1. Management of Anemia in Chronic Kidney Disease
Dr.

2. Overview CKD Anemia Anemia of CKD
Consultant pharmacist challenges with MRR for dialysis patients
Managing and treating patients on dialysis
Cases for review

3. Chronic Kidney Disease (CKD) in the U.S.
National Kidney Foundation (NKF) classification system 2002 for staging CKD
CKD previously called:
Chronic renal failure
Pre-ESRD
Renal failure
Renal damage
Kidney disease

4. KDOQI Defines CKD

5. Stages of Chronic Kidney Disease
NKF Kidney Disease Outcomes Quality Initiative (K/DOQI): CKD Stages1
Stage
Description
GFR (mL/min/1.73 m2) 1
Kidney damage with normal or ↑ GFR
≥90 2
Kidney damage with mild ↓ GFR
60-89 3
Moderate ↓ GFR
30-59 4
Severe ↓ GFR
15-29
GFR Is the Best Measure of Kidney Function
The NKF guidelines provide a classification system for CKD that combines information on the level of kidney function, measured using estimated GFR1
GFR is widely accepted as the best overall measure of kidney function and may be used to diagnose or stage the severity of CKD1 5
Kidney failure
<15 (or dialysis)
Reference: 1. National Kidney Foundation. Am J Kidney Dis. 2002;39(suppl 1):S1-S266.
Reference: 1. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(suppl 1):S1-S266.

6. NKF-KDOQI Stages of CKD50 40 30 20
<15 or
GFR (mL/min/1.73 m2) 1
Kidney Damage with normal or  GFR 2
Kidney Damage with Mild GFR  3
Moderate GFR  4
Severe GFR  60 70 80 90 5
Kidney Failure
CKD Continuum
Renal Insufficiency
ESRD
Dialysis/
Transplantation (RRT)
The National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) has released the Clinical Practice Guidelines in Chronic Kidney Disease. These include nomenclature changes and definitions to help clarify the staging of the chronic kidney disease (CKD) continuum.
CKD is defined as the entire continuum of kidney disease from its onset through and including dialysis or kidney transplantation. In stage 1, kidney damage has occurred, but the glomerular filtration rate (GFR) is still greater than 90 mL/min/1.73 m2. In stage 2, GFR has decreased to between 89 and 60, but is still considered mild. Patients in stages 1 and 2 are generally not treated. Stage 3, moderate CKD, is defined as a GFR of 30 to 59. Stage 4, severe CKD, is defined as a GFR between 15 and 29. Finally, stage 5 is defined as a GFR less than 15 or the need for renal replacement therapy (RRT), dialysis or kidney transplantation, sometimes called “end-stage renal disease (ESRD).”
Note: Stages 1 through 4 constitute what is called “CKD before RRT.”
References: NKF-K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(suppl 1):S1-S266.
NKF-K/DOQI. Am J Kidney Dis. 2002;37:S1-S266.

7. Markers of Renal Function
Serum creatinine
Cockcroft-Gault Equation
eCrCl
MDRD Equation
eGFR

8. Calculating Creatinine Clearance
Cockcroft-Gault Equation
CrCl men = (140 - Age) x LBW
Scr x 72
CrCl women = CrCl men x 0.85
Modification of Diet in Renal Disease Equation (MDRD)
CrCl men = (Scr) x (age)
CrCl women = CrCl men x 0.742
CrCl African American = CrCl men x 1.210

9. USRDS: ESRD Incidence by Age
Patients Age 65 Years or Older Are More Than Twice as Likely to Have ESRD as People Under Age 50 Years1
USRDS: ESRD Incidence by Age
CKD is highly prevalent in the elderly1
In fact, older age is a risk factor for CKD susceptibility2
The United States Renal Data System (USRDS) has shown that patients age 65 years or older are more than twice as likely to have ESRD than people under age 50 years3
Nearly half of all new ESRD patients are over age 65 years3
More than one third of ESRD patients are over age 70 years3
Adapted from the United States Renal Data System (USRDS).1 9
Reference: 1. United States Renal Data System annual data report reference tables: incidence. Available at:
References: 1. US Department of Health and Human Services. Vital and Health Statistics: Summary Health Statistics for US Adults: National Health Interview Survey, Hyattsville, Md: US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Health Statistics; August DHHS Publication No. (PHS) Hansberry MR, Whittier WL, Krause MW. The elderly patient with chronic kidney disease. Adv Chronic Kidney Dis. 2005;12: United States Renal Data System annual data report reference tables: incidence. Available at: Accessed February 6, 2008. 9

10. In LTC Residents, the Prevalence of CKD Increases With Age
40% of the population had a GFR of <60 mL/min/1.73 m2 (MDRD)
n=106
n=671
n=3354
n=977
n=1061
n=2644
Age-Related Prevalence of Low GFR (%)
n=646
n=472
Age in Years
n=9931
MDRD=Modification of Diet in Renal Disease.
Reference: Garg et al. Kidney Int. 2004;65:

11. Almost One Half of All LTC Residents Have GFR <60 mL/min/1.73 m2
Residents with CKD
(GFR <60 mL/min/1.73 m2) 44%
Residents without CKD 56%
N=4240 (residents with SCr, calculating GFR using MDRD)
SCr=serum creatinine.
Reference: Van Vleet et al. Poster presented at: American Geriatric Society Annual Meeting; May 11-15, 2005; Orlando, Fla.

12. CKD Risk Factors

13. Contributors to Renal Function Decline
Decline in kidney weight, loss of nephrons
Decline in renal perfusion
Decline in GFR
Est healthly adults lose 8-10ml/min of GFR every decade of life beginning around age 30
Decrease in ability to concentrate urine
Decreased reabsorption of sodium
Decreased bladder capacity
Beck LH. Long-term Care Forum. 5(3) 1995.

14. Risk Factors for ESRD 25 Year Follow-up
Retrospective review of 177,570 individuals from large MCO (1964-’73)
Followed for ESRD Tx (USRDS)
842 cases ESRD observed
Goal: evaluate value of potential novel risk factors for ESRD vs established risk factors
novel risk factors have not been rigorously examined in the context of a longitudinal cohort study design.
Compared with cross-sectional study or case-control study designs, the advantages
of a cohort study include reducing recall and ascertainment biases and establishing
temporal sequence, which is important for determining possible causality.
Chi-yuan Hsu, MD, MSc; Carlos Iribarren, MD, PhD, et al.Arch Intern Med. 2009;
169(4):

15. Risk Factors for ESRD 25 Year Follow-up cont’d
Established Risk Factors for ESRD:
Gender (M)
Age
Proteinuria* DM
HTN
AA race
Elevated SCr (or, decreased GFR)
Obesity*
Lower educational attainment
*most potent risk factors
Chi-yuan Hsu, MD, MSc; Carlos Iribarren, MD, PhD, et al.Arch Intern Med. 2009;
169(4):

16. Risk Factors for ESRD 25 Year Follow-up cont’d
Independent Risk Factors for ESRD:
Lower Hgb
Higher serum uric acid level (in females)
Self-reported Hx of nocturia
Family Hx of kidney disease
Chi-yuan Hsu, MD, MSc; Carlos Iribarren, MD, PhD, et al.Arch Intern Med. 2009;
169(4):

17. Complications of CKD Anemia CVD HTN (cause and complication)
“All patients with chronic kidney disease should be considered in the ‘‘highest risk’’ group for cardiovascular disease, irrespective of levels of traditional CVD risk factors.”
HTN (cause and complication)
Protein energy malnutrition
Central and peripheral neuropathy
Anemia
ESRD
Bone disease/disorders of calcium and phosphorus
National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification and Stratification. Am J Kidney Dis 39:S1-S266, 2002 (suppl 1)

18. Anemia

19. Defining Anemia (NKF)
Group of diseases characterized by a decrease in either Hgb, Hct or red blood cells (RBC) that reduce the oxygen carrying capacity of the blood.
Diagnose anemia if:
- Hemoglobin < 12 g/dL (adult females)
- Hemoglobin < 13.5 g/dL (adult males)
In patients with CKD the hemoglobin should be 11 g/dL or greater
KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S1-S146, 2006 (suppl 3)

20. World Health Organization
WHO definition of anemia:
Males Hgb< 13 gm/dL
Females Hgb < 12 gm/dL
World Health Organization: Nutritional anemia: report of a WHO Scientific Group.
Geneva, Switzerland: World Health Organization, 1968.

21. Common Causes of Anemia in Elderly Patients
Anemia of Chronic Inflammation (inflammatory disease, infections, CKD)
30% - 40%
Iron Deficiency Anemia
15% - 30%
Post Hemorrhagic Anemia
5% - 10%
Vitamin B-12 and Folate Deficiency Anemia
Chronic Leukemia or Lymphoma Anemia 5%
No Identifiable Cause
15% - 25%
Joosten E, et al, Prevalence and causes of anemia in a geriatric hospitalized population. Gerontology 1992; 38:

22. Cause of Anemia in Long Term Care
Chronic disease
Chronic kidney disease
Unknown
Fe, B12, folate
Other
n=481
LTC=long-term care.
Reference: Chernetsky et al. Harefuah. 2002;141:

23. Signs and Symptoms of Anemia Are Nonspecific
Central nervous system (CNS)
Fatigue
Headache
Dizziness
Syncope
Depression
Impaired cognition
Cardiorespiratory system
Dyspnea
Tachycardia
Systolic ejection murmur
Palpitations
Cardiac enlargement
Hypertrophy
Wide pulse pressure
Hypotension
Orthostasis
Vascular system
Cold intolerance
Edema
Pallor of skin, mucous membranes, and conjunctivae
Gastrointestinal system
Anorexia
Nausea
Genital tract
Impotence
Reference: Morley et al. Ann Long-Term Care. 2003:S1-S21. Available at: Accessed February 6, 2007.

24. Laboratory Tests for Anemia
Reticulocyte count (low indicates decreased RBC production; high count may be increased RBC destruction)
Sedimentation rate (ESR): index of inflammation
Stool for occult blood: evaluates GI loss
Morphology by peripheral smear: size, color, shape of RBC
Hepatic and renal function
Thyroid-stimulating hormone (TSH) 24

25. Medications That Can Cause Anemia
Red blood cell production*
Red blood cell loss (bleeding)
Red blood cell survival
Alcohol
Anticoagulants
High-dose penicillin
H2 blockers
Antiplatelet agents
Sulfa agents
Metformin
Aspirin
Phenobarbital
Bisphosphonates
Phenytoin
Corticosteroids
Proton pump inhibitors
Nonsteroidal
anti-inflammatory drugs
Chemotherapy agents
*Can impair vitamin B12 and folate absorption or metabolism, which impairs red blood cell production.
Reference: American Medical Directors Association. Clinical Practice Guideline. Columbia, MD: American Medical Directors Association; 2007.

26. Treating Anemia B-12 Deficiency B-12 replacement
Oral, sublingual, intranasal, IM
Folic Acid Deficiency
Folic acid replacement
Oral, subcutaneous, IM
Iron Deficiency
Iron replacement (several salt forms/dose forms)
Oral, IV, IM
Anemia of Chronic Kidney Disease (CKD)
Erythropoietic Stimulating Agents
Epoetin Alfa (Epogen™/Procrit™), Darbepoetin Alfa (Aranesp™)
KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis 47:S1-S146, 2006 (suppl 3)

27. Assessing Anemia JM 84 yo female
Dx: anemia, DM, dementia, incontinence, osteoarthritis, osteoporosis
Recurrent falls
CNAs report “she won’t use the call light”
What action, in general, should the CP take when requested to review resident for falls for an interim MRR?
Look at Dx, would she be on meds to treat these? Consider current meds; request labs to determine type of anemia; CBC, B-12, folate; inquire about non-specific Sx of anemia

28. Iron Products and Drug Interactions
Avoid administration with calcium, antacids, levothyroxine, levodopa, fluoroquinolones, PPIs, H-2 blockers

29. Iron and the State Operations Manual (SOM)
Iron does not stimulate rbc production
Iron does not correct anemia that is not caused by iron deficiency
Document chronic use
Document doses > once daily
Documentation for “clinical rationale” may include use of an ESA

30. When is “Enough” Iron “Too Much”?
F329 Unnecessary Drugs Table 1
“Iron therapy is not indicated in anemia of chronic disease when iron stores and transferrin levels are normal or elevated”
“Clinical rationale should be documented for long-term use (> 2 months) or > 1 daily > 1 week because of side effects and risk of iron accumulation in tissues”

31. Adverse Outcomes Associated With Anemia in Older Adults
Decreased muscle strength and physical function1
Increased risk
of stroke10
Increased heart disease2
Anemia
Increased frequency
of hospital admission7,8
and death7-9
Increased falls3 and
fall-related injuries4
Cognitive
impairment5,6
References: 1. Penninx et al. J Am Geriatr Soc. 2004;52: Zeidman et al. Isr Med Assoc J. 2004;6: Guse et al. WMJ. 2003;102: Herndon et al. J Am Geriatr Soc. 1997;45: Zuccala et al. Am J Med. 2005;118: Arygyriadou et al. BMC Fam Pract. 2001;2: Felker et al. J Cardiol. 2003;92: Li et al. Kidney Int. 2004;65: van Dijk et al. J Am Geriatr Soc. 2005;53: Abramson et al. Kidney Int. 2003;64:

32. Impact of Anemia on QIs Incidence of new fractures Prevalence of falls
Prevalence of behavioral symptoms
Prevalence of symptoms of depression
Incidence of cognitive impairment
Prevalence of weight loss
Prevalence of dehydration
Incidence of decline in ADLs
Prevalence of little or no activity
Prevalence of psychoactive medication use

33. Anemia of CKD

34. Anemia Worsens as Kidney Function Declines
Hb Levels
Hb=11-12 g/dL (n=181)
Hb=10-11 g/dL (n=105)
Hb=<10 g/dL (n=315)
Reference: Adapted from Kausz et al. Dis Manage Health Outcomes. 2002;10:

35. Etiology of CKD Anemia
Decreased rbc production due to lack of erythropoietin; kidneys responsible for 90% of epo production
Increased rbc destruction due to hemolysis
Increased blood loss due to multiple venipunctures
Decreased rbc production is present in CKD anemia and anemia of chronic disease, and both are normochromic, normocytic anemias
Anemia of Chronic Disease and Renal Failure.
Accessed Sept 12, 2009

36. Renal Anaemia damaged kidney impaired production of erythropoietin
reduced number of red blood cells
anaemia
NOTES FOR PRESENTERS
Anaemia is associated with kidney disease because damaged kidneys are unable to produce enough of the hormone erythropoietin, which stimulates the bone marrow to produce red blood cells by a process called erythropoiesis. Within these cells, oxygen is carried round the body by haemoglobin. When haemoglobin cannot be produced in normal amounts, the body does not receive enough oxygen to meet its needs.

37. Erythropoietin DeficiencyX
Iron
Erythropoietin
Erythroid
marrow RE
cells
Normally, in response to changes in oxygen delivery, renal interstitial cells produce the hormone erythropoietin. This stimulates the erythroid progenitors in the bone marrow to proliferate, increasing the maturation time for red blood cells in the marrow, and causing early release of these red blood cells from the marrow. The cumulative result of these steps is increased red blood cell production. This increased red blood cell mass signals the kidney to decrease erythropoietin release
As functional renal mass is reduced in CKD, production of endogenous erythropoietin is also reduced, thereby resulting in reduced erythropoiesis and anemia
Red blood cells
O2 delivery
RE=reticuloendothelial
Adapted from: Fauci AS, et al, eds. Harrison’s Principles of Internal Medicine. 1998; 334.
Hillman RS. Anemia. In: Fauci AS, Braunwald E, Isselbacher KJ, et al, (eds).
Harrison’s Principles of Internal Medicine. New York: McGraw-Hill; 1998: 37

38. Factors That Cause or Contribute to Anemia in CKDα
Erythropoietin deficiency (insufficient production of endogenous erythropoietin)
Iron deficiency
Acute/chronic inflammatory conditions
Severe hyperparathyroidism
Aluminum toxicity
Folate deficiency
Decreased RBC survival
Hemoglobinopathies (eg, alpha-thalassemia, sickle-cell anemia)
KDOQI. Am J Kidney Dis. 2001;37(1 Suppl 1):S
Agarwal AK. J Am Med Dir Assoc. 2006;7(9 Suppl):S7-S12. 38

39. Key goals in managing anaemia of CKD
increase exercise capacity
improve cognitive function
regulate and/or prevent left ventricular hypertrophy
prevent progression of renal disease
reduce risk of hospitalisation
decrease mortality
NOTES FOR PRESENTERS
What are we trying to achieve?
Not all of these goals may be achievable and there may be certain patients whose physical and mental status renders these goals unachievable from the outset.
For many older patients, improvement in quality of life is their paramount need and older people should not be excluded from treatment because of their age. (NICE recommendation : Age alone should not be a determinant for treatment of anaemia of CKD)

40. What the recommendations cover
Diagnosis of anaemia of CKD
Management of anaemia of CKD
Assessment and optimisation of erythropoiesis
Maintaining stable haemoglobin
Monitoring of ACKD treatment
NOTES FOR PRESENTERS
Appropriate diagnosis and assessment of anaemia of CKD will prevent adverse effects of anaemia translating into adverse outcomes. An algorithm is presented in the guideline to inform the diagnosis of anaemia of CKD.
Iron management forms an essential part of the treatment of anaemia associated with CKD and availability of iron is key for optimal erythropoiesis and maintenance of a stable haemoglobin. Therefore patients should have their iron status monitored before considering ESA therapy.
Erythropoiesis stimulating agents [ESAs] are agents stimulating production of red blood cells through a direct or indirect action on erythropoietin receptors of erythroid progenitor cells in the bone marrow
Initiation of ESA therapy is appropriate in iron-replete patients where existing co-morbidities or prognosis do not negate its effect. The potential benefits of ESA therapy are numerous and include avoidance of blood transfusions, improved quality of life and physical functioning.
Monitoring is part of care in ESA induction and maintenance, including the rate of haemoglobin change.
Monitoring of iron status should aim to ensure that patients undergoing treatment with ESAs maintain optimum levels of iron, i.e. that ensure effective erythropoiesis.

41. Assessment of Anemia in CKD
Test Hb at least annually in all patients, regardless of stage or cause of CKD
Hct is a derived value, affected by plasma water, and, therefore, can be imprecise as a direct assessment of erythropoiesis. In contrast to Hct, Hb values are absolute and directly impacted by decreased erythropoietin production by the kidney1
Assessment should include the following tests:
A complete blood count
Absolute reticulocyte count
Serum ferritin to assess iron stores
Serum transferrin saturation (TSAT) or content of Hb in reticulocytes to assess adequacy of iron for erythropoiesis
Stool for occult blood2
References: 1. National Kidney Foundation. Am J Kidney Dis. 2006;47(suppl 3):S1-S National Kidney Foundation. Available at: guidelines_updates/doqiupan_i.html.

42. Treatment for Anemia of CKD
Replete iron stores to maintain:
TSAT > 20% and
Serum ferritin >100ng/ml
Consider erythropoiesis-stimulating agent (ESA)
Continue to evaluate responsiveness to treatment
When treating with ESA, avoid Hgb > 12 gm/dL

43. Anemia of CKD Management
Supplement iron; most patients should receive oral iron supplement to prevent the development of iron deficiency even if iron studies are normal at initiation of therapy*
Select ESA therapy
Epoetin alfa
Darbepoetin alfa
Monitor Hgb, adjust dose by 25% no more frequently than monthly to reach and maintain target
*Wish JB, Coyne DW. May Clin Proc.2007;82:

44. Hgb Target and ESAs Consider risk to benefit Hgb targets Monitor Hgb:
11-12 g/dL per 2007 NKF KDOQI guidelines
10-12 g/dL per FDA package inserts
Do not exceed Hgb >12 g/dL; adjust dose as “Hgb approaches 12 gm/dL”
Monitor Hgb:
Weekly: darbepoetin
Twice weekly: epoetin

45. Black Box Warning
Renal Failure: Patients experienced greater risk for death and serious cardiovascular events when administered ESAs to a target higher versus lower hemoglobin level in two clinical studies. Individualize dosing to achieve and maintain a target hemoglobin within the range of 10 to 12 g/dL. Nov 07
Aranesp [package insert]. November 2007.
Epogen [package insert]. November 2007.
Procrit [package insert]. November 2007

46. Diagnosis of anaemia of CKD in adults
eGFR < 60ml/min/1.73m2
AND Hb ≤ 11 g/dl
Treat and repeat Hb
Yes No
Non renal and
haematinic
deficiency excluded? No
Consider
other causes
Yes
NOTES FOR PRESENTERS
The starting point is highlighted in Green. The key pathways will ‘fly in’ following a single click. When there is a pause, click again for the next pathway to ‘fly in’. Question points are highlighted in pink. The end point is highlighted in blue.
To minimise the adverse effects of anaemia of CKD early diagnosis is encouraged. This will include measurement of haemoglobin, eGFR, and iron status.
It is likely that management of patients with a diagnosis of anaemia of CKD will be shared between specialist nephrology services in secondary care and primary care
Using the suggested algorithm for diagnosis of anaemia of CKD in adults will ensure that non-renal causes of anaemia are excluded.
(Sections 1.2. and 1.3 of the guideline discuss the management of anaemia and the assessment and optimisation of erythropoiesis)
Recommendation Management of anaemia should be considered in people with anaemia of chronic kidney disease (CKD) when their haemoglobin (Hb) level is less than or equal to 11 g/dl (or 10 g/dl if younger than 2 years of age)
Recommendation an estimated glomerular filtration rate (eGFR) of < 60ml/min/1.73m2 should trigger investigation into whether anaemia is due to CKD. When the eGFR is > 60ml/min/1.73m2 the anaemia is more likely to be related to other causes
Recommendation Serum ferritin levels may be used to assess iron deficiency in patients with CKD. As serum ferritin is an acute-phase reactant and frequently raised in CKD, the diagnostic cut off value should be interpreted differently to non-CKD patients
Recommendation iron deficiency anaemia should be:
diagnosed in patients with stage 5 CKD with a ferritin of less than 100 µg/l
considered in stage 3 and 4 CKD if the ferritin is less than 100 µg/l .
Recommendation in people with CKD who have serum ferritin levels greater than 100 µg/l , functional iron deficiency (and hence, those patients who are most likely to benefit from IV iron therapy) should be defined by :
% hypochromic red cells > 6% where the test is available.
transferrin saturation < 20% when the measurement of % hypochromic red cells is unavailable
Recommendation measurement of erythropoetin levels for the diagnosis or management of anaemia should not be routinely considered for patients with anaemia of CKD. (anaemia is associated with increased EPO levels in individuals without evidence of CKD but the anaemia associated with CKD is characterized by a relative lack of EPO response.) No
See initial
management
algorithm
Patient on
haemodialysis?
See sections
1.2 & 1.3
Yes

47. Initial management algorithm
Ferritin < 500 µg/l?
Yes No
Ferritin < 200 µg/l?
TSAT < 20% Or
%HRC > 6% No
Yes
ESA
(s.c.or i.v.)
Yes – functional
iron deficiency No
Assess Hb
If Hb increase < 1g/dl
after 4 weeks, increase
ESA using dose
schedule
NOTES FOR PRESENTERS
The starting point is highlighted in Green. The key pathways will ‘fly in’ following a single click. When there is a pause, click again for the next pathway to ‘fly in’. Action points are highlighted in pink. Treatment points are highlighted in lilac. The end points are highlighted in dark blue
In this presentation, the algorithm assumes the patient has anaemia of CKD.
Additional iron therapy is not normally recommended if the ferritin is > 500 µg/l, because of the risk of iron overload.
ESA therapy should not be offered as a first line treatment. Iron deficiency should be corrected before or when starting ESAs, or before considering them for haemodialysis patients.
Once Hb is greater than 11 g/dl, enter the Hb maintenance algorithm and adjust ESA dose according to schedule (in NICE guideline)
Recommendation Age alone should not be a determinant for treatment of anaemia of CKD.
Recommendation Treatment with ESAs should be offered to patients with anaemia of CKD who are likely to benefit in terms of quality of life and physical function.
Recommendation management of anaemia should be considered in people with anaemia of CKD when the haemoglobin is less than or equal to 11 g/dl (or 10 g/dl if under 2 years of age)
Recommendation
Patients with anaemia of CKD who are receiving ESAs should be given iron therapy to maintain:
Serum ferritin level greater than 200 µg/l
Transferrin saturation greater than 20% (unless ferritin is greater than 800 µg/l)
Percentage hypochromic red blood cells (HRC) less than 6% (unless ferritin is greater than 800 µg/l)
ESA
(s.c.or i.v.)
and iron
Hb > 9 g/dl
Hb < 9 g/dl
Continue
monitoring Hb
and iron status
Hb < 11 g/dl
i.v. iron
Assess Hb
at 6 weeks
Hb > 11 g/dl

48. Assess and optimise erythropoiesis
Iron supplements should be given to maintain serum ferritin levels
ESA therapy is appropriate in iron-replete patients where existing comorbidities or prognosis do not negate its effect
Benefits of ESA therapy include improved quality of life and physical functioning
There is no evidence to distinguish between ESAs in terms of efficacy
NOTES FOR PRESENTERS
A little reminder:
Erythropoiesis stimulating agents [ESAs] are agents stimulating production of red blood cells through a direct or indirect action on erythropoietin receptors of erythroid progenitor cells in the bone marrow
Evidence statements on efficacy of available ESAs suggest that both darbopoetin and epoetin beta effectively maintain target Hb levels. There was no difference between darbopoetin and epoetin alfa, for the outcomes measured, in a selected group of patients who were stable.
Recommendation ESA therapy should be clinically effective, consistent and safe in people with anaemia of CKD. To achieve this, the prescriber should agree a plan that is patient centred and includes:
Provision of a secure drug supply
Flexibility of where the drug is delivered and administered
Lifestyle and preferences of the patient
Cost of drug supply
Desire for self care where appropriate
Regular review of the plan in light of changing needs
Recommendation People receiving ESA maintenance therapy should be given iron supplements to keep their:
Serum ferritin levels between 200 and 500µg/l in haemodialysis patients
Serum ferritin levels between 200 and 500µg/l in non-haemodialysis patients, and either
Transferrin saturation level above 20% (unless ferritin is > than 800µg/l) or
Percentage hypochromic red cells (%HRC) less than 6% (unless ferritin is > than 800µg/l).
In practice it is likely this will require intravenous iron.

49. Hb maintenance algorithm (assumes ESA therapy and maintenance i. v
Hb maintenance algorithm (assumes ESA therapy and maintenance i.v. iron)
Measure Hb
Hb < 11 g/dl
Hb 11–12 g/dl
Hb 12–15 g/dl
Hb > 15 g/dl
↑ ESA dose/
frequency as
per schedule
unless Hb
rising by
1/g/dl/month.
Check Hb
as per
Schedule.
No change
unless Hb
rising by
1g/dl/month
in which case
consider
ESA dose
adjustment
Consider
stopping i.v.
iron. ↓ ESA
dose/frequency
as per schedule
unless Hb
falling by more
than 1g/dl/month.
Check Hb as
per schedule.
Stop i.v. iron.
Consider
stopping
ESA or halve
dose/frequency.
Check Hb in
2 weeks.
If Hb is
persistently low
see poor
response
algorithm
NOTES FOR PRESENTERS
This algorithm assumes that patients are receiving ESA therapy and maintenance i.v. iron.
The full algorithm for Hb maintenance can be viewed on page 33 of the NICE guideline. For clarity, part of the algorithm is represented here.
When ferritin is ≤ 200 µg/l and the Hb is > 12 g/dl and if there is a ‘no’ response to the TSAT, 20% or HRC > 6% measurement point (refer to previous slide for visual support. In the maintenance algorithm the measurement of Hb is increased from 11 g/dl to 12 g/dl), this algorithm prompts measurement of Hb.
The prompt then re-enters the ferritin measurement at the beginning of the cycle of the maintenance algorithm.
It is important to take into account patient preferences, symptoms and comorbidity and revise the aspirational range and action thresholds accordingly.
The optimal haemoglobin range to be maintained following correction of anaemia associated with CKD is that which confers the most benefit, and least adverse effect in the most cost effective way.
Recommendation In people with anaemia of chronic kidney disease, treatment should maintain stable haemoglobin (Hb) levels between 10.5 and 12.5 g/dl for adults and children aged over 2 years and between 10 and 12 g/dl in children aged under 2 years, reflecting the lower normal range in that age group. This should be achieved by:
Considering adjustment to treatment, typically when Hb rises above 12.0 g/dL or falls below 11.0 g/dL
Taking patient preferences, symptoms and comorbidity into account and revising the aspirational range and action thresholds accordingly
The guideline also provides:
Suggested ESA adjustment schedules for adults
An example iron dosage schedule for adult haemodialysis patients over 50 kg
Frequency of haemoglobin monitoring in adults schedule
There are no benefits to raising haemoglobin levels above 12 g/dl in terms of outcomes based on current evidence with patients who have anaemia of CKD.
Ferritin < 200 µg/l?

50. Iron dosage schedule

51. Hb monitoring

52. Monitor treatment Iron status: Haemoglobin:
not earlier than 1 week after i.v. iron
routinely at intervals of between 4 weeks and 3 months
Haemoglobin:
induction phase of ESAs every 2–4 weeks
maintenance phase of ESAs every 1–3 months
more actively after ESA dose adjustment
NOTES FOR PRESENTERS
Iron Status
Monitoring of iron status should be aimed at ensuring that patients undergoing treatment with ESAs maintain levels of iron that ensure maximally effective erythropoiesis
Recommendation: people with anaemia of CKD should not have iron levels checked earlier than 1 week after receiving intravenous iron. The length of time to monitoring of iron status is dependent on the product used and the amount of iron given.
Recommendation: routine monitoring of iron stores should be at intervals of 4 weeks to 3 months
Haemoglobin
Recommendation In people with anaemia of CKD, Hb should be monitored:
Every 2–4 weeks in the induction phase of ESA treatment
Every 1–3 months in the maintenance phase of ESA treatment
More actively after a ESA dose adjustment
In a clinical setting chosen in discussion with the patient, taking into consideration their convenience and local health care systems
Detecting ESA resistance – it is important to distinguish between true resistance (a lack of bone marrow response to ESA therapy) and apparent resistance, where increased red cell destruction or red cell loss offsets ESA stimulated red cell production. This is discussed in the next slide

53. Epoetin Alfa Darbepoetin Alfa
Indications
• Anemia of CKD • Chemotherapy induced anemia
• HIV induced anemia
• elective, noncardiac,nonvascular surgery
• Anemia of CKD
• Chemotherapy induced anemia
Dosing
Starting: 50 to 100 Units/kg
TIW
Starting: 0.45 ug/kg
Initial: 1 dose/week or
.75mcg/kg qow
Target
Hgb 10-12gm/dL
Dose Response
2 to 6 weeks
Adapted from Package Inserts Data on File. Amgen, In; Thousand Oaks, CA

54. ESA Adverse Events Hypertension, or worsening of control
Headache, arthralgias, nausea
Rarely: seizures, MI, stroke, antibody-induced pure red cell aplasia (PRCA)
Adverse events from SQ administration
Stinging
Necrotic tissue lesions
Subcutaneous nodules

55. Hypo-responsiveness to ESAs
POTENTIAL CAUSES1-4
Missed doses
Inadequate iron stores
Iron deficiency is present in % of patients and is a common cause of hyporesponse1
Drug/disease interactions
Remember, iron needs an acidic environment to be maximally absorbed
B12 or folate deficiencies
Protein deficiencies
Occult blood loss
Infection/inflammation processes
Coexisting medical conditions
Malignancies, hematological disorders
Hemolysis
Response should be in 2-6 weeks; if no response in 12 weeks, eval and Tx hypo-responsiveness
1. Agarwal AK. J Am Med Dir Assoc Nov;7(9 Suppl):S7-S12.
2. KDOQI. Am J Kidney Dis. 2001;37(1 Suppl 1):S
3. Procrit [package insert]. November 2007.
4. Aranesp [package insert]. November 2007. 55

56. ESA Monitoring Hgb “at regular intervals” once stabilized1,2
CBC with differential and platelet count regularly1,2
Blood pressure should be controlled adequately before initiation of therapy1,2
Fe studies (TSAT, ferritin) prior to and during therapy1,2
Serum chemistry should be checked regularly (BUN, creatinine, phosphorus, uric acid, K+)1
References: 1. Procrit [package insert]. Raritan, NJ: Ortho Biotech Products, LP; Available at: Accessed October 23, Aranesp [package insert]. Thousand Oaks, CA: Amgen Inc; Available at: Accessed October 23, 2008.

57. The Role of the Consultant Pharmacist in the Management of the Dialysis Patient
CM 77yo male resident of short-stay facility
Rehab s/p laminectomy; spinal stenosis, gout, DM, HTN, CAD, COPD, RA, renal failure
Dialysis TIW
Weight
Pre-dialysis 79.6 kg
Post-dialysis 77.5 kg
Blood pressure
Pre-dialysis 192/76
Post-dialysis 163/74

58. Additional Information
Continuous oxygen at 2L/min
Renal diet
Fluid restriction 1000cc qd
Labs:
Hgb 9.9 gm/dL
Glucose 86 mg/dL
SCr 6.1; eGFR 10ml/min
K+ 4.7 mEq/L
Calcium 9.1 mg/dL

59. Current Medications Zyloprim 300mg qd Colchicine .6mg qd
Glipizide 10mg qd
Simvastatin 80mg qhs
Diovan 320mg bid
Clonidine .1mg q12h
Hydralazine 50mg bid
Metoprolol 25mg bid
Furosemide 40mg qd
Phos-Lo 667mg qd w/meal
Nephrocaps qd
Docusate 100mg bid
Chemsticks ac & hs
Fosrenal 2000mg w/ each meal

60. What’s a Consultant to do???

61. The Role of the Consultant Pharmacist in the Management of the Dialysis Patient
CM 77yo male resident of short-stay facility
Rehab s/p laminectomy; spinal stenosis, gout, DM, HTN, CAD, COPD, RA, renal failure
Dialysis TIW
Weight
Pre-dialysis 79.6 kg
Post-dialysis 77.5 kg
Blood pressure
Pre-dialysis 192/76
Post-dialysis 163/74

62. Additional Information
Continuous oxygen at 2L/min
Renal diet
Fluid restriction 1000cc qd
Labs:
Hgb 9.9 gm/dL
Glucose 86 mg/dL
SCr 6.1; eGFR 10ml/min
K+ 4.7 mEq/L
Calcium 9.1 mg/dL

63. Current Medications Zyloprim 300mg qd Colchicine .6mg qd
Glipizide 10mg qd
Simvastatin 80mg qhs
Diovan 320mg bid
Clonidine .1mg q12h
Hydralazine 50mg bid
Metoprolol 25mg bid
Furosemide 40mg qd
Phos-Lo 667mg qd w/meal
Nephrocaps qd
Docusate 100mg bid
Chemsticks ac & hs
Fosrenal 2000mg w/ each meal

64. The Role of the Consultant Pharmacist in the Management of
Case Studies
The Role of the Consultant Pharmacist in the Management of
Anemia of CKD

65. Case 1 RB is an 85yo male resident of a LTCF
Two months ago he was started on ferrous sulfate 325mg bid for “anemia”
Follow-up labs
Hgb 8.1 g/dl
Hct 32%
Iron 45 mcg/dl
Recent hospital return on epoetin alfa 30,000 units TIW (wt 75kg)

66. Case 1 cont’d CP recommends lab
Hgb 8.9 g/dl
Hct 35%
TSAT 18%
Ferritin 92 ng/ml
Hgb has not increased significantly over 4 weeks
TSAT should be >= 20%
Ferritin >= 100ng/ml

67. Case 1 cont’d Consider possible causes for lack of rise in Hgb
Appropriate dosing?
30,000 units TIW for 75 kg patient; the recommended starting dose for epo is units/kg TIW, IV or SC
The starting dose range based on weight would be 37,500 – 75,000 units TIW
If Hgb does not increase by 1g/dl after 4 weeks and iron stores are adequate, increase dose by 25%

68. Case 1 cont’d Are iron stores adequate in this resident?
No, based on reported labs
CP discusses administration of iron with nurses
PRN antacid is frequently given with the iron to reduce c/o of GI upset; or, doses are held
For optimal absorption, iron should be given 1 hr before or 2 hrs after meals, but may be given with food to reduce GI irritation

69. Case 1 cont’d What action should be taken by the CP?
Educate staff on proper administration of iron
Recommend to prescriber to increase epo dose to 40,000 units TIW
Check iron, ferritin, TSAT in about a month
Hgb should be checked at least weekly x 4 after a dosage change (then monthly, when stabilized)
Clinically significant improvements may not be seen for 2-6 weeks, but do not adjust dose any more frequently than once per month

70. Case 2 JC is an 80yo female resident of a LTCF
Primary Dx: HTN, anemia of CKD
Hgb 8.7 g/dl
Taking 45,000 units erythropoietin TIW x 4 weeks, Hgb results:
Week g/dl
Week g/dl
Week g/dl

71. Case 2
If there is a rapid increase in Hgb (>1g/dl in any 2 week period) OR
The Hgb is increasing and approaching 12
Reduce weekly dose by approximately 25%
Rapid rise increases risk of exacerbation of HTN
ESAs should not be used in patients with uncontrolled HTN