1. Anemia and Iron Management With CKD: The Challenge
Connie Gilet, ANP
UNC Healthcare/Kidney Center
May 23, 2012

2. Outline Brief history of anemia management
Guidelines: what they are and what they are not
Research about anemia management
Research about iron administration
Gaps in the research anemia & iron research
Information about ESA and Iron medications
Using the new guidelines: case studies

3. Brief History
Epogen approved for treatment of anemia of CKD, June 1989
Prior to 1989, blood transfusions used to treat anemia (about 15% received blood)
>Blood transfusions increased the likelihood
of developing antibodies that could make a
kidney donor transplant difficult/impossible
>Adverse effects, including vol. & iron overload

4. Comparing ESAs Chemical Structure Epotein alfa (Epogen, Procrit)
Darbepoetin (Aranesp) Approved 9/2001
Peginesatide
Synthesis
Genetically engineered from Chinese hamster ovary cells
Synthetic
Route of administration
IV/SC
CKD-ND
CKD-HD
Initial Dosing Amounts
units/kg
0.45 mcg/kg
0.04 – 0.08 mg/kg
Dosing Schedule
Adapted from Dutka 2012
3 times/week
Weekly – 2-8 wks
Every 4 weeks

5. Peginesatide: New ESA Studied in USA/Europe. Mean f/u 67.4 weeks
Studies funded by Affymax and Takeda
Drug was approved by FDA 3/2012
>Greater than 25,000 received medication
Pulled from the market 2/2013
>0.2% dialysis pts have severe allergic rx
>0.02% fatal rx with first dose, 30 mins after
administration (N = 3)
>Reasons for reactions are unclear
Emerald 1 & 2 (n=1626) = peginesatide and epogen for HD pts. Pearl 1 & 2 (n = 983) = peginestatide and aranesp for non dialysis pts. CV outcomes greater in peginestatide group than aranesp.

6. Definitions: KDOQI and KDIGO
>Kidney Disease Outcomes Quality Initiatives
>Created 1995 by National Kidney Foundation
>Publish practice guidelines
KDIGO
>Kidney Disease Improving Global Outcomes
>Created 2003
>Independent, non profit organization governed
by multi-discipline international board and
managed by the National Kidney Foundation

7. Brief History of Treatment Guidelines
KDOQI/KDIGO
Federal Drug Administration (FDA)
Hemoglobin Goal Year
Hemoglobin Goal Year
11-12 g/dl
10-11 g/dl Year?- initial
recommendation
Up to 13 g/dl
10-12 g/dl
11-12 g/dl
10-11 g/dl
More complex (KDIGO)
More complex guidelines:
-Lowest dose to avoid PRBC
-No epogen to treat anemia
symptoms or QOL
-Dec dose if Hgb inc > 1gm
2 wks
No longer recommend
Hgb range

8. Guidelines: What They Are And Are Not
What They Are Not
Provides information
Not a standard of care
Based on evidence and expert advice, helps with making informed decision
Not suitable for all; can not account for all variations in people (age, co-morbidities, genetics), provider, and system variants
Have been shown to improve quality of care for a population
One size DOES NOT fits all , while a guideline can apply to the population, it may not apply to an individual

9. Consequences Of Using Treatment Guidelines
Guidelines supported increasing Epogen
doses >>> Hgb values increased…
>Hgb 9.6 in 1991 >>>>>
>Hgb 12.0 in 2006
(90% of those receiving epogen on dialysis)
>Hypothesis: higher Hgb would decrease
cardiovascular complications (e.g. LVH)
>Improved quality of life (e.g. functional
status)
How did the research support the guidelines?

10. Evolution of Guidelines: Is More Better?
Since Epogen successful to increase Hgb, why not treat anemia to targeted “normal” levels?
>Women ~ 12 g/dl and men ~13 g/dl or
Hct 30% vs 42%
Larger doses of Epogen given to achieve these higher Hgb (without much research to support)

11. What Does the Research Tell Us How To Treat Anemia?

12. How Does One Interpret Research Data?
Few important facts about research studies….
Randomized control trial (RCT) done prospectively with a large number of subjects followed for a long time produces the most reliable data. May want to base therapy on results. VS
Observational study done retrospectively with a
few subjects, may provide ‘food for thought’ but
don’t want to base therapy on results
Can not generalize research results to groups other than the one(s) studied

13. Normal Hematocrit Trial
RCT, prospective study (1998) of 1233 people on
HD with cardiac disease compared “low” Hct
(30%) vs “normal” Hct (42%)
>Average age 65
>Many with diabetes
>Followed for average 14 months
>Epogen doses 160u/kg/week for “low” group vs
“normal” group 460u/kg/week
Besarab, et al, 1998

14. Normal Hematocrit Trial
Although difference did not meet statistical
significance, greater mortality, MI and
vascular clots in group with “normal” Hct
values, trial was stopped before all enrolled
No improvement in QOL with higher Hct levels
Besarab, et al, 1998

15. “CHOIR” Study Correction of Hemoglobin and Outcomes in Renal Insufficiency
RCT study (2006) looked at 1432 patients with CKD, stage 3 and 4
>Compared Hgb >= 13 to 11.3 gm/d: Group
with Hgb >= 13 had increased risk of MI,
hospitalization, stroke, and death.
>Terminated early
>Similar improvements in quality of life
After the study, goal Hgb reverted g/dl
Singh, et al 2006

16. “CREATE” Study CV Risk Reduction by Early Anemia Treatment with Epoetin Beta
RCT (2006) of 603 CKD-ND (c/s diabetes) people
>Compared Hgb to 10.5 to 11.5: risk of
CV events not lowered by correcting the anemia
>Epogen doses 5,000 VS 2,000 units per week
>After about 3 years, Hgb group 22%
greater first CV event (not statistically
significant)
>Renal function declined faster
>Higher QOL scores
Drueke, et al, 2006

17. “Treat” Study Trial to Reduce CV Events with Aranesp Therapy
RCT study (2009) of 4, 038 CKD 3 & 4 with diabetes. Compared treatment with placebo with Aranesp to achieve a Hgb of 13 gm/d
>No difference death or progression to ESRD
>Greater doses increased risk for stroke, venous clots
and possibly, malignancy.
>Reported a small improvement in fatigue and QOL
>54% of those had Hgb of 13
>49% of those receiving placebo also reported
improvements in fatigue and QOL
Pfeffer, et al, 2009

18. Children/PD And Anemia Studies?
None

19. Research About Anemia Management And Transplant?
Retrospective study (2009), non randomized.
>1794 transplant recipients
>Hgb > 12.5 g/dl associated with increased
mortality

20. What Are The Outcomes If Hgb Is High Without ESA?
DOPPS study
>DOPPS = Dialysis Outcomes and Practice
Patterns Study
>Prospective, observational with 20 counties
>545 of 29,796 (1.8%) folks on HD maintained
a Hgb >12.0 g/dl for 4 months without ESA
>No increase in mortality noted
Goodwin, et al, 2009

21. Anemia Management With ESA Resistance?
About 15% of ESRD are ESA resistance
“Choir” Study
>High dose Epogen associated with 57%
increased risk death, MI, HF and stroke
“Treat” Study
>Poor response to Aranesp >>increase risk of
CV adverse events

22. Summary Of Research Findings For Anemia Management
Most research done on adults with CKD-ND and some with those receiving HD
“Reasonable” dose of ESA probably has some benefits
Do not want Hgb >= 13 with ESA dosing
Individualize epogen therapy balancing
the pros (feeling better/dec blood transfusions) vs
the cons (inc chance MI, stroke and death)

23. Summary Of Research Findings
Those who are ESA resistant and treated
with high ESA doses may have more
adverse outcomes (e.g CV and death).
Naturally occurring high Hgb probably less risky than a high Hgb achieved with ESA

24. Gaps In Research Data
Most of the research done on those with CKD, not on dialysis, older than 60 years with many comorbitities (e.g. DM, HTN)
>Apply findings to groups not studied with
caution. For example, how much Epogen do you
give to a 25 year old who was started on HD due
to IgA nephropathy and has no comorbidities?
Little info on PD, children or those transplanted

25. Gaps In Research Data
What is the optimal Epogen dose frequency; one a week, twice a week, three times per week?
While research demonstrates Hgb > 13.0 are associated with adverse outcomes, no data on the benefits vs. adverse outcomes of Hgb between 11.5 and 13.0 g/dl

26. Gaps In Research Data Doses of Epogen varied widely to obtain Hgb
values greater than 13.
>ESA resistant patients received the highest
Epogen doses? How do we better ID those
who are resistant? How much Epogen is
too much? How does one decide how much
Epogen to administer in this group?

27. Most Recent KDIGO Guidelines: CKD-ND
Individualize dose; use the lowest dose that reduces need for blood transfusion
>Target Hgb range not provided
>Consider starting ESA when Hgb below 10
and reduce or stop ESA when Hgb above 10

28. Most Recent FDA Guidelines: CKD-ND
Consider ESA when Hgb < 10 g/dl.
If Hgb > 10, reduce or interrupt dose

29. UNC CKD-ND Anemia Guidelines
Outpatient anemia clinic guidelines for CKD III to V
>Start Aranesp at 50mg/kg
>Goal Hgb between 9.5 and 10.4
>If Hgb >= 11.0 hold Ananesp

30. Most Recent KDIGO Guidelines: CKD-HD
Use ESA therapy to avoid Hgb below 9.0
Start ESA between 9 & 10.
Initiate therapy less than 10 and reduce
or interrupt if Hgb exceeds 11.5

31. Most Recent FDA Guidelines: CKD-HD
CKD-D: start ESA when Hgb < 10.
>Reduce or interrupt when Hbg > 11.0

32. Recent KDIGO Guidelines For Both CKD-ND and CKD-HD
Base dosing decision/initiation of ESA
>How rapidly Hgb decreasing
>Response to Iron administration
>Risks of transfusion and ESA therapy
>Symptoms due to anemia
Don’t use ESA to maintain Hgb > 11.5, unless willing to take the risk
Don’t use ESA to inc Hgb > 13 g/dl

33. Recent KDIGO Guidelines For Both CKD-ND and CKD-HD
Prefer decreasing dose vs holding dose ESA
Use ESA’s with GREAT caution in people with CKD if malignancy, past or current, or history of stroke
Blood transfusions may be preferred if
> Hemoglobinopathies, ESA resistance,
Malignancy, Stroke
Address all correctable causes of anemia before starting ESA

34. Guidelines For Anemia Management With ESA Resistance
FDA-inadequate response to ESA over 12
week escalation period, no further dose
increases
Per KDOQI: Evaluate “for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered.”

35. KDIGO Guidelines For ESA Hyporesponsiveness
Initial
>No inc Hgb from baseline after 1 month of
weight-based dosing = hyporesponsive
> If hyporesponsive, suggest no inc dose beyond
doubling initial weight-based dose (50 to 100 u/kg)
Subsequent (acquired)
>If previously stable Hgb, may inc 50% beyond
dose at which stable (no data to support)
>Avoid inc dose beyond 2 x dose at which Hgb had
been stable

36. KDIGO Guidelines For ESA Hyporesponsiveness
Management
>Treat cause of poor ESA response
>If poor response remains, balance benefits/
burden of
>Decrease in Hgb
>Continuing ESA
>Blood transfusions
(All 2D = Suggest and very low quality evidence)

37. Correctable Vs Not Correctable Causes of Anemia
“Easily” Correctable
Potentially Correctable
Not Correctable
Non-adherence
Hyperparathyroidsm
PRCA (pure red cell aplasia)
Malignancy
Malnutrition
Hemoglobinopathies
(group of disorders affecting the red blood cells)
B12/Folate deficiency
Under dialyzed
Bone Marrow Disorders
Hypothyroidism
Hemolysis
ACE-inhibitors
Bleeding
Iron deficiency
Infection/inflammation
Adapted from Drueki & Parfrey 2012
PRCA-red cells don’t form normally in the bone marrow

38. Oral Iron Medications Dose Elemental Iron Side Effects
Ferrous Fumarate (buy on-line: 100 pills for about $30)
325 mg
108 mg iron
Upset stomach, constipation
Ferrous Sulfate
65 mg iron
Ferrous Gluconate
Vitamin C increases absorption of iron. Take between meals with 8 oz water.
35 mg iron

39. IV Iron Medications Elemental Iron Dosing Side Effects
Ferrlecit (Sodium ferric gluconate)
62.5 mg/ml
125 mg for 8 doses
Flushing, HA, fever, chills, dec BP
Venofer (Iron sucrose)
20 mg/ml
100 mg for 10 doses
Ferraheme (Ferumoxytol)
39 mg/ml
510 mg; 2 doses 3 to 8 days apart
INFed (Dextran)
50 mg/ml
Use formula
Test dose used. Can cause severe allergic reactions
Ferrlecit and Venofer had the lowest reported adverse events of this group.
Dailie 2012

40. Anemia Management and Iron
FDA Black Box warning is >> decreased Epogen doses
>As Epogen doses decreased, IV iron usage
increased
>% dialysis patients receiving IV iron
increased from 57% to 71% between
8/2010 to 8/2011.*
*Pisoni, et al 2011

41. Iron: Where It’s Found And How It’s Measured
Most iron found in liver and red blood cells. Also present in bone marrow, spleen and in all cells
>Body hoards and recycles iron
Two tests used to estimate iron stores, ferritin and transferrin saturation (TSAT)
>Ferritin: measures protein inside cells that
store iron
> TSAT: % serum iron and total iron binding
capacity. 20% sats = 20% of the binding sites of
transferrin occupied by iron

42. Why We Care About How to Measure Iron Stores
Can have too much of a good thing >>>
iron toxicity
Iron toxicity >> organ damage
>Lungs - fluid
>Liver failure - n/v and bleeding
>CV - hypotension
>Neuro - drowiness, seizures and coma
>Death

43. What Do Iron Tests Tell You?
If sats <30% and ferritin <500 = iron deficiency
If sats 25% and ferritin 650 ???
>Increase in ferritin can be due neoplasm,
inflammatory (including autoimmune dx) or
infectious state OR
>Iron overload
Should iron be given if sats low and ferritin high?

44. Research About Iron and CKD
Observational study (2004)
>No relationship between IV iron & mortality
>Subjects had depleted iron stores and no
systemic inflammation *
Several studies claim people on dialysis have iron overload per labs, yet no clinical symptoms of iron overload **
*Feldman, et al, 2004
**Conavese, et al, Ferrari, et al, Rostocker, et al, 2012

45. More Research About Iron and CKD: Drive I (2007)
RCT, prospective study of CKD-hemodialysis
>Low sats (<=25%) and high ferritin (500-
1200)
>Hgb <= 11 and Epogen >= 225u/kg/week
Group
Intervention
Outcomes
One
1 gm ferric gluconate + 25% increase epogen
1.6 g/dl inc Hgb
Two
25% inc epogen and no iron
1.1 g/dl inc Hgb

46. DRIVE I and II
Drive I
>Showed no adverse effect when ferritin levels
high (up to 1200) and sats low
>Only followed 134 people for 6 wks
Drive II
>Observational study: Those who received
iron maintained Hgb for 12 weeks despite
lower Epogen doses

47. Other Iron Studies Study (2011), prospective study with 25 people
with CKD III to VI found, after infusion of IV iron,
increases of iron in liver don’t correlate with
increases in serum ferritin or TSATs
Little data on long-term clinical benefit of iron administration other than increasing Hgb
Ferrari 2011

48. Summary of Iron Research Data
If the sats are low (< = 30) and ferritin
< = 500, ok to give oral or IV iron
If the sats are low and ferritin > 500, unclear status of iron stores >>> dosing???
>Individualize care: balance pros and cons of
giving IV iron

49. KDIGO Guidelines For Iron Administration
Balance potential benefits with risks of harm
For adults with CKD-ND, trial of iron if TSAT is <=30% & ferritin is <=500 ng/ml
CKD-HD: If Hb increase or Epogen dose decrease desired, try iron.
Avoid administering IV iron to patients with active systemic infections. (Not Graded)

50. KDIGO Guidelines For Iron Administration
For CKD ND patients who require iron supplementation, select
route of iron administration based on severity of iron deficiency,
availability of venous access, response to prior oral iron, side effects
with prior oral or IV iron therapy, patient compliance, and cost.
(Not Graded)
Guide subsequent iron administration in CKD patients based on
Hb responses to recent iron therapy, as well as ongoing blood losses,
iron status tests (TSAT and ferritin), Hb concentration, ESA
responsiveness and ESA dose in ESA treated patients, trends in each
parameter, and the patient’s clinical status. (Not Graded)

51. Iron Management And Children
For all pediatric CKD patients with anemia not on
iron or ESA therapy, we recommend oral iron (or IV
iron in CKD HD patients) administration when
TSAT is <=20% and ferritin is <=100 ng/ml 100 ug/l).
(1D)
For all pediatric CKD patients on ESA therapy who are not receiving iron supplementation, we recommend oral iron (or IV iron in CKD HD patients) administration to maintain TSAT >20% and ferritin >100 ng/ml. (1D)
(1D = Recommended but very low quality of evidence)

52. Anemia Management And Children
Data lacking for adults/very little data, if any, for children. KDIGO = Hgb between 11 & 12
UNC Kidney Center: Goal = Hgb 10-12 HD
PD/CKD
Children < 5yrs
units/kg/week
units/kg/week
Children > 5 yrs
150 units/kg/week
100 units/kg/week
Iron goals (give enough iron to achieve values)
Ferritin > 100 ng
TSAT > 20%

53. Case Study #1 Mr. C.C. is a 70 year old male with
>Hx: CKD IV, IDDM, CAD with two stents, TIA
>Meds = 3 HTN, Zocor, oral iron bid, ASA, insulin
>VS/Labs: BP 135/82, Creatinine 2.6, GFR 25 ml
Hgb 9.4, Ferritin 110 ng, Saturation 19%
Weight = 70 kg
Should Mr. C.C. receive an ESA? IV iron?

54. Case Study #1 Mr. C.C. receives IV iron, repeat labs are…
>Ferritin 350, Sats 35%, Hgb 9.5
Should Mr. C.C. receive epogen ?
>When Hgb below 10, consider…
>Rate of Hgb decrease
>Prior response to iron
>Risk of needing transfusion
>Symptoms 2/2 anemia

55. Case Study #1
Mr. C.C. was started on Aranesp 40 mcg. Labs drawn 2 weeks after dose given:
>Hgb inc from 9.5 to 9.6
>Ferritin inc from 350 to 500 ,
>Sats dec from 35 to 31%
>No c/o SOB or change in energy level
>With a history of TIA, CAD, do you want to
increase the Aranesp dose?

56. Case Study #2 Ms. A.A. is a 52 year old on HD with
>Hx: DM, HTN, CAD, PVD and SVC syndrome
>Meds: 4 HTN, ASA, Warfarin, Lantus
>VS/Labs: BP 150/90, Weight 60 kg
Hgb 9.6, Ferritin 750, Sats 29%
>Receiving Epogen 3,000 units 3 x per wk
Just completed 1000 mg of ferrlecit IV

57. Case Study #2 Ms. A.A. is a 52 year old on HD with
>Hx: DM, HTN, CAD, PVD and SVC syndrome
>Hgb 9.6, Ferritin 750, Sats 29%
Do the guidelines support giving additional iron?
Do the guidelines support increasing the Epogen dose?

58. Unanswered Questions Is there a maximum or toxic dose of ESA?
What makes someone ESA resistant?
How does one manage ESA resistance?
Does dosing frequency matter?
>Is it better to give 2,000 units 3 x per week or
6,000 units once per week?
How does Hgb variability due to ESA dosing changes affect outcomes?

59. What Is The Optimal Hgb Goal?
Is this the question we should be asking?
Our patients are all different; different genes,
comorbidities, functional abilities, needs and
expectations
>Should the question not be ?….
>For each individual, at what Hgb level are
the risks minimized (e.g. CV) and the
benefits maximized (less fatigue, feel “better”)
>Intern’l task force examining this question

60. Stay Tuned…

61. References
Bailie, G.R. (2012). Comparison of rates of reported adverse events associated with I.V. iron products in the United States. American Journal of Health-System Pharmacy, 69,(4),
Besarab, A., Bolton, W.K., Browne, J.K., Egrie, J.C., Nissenson, A.R., Okamoto, D.M., Schwab, S.J., & Goodkin, D.A. (1998). The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin (Normalized Hct). New England Journal of Medicine, 339, (9),

62. References
Cavanese, C., et al. (2004). Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients. Kidney International, 65,
Coyne, D.W. et al. (2007). Ferric gluconate is highly efficacious in anemic hemodialysis patients with high serum ferritin and low transferrin saturation: results from the dialysis patients’ response to IV iron with elevated ferrin (DRIVE) study. Journal of American Society of Nephrology, 18,

63. References
Drueke, T.B., Locatelli, F., & Clyne, N. (2006). Normalization of hemoglobin level in patients with chronic kidney disease and anemia(CREATE). New England Journal of Medicine, 355,
Drueke, T.B., Parfrey, P.S. (2012). Summary of the KDIGO guideline on anemia and comment: reading between the guideline(s). Kidney International, 82,
Dutka, P. (2012). Erythorpoiesis-stimulating agents for the management of anemia of chronic kidney disease: Past Advancements and Current Innovations. Nephrology Nursing Journal, 39 (6),

64. References
Feldman, H., et al. (2004). Administration of parenteral iron and mortality among hemodialysis patients. Journal of American Society of Nephrology, 15,
Ferrari, P, et al. (2011). Serum iron markers are inadequate for guiding iron depletion in chronic kidney disease. Clinical Journal of American Society of Nephrology, 6,
Goodkin, D.A. et al. (2011). Naturally occurring
higher hemoglobin concentration does not increase
mortality among hemodialysis patients. Journal of
American Society of Nephrology, 20,

65. References Heinz, G., Kainz, A., Horl, W., & Oberbauer, R.
(2009). Mortality in renal transplant
recipients given erythropoietins to increase
haemoglobin concentration: cohort study.
British Medical Journal, 339, 4081.
Kalantar-Zadeh, K. et al (2006). The fascinating but deceptive ferritin: to measure of not to measure it in chronic kidney disease. Clinical Journal of American Society of Nephrology, 1 (Supple 1), S9-S18.

66. References
Kapalon, T. et al (2008). Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. Journal of American Society of Nephrology, 19,
Pisoni, R.L. et al (2011). The DOPPS practice monitor for US dialysis care: trends throught August The American Journal of Kidney Diseases, 60, ,

67. References
Pfeffer, M. A., Burdmann,E.A., Chen, C.Y., Cooper, M.E., de Zeeuw, D., Eckardt, K., Ivanovich, P., Kewalramani, R., Levey, A.S., Lewis, E.F., McGill, J., McMurray, J., Parfrey, P., Parving, H., Remuzzi, G., Singh, A.K., Solomon, S.D., Toto, R., Uno, H. (2009). Baseline characteristics in the trial to reduce cardiovascular events with aranesp therapy (TREAT). American Journal of Kidney Diseases, 54 (1),

68. References
Rostocker, G. et al. (2012). Hemodialysis-associated hemosiderosis in the era of erythropoisis-stimulating agents. American Journal of Medicine, 125,
Singh, A.K., Szczech, L., Tang, K.L., Burnhart, H., Sapp, S., Wolfson, M., Reddan, D. (2006). Correction of anemia with epoetin alfa in chronic kidney disease, New England Journal of Medicine, 355,