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Anemia management in
Hemodialysis
Chan-on C. MD.
Content
• Definition
• Impact
• Causes
• Investigation and monitoring
• Management
• ESA in CKD,PD,HD patients in KKU
Take me home
Target Hb in HD < 11.5 g/dL, not more than > 13
g/dL intentionally
10-11.5 g/dL
Start ESA when Hb < 9 g/dL
 Correct Iron deficiency before start ESA
 Epoetin alfa and beta can be used as availability
 Darbepoetin alfa is more convenient for ND-CKD pt
Definition
Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for
Anemia in Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335.
Mortality/ QOL
Anemia in
CKD/HD
Impact
Health budget
Approach anemia in HD
eGFR< 60
ml/min/1.73m2
Anemic
symptoms
Infection/
inflammation
SI
Hb
TIBC
Hb < 13 g/dL Male
Hb < 12 g/dL Female
Normal: F/U
TSAT=SI/TIBC
Anemic work-up:
CBC: Rbc
indeces/reticulocyte/
serum iron/
TIBC/TSAT/Ferritin
/GI bleeding
TIBC > 200 mg/dL
TSAT < 20%
Ferritin > 200
Functional Iron
deficiency
TSAT < 20%
Ferritin < 200
Absolute Iron
deficiency
TSAT > 20%
Ferritin > 200
 No IDA
IV iron
ESA
hyporespon
siveness
ESA therapy
F/U at 4th wks no Hb
response ESA
hyporesponsiveness
Modified from National Kidney
Foundation. K/DOQI Clinical Practice
Guidelines for Anemia of Chronic
Kidney Disease, 2000. Am J Kidney Dis
37:S182-S238, 2001 (suppl 1)
Modified from Intravenous
Iron Versus ErythropoiesisStimulating Agents:
Friends or Foes in Treating
Chronic Kidney Disease
Anemia? Kamyar KalantarZadeh, Elani Streja,
Jessica E. Miller,
and Allen R. Nissenson.
Advances in Chronic Kidney
Disease, Vol 16, No 2
(March), 2009: pp 143-151
Hb levels and cardiovascular comorbidity
Impact of anemia in CKD
- left ventricular hypertrophy (LVH)
- Precipitating factor for congestive heart failure (CHF)
- Exacerbation of angina
Reductions in
- Aerobic capacity
- Overall well-being
- Cognition
Erslev AJ. NEJM 1991, 324: 1339-1344
ASHD: atherosclerotic heart disease CHF: congestive heart failure
other cardiovascular diseases, such as arrhythmias or cardiomyopathies
Prevalence of Anemia: KKU RRT unit
Prevalence Anemia in KKU RRT unit
> 12 g/dL
9%
< 10 g/dL
49%
10-12 g/dL
42%
< 10 g/dL 63 cases
10-12 g/dL 53 cases
> 50 % of pts Hb > 10 g/dL
> 12 g/dL 11 cases
Kidney function decline, Hb decrease,
LVH increase
LVH is an independent risk factor for death in patients with ESRD
Coresh J. et al. Arch Intern Med. 2001,161 1207-16. Levin A. et al. AJKD 1996;27:347-354. Levin A. et al. AJKD 1999,34.125-134.
LVMI: left ventricular mass index; RV, right ventricle; LV, left ventricle; LVH, left ventricular hypertrophy;
d, left ventricular chamber diameter; e, left ventricular wall thickness
Pressure overload
-arterial
hypertension
Hemodynamic
factor
Left
ventricle
Non-hemodynamic factors
Uremia
Sympathetic tone
Renin angiotensin system
Hyperparathyroidism
Chronic inflammation?
Genetic predisposition
Volume overload
-hypervolemia
-fistula flow
-anemia
Hemodynamic
factors
Increase events of
RWT > 0.45
-myocardial
ischemia
RWT< 0.45
Concentric LVH
Eccentric LVH/ LV dilatation
-heart failure
(RWT relative wall thickness = MWT/EDD)
-arrhythmia
LV end-diastolic diameter (EDD), LV mean wall thickness (MWT
The relationship between the risk of
Mortality and Hct in HD patients
Causes
Patient factors
Events
Service provider
Erythropoietin def
Infection/Inflammation
Service protocol
Decrease Rbc survival
Hospitalization
Protocol adherance
Iron def
Blood loss(acute/chronic)
Frequency of sample
drawn
Vitamin def
(Folic/ Vitamin B)
Blood loss from procedures/
samples
Target Hb from K/DIGO
Comorbidity
Malignancy/HIV/HCV/
Autoimmune
Malnutrition
Target iron from K/DIGO
DM
Drug –induced BM
suppression:
immunosuppressives
2nd hyperparathyroid
Interdialytic weight gain
Smoking/ high altitude
Vascular access/ temporary
catheter problems
Ethnicity
Dialysis mode
Management
• Diagnosis
• Therapeutic options
blood transfusion
ESA
Iron administration
• Monitoring
Investigation &
monitoring
Rbc needs EPO and Iron in maturation
Kamyar Kalantar-Zadeh, Elani Streja, Jessica E. Miller, and Allen R. Nissenson. Intravenous Iron Versus Erythropoiesis-Stimulating Agents: Friends or Foes in Treating Chronic
Kidney Disease Anemia? Advances in Chronic Kidney Disease, Vol 16, No 2 (March), 2009: pp 143-151
The tests in initial evaluation of the
anemia
• Complete blood count (CBC), which should include Hb
concentration, red cell indices, white blood cell count and
differential, and platelet count
• Absolute reticulocyte count
• Serum ferritin level
• Serum transferrin saturation (TSAT)
• Serum vitamin B12 and folate levels
Test for stool occult blood
Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for
Anemia in Chronic Kidney Disease. Kidney inter., Suppl. 2012; 2: 279–335.
Iron deficiency diagnostic labs
Therapeutic options
Pack red cell transfusion
• transfusion-transmitted infection
• immunologic sensitization
• iron overload syndromes
• volume overload
• transfusion reactions.
In Chronic anemia
 ESA ineffective: hemoglobinopathies/BM failure/ ESA
resistance
 ESA gives risk outweigh benefit: previous or current
malignancy, previous stroke
In Urgent treatment
 rapid correction of anemia: bleeding/ hemorrhagic shock
 rapid pre-operative Hb correction
Rapid correction of anemia
Murphy MF, Wallington TB, Kelsey P et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol 2001; 113: 24–31.
Pre-op transfusion in HD
Healthy/stable
• Hb > 10 g/dL not
recommended
• should be given Hb < 7
g/dl
High-risk patients
>65 years and/or
with CV or RS disease
tolerate anemia poorly
Hb < 8 g/dl
2 unit PRC transfusion then reevaluate
Hb 7-10 g/dL  unclear
Murphy MF, Wallington TB, Kelsey P et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol 2001; 113: 24–31.
Blood transfusion: High PRA longer waiting time
 be excluded from list
lower survival
Increased risk of early and late graft loss
the number of HLA molecules contributed by the red cells is
comparable to that of leukocytes
Balasubramaniam GS, Morris M, Gupta A et al. Allosensitization rate of male patients awaiting first kidney grafts after leuko-depleted blood transfusion. Transplantation 2012; 93: 418–422.
Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant 2004; 4: 438–443.
Terasaki PI, Ozawa M. Predictive value of HLA antibodies and serum creatinine in chronic rejection: results of a 2-year prospective trial.Transplantation 2005; 80: 1194–1197.
Erythropoietin stimulating agents
Erythropoietin stimulating agents
• The response to EPO is dose-dependent, but great
variation
• The response depends on the route (iv. versus sc.) and
the frequency of administration.
• The response may be limited by many factors
• Stroke, mortality, and hypertension may complicated
Erythropoietin stimulating agents





Improve cardiac morphology
Increase survival
Reduced hospitalization
Improve QOL/well-being
Improve energy/work capacity
Erythropoietin stimulating agents
• Stroke
• Vascular access loss
• Hypertension
Epoetin alfa and epoetin beta
Darbepoetin alfa
Continuous erythropoietin receptor activator: methoxy
polyethylene glycol-epoetin beta
Peginesatide
Epoetin alfa and beta = endogenous erythropoietin
(immunological/biological)
N-linked
oligosaccharide
Darbepoetin alfa structurally different from endogenous erythropoietin
- oligosaccharide chains
- amino acid sequence rearranged
- larger molecular weight
Clinical significance of different molecular structure is unknown
The terminal half-life of Aranesp® was ~ 3-fold longer than that of
Epoetin alfa when administered intravenously.
ESA dosing consideration
Iron repletion before ESA initiation
KDOQI. Am J Kidney Dis 2001;37 (suppl):S182-S238
Maintenance
q ½-1 /week
25%
NKF. Am J Kidney Dis 2001;37(1 suppl 1) S 182-238
q 1-2 /week
Darbepoietin
Krause MW, Raja R, Agarwal A, Silver MR, Scarlata D, Sciarra A, Kewalramani R. Every-other-week darbepoetin alfa in the correction and maintenance of haemoglobin levels in elderly
patients with chronic kidney disease: post hoc subanalysis of data from two clinical trials. Drugs Aging. 2009;26(8):665-75.
Darbepoietin
de novo q2w darbepoetin alfa is a well tolerated and effective
treatment for correcting anaemia in older patients with CKD not
receiving dialysis.
Continuous erythropoietin receptor
activator: methoxy polyethylene glycolepoetin beta
Peginesatide (Hematide)
A peptide-based erythropoietin receptor agonist.
No structural homology with endogenous EPO no
cross react with anti-EPO Ab  apply in PRCA pts




once-monthly therapy
intravenously or subcutaneously.
starting dose: 0.025–0.075 mg/kg.
starting dose in PRCA: 0.05 mg/kg.
1.Fan Q, Leuther KK, Holmes CP, et al. Preclinical evaluation of Hematide, a novel erythropoiesis stimulating agent, for the treatment of anemia. Exp Hematol. 2006;34:1303–1311.
2.Woodburn KW, Fan Q, Winslow S, et al. Hematide is immunologically distinct from erythropoietin and corrects anemia induced by antierythropoietin antibodies in a rat pure red cell aplasia
model. Exp Hematol. 2007;35:1201–1208.
3.Macdougall IC, Rossert J, Casadevall N, et al. A peptidebased erythropoietin-receptor agonist for pure red-cell aplasia. N Engl J Med. 2009;361:1848–1855.
ESA hyporesponsiveness
Causes of ESA hyporesponsiveness
- Iron content and availability
- inflammation
- nutritional status
- specific nutrients availability: folic B
- delivered dialysis dose
- parathyroid function
- demographic eg. race gender age
- functioning bone marrow
KDOQI 2000 Anemia Guidelines Am J Kidney Dis. 2001 Jan;37(1 Suppl 1):S182-238.
Kotanko P et al. Semin Dial. 2006 Sep-Oct;19(5):363-72.
• Hemolysis
• Aluminum toxicity
• Osteitis fibrosa
cystica
Iron therapy
Alteration of iron balance in
CKD
Hb Stability, IV Iron, and ESA: What We Know Suzann VanBuskirk,
TSAT < 20%
Ferritin > 200
Functional Iron deficiency
or RE blockade
Iron deficiency diagnostic labs
IV. iron
 Prefer IV route of iron administration in CKD 5HD
patients over oral iron with and without concomitant
ESA treatment
Inadequacy of oral iron
- Low intestinal absorption of oral iron
- Poor patient adherence
 Additional IV iron should not routinely be administered
Iron targets
Individualized depend
on pt status
If serum ferritin > 500 ng/ml
Serum ferritin is not predictive for iron response
AJKD
2006
TSAT > 25 is not predictiveKDOQI
for iron
response
IV. Iron
IV Iron therapy
Common approach IV iron treatment in CKD 5HD
patients:
(1) periodic iron repletion, consisting of a series of IV
iron doses administered episodically to replenish iron
stores
(2) maintenance treatment, smaller doses at regular
intervals to maintain iron status in specific limits
IV. Iron
Disadvantages of IV Iron in CKD
•
•
•
•
•
•
Reducing ESA dose
Improving ESA hyporesponsiveness
Mitigating hemoglobin variability
Mitigating risk of thrombocytosis
Reducing likelihood of blood transfusion
Circumventing the need for oral iron
•
•
•
•
•
•
•
•
supplementation
Beyond anemia effects
Treatment of restless leg
Improving cognitive function
• Increased death risk (?)*
• *Both decreased and increased
death risk have been postulated
with IV iron administration.
Short-term adverse events
Iron overload
Increased risk of infection
Increased oxidative stress
• Decreasing death risk (?)*
Kamyar Kalantar-Zadeh, Elani Streja, Jessica E. Miller, and Allen R. Nissenson. Intravenous Iron Versus Erythropoiesis-Stimulating Agents: Friends or Foes in Treating Chronic
Kidney Disease Anemia? Advances in Chronic Kidney Disease, Vol 16, No 2 (March), 2009: pp 143-151
Target
Current concept: partial correction
Trials in predialysis-CKD, suggest that
Hb levels near normal range ~ moderate anemia
same in clinical benefit but increased risk of adverse outcomes
D-CKD : dialysis dependent CKD
ND-CKD: non-dialysis dependent CKD
FDA:
• Individualizing therapy for each pt
• Using the lowest possible ESA dose required
to reduce the need for transfusions
• The new labels recommend reducing the ESA dose
when Hb > 10 g/dL in ND-CKD and
Hb > 11 g/dL in D-CKD patients
Does not seem to be factually correct, because trials found higher risks in patients randomized to near-normal
hemoglobin targets (i.e., >130 g/L and not >110 g/L). Information from clinical trials is not available to inform the
selection
offora ESA—Implications
hemoglobin target
between
11.5 Band
13 g/L.
The New
FDA Labeling
for Patients
and Providers
J. Manns,
M Tonelli.
FDA:
For D-CKD
Initiate ESA when Hb <10 g/dl.
If the Hb level > 11 g/dl, reduce or interrupt the dose of ESA.
When initiating or adjusting therapy, monitor Hb levels at least
q1wk until stable, then at least q1mo.
If pts do not respond adequately over a 12-wk escalation period,
increase ESA dose further  unlikely to improve response
 may increase risks.
FDA: FDA Drug Safety Communication: Modified Dosing Recommendations to Improve the Safe Use of Erythropoiesis-Stimulating Agents in CKD, 2011.
The New FDA Labeling for ESA—Implications for Patients and Providers. B J. Manns, M Tonelli. Clin J Am Soc Nephrol. 2012 February; 7(2): 348–353.
Recent clinical trials comparing in
CKD
Strokeuse of ESA targeting low (HB 9 –11.5 g/dL)
•the
and
near-normal Hb targets (Hb >13.0 g/dL)
 no improvements in clinical outcomes
 potential harm for ESA use targeting nearnormal Hb targets.
Persistent in
target
Persistent
low
Too low or too high Hb and high
variability
increase
risk
of
adverse
Medicare: all hemodialysis patients who survived the first 6 mo of 2004
low (L; <11 g/dl), intermediate (I; 11 - 12.5 g/dl) high (H; >12.5 g/dl).
outcome
Highest and lowest Hb during 6 month
Ebben JP et al. Clin J Am Soc Nephrol. 2006 Nov;1(6):1205-10.
CREATE
CHOIR
TREAT trial
The Normal Hematocrit Cardiac Trial (NHCT)
the TREAT trial
Hb 13 g/dL
4038 patients
Type 2 DN
ND-CKD
Darbepoetin alfa
vs placebo
Hb > 9 g/dL
Minimal improvement in patient-reported fatigue in the darbepoetin alfa group
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N
Engl J Med. 2009 Nov 19;361(21):2019-32. doi: 10.1056/NEJMoa0907845. Epub 2009 Oct 30.
the TREAT trial
 Darbepoetin in T2DM + CKD did not reduce the risk of
either death or a cardiovascular event or death or a renal
event
.
 associated with an increased risk of stroke.
Pfeffer MA, Burdmann EA, Chen CY, Cooper ME, de Zeeuw D, Eckardt KU, et al; TREAT Investigators. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N
Engl J Med. 2009 Nov 19;361(21):2019-32. doi: 10.1056/NEJMoa0907845. Epub 2009 Oct 30.
Francesco Locatelli, et al and On behalf of the Anaemia Working Group of ERBP. Target haemoglobin to aim for with erythropoiesis-stimulating agents: a position statement by
ERBP following publication of the Trial to Reduce Cardiovascular Events with Aranesp® Therapy (TREAT) Study Nephrol. Dial. Transplant.(2010) 25 (9): 2846-50.
the United States Normal Hematocrit trial
Mean 42+/- 3%
Mean 30 +/- 3%
a target hematocrit value of 42% in this patient with cardiac
disease who are undergoing hemodialysis cannot be
recommended.
Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with
cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med 1998; 339: 584–590.
Meta-analysis: ESA in CKD
in the higher Hb target group
 significantly higher risk of all-cause mortality (RR 1·17,
95% CI 1·01—1·35; p=0·031)
 VA thrombosis (1·34, 1·16—1·54; p=0·0001)
 significantly higher risk of poorly controlled BP (1·27,
1·08—1·50; p=0·004)
Evidence
1. Target Hb in HD & PD  extrapolated
from results of trials in CKD patients
2. Outcome: target Hb surrogate outcome
ESA in CKD,PD,HD patients in
KKU
• Setting: CKD clinic, HD unit, PD unit
• Population: PD, HD, CKD patients received ESA
treatment
• Data collection and analysis: Kridsada Sirichaisit MD.
Wilaiporn Wasuthapitak MD.
Total
Sex male
Age (Median) ปี
DM
จำนวน (คน)
154
75
60.5 (17-88)
54
%
48.7
35
Hb (Mean) g/dl
9.9
Hct (Mean) %
30.3
Duration on ESA
28 mo ± 25.9 (1-122 mo)
Take me home
Target Hb in HD < 11.5 g/dL, not more than > 13
g/dL intentionally
10-11.5 g/dL
Start ESA when Hb < 9 g/dL
 Correct Iron deficiency before start ESA
 Epoetin alfa and beta can be used as availability
 Darbepoetin alfa is more convenient for ND-CKD pt