PRACTICE AID Snapshot of Anemia in Chronic Kidney Disease Common Causes of Evaluation of Diagnosis of CKD2 Anemia in CKD1 Anemia in CKD1 • Relative erythropoietin deficiency • Focused history and physical examination The KDIGO Anemia Work Group recommends that • Iron deficiency • Blood testing HCPs diagnose anemia in • Blood loss – Chemistries • Males aged >15 when Hb falls <13 g/dL • Reduced erythrocyte survival duration – Complete blood cell count • Females aged >15 when Hb falls <12 g/dL • Inflammation (including RBC indexes) • Infection – Reticulocyte count If a patient has lost at least half of normal kidney • Underlying hematologic disease – Serum ferritin function and has low Hb, cause of anemia may be • Hyperparathyroidism (dialysis patients) – Transferrin saturation decreased EPO production • Hemolysis – Folic acid • Nutritional deficits – Vitamin B12 Two other blood tests help measure iron levels • Ferritin level helps assess amount of iron stored in the body; ferritin score <200 ng/mL may mean iron deficiency that requires treatment • Transferrin saturation score indicates how much iron is available to make RBCs; transferrin saturation score <30% can mean low iron levels that require treatment The diagnosis of erythropoietin deficiency in an anemic patient with CKD is a diagnosis of exclusion. Access the activity, “Evolving Management Approaches to Anemia in Chronic Kidney Disease: Implications for the Nephrology Nurse,” at PeerView.com/MVV40 PRACTICE AID Snapshot of Anemia in Chronic Kidney Disease Flowchart for the Evaluation of the Chronic Kidney Disease Patient With Anemia2,3 CKD stages 1-5 Further Blood loss, Yes No hematology hemoglobinopathy, workup vitamin B12, folate No Iron deficiency Fe Yes Treat with iron Yes ≤13.0 (men) Workup Normal? ≤12.0 (women) Anemia corrected, CBC, RBC indices, periodic follow-ups iron studies, stool No Yes for occult blood Treat with epoetin if indicated and Hb <10 g/dL No workup Anemia not corrected CKD: chronic kidney disease; EPO: erythropoietin; KDIGO: Kidney Disease: Improving Global Outcomes; RBC: red blood cell. 1. Fishbane S, Spinowitz B. Am J Kidney Dis. 2018;71:423-435. 2. Kidney Int Suppl (2011). 2012;2:288-291. 3. Adapted from: Kidney Disease Outcomes Quality Initiative. Am J Kidney Dis. 2006;47(suppl. 3):S1-S145. Access the activity, “Evolving Management Approaches to Anemia in Chronic Kidney Disease: Implications for the Nephrology Nurse,” at PeerView.com/MVV40 PRACTICE AID Hypoxia-Inducible Factor (HIF) Pathway1 Proline hydroxylation Normoxia Proteasomal 0 HIF-α degradation H 02 HIF-PH-1 HIF-PH-2 HIF-PH inhibitor 02 02 HIF-PH-3 HIF 02 stabilization Nucleus HIF-α HIF-2α HIF-1α HIF-β Heterodimerization HIF-3α & translocation HIF Transcription stabilization HIF-β 0 2 Complete HIF-PH-1 HIF-β erythropoiesis HIF-PH-2 HIF-β # Erythropoietin HIF-PH-3 HIF-β # Erythropoietin receptor $ Hepcidin # DMT1 Hypoxia # DcytB # Transferrin # Transferrin receptor # Ceruloplasmin EPO: erythropoietin; HIF-PH: hypoxia inducible factor prolyl hydroxylase. 1. Gupta N, Wish JB. Am J Kidney Dis. 2017;69:815-826. Access the activity, “Evolving Management Approaches to Anemia in Chronic Kidney Disease: Implications for the Nephrology Nurse,” at PeerView.com/MVV40 PRACTICE AID HIF-PHIs in Phase 3 of Clinical Development in the United States: Clinical Trial Updatesa,b Roxadustat1-8 DD-CKD Studies N Population, Comparator Efficacy Results HIMALAYAS N = 1,043 Incident dialysis vs EPO Superior to EPO SIERRAS N = 741 Stable dialysis vs EPO Superior to EPO ROCKIES N = 2,133 Stable/incident dialysis vs EPO Superior to EPO PYRENEES N = 836 Stable dialysis vs EPO or darbepoetin Superior to ESA NDD-CKD Studies N Population, Comparator Efficacy Results ALPS N = 594 Nondialysis vs placebo Superior to placebo ANDES N = 922 Nondialysis vs placebo Superior to placebo OLYMPUS N = 2,781 Nondialysis vs placebo Superior to placebo DOLOMITES N = 616 Nondialysis vs darbepoetin Noninferior to ESA Pooled Safety Analysis Population, All-Cause MACE MACE+ Conclusion Comparator Mortality HR = 1.08 HR = 1.04 HR = 1.06 NDD Risk of MACE, MACE+, and all-cause mortality in roxadustat (95% CI, (95% CI, (95% CI, (n = 4,270) Placebo patients comparable with placebo 0.94-1.24) 0.91-1.18) 0.91-1.23) HR = 0.70 HR = 0.66 HR = 0.76 Those taking roxadustat had 30% ↓ risk of MACE and 34% ↓ risk of ID (95% CI, (95% CI, (95% CI, MACE+ compared with those taking EPO, with a trend toward (n = 1,526) EPO 0.51-0.96) 0.50-0.89) 0.52-1.11) ↓ all-cause mortality for roxadustat, relative to EPO HR = 0.96 HR = 0.86 HR = 0.96 DD No ↑ risk of MACE and all-cause mortality (95% CI, (95% CI, (95% CI, (n = 3,880) EPO and a ↓ risk of MACE+ compared with EPO 0.82-1.13) 0.74-0.98) 0.79-1.17) Access the activity, “Evolving Management Approaches to Anemia in Chronic Kidney Disease: Implications for the Nephrology Nurse,” at PeerView.com/MVV40 PRACTICE AID HIF-PHIs in Phase 3 of Clinical Development in the United States: Clinical Trial Updatesa,b Ongoing phase 3 trials • ASCEND-ID (N = 300): daprodustat vs darbepoetin alfa in ID patients • ASCEND-TD (N = 407): daprodustat administered three times weekly vs epoetin alfa Daprodustat9 • ASCEND-NHQ (N = 600): daprodustat vs placebo in NDD patients • ASCEND-D (N = 2,698): daprodustat vs rhEPO in HD patients switching from an ESA • ASCEND-ND (N = 4,500): daprodustat vs darbepoetin alfa in NDD patients; will include patients either switching from or naïve to an ESA Ongoing phase 3 trials • INNO2VATE-CORRECTION/CONVERSION (N = 369): vadadustat noninferior to darbepoetin alfa in incident DD patients 9-10 • INNO2VATE-CONVERSION (N = 3,554): vadadustat noninferior to darbepoetin alfa in Vadadustat ESA-treated DD patients • PRO2TECT-CORRECTION (N = 1,761): vadadustat vs darbepoetin alfa in NDD patients • PRO2TECT-CONVERSION (N = 1,752): vadadustat vs darbepoetin alfa in ESA-treated NDD patients a As of November 20, 2019. b As of November 25, 2019, all results presented herein have been given only in abstract form and need to be verified in a peer-reviewed publication. AE: adverse event; CKD: chronic kidney disease; DD: dialysis-dependent; EPO: erythropoietin; ESA: erythropoiesis-stimulating agent; HD: hemodialysis; ID: incident (newly initiated) dialysis; MACE: major adverse cardiovascular event; NDD: non–dialysis-dependent; PD: peritoneal dialysis; rhEPO: recombinant human erythropoietin; SAE: serious adverse event. 1. Provenzano R et al. American Society of Nephrology Kidney Week 2019 (ASN 2019). Abstract TH-OR021. 2. Charytan C et al. ASN 2019. Abstract SA-PO227. 3. Fishbane S et al. ASN 2019. Abstract TH-OR022. 4. Esposito C et al. ASN 2019. Abstract SA-PO225. 5. Coyne D et al. ASN 2019. Abstract SA-PO228. 6. Fishbane S et al. ASN 2019. Abstract TH-OR023. 7. Barratt J et al. 57th European Renal Association-European Dialysis and Transplant Association Virtual Congress. Abstract MO001. 8. Provenzano R et al. ASN 2019. Abstract FR-OR131. 9. https://clinicaltrials.gov/. 10. https://www.prnewswire.com/news-releases/akebia-therapeutics-announces-positive-top-line-results-from-global-phase-3-program-of-vadadustat-for-treatment-of-anemia-due-to-chronic-kidney-disease-in-adult-patients-on-dialysis-301052824.html. Access the activity, “Evolving Management Approaches to Anemia in Chronic Kidney Disease: Implications for the Nephrology Nurse,” at PeerView.com/MVV40 PRACTICE AID Current Status of Anemia Management1,2 CKD 3 CKD 4 CKD 5 CKD 5Da Complete blood count Investigation Absolute reticulocyte count Serum B12 and folate Serum ferritin and transferrin saturation Diagnosis of Anemia Adults and children aged >15 years: Hb <13.0 g/dL in males; Hb <12.0 g/dL in females Children: Hb <11.0 g/dL for 0.5-5 years; Hb <11.5 g/dL for 5-12 years; Hb <12.0 g/dL for 12-15 years Not Annually Twice annually At least monthly Testing and Anemic Monitoring Anemic but Every 3 months At least monthly Not on ESA Adults with anemia not on iron or ESAs • IV iron trial if ↑ in Hb or ↓ in ESA dose desired, TSAT <30%, and ferritin <500 ng/mL Adults on ESAs but not on iron Iron Therapy • IV iron trial OR 3-month oral iron trial if ↑ in Hb or ↓ in ESA dose desired Children with anemia not on iron or ESAs or on ESAs but not iron IV iron if TSAT<20% • Oral iron if TSAT <20% and ferritin <100 ng/mL and ferritin <100 ng/mL Iron Monitoring TSAT and ferritin every 3 months during ESA therapy or more frequently if ESA dose changing or blood loss present Monitor for 60 minutes after IV iron infusion with iron dextran Precautions Resuscitative facilities and trained personnel Monitor for 60 minutes after IV iron infusion with non-dextran iron Caveats Avoid in setting of infection Address correctable causes of anemia prior to initiation Adults with Hb <10 g/dL: initiate based on individual rate of Hb fall, Initiate at Initiation prior response to iron, risk of needing transfusions, risks related to ESAs, Hb <10 g/dL to and presence of anemia-related symptoms avoid fall to <9 g/dL ESA Therapy Children: initiate based on balance of risk vs potential benet Adults: dose to achieve a Hb <11.5 g/dl Maintenanceb Children: dose to achieve a Hb between 11.0 and 12.0 g/dL Use with caution if at all in setting of active malignancy, history of stroke Precautions Use with caution when history of malignancy Do not use ESAs to target a Hb >13 g/dL Grade 1 Grade 2 Not Graded A - D A - D Stages of Chronic Kidney Disease CKD Stage Description GFR, mL/min/1.73 m2 1 Kidney damage with normal or ↑ GFR ≥90 2 Kidney damage with mild ↓ GFR 60-89 3 Moderate ↓ GFR 30-59 4 Severe ↓ GFR 15-29 5 Kidney failure <15 (or dialysis) a 5D if dialysis (HD or PD).