ANEMIA IN CHRONIC KIDNEY DISEASE

Dr Sariu AliMedical Officer

Supervisor: Dr Ibrahim Shiham MBBS,MD,DM Nephrology

Contents Definition of CKD Stages of CKD Definition of anemia in CKD Effects of Anemia in patients with

CKD. Normal Erythropoiesis Causes of anemia in CKD. Evaluation of patients Iron therapy. ESA

Definition of Chronic Kidney

Disease

1. Kidney damage for 3 months with or without decreased GFR, manifest by either:

Pathological abnormalities; or

Markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests.

2. GFR <60 mL/min/1.73m2 for 3 months

Stages of CKD Stage GFR

(ml/min/1.73m2)

Description

1 > 90 Normal or increased GFR, with other evidence of kidney damage

2 60–89 Slight decrease in GFR, with other evidence of kidney damage

3a 45–59 Moderate decrease in GFR, with or without other evidence of kidney damage3b 30–44

4 15–29 Severe decrease in GFR, with or without other evidence of kidney damage

5 < 15 Established renal failure

Diagnosis should be on the basis of evidence of CKD for ≥ 3 months

Defining anaemia in CKDAge or gender group Hb below

(g/dl)

Children

6 months to 5 years 11.0

5 to 11 years 11.5

12 to 14 years 12.0

Women > 15 years

(non-pregnant)

12.0

Men > 15 years 13.0

Hb cut-off levels – World Health OrganizationKDIGO 2011

Effects of anemia (QOL)• QUALITY OF LIFE:

o Anemia results in poorer quality of life in patients with renal failure.

o This correlation can be proven by the poor quality of life scores in patients with lower Hb values.

o Many observational as well as RCT have positively demonstrated that the QOL scores improved in patients who were given ESA and iron to increase their Hb

Effects of anemia(mortality)• Generation of hypoxia due to anemia is poorly

tolerated in patients with preexisting cardiac and vascular diseases. Compensatory mechanisms leads to development of LVH.

• Observational studies do show an increase in mortality in patients with CKD but not direct casualty.

• Interventional studies (DOPPS) show that for an increase of 1g/dL of Hb results in 4% decline in mortality.

• Also, Medicare data show that CKD=100% and CKD+Anemia=270% in 2-yr mortality risk.

EFFECTS of anemia on CV health

• 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

Normal erythropoiesis

This activation promotes increased survival of precursor cells.

Normal Iron cycle

Prevalence of anemia in CKD

68

51.5

-5

WHAT CAUSES ANEMIAIN CHRONIC KIDNEY DISEASE?

Relative Erythropoietin (EPO) deficiency

Iron deficiency Blood loss Shortened red cell life span Vitamin deficiencies The “uremic milieu” /Bone marrow

suppression Inflammation Hyperparathyroidism

Unfortunately, we know little about the relative contributions of the different factors and conditions in the early stages of chronic kidney disease.

Relative EPO deficiency• Erythropoietin regulates Erythropoiesis• Glycosylated polypeptide

• 90% produced in the peritubular interstitial Fibroblasts like cells of kideny ,10 % in the liver

• No preformed stores

• Produced in response to low oxygen tension in the tissues of kidneys

CAUSES ANEMIAIN CKD

IDA in CKD • Blood loss from GI tract

• In HD patients : Repeated Blood Loss ; retention of Blood in Dialyzer and blood lines.

• Frequent Blood Sampling for Ix• Loss from Surgical Procedures ( vascular

access) • Interference with absorption due to Meds

( Gastric acid inhibitors ,Phosphate Binders )

Reduced absorption due to inflammation

CAUSES ANEMIAIN CKD

Blood loss

• Risk of blood loss due to platelet dysfunction.

• The main cause of blood loss is

dialysis, especially hemodialysis, and the loss results in absolute iron deficiency.

• Hemodialysis patients may lose 3 to 5 g of iron per year.

CAUSES ANEMIAIN CKD

Shortened red blood cell life span

• The life span of red cells is reduced by approximately one third in hemodialysis patients

CAUSES ANEMIAIN CKD

“uremic milieu”• The “uremic milieu” is a term that is overused in attempts to explain the multiple organ dysfunction of chronic kidney disease.

• In studies in vitro, the term has been invoked when cultured cells were exposed to serum from patients with chronic kidney disease,with results that mimicked some of the clinical observations.

• For example, “uremic” serum has been shown to inhibit primary bone marrow cultures of early erythroid cell lines.

CAUSES ANEMIAIN CKD

Diagnosis and evaluation of anemia in CKD

Age or gender group Hb below (g/dl)

Children

6 months to 5 years 11.0

5 to 11 years 11.5

12 to 14 years 12.0

Women > 15 years(non-pregnant)

12.0

Men > 15 years 13.0

 When estimated glomerular filtration rate ( eGFR ) of less than 60 ml/min/1.73m2 should trigger investigation into whether anaemia is due to CKD

Preliminary investigations:

Complete blood count (CBC), red cell indices, white blood cell count, and differential, and platelet count

Absolute reticulocyte countSerum ferritin levelSerum transferrin saturation (TSAT)Serum vitamin B12 and folate levels

Iron status

Presence or Absence of Storage iron

Serum Ferritin

Availability of iron to support ongoing erythropoiesis

TSAT ;(serum Iron x 100)/TIBC

Use of iron to treat anemia in CKD

Iron supplementation is widely used in CKD patients:

To treat iron deficiencyPrevent its development in ESA treated

patientsRaise Hb levels in the presence or absence of

ESA treatmentReduce ESA doses in patients receiving ESA

treatment.

When to start iron therapy?For adult CKD patients with anemia not on iron or ESA therapy, a trial of IV iron (or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if:

an increase in Hb concentration without starting ESA treatment is desired and

TSAT is <30% and ferritin is <500 ng/ml (<500 mg/l)

For adult CKD patients on ESA therapy who are not receiving iron supplementation, a trial of IV iron(or in CKD ND patients alternatively a 1–3 month trial of oral iron therapy) if :

an increase in Hb concentration or a decrease in ESA dose is desired and

TSAT is <30% and ferritin is <500 ng/ml (<500 mg/l)

• High ferritin levels in some studies have been associated with higher death rates, but whether elevation of ferritin levels is a marker of excessive iron administration rather than a nonspecific acute phase reactant is not clear.

• At increasingly higher ferritin levels, there is some evidence to indicate that hepatic deposition of iron increases

• Routine use of iron supplementation in patients with TSAT >30% or serum ferritin >500 ng/ml (>500mg/l) is not recommended

IV or Oral?

• Available evidence supports an efficacy advantage of IV compared with oral administration of iron although the effect is rather small.

• There is evidence supporting a preference for the IV route of iron administration in CKD 5HD patients

• IV iron administration led to a greater increase in Hb concentration, a lower ESA dose, or both.

• Oral iron is typically prescribed to provide approximately 200 mg of elemental iron daily

(for instance ferrous sulfate 325 mg three times daily; each pill provides 65 mg elemental iron).

Iron therpy• Oral formulations (sulfate, gluconate, fumarate,

polysaccharide complex)• Parenteral (iv) formulations (dextran, gluconate,

sucrose, ferric carboxy maltose).

• In patients with HD-CKD iv formulations are the only form to be used (KDOQI)

• Newer formulations are associated with significantly fewer side effects.

• Iv iron therapy should be guided by the iron status of the patient rather than empirical Rx. Approx 1000mg of Fe over 2-3 weeks is necessary to overcome the deficiency

Monitoring therapy

ESA Therapy

Erythropoietic Stimulating Agents (ESA) Recombinent erythropoietin : Trade names:

Epogen (EPO), Procrit

Darbepoietin alfaTrade name: Aranespo 3x longer half-life and greater biological activity

than recombinant erythropoietin. CERA

• Continuous Erythropoiesis Receptor Activator• A pegylated form of recombinant human

erythropoietin• Has the ability to repeatedly activate the

erythropoiesis receptor

Erythropoietic Stimulating Agents (ESA)

• Future therapies:o EPO mimetics

• Drugs that mimic the action of erythropoietinoShort peptide sequences (14 AA) that

bind to and activate the EPO receptor• Trade name = Hematide

When to start ESA ?

CKD NDHb > 10g/dL - ESA not to be initiated

Hb < 10g/dL - initiation of ESA therapy be individualized

CKD 5D ESA therapy should be initiated when

the Hb is between 9.0–10.0 g/dL

Address all correctable causes of anemia prior to initiation of ESA therapy.

HOW? Epoetin-alfa or epoetin-beta

20 -50 IU/kg three times a week.

(SC) or IV

Darbepoetin-alfa

0.45 mcg/kg once weeklyby subcutaneous

(SC) or IV

0.75 mcg/kg once every 2 weeks

SC

CERA 0.6 mg/kg once every 2 weeks

SC - CKD ND IV - CKD 5D

1.2 mg/kg once every 4 weeks by

SC - CKD ND For CKD 5HD patients and those on hemofiltration or hemodiafiltration therapy,

either IV or SC administration of ESA. For CKD ND and CKD 5PD patients, subcutaneous administration of ESA.

ESA Therapy

TARGET HB LEVEL: • Objective of initial ESA therapy is a rate of increase in (Hb) of

1.0 to 2.0 g/dl (10 to 20 g/l) per month

• Rise in Hb of > 2.0 g/dl (20 g/l) over a 4-week period should be avoided

• Target Hb ; not to exceed > 11.5g/dL

• HB initially monitored weekly , dose adjustment made every 4 weekly.

• Once stable HB achieved , monitor 4 weekly to 3 monthly , or in between any intercurrent illness or symptomatic.

ESA Therapy

DOSE MODIFICATION

If HB level increases by >1gm%/2wks, then reduce dose of EPO by 25%.

If HB level not increases by >1gm%/ mnth , then increase dose of EPO by 25%.

ESA Therapy

ADVERSE EVENTS OF rHuEPO: 

Hypertension,-30% Hypertensive encephalopathy Vascular access failure Increase in pre dialysis CKP ,and potassium Increases risk of stroke in DM type 2.

ESA Therapy

References • Emed • Davidson • Kumar and clark • Harrisons • Anaemia management in chronic kidney disease

NICE clinical guideline 39

Thank you