Lecture 15-18 Anemia in CKD Cho

ETIOLOGY:

DEFINITION:

Anemia = reduction in circulating red cell mass

Not a diagnosis but is an objective sign of disease

Diagnostic terminology requires inclusion of the pathogenesis

HEMATOPOIESIS:

Hematopoiesis begins with the hematopoietic stem cell

Stem cells RBCs, granulocytes, monocytes, PLTs, immune cells

Following lineage commitment, progenitor cells are influenced by growth factors hormones

ERYTHROPOEISIS:

EPO = regulatory hormone for erythropoiesis o Required for maintenance of committed erythroid progenitor cells o Apoptosis occurs without EPO present o EPO stimulation can ↑ RBC production by 4-5 x within 1-2 wk

Pronormoblast = first recognizable RBC precursor in the bone marrow o Mature RBC is 8 um in diameter, anucleate, discoid in shape o Normal RBC production results in the daily replacement of 0.8 – 1% of all circulating

RBCs in the body

90% of EPO is produced & released by peritubular capillary lining cells in the kidneys; small amount (10%) is produced by hepatocytes

↓ availability of O2 = stimulus for EPO production o O2 present hypoxia-inducible factor (HIF-1α) gets hydroxylated degraded via

the proteasome pathway o O2 limited HIF-1α hydroxylation does not occur works with other proteins to

upregulate the EPO gene

In summary, for effective erythropoiesis, one requires: o Adequate EPO production (kidneys)

In CKD, decreasing kidney function hinders EPO production; without adequate EPO production, the process of RBC production is impaired

o Functional bone marrow o Adequate iron

IRON & HEMOGLOBIN:

Provides RBC with their red pigment

Globular molecule consisting of 4 subunits o Each subunit contains an iron-containing

heme moiety conjugated to a polypeptide o 2 pairs of polypeptides in each Hb

molecule (α and β chains) o O2 binds to the Fe2+ in the heme moiety to

form oxyhemoglobin

MECHANISMS OF ANEMIA:

Impaired O2 delivery to kidney caused by: o ↓ RBC mass o Hb defects (impaired O2 loading; excessively high O2 affinity) o Impaired renal blood flow (RAS)

Ambient EPO levels in plasma 10 – 25 U/L

When Hb levels drop below 100 – 120 g/L, plasma EPO levels ↑ logarithmically in proportion to anemia severity

Anemia can be classified in different ways o By elements of erythropoiesis o By alterations in RBC morphology

ANEMIA CLASSIFICATION:

By elements of erythropoiesis o EPO production o Iron availability o Bone marrow function o Effective maturation of RBC precursors

By alterations in RBC morphology o RBC size

(micro, normo, macro -cytic) o Degree of hemoglobinization (normo or

hypo -chromic) o Shape

ANEMIA PREVALENCE IN CKD:

eGFR 60 – 1%

eGFR 30 – 9%

eGFR 15 – 33% men; 67% women

CAUSES OF ANEMIA IN CKD:

Blood loss

EPO deficiency

↓ bone marrow responsiveness to EPO

Shorter RBC life span

Uremia

Vitamin deficiencies

Iron deficiency

Intoxication impairing RBC development

Hemolysis

Chronic inflammation EVALUATION OF ANEMIA:

Thorough history & physical exam

Previous lab work

Transfusion history

Family history

Occupational, environmental, and social histories

Thorough medication history

Timeline o Establish onset of symptoms and

surrounding events o Evolution of sx o Current status

EVALUATION FOR CAUSE OF ANEMIA:

Hematologic indices (Hb, RBC indices, WBC/diff, PLT, retics)

Iron indices (ferritin, TSAT)

Other indices (B12, folate)

Fecal occult blood

CAUSES OF ANEMIA:

Genetic

Nutritional

Hemorrhage

Blood loss

Immunologic

Physical effects

Drugs/chemicals

Infection

Chronic disease

GUIDELINES FOR Hb MONITORING:

CKD pts without anemia CKD 3: at least annually

CKD 4 – 5ND: at least 2x / year

CKD 5D: at least q3 months

CKD pts with anemia not being treated with ESA

CKD 3 – 5ND: at least q3 months

CKD 5PD: at least q3 months

CKD 5HD: at least monthly

CKD pts with anemia and being treated with ESA

During initiation phase of ESA therapy: at least monthly

CKD ND: at least q3 months

CKD 5D: at least monthy

When clinically indicated Clinical sx (fatigue, SOB, chest pain)

Trends of Hb unstable/decreasing

Lecture 15-18 Anemia in CKD Cho

CLINICAL PRESENTATION:

SYMPTOMS:

Can be asymptomatic

Pallor, jaundice

Fatigue, SOB, cold intolerance

Impaired cognitive function

Reduced exercise capacity & QOL

Tachycardia (especially with physical exertion); angina; cardiac dysfunction (LVH); heart failure o Systolic murmurs, pulmonary congestion, ascites, edema o Often not well-tolerated in pts with cardiac disease

Impaired immune response

Decreased survival

COMPENSATORY MECHANISMS

Gradual onset of anemia may not be associated with s/s until the anemia is severe due to compensatory mechanisms

When anemia develops gradually o Total blood volume is normal to slightly decreased o Changes in cardiac output and regional blood flow o Intracellular levels of 2,3-bisphosphoglycerate rise, which promotes O2

unloading near-normal tissue O2 delivery can still occur with a 20-30 g/L drop in Hb

o Blood is shunted away from organs that are relatively rich in O2 supply and non-vital tissues to vital organs

LABORATORY EVALUATION:

COMPLETE BLOOD COUNT (CBC)

RBC Hb = hemoglobin – measured per L of blood

Hct = % of volume of whole blood comprised of RBCs

Reticulocyte count = RBC recently released from the bone marrow (normally 1-2% of RBCs) o Identified via dye that precipitates ribosomal RNA (residual RNA metabolized over 24-36h) o Pt’s reticulocyte count compared with the expected reticulocyte response

Intact EPO & bone marrow: RBC production rate increases 2-3x normal within 10 days following onset of anemia

Inadequate bone marrow response: reticulocyte response < 2-3x normal

RBC indices conversion factors available b/w these parameters

MCV = mean corpuscular volume

MCH = mean corpuscular hemoglobin (measured per cell)

MCHC = mean corpuscular Hb concentration (measured per L of blood)

RDW = red cell distribution width

WBC Differential

Neutrophils

Platelets

Cell morphology (peripheral blood smear)

Hb count

Anisocytosis = variations in cell size

Poikilocytosis = variations in cell shape

Polychromasia = RBCs slightly larger than normal & grayish-blue on Wright-Giemsa stain o RBCs that were prematurely released from bone marrow o In response to EPO stimulation or to architectural damage of bone marrow

Presence of specific cell types

Nucleated RBCs = immature RBCs in circulation

Howell-Jolly bodies = asplenic

Target cells (bull’s eye appearance) = liver disease, thalassemia

Red cell fragmentation = foreign bodies (mechanical heart valves)

Sickle cells (crescent-shaped RBCs)

Spur cells / acanthocytes (irregularly spaced projections) = liver disease, chronic alcoholism, inherited diseases

Burr cells / echinocytes (regularly spaced thorn-like projections) = uremia, low Mg, low PO4, hemolytic anemia

IRON STUDIES

Ferritin Measure of iron studies – reflect total body iron stores o Adult males: 100 ug/L (= total iron 1000 mg); adult females: 30 ug/L (= total iron 300 mg)

Serum ferritin of 10-15 ug/L = depletion of body iron stores

General rule: serum ferritin > 200 ug/L suggests presence of some iron in tissue stores

Acute phase reactant: will increase in inflammation (but not related to actual iron stores)

TSAT Circulating iron that is available for use (TSAT % = serum iron x 100 / TIBC)

TIBC Total transferrin available to bind iron

Iron Level of iron in blood (diurnal variation diurnal variation in TSAT as well)

MARROW EXAM: in select pts where hypoproliferataive anemia is suspected in the presence of adequate iron stores

Aspirate (removal of bone marrow fluid)

M/E (myeloid/erythroid) ratio o 2:1 or 3:1 = hypoproliferative disorder o 1:1 in pt with hemolytic disease = normal proliferation

Cell morphology

Iron stain (stored in form of ferritin or hemosiderin)

Biopsy (removal of bone marrow tissue)

Cellularity

Morphology

Lecture 15-18 Anemia in CKD Cho

MECHANISMS OF IRON DEFICIENCY:

Absolute iron deficiency Functional iron deficiency Inflammatory block

Description Inadequate total body stores of iron

25% of CKD pts

Adequate iron stores

Inability to mobilize iron from storage sites to adequately support erythropoiesis with the administration of ESAs

If untreated absolute iron deficiency

Iron administration fails to increase erythropoiesis, but results in increased ferritin

Caused by inflammation

Be conservative with iron until inflammatory condition has resolved

TSAT < 20% ≤ 20 %

Ferritin Levels

ND/PD: < 100 mcg/L

HD: < 200 mcg/L

100 – 800 mcg/L or higher

PATIENT WORKUP

Normocytic

High retics

Direct Coombs + = autoimmune

hemolysis

Direct Coombs -ve = PNH? DIC? Sickle

cell? G6PD deficiency?

Macrocytic

High retics = hemolysis

Low retics

Chemotherapy related

Serum B12 or folate levels

Normal = myelodysplastic syndrome, liver

disease

Low B12 = malabsorption,

pernicious anemia

Low folate = folate deficiency

Microcytic

Stool guaiac x 3 times

Positive or suspicious = GI

Negative --> check serum ferritin

Low = iron-deficiency anemia

Normal or high ferritin --> check iron,

TIBC

Low iron, high TIBC = iron deficiency

Normal/high iron, normal TIBC = thalassemia

Low iron, low TIBC = anemia of chronic

disease

IRON DEFICIENCY: NON-PHARMACOLOGICAL MANAGEMENT

Maintain adequate dietary intake (only 10% of intake is absorbed)

Debate about whether GI absorption of iron is altered in patients with severe CKD

Once on ESA, iron from dietary sources alone = insufficient to meet iron requirements

MANAGEMENT OF ANEMIA: 1. Management of iron deficiency

Increase iron intake or supplementation

Monitoring serum ferritin, TSAT, and Hb on a regular basis 2. Reverse underlying causes

Bleeding source

EPO deficiency

ESA hyporesponsiveness/resistance

DESIRED OUTCOMES:

↑ O2 carrying capacity

Correct underlying causes of anemia

↑ QOL

↓ need for blood transfusions

Rational use of drug therapy, minimizing ADRs

Lecture 15-18 Anemia in CKD Cho

TREATMENT OF IRON DEFICIENCY: IRON SUPPLEMENTATION:

To replete iron stores and/or maintain adequate iron for transport to bone marrow

MOA: provide elemental iron required for production of Hb incorporated into RBCs increase O2 carrying capacity

Heme vs. non-heme iron o Heme: 40% of iron from meat,

poultry, fish o Non-heme: 60% of iron from meat,

poultry, fish; 100% of iron from plants

Bind to different receptors in GIT – heme iron better absorbed and better tolerated

ORAL VS. PARENTERAL IRON SUPPLEMENTATION:

Oral Parenteral

Advantages Inexpensive

Ease of administration

Good bioavailability

Effective

Allows reduction in ESA dose

Disadvantages Poorly absorbed (10% by duodenum and jejunum)

Poorly tolerated (GI SEs)

PO = placebo for HD patients

Expensive

Potential ADRs (hypotension, muscle pain, anaphylaxis)

Used in CKD ND

CKD PD

CKD HD pts use ONLY IV

CKD ND or PD who don’t tolerate PO or don’t meet iron targets despite max PO

ORAL IRON

Elemental iron Comparison

Ferrous sulfate 20% (60 mg elemental per 300 mg tablet) Effective for iron-deficiency anemia

Generally well tolerated

Low cost

Ferrous gluconate 11% (35 mg elemental per 300 mg tablet)

Ferrous fumarate 33% (100 mg elemental per 300 mg tablet)

Heme-iron polypeptide

11 mg elemental iron per tablet Derived from a food/animal source – Hb extracted from porcine RBCs

More bioavailable than iron salts

Well tolerated

Iron polysaccharide complex

150 mg elemental iron per capsule Ferric iron complexed to hydrolyzed starch, making it tasteless and odorless

Promote to cause less GI irritation (?)

CLINICAL PEARLS:

↑ elemental iron ↑ GI SE o ↑ soluble elemental iron in contact with

stomach & duodenum

SR iron preparations: some evidence they may cause less nausea & epigastric pain BUT may lead to drug being transported past sites of absorption

Once-daily dosing may improve compliance

Food can ↓ absorption by 40-50%

Vitamin C may ↑ absorption o But 500-1000 mg only increases by 10%

DOSE: 100 – 200 mg elemental iron/day at HS (minimize interactions) AEs: NVD, constipation, dark stools, urine discoloration, stomach cramping, dyspepsia DRUG INTERACTIONS: antacids, calcium, cholestyramine, levodopa, methyldopa, quinolones, sodium bicarbonate, tetracyclines FOOD: cereals, dietary fibre, tea, coffee, eggs, milk = decrease absorption Separate iron from these drugs/food by 2-4 hours

IV IRON PRODUCTS (INFUSIONS):

Dose Adverse effects

Iron dextran CKD ND: 500 mg IV over 3-4 h

CKD HD: o Loading: 100 mg qHD x 10 doses o Maintenance: 100 mg 1-2x/month

Angioedema, anaphylaxis = TEST DOSE REQUIRED

CNS: headache, dizziness

RESP: bronchospasm, wheezing, dyspnea

CV: tachy/brady-cardia, arrhythmias, chest pain

OTHER: diarrhea, back pain

Ferric gluconate CKD HD: o Loading: 125 mg qHD x 8 doses o Maintenance: 125 mg 1-2x/month

Angioedema, anaphylaxis

CNS: headache, dizziness

RESP: dyspnea

CV: hypotension

Other: NVD, myalgia

Iron sucrose CKD ND: 200 mg IV x 5 doses (over 14 days)

CKD PD: 300 mg + 300 mg + 400 mg, each dose 14 days apart

CKD HD: o Loading: 100 mg qHD x 10 doses o Maintenance: 100 mg 1-2x/month

Angioedema, anaphylaxis

CNS: headache, dizziness

RESP: bronchospasm

CV: bradycardia, CVS collapse

OTHER: back pain

MONITORING:

Hb, ferritin, TSAT: repeat q3 months

Vital signs: pre/post infusion

Hypersensitivity and AEs: during and post infusion

LONG-TERM SAFETY:

Not well defined

Bacterial infection? Oxidative stress? Inflammation? Acceleration of atherosclerosis? CVS disease?

HOLD IV IRON:

Ferritin level > 1000 mcg/L

Is on IV antibiotics

Appears septic o Fe essential for food and

proliferation of pathogens

IRON OVERLOAD: 1. Amount of iron in body builds up beyond amount required and transferrin becomes saturated 2. Iron binds to other proteins and molecules and is taken up by cells 3. Excess iron chemically interacts with hydrogen peroxide, releasing reactive oxygen species 4. Iron deposition tissue damage, inflammation, fibrosis

Cardiomyopathy, CHF, conduction defects, abnormal LFTs, cirrhosis, diabetes, hypogonadism, decreased libido, impotence, hyperpigmentation, arthropathy

Lecture 15-18 Anemia in CKD Cho

ERYTHROPOIESIS-STIMULATING AGENTS (ESAs)

WHEN TO START ESAs:

Treat all correctable causes of anemia before initiating ESAs

Consider benefits & risks of therapy

Not recommended to start ESA if Hb > 100

CKD ND based on: o Rate of Hb drop o Prior response to iron therapy o Pt’s symptoms of anemia o Risk of needing transfusion o Risks related to ESA therapy

CKD 5D: o Start ESA when Hb 90 – 100 g/L o Avoid having Hb drop < 90 g/L (but should

still use ESA) o Individualize depending on sx and risk of

requiring blood transfusions

Usual Hb target in BC: 95 – 115 g/L

Goal: achieve ↑ Hb 10-20 g/L per month

ESAs: EPOETIN ALFA & DARBOPOETIN ALFA

Epoetin alfa Darbopoetin alfa

Initial dose (BCPRA)

CKD ND: 50 units/kg SC qweekly

HD: 100 units/kg/wk (given 2-3/wk)

PD: 100 units/kg/week (given qweekly)

CKD ND: 0.22 mcg/kg/week (given q2weeks)

CKD HD: 0.45 mcg/kg/wk (given qwkeely)

CKD PD: 0.9 mcg/kg q2weeks

Route CKD ND and PD: SC

HD: usually IV

MOA Induce erythropoiesis by stimulating division & differentiation of progenitor cells

Induce release of reticulocytes from bone marrow bloodstream

Dose adjust

If Hb does not increase by > 10 g/L after 4 weeks: ↑ dose by 25% o Do not increase dose more frequently than once q4wk

If Hb increases > 10 g/L in a 2-week period: ↓ dose by ≥ 25% o Dose reductions CAN occur more frequently than once q4wk

Avoid frequent dosage adjustments – wait min 4 wks b/w adjustments

Inadequate or no response over 12-week escalation period o Use minimum effective dose that will maintain a Hb level sufficient

to avoid RBC transfusions o Evaluate pt for other causes of anemia o D/C therapy if responsiveness does not improve

AEs Stroke, seizure; PE; HTN; thrombosis/DVT; PRCA; tumor progression

Anaphylaxis, allergic reaction

Cancer ESAs may increase risk of tumor growth and decrease survival

Pure red cell aplasia

Neutralizing antibodies to ESAs and endogenous erythropoietin complete resistance to ESA therapy & requires blood transfusions

Associated with SC epoetin alfa but current incidence is rare

Suspect in pts receiving ESA for > 4 weeks who o Develop sudden, rapid drop in Hb (5-10 g/L per week) o Require 1-2 pRBC transfusions / wk (despite ESA therapy) o Normal PLT and WBC o Reticulocyte count < 10,000 uL

DISCONTINUE ESA

Other drugs

Additive risk of adverse effects when used with certain medications

MANAGEMENT IN BC:

Anemia management is protocolized o Bloodwork cycle q4-6 wks o Protocols based on Hb target 95-115 g/L o Advantages:

Transfer responsibility to RN / Rxist Consistency Time & cost

Patients may be excluded from protocol: o Specific clinical situations o Tumor/active cancer/malignancy o Recent stroke o Altered Hb target

EPO HYPORESPONSIVENESS:

Initial: no increase in Hb after 1 month of ESA

Subsequent: after stable on ESA, requires 2 increases in ESA dose up to > 50%

MANY CAUSES

RBC TRANSFUSIONS:

INFECTIOUS RISKS:

Bacterial transmission

Parasitic transmission

Viral transmission FACTORS:

Storage temp of RBC inhibits bacterial growth

Longer RBC storage time increases probability of bacterial contamination

Bacterial contamination presumed to be from asymptomatic donors who have transient bacteremia

NON-INFECTIOUS RISKS OF RBC TRANSFUSION:

Hemolytic transfusion reactions

Febrile non-hemolytic transfusion reactions

Allergic reactions

Transfusion-related acute lung injury o Neutrophils sequestered to lungs as result of surgery, sepsis, severe illness activated by

infusion of Ab damage basement

Transfusion-associated circulatory overload

Post-transfusion purpura o Antibody-mediated destruction of PLT following transfusions

Transfusion-related graft vs. host disease

Iron overload (discussed before in IV iron AEs)

Alloimmunization o Donor-specific anti-HLA Ab transplant graft rejection

Citrate toxicity o Citrate used as anticoagulant in blood products

Hyperkalemia o Leakage of intracellular K from RBCs during storage, as well as lysis of some transfused cells