1. Anemia in Chronic Kidney Disease Dr Abdullah AlHwiesh Associate Professor Consultant Internist/Nephrologist Dammam University AlKhober

2. Outline Impact of anemia in patients (CKD) Prevalence of anemia in CKD
Cardiovascular effects of anemia in CKD
Target hemoglobin in CKD
Erythropoietin stimulating agents (ESAs) available
New anemia therapies
Summary of clinical practice guidelines

3. What is anemia? Diagnosis of anemia should be made
and further evaluation if:
Hb < 13.5 g/dl in adult males
Hb < 12 g/dl in adult females

4. Impact of anemia in CKD Symptoms Diminished quality of life
Associated with LVH

5. Impact of anemia in CKD
deterioration in cardiac function decreased cognition and mental acuity. fatigue, weakness, lethargy, anorexia, and sleep disturbances.

6. Impact of anemia in CKD increased risk of morbidity and mortality
increased risk of hospitalizati
mortality in patients with predialysis

7. General Population
General Population
Transplant
Transplant
Dialysis
Dialysis
USRDS 2006

8. AJKD 2002: 39(2)

9. Mortality increases exponentially as GFR declines15 14 13 12 11 10 9 8 7 6 5 4 3 2 1
From Any Cause (per 100 person-yr)
Age Standardized Rate of Death
Data from 1 million KP patients published by Go and colleagues, outlines a relationship that many of us will be familiar with. As GFR declines, all cause mortality increases
> <15
Estimated GFR (ml/min/1.73 m2)
Number of Events , , , , ,842
1M Kaiser Permanente patients
Go et al NEJM :

10. Adjusted Prevalence of Anemia (NHANES III)

11. Anemia Prevalence by CKD Stage
NHANES III
NHANES
Patients With Anemia* (%)
CKD Stage
*NHANES participants aged ≥20 y with anemia as defined by WHO criteria: hemoglobin (Hgb) <12 g/dL for women, and Hgb <13 g/dL for men.

12. 9 percent at an estimated GFR of 30 mL/min per 1.73 m2
based upon over 15,000 participants in the NHANES survey, the prevalence of anemia (Hbg <12 g/dL in men and <11 g/dL in women)
1% GFR 60 ml/min per 1.73 m2
9 percent at an estimated GFR of 30 mL/min per 1.73 m2
33 to 67 percent at an estimated GFR of 15 mL/min per 1.73 m2

14. Anemia is involved in cardiac remodeling
Reduced hemoglobin
Tissue hypoxia
Increased cardiac work
Left ventricular
hypertrophy
Ischemic heart
disease
Worsening or precipitation of:
Congestive heart failure
Angina pectoris
Myocardial infarction
Metivier F, et al. Nephrol Dial Transplant. 2000; 15(suppl 3): 14-18

19. Early versus late initiation of EPO
R,C,T early versus deferred initiation of erythropoietin in nondiabetic predialysis patients with serum creatinine 2 to 6 mg/dL and hemoglobin 9 to 11.6 g/dL. The early treatment arm was immediately started on 50 U/kg/wk of erythropoietin alpha with appropriate titration aiming for hemoglobin of ≥13 g/dL
Internati onal Society of Nephrology 2006

20. The primary end point doubling of creatinine renal replacement death
Internati onal Society of Nephrology 2006

25. Clinical Benefit of Anemia Correction: CHF and CKD
Patients With CHF and Anemia (n = 126, 91% 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
Hospitalizations
3.7
0.2
Systolic BP (mm Hg)
132
131
Diastolic BP (mm Hg) 75 76
NYHA class = New York Heart Association classification; SOB = shortness of breath.
Silverberg et al. Perit Dial Int. 2001;21(suppl 3):S236-S240.

26. Prevalence of LVH increases with decreased kidney function
Levin et al. Am J Kidney Dis. 1999;34:

27. LVH is present in 74% of patients at initiation of dialysis
Foley et al. Kidney Int. 1995; 47:

30. LVH and anemia of CKD Clear association between anemia and LVH
Can correction of anemia of CKD result in LVH regression?

38. When to start ESA treatment
Anemia develops early in CKD
ESA treatment:
Reduces symptoms
Improves quality of life
May help for LVH
May increase thrombotic risks and BP
Decision to initiate treatment based on clinical balancing of risks and benefits

39. What is the target Hemoglobin?

40. Choir (Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease)
Open label, RCT,130 centers in US, epoetin alfa SC weekly
CKD (eGFR ml/min/1.73m2); Hb < 11g/dl
High Hb target: 13.5 g/dl
Low Hb target: 11.3 g/dl
Study terminated early because conditional power poor for showing a benefit of high Hb was <5%

41. Choir
Main results:
34% increased risk of composite outcome of death, MI, hospitalization for CHF, stroke (p= 0.03)
No significant difference in patients requiring RRT
Similar quality of life measures
Singh AK et al. N Engl J Med Nov 16;355(20):

42. Singh AK et al. N Engl J Med. 2006 Nov 16;355(20):2085-98

43. Choir
Drop out rate is high
High Hb target achieved in few patients

44. Choir
Singh AK et al. N Engl J Med Nov 16;355(20):

45. Choir
Singh AK et al. N Engl J Med Nov 16;355(20):

52. CREATE Drueke TB, et al. N Engl J Med. 2006 Nov 16;355(20):2071-84
The survival without dialysis And this is the data showing the survival without dialysis. Just to point out that, again, there was in the higher hemoglobin group, a faster or greater rate of having to go on to renal replacement therapy than in the lower hemoglobin group.
Drueke TB, et al. N Engl J Med Nov 16;355(20):

54. ACORD Open label, RCT, 64 centers in 16 countries, N=170
Epoetin beta SC weekly
Creatinine clearance > 30ml/min
High Hb target: g/dl
Low Hb target: g/dl after Hb < 10.5 g/dl twice or<10.0 g/dl once
Ritz E et al. Am J Kidney Dis Feb;49(2):

55. ACORD Main results: No significant difference in LVMI
No significant difference in decline in creatinine clearance
Better QOL in high Hb group
Ritz E et al. Am J Kidney Dis Feb;49(2):

56. Ritz E et al. Am J Kidney Dis. 2007 Feb;49(2): 194-207

57. KDOQI. Am J Kidney Dis. 2007 Sep;50(3):471-530.
Meta-analysis: Non-Dialysis CKD Patients The last new recommendation was that in dialysis and nondialysis patients with CKD receiving ESA therapy, the hemoglobin target, again, should not be greater than 13.0 g/dL. And this was termed a clinical practice guideline based upon the new moderately strong evidence showing absence of benefit and potential harm, again when hemoglobin levels are targeted to be above 13 g/dL. And again, I will emphasize the point that I just made that these guidelines are not meant to imply that there is harm to occasionally having a hemoglobin level in this range as you are targeting therapy in the range of 11 to 12 g/dL. As we sat through and pondered these potential guidelines, we asked the evidence review team which supports the DOQI process to do its own meta-analysis, and this was published as part of the supplement in the recent AJKD, and these are shown here. We separated nondialysis CKD patients shown here. Looking at relative overall mortality risk, there was no statistically significant difference in the high-hemoglobin versus the low-hemoglobin group. When the analysis was done—and the studies are shown here—looking at the relative risk of adverse cardiovascular events, there was in fact a statistically significant increase in cardiovascular events in the high-hemoglobin group or favoring control—again, assembling these various studies including CHOIR and CREATE that looked at non-dialysis-dependent CKD.

58. KDOQI. Am J Kidney Dis. 2007 Sep;50(3):471-530.
Meta-analysis: Dialysis CKD Patients Similarly, in dialysis patients shown here, same kind of meta-analysis, many fewer studies. The normal hematocrit trial with Tony Besarab was the the largest and had the largest number of patients. And there was no statistically significant difference in the combined meta-analysis of these studies.

59. (TREAT Study RDPCT 24 countries)
Treal of Darbepoetin Alfa in Type 2 Diabetes and Chronic Kidney disease
(TREAT Study RDPCT 24 countries)
CRF GFR 20-60ml,Dm and Anaemia
4038
2012 darpoboitin
HB 13g/dl
2026 placepo
Rescue if HB < 9
Death, MI,CHF,Srok,Hospitalizationfor MI
NEJM2009

61. Death or cardiovascular event
602 Placepo
632 darbpoitin
(hazard ratio 1.05; 95% confidence interval [CI], 0.94 to 1.17; P = 0.41).
NEJM2009

63. Death Or ESRD
618 Palcepo
652 Darbepoetin
(hazard ratio, 1.06; 95% CI, 0.95 to 1.19; P = 0.29
NEJM 2009

65. Fatal and non Fatal Strock
101 Darbepoetin
53 Placepo
(hazard ratio, 1.92; 95% CI, 1.38 to 2.68; P<0.001
NEJM2009

67. The use of darbepoetin alfa in patients with diabetes, chronic kidney disease, and
moderate anemia who were not undergoing dialysis did not reduce the risk of either
of the two primary composite outcomes
death
cardiovascular
and was associated with an increased risk of stroke.
NEJM 2009

68. KDOQI 2007 update
In the opinion of the Work Group, selection of the Hb target and selection of the Hb level at which ESA therapy is initiated in the individual patient should include considerations of potential benefits and potential harms

69. ESA hyporesponsiveness
Definition:
Hb level consistently less than 11 g/dl despite reasonable doses of ESA

71. ESAs in the treatment of anemia in Chronic Kidney Disease
Recombinant version of endogenous human EPO, first ESA approved for tx anemia in CKD (1989)
Epoetin alfa
Lower binding affinity for EPO receptor, but 3 times longer half life
Darbepoetin alfa

72. ESAs in the treatment of anemia in Chronic Kidney Disease
First approved chemically synthesized ESA, large molecule, prolonged duration of action
CERA

73. ESAs in the treatment of anemia in Chronic Kidney Disease
Pegylated synthetic peptide-based ESA, investigational
Hematide
Transcription factor, stimulates erythropoiesis and iron mobilization, investigational
HIF stabilizer

74. Does half-life correlates with response?
Half-life ,h
Agent
4-13 (20% longer in CRF patients)
Epoetin alfa
49 (SC)
Darbepoetin alfa
130
CERA 24
Hematide
10.4
HIF stabilizer

75. PEGINESATIDE

76. a peptide could activate the erythropoietin
receptor and stimulate erythropoiesis was
described first byWrighton et al15 in 1996

78. 0.025-0.075 mg/kg. given once monthly

80. HIF STABILIZATION

82. 1- fatal hepatic necrosis 2- up regulate VEGF (vascular endothelial growth factor), which may have potential adverse effects on enhancing tumor growth and proliferative diabetic retinopathy.

83. Extended dosing
Extending dosing of EPO up to every 6 weeks is possible
Darbepoietin and CERA have much longer half-lives

84. R,O,L,M ,16 week 37 Center 262pt <18 yr old GFR< 15-90
IU QWK
20,000 Iu Q2WK
20,000 IU Q 4WK
IU Q4WK
CJASN 2008

85. CJASN 2008

88. CJACN 2008

89. CJACN 2008

90. CJACN 2008

91. -0.21,0,44

92. The results of this study demonstrate that epoetin alfa can be
initiated Q4W. Although the half-life of epoetin alfa is shorter
than other ESAs, it may ultimately be the life span of the red
cell that determines the pharmacodynamic effect of these compounds.Therefore, epoetin alfa can provide the flexibility and
convenience needed by nondialysis patients with anemia of CKD

93. Intrapatient Hb variability is not due to choice of ESA
Multicenter, randomized, double-blind study of 404 patients on HD
Nissenson AR et al. ASN 2006

94. CERA and Hb Control in CKD Patients on Dialysis
Mean change in Hb levels from baseline over time
Lunde NM et al. ASN 2007 (poster presentation)

95. Clinical practice guidelines: target hemoglobin
Better quality of life without an increase in adverse reactions are associated with Hgb >11 g/dL compared to values below this level
There is also increasing evidence that there is little benefit, and even potential risk, with increased morbidity and mortality, to targeting and maintaining Hgb levels of >13 g/dL in dialysis and predialysis patients

96. Clinical practice guidelines
The 2007 DOQI update for the hemoglobin target recommends that the selected Hgb target should generally be in the range of 11 to 12 g/dL in all patients with CKD
They also recommend that the Hgb target should not exceed 13 g/dL
NKF-K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease. Am J Kidney Dis JASN 2007,50: 474

97. Guidelines for management of anemia in CKD
Start work up:
If Hb < 11g/dl in females
If Hb < 13 g/dl in males and postmenopausal females
Hx and lab tests: blood loss, nutrition, adequacy of dialysis, OB, CBC, retc, iron studies, B12, folate, Hb electropheresis

98. Guidelines for management of anemia in CKD
ESA treatment is indicated if Hb <11 g/dl and no other cause of anemia
EPO: 150 ug/kg/wk (SC), increase dose if given (IV)
Darbepoietin: 0.45ug/kg/wk IV or SC, 0.75 ug/kg/2wks in predialysis

99. Guidelines for management of anemia in CKD
Adequate response: Hb increases 1 g/dl/month
Target Hb g/dl
Avoid Hb > 13g/dl
Monitor Hb

100. Guidelines for management of anemia in CKD
Titrate ESA dose:
If Hb decrease < 1 g/dl/month, increase dose by 25-50%
If Hb increases > 2-3 g/dl/month, decrease dose by 25-50%
Side effects: worsening of BP control, access thrombosis

101. ESA hyporesponsiveness: iron deficiency
Iron deficiency: Tsat < 20%, S ferritin < 100
IV Iron supplement: iron sucrose or gluconate (1000 mg in 10 doses), maintain with 100mg Q 1-2 wks
Monitor iron stores
Do not supplement if ferritin> 800 ng/ml and/or Tsat >50%

102. Thank You