4. ANEMIA IN CKD
STAGE eGFR
(ml/min/1.73m2)
ANEMIA
PREVALENCE
3 30-59 5.2%
4 15-29 44.1%
5 <15 or on dialysis 100%
5. CAUSES OF ANEMIA IN CKD
EPO deficiency
Blood loss
Shorter RBC life span
Decreased bone marrow responsiveness to
EPO
Vitamin deficiencies
Iron deficiency (poor iron absorption)
High uremia level
Chronic inflammation
6. ANEMIA IN CKD LEADS TO :
↓ QOL
↓ energy and exercise capacity
↓ neurocognitive function
↑ mortality (27.3% of all cause
mortality)
↑ LVH
Onset of cardiac events
7. EFFECT OF ANEMIA ON
CARDIOVASCULAR SYSTEM
CV disease related mortality is 15 times more in patients with CKD.
50% of deaths in patients with CKD are due to CV disease.
LVH is the most common abnormality seen in patients with CKD and
there is a strong correlation between anemia and LVH.
Tissue hypoxia due to anemia is the principal stimuli triggering the
compensatory changes that stresses the CV system
8.
9. ERYTHROPOIESIS-STIMULATING
AGENTS
Erythropoiesis-stimulating agents (ESA) are effective in
achieving and maintaining target haemoglobin levels.
Traditional ESA include epoetin α and epoetin β.
Epoetin α and β resemble closely the endogenous molecule
and have similar pharmacokinetics.
Second-generation ESA include darbepoetin and continuous
erythropoiesis receptor activator (CERA).
Acta Nephrologica 26(3): 137-142, 2012
10.
11. RECOMBINANT HUMAN
ERYTHROPOIETIN (rHuEPO)
Although rHuEpo has proven highly effective in treating renal
anaemia, administration two or three times weekly is recommended
for most patients because of its short circulating half-life.
The chronic nature of the disease and its treatment means that
multiple weekly injections of rHuEpo may be inconvenient for both
patients and healthcare providers.
Asakawa et al. Renal Replacement Therapy (2016) 2:12
J Intern Med 2006; 260: 577–585
12. DARBEPOETIN ALFA
The recombinant human erythropoetin, epoetin alfa, was approved by
the FDA in 1993 for the treatment of anemia associated with
chemotherapy.
Darbepoetin, was created by site-directed mutagenesis and differs from
epoetin at five amino acid positions.
Darbepoetin was approved by the FDA for the treatment of anemia
associated with chemotherapy in July of 2001.
13. DESCRIPTION
Darbepoetin alfa is a erythropoiesis-
stimulating protein that is produced in
Chinese hamster ovary (CHO) cells by
recombinant DNA technology.
165-amino acid protein : contains 5 N-
linked oligosaccharide chains, whereas
recombinant human erythropoietin
contains 3 chains. The approximate
molecular weight is 37,000 daltons.
NESP = Novel erythropoiesis stimulating protein-
Darbepoeitin Alfa
The "X"s in darbepoetin alfa represent the five
amino acid exchange sites that were required to
allow the attachment of two extra N-linked
carbohydrate chains.
14. STRUCTURAL AND CHARACTERISTIC DIFFERENCE
BETWEEN RECOMBINANT HUMAN
ERYTHROPOIETIN ALFA AND DARBEPOETIN ALFA.
CHARACTERISTICS HUMAN
ERYTHROPOIETIN ALFA
DARBEPOETIN ALFA
Structure 3-linked CHO chains 5-linked CHO chains
Sialic acid 14 sialic acid residues 22 sialic acid residues
Molecular weight 30,400 daltons 38,500 daltons
Carbohydrates 40% 52%
Plasma half life 4-8 hours 24 hours
15. MECHANISM OF ACTION
Erythropoietin deficiency is the primary
cause of their anemia.
Darbepoetin alpha stimulates
erythropoiesis by the same mechanism
as endogenous erythropoietin.
A primary growth factor for erythroid
development, erythropoietin is
produced in the kidney and released
into the bloodstream in response to
hypoxia.
16. MECHANISM OF ACTION
In respond to hypoxia, erythropoietin
interacts with progenitor stem cells to
increase red blood cell (RBC)
production.
Increased hemoglobin levels are not
generally observed until 2 to 6 weeks
after initiating treatment with
Darbepoetin alpha.
21. INDICATIONS
DARBEPOETIN ALFA is erythropoiesis-stimulating agent (ESA)
indicated for the treatment of anemia due to:
Chronic Kidney Disease (CKD) in patients on dialysis and
patients not on dialysis.
In patients with non-myeloid malignancies where anemia is
due to the effect of concomitantly administered
chemotherapy.
Arensp FDA international pi
22. DOSAGE AND ADMINISTRATION
Recommended starting dose for CKD patients on dialysis :
0.45 mcg/kg intravenously or subcutaneously weekly, or
0.75 mcg/kg intravenously or subcutaneously every 2 weeks
Intravenous route is recommended for patients on hemodialysis
Recommended starting dose for patients with CKD not on dialysis :
0.45 mcg/kg intravenously or subcutaneously at 4 week intervals
Recommended starting dose for cancer patients on chemotherapy :
2.25 mcg/kg subcutaneously weekly, or 500 mcg subcutaneously every 3 weeks
Arensp FDA international pi
23. Ref:PI
Lesser incidence of vascular access thrombosis
CKD : Chronic Kidney Disease
QW: Once weekly Q2W : biweekly TIW : Thrice in a week
FEWER PRICKS FOR BETTER
COMPLIANCE
24. DOSING ADJUSTMENT INSTRUCTION
CKD:
• If Hb does not increase by >1 g/dL after 4 weeks: Increase dose by 25%; do not
increase the dose more frequently than once every 4 weeks
• If Hb increases >1 g/dL in 2-week period: Reduce dose by ≥25%
• Inadequate or lack of response over a 12- week escalation period: Discontinue
therapy
Cancer:
• If Hb does not increase by >1 g/dL after 4 weeks: Increase to 300 units/kg 3
times/week or 60,000 units weekly
• If Hb increases >1 g/dL in 2-week period or exceeds target: Withhold dose and
resume with 25% dose reduction if needed
Inadequate response at 8 weeks: Discontinue Arensp FDA international pi
26. ADVERSE REACTIONS
Patients with CKD: Adverse reactions in ≥ 10% of Darbepoetin-
treated patients in clinical studies were hypertension, dyspnea,
peripheral edema, cough, and procedural hypotension.
Cancer Patients Receiving Chemotherapy: Adverse reactions in ≥ 1%
of Darbepoetin-treated patients in clinical studies were abdominal
pain, edema, and thrombovascular events .
Arensp FDA international pi
27. USE IN SPECIFIC POPULATIONS
Pregnancy category C: Based on animal data, may cause fetal harm.
Pregnancy Surveillance Program is available.
Nursing Mothers: Exercise caution when Darbepoetin is administered to
a nursing woman.
Pediatric Use: Safety and efficacy not established in the initial treatment
of anemic patients with CKD, in the transition from another
erythropoietin in patients with CKD who are less than 1 year of age, or
in pediatric patients with cancer.
Arensp FDA international pi
28. CONTRAINDICATIONS
Uncontrolled hypertension
Pure red cell aplasia (PRCA) that begins after treatment with
darbepoetin alfa or other erythropoietin protein drugs
Serious allergic reactions to darbepoetin alfa
Arensp FDA international pi
29. WARNINGS AND PRECAUTIONS
Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using
Darbepoetin to target a hemoglobin level of greater than 11 g/dL increases the risk
of serious adverse cardiovascular reactions and has not been shown to provide
additional benefit. Use caution in patients with coexistent cardiovascular disease
and stroke.
Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in
Patients With Cancer.
Hypertension: Control hypertension prior to initiating and during treatment
Seizures: increases the risk for seizures in patients with CKD. Increase monitoring of
these patients for changes in seizure frequency or premonitory symptoms.
Arensp FDA international pi
30. CONVERSION FROM EPOETIN ALFA TO
DARBEPOETIN IN PATIENTS WITH CKD ON
DIALYSIS
Due to the longer serum half-life, Darbepoetin alfa is
administered less frequently than epoetin alfa.
Administer darbepoetin once weekly in patients who were
receiving epoetin alfa 2 to 3 times weekly.
Administer darbepoetin once every 2 weeks in patients who
were receiving epoetin alfa once weekly.
Arensp FDA international pi
31. ESTIMATED DARBEPOETIN STARTING DOSES (MCG/WEEK) FOR
PATIENTS WITH CKD ON DIALYSIS BASED ON PREVIOUS EPOETIN
ALFA DOSE (UNITS/WEEK)
Previous weekly epoetin alpha dose (units/week) Darbepoetin alpha dose(mcg/week)
Adult Pediatric
< 1,500 6.25 *
1,500 to 2,499 6.25 6.25
2,500 to 4,999 12.5 10
5000 to 10,999 25 20
11,000 to 17,999 40 40
18,000 to 33,999 60 60
34,000 to 89,999 100 100
≥90000 200 200
Arensp FDA international pi
33. Studies from Europe and United States had shown that
darbepoetin α maintained haemoglobin levels as safely and
effectively as epoetin in dialysis patients at a reduced dosing
frequency and no antibodies to darbepoetin were detected.
34. Comparison between short and long acting ESAs in Hemodialysis patients
Darbepoetin EPO
No. of dose changes
• Hb variability is less frequent with Darbepoetin group with respect to EPO
Group.
• Fewer dose changes in Darbepoetin group compared to EPO Group.
Darbepoetin EPO
Randomized
prospective open label
study
N=139
(Darbepoetin
:72,EPO:67)
Study duration:24
weeks
Int Urol Nephrol 2014 ;46:453–459
Hb : Hemoglobin , ESA Erythropoetin Stimulating Agents
EPO : Erythropoetin
*
CONSISTENT HB LEVEL IN
DIALYSIS PATIENTS
35. STAAR Study
52 weeks multicenter study to access the efficacy of Q2W Darbepoetin in CKD patients who
were on rHuEPO before Darbepoetin but not on dialysis
Hb levels were maintained over 52 weeks without a significant change
in darbepoetin dose
Mean Hb concentrations (±SD) by study week
Mean Q2W darbepoetin alfa dose (±SD) by study week
Subgroup analysis
N=524
Study Duration:52 weeks
Am J Nephrol 2006;26:149–156CKD : Chronic Kidney Disease
CONSISTENT HB LEVEL IN CKD PATIENTS
NOT ON DIALYSIS
36. Comparison between Darbepoetin and Epoetin
for Treatment of Anemia in Hemodialysis Patients
Acta Nephrologica 26(3): 137-142, 2012
37. Darbepoetin at a reduced dosing frequency for treatment of
anemia in chronic renal insufficiency not yet on dialysis
• NESP administered subcutaneously (starting
dose 0.45µg/kg once weekly)
Multicenter,
randomized, open-
label study.
Patients:
• >=18 years, with
a diagnosis of CRI,
• hemoglobin
concentration11.0
g/dL,
• serum vitamin B12
and folate levels
above the lower
limit of the normal
range, and
• a creatinine
clearance of 30
mL/min
Primary measure of
efficacy:
• Proportion of patients
achieving Hb response
during the 24-week
treatment period,
(defined as an increase
in hemoglobin of 1.0
g/dL from baseline and
a hemoglobin
concentration of 11.0
g/dL).
Safety:
• Adverse events,
laboratory variables
(hematology,
biochemistry, and
• iron status), vital signs,
and antibody formation
to NESP or rHuEPO
Kidney International, Vol. 60 (2001), pp. 741–747
Study drug dose was adjusted by 25% of the starting dose as necessary to achieve a hemoglobin increase of 1.0 g/dL from baseline and to maintain
hemoglobin concentrations within a range of 11.0 to 13.0 g/dL.
If a patient’s hemoglobin increased by 2.0g/dL during any four-week period, study drug doses were reduced by 25% of the starting dose.
If a patient’s hemoglobin concentration increased to 14.0 g/dL, study drug was withheld until the hemoglobin concentration fell below 12.0 g/dL and was
restarted at a dose 25% lower than the previous dose.
• rHuEPO administered subcutaneously (starting
dose 50 U/kg twice weekly).
Randomized to receive NESP or rHuEPO in a 3:1
ratio
38. Cont..
Results
A hemoglobin response (defined as an increase of 1.0 g/dL from baseline and a
concentration11.0 g/dL) was achieved by 93% (95% CI, 87 to 97%) of patients
receiving NESP during the 24-week treatment period.
Similarly, 92%(95%CI, 78 to 98%) of patients achieved a response in the rHuEPO
group.
Mean hemoglobin concentrations at
four-week intervals.
The shaded area indicates target range.
Symbols are the patients receiving:
(DOT) recombinant human erythropoietin
(rHuEPO);
(Triangle) novel erythropoiesis
stimulating protein (NESP).
Abbreviations are:
E, number of patients receiving rHuEPO;
N, number of patients receiving NESP.
41. Darbepoetin alfa administered once monthly (QM) maintains Hb
concentrations in patients with CKD.
OBJECTIVE: To evaluate the effect of extending the darbepoetin alfa dosing interval to once
monthly in patients with chronic kidney disease (CKD) not receiving dialysis.
PATIENTS AND METHODS:
• Mlticenter, open-label study of 97 patients with CKD
ND.
• Patients receiving stable subcutaneous doses of
darbepoetin alfa once every two weeks were converted
to once monthly for 29 weeks.
• The proportion of patients who successfully maintained
hemoglobin concentrations between 10.0 and 12.0 g/dl
and the mean dose were evaluated.
• Safety measurements (e.g. adverse events, laboratory
parameters, blood pressure) and sero-reactivity were
assessed.
RESULTS:
• Hemoglobin concentration was maintained within
the target range in 79% of all patients receiving
darbepoetin alfa and in 85% of patients who
completed study period.
• The safety profile for monthly darbepoetin alfa
administration was comparable with that previously
observed with more-frequent administration.
CONCLUSION: Patients with CKD who are clinically stable on darbepoetin alfa administered
once every two weeks can be safely and effectively converted to darbepoetin alfa administered
once monthly. Clin Nephrol. 2005 May;63(5):327-34.
42. Darbepoetin alfa administered once monthly for the
maintenance of Hb concentrations in patients with CKD-
OBJECTIVE: To demonstrate the efficacy and safety of once-monthly (QM) darbepoetin alfa administration in
maintaining haemoglobin (Hb) 11.0-13.0 g/dL in subjects with chronic kidney disease (CKD) not receiving dialysis
and previously treated with darbepoetin alfa every other week (Q2W).
SUBJECTS: Open-label study
subjects >=18 years of age
GFR >=15 and <=60 Ml/min/1.73 m(2), had Hb 11.0-
13.0 g/dL, and were receiving Q2W darbepoetin alfa.
DESIGN:
Subjects were switched to QM darbepoetin alfa
therapy for 28 weeks; the QM dose was titrated to
maintain Hb levels.
Primary end-point: proportion of subjects maintaining
Hb > or =11.0 g dL(-1) during the final 8 weeks of the
study (evaluation phase).
Secondary end-points:
Hb concentration during evaluation, darbepoetin alfa
dose during the study, adverse events, laboratory
parameters, and blood pressure.
RESULTS:
• Mean Hb >=11.0 g/dL (during evaluation was achieved by
76% of the 150 subjects who received at least one dose of
darbepoetin alfa
• Mean (SD) Hb during evaluation was 11.71 (0.92) g/dL.
• 85% of 129 subjects who completed the study had Hb
>=11.0 g/dL during evaluation.
• The dose of darbepoetin alfa over the study period was
124.4 mug.
CONCLUSION: Darbepoetin alpha administered QM maintained Hb in patients
with CKD not receiving dialysis.
J Intern Med. 2006 Dec;260(6):577-85
43. High target hemoglobin with ESAs has advantages in the renal
function of CKD-ND patients.
OBJECTIVE: We investigated the long-term effects of maintaining high hemoglobin (Hb) on renal function in
patients with chronic kidney disease not on dialysis.
SUBJECTS:
• Hb < 10 g/dL and serum creatinine (Cr) 2-6
mg/dL)
• Randomized to either
• a high Hb group (N = 161, 11.0 ≤ Hb <
13.0 g/dL) receiving darbepoetin alfa or
• a low Hb group (N = 160, 9.0 ≤ Hb < 11.0
g/dL) with epoetin alfa,
• Stratified according to baseline Hb and
serum Cr levels, comorbidity of diabetes,
and study centers.
• Primary endpoints: doubling of serum Cr,
initiation of dialysis, renal transplantation, or
death.
RESULTS:
• Three-year cumulative renal survival rates were 39.9% and 32.4%
in the high and low Hb groups, respectively.
• The estimated hazard ratio for the high versus the low Hb group
was 0.71, the risk reduction was 29% in the high Hb group.
• Incidences of serious adverse cardiovascular events did not differ
significantly between the high and low Hb groups (3.1% and 4.4%,
respectively).
• No safety issues were noted in either group.
CONCLUSION: Maintaining higher Hb levels with darbepoetin alfa better preserved renal
function in patients with chronic kidney disease not on dialysis.
Ther Apher Dial. 2012 Dec;16(6):529-40
46. ANEMIA POST RENAL
TRANSPLANT
Darbepoetin alfa has also been evaluated as a treatment option for anemia
after transplantation.
Pankewycz and colleagues in a prospective study have shown correction of
anemia in 60% post transplant patients at 3 months.
A retrospective study (n=129) demonstrated that Administering darbepoetin
alfa in the first week following renal transplant reduces anaemia incidence
during the first month without increase cardiovascular events.
47. ANEMIA POST RENAL
TRANSPLANT
In a small study (n=20) subcutaneous darbepoetin alfa 200μg was given every
2 weeks to the patients with post stem-cell transplantation anemia.
Darbepoetin was found to be effective without any major safety concerns.
In an observational, single centre study among renal transplant patients,
darbepoetin corrected anemia both in previously treated as well as EPO naïve
patients. It was found to be well tolerated.
48. COMPARISON WITH CERA
20 CKD patients at the pre-dialysis stage who had been administered DA for over
24 weeks were randomly assigned to receive subcutaneous CERA or DA once
every four weeks during 48 weeks.
In both groups, the rate of achievement of target Hb level changed from 70% to
100% in weeks 0 to 48, with no significant difference between the groups.
There was no significant difference in the levels of estimated glomerular filtration
rate and iron status between both groups.
Results suggest that subcutaneous administration of DA or CERA once every four
weeks to predialysis patients has similar effects on achievement of target Hb levels
50. POINTS TO REMEMBER
Efficacious in patients converting from previous once-weekly (QW)
erythropoietic therapy with recombinant human erythropoietin(rHuEPO),
and in those naive to erythropoietic therapy.
Less dosage frequency compared to rHuEPO due to threefold longer serum
half life and greater biological activity.
More preferred for “pre-dialysis” and “maintenance therapy” in CKD Patients
with anemia.
51. POINTS TO REMEMBER
It gives slow and steady rise in Hb and maintains target levels while EPO
gives fast rise.
Increases convenience & better treatment compliance
Recently published cochrane review concluded that CERA has little or no
effects on patient-centred outcomes compared with darbepoetin alfa for
adults with CKD.
52. The only place success comes before
work is in a dictionary…!