ANEMIA IN CHRONIC KIDNEY DISEASE

dr. Stella Palar, SpPD-KGH

PRELIMINARY
CKD  a clinical condition characterized by decreased kidney
function that chronic, progressive and irreversible

Specific treatment is needed to prevent the progression of decreased

kidney function
 CKD criteria (KDIGO, 2013)
1.
Kidney damage > 3 months  abnormalities
structural / functional, with / without  GFR,
manifestations in the form of:
• Pathological abnormalities
• There are signs of kidney damage (abnormalities
in the blood or urine, or radiological imaging)
2.
GFR <60 ml / min / 1.73 m2 During 3 months,
with or without kidney damage
Criteria CKD (where it appears > 3 months)
Sign Kidney • Albuminuria> 30 mg / day
Damage
• Abnormalities urine sediment
(hematuria, erythrocyte cylinders,
etc.)
• Electrolyte abnormalities
• Abnormal histology
• Structural abnormalities on
radiological imaging
• History of kidney transplant
www.kdigo.org
 The number of CKD cases increases every year,
especially in developing countries

The progression of CKD to become the final stage of CKD cannot be

avoided,
which will be a major health problem,
where its management imposes a large economic burden

• New Case  >100,000 people per year (USA)

• Average 200-300 case / 1,000,000 person per year (INA)
 The prevalence tends to increase
NHANES: 12% (1988-94) → 15% (2003-06)
SEEK Study: 14.4% (4.3% → 13.8%)
INDONESIA: 12.5% ​(CG), 8.6% (MDRD)

CKD High medical costs

global health problems ESRD program (USA): 80 trillion dollar per year
Indonesia: 6.24 trillion rupiah/year

High Morbidity and Mortality

Long Take care: 14 day/patient/year
Mortality : 20% / year, 5 year → 35%

Complications Cardiovascular :
(10 - 20 times greater)

Kidney Disease: Act early to prevent it www.kdigo.org

PREVALENCE CKD (Riskesdas 2013)

0.4%

0.5%
0.4%

Province with the second most

incidence
 An Epidemic of Kidney Disease
Prevalence CKD stages 1- 4
10% 1988-94 Not enough
13% 1999-2004
Coresh, JAMA 298: 2038, 2007 nephrologists

Stage 5: GFR <15 0.1% (n = 300,000)

Stage 4: GFR 15–29 0.2% (n = 400,000)

Stage 3: GFR 30–59 4.3% (n = 7,600,000)

Stage 2: GFR 60–89 * 3% (n = 5,300,000)

3.3% (n = 5,900,000)
Stage 1: GFR ≥90 *
Total = 23 million USA

Clinical Practice Guidelines for CKD Am J Kidney Dis. 2002; 39 (suppl 1): S17 – S31.
GFR = glomerular filtration rate (mL / min / 1.73 m 2); * with kidney damage
CKD Development

Step 3 Step 4
Step 2 Step 5
Step 1
Kidney Injury
Kidney Injury Severe
Kidney Injury Moderate Kidney
Mild decline in decline in
Normal Function decline in Failure
function function
function
Stenvinkel P. Cardiovascular disease in CKD
Definition Anemia and Renal Anemia

 PERNEFRI: WHO: ANEMIA  if the Hb level <14 g / dl (male) or

<12 g / dl (female)
 KDIGO, 2012: ANEMIA  if the Hb level <13 g / dl (male) or
<12 g / dl (female)

 RENAL ANEMIA  anemia in chronic kidney disease which is mainly due to decreased erythropoetin
production capacity

Consensus Management Anemia on Disease Kidney Chronic. PERNEFRI.2011, KDIGO 2012

 CAUSES OF ANEMIA ON CKD
High levels hepsidin, inflammation,
infection , all could contribute to
deficiency iron functional and distraction EERTHROPOIETIN Absolute Iron deficiency
of the responsiveness from marrow on PRODUCTION (malnutrition and bad
erythropoietin REDUCTION absorption)

Bloodlost
Anemia on CKD
Deficiency from
Vitamin B12 and Decreased
Folic acid red blood
cell age

Mineral Disease
Medicines Suppression of Other
mineral and
(ACE –I, ARB) bonemarrow comorbid
bone
because uremia
Adapted from: Agarwal AK., JA Med DirAssoc. 2006; 7: S7-12 abnormalities
 Other contributing factors
in renal anemia

 Hyperparathyroidism severe
 Infection and inflammation
 Aluminum toxicity
 Hypothyroidism
 Hemoglobinopathy

Consensus Management Anemia on Disease Kidney Chronic. PERNEFRI. 2011

 ANEMIA COMPLICATIONS OF PATIENTS CKD
3
2 Lowered immunity / patients are often
CHRONIC KIDNEY FAILURE treated
Increase the risk of death from
production of cytokines (IL-1, IFN, TNF
cardiovascular disorders and CSF) is stimulated by hemoglobin
level
1 Lack of EPO
4
LEFT VENTRICLE HYPERTROPHY / LEFT
VENTRICLE ENLARGEMENT
Anemia
Nerve cell damage: Decreased
Hb <13.5 (Male) Cognitive Function
Hb <12 (female)
5
LEFT VENTRICLE compensate to pump Kidney cell damage: Worsening
more blood to overcome TISSUE Low Oxygen distribution Kidney Function
HYPOXIA throughout the tissue
6
Worsening Quality of life of
patients
HYPOXIA
Anemia could increase risk progressions CKD
towards dialysis

60 Baseline Hb per quartile (Q, g /dL)

Q1: 6.8–11.3 Q1 (n = 378) *
50 Q2: 11.3–12.5
Q3: 12.5–13.8
Patient dialyzed (%)

40 Q4: 13.8–18.0
Q2 (n = 377) *
30
Q3 (n = 363) *
20

10 Q4 (n = 395)

0
01234
Time (year)

*P<0.05 versus Q4 Mohanramet al. Kidney Int. 2004; 66: 1131-1138

Anaemia related with enhancement mortality and morbidity
significantly on dyalisis patient

Relative risk of death Relative risk of hospitalization

RR
1,4
RR overall = 0.95 per RR overall = 0.96 per
1,29
1 g /dL Hb that higher (P= 0.03) 1 g /dL Hb that higher (P= 0.02)
1,22
1,2

1,09
1,07
1,02
1,00 1,00
1,0
0,91

0,8
<10 10−10.9 11−11.9 ≥12 <10 10−10.9 11−11.9 ≥12

Hb (g /dL) on early studies

RR = relative risk Locatelli et al. NephrolDial Transplant. 2004; 19: 121-132
 Increase in Hb fix the quality of life in CKD
patient with non-dialysis

65 26
Score LASA overalls QoL (mm)

60 25
24

Score KDQ whole

55
23
50
22
45 Overall QoL
21
40
20
35 19
30
Overall KDQ
18

7 8 9 10 11 12 13 14
Levels Hb (g /dL)
n = 1326 patient non-dialysis
KDQ = kidney disease questionnaire Lefebvre et al. Curr Med Res Opin. 2006; 22: 1926-1937
 Impact of stable Hb maintenance:
The risk of mortality is greater for Hb beyond 11.0−12.9 g / dL

5 12000
n = 58 058 incident
Unadjusted
and prevalent patients
All-cause mortality hazard

10000

Number of patients
Mix Case
3
Mix Case & MICS 8000
ratio

2 6000

4000

1 2000

0.8 0

Hb level (6 months)
MICS = malnutrition-inflammation
complex syndrome Regidor et al. J Am Soc Nephrol. 2006; 17: 1181-1191
 The cause of anemia therapy is not optimal

 The severity of anemia has not been taken seriously

 Inadequate screening of at-risk patients
 Lack of understanding of the consequences of anemia
 Perceptions of costs therapy
 Focus on short and long term costs
 Concern about hypertension
 Drug logistics / availability issues

Macdougal IC. Nephron 2000; 85 (suppl 1): 15-22

 History of the development of therapy

1600s 1800-1900 1901 1945 1990

1800s 1940 1990
Blood Tranfusion Person to A,B,O
American Erytropoeti 2007
Rhesus Red Cross Erytropoeti n beta CERA
using animal Bloodletting person blood
Factor start in Blood n alpha
blood tranfusion group
Donor
4 STEPS TO HANDLING ANEMIA IN CKD

Blood Transfusion

ESA Therapy

Iron Management

Exclusion Other Cause of anemia

IC Mcdougall, 2013.
 Therapeutic options in CKD patients

 Epoetin alpha & beta

 Used in conjunction with iron supplementation if needed
 CERA (Continuous Erythropoietin Receptor Activator)
 Used in conjunction with iron supplementation if needed
 Red blood cell transfusion
 For severe anemia (Hb <8 g / dL)
 Acute anemia
 Correction of nutritional deficiencies

NKF. Am J Kidney Dis 2001; 137 (1 Suppl 1): S182-238

Blood Transfusion : Indication and the risk

Indication & target blood transfusion Risk of blood transfusion

 Blood transfusion indicated on:  Circulation overload
 Hb <7 g / dl with or without symptoms anemia
 Transmission of infection (hepatitis, HIV, malaria and
etc)
 Hb <8 g / dl with distraction cardiovascular that  Febrile non hemolytic reaction
real
 Allergic reaction or anaphylactic
 Bleeding with hemodynamics symptoms
 Haemolytic reaction
 Patient that will undergo operation  Iron overload
 Target achievement Hb with transfusion:  Allloimmunization
7-9 g / dl  Transfusion Related Acute Lung Injury (TRALI)

Consensus Management Anemia on Disease Kidney Chronic. PERNEFRI. 2011

 Erythropoetin Stimulating Agent (ESA)

 Synthesis in peritubular fibroblasts kidney.

 Glycoproteins with BM 30,400 dalton.
 Consist 165 AA and 4 chain KH, Ditub with 4 glycosilation sites
 Epo bonded pd EpoR in surface BFU-E, CFU-E, proeritroblast, and
erythroblast basophilic SST.
 Way of work : inhibition apoptosis
 stimulation proliferation cell
 induction differentiation cell
 Guidelines for managing anemia
in CKD with ESA

ESA & Target Hb ESA therapy phase

 The one agree in Indonesia  Correction Phase
 Epoetin α  Objective: to correct renal anemia until the Hb target is
achieved
 Epoetin β
 ONE α biosimilar
 Maintenance phase

 CERA  Goal: maintain Hb levels within the therapeutic target

range (10-12 g / dl)
 Target Hb on therapy ONE:
 Requires dosage adjustments according to patient needs.
 Therapy ESA started on levels Hb <10 g / dl
 Target Hb on ESA therapy : 10-12 g / dl
 Levels Hb no more than > 13 g / dl
Consensus of Anemia Management in Chronic Kidney Disease. PERNEFRI. 2011
 Erythropoietin Stimulating Agents (ESA):
Indications, targets and contraindications

Indication Contraindication & Risk

 Therapy ESA started on Hb <10 g / dl and  ESA Contraindication : Hypersensitivity to ESA
rule out other cause anemia  Circumstances that should be noticed:
 Terms of giving:  Hypertension
 There is absolute anemia deficiency  Blood Pressure should be monitored
 There is no severe infection during ESA therapy
 SBP ≤ 160 mmHg  Generally related with enhancement Hb is
too fast and higher dose os ESA
 Hypercoagulation

Consensus of Anemia Management in Chronic Kidney Disease. PERNEFRI. 2011

Factors affecting Hb variability

Patient related Condition related Factor related in clinical

that occur simultaneously practice
• Access vascular modality • Hospitalization • Change dose of ESA
• Survival of red blood cell • Infection • Design protocol and lab
• Secondary • Inflammation monitoring
hyperparathyroidism • Bleeding/hemolysis • Target range Hb that narrow
• Cancer • Nutrition Deficiency • Iron management
• Hematology disorder • PRCA • Adequacy dialysis
• Diabetes • Drugs • Restrictions in insurance
• Increase in body weight • Water Purity
Deficiency iron (absolute,
interdialysis
relatively , reserve iron less)

Doctor Influence is very limited Fishbane & Berns. Kidney Int. 2005; 68: 1337-1343;
Gilbertson et al. Nephrol Dial Transplant. 2006; 21 (Suppl 4): iv169
 Why Giving ESA Sub Cutant are more efficient ?

Increase in halflife

Neocytolysis 

 Effect Inflammation

More Economical
 Changing from IV administration to SK improves
blood pressure control
Epoetin dose (IU / kg / week)

MAP (mmHg)
*

MAP = mean arterial pressure

* p <0.05, compared with baseline Navarro et al Scand J Urol Nephrol 1995
Profile pharmacokinetics giving epoetin alpha and epoetin Beta
through giving path IV & SC on healthy patient
Value (Mean + SD) Epoetin alpha (n = 18) Epoetin beta (n = 18)
IV administration
C max (your/ ml) 1796 + 367 1763 + 362
Half-life (h) 6.8 + 2.7 8.8 + 2.2 *
Mean residence time 7.9 + 1.0 8.9 + 1.1 *
Vss (ml / kg) 63.8 + 6.1 70.0 + 10.4 *
Clearance (ml / hour / kg) 8.1 + 1.0 7.9 + 1.2
Maximum absolute reticulocyte count (106/ 0.102 + 0.028 0.099 + 0.044 Table7.1.
mm3) * p <0.05 epoetin beta vs. epoetin alfa
SC Administration ** Terminal elimination rate constant gives a
measure of subcutaneous (SC) drug
C max (your/ ml) 140.8 + 72.2 130.9 + 55.2 absorption, as the absorption process is
longer than the elimination process.
T max (h) 15 + 8 15 + 7
*** Maximum absolute reticulocyte count
Terminal elimination rate constant ** (p-1) 0.046 + 0.023 0.035 + 0.017 * occurred at the 96-hour assessment
following intravenous (IV) and SC
administration. SD, standard deviation; C max,
Half-life (h) 19.4 + 10.7 24.2 + 11.2 * peak serum concentration; V ss,volume of
Bioavailability (%) 31.9 + 9.1 32.7 + 8.2 distribution at steady state; Tmax, time to
Cmax. Adapted from (53)
Maximum absolute reticulocyte count (106/ 0.116 + 0.042 0.137 + 0.050 *
mm3)
Iron deficiency management:
An important factor in the management of anemia in
CKD
 Iron deficiency on CKD
Iron Deficiency that already Deficiency iron related therapy epoetin
occur
Poor Nutrition Increase needs of iron
Blood lost

 Why iron oral preparations is not adequate on patient CKD?

 Absorption intestinal ones low, even on people who healthy
 Obedience patient that low
 Use iron intravenous could fix anemia on CKD if oral preparations failed.
 IV Iron Therapy at 20-50% Transferrin Saturation

Iron Sucrose or Iron Dextran

Ferritin ESA
(ng / ml) Dose Duration of therapy
Interval
evaluation
every 2
<200 100 mg 3 months continue
weeks
every 4
200-300 100 mg 3 months continue
weeks
every 6
301-500 100 mg 3 months continue
weeks
> 500 cancel
Consensus Anemia 2011
 IV Iron Therapy at Transferrin Saturation <20%

Iron Sucrose or Iron Dextran

Ferritin (ng / ml) Duration of ESA therapy

Dose Interval
evaluation

<200 100 mg every HD 1-2 months cancel

200-300 100 mg every 1 week 3 months continue

301-500 100 mg every 2 weeks 3 months continue

501-800 cancel see description 1 month continue

> 800 cancel see description

Information:
•If ST <20% and FS 501-800 ng / ml continue ESA therapy and postpone iron therapy, observe for one month. If Hb does not increase, it can be giveniron sucrose or iron dextran 100 mg once
every 4 weeks, observe 3 months.
•If ST <20% and FS> 800 ng / ml iron therapy is delayed. The cause of the possible infection-inflammatory state is sought.
BB (Kg) 60 INFORMASI KEBUTUHAN DOSIS EPO DEWASA 1,2,3

Dosis Dosis Rekomendasi (PI) Asumsi yang Diberikan BPJS Selisih Dosis
Asumsi Total
Sediaan (Per Total Dosis Total Syringe Total IU yang IU (Asumsi
Fase Koreksi

Epo Berat Syringe Keterangan

(IU) IU/kgbb/ (per IU yang diberikan BPJS vs Dosis
Badan yang
minggu) /kgbb/minggu) diberikan BPJS Rekomendasi)
dibutuhkan
Recormon ADEKUAT / LEBIH :
2000 60 60 3600 1,8 2 4000 400
(Epo Beta) 400
2000 150 60 9000 4,5 2 4000 -5000 KURANG: -5000
Epo Alfa
3000 150 60 9000 3 2 6000 -3000 KURANG: -3000
Fase Pemeliharaan

Dosis Dosis Rekomendasi (PI) Asumsi yang Diberikan BPJS Selisih Dosis
Asumsi Total
Sediaan (Per Total Dosis Total Syringe Total IU yang IU (Asumsi
Epo Berat Syringe Keterangan
(IU) IU/kgbb/ (per IU/kgbb/ yang diberikan BPJS vs Dosis
Badan yang
minggu) minggu) diberikan BPJS Rekomendasi)
dibutuhkan
Recormon ADEKUAT / LEBIH :
2000 30 60 1800 0,9 1 2000 200
(Epo Beta) 200
2000 75 60 4500 2,3 1 2000 -2500 KURANG: -2500
Epo Alfa
3000 75 60 4500 1,5 1 3000 -1500 KURANG: -1500

Referensi: 1. Produk Informasi Recormon - Indonesia

2. Produk Informasi Eprex - Indonesia
3. Produk Informasi Hemapo - Indonesia
 Conclusion

 Anemia have an impact in morbidity and mortality on CKD

 Anemia on CKD often underdiagnosed and undertreated.
 Overall in anemia management will improve the patient's quality of life and decrease
progression
 Blood transfusion has a bad impact on CKD
 ESA provides good efficacy and tolerability, both in pre- and dialysis patients.
THANK YOU