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Anemia and Iron Management With CKD: The Challenge. Connie Gilet, ANP UNC Healthcare/Kidney Center May 23, 2012. Outline. Brief history of anemia management Guidelines: what they are and what they are not Research about anemia management Research about iron administration

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anemia and iron management with ckd the challenge

Anemia and Iron Management With CKD: The Challenge

Connie Gilet, ANP

UNC Healthcare/Kidney Center

May 23, 2012

  • 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
brief history
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

peginesatide new esa
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

definitions kdoqi and kdigo
Definitions: KDOQI and KDIGO

>Kidney Disease Outcomes Quality Initiatives

>Created 1995 by National Kidney Foundation

>Publish practice guidelines


>Kidney Disease Improving Global Outcomes

>Created 2003

>Independent, non profit organization governed

by multi-discipline international board and

managed by the National Kidney Foundation

consequences of using treatment guidelines
Consequences Of Using Treatment Guidelines
  • Guidelines supported increasing Epogen

doses >>> Hgbvalues 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


  • How did the research support the guidelines?
evolution of guidelines is more better
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)
how does one interpret research data
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.


  • 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
normal hematocrit trial
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

normal hematocrit trial1
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

choir study correction of hemoglobin and outcomes in renal insufficiency
“CHOIR” StudyCorrection 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 11-12 g/dl

Singh, et al 2006

create study cv risk reduction by early anemia treatment with epoetin beta
“CREATE” StudyCV Risk Reduction by Early Anemia Treatment with Epoetin Beta
  • RCT (2006) of 603 CKD-ND (c/s diabetes) people

>Compared Hgb 13-15 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 13-15 group 22%

greaterfirst CV event (not statistically


>Renal function declined faster

>Higher QOL scores

Drueke, et al, 2006

treat study trial to reduce cv events with aranesp therapy
“Treat” StudyTrial 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

research about anemia management and transplant
Research About Anemia Management And Transplant?
  • Retrospective study (2009), non randomized.

>1794 transplant recipients

>Hgb > 12.5 g/dl associated with increased


what are the o utcomes if hgb is high without esa
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

anemia management with esa resistance
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

summary of research findings for anemia management
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)


the cons (inc chance MI, stroke and death)

summary of research findings
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
gaps in research data
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
gaps in research data1
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
gaps in research data2
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?

most recent kdigo guidelines ckd nd
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

most recent fda guidelines ckd nd
Most Recent FDA Guidelines: CKD-ND
  • Consider ESA when Hgb < 10 g/dl.

If Hgb > 10, reduce or interrupt dose

unc ckd nd anemia guidelines
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

most recent kdigo guidelines ckd hd
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

most recent fda guidelines ckd hd
Most Recent FDA Guidelines: CKD-HD
  • CKD-D: start ESA when Hgb < 10.

>Reduce or interrupt when Hbg > 11.0

recent kdigo guidelines for both ckd nd and ckd hd
Recent KDIGO GuidelinesFor Both CKD-ND and CKD-HD
  • Base dosing decision/initiation of ESA

>How rapidly Hgbdecreasing

>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 incHgb > 13 g/dl
recent kdigo guidelines for both ckd nd and ckd hd1
Recent KDIGO GuidelinesFor 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
guidelines for anemia management with esa resistance
Guidelines For Anemia Management With ESA Resistance
  • FDA-inadequate response to ESA over 12

week escalation period, no further dose


  • Per KDOQI: Evaluate “for specific causes of hyporesponse whenever the Hb level is inappropriately low for the ESA dose administered.”
kdigo guidelines for esa hyporesponsiveness
KDIGO Guidelines For ESA Hyporesponsiveness
  • Initial

>No incHgb 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 inc50% beyond

dose at which stable (no data to support)

>Avoid inc dose beyond 2 x dose at which Hgb had

been stable

kdigo guidelines for esa hyporesponsiveness1
KDIGO GuidelinesFor 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)

anemia management and iron
Anemia Management and Iron
  • FDA Black Box warning is 2007 >> decreased Epogen doses

>As Epogen doses decreased, IV iron usage


>% dialysis patients receiving IV iron

increased from 57% to 71% between

8/2010 to 8/2011.*

*Pisoni, et al 2011

iron where it s found and how it s measured
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

why we care about how to measure iron stores
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


what do iron tests tell you
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


>Iron overload

  • Should iron be given if sats low and ferritin high?
research about iron and ckd
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, 2004. Ferrari, et al, 2001. Rostocker, et al, 2012

more research about iron and ckd drive i 2007
More Research About Iron and CKD: Drive I (2007)
  • RCT, prospective study of CKD-hemodialysis

>Low sats (<=25%) and high ferritin (500-


>Hgb <= 11 and Epogen >= 225u/kg/week

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

other iron studies
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

summary of iron research data
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

kdigo guidelines for iron administration
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)
kdigo guidelines for iron administration1
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

Hbresponses 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)

iron management and children
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).


  • 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)

anemia management and children
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
case study 1
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?
case study 11
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

case study 12
Case Study #1
  • Mr. C.C. was started on Aranesp 40 mcg. Labs drawn 2 weeks after dose given:

>Hgbinc from 9.5 to 9.6

>Ferritin inc from 350 to 500 ,

>Satsdec 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?

case study 2
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

case study 21
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?
unanswered questions
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?
what is the optimal hgb goal
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


>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’ltask force examining this question

  • 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), 310-320.
  • 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), 584-590.
  • Cavanese, C., et al. (2004). Validation of serum ferritin values by magnetic susceptometry in predicting iron overload in dialysis patients. Kidney International, 65, 1091-1098.
  • 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, 975-984.
  • 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, 2071-2084.
  • Drueke, T.B., Parfrey, P.S. (2012). Summary of the KDIGO guideline on anemia and comment: reading between the guideline(s). Kidney International, 82, 952-960.
  • 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), 447-457.
  • Feldman, H., et al. (2004). Administration of parenteral iron and mortality among hemodialysis patients. Journal of American Society of Nephrology, 15, 1623-1632.
  • 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, 77-83.
  • 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, 358-365.

  • 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.
  • Kapalon, T. et al (2008). Ferric gluconate reduces epoetin requirements in hemodialysis patients with elevated ferritin. Journal of American Society of Nephrology, 19, 372-379.
  • Pisoni, R.L. et al (2011). The DOPPS practice monitor for US dialysis care: trends throught August 2011. The American Journal of Kidney Diseases, 60, 160-165,
  • 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), 59-69.
  • Rostocker, G. et al. (2012). Hemodialysis-associated hemosiderosis in the era of erythropoisis-stimulating agents. American Journal of Medicine, 125, 991-999.
  • Singh, A.K., Szczech, L., Tang, K.L., Burnhart, H., Sapp, S., Wolfson, M., Reddan, D. (2006). Correction of anemia with epoetinalfa in chronic kidney disease, New England Journal of Medicine, 355, 2085-2098.