1. Updates From Kidney Week Chronic Kidney Disease and Associated Anemia
Moderator
Steven N. Fishbane, MD
Professor of Medicine
Hofstra Northwell School of Medicine
Chief, Division of Kidney Diseases and Hypertension
North Shore University Hospital
Long Island Jewish Medical Center
Great Neck, New York

2. Panelists Jeffrey S. Berns, MD Myles S. Wolf, MD Professor of Medicine
Associate Dean for Graduate Medical Education
University of Pennsylvania
Director
Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania
Myles S. Wolf, MD
Professor of Medicine
Chief of Nephrology
Duke University School of Medicine Durham, North Carolina
Panelists Layout (Title slide layout)

3. This program will include a discussion of off-label treatment options and investigational agents not yet approved by the FDA for use in the United States.
There will also be a discussion of data that were presented in abstract form. These data should be considered preliminary until published in a peer-reviewed journal.
FDA = US Food and Drug Administration

4. Introduction Anemia is a frequent and significant complication of CKD
Associated with a high prevalence of cardiovascular disease in this patient population
There are a number of options for treating anemia in this patient population; however, there continue to be limitations with current treatments
CKD = chronic kidney disease

5. Pattern Changes in Anemia Treatment in Patients With NDD-CKD
Evaluate the use and time to use of ESA, IV iron, and RBC transfusion after diagnosis of anemia during baseline year
Objective
Two study cohorts of Medicare patients with stage 3 to 5 NDD-CKD and anemia
• 2008: 71, • 2012: 109,251
Consistent ESA treatment: ≥1 ESA monthly administration in ≥80% of 12 follow-up months
Methods
Anemia Treatment Pattern Changes in Non-Dialysis-Dependent Chronic Kidney Disease Patients before and after Revised Food and Drug Administration Label and New Anemia Guidelines for Erythropoiesis-Stimulating Agents"
Wendy L. St. Peter, Haifeng Guo, Shaum Kabadi, Sean Zhao, David T. Gilbertson, Louise Janice Sargent Heuer, Yi Peng, Trudy Pendergraft, Suying Li.
ESA = erythropoiesis-stimulating agent
IV = intravenous
NDD-CKD = non-dialysis-dependent chronic kidney disease
RBC = red blood cell
ESA use decreased by 57% from 2008 to 2012
IV iron use and RBC transfusions remained stable
Patients received transfusions sooner, corresponding to decline in ESA use
Results
St Peter WL, et al. J Am Soc Nephrol. 2016;27. Abstract FR-PO767.

6. Changes in ESA Labels 2011 FDA update for ESA use in patients with CKD
Start ESA treatment when the hemoglobin level is <10 g/dL
Does not specify if goal is Hb of ≥10 g/dL
Dosing should be individualized
Use lowest dose of ESA sufficient to reduce the need for RBC transfusions
Adjust dosing as appropriate
US Food and Drug Adminisration. FDA drug safety communication: modified dosing recommendations to improve the safe use of erythropoiesis-stimulating agents (ESAs) in chronic kidney disease. Accessed December 12, 2016.
FDA website.

7. Unexpected Medical Consequences of Revised ESA Label
Objective: Examine the changes in treatment of anemia, comorbidities and outcomes after FDA label revisions for ESA use in patients with NDD-CKD and anemia
CV outcomes in the 2012 cohort:
HE ↑ 100%
DVT ↑31%
PE ↑45%
All-cause death and MACE incidence did not decline
Based on table from abstract pg 814A
Suying Li, Haifeng Guo, Shaum Kabadi, Sean Zhao, Trudy Pendergraft,
Louise Janice Sargent Heuer, Yi Peng, Wendy L. St. Peter, David T. Gilbertson.
CV = cardiovascular
DVT = deep vein thrombosis
HE = hypertensive emergency
MACE = major adverse cardiac events 
PE = pulmonary embolism
Li S, et al. J Am Soc Nephrol. 2016;27. Abstract SA-PO795.

8. Decrease in Adverse Events Post-FDA Label Changes to ESA Treatment
Chertow, et al[a]
Wang, et al[b]
Patient population
≈ 250,000 patients receiving maintenance dialysis between 2005 and 2012
69,718 patients who had undergone incident hemodialysis between 2008 and 2013
Reduction in events
Absolute deviation
from trend per 100 patient-years (95% CI):
Stroke: (-0.08, -0.37)
VTE: (-1.35, -3.70)
Heart failure: (-0.28, -1.27)
Decreased risk of stroke
(HR: 0.77, 95% CI: 0.64, 0.93; P = .01)
Chertow GM, Liu J, Monda KL, et al. Epoetin Alfa and Outcomes in Dialysis amid Regulatory and Payment Reform. J Am Soc Nephrol. 2016;27:
Wang C, Kane R, Levenson M, et al. Association between changes in CMS reimbursement policy and drug labels for erythrocyte-stimulating agents with outcomes for older patients undergoing hemodialysis covered by fee-for-service Medicare. JAMA Intern Med Dec 1;176(12):
HR = hazard ratio
VTE = venous thromboembolism
a. Chertow GM, et al. J Am Soc Nephrol. 2016;27:
b. Wang C, et al. JAMA Intern Med. 2016;176:

9. Use of High ESA Doses in Patients With NDD-CKD
Looked at the association of increased adverse events, comorbidities, and healthcare resource utilization in patients with NDD-CKD and anemia
Objective
Medicare data
12,901 patients with stage 3-5 NDD-CKD with anemia receiving ESAs
Definition of high dose ESA: average monthly ESA dose >90th percentile of monthly doses
Methods
High dose ESA was associated with:
Significantly increased burden of CV and thromboembolic events
60% ↑ risk of death
46% ↑ risk of major cardiac event
52% ↑ in Medicare payments
Results
David T. Gilbertson, Suying Li, Yi Peng, Haifeng Guo, Shaum Kabadi, Sean Zhao, Trudy Pendergraft, Louise Janice Sargent Heuer, Wendy L. St. Peter.
Gilbertson DT, et al. J Am Soc Nephrol. 2016;27. Abstract SA-PO794.

10. Role of HIF and HIF-PH in Erythropoiesis
Low Oxygen
(eg, high altitude)
Normal Oxygen
HIF-PH Enzymes
Gene Transcription
Degradation
HIF-α degrades rapidly
HIF = hypoxia inducible factor HIF-PH = hypoxia inducible factor-prolyl hydroxylase

11. Effect of Vadadustat* on Hemoglobin Levels in Patients With DD-CKD
Randomized, phase 2 open-label study
Objective: assess Hb response to 3 starting doses of vadadustat over 16 weeks in 94 DD-CKD patients who were maintained on ESAs prior to study entry
Hb response and vadadustat dose requirements for Hb maintenance are independent of underlying systemic inflammation and baseline ESA dose in patients with DD-CKD
Vadadustat Maintains Hemoglobin (Hb) Levels in Dialysis-Dependent Chronic Kidney Disease (DD-CKD) Patients Independent of Systemic Inflammation or prior Dose of Erythropoiesis-Stimulating Agent (ESA)
DD-CKD = dialysis-dependent chronic kidney disease
Hb = hemoglobin
*This agent is not approved by the FDA for use in the United States. Haase VH, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO960.

12. Effect of Daprodustat* on Hemoglobin Maintenance
Objective: examine the relationship between the dose of daprodustat and hemoglobin at 4 weeks, and safety and efficacy over 24 weeks
Participants: 216 subjects on HD previously receiving recombinant human EPO
Results
Switching from a stable dose of EPO to daprodustat produced dose-dependent mean changes in Hb from baseline after week 4
Hepcidin levels were reduced at week 24 (20.6% in daprodustat group vs 3.6% in control group)
Adverse event profile in daprodustat group was consistent with the HD population
Daprodustat, a HIF-Prolyl-Hydroxylase Inhibitor, Maintains Hemoglobin Levels over 24 Weeks in Anemic Hemodialysis Subjects Switching from Recombinant Human Erythropoietin
EPO = erythropoietin
HD = hemodialysis
*This agent is not approved by the FDA for use in the United States. Cobitz, AR, et al. J Am Soc Nephrol. 2016;27. Abstract SA-OR114.

13. P < .0001 for all doses of roxadustat compared with placebo
Treatment of CKD-Associated Anemia With Roxadustat* in Patients Not on Dialysis
P < for all doses of roxadustat compared with placebo
Phase 2, double-blind, 24-week study
Objective: evaluate safety and efficacy of roxadustat
Participants: 107 Japanese patients with NDD-CKD and anemia
Results
Dose-dependent increase in hemoglobin
No MACE occurred in roxadustat group
Roxadustat for the Treatment of Chronic Kidney Disease-Associated Anemia
in Japanese Patients Not on Dialysis Tadao Akizawa,1 Manabu Iwasaki,2
Tetsuro Otsuka,3 Michael Reusch,4 Toshihiro Misumi.
n=27
n=26
n=27
n=27
*This agent is not approved by the FDA for use in the United States. Akizawa T, et al. J Am Soc Nephrol. 2016;27. Abstract FR-PO1142.

14. Potential Future of HIF-PH Inhibitors
Individuals living at high altitudes have HIF stabilization and elevated erythropoietin levels[a]
Can HIF-PH inhibitors used concomitantly with ESAs diminish adverse events of ESAs and increase erythropoietin?
Larger phase 3 trials are necessary to determine safety of this drug class
Potential to increase VEGF production (can enhance tumor progression)[b]
HIF is also involved in vascular tone and blood pressure regulation (concern for development of pulmonary hypertension)[c]
Krock BL, Skuli N, Simon MC. Hypoxia-induced angiogenesis: good and
evil. Genes Cancer. 2011;2:1117–1133.
Semenza GL. Oxygen sensing, hypoxia-inducible factors, and disease
pathophysiology. Annu Rev Pathol. 2014;9:47–71.
a. Hopfl G, et al. Hypoxia: Through the Lifecycle. 2003:89-115; b. Krock BL, et al. Genes Cancer. 2011;2: ; c. Semenza GL. Annu Rev Pathol. 2014;9:47-71.

15. HIF-PH Inhibitors and Hepcidin Levels
Hepcidin is a small peptide produced in the liver
Regulates iron homeostasis
In CKD, hepcidin levels go up as a result of decreased renal clearance and inflammation
Decrease in duodenal absorption of iron
Iron release from storage sites blocked
HIF-PH inhibitors play a role in decreasing levels of hepcidin
Ganz T, et al. Semin Nephrol. 2016;36: Maxwell PH, et al. Nat Rev Nephrol. 2016;12:

16. Effects of Ferric Citrate
Effects of Ferric Citrate* in the Treatment of Iron Deficiency Anemia in Patients With NDD-CKD
234 patients with NDD-CKD stages 3 to 5 and iron deficiency anemia randomized to ferric citrate or placebo for 16 weeks
52.1% (ferric citrate) vs 19.1% (placebo) achieved ≥1 g/dL increase in hemoglobin
48.7% (ferric citrate) vs 14.8% (placebo) achieved a sustained increase in hemoglobin
Most common adverse events are GI (diarrhea, nausea, constipation)
GI = gastrointestinal
*This drug is currently not approved by the FDA for this indication.
Fishbane S, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO901.

17. Regulation of FGF23 and Iron Status
FGF23 is an endocrine hormone secreted by osteocytes and osteoblasts
It is involved in regulating serum phosphate
Increases fractional phosphate excretion and reduces serum phosphate levels
Levels increase as kidney function declines
FGF23 plays a role in the pathogenesis of left ventricular hypertrophy, a risk factor for mortality in CKD
Iron deficiency, as well as some IV iron preparations, can lead to an increase in FGF23 production
FGF23 = fibroblast growth factor 23
Wolf M. Kidney Int. 2012;82:

18. Iron Therapy and Fibroblast Growth Factor-23 in Hemodialysis
Objective
Evaluate effect of IV iron on levels of iFGF23 and cFGF23 in hemodialysis patients
Serum hepcidin, ferritin, and PO4 were also measured
Results
IV ferric carboxymaltose group (n=22)
Ferritin and hepcidin levels increased significantly
cFGF23 increased
iFGF23 and PO4 decreased
Iron sucrose group (n=20)
Roberts MA, et al. J Am Soc Nephrol. 2016;27. Abstract TH-PO539.

19. Concluding Remarks
Over the years there have been treatment pattern changes seen with the use of ESAs
HIF-PH inhibitors are a newer class of drugs with potential for treating anemia
Ferric citrate currently acts as a phosphate binder but can potentially be used for the treatment of anemia
Recent data suggest that iron deficiency and elevated phosphate levels stimulate FGF23 production

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