non-erythroid cellsRelevant for acute cardiac, renal, and cerebral ischaemia? Therapeutic benefit in : – Acute MI – Acute stroke – Reperfusion injury – Post-transplantation1
67ConclusionsOur understanding of erythropoiesis in 2009 has advanced to include the role of hepcidin and pro-inflammatory cytokinesUntil further evidence is forthcoming, we should generally target an Hb of 11–12 g/dlEven in 2009, there is still a need for additional grade A level evidence in the management of anaemia in CKDSeveral new ESAs and IV iron preparations are appearing, and the non-erythropoietic effects of ESAs are being exploredBA16738 – 132 patients in CERA arm SC, 52 week treatment period (18 week correction, 10 week evaluation, 24 week extension) 264BA16736 – 126 patients in the CERA arm IV, 52 week treatment period (24 week correction, 28 week evaluation) 168BA16739 – 310 patients in 2 CERA arms IV, 52 week treatment period 465BA16740 – 310 patients in 2 CERA arms SC, 52 week treatment period 465BA17284 – 132 patients in the CERA arm pre-filled syringes, 36 week treatment period 264BA17283 – 132 patients in the CERA arm IV, 52 week treatment period 264Total 897 IV patientsTotal 729 SC patients