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
• Gaps in the research anemia & iron research
• Information about ESA and Iron medications
• Using the new guidelines: case studies
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
Comparing ESAs
Chemical Structure
Epotein alfa (Epogen, Darbepoetin
Procrit)
(Aranesp)
Approved 9/2001
Peginesatide
Synthesis
Genetically
engineered from
Chinese hamster
ovary cells
Genetically
engineered from
Chinese hamster
ovary cells
Synthetic
Route of
administration
IV/SC
IV/SC
CKD-ND
CKD-HD
Initial Dosing
Amounts
50-100 units/kg
0.45 mcg/kg
0.04 – 0.08 mg/kg
Dosing Schedule
3 times/week
Weekly – 2-8 wks
Every 4 weeks
Adapted from Dutka 2012
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
• KDOQI
>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
Brief History of Treatment Guidelines
KDOQI/KDIGO
Federal Drug Administration (FDA)
Hemoglobin Goal
Year
Hemoglobin Goal
Year
11-12 g/dl
1997
10-11 g/dl
Up to 13 g/dl
2006
10-12 g/dl
1994
11-12 g/dl
2007
10-11 g/dl
1997
More complex (KDIGO)
2012
More complex guidelines:
-Lowest dose to avoid PRBC
-No epogen to treat anemia
symptoms or QOL
-Dec dose if Hgb inc > 1gm
2 wks
2006
No longer recommend
Hgb range
2011
Year?- initial
recommendation
Guidelines: What They Are And Are
Not
What They Are
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
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?
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)
What Does the Research Tell Us How
To Treat Anemia?
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
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 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
• 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
• 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%
greater first CV event (not statistically
significant)
>Renal function declined faster
>Higher QOL scores
Drueke, et al, 2006
“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
Children/PD And Anemia Studies?
• None
Research About Anemia Management
And Transplant?
• Retrospective study (2009), non randomized.
>1794 transplant recipients
>Hgb > 12.5 g/dl associated with increased
mortality
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?
• 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
• 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)
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
• 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 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 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
• 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
• Consider ESA when Hgb < 10 g/dl.
If Hgb > 10, reduce or interrupt dose
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
• 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
• CKD-D: start ESA when Hgb < 10.
>Reduce or interrupt when Hbg > 11.0
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
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
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.”
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
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)
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
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
325 mg
65 mg iron
Upset stomach,
constipation
Ferrous Gluconate
325 mg
35 mg iron
Upset stomach,
constipation
Vitamin C increases absorption
of iron. Take between meals
with 8 oz water.
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
Flushing, HA, fever,
chills, dec BP
Ferraheme
(Ferumoxytol)
39 mg/ml
510 mg; 2 doses 3
to 8 days apart
Flushing, HA, fever,
chills, dec BP
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
Anemia Management and Iron
• FDA Black Box warning is 2007 >> 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
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
• 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
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?
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)
• RCT, prospective study of CKD-hemodialysis
>Low sats (<=25%) and high ferritin (5001200)
>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
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
• 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
• 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
• 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
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)
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)
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
200-300
units/kg/week
100-150
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%
Ferritin > 100 ng
TSAT > 20%
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 #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 #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?
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 #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
•
•
•
•
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?
• 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
Stay Tuned…
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), 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.
References
• 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.
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, 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.
References
• Feldman, H., et al. (2004). Administration of parenteral
iron and mortality among hemodialysis patients.
Journal of American Society of Nephrology, 15, 16231632.
• 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.
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.
References
• 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,
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), 59-69.
References
• Rostocker, G. et al. (2012). Hemodialysisassociated 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 epoetin alfa in
chronic kidney disease, New England Journal
of Medicine, 355, 2085-2098.