4. Handout_Anemia-Nutrition-HBV vaccine_Naowanit_24 June 2022 (1)

Optimum Anemia and Nutrition Management in CKD Asst. Prof. Naowanit Nata, MD Nephrology Division, Department of Medicine Phramongkutklao Hospital & College of Medicine

Disclosure Information  Asst. Prof. Naowanit Nata, MD  Scientific Advisor/Honoraria: – Boehringer Ingelheim, Astra Zeneca, LG Life Sciences, Janssen-Cilag, MSD, Novo Nordisk, Astellas, Sanofi Aventis, Novartis, and Thai Otsuka  DISCLAIMER: – This presentation is intended for educational purpose for HCPs only. It may contain new science data which is currently not in approved package insert information and is not intended for off-label promotion.

Outlines  Evaluation and management of anemia in CKD  Clinical efficacy and clinical benefit of Espogen  PRCA  Brief nutrition management in CKD

Evaluation and Management of CKD Grade GFR Terms Management G1 ≥ 90 Normal or high - Specific therapy, based on diagnosis G2 60-89 Mildly decreased - Management of comorbid diseases Systemic Complications in CKD: G3a 45-59 Mildly to moderate - Treatment CVD risk factors 1. Anemia of CKD decreased Slowing loss of kidney function 2. Malnutrition G3b 30-44 Moderate to 3. Hyperkalemia severe decreased Prevention and treatment of 4. Metabolic acidosis G4 15-29 severe decreased complications 5. Mineral and bone disorders 6. Cardiovascular complication G5 < 15 Kidney failure Preparation for kidney replacement therapy GFR (mL/min/1.73m2) Kidney replacement therapy Adapted from: KDIGO CKD Work Group: Kidney International Supplements (2013) 3:1, 1–150. UpToDate 2021

Role of Erythropoietin in Normal Mature RBC Production Erythropoietin-Dependent Iron-Dependent Prevents apoptosis Hemoglobin synthesis enucleation Pluripotent Progenitor cells Erythroblasts Reticulocyte RBC hematopoietic PolyEB BFU-E CFU-E ProEB BasoEB OrthoEB stem cells (Contains the highest concentration of EPO-R) ~8-13 days 4 days BasoEB = basophilic erythroblast; BFU-E = burst-forming units-erythroid; CFU-E = colony-forming units-erythroid; EPO-R = erythropoietin receptor; OrthoEB = orthochromatic erythroblast; PolyEB = polychromatic erythroblast; ProEB = proerythroblast; RBC = red blood cell. 1. Erslev AJ et al. Med Oncol Tumor Pharmacother. 1986;3:159-164; 2. Elliott S et al. Ann Hematol. 2014;93:181-192; 3. Brugnara C et al. Hematologic aspects of kidney disease. 2016: 1875-1911; 4. Koury MJ et. Nat Rev Nephrol. 2015;11:394-410; 5. Besarab A. Nat Rev Nephrol. 2010;6:699-710; 7. Valent P et al. Haematologica. 2018;103:1593-1603.

Mechanisms of Anemia in CKD Babitt JL, Lin HY. J Am Soc Nephrol. 2012 Oct;23(10):1631-4.

Definition of Anemia 2012 2012 Hb (g/dL) Hct (%) Hb (g/dL) Hct (%) Men < 13.0g/dL < 39.0% < 13.5 g/dL < 40.5% Women < 12.0 g/dL < 36.0 % < 12.0 g/dL < 36.0 % 1. KDIGO Anemia Work Group. Kidney Int Suppl 2013;2(4):279-335. 2. KDOQI Clinical Practice Guideline for Anemia, Am J Kidney Dis., 2013;62(5): 849-859

Anemia of Chronic Kidney Disease  Normocytic, normochromic anemia  Starts when the eGFR < 30-60 (stage 3-4 CKD)

Prevalence of Anemia in Thailand Prevalence of Anemiaa (%) 100% 100% 80% 66.70% 60% 40% 43.20% 20% 21.40% 23.00% 0% II III IV V I Stage I Stage II Stage III Stage IV Stage V Hbb (g/dL) 13.2±1.6 13.4±1.7 12.5±1.7 10.7±1.6 9.7±1.6 Thai SEEK Project: aged ≥ 18 years 2,568 from 3,459 participants aAnemia by WHO criteria; Hb M12 g/dL in women, <13 g/dL in men bHemoglobin level was espressed as mean±SD Chaiprasert A., Prevalence and awareness of anemia in chronic kidney disease in Thailand, Proceeding of the World Congress of Nephrology; 2009 May 22-26; Milan, Italy

Laboratory for Evaluate in Anemia  CBC: Hb, Hct, WBC, platelet count, Red blood cell indices (MCV, MCHC)  Iron status: Serum ferritin level, TSAT (serum transferrin saturation)  Absolute reticulocyte count  Serum vitamin B12, folate levels (If indicated) MCV: Mean corpuscular volume 1. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease, Kidney Int Suppl 2012;2 283-287. MCHC: Mean corpuscular Hb 2. Thailand Hemodialysis Guideline 2014 3. Thailand CKD Guideline 2015 4. Thai Anemia Guideline 2021

Frequency of Hb Testing for Anemia Stage No anemia Anemia CKD 3 ≤yearly without ESA with ESA CKD 4-5 ≤6 months CKD 5 PD ≤3 months ≤3 months At least monthly at CKD 5 HD ≤3 months ≤3 months initiation then q ≤3 months ≤3 months** ≤1 month* 1 month** Adapted from Thai Anemia Guideline 2021 Adapted from KDIGO Guideline for Anemia. Kidney Int. vol2 issue 4, August 2012

Laboratory for Evaluate in Anemia  CBC: Hb, Hct, WBC, platelet count, Red blood cell indices (MCV, MCHC)  Iron status: Serum ferritin level, TSAT (serum transferrin saturation)  Absolute reticulocyte count  Serum vitamin B12, folate levels (If indicated) MCV: Mean corpuscular volume 1. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease, Kidney Int Suppl 2012;2 283-287. MCHC: Mean corpuscular Hb 2. Thailand Hemodialysis Guideline 2014 3. Thailand CKD Guideline 2015 4. Thai Anemia Guideline 2021

Ferritin: เก็บ Transferrin (TIBC): ขนสง่  Tissue ferritin: Iron binding protein  Iron transport protein  Shuttle iron from storage sites in for storage RES to marrow  Serum ferritin: Little or no iron,  Level decreased during balance between its inflammation/uremic/malnutrition secretion/leakage TSAT ( transferrin saturation):  Iron/TIBC  % of transferrin iron binding capacity occupied by iron in serum  Deceivably high in malnutrition/inflammation

Management of Anemia in CKD

Adverse Consequences of Anemia 1. Left ventricular hypertrophy 2. Heart failure 3. Fatigue, dizziness, shortness of breath 4. Poor quality of life, exercise capacity 5. Progression of CKD 6. Increase hospital days 7. Increased CV morbidity and mortality UpToDate 2022

Treatment Goal of Renal Anemia Corrects anemia leading to Improve QOL1 Improve Improve Reduce CV risks2 Energy Levels1 Functional Capacity1 Reduce LVH3 Reduce May Slow Delay dialysis Blood transfusion3 Progression of CKD3 initiation3 QOL = Quality of life, CV = Cardiovascular , LVH = Left ventricular hypertrophy, CKD = Chronic kidney disease 1. Singh A J et al. NEJM 2006;355(20):2085-2098 2. Locatelli F et al Nephrol Dial Transplant 1988; 13:1642-44 3. Kausz At, et al, Am J Kidney Dis, 2000, 36(6 suppl 3): S39-S51

Treatment of Anemia in Dialysis Patients 1. Find out cause and correct cause 2. Iron supplement 3. Erythropoietin stimulating agent (ESA) 4. Blood transfusion if indicated 5. Adjuvant therapy

Cause of Anemia in CKD Patient 1. Erythropoietin deficiency 11. Malnutrition: 2. Iron Deficiency 12. Hemoglobinopathies 3. Uremia 13. Hemolysis 4. Inadequate dialysis 14. Drugs 5. Inflammation 15. PRCA 6. Infection 16. Bone marrow suppression/disease 7. Shortening RBC survival 17. Hypothyroid 8. Blood loss 9. Hyperparathyroidism 10. Folic, B12 deficiency UpToDate 2021

Potentially Correctable versus Non Correctable Factors Involved in the Anemia of CKD KDIGO Guideline for Anemia. Kidney Int. vol2 issue 4, August 2012

Compare Iron supplement : IV vs. Oral in CKD stage 3-5: 1. Achieve Hb increase >1 g/dL more than oral iron RR 1.6 for CKD 3-5, RR 2.1 for CKD 5D 2. Higher risk for hypotension; RR 3.7 3. Fewer gastrointestinal adverse events; RR 0.43 Am J Kidney Dis. 68(5): 677-690, 2016

Iron Therapy for Anemia in CKD When prescribing iron therapy, balance the potential benefits of avoiding or minimizing blood transfusions, ESA therapy, anemia related symptoms against the risks of harm in individual patients e.g. anaphylactoid and other acute reactions (Not graded) For adult CKD with anemia not on iron or ESA we suggest a trial of IV iron (or in CKD ND alternatively a 1-3 month trial of oral iron) if (2C) – An increased in Hb concentration without starting ESA is desired AND – TSAT ≤ 30% and ferritin ≤ 500 ng/mL KDIGO Guideline for Anemia. Kidney Int. vol2 issue 4, August 2012

Dose of Iron Therapy  Oral iron: FeSO4 ( 20% elemental Fe), Fe fumarate (33% )  Elemental iron at least 200 mg/day – Equivalent to Fe sulfate (325) 1X3 po ac or Ferrous fumarte (200) 1X3 po ac – If not met the goals with 1-3 month course of oral iron, consider IV iron  IV iron – Iron dextran : incidence of anaphylactoid reaction, less use – Iron sucrose : free iron can lead to oxidative stress – atherosclerosis – Ferric caroxymaltose/ ferumoxytol/ iron isomaltoside : efficiency with less ADR KDIGO Guideline for Anemia. Kidney Int. vol2 issue 4, August 2012

Erythropoiesis stimulating agents (ESA)

Type of Erythropoiesis stimulating agents (ESA)  Protein-based ESA: - 1st generation: Recombinant human erythropoietin (rHuEPO) Epoetin α, ������ - 2nd generation: Darbepoetin α - 3rd generation: Methoxypolyethylene glycol epoetin ������ = CERA  Biosimilar EPO  Others: Prolyl hydroxylase inhibitor (HIF stabilizer) CERA: Continuous EPO receptor activator

Epoetin alpha Epoetin beta Darbepoetin Methoxy PEG erythropoietin Half life IV 4-13 hours IV 4-12 hours IV 12-39 hours SC 13-37 hours SC 8-22 hours SC 21-144 hours SC 139-142 hours Darbepoetin alpha 1 mcg = Epoetin 200 unit Macdougall LC, Eckardt KU. Lancet 2006; 368: 947-53

Dose at Initiation of ESA ESA Hemodialysis Non-dialysis CKD Epoetin α Darbepoetin α 50-120 unit/kg x 2-3/week 50-120 unit/kg q 1week CERA 0.45 µg/kg x 1/week SC or IV or 0.45 µg/kg q2-4 week 0.75 µg/kg q 2 week SC 0.6 µg/kg q 2 week SC/IV correction phase 0.6 µg/kg q 4 week SC/IV maintenance phase Darbepoetin alpha 1 mcg = epoetin 200 unit

Recommendation ESA: Dialysis Conditions Management  Hb <10 g/dL, TSAT ≤ 30%, ferritin ≤ 500 ng/mL Start IV iron before ESA  Hb < 10 g/dL, TSAT ≥ 30% Start ESA  Hb ≥ 10 g/dL, TSAT ≤ 20%, ferritin ≤ 200 ng/mL Iron deficient treatment  Hb ≥ 10 g/dL, TSAT ≥ 20%, ferritin ≥ 200 ng/mL Continue monitoring Recommendation: KDIGO Guideline for Anemia. Kidney Int. vol2 issue 4, August 2012 1. Start ESAs when Hb < 10 g/dL 2. Rate of Hb rise 1.0 to 2.0 per month

ESAs Therapy in CKD: Target of Treatment Target Hb Hb 10 – 11.5 g/dL Hb: Not more than 13 g/dL 1. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease, Kidney Int Suppl 2012;2 283-287. Recommendation : 2. Thailand Hemodialysis Guideline 2014, Thailand CKD Guideline 2015 1. Start ESAs when Hb < 10 g/dL 2. Rate of Hb rise 1.0 to 2.0 per month

Frequency of Hb Testing for Anemia Stage No anemia Anemia CKD 3 ≤yearly without ESA with ESA CKD 4-5 ≤6 months CKD 5 PD ≤3 months ≤3 months At least monthly at CKD 5 HD ≤3 months ≤3 months initiation then q ≤3 months ≤3 months** ≤1 month* 1 month** Adapted from Thai Anemia Guideline 2021 Adapted from KDIGO Guideline for Anemia. Kidney Int. vol2 issue 4, August 2012

Hemoglobin level Adapted from Thai Anemia Guideline 2021

Intravenous Dose of Iron Supplement Iron product Loading dose in chronic HD Loading dose in PD or CKD Iron dextran 100 mg IV q 1 week (total x 10 doses) 200-500 mg IV on 2-5 different occasions (total dose ≤1000 mg) Iron sucrose 100 mg IV q 1 week (total x 10 doses) 200-500 mg IV on 2-5 different occasions (total dose ≤1000 mg) Na ferric gluconate 125 mg iv q dialysis x 8 doses 250 mg IV slow infusion Ferumoxytol 510 mg IV x 2 doses 3-8 days apart 510 mg IV x 2 doses 3-8 days apart Iron dextran: Test dose 25 mg then close observe 30-60 minute  Loading: 100 mg IV slowly in 3-5 min or add in NSS 50-100 mL IV drip over 15 minutes x 10 dose  Maintenance dose: 25-100 mg q 2-4 weeks (iron dextran), 100 mg q 2-4 weeks (iron sucrose) 125 mg q 2-4 weeks (iron gluconate)

ESA Hyporesponsiveness  KDOQI: Inability to achieve or maintain a desired Hb concentration using - IV EPO 450 unit/kg/week or - SC EPO 300 unit/kg/week  EBPG and KDIGO 2012 - Failure to attain or maintain desired Hb with 300 u/kg/wk of erythropoietin and 1.5 mcg/kg/wk of darbepoetin alfa - No increase in Hb after the first month of appropriate weight-based dosing and/or require two increases in ESA doses up to 50% beyond the dose at which the patient had originally been stable

Approach in Presence of ESA Hyporesponsiveness

Adjuvant Therapy 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) KDIGO Clinical Practice Guideline for Anemia in CKD. Kidney Int. 2012; 2: 279–335.

Outlines  Evaluation and management of anemia in CKD  Clinical efficacy and clinical benefit of Espogen  PRCA  Brief nutrition management in CKD

ESAs Medication Short Acting Epoetin-alfa Epoetin-beta Long Acting Darbepoetin-alfa PEGlyated epoetin-beta



Clinical Studies in Thailand: ESRD patients

12-Week Clinical Effects of Erythropoietin EspogenTM in End Stage Renal Patients undergoing Hemodialysis Published in J Med Assoc Thai 2007; 90(4): 636-42

Study design Study Design Objectives: To evaluate the clinical efficacy, safety and usefulness of ESPOGEN in ESRD undergoing hemodialysis Methods: An open, non-comparative, prospective, study was conducted in 30 ESRD patients undergoing hemodialysis for a 12-week period. Dose: Initial dose : Epoietin alfa (ESPOGEN): 150 units/kg/week, s.c., 2-3 times/week Dose Adjustment:  Reduce by 25 units/kg/week if Hb increase more than 1.4g/dL within 2 weeks  Add by 50 units/kg/week if Hb do not increase more than 1g/dL within the first 4 weeks  Adjust dose to maintain Hb at 10-12 g/dL, if Hb reach 10 g/dL J Med Assoc Thai 2007; 90(4): 636-42

Eeficacy F: Hb Increase from 7.1 to 10.1 g/dL Change in hematocrit level (%) Change in hemoglobin level (g/dL) J Med Assoc Thai 2007; 90(4): 636-42

Safety Mean arterial pressure of pre-dialysis increased Mean arterial pressure of post-dialysis was not from 101.0+17.65 mmHg at week 0 to 111.4+14.4 significant change from 104.7+17.20 mmHg at mmHg at week 12 and continue at 110.4+16.8 week 0 to 106.6+17.4 mmHg at week12 mmHg at the end of the study (week12) p=0.0223 p=0.5668 J Med Assoc Thai 2007; 90(4): 636-42

Hemoglobin Response and Influence on Left Ventricular Hypertrophy after 24-Weeks Treatment of a Biosimilar Epoetin-Alfa in Hemodialysis Patients with Anemia J Med Assoc Thai 2007; 90(12): 2574-86

Study Design and Methods Objective:  To conduct a prospective trial to evaluate the efficacy and safety of a biosimilar epoetin-alfa (epoetin) (EspogenTM) in ESRD patients receiving chronic hemodialysis complicated by anemia  To address its impact on the left ventricular mass index (LVMI) and volume index (LVVI) in these patients. 22 Chronic HD subjects from Rajavithi and Huachiew HPs hemoglobin (Hb) < 10 g/dL No treatment Epoetin or transfusion for 1 month 24 weeks EspogenTM 4,000 IU S.C. twice a week, titrated biweekly, Hb range of 11 - 12 g/dL (titration period 12 wks), Record: blood tests, blood pressure, amount of drugs needed to control blood pressure, adverse events, Echocardiogram J Med Assoc Thai 2007; 90(12): 2574-86

Average Weekly Dose during 24 weeks = 164.5 IU/kg/week 143.6+37.8 149.7+73.3 week Average dose/week at 8,225 IU for patient 50 kg BW J Med Assoc Thai 2007; 90(12): 2574-86

EchocardiogEracphhoy cRaesrudltio(2g/2r)aphy Result * p=0.028 vs baseline LVVI reduce from 103.7+25.2 to 79.6+21.9 mL/m2 (p=0.028) within 24 weeks LVVI (mL/m2) 120 * Baseline 100 End of study >130 to 160 >160 80 Tertiles by baseline LVMI (g/m2) 60 40 J Med Assoc Thai 2007; 90(12): 2574-86 20 0 ≤130

Lee YK, et al. Nephrol Dial Transplant (2008) 23: 3240–3246.

Study Design 146 pts. 44 pts. 40 pts. 35 pts. 83 pts. 39 pts. Lee YK, et al. Nephrol Dial Transplant (2008) 23: 3240–3246.

Hemoglobin (g/dL) Results 10.66 10.61 Hematocrit (%) 11.40 31.90 33.75 10.9 31.41 33.00 No statistically significant between-group (once weekly & control) differences were apparent for changes in haemoglobin levels or epoetin alfa dosages at week 12 Lee YK, et al. Nephrol Dial Transplant (2008) 23: 3240–3246.

Safety There was no significant difference between groups in both systolic and diastolic blood pressure during the trial Lee YK, et al. Nephrol Dial Transplant (2008) 23: 3240–3246.