Esa

ERYTHROPIETIN STIMULATING AGENTS

1. Erythropoietin Stimulating Agents (ESA) Moderator- Dr Satish Chhabra Presenter- Dr Prem Mohan Jha Registrar, DNB Nephrology Max Super Speciality Hospital, Vaishali . 1

2. 2 Normal Erythropoiesis

3. Human erythropoietin gene is encoded in chromosome 7q11-22. Human erythropoietin is a sialoglycoprotein consisting of a 165 amino acid backbone with Three  n - glycosylation and One  o - glycosylation sites. The  N - glycosylation confers the biological activity of erythropoietin. 3 Erythropoietin Hormone

4. RHuEPO has the same polypeptide backbone and has the equal number of glycosylation sites as the endogenous form. Differences in the glycosylation pattern confers some variations in both pharmacokinetic and pharmacodynamic profiles between the natural and the recombinant forms, and among the RHuEPOs . 4 Erythropoietin Hormone

5. 90% produced by interstitial fibroblasts   in the kidney in close association with the  peritubular capillary and proximal convoluted tubule. This production is expanded into the outer cortex in response to hypoxia and anemia. 10% produced in  perisinusoidal  cells in the liver . Liver production predominates in the fetal and perinatal period; renal production predominates in adulthood . 5 Erythropoietin Hormone

6. 6

7.  Low levels of EPO (around 10  mU / mL ) are constantly secreted sufficient to compensate for normal red blood cell turnover. Common causes of cellular hypoxia resulting in elevated levels of EPO (up to 10000   mU / mL ) include any anemia, and hypoxemia due to chronic lung disease. 7 Erythropoietin Hormone

8. In circulation, EPO has a HALF LIFE of 6–9 h . EPO acts by binding to specific receptors on the surface of marrow erythroid precursors, inducing them to proliferate and to mature. With EPO stimulation, red cell production can increase four- to fivefold within a 1- to 2-week period, but only in the presence of adequate nutrients, especially iron. 8 Erythropoietin Hormone

9. 9 Mechanism Of Action

10. 10 Mechanism Of Action

11. Key to EPO gene regulation is hypoxia-inducible factor (HIF)-1. In the presence of O 2 , HIF-1 is hydroxylated at a key proline , allowing HIF-1 to be degraded via the ubiquitin proteasome pathway. If O 2 becomes limiting, this critical hydroxylation step does not occur, allowing HIF-1 to partner with other proteins, translocate to the nucleus, and upregulate the EPO gene, among others. 11 The Physiologic Regulation

12. 12 The Physiologic Regulation

13. EPO governs the day-to-day production of red cells, and ambient levels of the hormone can be measured in the plasma by sensitive immunoassays—the normal level being 10–25 U/L. When the hemoglobin concentration falls below 10–12 g/ dL , plasma EPO levels increase in proportion to the severity of the anemia. 13 The Physiologic Regulation

14. 14

15. 15 What is EPO primarily used for?

16. WHO Definition of Anemia Hemoglobin level <13 g/ dL in men and <12 g/ dL in women. 16

17. 17 Laboratory Tests in Anemia Diagnosis

18. 18

19. 19 Red Blood Cell Indices

20. 20 Changes in Normal Hemoglobin/ Hematocrit Values with Age and Pregnancy

21. 21 Peripheral Blood Smear

22. 22 Normal blood smear (Wright stain)

23. 23 Severe iron-deficiency anemia

24. 24 Macrocytosis

25. 25 Target cells

26. 26 Red cell fragmentation

27. The red cells in uremia may acquire numerous regularly spaced, small, spiny projections. Such cells, called burr cells or echinocytes , are readily distinguishable from irregularly spiculated acanthocytes 27 Uremia

28. Spur cells are recognized as distorted red cells containing several irregularly distributed thornlike projections. Cells with this morphologic abnormality are also called acanthocytes . 28 Spur cells

29. Methylene blue stain demonstrates residual RNA in newly made red cells 29 Reticulocytes

30. An accurate reticulocyte count is key to the initial classification of anemia. Normally, reticulocytes are red cells that have been recently released from the bone marrow. They are identified by staining with a supravital dye that precipitates the ribosomal RNA. These precipitates appear as blue or black punctate spots. 30 Reticulocyte Count

31. This residual RNA is metabolized over the first 24–36 h of the reticulocyte's life span in circulation. Normally, the reticulocyte count ranges from 1 to 2% and reflects the daily replacement of 0.8–1.0% of the circulating red cell population. A corrected reticulocyte count provides a reliable measure of red cell production. 31 Reticulocyte Count

32. In the initial classification of anemia, the patient's reticulocyte count is compared with the expected reticulocyte response. In general, if the EPO and erythroid marrow responses to moderate anemia [hemoglobin < 10 g/ dL )] are intact, the red cell production rate increases to two to three times normal within 10 days following the onset of anemia. 32 Reticulocyte Count

33. In order to use the reticulocyte count to estimate marrow response, two corrections are necessary. The first correction adjusts the reticulocyte count based on the reduced number of circulating red cells. To correct for this effect, the reticulocyte percentage is multiplied by the ratio of the patient's hemoglobin or hematocrit to the expected hemoglobin/ hematocrit for the age and gender of the patient. 33 Corrected Reticulocyte Count

34. In order to convert the corrected reticulocyte count to an index of marrow production, a second correction is required, depending on whether some of the reticulocytes in circulation have been released from the marrow prematurely. For this second correction, the peripheral blood smear is examined to see if there are polychromatophilic macrocytes present. 34 Corrected Reticulocyte Count

35. The correction is necessary because these prematurely released cells survive as reticulocytes in circulation for >1 day, thereby providing a falsely high estimate of daily red cell production. If polychromasia is increased, the reticulocyte count, already corrected for anemia, should be divided again by 2 to account for the prolonged reticulocyte maturation time. 35 Corrected Reticulocyte Count

36. The second correction factor varies from 1 to 3 depending on the severity of anemia . In general, a correction of 2 is commonly used. If polychromatophilic cells are not seen on the blood smear, the second correction is not required. The now doubly corrected reticulocyte count is the reticulocyte production index , and it provides an estimate of marrow production relative to normal. 36 Corrected Reticulocyte Count

37. 37 Calculation of Reticulocyte Production Index

38. 38

39. 39 Normal Marrow Response to Anemia

40. The laboratory measurements that reflect the availability of iron for hemoglobin synthesis include the serum iron, the TIBC, and the percent transferrin saturation. The percent transferrin saturation is derived by dividing the serum iron level (x 100) by the TIBC. The normal serum iron ranges from 9 to 27 mol/L (50–150 g/ dL ), while the normal TIBC is 54–64 mol/L (300–360 g/ dL ); the normal transferrin saturation ranges from 25 to 50%. 40 Tests of Iron Supply and Storage

41. The serum ferritin is used to evaluate total body iron stores. Adult males have serum ferritin levels that average ~100 g/L , corresponding to iron stores of ~1 g. Adult females have lower serum ferritin levels averaging 30 g/L , reflecting lower iron stores (~300 mg). 41 Tests of Iron Supply and Storage

42. A serum ferritin level of 10–15 g/L represents depletion of body iron stores. However, ferritin is also an acute-phase reactant and, in the presence of acute or chronic inflammation, may rise several-fold above baseline levels. As a RULE , a serum ferritin >200 g/L means there is at least some iron in tissue stores . 42 Tests of Iron Supply and Storage

43. A bone marrow aspirate and smear or a needle biopsy can be useful in the evaluation of some patients with anemia. In patients with hypoproliferative anemia and normal iron status, a bone marrow is indicated. Marrow examination can diagnose primary marrow disorders such as myelofibrosis , a red cell maturation defect, or an infiltrative disease 43 Bone Marrow Examination

44. This is a low-power view of a section of a normal bone marrow biopsy stained with hematoxylin and eosin (H&E). Note that the nucleated cellular elements account for ~40–50% and the fat (clear areas) accounts for ~50–60% of the area. (From Hillman et al.) 44

45. The increase or decrease of one cell lineage (myeloid vs. erythroid ) compared to another is obtained by a differential count of nucleated cells in a bone marrow smear [the myeloid/ erythroid (M/E) ratio]. A patient with a hypoproliferative anemia and a reticulocyte production index <2 will demonstrate an M/E ratio of 2 or 3:1. In contrast, patients with hemolytic disease and a production index >3 will have an M/E ratio of at least 1:1. 45 Bone Marrow Examination

46. Maturation disorders are identified from the discrepancy between the M/E ratio and the reticulocyte production index (Either the marrow smear or biopsy can be stained for the presence of iron stores or iron in developing red cells). The storage iron is in the form of ferritin or hemosiderin . On carefully prepared bone marrow smears, small ferritin granules can normally be seen under oil immersion in 20–40% of developing erythroblasts. Such cells are called sideroblasts . 46 Bone Marrow Examination

47. 47 This marrow shows an increase in the fraction of cells in the erythroid lineage as might be seen when a normal marrow compensates for acute blood loss or hemolysis . The M/E ratio is about 1:1. M/E, myeloid/ erythroid . (From Hillman et al.)

48. 48 This marrow shows an increase in the fraction of cells in the myeloid or granulocytic lineage as might be seen in a normal marrow responding to infection. The M/E ratio is >3:1. M/E, myeloid/ erythroid . (From Hillman et al.)

49. 49 The physiologic classification of anemia

50. Relative deficiency of erythropoietin Diminished red blood cell survival Bleeding diathesis Iron deficiency Hyperparathyroidism/bone marrow fibrosis "Chronic inflammation" Folate or vitamin B12 deficiency Hemoglobinopathy Comorbid conditions: hypo/hyperthyroidism, pregnancy, HIV-associated disease , autoimmune disease, immunosuppressive drugs. 50 Causes of Anemia in CKD

51. Exogenous Erythropoietin. Also called recombinant human erythropoietin  ( rHuEPO ) Produced by recombinant DNA technology in cell culture. Collectively called  erythropoiesis -stimulating agents (ESA). 51 ESA

52. First generation Epoietin alpha Second generation Darbepoietin alpha Third generation Mircera Fourth generation/newer 52

53. 53 Newer Agents

54. 54 Newer Agents

55. The original recombinant human EPOs ( epoetin alfa and epoetin beta ) have now been in clinical use for nearly 20 yr. Both products are synthesized in cultures of transformed Chinese hamster ovary (CHO) cells that carry cDNA encoding human EPO. The amino acid sequence of both epoetins is therefore identical, and the major difference between these products lies in their glycosylation pattern. 55 Protein-Based ESA Therapy

56. Other epoetins that have recently become available or are still being developed include epoetin omega and epoetin delta , as well as the copy products of epoetin alfa and other biosimilar epoetins . With epoetin omega, baby hamster kidney (BHK) cell cultures are used for the manufacture of this product, which has been used clinically in some Eastern European, Central American, and Asian countries. 56 Protein-Based ESA Therapy

57. Epoetin delta is another recombinant EPO that has been used for treating patients with CKD Epoetin delta is synthesized in human fibrosarcoma cells . The product is also called gene-activated EPO because the expression of the native human EPO gene is activated by transformation of the cell with the cytomegalovirus promoter. 57 Protein-Based ESA Therapy

58. More potent. More stable. Elimination half-life in human after a single intravenous injection increasing three fold ( 25.3 h ) compared with epoetin alfa ( 8.5 h ). The half-life after subcutaneous administration is doubled from approximately 24 h to approximately 48 h . This latter characteristic has allowed less frequent dosing, with most patients receiving injections once weekly or once every other week. 58 Darbepoetin Alfa

59. The strategy used to synthesize CERA was to integrate a large methoxy-polyethyleneglycol polymer chain into the EPO molecule via amide bonds between the N-terminal amino group of alanine and the o-amino groups of lysine (Lys45 or Lys52) by means of a succinimidyl butanoic acid linker. Because the mass of the polymer chain is approximately 30 kD , this doubles the molecular weight of CERA to approximately 60 kD , compared with EPO (30.4 kD ). 59 CERA

60. As with other pegylated therapeutic proteins, the half-life of circulating CERA is considerably prolonged compared with that of epoetin : at approximately 130 h. Thus, less frequent dosing regimens of once every 2 wk and once every month have been tested in Phase II and Phase III clinical trials, and the product recently received a license in both the US and Europe. 60 CERA

61. Administered intravenously or subcutaneously. Adverse events seem to be similar to those associated with the epoetins or darbepoetin alfa . It is possible that the metabolic fate of CERA is different from the existing products, with less cellular internalization after interaction with the EPO receptor. In addition to CERA, other pegylated molecules, including epoetin alfa and an epoetin analogue have been tested for their efficacy in experimental animals. These products have not yet entered clinical trials. 61 CERA

62. Several other EPO-like molecules and derivatives are in preclinical or clinical trials. A further hyperglycosylated analogue of darbepoetin alfa was synthesized, with additional carbohydrate residues ( AMG114 ). Longer circulating half-life , compared with darbepoetin alfa . EPO receptor binding affinity was too low to develop this molecule further as a therapeutic agent, and clinical trials have now ceased. 62 Other Protein-Based EPO Derivatives

63. Another novel product is Synthetic Erythropoiesis Protein (SEP). Synthesized containing two covalently attached polymer moieties. Stimulates erythropoiesis through activation of the EPO receptor, and with a longer circulating half-life than for EPO alone. The erythropoietic effect of synthetic erythropoiesis protein has been shown to vary in experimental animals depending on the number and type of the attached polymers. 63 Other Protein-Based EPO Derivatives

64. EPO-EPO GM CSF-EPO Fc -EPO : Aerosol, Oral, Transdermal . CTNO 528 Single SC dose of CTNO 528, showed a more prolonged reticulocytosis and hemoglobin rise compared with treatment with Epoetin or Darbepoetin Alfa. Phase I studies in healthy volunteers showed a similar effect after a single intravenous administration of CTNO 528, with a peak reticulocyte count occurring after 8 d, and the maximum hemoglobin concentration being seen after 22 d. None of the 24 participants in this study developed antibodies against the molecule. 64 EPO Fusion Proteins

65. Peptide based ESA : Hematide Half life in monkey : 14 – 60 hrs. Route of elimination : kidneys . Phase 1 & 2 studies done. Found benificial . Dosage : 0.025 – 0.05 mg/kg. IV OR SC. Once a month. Advantage : stable at room temp. low immunogenesity . Anti hematide ab do not cros react with EPO. 65 Small Molecules ESA

66. HIF stabilizers Advantage – Orally active Disadvantage – Upregulate around 100 other genes. Fatal hepatic necrosis FDA suspended any further clinical trials . 66 Other Strategies For Stimulating Erythropoiesis

67. 67 HIF Stabilizers

68. 68

69. GATA inhibition The GATA family consists of six transcription factors, GATA 1 through 6. GATA-4 is critically involved in EPO gene expression and may be responsible for the switch in the site of EPO production from the fetal liver to the adult kidney. GATA-2 acts as a negative regulatory molecule of EPO gene expression. Disrupting this negative signal is therefore a potential future strategy in the management of renal anemia. 69

70. Several molecules are under investigation, including K-11706. Enhance EPO production both in vitro and in vivo . Oral administration of K-11706 restored the hemoglobin con- centrations , reticulocyte counts, EPO levels, and numbers of CFU-E induced by IL-1beta or TNF- alfa in a mouse model of anemia. These results raise the possibility of using orally administered K-11706 in the treatment of renal anemia, but clinical trials are not yet under way. 70

71. These orally active agents, however, could potentially be used as adjuvant therapy to enhance the re- sponse to other ESAs or even to enhance the patient’s own endogenous EPO. 71 Hematopoietic Cell Phosphatase Inhibition

72. Animal experiments have shown that linking the EPO transgene to a hypoxia-responsive DNA element (the HIF binding site) can establish an oxygen-dependent feedback regulation of the transgene , similar to that of the endogenous EPO gene 72 EPO Gene Therapy

73. The side effects that occur most often with ESA use include: High blood pressure Swelling Fever Dizziness Nausea Pain at the site of the injection . PRCA 73 Side Effects

74. 74 KDIGO Guidelines

75. Diagnose anemia in adults and children >15 years with CKD when the Hb concentration is <13.0 g/dl in males and <12.0 g/dl in females . (Not Graded) Diagnose anemia in children with CKD if Hb concentration is <11.0 g/dl in children 0.5–5 years , <11.5 g/dl in children 5–12 years, and <12.0 g/dl in children 12–15 years . (Not Graded) 75 Diagnosis Of Anemia

76. In patients with CKD and anemia (regardless of age and CKD stage), include the following tests in initial evaluation of the anemia ( Not Graded ): Complete blood count (CBC), Absolute reticulocyte count Serum ferritin level Serum transferrin saturation (TSAT) Serum vitamin B 12 and folate levels 76 Investigation Of Anemia

77. For CKD Patients Without Anemia For children), measure Hb concentration when clinically indicated and ( Not Graded ): At least annually in patients with CKD 3 At least twice per year in patients with CKD 4–5ND At least every 3 months in patients with CKD 5HD and CKD 5PD 77 Frequency Of Testing For Anemia

78. For CKD patients with anemia not being treated with an ESA, measure Hb concentration when clinically indicated and ( Not Graded ): At least every 3 months in patients with CKD 3–5ND and CKD 5PD. At least monthly in patients with CKD 5HD. 78 Frequency Of Testing For Anemia

79. 79 Use Of ESAs And Other Agents To Treat Anemia In CKD

80. Address all correctable causes of anemia prior to initiation of ESA therapy. ( Not Graded) Balance the potential benefits of reducing blood transfusions and anemia-related symptoms against the risks of harm in individual patients (e.g., stroke, vascular access loss, hypertension). ( 1B) 80 ESA Initiation

81. Use ESA therapy with great caution, if at all, in CKD patients with active malignancy—in particular when : Cure is the anticipated outcome—( 1b ), A history of stroke ( 1B ), or A history of malignancy ( 2C ). For adult CKD ND patients with Hb concentration >10.0 g/dl, ESA therapy not be initiated. ( 2D ) 81 ESA Initiation

82. For adult CKD ND patients with Hb concentration <10.0 g/dl, the decision whether to initiate ESA therapy be individualized based on : The rate of fall of Hb concentration, Prior response to iron therapy, The risk of needing a transfusion, The risks related to ESA therapy and The presence of symptoms attributable to anemia. ( 2c ) 82 ESA Initiation

83. For adult CKD 5D patients, ESA therapy be used to avoid having the Hb concentration fall below 9.0 g/dl (90 g/l) by starting ESA therapy when the hemoglobin is between 9.0–10.0 g/dl . ( 2B ) Individualization of therapy is reasonable as some patients may have improvements in quality of life at higher Hb concentration and ESA therapy may be started above 10.0 g/dl. ( Not Graded ) 83 ESA Initiation

84. For all pediatric CKD patients, the selection of Hb concentration at which ESA therapy is initiated in the individual patient includes consideration of potential benefits e.g., Improvement in quality of life, School attendance/performance, and Avoidance of transfusion and potential harms. ( 2D ) 84 ESA Initiation

85. In general, ESAs not be used to maintain Hb concentration above 11.5 g/dl in adult patients with CKD. ( 2C) Individualization of therapy will be necessary as some patients may have improvements in quality of life at Hb concentration above 11.5 g/dl and will be prepared to accept the risks. ( Not Graded ) 85 ESA Maintenance Therapy

86. In all adult patients, ESAs not be used to intentionally increase the Hb concentration above 13 g/dl. ( 1A ) In all pediatric CKD patients receiving ESA therapy, the selected Hb concentration be in the range of 11.0 to 12.0 g/dl. ( 2D ) 86 ESA Maintenance Therapy

87. Determine the initial ESA dose using the patient’s Hb concentration, body weight, and clinical circumstances. ( 1D ) ESA dose adjustments be made based on the patient’s Hb concentration, rate of change in Hb concentration, current ESA dose and clinical circumstances. ( 1B ) 87 ESA Dosing

88. Decrease ESA dose in preference to withholding ESA when a downward adjustment of Hb concentration is needed. ( 2C ) Re-evaluate ESA dose if ( Not Graded ): The patient suffers an ESA-related adverse event The patient has an acute or progressive illness that may cause ESA hyporesponsiveness . 88 ESA Dosing

89. Objective of initial ESA therapy is rate of increase in Hb conc. of 1.0 – 2.0 g/dl per month. Avoid rise of >2.0 g/dl over 4 weeks period. Epoietin alfa /beta : start with 20 – 50 IU/kg thrice weekly. Darbepoietin alfa : Start with 0.45 mcg/kg 1/week by SC or IV route. 0.75 mcg/kg 1/2week by SC route. CERA : Start with 0.6 mcg/kg 1/2week by SC or IV route for CKD5ND or CKD5D respectively. 1.2 mcg/kg 1/month sc for CKD-5ND. 89 ESA Dosing

90. Epoietin alfa or beta dosage can be increased every 4 weeks if increase of Hb is not adequate. If Hb is increased to 11.5 g/dl, decrease dose by 25%. If Hb increases by more than 1.0 g/dl in any 2 week period, the dose should be increased by 25%. 90 ESA Dosing

91. For CKD 5HD patients and those on hemofiltration or hemodiafiltration therapy, recommendation is either intravenous or subcutaneous administration of ESA. ( 2C ) For CKD ND and CKD 5PD patients, recommendation is subcutaneous administration of ESA. ( 2C ) 91 ESA Administration

92. Frequency of administration Based on CKD stage, treatment setting, efficacy considerations, patient tolerance and preference, and type of ESA. ( 2C ) In pts on HD, receiving SC or IV short acting ESA, efficacy decreases when the dosing is increases from 3/week to 1/week Darbepoietin : max efficacy : every 2 week For CERA : every 4 weeks. 92 ESA Administration

93. Choose an ESA based on the balance of Pharmacodynamics , Safety Information, Clinical Outcome Data, Costs, & Availability . ( 1D ) Use only ESAs that have been approved by an independent regulatory agency. Specifically for ‘copy’ versions of ESAs, true biosimilar products should be used. ( 2D) 93 Type Of ESA

94. 94 Evaluating And Correcting Persistent Failure To Reach Or Maintain Intended Hemoglobin Concentration

95. During the initiation phase of ESA therapy, measure Hb concentration at least monthly . ( Not Graded ) For CKD ND patients, during the maintenance phase of ESA therapy measure Hb concentration at least every 3 months . ( Not Graded ) For CKD 5D patients, during the maintenance phase of ESA therapy measure Hb concentration at least monthly. ( Not Graded ) 95 Frequency Of Monitoring

96. Classify patients as having ESA hyporesponsiveness if they have no increase in Hb concentration from baseline after the first month of ESA treatment on appropriate weight-based dosing . ( Not Graded ) In patients with ESA hyporesponsiveness , avoide repeated escalations in ESA dose beyond double the initial weight-based dose . ( 2D ) 96 Initial ESA Hyporesponsiveness

97. Classify patients as having ACQUIRED ESA hyporesponsiveness if after treatment with stable doses of ESA, they require 2 increases in ESA doses up to 50% beyond the dose at which they had been stable in an effort to maintain a stable Hb concentration. ( Not Graded ) In patients with acquired ESA hyporesponsiveness , avoide repeated escalations in ESA dose beyond double the dose at which they had been stable. ( 2D ) 97 Subsequent ESA hypo-responsiveness

98. 98 Causes

99. Evaluate and treat for specific causes of poor ESA response. ( Not Graded ) For patients who remain hyporesponsive despite correcting treatable causes, recommendation is - individualization of therapy , accounting for relative risks and benefits of ( 2D ): Decline in Hb concentration. Continuing ESA, if needed to maintain Hb concentration, with due consideration of the doses required, and blood transfusions . 99 Management of poor ESA responsiveness

100. 100

101. We recommend NOT USING ANDROGENS as an adjuvant to ESA treatment. ( 1B) We suggest NOT USING adjuvants to ESA treatment including VITAMIN C, VITAMIN D, VITAMIN E, FOLIC ACID, L-CARNITINE, AND PENTOXIFYLLINE . ( 2D ) 101 Adjuvant Therapies

102. Hyporesponse To Erythropoiesis -stimulating Agents (ESAs) UpToDate.com 102

103. Criteria for ESA resistance are not well defined . We use the Kidney Disease Outcomes Quality Initiative (KDOQI) criteria of inability to achieve or maintain a desired Hb concentration using a maximum dose of 450 units/kg per week intravenous erythropoietin or 300 units/kg per week subcutaneous erythropoietin . 103 Definition And Criteria

104. Criteria for other ESAs, such as darbepoetin and methox y p ol yethylene glycol- ep oetin beta , have not been defined , since precise dose conversions are not known. Package inserts suggest that 45,000 units/week of epoetin corresponds roughly to 100 mcg/week of darbepoetin . 104 Definition And Criteria

105. Other criteria have been suggested by European Best Practice Guidelines and Kidney Disease: Improving Global Outcomes (KDIGO) Failure to attain or maintain desired Hb concentration with 300 units/kg per week of erythropoietin (approximately 20,000 units/week) and 1.5 mcg/kg per week of darbepoetin alfa (approximately 100 mcg/week). 105 Definition And Criteria

106. Having no increase in Hb concentration after the first month of appropriate weight- based dosing and/or requiring two increases in ESA doses up to 50 percent beyond the dose at which the patient had originally been stable. A practical definition of an ESA-resistant patient is one who requires a dose that is greater than that given to 90 percent of patients in a given facility . 106 Definition And Criteria

107. Iron deficiency Infection or inflammation Inadequate dialysis Other conditions 107 Causes

108. Other causes- Severe hyperparathyroidism with osteitis fibrosis cystica , Malignancy, Bone marrow disorders such as myelodysplastic syndrome and multiple myeloma, and hemoglobinopathies , such as sickle cell disease. B12 and folate deficiencies have also been reported in ESA hyporesponsive patients. 108 Causes

109. ESA can be stopped or continued at a low dose that helps to minimize transfusion requirements. Use of transfusions as needed to manage anemia-related symptoms. Results of a single, phase IIa , exploratory study indicated that the hypoxia-inducible factor prolyl hydroxylase inhibitor DAPRODUSTAT increased hemoglobin ( Hb ) in two of seven hemodialysis patients who remained on treatment for 16 weeks. 109 Treatment

110. A number of non-iron pharmacologic agents have been evaluated as adjuvants to ESAs. These agents include L- carnitine , ascorbic acid, androgens, p entoxif ylline , statins , and others. We do not use any of these agents for treating anemia or reversing ESA resistance. 110 Treatment

111. Harrisons textbook of internal medicine, 20 th edition Uptodate.com AJKD.2016.67.1.133-142. CJASN.3.1.2008 Kidney International Supplements. 2017.7157-163. Kidney International 2016.90.1115-1122. KDIGO guidelines. 111 References

112. 112 Thank You For Your Patience