Caution of using ESA therapy ❖ Active malignancy in particular when cure is the anticipated outcome (1B) ❖ History of stroke (1B) ❖ History of malignancy (2C) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
KDIGO Guideline Recommendations for Initiation and Maintenance of ESAs ❖ In initiating and maintaining ESA therapy ❖ We recommend balancing 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) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Indications for blood transfusions ❖ Rapid correction of anemia for stabilize the patient’s condition (e.g. acute hemorrhage) ❖ Rapid pre-operative Hb correction ❖ Symptoms and signs related to anemia ❖ ESA therapy is ineffective (bone marrow failure, hemoglobinopathies, ESA resistance) ❖ Risks of ESA therapy KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Outline ❖ Physiologic changes and anemic evaluation ❖ Target of hemoglobin in patients with CKD ❖ ESA treatment of anemia in CKD and dialysis ❖ ESA resistance and side effects ❖ Iron treatment in hemodialysis ❖ Novel treatment in anemia of CKD
Inadequate Response to Epoetin ❖ Infection/inflammation ❖ Folate or vitamin B12 deficiency ❖ Osteitis fibrosa ❖ Multiple myeloma ❖ Aluminum toxicity ❖ Hemolysis ❖ Chronic blood loss ❖ Antibody-mediated PRCA ❖ Iron deficiency anemia ❖ Malnutrition ❖ Hemoglobinopathies (eg, alpha ❖ Inadequate dialysis and beta thalassemias, sickle cell anemia) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Potentially correctable versus non correctable factors involved in the anemia of CKD Easily correctable Potentially correctable Impossible correct Hemoglobinopathies Absolute iron deficiency Infection/inflammation BM disorders Vit B12/folate deficiency Underdialysis Hypothyroidism Hemolysis Non-adherence Bleeding ACE-/ARB Hyperparathyroidism PRCA Malnutrition Malignancy KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Practical approach in ESA hyporesponsiveness Tests Finding and action Check adherence If poor, attempt to improve (if self-injection) If >130,000/ml, look for blood loss or hemolysis: endoscopy, colonoscopy, Reticulocyte count hemolysis screen Serum vitamin B12, If low, replenish folate Iron status If low, replenish Serum PTH If elevated, manage hyperparathyroidism Serum CRP If elevated, check for and treat infection or inflammation Underdialysis If underdialyzed, improve dialysis efficiency ACEi/ARB use If yes, consider reducing dose or discontinuing drug Bone marrow biopsy Manage condition diagnosed e.g., dyscrasia, infiltration, fibrosis KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Factors involved in the pathogenesis of ESA induced PRCA Macdougall IC, et al. Kidney International (2012) 81, 727–732
Antibody-Mediated PRCA ❖ Bio-similar in Thailand ❖ 30 patients with CKD treated by SC biosimilar r-HuEpo and developed a sudden loss of efficacy ❖ 23 patients were positive for r-HuEpo-neutralizing antibodies, and PRCA ❖ Estimation of risk for EPO-associated PRCA: 1: 2608 patients Praditpornsilpa K, et al. Kidney Int. 2011; 80: 88-92
EVALUATION FOR PURE RED CELL APLASIA (PRCA) ❖ Patient receiving ESA therapy for more than 8 weeks develops the following (Not Graded): 1. Sudden decrease in Hb at the rate of 0.5-1.0 g/dL per week OR requirement of transfusions at the rate 1-2 per week 2. Normal platelet and white cell counts 3. Absolute reticulocyte count < 10,000/mL KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
EVALUATION FOR PURE RED CELL APLASIA (PRCA) 4. BM biopsy: reduced numbers or absence of erythroblasts 5. Neutralizing antibodies against erythropoietin KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335. Pollock C, et al. Clin J Am Soc Nephrol 2008: 3: 193–199.
Erythropoietin(EPO) ❖ ESA therapy be stopped in patients who develop antibody- mediated PRCA (1A ) ❖ Recommend peginesatide be used to treat patients with antibody-mediated PRCA. (1B ) Peginesatide: synthetic peptide that activates the EPO receptor Withdrawn from the market due to serious hypersensitivity reactions (0.2 %) following the first dose of IV administration Peginesatide was withdrawn from the market due to serious hypersensitivity reactions reported in approximately 0.2 percent of patients following the first dose of IV administration KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Antibody-Mediated PRCA ❖ Immunosuppressive therapy is usually required to lower the anti-EPO antibodies ❖ Recovery rates from PRCA ❖ 2% without immunosuppressive therapy ❖ 52% after immunosuppressive therapy ❖ Prednisone 1 mg/kg: 50% ❖ Corticosteroids + cyclophosphamide: 87% ❖ Humanized mAb to the IL-2 receptor (daclizumab): 40% ❖ 95% after kidney transplantation Bennett CL, et al. Blood 2005; 106: 3343-7. Pollock C, et al. Clin J Am Soc Nephrol 2008: 3: 193–199.
Rx Epoetin-Resistant Patients ❖ Androgens ❖ Vitamin C ❖ Carnitine ❖ Pentoxyphyllin ❖ Dialysis prescription; dialysis efficiency; hemodialysis with biocompatible membranes
Oxymetholone in combination with EPO on hematologic parameters in CAPD patients Treatment group (n = 11) received rHuEPO plus oral oxymetholone (50 mg twice daily). Placebo group (n = 13) received rHuEPO plus a placebo. 40 p = 0.001 38.1 30 32.8 20 p = 0.001 10 12.9 11 0 oxymetholone placebo oxymetholone placebo Oxymetholone significantly enhances the erythropoietic effects of rHuEPO in CAPD patients Significant increases in liver enzymes Aramwit P, Palapinyo S, Supasyndh O Int J Clin Pharmacol Ther. 2010;48:803-13.
Meta-analysis of Ascorbic Acid in Dialysis ❖ Ascorbic acid is believed to improve anemia in patients with end-stage renal disease Change Hemoglobin levels Deved V, et al. Am J Kidney Dis 2009; 54: 1089–1097.
Meta-analysis of Ascorbic Acid in Dialysis ❖ Ascorbic acid is believed to improve anemia in patients with end-stage renal disease Change EPO dose Deved V, et al. Am J Kidney Dis 2009; 54: 1089–1097.
Vitamin C ❖ Vitamin C has been reported to increase the release of iron from ferritin and the reticuloendothelial system and increase iron utilization during heme synthesis ❖ Vitamin C may result in larger increases in Hb and may limit the use of ESAs ❖ Long-term safety of IV ascorbic acid in HD patients remains undefined KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Rx Epoetin-Resistant Patients ❖ Androgens ❖ Vitamin C ❖ Carnitine ❖ Pentoxyphyllin ❖ Dialysis prescription; dialysis efficiency; hemodialysis with biocompatible membranes Insufficient data to support the conclusions that any of these therapies enhances the response to Epoetin
Outline ❖ Physiologic changes and anemic evaluation ❖ Target of hemoglobin in patients with CKD ❖ ESA treatment of anemia in CKD and dialysis ❖ ESA resistance and side effects ❖ Iron treatment in hemodialysis ❖ Novel treatment in anemia of CKD
A RCT: iron supplementation in patients treated with erythropoietin IV iron supplement have an enhanced hemoglobin and lower dosage requirements of EPO Macdougall IC, et al. Kidney Int. 1996; 50(5):1694.
Reached a hemoglobin level response >1 g/dL, IV iron vs. oral iron Safety analysis showed similar rates of mortality and serious and any adverse effects Patients treated with IV iron were more likely to reach an Hb response > 1 g/dL (RR 1.61 [95% CI, 1.39-1.87] for CKD stages 3-5 Shepshelovich D, et al. Am J Kidney Dis. 2016;68(5):677-690.
Recommendations for When to Treat With Iron in CKD ❖ For adult CKD patients on ESA therapy who are not receiving iron supplementation, we suggest a trial of IV iron or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if (2C): ❖ An increase in Hb concentration or a decrease in ESA dose is desired and ❖ TSAT is <30% and ferritin is <500 ng/mL KDIGO Clinical Practice Guideline for Anemia in CKD Kidney Int. 2012; 2: 279–335.
IV iron dosing ❖ Loading dose iron ❖ Iron sucrose 100 mg given at each consecutive hemodialysis treatment for a total of 10 doses (1000 mg in total) ❖ Maintenance dose iron ❖ Iron sucrose at a dose of 25 to 100 mg administered once weekly or every other week Aronoff GR, et al. Kidney Int. 2004;66(3):1193. Charytan C, et al. Am J Kidney Dis. 2001;37(2):300.
Iron formulations introduced in the United States Iron dextran (high molecular weight): anaphylactoid-type reactions 82/100,000 vs. 21/100,000 Vaziri ND, et al. Am J Kidney Dis. 2016;67(3):367-375
Adjusted OR of anaphylaxis for iron dextran was 3.6 (95% CI, 2.4-5.4); for iron gluconate, 2.0 (95% CI 1.2, 3.5); and for ferumoxytol, 2.2 (95% CI, 1.1-4.3) compared with iron sucrose, Test dose Wang C, et al. JAMA 2015;314:2062-8.
Reached a hemoglobin level response >1 g/dL, IV iron vs. oral iron IV iron therapy is associated with an increased risk of serious adverse events, including those from CVD and infectious diseases Shepshelovich D, et al. Am J Kidney Dis. 2016;68(5):677-690.
Iron during infection Hougen I, et al. Clin J Am Soc Nephrol 2018: 13: 457–467.
Iron during infection Higher-dose intravenous iron does not seem to be associated with higher risk of mortality, infection, cardiovascular events, or hospitalizations in adult patients on dialysis Hougen I, et al. Clin J Am Soc Nephrol 2018: 13: 457–467.
❖ 2141 patients underwent randomization (1093 patients to the high-dose group (400 mg/month) and 1048 to the low-dose group (0-400 mg/month). Macdougall IC, et al. N Engl J Med. 2019; 380(5):447-458.
A high-dose IV iron regimen administered proactively was noninferior to a low-dose Primary and Secondary End Pointsregimen administered reactively and resulted in lower doses of ESA being administered. Macdougall IC, et al. N Engl J Med. 2019; 380(5):447-458.
Treatment with iron agents ❖ When prescribing iron therapy ❖ Balance: ❖ Potential benefits of avoiding or minimizing blood transfusions, ESA therapy, and anemia-related symptoms ❖ Risks of harm in individual patients (e.g., anaphylactoid and other acute reactions, unknown long-term risks) (Not Graded) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Cations regarding iron therapy ❖ When the initial dose of IV iron dextran is administered, we recommend (1B) and when the initial dose of IV non-dextran iron is administered, we suggest (2C) that ❖ Patients be monitored for 60 minutes after the infusion, and that resuscitative facilities and personnel trained to evaluate and treat serious adverse reactions be available KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Balancing benefits and risks in IV Iron Treatment Fishbane S. Seminars in Nephrology, 2016, 36: 119–123 .
Iron during infection ❖ Avoid administering IV iron to patients with active systemic infections. (Not Graded) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.
Outline ❖ Physiologic changes and anemic evaluation ❖ Target of hemoglobin in patients with CKD ❖ ESA treatment of anemia in CKD and dialysis ❖ ESA resistance and side effects ❖ Iron treatment in hemodialysis ❖ Novel treatment in anemia of CKD
Hematopoietic actions of PHD inhibitors. HIF induces EPO and facilitates red blood cell production in the bone marrow. HIF also induces genes related to iron absorption and utilization for effective erythropoiesis. Serum hepcidin levels are increased in CKD patients, which inhibits iron absorption from the duodenum, release from the liver, and recycle from macrophages. HIF decreases hepcidin through accelerated erythropoiesis Tanaka T. Seminars in Nephrology, 2018: 38: 267–276.
HIF-prolyl hydroxylase inhibitors activate HIF signaling Neil S, et al. Adv Chronic Kidney Dis. 2019;26(4):253-266.
Hypoxia-inducible factor stabilizers ❖ Oral inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylase ❖ Increased levels of endogenous erythropoietin to within physiologic range, ❖ Increasing hemoglobin levels ❖ Improving iron homeostasis ❖ Stimulates erythropoiesis and regulates iron metabolism Tanaka T. Seminars in Nephrology, 2018: 38: 267–276.
Hypoxia-inducible factor stabilizers for treatment of anemia in CKD Coyne DW, et al. Kidney Int Supplements 2017: 7, 157–163 .
Roxadustat: correction of anemia in incident dialysis patients Besarab A, et al. J Am Soc Nephrol. 2016;27:1225–1233
❖ 154 patients with CKD in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner In patients with CKD without dialysis, Roxadustat group had a higher mean hemoglobin level and lower serum hepcidin level after 8 weeks Chen N, et al. N Engl J Med. 2019; 381(11):1001-1010.
❖ 154 patients with CKD in a 2:1 ratio to receive roxadustat or placebo three times a week for 8 weeks in a double-blind manner In patients with CKD without dialysis, Roxadustat group had a lower serum hepcidin level after 8 weeks Chen N, et al. N Engl J Med. 2019; 381(11):1001-1010.
Hyperkalemia and metabolic acidosis occurred more frequently in the roxadustat Adverse Events (Safety Population)group than in the placebo group Chen N, et al. N Engl J Med. 2019; 381(11):1001-1010.
Neil S, et al. Adv Chronic Kidney Dis. 2019;26(4):253-266.
Benefits, Potential Disadvantages, and Safety of HIF stabilizers Neil S, et al. Adv Chronic Kidney Dis. 2019;26(4):253-266.
Benefits, Potential Disadvantages, and Safety of HIF stabilizers Neil S, et al. Adv Chronic Kidney Dis. 2019;26(4):253-266.
Outline ❖ Physiologic changes and anemic evaluation ❖ Target of hemoglobin in patients with CKD ❖ ESA treatment of anemia in CKD and dialysis ❖ ESA resistance and side effects ❖ Iron treatment in hemodialysis ❖ Novel treatment in anemia of CKD
Thank you for your attention Intelligence Dialysis Center Nephrology Unit Phramongkutklao Hospital and College of Medicine
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