DR ANJANI KUMAR JHA,NOMC,NEPAL

1. CHRONIC KIDNEY
DISEASE AND
ANEMIA
Dr. Anjani kumar Jha
PG Resident, Dept. of internal medicine
Nobel Medical College Teaching Hospital..

2. Contents:
• Epidemiology and pathogenesis
• Clinical manifestations
• Laboratory evaluation
• Erythropoiesis stimulating agents
• Pure red cell aplasia
• Target hemoglobin level
• New agents
• Iron therapy
• Resistance to erythropoiesis stimulating agents and adjuvant
therapy
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3. Epidemiology:
• WHO :(Hb) concentration of less than 13.0 g/L in adult
men and nonmenstruating women, and less than 12.0 g/dl
in menstruating women
• The incidence of anemia in patients with chronic kidney
disease (CKD) increases as the glomerular filtration rate
(GFR) declines.
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4. • Population studies including the united states national health
and nutrition examination survey(NHANES) and the
prevalence of anemia in early renal insufficiency(PAERI)
study suggests that the incidence of anemia is less than 10% in
ckd stages1 and 2, 20 to 40% in ckd satge 3, 50 to 60% in ckd
stage 4 and more than 70% in ckd satge 5.
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5. pathophysiology
• Factors that contributes to the anemia in ckd:
1. Insufficient production of endogenous EPO
2. Iron deficiency
3. Acute and chronic inflammatory conditions
4. Severe hyperparathyroidism
5. Aluminum toxicity
6. Folate deficiency
7. Decreased survival of RBCs
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6. EPO
• contribution of erythropoietin (EPO) deficiency becomes greater as
GFR declines.
• HIF leads to signal transduction and the synthesis of EPO.
• loss of EPO production in the setting of CKD is the primary cause
of anemia in these patients.
• The absence of EPO causes these cells to undergo programmed
death or apoptosis, which is mediated by Fas ligand.
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9. Clinical manifestations:
• Fatigue both with exercise and at rest.
• Decreased cognitive function, loss of libido and decreased sense of
well being(syptomatic if hb less than 10 percent)
• contribute to the adverse cardiovascular morbidity and mortality
outcomes observed among patients with CKD.
• Anemia may lead to an exacerbation of angina because of
decreased myocardial oxygen delivery.
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10. Contd..
• The evidence for inhibition of RBC production by uremic toxins in
patients with CKD is poor
• RBC survival is decreased from 120 days in normal individuals to
60 to 90 days in patients with CKD.
• result of RBC trauma from microvascular disease as well as
decreased resistance to oxidative stress.
• The reduction of EPO in patients with CKD also contributes to
neocytolysis, a physiologic process that leads to hemolysis of the
youngest RBCs in the circulation.
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11. • Decreased peripheral oxygen delivery peripheral vasodilation,
increased sympathetic nervous system activityincreased heart rate and
stroke volumeLVH.
• decrease in Hb of 0.5 g/dl below normal correlates with a 32% increase
in LVH risk, whereas a 5 mm Hg increase in systolic blood pressure
correlates with only an 11% increase in LVH risk.
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12. •Diagnosis and evaluation of anemia in
CKD
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13. Frequency of testing for anemia
• For CKD patients without anemia ; Measure Hb concentration
when clinically indicated and:
1.at least annually in patients with CKD 3
2.at least twice per year in patients with CKD 4–5ND
3.at least every 3 months in patients with CKD 5HD and CKD
5PD
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14. Contd…
• For CKD patients with anemia not being treated with an ESA,
measure Hb concentration when clinically indicated
1.at least every 3 months in patients with CKD 3–5ND and CKD
5PD
2.at least monthly in patients with CKD 5HD
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15. Diagnosis of anemia
• Diagnose anemia in adults and children >15 years with CKD when
the Hb concentration is <13.0 g/dl (<130 g/l) in males and <12.0
g/dl (<120 g/l) in females.
• Diagnose anemia in children with CKD if Hb concentration is
<11.0 g/dl (<110 g/l) in children 0.5–5 years,<11.5 g/dl (<115 g/l)
in children 5–12 years, and <12.0 g/dl (120 g/l) in children 12–15
years
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16. Investigation of anemia
• In patients with CKD and anemia (regardless of age and CKD stage),
include the following tests in initial evaluation of the anemia :
1.Complete blood count (CBC), which should include Hb
concentration, red cell indices, white blood cell count and differential,
and platelet count
2.Absolute reticulocyte count
3.Serum ferritin level
4.Serum transferrin saturation (TSAT)
5.Serum vitamin B12 and folate levels
6.crp
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17. In some selected cases:
• Hb electrophoresis
• Plasma/serum/ or urine protein electrophoresis
• Free light chains and bone marrow examiantion.
• Tests for hemolysis(haptoglobins,LDH,billirubin,coomb’s test)
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18. • The serum ferritin level correlates with iron bound to tissue ferritin in RE system.
• TSAT is a measure of circulating iron available for the delivery to the erythroid
marrow and is calculated by dividing the serum iron concentration by the total iron
binding capacity.
• TSAT < 16% in an anemic pts with ckd is consistent with absolute or functional iron
deficiency both of which are characterized by decreased delivery of iron to the
erythroid marrow.
• Absolute iron deficiency occurs in the setting of decreased total body iron stores and
is accompanied by serum ferritin less than 25ng/ml in men and less than 12ng/ml in
women.
• Functional iron deficiency anemia is seen in patients with low TSAT and normal or
elevated serum ferritin.
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19. Use of iron to treat anemia in CKD
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20. • Iron deficiency frequently coexists with EPO deficiency as a cause of anemia in
nondialysis CKD and it almost universally develops in pts treated with hemodialysis
because of blood losses in the extracorporeal circuit, frequent blood testing, oozing
from vascular access sites after dialysis needles are withdrawn, and vascular access
procedures.
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21. TREATMENT WITH IRON AGENTS
• When prescribing iron therapy, balance the potential
benefits of avoiding or minimizing blood transfusions,
ESA therapy, and anemia-related symptoms against the
risks of harm in individual patients (e.g., anaphylactoid
and other acute reactions, unknown long-term risks).
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22. TREATMENT WITH IRON AGENTS
• For adult CKD patients with anemia not on iron or ESA therapy it’s
suggested a trial of IV iron (or in CKD ND patients alternatively a
1–3 month trial of oral iron therapy)if
1.an increase in Hb concentration without starting ESA treatment
is desired and
2.TSAT is =or<30% and ferritin is = or < 500 ng/ml (= or < 500
mg/l)
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23. TREATMENT WITH IRON AGENTS
• For adult CKD patients on ESA therapy who are not receiving iron
supplementation, suggestion is a trial of IV iron (or in CKD ND
patients alternatively a 1–3 month trial of oral iron therapy) if:
1.an increase in Hb concentration or a decrease in ESA dose is
desired and
2.TSAT = if < 30% and ferritin is = or <500 ng/ml (= or < 500
mg/l)
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24. TREATMENT WITH IRON AGENTS
• For CKD ND patients who require iron supplementation, select
the route of iron administration based on
• The Severity Of Iron Deficiency,
• Availability Of Venous Access,
• Response To Prior Oral Iron Therapy,
• Side Effects With Prior Oral Or IV Iron Therapy,
• Patient Compliance,
• Cost.
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25. TREATMENT WITH IRON AGENTS
• Guide subsequent iron administration in CKD patients based
on:
1. Hb responses to recent iron therapy,
2. Ongoing blood losses,
3. Iron status tests (TSAT and ferritin),
4. Hb concentration,
5. ESA responsiveness
6. ESA dose in ESA treated patients, trends in each parameter,
7. The patient’s clinical status
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26. TREATMENT WITH IRON AGENTS
• For all pediatric CKD patients with anemia not on iron or ESA
therapy, recommendation is oral iron (or IV iron in CKD HD
patients) administration when TSAT is = or< 20% and ferritin is =
or <100 ng/ml .
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27. TREATMENT WITH IRON AGENTS
• Oral agents:
• Minimal dose to repair iron deficit: 200mg elemental iron daily
• Ferrous sulphate 325 mg tablet contains ’65mg elemental iron’
• Ferrous fumarate 325 mg tablet contains ’100mg elemental iron’
• Ferrous gluconate 325mg tablet contains ’39 mg elemental iron’
• Oral polysaccharide iron complex : ‘150 mg elemental iron’
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28. TREATMENT WITH IRON AGENTS
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29. IRON STATUS EVALUATION
• Evaluate iron status (TSAT and ferritin) at least every 3 months
during ESA therapy, including the decision to start or continue iron
therapy.
• Test iron status (TSAT and ferritin) more frequently:
1. when initiating or increasing ESA dose,
2. when there is blood loss,
3. when monitoring response after a course of IV iron,
4. circumstances where iron stores may become depleted.
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30. CAUTIONS REGARDING IRON THERAPY
• When the initial dose of IV iron dextran is administered and when
the initial dose of IV non dextran iron is administered; patients
should be monitored for 60 minutes after the infusion.
• Resuscitative facilities (including medications) and personnel
trained to evaluate and treat serious adverse reactions be available.
• Avoid administering IV iron to patients with active systemic
infections
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31. •Use of ESAs and other agents to treat anemia
in CKD
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32. ESA INITIATION
• Address all correctable causes of anemia (including iron deficiency
and inflammatory states) prior to initiation of ESA therapy.
• In initiating and maintaining ESA therapy, balancing the potential
benefits of reducing blood transfusions and anemia-related against
the risks of harm in individual patients (e.g., stroke, vascular access
loss, hypertension).is recommended.
• ESA therapy with great caution, if at all, in CKD patients with
active malignancy—in particular when cure is the anticipated
outcome;a history of stroke or a history of malignancy
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33. ESA INITIATION
• For adult CKD ND patients with Hb concentration > OR =10.0 g/dl ;
ESA therapy RECOMMENDED not to be initiated.
• For adult CKD ND patients with Hb concentration < or = 10.0 g/dl;it is
suggested that the decision whether to initiate ESA therapy be
individualized based on:
1. The rate of fall of hb concentration,
2. Prior response to iron therapy,
3. The risk of needing a transfusion,
4. The risks related to ESA therapy,
5. The presence of symptoms attributable to anemia.
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34. ESA INITIATION
• For adult CKD 5D patients, it is suggested that ESA therapy be
used to avoid having the Hb concentration fall below 9.0 g/dl (90
g/l).
• Individualization of therapy is reasonable as some patients may
have improvements in quality of life at higher Hb concentration
and ESA therapy may be started above 10.0 g/dl (100 g/l).
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35. ESA INITIATION
• For all pediatric CKD patients, it’s suggested that the selection of
Hb concentration at which ESA therapy is initiated in the
individual patient includes consideration of potential benefits (e.g.,
improvement in quality of life, school attendance/performance, and
avoidance of transfusion) and potential harms
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36. ESA MAINTENANCE THERAPY
• In general, suggestion is that ESAs not be used to maintain Hb
concentration above 11.5 g/dl (115 g/l) in adult patients with CKD.
• Individualization of therapy will be necessary as some patients may
have improvements in quality of life at Hb concentration above
11.5 g/dl (115 g/l) and will be prepared to accept the risks.
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37. ESA MAINTENANCE THERAPY
• In all adult patients, it’s recommended that ESAs not be used to
intentionally increase the Hb concentration above 13 g/dl (130 g/l).
• In all pediatric CKD patients receiving ESA therapy, we suggest
that the selected Hb concentration be in the range of 11.0 to 12.0
g/dl
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38. ESA DOSING
• It recommended determining the initial ESA dose using the patient’s Hb
concentration, body weight, and clinical circumstances
• It’s recommended that ESA dose adjustments be made based on :
1.Hb concentration,
2.Rate of change in hb concentration,
3.Current ESA dose and
4.Clinical circumstances.
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39. • It suggested that decreasing ESA dose in preference to withholding
ESA when a downward adjustment of Hb concentration is needed.
• Re-evaluate ESA dose if :
1. The patient suffers an ESA-related adverse event
2. The patient has an acute or progressive illness that may cause
ESA hyporesponsiveness
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40. ESA ADMINISTRATION
• For CKD 5HD patients and those on hemofiltration or
hemodiafiltration therapy, it’s suggested that either intravenous or
subcutaneous administration of ESA.
• For CKD ND and CKD 5PD patients, it’s suggested that
subcutaneous administration of ESA.
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41. FREQUENCY OF ESA ADMINISTRATION
• The frequency of ESA administration SHOULD based on
1. CKD stage,
2. Treatment setting,
3. Efficacy considerations,
4. Patient tolerance
5. Preference,
6. Type of ESA.
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42. TYPE OF ESA
• It recommended that choosing an ESA based on the balance of
pharmacodynamics, safety information, clinical outcome data,
costs, and availability.
• It recommended that using only ESAs that have been approved by
an independent regulatory agency.
• Specifically for ‘copy’ versions of ESAs, true biosimilar products
should be used
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43. ESA
GENERIC NAME DOSING FREQUENCY STARTING DOSE
EPOETIN 3 times weekly iv in HD patient;every1-2 Scweeks
in ND/PD
50U/Kg based on 3 times weekly
dosing
DARBEPOETIN Every 1-2 weeks iv/sc in ESRD; every 4 weeksSC in
ND pts.
0.45mcg/kg weekly or 0.75mcg/kg
every 2wks in ESRD;0.45mcg/kg
every 4 weeks in ND
METHOXYPOLYTHYLEN
EGLYCOLEPOTOEIN
BETA
Initiation every two weeks:maintenance monthly IV
in HD; SC in ND/PD
0.6mcg/kg every 2 weeks;monthly
when Hb is stable at twice the every
2 weeks dose
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46. Frequency of monitoring
• During the initiation phase of ESA therapy, measure Hb
concentration at least monthly.
• For CKD ND patients, during the maintenance phase of ESA
therapy measure Hb concentration at least every 3 months
• For CKD 5D patients, during the maintenance phase of ESA
therapy measure Hb concentration at least monthly.
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48. RECENT ADVANCE:
• NOVEL ANEMIA TREATMENTS UNDER DEVELOPMENT INCLUDE AGENTS
THAT POTENTIATE HIF ACTIVITY BY INHIBITING THE
PROLYLHYDROXYLASE ENZYME THAT NORMALLY DEGRADES HIF.
• This stimulates the production of endogenous EPO even in pts with ESRD suggesting
that significant extrarenal EPO production can be induced. These agents also down
regulate hepcidin production . Moreover these agents are oral .
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49. EVALUATING AND CORRECTING
PERSISTENT FAILURE TO REACH OR
MAINTAIN INTENDED
HEMOGLOBIN CONCENTRATION
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50. Initial 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.
• In patients with ESA hyporesponsiveness, it’s suggested that
avoiding repeated escalations in ESA dose beyond double the
initial weight-based dose.
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51. Subsequent ESA hyporesponsiveness
• Classify patients as having acquired ESA hyporesponsiveness if
after treatment with stable doses of ESA, they require 2 increases
in ESA doses up to 50% beyond the dose at which they had been
stable in an effort to maintain a stable Hb concentrationo.
• In patients with acquired ESA hyporesponsiveness, suggestion is to
avoid repeated escalations in ESA dose beyond double the dose at
which they had been stable.
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52. Management of poor ESA responsiveness
• Evaluate patients with either initial or acquired ESA
hyporesponsiveness and treat for specific causes of poor ESA
response.
• For patients who remain hyporesponsive despite correcting
treatable causes, individualization of therapy, accounting for
relative risks and benefits of:
1. decline in Hb concentration
2. continuing ESA, if needed to maintain Hb concentration, with
due consideration of the doses required, and
3. blood transfusions
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53. ADJUVANT THERAPIES
• Its not recommended for using androgens as an adjuvant to ESA
treatment.
• It suggested not to use adjuvants to ESA treatment including
vitamin C, vitamin D, vitamin E, folic acid,L-carnitine, and
pentoxifylline
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54. EVALUATION FOR PURE RED CELL APLASIA
(PRCA)
• Investigate for possible antibody-mediated PRCA when a patient
receiving ESA therapy for more than 8 weeks develops the
following:
1. Sudden rapid decrease in Hb concentration at the rate of 0.5 to
1.0 g/dl (5 to 10 g/l) per week OR requirement of transfusions at
the rate of approximately 1 to 2 per week, AND
2. Normal platelet and white cell counts, AND
3. Absolute reticulocyte count less than 10,000/ml
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55. EVALUATION FOR PURE RED CELL APLASIA
(PRCA)
• Recommendation is that ESA therapy be stopped in patients who
develop antibody-mediated PRCA.)
• Peginesatide can be used to treat patients with antibody-mediated
PRCA.
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56. •RED CELL TRANSFUSION TO TREAT ANEMIA
IN CKD
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57. USE OF RED CELL TRANSFUSION IN CHRONIC
ANEMIA
• When managing chronic anemia, its recommended avoiding, when
possible, red cell transfusions to minimize the general risks related
to their use.
• In patients eligible for organ transplantation, its specifically
recommended avoiding, when possible, red cell transfusions to
minimize the risk of allosensitization.
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58. USE OF RED CELL TRANSFUSION IN CHRONIC
ANEMIA
• When managing chronic anemia, its suggested that the benefits of
red cell transfusions may outweigh the risks in patients in whom:
1. ESA therapy is ineffective (e.g., hemoglobinopathies, bone
marrow failure, ESA resistance)
2. The risks of ESA therapy may outweigh its benefits (e.g.,
previous or current malignancy, previous stroke)
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59. USE OF RED CELL TRANSFUSION IN CHRONIC
ANEMIA
• Decision to transfuse a CKD patient with non-acute anemia should
not be based on any arbitrary Hb threshold.
• Should be determined by the occurrence of symptoms caused by
anemia.
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61. URGENT TREATMENT OF ANEMIA
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62. Anaemia of CKD: Post Transplant Anaemia
• Factors causing anemia:
1. Gfr
2. Immunosupressive MMF Azathioprine calcinerin inhibitors
3. Acei/ARBS
4. rejection
5. Antibiotics:TMP_SMX Gangciclovir
6. Viral infection: CMV parvo B19
7. Malignancy
8. Chronic inflammation
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63. Anaemia of CKD: Post Transplant Anaemia
• The treatment guidelines for anaemia in renal transplant patients
should be similar to those for CKD patients not on dialysis.
• Correcting anaemia in transplant patients reduces the rate of
decrease of renal function and reduces the number of grafts lost
• Studies in the early post-transplant period have shown that ESA is
effective in these patients.
• Studies in late post-transplant period have shown efficacy of ESA
in these patients
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64. References:
• KDIGO Clinical Practice Guideline for Anaemia in Chronic
Kidney Disease. Kidney Int Suppl 2012; 2:279-335.
• Mikhail et al:Clinical Practice Guideline Anaemia of Chronic
Kidney Disease.BMC Nephrology (2017) 18:345.
• Jay B. Wish:Anemia and other hematological complications of
ckd;editors et al;National kidney foundation primer on kidney
disease 7th edn : elsveir publication:515-524.
• Fishbane S, Spinowitz B. Update on anemia in ESRD and earlier
stages of CKD: core curriculum 2018. American Journal of Kidney
Diseases. 2018 Mar 1;71(3):423-35.
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