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Erythropoietin-stimulating agents resistance and new anemia therapies Narrative Review Fellow 潘恆之 /VS 鄭昌錡.

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Presentation on theme: "Erythropoietin-stimulating agents resistance and new anemia therapies Narrative Review Fellow 潘恆之 /VS 鄭昌錡."— Presentation transcript:

1 Erythropoietin-stimulating agents resistance and new anemia therapies Narrative Review Fellow 潘恆之 /VS 鄭昌錡


3 Outline Introduction EPO resistance New anemia therapies

4 Introduction Brenner & Rector’s The Kidney 9 th Edition Chapter 56 Hemotologic Aspects of Kidney Disease

5 Introduction Definition of anemia in CKD : Hgb <13.5 g/dl for male; Hgb <12.0 g/dl for female Erythropoietin-stimulating agents :  Recombinant human erythropoietin was introduced as a treatment for the anemia associated with chronic kidney disease (CKD) since 1989.  Erythropoietin therapy rendered many patients free of blood transfusions with dramatic benefits on quality of life (particularly physical capacity) and other physiologic effects of increasing hemoglobin levels from ~6 g/dL up to approximately 11-12 g/dL.

6 Introduction Limitations of EPO : inconveniences of the need for regular administration 3 times a week and the need to inject this protein parenterally. => Longer acting erythropoietin analogue, darbepoetin alfa (2001) and pegylated epoetin beta (2007)

7 Several studies showed that partial correction of anemia (to hemoglobin levels in the range of 10-12 g/dL) was a safer strategy, reducing the risk of increased arterial and venous thromboembolism and other possible harmful effects in CKD patients. Introduction Rajiv Agarwal, Clin J Am Soc Nephrol, 2010 (5): 1340–1346

8 Large Randomized Controlled trials Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) -- the first large trial to compare ESA therapy with placebo in patients with CKD not on dialysis CREATE trial

9 TREAT Objectives to determine whether treating the anemia associated with CKD with DPO to a target Hgb of 13g/DL would reduce the occurrence of primary composite endpoints – 1. CV primary end point : All- cause death, MI, stroke, CHF requiring medical attention or hospitalization for MI 2. Renal primary end point : All-cause death or progression to ESRD

10 TREAT: Study design Darbepoetin alfa To target Hgb 13 Darbepoetin alfa To target Hgb 13 Randomize 4038 subjects with CKD (eGFR ≥ 20 and ≤ 60 ml/min/1.73 m 2 Type 2 DM Anemia Hgb ≤ 11 g/dL Iron Replete transferrin sat ≥ 15% 1:1 N=2026 N=2012 Control (“rescue” darb if Hgb < 9) Randomized, controled, double blind, international trial Stratified by baseline proteinuria and cardiovascular disease Control subjects received darbepoetin if Hgb dropped below 9 g/dL All subjects could receive RBC transfusion if needed Event driven – to conclude when 1203 subjects experienced a primary event

11 Normal Hct Caridac Trial (NHCT)

12 Cardiovascular risk Reduction by Early Anemia Treatment with Epoetin Beta (CREAT) trial

13 CHOIR study

14 Hb EPO dose erythropoiesis 1.CV risk 2.Mortality 3.Stroke 4.Vascular access thrombosis 1.CV risk 2.Mortality 3.Stroke 4.Vascular access thrombosis Hb > 13 g/dL

15 Naturally Occurring Higher Hemoglobin Concentration Does Not Increase Mortality among Hemodialysis Patients Goodkin D A et al. JASN 2011;22:358-365  Among 29,796 HD patients in 12 nations  545 Endogenous EPO patients were included in each model.  Adjusted risk of mortality does not differ significantly for Endogenous EPO patients compared with Other patients( RR 0.94 (95% CI, 0.72 to 1.22 RR, 0.98; 95% CI, 0.80 to 1.19 RR, 0.81; 95% CI, 0.66 to 0.98

16  Cumulative all- cause mortality among 428 CKD 1~2 patient aged 86 at baseline, by tertile of erythropoietin level at baseline (lowest = 3.4– 8.6 IU/L, middle = 8.7–12.3 IU/L, highest = 12.4– 103.0 IU/L). Higher concentration of endogenous EPO => fatal outcome ↑ Excessive EPO synthesis => off-target biological consequences ↑ ?? Limitations: undiagnosed hypoxemia? Impaired bone marrow response? EPO resistance? Effect of erythropoietin levels on mortality in old age: the Leiden 85-plus study den Elzen W P et al. CMAJ 2010;182:1953-1958

17 Association of Mean Weekly Epoetin Alfa Dose with Mortality Risk in a Retrospective Cohort Study of Medicare Hemodialysis Patients Am J Nephrol 2011;34:298–308  The cohort included 137,918 HD patients. Mean age was 63.2 years  Relative hazards of death over mean EPO dose per week during 3-month exposure period, in patient- months with mean hemoglobin  The distribution of mean EPO dose per week is displayed in the shaded area, and the referent dose is shown by the solid vertical line.

18  Uremic toxins/Oxidative stress/ Inflammation  Nutrition deficiency  Heavy metal  Hematologic disorders  Angiotensin-modulating agents  EPO inhibitors Pattern of resistance to erythropoietin- stimulating agents in chronic kidney disease Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474 Review

19 Erythropoietin-stimulating agents (ESA) resistance : Hb < 11g/dL over 3 month despite of EPO dose > 400 IU/kg/wk or 20000 IU/wk (≥1.0μg/ kg for darbepoietin)

20 The risk factors, pathogeneses, and therapeutic modulation of erythropoietin resistance in chronic kidney disease


22 Uremic toxins The mechanism is uncertain There is fair correlation of urea nitrogen clearance with improved cytokine profiles (IL-6, CRP) and lower requirement for ESA. Uremia may be related to :  Poor bone marrow response to ESA  Accelerated turn over rate of RBC from altering erythrocyte morphology by inducing outward expression of the phosphatidyl-serine content of its inner membrane

23 Oxidative stress Depletes the capacity of ATP generation Downregulates the generation of hypoxic- inducible factor (HIF) protein, thereby reducing EPO synthesis.

24 Oxidative stress Haase V H Am J Physiol Renal Physiol 2010;299:F1-F13 ✗ * Oxidative stress downregulates the generation of hypoxic inducible factor (HIF) protein.

25 Inflammation * Pro-inflammatory cytokines such as IL-1, IL-6, INF-γ, TNF could disrupt iron recycling and absorption DMT 1, divalent methyl transporter-1 CKD pro- inflammatory cytokines: IL-6 Process of physiological iron recycling involving macrophages and enterocytes Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474

26 Erythropoietin receptor activation and intracellular signal transduction SOCS, suppressor of cytokine signaling; STAT-5 signal transducer and activator of transcription-5 Pro-inflammatory cytokines (+) Inflammation * Pro-inflammatory cytokines promote EPO resistence by activation of suppressor of cytokine signaling and inhibition of nuclear factor κB Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474

27 Inflammation Failed allograft – nephrectomy is a reasonable approach for transplant rejection with persistent elevation of inflammatory indices and intractable anemia. Dialysis catheters – additional sources of oxidative inflammation are the use of per-cath and synthetic grafts as vascular access in HD subjects.

28 NUTRITION DEFICIENCY 1. Iron 2. Folate 3. Vitamin C

29 Nutrients deficiency Iron  Principally due to poor diet, frequent blood sampling and high frequency of infection  Annual loss of 2g of elemental Fe among HD patient  Diagnosis: serum iron < 100 mg/dl, TSAT <20%, and serum Ferritin < 100mg/dl ~ at least 2 indices  Treatment: 1. Iron therapy 2. Vit-C – mobilize iron from RES

30 Nutrients deficiency Folate  Principally due to poor gastrointestinal absorption, poor diet, water-soluble nutrient loss, and high catabolic status  An essential ingredient for nucleotide synthesis, DNA repair, and re-methylation of homocysteine  Folic acid deficiency produces oxidative vascular injury by potentiating uremic inhibition of homocysteine catabolism

31 Nutrients deficiency Vitamin C  A cofactor for several enzymatic metabolism  Promotes GI absorption of iron and enhances its mobilization from RES.  Increases Hb synthesis by facilitating incorporation of Fe into protoporphyrin  An anti-oxidative free oxygen scavenger, downregulates hepatic synthesis of cytokines  Greater loss of Vit-C in HD compared with PD

32 HEAVY METAL 1. Aluminum 2. Cadmium 3. Lead 4. Mercury

33 Heavy metal Bone marrow function is often impaired in individuals with heavy metal poisoning Aluminum toxicity – P-binder, dialysate, poor control of pharmaceutical standards Cadmium, lead, mercury – industrial pollution, some folk remedies of Indian and Middle Eastern origins

34 Heavy metal Lead toxicity is more likely to occur in patient with CKD due to :  Iron and calcium deficiencies => GI absorption   Uremia may increase mobilization of lead from bone tissue stores Lead toxicity causes anemia by precluding incorporation of iron into a protoporphyrin ring for heme synthesis


36 Hematological disorders The mechanism of EPO resistance includes bone marrow infarction, hemolysis, hypersplenism, and ineffective erythropoiesis. Common chronic hemolytic conditions are auto- immune diseases, sickle cell disease, thalassemia, hereditary spherocytosis, glucose 6-phosphate dehydrogenase deficiency.

37 Hematological disorders Autoimmune hemolytic anemia occurs in 5-10% of patient with SLE. It is frequently associated with renal or neurological involvement. As reticulocytosis is common in patients on ESA therapy, early diagnosis of hemolytic events may be missed. It should be suspected when there is a progressive increase in EPO requirement while there is rapidly decreasing Hb concentration with megakaryocytic cell line  and serum titer of anti- DS DNA .


39 Angiotensin-modulating agents The influlence is controversial. A prototype study showed there is a higher EPO requirement in dialysis hypertensive patients who were treated with ACEI/ARB compared with CCB. ACEI suppresses the enzymatic degradation of N- acetyl-seryl-aspartyl- lysyl-proline (AcSDKP), a naturally occurring inhibitor of erythropoiesis. Stimulation of erythroid cellular proliferation by angiotensin binding of its type II surface receptor is inhibited by ARB => therapeutic use of ARB in post-transplant erythrocytosis.


41 Circulating EPO inhibitors Circulating EPO inhibitors may result in pure red cell aplasia. Pure red cell aplasia should be suspected : 1. Received ESA therapy for 44 weeks 2. Rapid decrease in Hb mass (> 0.5 g/dl per week), 3. Reduction in absolute reticulocyte count <10, 000/ ml and/or 1U of RBC transffusion per week 4. Leucocytes and platelets are normal. 5. The more common causes of EPO-resistant anemia should be excluded.

42 Circulating EPO inhibitors Diagnosis : 1. Absence of erythroid precursors on bone marrow sample and low EPO content of the serum. 2. The serum sample inhibits growth of erythroid colonies in a bone marrow culture. 3. Radioimmunoassay identifies circulating neutralizing anti-EPO IgG in serum Treatment : 1. Discontinuation of rhEPO 2. Steroid and/or calcineurin inhibitor 3. Plasma exchange and/or allograft transplantation


44 Secondary hyperparathyroidism There is a higher prevalence of anemia and greater EPO requirement HD subjects who are in the upper 50th percentile of intact parathyroid hormone. As a proof of causal relationship, surgical parathyroidectomy led to an improved control of anemia and a lower need for ESA Nevertheless, there is no evidence for a direct inhibition of erythropoiesis by excessive PTH.

45 1,25-vitamin D deficiency Vit-D may have synergistic effect on ESA control of anemia Calcitriol treatment in subjects with uremic bone disease increases the proliferation of erythroid precursors. Lower EPO requirement among subjects with BB gene of vitamin D receptor genotype compared with those with the Bb/bb gene.

46 Etiology of ESA resistance Risk factorMechanism of ESA resistanceTherapeutic intervention Uremic toxins  EPO synthesis /  erythroid response Longer effective dialysis Oxidative stressDownregulation of HIFVit E and Vit C InflammationCytokines: IL-1, IL-6, TNF-αAvoid sepsis and malnutrition Iron deficiencyHemoglobin synthesisReplenish iron/  blood loss Hyperparathyroidism / Vit D deficiency Vitamin D synergism (erythropoiesis)Low P diet/ 1,25 (OH) 2 vit D Aluminum toxicityAluminum bone diseaseAvoid aluminum intake HemolysisHbSS/G6PDD/AIHATreat underlying diesease Drug: angiotensin- modulating agents  Erythroid ANG II receptors/  endogenous EPO inhibitor, AcSDKP  Dose of ACEI/ARB

47 Potential Pharmacological intervention in EPO resistance Anti-inflammatory agents Nutritional supplements EPO-mimetic peptide Endogenous induction of EPO

48  EPO-mimetic peptide  HIF Stabilization  Hepcidin Modulation  GATA-2 Inhibitors  EPO gene therapy New anemia therapies: Translating Novel Strategies From Bench to Bedside Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451 Narrative Review


50 EPO-mimetic peptide The concept that a peptide could activate the erythropoietin receptor and stimulate erythropoiesis was described first by Wrighton et al in 1996 in Science. EMP-1 (erythropoietin-mimetic peptide 1) was able to stimulate cellular proliferation of erythroid cells in a dose- dependent manner and also increase reticulocyte counts in animal models. However, EMP-1 had low affinity for the erythropoietin receptor and low biological activity.

51 EPO-mimetic peptide Peginesatide is a dimeric peptide joined with a spacer linker to a pegylation chain to enhance its metabolic stability in vivo. No structural homology between peginesatide and erythropoietin. Antibodies against erythropoietin do not cross-react with peginesatide, and vice versa. => potential therapeutic use for pure red cell aplasia Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444- 451

52 Peginesatide Phase 3 Clinical Trials Overview Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451


54 HIF Stabilization It is now clear that the anemia associated with CKD is not due simply to deficient erythropoietin production, but rather to defective EPO gene regulation. Prolyl hydroxylase inhibitors results stabilization of HIF and consequently transcription of the EPO gene.

55 Regulation of hypoxia inducible factor (HIF) activity HIF stabilization HIF stabilization Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451

56 HIF Stabilization Prolyl hydroxylase inhibitors  Advantages – 1. Orally active 2. Modulate other genes involved in erythropoiesis in addition to the EPO gene.  Disadvantages – 1. Upregulate several hundred other hypoxia-sensitive genes, including those involved in glucose regulation, angiogenesis, such as VEGF (vascular endothelial growth factor) => enhance tumor growth or proliferative diabetic retinopathy ??

57 HIF Stabilization The first-generation HIF stabilizer molecule (prolyl hydroxylase inhibitors) -- FG 2216 => Patients developed abnormal liver enzyme test results, and one developed fatal hepatic necrosis in phase 2 clinical trial The second-generation HIF stabilizer molecule – FG 4592 => Significantly increase Hct and decrease serum Hepcidin levels => This is now in phase 2 clinical trial.

58 Hypoxia coordinates EPO synthesis with iron metabolism Haase V H Am J Physiol Renal Physiol 2010;299:F1-F13 ©2010 by American Physiological Society


60 Hepcidin Modulation Hepcidin is a small defensin-like peptide produced largely by the liver, macrophage and adipocyte. Hepcidin has antimicrobial properties and it is the master regulator of iron metabolism.

61 Hepcidin Modulation Hepcidin is a small defensin-like peptide produced largely by the liver, macrophage and adipocyte. Hepcidin has antimicrobial properties and it is the master regulator of iron metabolism.

62 Hepcidin Modulation * Hepcidin inhibits ferroportin, which controls iron efflux from duodenal enterocytes, hepatocytes, and macrophages * Uremia is a chronic inflammatory state. Dialysis patients have much higher serum hepcidin levels. Babitt JL, Molecular mechansms of hepcidin regulation: implications for the anemia of CKD. Am J Kidney Dis. 2010 (55):726-741

63 Hepcidin Modulation It currently is believed that this has a part in the pathogenesis of anemia in CKD by limiting iron availability to the bone marrow. At a molecular level, hepcidin binds to the main iron exporter protein ferroportin, which controls iron efflux from duodenal enterocytes, hepatocytes, and macrophages.

64 Hepcidin Modulation Strategies :  Monoclonal antibody against hepcidin (NOX-H94) has been shown the effect on inhibition of IL-6 induced anemia in mouse models.  Inhibition of the hepcidin production by using antisense oligonucleotides or sliencing messenger RNA transcribed from the hepcidin gene(HAMP) None of the strategies have been subjected to clinical trials. => Hepcidin has antimicrobial properties. Inhibition of hepcidin might exacerbate the risk of infection ?


66 GATA-2 inhibitors: K-7174 and K-11706. Iain C. Macdougall, Am J Kidney Dis. 2012;59(3):444-451 GATA-2 inhibitor GATA-2 inhibitor Imagawa S. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood. 1997(89):1430-1439 GATA-2 Inhibitors

67 K-11706 was found to evoke greater hypoxic induction compared with K-7174, possibly through stimulation of HIF-1 binding activity in addition to GATA inhibition. Potential role for an orally administered GATA inhibitor in the treatment of anemia. Imagawa S. Negative regulation of the erythropoietin gene expression by the GATA transcription factors. Blood. 1997(89):1430-1439


69 Erythropoietin Gene Therapy In 2005, a group of Israeli scientists developed a functional delivery system for the EPO gene using skin cells on SCID mice (using adenovirus vector). The mice responded by producing increased levels of erythropoietin, and this was associ- ated with an increase in hematocrit. No such effect was seen with the vector alone.

70 Erythropoietin Gene Therapy

71 Erythropietin Gene Therapy In 2010, a small group of patients with CKD in Israel have taken part in a proof-of-concept phase 1-2 clinical trial of this delivery system for the EPO gene. All patients showed increased erythropoietin production, with most showing sustained eleva- tion of hemoglobin levels (the primary end point) in the target range of 10-12 g/dL for 6-12 months without receiving additional erythropoietin injections.


73 Conclusion It took us nearly 20 years to realize the limitations of ESAs and the potential for harm if used too aggressively. This review summarizes our current knowledge about a variety of new strategies for stimulating erythropoiesis. They will need to be subjected to the same degree of scientific investigation as the existing ESAs, and it may be many years before the true efficacy-safety balance of these novel scientific strategies is realized.

74 Currently Available Erythropoiesis- Stimulating Agents

75 Future Erythropoiesis-Stimulating Agents

76 Clinical evaluation of resistance to erythropoietin stimulating agent in chronic kidney disease Oluwatoyin F. Bamgbola, Kidney international (2011) 80, 464-474 Al toxicity Pb toxicity Cu deficiency Hypothyroidism Al toxicity Pb toxicity Cu deficiency Hypothyroidism

77 Proposed role of the bone morphogenetic protein(BMP) signaling pathway, HJV, HFE, and TFR 2 in iron sensing and hepcidin regulation in the liver

78 Hypoxia-inducible factor (HIF)-2 regulates erythropoietin (EPO) Haase V H Am J Physiol Renal Physiol 2010;299:F1-F13 ©2010 by American Physiological Society

79 Thanks For You Attention !!

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