anemia in CKD

how is anemia defined in CKD for males?

HBG < 13 g/dL

how is anemia defined in CKD for females?

HGB < 12 g/dL

goals of therapy for anemia in CKD:

increase oxygen-carrying capacity, improve quality of life, prevent/alleviate symptoms and complications of anemia, decrease the need for blood transfusion

where is 90% of the circulating erythropoietin (EPO) produced in healthy patients?

kidney

EPO stimulates the _________ and _______ of erythroid progenitor cells in response to hypoxia

proliferation, differentiation

what are some factors that decrease oxygenation?

low blood volume, anemia, low hemoglobin, poor blood flow, and pulmonary disease

where are oxygen levels detected in the kidneys?

peritubular interstitial cells

what are immature RBCs called?

reticulocytes

when the peritubular interstitial cells detect low oxygen levels in the blood what is secreted into the blood?

erythropoietin

T/F: RBC have a shortened lifespan in CKD patients

true

when does anemia begin to develop in CKD?

when GFR declines to < 45 mL/min/1.73m2

what type of anemia typically occurs in CKD? (normocytic, macrocytic, microcytic)?

normochromic normocytic

when is anemia not normocytic?

if there is iron, folate, or B12 deficiency

what does a red blood cell count tell us?

the number of RBC’s

what does hemoglobin tell us on labs?

the oxygen carrying capacity of RBCs

what does hematocrit tell us?

the percent of blood volume occupied by RBCs

what does mean cell volume tell us?

the average size of RBCs (decreased in iron deficiency)

what does reticulocyte tell us?

the amount of immature RBCs that reflects the production of RBCs (erythropoiesis)

what does serum iron mean?

the iron bound to transferrin

what is serum ferritin?

the storage form of iron

what is the total iron binding capacity?

the capacity of transferrin to bind iron

what is transferrin saturation?

reflects iron available for immediate erythropoieisis

what is the role of iron?

essential factor for biosynthesis of hemoglobin

where is most of our iron located?

in the bone marrow (~1800 mg)

what is hepcidin?

a hormone that regulates irone levels

why is there less iron mobilization in CKD patients?

hepcidin is eliminated via the kidneys which leads to less iron mobilization

what occurs when there are low hepcidin levels?

promotes the uptake of iron and an increase in ferroportin activity which enhances iron export from cells into the plasma

what occurs when there are high hepcidin levels?

reduced iron absorption and traps the iron within the cells by degrading ferroportin

examples of iron-exporting cells:

duodenal enterocytes, macrophages, and hepatocytes

what is the most common cause of erythropoietin resistance?

iron deficiency

what must be corrected first prior to using erythropoietin so hemoglobin production is adequate and included in RBCs?

iron deficiency

when should iron panel be monitored for dialysis patients or patients receiving ESA for anemia?

every 3 months

how long does it take to increase reticulocyte count with iron supplementation?

7-14 days

how long does it take to increase HGB and HCT with iron supplementation?

3-4 weeks

what are the goals of iron therapy?

TSat > 30% and serum ferritin > 500 ng/mL

when should IV iron be held?

if TSat > 50% or ferritin > 1200ng/mL

when to check HGB and HCT in iron therapy?

weekly

when should you check TSat and serum ferritin levels?

every 3 months

pearls of oral iron therapy:

poor absorption, GI complications, poor adherence, inexpensive, and slow replenishment of irone stores

pearls of parenteral iron therapy:

expensive, better absorption, rapid replenishment of irone stores, risk of iron overload, infusion reactions, anaphylactic reactions, and avoid IM use (variable absorption, painful, and bleeding risk)

ADRs of oral iron therapy:

GI upset (nausea, cramping, constipation), dark stool, many drug interactions (e.g. calcium carbonate, antacids)

ADRs of IV iron therapy:

dyspnea/wheezing, itching, myalgias, hypotension, flushing, edema, chest pain, cardiac arrest, injection site reaction, anaphylactoid and anaphylactic reactions, and infections

what is the approximate oral bioavailability of iron?

10-15% regardless of salt form

what is the traditional dosing of oral iron?

200 mg elemental iron/day in divided doses

what are some other oral dosing regimens that have not been studied in CKD patients?

once daily or every other day dosing

pearls of the once daily/every other day dosing of iron:

decreases the rise in hepcidin, increases the relative bioavailability, and may improve compliance and/or reduce GI adverse effects

which drugs decrease the absorption of iron?

Al, Mg, and Ca containing antacids, tetracyclines, H2 antagonists, PPIs, and cholestyramine.

which drugs are affected by iron due to chelation?

fluoroquinolones, levothyroxine, tetracyclines, mycophenolate, methyldopa, and levodopa

oral iron needs what to be absorbed?

gastric acid (ascorbic acid is added to certain preparations)

how far apart should other meds be taken from oral iron?

~2 hours

what type of iron therapy is preferred in dialysis patients?

IV

a 1-3 month trial of oral iron can be used in which patients?

non-dialysis patients - but is based on severity of iron deficiency and severity of anemia

when should IV iron be avoided?

if patient has an active systemic infection

what is the goal TSat from iron therapy in CKD?

>= 30%

what is the goal serum ferritin from iron therapy in CKD?

>= 500 ng/mL

what do ESAs promote?

differentiation of erythroid colony-forming units (CFUs) and proerythroblasts

what are the early biomarkers for ESA response?

reticulocytes (1-2 weeks after dose initiation)

how long does it take to see response of HGB within mature RBCs from ESAs?

4-6 weeks

brand name of epoetin alfa

Epogen

brand name of darbepoetin alfa

Aranesp

brand of methoxy polyethylene glycol epoetin beta

Mircera

brand of epoetin alpha epbx

Retacrit

notes regarding Epogen:

can be given in once weekly doses and SQ uses 20% less drug (cost saving)

notes regarding Aranesp

200:1 conversion from epoetin to darbepoetin, can be given every 2 weeks

notes regarding Mircera

CERA: continuous erythropoietin receptor agonist, longest acting ESA, can be given every 4 weeks

notes regarding Retacrit

Biosimilar of Epogen, 1:1 dose conversion to Epogen, 33% costs Savings

what is the goal change in HGB for ESAs

1-2 g/dL/month

when can dose adjustments be made for ESAs

at 4 weeks (steady-state)

When should you reduce the ESA dose by >= 25%

as the patient’s HGB approaches 12 g/dL or if HGB increases >1 g/dL in 2 weeks or less

When should you increase the ESA dose by >= 25%

if HGB is below target after 4 weeks of treatment

What is hyporesponsiveness to ESAs

No increase in HGB after first month of appropriately dosed ESA or two ESA dose increases after stable period to maintain HGB

what is resistance to ESAs?

failure to achieve to target HGB at a dose of >500 units/kg/week

Causes of ESA resistance:

iron deficiency, ACEi, hyperparathyroidism, aluminum toxicity, folate and/or vitamin B12 deficiency, infection, malignancy, trauma, inflammation

ESA adverse effects:

HTN, hypercoagulability (increased risk of thrombosis), HS rxns, PRBCA (pure red blood cell aplasia), headache, fatigue, edema, progression of malignancy

what is the BBW for ESAs in CKD?

greater risks for death, serious adverse cardiovascular reactions, and stroke when administered agents to a target hemoglobin level of greater than 11 g/dL

T/F: ESAs have not been shown to improve quality of life, fatigue, or patient well-being

true

when do you need to monitor HCT/HGB when initiating ESAs?

2x a week

when do you need to monitor BP when initiating ESAs?

3x a week

when do you need to monitor ferritin when initiating ESAs?

monthly

when do you need to monitor TSat when initiating ESAs?

monthly

when do you need to monitor serum chemistries including CBC with diff, BUN/Cr, potassium, and phosphorus when initiating ESAs?

2x a month

when do you need to monitor reticulocytes when initiating ESAs?

once a week

when do you need to monitor HCT/HGB when in the maintenance phase of ESA treatment?

1-2 x a month

when do you need to monitor BP when in the maintenance phase of ESA treatment?

3x a week

when do you need to monitor ferritin when in the maintenance phase of ESA treatment?

quarterly

when do you need to monitor TSat when in the maintenance phase of ESA treatment?

quarterly

when do you need to monitor serum chemistries including BCB with diff when in the maintenance phase of ESA treatment?

once a month

when do you need to monitor reticulocytes when in the maintenance phase of ESA treatment?

quarterly

ESA goals of therapy:

prevent blood transfusions and improve quality of life

ESA clinical pearls:

DO NOT IMPROVE MORTALITY! 200 units of epoetin = 1 mcg darbepoetin (300:1 also used), can be administered IV or SQ

when should ESAs not be used?

active malignancy, high risk of CVA, or HGB > 11 g/dL

when are packed red blood cells (PRBCs) typically given?

when severe anemia occurs (HGB < 7 g/dL)

every 1 unit of PRBC = ___________ increase of HGB

1 g/dL

every 1 unit of PRBC contains ~ ________ elemental iron

200 mg

what are the risks of blood transfusions?

TRALI (transfusion-related acute lung injury), hypervolemia, hypocalcemia, HS rxn, immune activation (problematic for renal transplant candidates)

which vitamins are depleted with dialysis and should be supplemented?

water soluble (B, C, and folic acid)

Examples of vitamin supplementation in dialysis:

Nephrovite, Nephrocaps, Rena-Vite

how do HIF-PH inhibitors work for anemia in CKD?

work to stabilize hypoxia inducible factor (HIF) by inhibiting prolyl hydroxylase (PH) enzymes which promotes HIF accumulation and stimulates endogenous EPO and RBC formation

HIF-PH inhibitor impact on iron utilization:

decreases hepcidin, increases iron absorption, and improves functional iron deficiency

what are the HIF target genes?

vascular (VEGF), erythropoietin (EPO) production/receptor, DMt1 (iron absorption), transferrin receptor (iron uptake), reduce hepcidin (liver), and cellular metabolism (anaerobic glucose)