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Anemia Guidelines
Şehsuvar Ertürk, MD, FASN
Ankara University School of Medicine
Across seacoast is motherland
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Do you hear me?
Memet, Memet!
Nazım Hikmet
Goals of the lecture


To know impact of anemia on
clinical outcomes in patients with
chronic kidney disease.
To approach management of
anemia of chronic kidney disease in
terms of evidence-based medicine.
Plan

Background
Epidemiological aspects
Pathophysiology
Consequences of anemia management


Guidelines/recommendations
Current practice patterns
Bright-1830s
“Anemia is a characteristic manifestation
of chronic kidney disease”
Prevalence of anemia in CKD
Levin A. Kidney Int 61 (Suppl 80):S35-S38, 2002.
Etiology of anemia

Bone marrow depression
Relative EPO deficiency / resistance to EPO
Inflammatory cytokines
Apopitosis / decreased eryhtroid progenitors

Reduced availability of iron
Malnutrition
Decreased absorption
GIS losses (ASA, NSAID)
Iatrogenic (repeated blood testing)

Hemodilution (water and sodium retention)
Rao M and Pereira BJG. Kidney Int 68:1432-38, 2005
Lewis BS, et al. Nephrol Dial Transplant 20(Suppl 7):vii3-6, 2005
Pathophysiology of anemia
Hemodynamic
Non-hemodynamic
(Increased Cardiac Output)
(Increased O2 extraction)
Systemic arterial dilatation
Decreased TPR
Reduced afterload
Increased stroke volume
Decreased blood viscosity
Increased venous return
Increased preload
Symphatetic activation
Increased heart rate
Increased EPO production (?)
Increased 2,3-DPG
Pereira AA and Sarnak MJ. Kidney Int 64(Suppl 87):S32-S39, 2003
Silverberg D. Nephrol Dial Transplant 18(Suppl 2):ii7-12, 2003
Levin A. Kidney Int 61(Suppl 80):S35-S38, 2002
Consequences of anemia
Exercise capacity
Coagulation
Immune response
Cognitive function
Sexual function
Appetite/Nutrition
Growth (in children)
Quality of life
Depression
Angina
LVH
Cardiac failure
Myopathy
Renal disease progression
Morbidity
Mortality
Gomez JML and Carrera F. Kidney Int 61 (Suppl 80):S39-S43, 2002
Impact of anemia on outcomes
General population
>1 Million Medicare subjects, Age>67y
1-y mortality
Anemia
CKD
CHF
None
All
8%
8%
13%
4%
23%
Herzog CA, et al. J Card Fail 10:467-72, 2004
Anemia and clinical outcomes
CKD (pre-dialysis)

Increased risk for
Mortality
CVD (LVH, LVD, CHF)
Progression of kidney disease
Anemia and clinical outcomes
CKD (pre-dialysis)

246 patients, 12 months follow-up,
>20% increase in LVMI
Hb 0.5 g/dL
OR
1.32
Levin A, et al. Am J Kidney Dis 27:347-54, 1996

853 male patients,
Mortality and ESRD
Hb<12 g/dL
Hb<11 g/dL
1.97
2.57
Kovesdy CP, et al. Kidney Int 69:560-64, 2006
Anemia and clinical outcomes
CKD (pre-dialysis) (RENAAL Study)
Shahinfar S, et al. Kidney Int 67(Suppl 93):S48-S51, 2005
Anemia and clinical outcomes
ESRD
Mortality

432 patients
Hb
1 g/dL
14%
Foley RN, et al. Am J Kidney Dis 28:53-61, 1996.

93.087 patients
Hb (g/dL) <10
Hb (g/dL) 12-13
64%
21%
Roberts TL, et al. Nephrol Dial Transplant 21:1652-62, 2006.
Anemia and clinical outcomes
ESRD
Mortality HR (95% CI)
12.733 patients

Whites
Hb (g/dL)

<10
1.32 (1.16-1.48)
<10
10-<11
1.50 (1.27-1.76)
1.60 (1.37-1.84)
AAs
Hb (g/dL)
Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009.
Anemia and clinical outcomes
ESRD

Longer time to target Hb levels
Hospitalization
Mortality
HR (95% CI)
1.15 (1.12–1.19)
1.26 (1.20–1.33)
Ishani A, et al. Nephrol Dial Transplant 22:2247-55, 2007.

More months below target Hb levels
Hospitalization
Mortality
RR (95% CI)
1.70 (1.63–1.76)
2.48 (2.28–2.69)
Ishani A, et al. Nephrol Dial Transplant 23:1682-89, 2008.
Economic issues
Cost difference between anemic and non-anemic
patients:
CHF
CKD
Cancer
29.511 USD / patient / year
20.529
18.418
Ershler WB, et al. Value Health 8:629-38, 2005
Potential benefits/risks of treatment
of anemia with ESAs and iron
Benefits
Risks
Improved quality of life (QOL)
Hypertension
Thrombosis
Decrease in LVMI
Slowing the progression
Decrease in hospitalizations
Improved survival
Increase in mortality
?
?
Effect of treatment
CKD-predialysis (RCTs)

Increased exercise capacity, QOL
Teehan BP, et al. Am J Kidney Dis 18:50-9, 1991.
Revicki DA, et al. Am J Kidney Dis 25:548-54, 1995.
Ritz E, et al. Am J Kidney Dis 49:194-207, 2007.
Effect of treatment
CKD-predialysis (RCTs)


No effect on LVMI

Decrease in LVMI
155 patients,
Hb 12.1 vs. 10.8 g/dL
101 patients,
Hb 11.3 vs. 9.1g/dL
Roger SD, et al. JASN 15:148-56, 2004.
Ayus JC, et al. Kidney Int 68:788-95, 2005.
No effect on LVMI,
prevention of new LVH
172 patients, DM Type 1 and 2,
Hb 13.5 vs.12.1 g/dL
Ritz E, et al. AJKD 49:194-207, 2007.
Effect of treatment
CKD-predialysis (Recent RCTs)
CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency)
CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment with Epo beta)
TREAT (Trial to Reduce Cardiovascular Events with Aranesp Therapy)
No cardiovascular or renal benefits or even
detrimental outcomes of higher targets.
Singh AK, et al. N Engl J Med 355:2085-98, 2006.
Drüeke TB, et al. N Engl J Med 355:2071-84, 2006.
Pfeffer MA, et al. N Engl J Med 2009 (doi: 10.1056/NEJMoa0907845)
Effect of treatment
ESRD-dialysis (RCTs)

Increase in mortality
(1.236 pts., Hb 14 vs. 10 g/dL)
Besarab A, et al. N Engl J Med 339, 584-90, 1998.

No effect on LVMI,
prevention of new LVD
(146 pts., Hb 13 vs. 10 g/dL)
Foley RN, et al. Kidney Int 58:1325-35, 2000.

No effect on LVMI,
improvement in QOL
(596 pts., Hb 13.3 vs. 10.9 g/dL)
Parfrey PS, et al. J Am Soc Nephrol 16:2180-89, 2005.
Effect of treatment
(CKD-predialysis+dialysis) (Metaanalysis)
A: Study cohorts with severe anemia at baseline and lower target Hb.
B: Study cohorts with moderate anemia at baseline and lower target Hb.
Parfrey PS, et al. CJASN 4:755-62, 2009.
High Hb vs. ESA dose
Goodkin DA. Semin Dial 22:495-502, 2009.
High Hb vs. ESA dose
Regidor DL, et al. JASN 17:1181-91, 2006.
High Hb vs. ESA dose
Mortality HR (95% CI)
Whites
EPO dose (UI/wk) <4,500
0.82 (0.72-0.93)
AAs
EPO dose (UI/wk) >20,000
1.32 (1.12-1.53)
Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009.
High Hb vs. ESA dose
Szczech LA, et al. Kidney Int 74:791–98, 2008.
Ağaoğlu Ö. Train, Yenice, 2001
Clinical Practice
Guidelines/Recommendations
EBPG
KDOQI
Diagnosis/Evaluation/Target Hb/Using ESAs-Iron-Adjuvants/Resistance
Diagnosis of anemia

Hb levels should be measured at least
annually in all patients with CKD
(regardless of stage or cause).

Diagnosis of anemia should be made if
Hb concentrations
<13.5 g/dL in adult males.
<12.0 g/dL in adult females.
Evaluation of anemia


Hb concentration, white blood cell count and
platelet count
Red blood cell indices
mean corpuscular volume [MCV]
mean corpuscular hemoglobin [MCH]
mean corpuscular hemoglobin concentration [MCHC])



Absolute reticulocyte count
Serum ferritin
Serum TSAT or
Content of Hb in reticulocytes (CHr)
Target Hb levels

Hb levels of 11-12 g/dL should be sought,
without intentionally exceeding 13 g/dL.
Using ESAs

ESAs should be given to all patients
with CKD with Hb levels consistently
(i.e., measured twice at least 2 weeks apart)
below 11 g/dL,
where all other causes of anemia
have been excluded.
Using ESAs

The initial ESA dose and ESA dose
adjustments should be determined by
Patient’s Hb level
Target Hb level
Observed rate of increase in Hb level

The frequency of Hb monitoring in patients
treated with ESAs should be at least monthly.
Using ESAs

The objective of initial ESA therapy
is a rate of increase in Hb levels of
1-2 g/dL per month.

ESA doses should be decreased
by 25%, but not necessarily held,
when a downward adjustment of
Hb level is needed.
Using ESAs

The route and frequency of ESA administration
Non–HD-CKD patients
HD-CKD patients
Subcutaneous
Intravenous
Less frequent administration, particularly in
non–HD-CKD patients.
Using iron agents



Iron status should be evaluated every month
during initial ESA treatment and
at least every 3 months during stable ESA
treatment or in patients with HD-CKD not
treated with an ESA.
Targets levels:
TSAT >20% and
Serum ferritin >200 ng/mL HD-CKD
>100 ng/mL ND-CKD, PD-CKD
Upper limit of ferritin level?
Using iron agents

Route of administration
HD-CKD
ND-CKD or PD-CKD

I.V.
I.V. or oral
Hypersensitivity reactions
Iron dextran
Resuscitative medication
and personnel
All forms of IV iron (iron dextran, gluconate, and sucrose) may be
associated with acute adverse events.
Using adjuvants to ESA

There is insufficient evidence to
recommend the use of vitamin C
(ascorbate) and L-carnitine.

Androgens should not be used as
an adjuvant to ESA treatment in the
management of anemia in patients
with CKD.
Transfusion therapy

No specific Hb concentration justifies or
requires transfusion.
Causes of hyporesponsiveness
Hyporesponse

Definition
A significant increase in the ESA dose requirement to
maintain a certain Hb level or a significant decrease
in Hb level at a constant ESA dose,
A failure to increase the Hb level to >11 g/dL despite
an ESA dose equivalent to epoetin > 500 IU/kg/wk.

Causes
Persistent iron deficiency
Infection/Inflammatory disease/Catheter insertion/
Hypoalbuminemia/Elevated C-reactive protein level
Pancytopenia/aplastic anemia/hemolytic anemia
Cancer/Chemotherapy/Radiotherapy
Acquired immune deficiency syndrome
Antibody-mediated PRCA

Diagnosis
Sudden rapid decline in Hb level at the rate of 0.5 to 1.0 g/dL/wk,
or requirement of red blood cell transfusions at the rate of
approximately 1 to 2 per week;
normal platelet and white blood cell counts; and absolute
reticulocyte count less than 10,000/L.
The definitive diagnosis is dependent upon demonstration of the
presence of neutralizing antibodies against erythropoietin.

Management
Discontinue the administration of any ESA product
Transfusion support
Treatment with immunosuppressive approaches
 Retreatment with ESAs can be considered if anti-EPO
antibodies are not detectable.
Music therapy
Sultan Bayezid II Medical School, 17th Century
Health Museum, Trakya University, Edirne, Turkey
Are the guidelines useful?
Satisfying KDOQI guidelines and mortality risk:
(Hematocrit, Serum albumin, Phosphorus, Calcium, PTH, and spKt/V)
Frequency, 1%
HR (95% CI)
0.11 (0.06-0.19)
------------------------------------------------------------------------------------------------------------
Hematocrit
Frequency
Mortality
(33 to 36%)
(%)
HR (95% CI)
-----------------------------------------------------------------------------------------------0 of 3
28.1
1.00
1 of 3
36.5
0.88 (0.82 to 0.94)
2 of 3
25.4
0.81 (0.75 to 0.87)
3 of 3
10.0
0.68 (0.61 to 0.76)
------------------------------------------------------------------------------------------------
Tentori F, et al. JASN 18:2377-84, 2007.
Current practice
Predialysis

24.778 patients, age>67y
Claims for anemia testing during 2 years prior
to dialysis <50%
Kausz AT, et al. J Am Soc Nephrol 16:3092-101, 2005.
Current practice
DOPPS
Locatelli F, et al. Am J Kidney Dis 44(Suppl 2):S27-S33, 2004.
Current practice
USRDS 2006
Foley RN and Collins AJ. JASN 18:2644-48, 2007.
Practice vs. Guidelines
Differences between the dialysis providers:

Percentage of monthly
rHuEPO claims when
Hb>13 g/dL
2.0% to 16.7%

Monthly rHuEPO dose
38,687 to 54,299 units
Collins AJ, et al. Am J Kidney Dis 49:135-42, 2006.
Practice vs. Guidelines
Not Receiving Epoetin
(%)
Median Epoetin Dose
(U/wk)
Overall
2.3
11,270
Hb (g/dL)
<10
10-<11
11-<12
12-<13
>13
1.9
0.8
0.6
1.4
21.7
25,122
16,427
10,982
9,162
8,097
Servilla KS, et al. Am J Kidney Dis 54:498-510, 2009.
FDA vs. Guidelines
……The new boxed warning advises physicians
to monitor red blood cell levels (hemoglobin) and to
adjust the ESA dose to maintain
the lowest hemoglobin level needed
to avoid the need for blood transfusions.
Physicians and patients should carefully weigh the risks of
ESAs against transfusion risks.
http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108864.htm
(Accessed on November 15th, 2009).
Practice vs. FDA
Dialysis-Medicare
Percentage of patients receiving at least one transfusion (left Y axis), and
mean hemoglobin (dark red line, right Y axis) from 1987 through 2006.
Coyne DW and Brennan DC. Semin Dial 22:590-91, 2009.
Conclusion

Anemia is common among patients with
chronic kidney disease, and is associated
with higher morbidity and mortality rates.

Individualized treatment with the use of
moderate ESA doses in conjunction with
iron therapy to keep hemoglobin between target
levels of the currently available guidelines seems
to be reasonable.
Conclusion

Further studies to understand the
relationships between target hemoglobin
level, ESA dose, and outcomes is essential in
designing effective anemia management and
reimbursement policies.