1 / 59

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

tricia
Télécharger la présentation

E rythropoietin -stimulating agents resistance and new anemia therapies

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related