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E rythropoietin -stimulating agents resistance and new anemia therapies

E rythropoietin -stimulating agents resistance and new anemia therapies. Narrative Review. Fellow 潘恆之 /VS 鄭昌錡. Outline. Introduction. EPO resistance. New anemia therapies. Introduction. Definition of anemia in CKD ： Hgb <13.5 g/dl for male ; Hgb <12.0 g/dl for female

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E rythropoietin -stimulating agents resistance and new anemia therapies

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

  2. Outline Introduction EPO resistance New anemia therapies

  3. Introduction • Definition of anemiain 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.

  4. Introduction • 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. Rajiv Agarwal, ClinJ Am SocNephrol, 2010 (5): 1340–1346

  5. erythropoiesis • Hb>13 g/dL CV risk Mortality Stroke Vascular access thrombosis

  6. 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, 0.81; 95% CI, 0.66 to 0.98 RR, 0.98; 95% CI, 0.80 to 1.19 RR 0.94 (95% CI, 0.72 to 1.22

  7. 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 • Cumulative all- • cause mortality • among 428 • CKD 1~2 patient • aged 86 at • baseline, by • tertileof • 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?

  8. 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 • thesolid vertical line.

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

  10. 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)

  11. Uremic toxins/Oxidative stress/Inflammation

  12. 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

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

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

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

  16. 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.

  17. Nutrition deficiency 1. Iron 2. Folate 3. Vitamin C

  18. 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

  19. 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

  20. 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

  21. 1. Aluminum 2. Cadmium 3. Lead 4. Mercury Heavy metal

  22. 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

  23. 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

  24. Hematologic disorders

  25. 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.

  26. 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 Hbconcentration withmegakaryocytic cell lineand serum titer of anti-DS DNA.

  27. Angiotensin-modulating agents

  28. 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. • ACEIsuppresses 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.

  29. Circulating EPO inhibitors

  30. 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.

  31. 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 IgGin serum • Treatment： 1. Discontinuation of rhEPO 2. Steroid and/or calcineurin inhibitor 3. Plasma exchange and/or allograft transplantation

  32. Secondary hyperparathyroidism and 1,25-vitamin D deficiency

  33. 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.

  34. 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.

  35. Etiology of ESA resistance

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

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

  38. EPO-mimetic peptide

  39. 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.

  40. 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

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

  42. HIF Stabilization

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

  44. 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 ??

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

  46. Hepcidin Modulation

  47. 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

  48. 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. => Hepcidinhas antimicrobial properties. Inhibition of hepcidin might exacerbate the risk of infection ?

  49. GATA-2 inhibitors

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

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