Anemia Management

ANEMIA

Prof. M A Bakr (MD)Urology & Nephrology CenterMansoura University - Egypt

I. Anemia and kidney

II. Biosimilars

III. Recommendations

AGENDA


Cairo At Night

1. Introduction.

2. Iron stores.

3. Treatment options.

4. Principles for ESA therapy.

5. Non iron adjuvant therapy.

6. Studies.

7. Complications.

8. Post transplant anemia.


1- Introduction: Definition: Hb below 13 gm/dl for adult males, post

menopausal women and Hb below 12 gm/dl for

premenopausal women. Nearly 90% of patients with GFR 25-30 ml/min. have

anemia, Hb may be below 10 gm/dl.

(Kazmi et al., Am J Kidney Dis, 2001) Prevalence of anemia in stage 3-5 CKD is 58.5%.

(Cases-Amenos et al., Nefrologia, 2014)


1- Introduction: Kidney is the primary site of EPO production in

adults. Liver making only a minor contribution. EPO enhances growth, differentiation of erythroid

progenitors. With renal dysfunction, EPO levels decreased leading

to progressive anemia.(Ratcliffe et al., NDT, 1995)


I. Anemia and kidney1- Introduction:

Evaluated outcomes include:• Overall mortality.• CV mortality.• CV morbidity.• Cerebro vascular morbidity.• Blood pressure control.• Access thrombosis.• Quality of life.

(Pfeffer et al., NEJM, 2009)

1- Introduction:

Improved anemia leads to:

• Better quality of life.

• Increased energy levels.

• Greater capacity for work.

• Greater capacity for exercise.

• Restored sexual function.

• Improved appetite and social activities.

(Metivier et al., NDT, 2003)


2- Assess Iron stores: Red blood cell indices. Reticulocytic count. Serum iron. Total iron binding capacity. Percent transferrin saturation. Serum ferritin. Blood in stool.

(Berns et al., Up-to-date, March 2013)


2- Assess Iron stores:Iron deficiency and ESKD

1. Transferrin saturation percent falls below 20%

2. Serum ferritin is less than 100 ng/ml in predialysis and

PD patients.

3. Serum ferritin is less than 200 ng/ml in HD patients.

(Berns et al., Up-to-date, March 2013)


)( 100CapacityBindingIronTotal

IronSerum

2- Assess Iron stores:

a) Functional Iron deficiency: respond to iron therapy.

Adequate iron stores with inability to mobilize to

support erythropoiesis.

b) Inflammatory Iron block: does not respond to iron

therapy. Occurs in patients with refractory anemia

due to underlying inflammatory state.

(Bernz et al., Up-to-date, March 2013)


2- Iron therapy in HD patients: Iron ± ESAs are administered to achieve target Hb 10-11.5 gm/dl

for HD patients. HD patients with iron deficiency (TSAT ≤ 20%, ferritin ≤200

ng/ml), Iron therapy is adminsteed to treat anemia. If TSAT ≤30%, ferritin ≤ 500 ng/ml, iron is administered prior to

ESAs after exclusion of infection. In HD patients parentral iron is preferred than oral route. Different iron preparations are largely equivalent in efficacy but

iron sucrose is safer than iron dextran.

(Coyne et al., JASN, 2007)


2- Iron therapy in HD patients: For loading therapy:

- 125 mg ferric gluconate complex in sucrose/session for 8 doses.- Or 100 mg iron sucrose/session for 10 doses (1000 mg).- Or Ferumoxytol, rapid infusion, second dose 1-4 w later if indicated.

(Provenzane et al., JASN, 2009)

Repeat loading therapy if TSAT remains below 30%. Do not adminster IV iron if ferritin is above 500 ng/ml. Initial test dose in case of iron dextran. Recommend IV rather oral iron in HD patients.

(Schiesser et al., NDT, 2006)


3- Treatment options: Candidate for treatment: Hb below 10 gm/dl. Evaluate iron states and correct deficiency. Search for treatable causes (hemolysis, nutritional

deficiency as B12, folate). No history of stroke, malignancy, active malignancy. In predialysis, ESAs is given SC rather than IV. For PD, predialysis, iron supplement to maintain TSAT 20-

50%, serum ferritin 100-500 ng/ml.

(Jeffery et al., Up-To-date, March 2013)


3- Treatment options:

a) Blood transfusions.

b) Androgens.

c) ESAs: • Primary option for anemia management in CKD.

• Individualize the ESAs therapy according to symptoms, Hb

below 10 gm/dl.

d) Peginesatide.

(Jeffery et al., Up-To-date, March 2013)


3- Treatment options:a) Transfusions

Successful to raise Hb levels. Ameliorate patients symptoms Improve health related quality of life. May be associated with complications:

• Sensitization.• Iron overload.• Volume overload.• Transfusion reactions.• Transmitted infections.

(Berns et al., Up-To-Date, 2013)


3- Treatment options:b) Androgens

Prior to ESAs. May increase endogenous Epo production. May increase RBCs survival. May increase the sensitivity of erythroid progenitors

to Epo effect. Side effects:

• Acne, virilization. - Priapism.• LFT abnormalities. - Risk of HCC.• IM injection.

(Berns et al., Up-To-Date, 2013)



c) ESAs

Additional new treatment option.

Balance between benefits and harms.

Phase III clinical trial showed that ESAs was

effective and eliminated the need for continued

transfusions. (KDIGO, Kidney Int, 2012)



d) Peginesatide: Synthetic peptide activates EPO receptor. Stimulates erythroid colony growth, reticulocyte count and

Hct in animals. EMERALD I and II studies compare peginesatide (once/M)

Vs ESAs in 1418 HD patients with followed up 52 w. Comparable CV safety.

It was not inferior to maintain Hb.

(Fishbane et al., NEJM, 2013)



d) Peginesatide Another 2 phase III trials (PEARL I and II) comparing

peginesatide to ESAs among non dialysis CKD. Increased CV events with peginesatide. FDA approved peginesatide for dialysis patients only

but not for CKD patients not on dialysis. It was withdrawn from the market due to serious

hypersensitivity reactions in 0.2% of patients with

death in 0.02%.

(Berns et al., Up-To-Date, March 2013)


4- General principals for ESAs therapy:

Response to EPO is dose dependent, varies greatly

among patients.

Response is dependent on route of administration

(IV, SC) and the frequency of administration.

With SC route, frequency is not as important as with

IV route. (Ifudu et al., Am J Kidney Dis, 2000)


4- General principals for ESAs therapy: Response may be limited by low iron stores, bone

marrow fibrosis, infections and inadequate dialysis.

(Ifudu et al., Am J Kidney Dis, 2000)

Over 90% of dialysis patients in USA received ESAs and

over 80% have Hb level greater than 11 gm/dl.

(Centers et al., Am J Kidney Dis, 2006)

More than 30% of lupus nephritis patients approaching

ESKD received ESAs.

(Gomez-Puerta et al., J Clin Cell Immunol, 2013)



Either short or long acting ESAs can be used with

choice determined by patients, staff, compliance,

availability and cost.

ESAs became the standard of care for treatment

of anemia in CKD patients.




Advantages of SC route for HD, PD and CKD:

- Improved cost effectiveness.

- Longer half-life.

- Lower incidence of HTN.

- Lack of IV access.

(Henrich et al., Up-To-Date, March 2013)


5- Non Iron Adjuvants to ESAs in HD Patients:

Objective is to:

- Enhance EPO response.

- Reduce the economic impact.

- Address EPO hyporesponsiveness.



5- Non Iron Adjuvants to ESAs in HD Patients: L-carnitine: Unknown mechanism.

(Hothi et al., NDT, 2006) Ascorbic acid: increases release of iron from ferritin.

(Sirover et al., Ren Fail, 2008) Pentoxifylline benefits in Epo resistant anemia.

(Cooper et al., JASN, 2004) Statins: anti inflammatory and antioxidant properties

(Chiang et al., Am J Nephrol, 2009) Non of these agents is recommended.

(KIDOQI, Am J Kidney Dis, 2006)


6- Studies:

Retrospective studies suggested better outcomes

associated with Hb values 11-13 gm/dl (Hct 33-

39%) compared to values below 11 gm/dl among

HD patients.

(Messana et al., Am J Kidney Dis, 2009)


6- Studies: Meta-analysis, 27 trials, 10453 patients. Comparison high Hb target with lower target or

placebo. Higher target is associated with increased risks

for:- Stroke (RR 1.5, 95% CI 1.03-2.21).- Hypertension (RR 1.67, 95% CI 1.31-2.12).- Vascular thrombosis (RR 1.33, 95% CI 1.16-1.53).

(Palmer et al., Ann Intern Med, 2010)


6- Studies: Trends favored lower target or placebo (not

different) are:- Mortality (RR 1.09, 95% CI 0.99-1.2)- ESRD (RR 1.08, 95% CI 0.97- 1.2)- Serious CV events (RR 1.15, 95% CI 0.98-1.33).

Treatment effects were consistent across all stages of CKD.

Limited interpretation due to heterogeneity of patients and interventions.

(Palmer et al., Ann Intern Med, 2010)


6- Studies:

In HD patients:

• Normal Hct trial.

• CHOIR trial.

In pre dialysis:

• CREATE trial.

• TREAT trial.


6- Studies:

a) Normal Hct trial:- Should normal Hct value be the target level in dialysis

patients based on CV morbidity and mortality.- 1233 HD patients were enrolled with HF, IHD.- Baseline Hct is 27-33% on ESAs.- Randomization to • 42% • 30%- Endpoints : death or nonfatal MI.

(Coyne et al., Kidney Int, 2012)


6- Studies:

a) Normal Hct trial:- Terminate the study after 29 M due to:• Mortality were 7% higher in normal Hct group.

• Significant higher vascular access thrombosis in the same group.

• Comparable, nonfatal MI and stroke.

- However higher Hct had higher rate of hospitalization

with marginal statistical difference (RR 1.14, 95% CI

0.94-1.3) according to trial report to FDA.

(Coyne et al., Kidney Int, 2012)


6- Studies:

b) CHOIR trial:- 1432 patients.

- GFR 15-50 ml/min/1.73 m2, Hb less than 11 gm/dl.

- Randomized GI: Target Hb 13.5 gm/dl.

GII: target Hb 11.3 gm/dl

- Primary endopoints: death, MI, stroke and

hospitalization for heart failure (without RRT).

(Singh et al., NEJM, 2006)


6- Studies:b) CHOIR trial

Terminated early (median duration 16M) as GI had :• Less than 5% chance of CV benefits.• Significant higher events (125 Vs 97, HR 1.34, 95% CI

1.03-1.7).• Trend of increased risk of death (52 Vs 36 HR 1.48,

95% CI 0.97-2.27).• More hospitalization for HF (64 Vs 47, HR 1.41, 95%

CI 0.97-2.05)(Singh et al., NEJM, 2006)


6- Studies:

b) CHOIR trial:

Higher comorbid conditions with poor prognosis and

adverse outcome.

Higher numbers of patients with:• HTN (95 Vs 92).

• Severe HF (26.6 Vs 21.1).

• History of CABG (17 Vs 14).



6- Studies:

b) CHOIR trial:

After multivariate analysis and adjustment for HF,

AF, lower albumin, high reticulocyte count and older

age, no significant difference was found compared to

GII (HR 1.2, 95% CI 0.95-1.6).



6- Studies:

b) CHOIR trial:

- Patients withdrawal for many reasons was

comparable (21%) .

- Need for RRT in GI, GII was 17%.

- No baseline informations for 800 patients who

completed the study.



6- Studies:

In HD patients:

• Normal Hct trial.

• CHOIR trial.

In pre dialysis:

• CREATE trial.

• TREAT trial.


6- Studies:c) CREATE trial:

- 603 patients, GFR 15-35 ml/min with anemia.- Assigned to normal Hb (13-15 gm/dl)

or subnormal (10.5-11.5 gm/dl)- Primary endpoints: death, MI, acute HF, stroke,

transient ischemic attack, hospitalization for angina

or arrhythmia, complications of peripheral vascular

disease.(Drueke et al., NEJM, 2006)


6- Studies:c) CREATE trial:

- Achieved Hb levels were 13.5, 11.5 gm/dl for normal

and subnormal groups.- At 3 years:• Similar changes in LV mass.• Similar rates of progression of CKD.• But increased general health, QOL in high Hb group.• Similar risk of endopoints (HR 0.78, 95% CI 0.53-1.14).

(Drueke et al., NEJM, 2006)


6- Studies:d) TREAT trial :

- 4038 patients with type 2 DM and CKD (eGFR 20-60

ml/min/1.73 m2).- Randomized:

• Darbepoetin alfa to achieve Hb level of 13 gm/dl • or placebo with darbepoetin if Hb was below 9 gm/dl.

- Primary endpoints death, CV events, ESRD.- Achieved Hb was 12.5 and 10.6 gm/dl for both groups.



6- Studies:d) TREAT trial:

- Median follow up was 29 M.- Both arms had similar risks of:

• Death, CV events (HR 1.05, 95% CI 0.94-1.17).• ESRD (HR 1.06, 95% CI 0.95-1.19).

- Increased risk of strokes in first group (101 Vs 53 patients, HR 1.92, 95% CI 1.38-2.68).

- Significant transfusion needs in the second group (496 Vs 297 patients).



6- Studies:d) TREAT trial :

- Increased risk of death due to malignancy in the first group especially in those with past history of malignancy.

- LVH, powefrul prognostic marker for adverse CV outcomes in CKD patients, appears to regress with improvement in Hb levels from below 10 to above 10 gm/dl.

- It does not appear that raising Hb further to more normal levels leads to further regression of LVH.



6- Studies:

d) TREAT trial : QOL

• At 25 weeks: modest improvement in fatigue

was noted in those assigned for ESAs, but there

was no change in energy or physical function.

• At 95 weeks: Fatigue improvement was noted

among 2295 patients.

(Lewis et al., CJASN, 2011)


6- Studies:

Other Studies:

• PATRONUS study: IVMIRCERA Vs IVdarbepoetin

alfa. (Carrera et al., NDT, 2010)

• CORDATUS study: CERA/Month.

(Roger et al., NDT, 2011)

• CAPRI study: CERA/M for PD patients.

(Gonzalez et al., Ren Fail, 2013)


7- Complications of ESAs:a) HTN: 20-30%

Aetiology• High ESAs dose.• Positive family history of HTN.• Prior personal history of HTN.• Diminished production of nitric oxide.• Increased intracytosolic calcium.• Enhanced vascular alpha adrenergic sensitivity.• Increased plasma endothelin levels.• Activation of renin-Angiotensin system.• Elevated thromboxane/prostacyclin in vascular tissue.

(Kraphfet al., CJASN, 2009)


7- Complications of ESAs:

a) HTN: Prevention and treatment• Close monitoring.

• Raise Hct slowly.

• Adjust ESAs dose.

• Target Hb level 10-11 gm/dl.

• Fluid removal.

• Anti hypertensives: first choice is B blockers, and vasodilators.

Also, ca channel blockers, ACEI may be effective.

(Novak et al., Pharmaco Therapy, 2003)


7- Complications of ESAs:b) PRCA:• Rare• Serum of PRCA patients inhibits growth of erythroid

progenitor cells in BM cultures.• Neutralizing IgG antibodies to the protein component of

exogenous Epo cross react with endogenous Epo.• Polysorbate as stabilizing agent in both Epo alpha (eprex

or beta (recormon).• In apporopriate storage, handling (high temperature)

Epo molecule may aggregate and elicit antibody response. (Hermeling et al., Pharm Res, 2003)


7-Complications of ESAs:

b) PRCA Suggestions:• Organic compounds leached by polysorbate from

uncoated rubber stoppers in prefilled syringe.

• Replacing uncoated rubber stoppers with fluoro-resin

coated ones and change the prescribing information of

eprex with polysorbate to IV route for CKD results in

rapid fallen of PRCA to its baseline.

(Cournoyer et al., JASN, 2004)


7- Complications of ESAs:

b) PRCA: Diagnosis• Hb decline (0.7-1 gm/dl/week without transfusion).

• Transfusion requirement at least once weekly.

• Marked reduced reticulocyte count.

• Drop platelets count.

• Normal WBCs.

• Elevated transferrin saturation and ferritin.

• ± Allergic utircarial skin reactions at sites of SC injection.

(Casadevall et al., Eur J Haematol, 2004)


7-Complications of ESAs:

b) PRCA: Treatment

1. Transfusion for symptomatic anemia.

2. Discontinue ESAs.

3. Immunosuppression to eradicate antibodies.

4. Re challenge may lead to anaphylaxis but case report of

patient tolerance is seen especially if anti Epo antibody

levels are below or closer to lower limit of detection.

(Rossert et al., NDT, 2005)


8- Anemia and renal transplantation:

Common.

Frequently undertreated.

Incidence is 40% at one year after transplant.

Renal transplant recipients restarting dialysis have lower

Hb compared to non transplant CKD (8.9 Vs 10.2 gm/dl).

(Arias et al., Kidney Int, 2002)



Risk factors:

- Increased acute rejection events.

- Increased donor age (above 60 y).

- Decreased creatinine clearance.

- Retransplantation.

(Vanrenterghem et al., Am J Transplant, 2003)



Risk factors:- Female gender.- Non white race.- Non diabetic patients.- Lower serum albumin.- Recipient age below 45 y.- Living Vs Deceased donors.

(Shah et al., Transplantation, 2006)


8- Anemia and renal transplantation: Risk factors, Immunosuppression:

- Antimetabolites (Aza, MMF, MPS) cause marrow suppression and result in anemia.

(Imaogene-Dyedeji et al., JASN, 2006)- SIR causes anemia early after transplant, but this effect

lessen over time.(Fishbane et al., Kidney Int, 2009)

- CNIs do not cause marrow suppression.- SIR + CNIs can cause hemolytic anemia, HUS.

(Kim et al., Transplant Proc, 2003)



Treatment

- ESAs if Hb is below 10 gm/dl.

- Transfusions are a concern.

- Maintain Hb 10-12 gm/dl.

- Close monitoring of blood pressure.

(Mehrotra et al., JASN, 2012)


EPO receptor EPO receptorrHuEPO

II. Biosimilars

Medicine which is similar to the biological

medicine that has already been authorized.

In Europe it is biosimilar.

In USA, it is follow on biologic.

(Covic et al., NDT, 2008)

II. Biosimilars

Two issues:

a) Variable potency/response.

b) Immunogenecity:- Glycosylation.- Contamination.- Change to 3D structure:

• Protein aggregation.

• Protein oxidation.

(Yang et al., Pharm Res, 2007)

II. Biosimilars

Basics:

a)Pharmacodynamic studies:i. In vivo animal studies.

ii. In vitro studies.

b) Analytical data:i. Physical characteristics.

ii. Epo content.

iii. Potency assay.

iv. Isoform testing.


II. Biosimilars

Basics:

c) Clinical studies:

I. Pharmacokinetic studies.

II. Pharmacodynamic studies.

III. Clinical efficacy studies.

IV. Clinical safety data.


II. Biosimilars

Recombinant biological products:- Develop host. - Establish cell bank.- Protein production system.- Purification.- Anaylsis.- Formultion.- Distribution.


II. Biosimilars

Avaliable forms:

- Epoetin alfa.

- Epoetin Beta.

- Epoetin delta.

- Epoetin omega.

- Epoetin zeta.

- Miscellaneous.

(Variety of glycosylation pattern)

(Macdougall et al., ASN , 2005)

II. Biosimilars

2. Biosimilars

(Macdougall et al., ASN , 2005)

Agent Population Half-life (h)Mean (± SE)

IV SC

Epoetin alfa Healthy volunteers 6.8 ± 0.6 19.4 ± 2.5

Epoetin beta Healthy volunteers 8.8 ± 0.5 24.2 ± 2.6

Darbepoetin alfa PD patients 25.3 ± 2.2 48.8 ± 5.2

C.E.R.A. Healthy volunteers 133 ± 9.8 137 ± 21.9

PD patients 134 ± 19 139 ± 20

Expiration of patency for epoetins allows

development of new versions which may increase

competition.

For traditional pharmaceutical products, generics

are easily developed.

II. Biosimilars

(Crommelin Eur J Hosp Pharm, 2008)

The use of the same cell line and gene and similar

production, purification and formulation process does

not guarantee the product will be equivalent to the

original compound.

In addition a study that analysed epoetin products from

various manufactures reported batch-to-batch variation

and detection of unacceptable levels of bacterial

endotoxins.

2. Biosimilars

(Schellekens, Eur J Hosp Pharm, 2004)

Different epoetin isoforms have different biological

activity.

The presence of more acidic or basic isoforms to reduce

specific activity.

Immunogenicity is a concern with epoetin since anti-

erythropietin antibodies are neutralizing to the native

protein, resulting in progressive and resistant anemia.

2. Biosimilars


The Eprex (epoetin alfa) reference standard, which is

calibrated against the WHO references standard, was

used as the control for all analysis.

The products were evaluated for adherence to epoetin

alfa specialization (physical measures) and the

European Pharmacopoeia guidelines (protein identity

and content).

2. Biosimilars

(Schellekens, Eur J Hosp Pharm, 2004)

The most alarming aspect of this comparison was

the variation observed between different lots of the

same product.

The clinical and safety data available in the public

domain are not very convincing with respect to

safety and efficacy for many patients.

2. Biosimilars


Some of the products failed to meet their own

specifications, indicating that some of the manufacturers

do not have adequate control over their own production

process. In addition, the content of the vials often exceeded the

acceptable limits based on the labeling activity. This mislabeling could lead to under or overdosin

resulting in undesirable clinical effects.

2. Biosimilars


III- Recommendations

Mansoura at Night

EBPG, 2004

KDOQI, 2006/2007.

ERBP, 2008

KDIGO, Kidney Int, 2012

III. Recommendations

Frequency of testing for anemia in CKD:– For patients without anemia, measure Hb concentration

when clinically indicated and (Not Graded):• At least annually in patients with CKD 3.

• At least twice per year in patients with CKD 4–5ND.

• At least every 3 months in patients with CKD 5HD, PD.

– For patients with anemia (Not Graded):• At least every 3 months in patients with CKD 3–5ND and CKD

5PD.

• At least monthly in patients with CKD 5HD.


)KDIGO, Kidney Int, 2012(

Diagnosis of anemia in CKD:- Diagnose anemia in adults and children >15 years with CKD when the Hb

concentration is <13 gm/dl in males and <12 gm/dl in females (Not

Graded).- Diagnose anemia in children with CKD if Hb concentration is <11 g/dl in

children 0.5–5 years, <11.5 g/dl in children 5–12 years, and <12 g/dl in

children 12–15 years (Not Graded).- In patients with CKD and anemia, include the following tests (Not Graded).

• CBC, Red cell indices.• Absolute reticulocyte count.• Serum ferritin level.• Serum transferrin saturation (TSAT).• Serum vitamin B12 and folate levels.



Iron to treat anemia in CKD:– When prescribing iron therapy, balance the potential benefits against the

risks of harm in individual patients (Not Graded).

– For adult CKD patients with anemia not on iron or ESA therapy we

suggest a trial of IV iron (or in CKD patients alternatively a 1–3 month

trial of oral iron) (2C) if:• An increase in Hb without starting ESA treatment is desired and

• TSAT is ≤30% and ferritin is ≤500 ng/ml.

– For adult CKD patients on ESA therapy who are not receiving iron, we

suggest a trial of IV iron (or in CKD ND patients alternatively a 1–3

month trial of oral iron (2C) if:• An increase in Hb or a decrease in ESA dose is desired and

• TSAT is ≤30% and ferritin is ≤500 μg/ml.



Iron to treat anemia in CKD– For CKD ND patients who require iron, select the route of iron

therapy based on the severity of iron deficiency (Not Graded).

– Guide subsequent iron administration in CKD patients based on

Hb response to recent iron therapy (Not Graded).

– For all pediatric CKD patients with anemia not on iron or ESA

therapy, we recommend oral iron (or IV iron in HD patients) when

TSAT is ≤20% and ferritin is ≤100 ng/ml. (1D)

– For all pediatric CKD patients on ESA therapy who are not

receiving iron, we recommend oral iron (or IV iron in CKD HD

patients) to maintain TSAT >20% and ferritin >100 ng/ml (1D).



Iron to treat anemia in CKD:

– For CKD ND patients requiring iron therapy, select the

route of evaluate iron status (TSAT and ferritin) at least

every 3 months during ESA therapy, (Not Graded).

– Test iron status more frequently when initiating or

increasing ESA dose, (Not Graded).



Iron to treat anemia in CKD:

– When the initial dose of IV iron dextran is administered, we

recommend (IB) and when the initial dose of IV non-dextran

iron is administered, we suggest (2C) that patients be

monitored for 60 minutes after the infusion, and that

resuscitative facilities and personal trained to evaluate and

treat serious adverse reactions be available.

– Avoid administering IV iron to patients with active systemic

infections. (Not Graded).



ESA Initiation in CKD:– Address all correctable causes of anemia prior to initiation of ESA

therapy. (Not Graded).– In initiating ESA therapy, we recommend balancing the potential

benefits of reducing blood transfusions and anemia-related

symptoms against the risks of harm in individual patients. (1B).– We recommend using ESA therapy with great caution, in CKD

patients with active (1B), a history of stroke (1B), or a history of

malignancy (2C).– For adult CKD ND patients with Hb ≥10 gm/dl, we suggest that

ESA therapy not be initiated (2D).



ESA Initiation in CKD:– For adult CKD ND patients with Hb >10 gm/dl we suggest that the

decision to initiate ESA therapy be individualized based on the rate of fall of Hb, prior response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy. (2C).

– For adult CKD 5D patients, we suggest that ESA therapy be used to avoid Hb fall below 9 gm/dl by starting ESA therapy when the hemoglobin is between 9–10 gm/dl (2B).

– Individualization of therapy with improvements in quality of life at higher Hb and ESA therapy may be started above 10 gm/dl (Not Graded).

– For all pediatric CKD patients, we suggest that the selection of Hb at which ESA therapy is initiated in the individual patient includes consideration of potential benefits and potential harms (2D).



ESA Maintenance in CKD:– We suggest that ESAs not be used to maintain Hb above

11.5 gm/dl in adult patients with CKD (2C).

– Individualize therapy with improvements in quality of life

at Hb above 11.5 gm/dl (Not Graded).

– In adult patients, we recommend that ESAs not be used to

intentionally increase the Hb above 13 gm/dl (1A).

– In pediatric CKD patients receiving ESA therapy, we

suggest that the selected Hb be in the range of 11 to 12

gm/dl (2D).



ESA Dosing in CKD:– We recommend determining the initial ESA dose using Hb level,

body weight and clinical circumstances (1D).– We recommend that ESA dose adjustments be made based on the

patient’s Hb, rate of change in Hb, current ESA dose and clinical

circumstances (1B).– We suggest decreasing ESA dose in preference to withholding ESA

when a downward adjustment of Hb concentration is needed. (2C).– Re-evaluate ESA dose if the patient (Not Graded):

• Suffers an ESA-related adverse event. • Has an acute illness that may cause ESA hyporesponsiveness.



ESA Administration in CKD:– For CKD 5HD patients, we suggest either IV or SC

administration of ESA. (2C).

– For CKD ND and CKD 5PD patients, we suggest SC

administration of ESA. (2C).

– We suggest determining the frequency of ESA

administration based on CKD stage, treatment setting,

efficacy considerations, patient tolerance beside preference,

and type of ESA. (2C)



Type of ESA in CKD:– We recommend choosing an ESA based on the balance of

pharmacodynamics, safety information, clinical outcome data, costs, and

availability (1D).– We suggest using only ESAs that have been approved by an independent

regulatory agency. Specifically for ‘copy’ versions of ESAs, true

biosimilar products should be used. (2D).– During the initiation phase of ESA therapy, measure Hb at least

monthly. (Not Graded).– For CKD ND patients, during the maintenance phase of ESA therapy

measure Hb concentration at least every 3 months. (Not Graded).– For CKD 5D patients, during the maintenance phase of ESA therapy

measure Hb concentration at least monthly. (Not Graded).



ESA Hyporesponsiveness:

– Classify patients as having ESA hyporesponsiveness if they

have no increase in Hb concentration from baseline after the

first month of ESA treatment on appropriate weight-based

dosing (Not graded).

– In patients with ESA hyposponsiveness, we suggest avoiding

repeated escalation in ESA dose beyond double the initial

weight-based dose (2D).



ESA Hyporesponsiveness:– Classify patients as having acquired ESA hyporesponsiveness

if after treatment with stable doses of ESA, they require two

increases in ESA doses up to 50% beyond the dose at which

they had been stable in an effort to maintain a stable Hb

concentration. (Not Graded).

– In patients with acquired ESA hyporesponsiveness, we

suggest avoiding repeated escalations in ESA dose beyond

double the dose at which they had been stable. (2D).



ESA Hyporesponsiveness:– Evaluate patients with either initial or acquired ESA

hyporesponsiveness and treat for specific causes of poor ESA

response. (Not Graded).– For patients who remain hyporesponsive despite correcting

treatable causes, we suggest individualization of therapy,

accounting for relative risks and benefits of (2D):• Decline in Hb concentration.• Continuing ESA, if needed to maintain Hb, with due consideration of

the doses required, and• Blood transfusions.



Transfusions:– We recommend avoiding, when possible, transfusions to minimize the

general risks related to their use (1B).– In patients eligible for organ transplantation, we recommend avoiding,

transfusions to minimize the risk of allosensitization (1C).– We suggest that the benefits of transfusions may outweight the risks in

patients in whom (2C):• ESA therapy is ineffective (e.g., hemoglobinopathies, bone marrow failure,

ESA resistance).• The risks of ESA therapy may outweight its benefits (e.g., previous or

current malignancy, previous stroke).– We suggest that the decision to transfuse a CKD patient with non-acute

anemia should not be based on any arbitrary Hb threshold, but should be determined by the occurrence of symptoms caused by anemia (2C).



Transfusions:

– In certain acute clinical situations, we suggest patients

are transfused when the benefits of red cell transfusion

out weight the risks; these include (2C):• When rapid correction of anemia is required to stabilize the

patient’s condition (e.g., acute hemorrhage, unstable

coronary artery disease).

• When rapid pre-operative Hb correction is required.



Alex At Night

Lastly

Anemia is a comorbid condition in CKD.

(Weir and Fink, Curr Opin Nephrol Hypertens, 2014)

Recommendations for anemia treatment in CKD.

(Bover-Sanjuan et al., Nefrologia, 2014)

Balancing ESA and iron therapy through physiologically

compatible dosing protocol will drive new guidelines.

(Arnoff and Gameda, Nephrol Nes Issues, 2014)

Lastly (2014):

Thank You

Anemia Management

Health & Medicine

ann intern

assess iron

normal hct

cv events

cv morbidity

iron deficiency

increased

iron therapy