1. Anemia in Chronic Kidney Disease
Jatin Kothari MD, DM
Hinduja Hospital, Hinduja Healthcare &
Apex Kidney Foundation
Mumbai, India.

2. Defining “CKD”
 Kidney damage for ≥ 3 months, defined by structural or functional
abnormalities of the kidney, with or without decreased GFR, manifest by
either
 Pathologic abnormalities, or
 Markers of kidney damage, such as abnormalities of the blood or
urine, or in imaging tests (but NOT HTN).
 GFR < 60 mL/min/1.73 m2
for ≥ 3 months with or without kidney damage.
 Pathologic Abnormalities?
 By Radiology (US, CT, MR, etc)--e.g.
 Multiple cysts consistent with PKD
 Extensive scarring
 Small kidneys--but be careful of the term “medical renal disease”.
 REMEMBER: Renal masses or cysts that are not simple should be
referred to a UROLOGIST!!
 By Histology--ie, renal biopsy

3. CKD Patients Are More Likely to Die than to Progress to ESRD
0% 20
%
40
%
60
%
80
%
100
%
GFR 60-89, No Proteinuria
GFR 60-89; + Proteinuria
GFR 30-59
GFR 15-29
Died
RRT
Event Free
Disenrolled
Keith, et al, Arch Int Med; 2004; 164:659-663
5 year follow-up
N=27998

4. The Patient with early stage CKD is 5 to 10
times more likely to die from a cardiovascular
event than progress to ESRD.
Foley RN, Murray AM, Li S, Herzog CA, McBean AM, Eggers PW, Collins AJ.
Chronic kidney disease and the risk for cardiovascular disease, renal
replacement, and death in the United States Medicare population, 1998 to
1999. J Am Soc Nephrol 2005; 16:489-95.

5. Anemia and CKDAnemia and CKD
• Anemia usually develops during the course of chronic kidney
disease and may be associated with adverse outcomes.
• Anemia is one of the modifiable complications of CKD.
• All individuals with hemoglobin (Hb) levels lower than physiologic norms
are considered anemic.
 Erythropoietin deficiency is the primary cause of anemia of CKD.
 The NKF recommends that evaluation for anemia should occur when GFR
<60 mL/min/1.73 m2
; measurement should include Hb level.
 Anemia should be treated according to the K/DOQITM
guidelines for anemia
of CKD.

6. Consequences of Anemia in CKD
• Reduced oxygen delivery to tissues
• Decrease in Hgb compensated by increased cardiac output
• Progressive cardiac damage and progressive renal damage1
• Increased mortality risk2
• Reduced quality of life (QOL)3
– Fatigue
– Diminished exercise capacity
– Reduced cognitive function
• Left ventricular hypertrophy (LVH)4
1. Silverberg et al. Blood Purif. 2003;21:124-130. 2. Collins et al. Semin Nephrol. 2000;20:345-349; 3. The US Recombinant Human
Erythropoietin Study Group. Am J Kidney Dis. 1991;18:50-59; 4. Levin. Semin Dial. 2003;16:101-105.
© 2005 The Johns Hopkins University School of Medicine.

7. K/DOQI:K/DOQI: Evaluation and Management ofEvaluation and Management of
AnemiaAnemia
 For Adults with ≥ Stage 3 CKD:
 Assess Hemoglobin level
 If anemia (HgB ≤ 12)
 RBC indices/CBC
 Reticulocyte count
 Iron studies
 Test for occult GI bleeding as indicated
 Medical evaluation of comorbid conditions
 Erythropoetin levels are usually NOT indicated.

8. Patients With CHF and Anemia (n = 126, 91% CKD)
NYHA class = New York Heart Association classification;
SOB = shortness of breath.
Silverberg et al. Perit Dial Int. 2001;21(suppl 3):S236-S240.
Clinical Benefit of Anemia Correction: CHF and CKD
Parameter Before After
Hgb (g/dL) 10.3 13.1
Serum creatinine (g/dL) 2.4 2.3
∆GFR (mL/min/mo) -0.95 0.27
NYHA class (0-4) 3.8 2.7
Fatigue/SOB index (0-10) 8.9 2.7
Hospitalizations 3.7 0.2
Systolic BP (mm Hg) 132 131
Diastolic BP (mm Hg) 75 76
© 2005 The Johns Hopkins University School of Medicine.

9. Pathway: treatment
Iron
Iron correction should maintain:
• serum ferritin > 200 μg/l
• transferrin saturation > 20% (unless ferritin > 800 μg/l)
• % hypochromic red cells < 6% (unless ferritin > 800 μg/l)
Review iron dose:
• when serum ferritin reaches 500 μg/l (should not rise above 800 μg/l)
Optimise iron status:
• before or when starting ESAs
• before deciding whether to use ESAs in non-dialysis patients

10. Oral vs parenteral iron
• Oral iron is not as effective as parenteral
iron in hemodialysis, peritoneal dialysis, and
CKD patients
• Causes include:
– Iron malabsorption
– Lack of patient compliance due to GI effects

11. IV iron is superior to oral iron in
managing anemia of NDD-CKD
Time after initiating treatment (d)
0 14 28 42 56
Delta Hb
(g/dl)
0.0
0.2
0.4
0.6
0.8
1.0 IV iron
Oral iron * *
*P < 0.05
Source: Iron Sucrose US Clinical Trials Group; Kidney Int: in press

12. Reevaluating traditional
parameters
• Ferritin:
– Storage iron
– Also an acute-phase reactant
– Should focus less on high ferritin levels and more
on indicators of iron available for erythropoiesis
• Newer measurements:
– Reticulocyte hemoglobin content
– Percent hypochromic RBCs
– Soluble transferrin receptors (sTfR)

13. Which iron marker to use?
• Patient needs increased EPO to meet target
hemoglobin levels
– Significant iron requirement
– Oral iron not enough, IV iron necessary
– TSAT is the best marker for iron available for
erythropoiesis
– Iron should be given to increase TSAT to the 20-
30% range

14. Ferritin should not limit the physician
• Before EPO therapy, patients could reach ferritin levels of 4000-
5000 ng/mL
– Physicians should not be too focused on ferritin level
• K/DOQI guideline updates:
– Based on studies showing that iron responsiveness decreases with
ferritin >500 ng/mL
• Distinction between:
– Patient with low TSAT and high ferritin with inflammation
– Patient with functional iron deficiency
• The latter can benefit from iron therapy

15. Adverse events with IV iron!
• No reported cases of hemochromatosis or hemosiderosis
with IV iron in the erythropoietin era
• Guidelines were updated for physicians not to use iron
indiscrimately
• Acute infusion of IV iron on immune system:
– Avoid in infected patients
– Avoid in patients with high CRP and high ferritin

16. Safety of IV iron:
CV morbidity?
• In vitro iron can be proinflammatory and induce
lipid peroxidation
• Could parenteral iron lead to accelerated
atherosclerosis, inflammation and thus CV
morbidity?
– In vitro doses required to have an effect are much
higher than used in IV iron
– Feldman et al saw no correlation between iron use and
CV mortality and morbodity

17. Safety of IV iron
• Higher risk with undertreatment
• Benefits of correcting anemia far outweigh
the theoretical risk of CV toxicity

18. Erythropoietin Stimulating Agents
• Erythropoietin Stimulating Agents (ESA)
– Epoetin alfa
• Starting dose range is 80-120 units/kg/week
– Darbepoetin
• Starting dose is usually 0.45 mcg/kg.week

19. Anemia Management Program
Agent Similarity to
Endogenous
Erythropoietin
Estimated
T 1/2
Initial Dosing Maintenance
Dosing
Epoetin alfa Identical
Immunologically
~ 16 to 19
hours
50-150 units/kg
TIW
Typical Dosing
is 150-300 u/kg
weekly
Generally
weekly or QOW
dosing
Darbepoetin
alfa
20% more
carbohydrate
content
~ 33 to 48
hours
0.45 mcg/kg/wk
Typical Dosing
is 0.9 mcg/kg
QOW
Generally every
2 to 4 week
dosing
Erythropoietin Stimulating Agents (ESA)
Available for Stage 1 – 5 CKD Patients
McClellan, Schoolwerth A., Gehr, T. Clinical Management of Chronic Kidney Disease.
Cadido, OK: Professional Communications, Inc.; 2006:185-208.

20. ESA Approval Timeline
Date Action
1989 Epoetin alfa approved: anemia
associated with chronic renal failure
1993 Epoetin alfa approved: anemia
associated with cancer chemotherapy
2001 Darbepoetin alfa approved: anemia
associated w/ chronic renal failure
2002 Darbepoetin alfa approved: anemia
associated w/ cancer chemotherapy

21. ESA Agents
Epoetin alfa Dose
(Units/week)
Darbepoetin alfa Dose
(mcg/week)
< 2,500 6.25
2,500 to 4,999 12.5
5,000 to 10,999 25
11,000 to 17,999 40
18,000 to 33,999 60
34,000 to 89,999 100
> 90,000 200

22. ESA Agents
Side Effect Profile
• HTN and Headaches
• Myalgias
• Diarrhea
Contraindications
• Uncontrolled HTN
• Known hypersensitivity to the active substance or
any of the excipients

23. ESA Agents
FDA Black Box Warning
Issued 3/9/07
• Use the lowest dose of ESA that will gradually increase the
Hgb concentration to the lowest level sufficient to avoid
the need for RBC transfusion.
• ESAs increase the risk for death and serious CV events
when administered to target a Hgb > 12 gm/dL.

24. ESA Utilization Guidelines
• Target Hgb at or above 11.0 gm/dL
• Caution when intentionally maintaining Hgb >
13.0 gm/dL
• Monitor Hgb minimum of every 30 days
• Target Ferritin > 100 ng/mL and T. Saturation
> 20%
• Monitor Iron Indices Quarterly

25. ESA Utilization Guidelines
Dose Adjustments
• If Hgb increases by > 2 gm/dL per 4 weeks
and/or Hgb level > 12 gm/dL, decrease dose
by 20 to 25%
• If Hgb level is increasing < 1 gm/dL per 4
weeks, increase dose by 20 to 25%

26. ESA Utilization Guidelines
Dose Adjustments
20 to 25% dose adjustments may be achieved
by:
• Altering the ESA dose
• Altering the time interval between injections

27. ESA Utilization Guidelines
Dose Adjustments
• Increases in dose should not be made more
frequently than once a month.
• Avoid holding doses to avoid marked drop in
ESA sensitive RBC precursors and the ‘seesaw’
effect of Hgb poor response pattern.

28. ESA Utilization Guidelines
ESA Resistance
• Infection/Inflammation
• Blood Loss, Guiac Positive Stools
• Hyperparathyroidism
• B12, Folate Deficiencies
• Sickle cell, Thalassemia
• Multiple Myeloma/Malignancy
• ACE Inhibitor Use

29. TREAT1
CHOIR2
CREATE3
1000 2000 3000 4000
Number of Patients
1
Pfeffer MA, et al. Pfeffer MA, et al. N Engl Med. 2009;361:2019-2032.
2
Drüeke TB, et al. N Engl J Med. 2006;355:2071–2084.
3
Singh AK, et al. N Engl J Med. 2006;355:2085–2098.
TREAT is the Largest Trial to Date That Has Studied ESA Use in Patients
With CKD
TREAT = Trial to Reduce cardiovascular Events with Aranesp®
Therapy
CHOIR= Correction of Hemoglobin and Outcomes In Renal insufficiency
CREATE = Cardiovascular Risk reduction in Early Anemia Treatment with Epoetin beta
CKD = chronic kidney disease
222 events
105 events
417 events
1,234 events* N = 4,038
N = 1,432
N = 603
*Cardiovascular endpoint

30. TREAT: Trial to Reduce Cardiovascular Events
With Aranesp®
(Darbepoetin alfa) Therapy
Pfeffer MA, et al. Am J Kidney Dis. 2009;54:59-69.
Pfeffer MA, et al. N Engl Med. 2009;361:2019-2032.
Hypotheses:
Treatment of anemia with Aranesp® in subjects with chronic kidney disease (CKD)
and type 2 diabetes mellitus decreases mortality and cardiovascular (CV) morbidity
Treatment of anemia with Aranesp® in subjects with CKD and type 2 diabetes
mellitus will delay the progression to ESRD
Aranesp®
(Target Hb 13 g/dL)
Placebo
(rescue if Hb < 9 g/dL)
Study Population
• Hb ≤ 11 g/dL
• eGFR 20-60
mL/min/1.73 m2
• Type 2 DM
N ~ 2000
N ~ 2000
Design –
randomized (1:1), double blind, placebo-controlled
Event-driven: :~1,203 patients with cardiovascular primary endpoint
Hypotheses:
Treatment of anemia with Aranesp® in subjects with chronic kidney disease (CKD)
and type 2 diabetes mellitus decreases mortality and cardiovascular (CV) morbidity
Treatment of anemia with Aranesp® in subjects with CKD and type 2 diabetes
mellitus will delay the progression to ESRD
Aranesp®
(Target Hb 13 g/dL)
Placebo
(rescue if Hb < 9 g/dL)
Study Population
• Hb ≤ 11 g/dL
• eGFR 20-60
mL/min/1.73 m2
• Type 2 DM
N ~ 2000
N ~ 2000
Design –
randomized (1:1), double blind, placebo-controlled
Event-driven: :~1,203 patients with cardiovascular primary endpoint

31. Safety Concerns in the TREAT Study
• Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT)
– Randomized, placebo-controlled, double-blind trial: 623 sites, 24 countries,
4038 patients (2012 darbepoetin alfa)
– Primary endpoint: composite outcomes of death or a cardiovascular event and
of death or end-stage renal disease
Pfeffer MA et al. N Engl J Med 2009;361:2019–2032
ESA
Placebo
5.0†
2.0‡
8.9§
7.5‡
2.6
1.1
7.1
0
2
4
6
8
10
Stroke Venous
thromboembolic
event
Arterial
thromboembolic
event
Cancer-related
mortality*
Patients(%)
0.6
†, p<0.001 versus placebo
‡, p=0.02 versus placebo
§, p=0.04 versus placebo
*Amongst patients with a history of malignancy at baseline
Coronary
revascularization
4.2‡
5.8

32. • A higher target Hgb increased cardiovascular events; a
higher achieved Hgb was associated with fewer
cardiovascular events.
•Targeted to near normal levels of Hgb often did not
achieve the target and more ESAs is prescribed to
achieve these targets
The anemia paradox:
• ESAs themselves
• Conditions that conferred hyporesponsiveness
The Culprit
Hyporesponsiveness increases cardiovascular risk

33. EPO has Non-erythropoietic Actions
High EPO levels
↑ VSMC [Ca2+
]i
↑ RAS activation
↑ ET-1
↑ Thromboxane
↓ Prostacyclin
↑ ADMA
↓
↓ NO
Hypertension
↑ Platelet production
↑ Platelet activity
↑ E selectin
↑ P selectin
↑ vWF
↑ PAI-1
Thrombosis
VSMC proliferation
EC proliferation
Angiogenesis
Blood access stenosis
Proliferative retinopathy
Vascular remodeling
Tumor growth
Vaziri ND & Zhou X. Nephrol Dial Transplant 2009;24:1082–1088
VSMC, vascular smooth muscle cell; RAS, renin–angiotensin system;
EC, endothelial cell; ADMA, asymmetrical dimethylarginine;
PAI-1, plasminogen activator inhibitor; vWF, von Willebrand factor;
NO, nitric oxide; ET-1, endothelin-1

34. t
Resistance to ESAs
Conclusions
A poor initial hematopoietic response to ESAs was associated with an increased
subsequent risk of death or cardiovascular events as doses were escalated to
meet target hemoglobin levels
N Engl J Med. 2010 ;363(12):1146-55
hemoglobin level
achieved after 4
weeks

35. Locatelli, Del Vecchio, Casartelli N ENGL MED 362; 7 Feb 18, 2010
Should we stop treating our patients?

36. USE OF ESAs AND OTHER AGENTS TO TREAT ANEMIA IN CKD
KDIGO CLINICAL PRACTICE GUIDELINE
FOR ANEMIA IN CKD
ESA INITIATION CKD
3.4.1 For CKD ND patients with Hb ≥10.0 g/dL (≥ 100 g/L), we suggest that ESA
therapy not be initiated. (2D)
3.4.2 For CKD ND patients with Hb <10.0 g/dL (<100 g/L) we suggest
that the decision whether to initiate ESA therapy be individualized
based on the rate of fall of Hb, the risk of needing a transfusion, the
risks related to ESA therapy and the presence of symptoms
attributable to anemia. (2C)
3.4.3 For CKD 5D patients, we suggest that ESA therapy be used to
avoid having the Hb concentration fall below 9.0 g/dL (90 g/L) by
starting ESA therapy when the hemoglobin is between 9.0-10.0 g/dL
(90-100 g/L).(2B) Individualization of therapy will be necessary as
some patients may have improvements in quality of life at higher Hb
concentration and ESA therapy may be started above10.0 g/dL (100
g/L). (Not Graded)

37. Hb target
Experts of the KDIGO group concluded that levels of 9.5–11.5 g/dL were
considered associated with better outcomes than those of >13 g/dL, but that there
was no evidence either way for intermediate levels (11.5–13 g/dL)

38. USE OF ESAs AND OTHER AGENTS TO TREAT ANEMIA IN CKD
KDIGO CLINICAL PRACTICE GUIDELINE
FOR ANEMIA IN CKD
ESA MAINTENANCE THERAPY
3.5.1: In general, we suggest that ESAs not be used to maintain Hb
concentration above 11.5 g/dL (115 g/L) in adult patients with CKD. (2C)
3.5.2: Individualization of therapy will be necessary as some patients may
have improvements in quality of life at Hb concentration above 11.5 g/dL
(115 g/L) and will be prepared to accept the risks. (Not Graded)
3.6: In all adult patients, we recommend that ESAs not be used to intentionally
increase the Hb concentration above 13 g/dL (130 g/L). (1A)

39. Individualization
CONCLUSIONS
There is no single ideal target Hb for all CKD patients, but rather that such
targets will and should be tailored to the individual patient based on a
multitude of underlying factors.

40. Male 26 years
 CKD after glomerulonephritis
 Haemodialysis (HD)
 Living renal transplantation
 Professional sportsman
Women 74 years
 CKD after diabetes
 HD for 13 years
 ESA for 12 years
 2 vascular access thrombosis
 2 MIs (1994 and 1997) – NYHA III CHF
 Family support for mental deterioration
 Cerebral scan severe diffuse atherosclerosis
Do they need to target the same Hb level
with the same therapy?

41. It's more important to know what kind of person has a
disease than to know what kind of disease this person
has
- Hippocrates

42. Disease severity
Age
Gender
lifestyle (e.g. active
vs sedentary)
Genes
Comorbidity
-Diabetes
-Stroke
-Cancer
-CV
Physiology
Iron status
Altitude residence
Inflammation
activity
Vascular Access
ESA sensitivityBlood losses
CKD
HD
Peritoneal D
Tx
The CKD population is diverse: The need of Individualization
Medication(ACE?)
Tx waiting list
De Francisco, NDT Plus (2010) 3:519–526

43. Final comment
Use IV iron wisely
Use ESA´s wisely:
- None for some
- Some for the most
- More for a few

44. Thank You!