Anemia, Iron, B12, and Erythropoietin

- tissue hypoxia - free radical formation - endothelial dysfunction - vascular damage

Cardiovascular disease progression due to chronic anemia include:

- Nutritional deficiencies - Decreased red blood cell survival because of uremic toxins - Oxidative stress - Inflammation - The use of angiotensin-converting enzyme (ACE) inhibitors

Causes of Anemia in CKD:

- Nutritional: insufficient B12 intake - Abnormal intragastric events: poor dissociation of food-B12 - Deficient or defective IF (pernicious anemia) - Abnormal events in small bowel: inadequate pancreatic protease, usurping of luminal B12 by bacteria - Disordered mucosa and/or IF receptors and/or trans-enterocytic transport

Causes of Cobalamin (B12) deficiency:

- inadequate erythropoiesis or hemoglobin synthesis - inadequate vitamin B12 from poor nutrition - lack of intrinsic factor from glands of the stomach (pernicious anemia) - iron-deficiency anemia - kidney failure & insufficient erythropoietin hormone

Causes of anemia:

Male: 0.5-1 mg Female: 1-2 mg Children: 25 mg

Daily iron requirement:

kidney

EPO (90%) is produced in the ___, with the remainder manufactured by hepatocytes

peritubular fibroblasts

EPO is an endogenous hormone produced by ___ in the renal cortex.

erythropoiesis; progenitor cells

EPO stimulates ___ in bone marrow --> Binds to EPO receptor on erythrocyte ___ in bone marrow --> Activates signaling cascade increases reduces apoptosis of CFU-E and other progenitor cells that develop into mature erythrocytes

- tissue hypoxia and necrosis (shortness of breath & lethargic feeling) - low blood osmolarity (tissue edema) - low blood viscosity (heart races & pressure drop)

Effects of anemia:

- Blood loss - Decreased oxygen tension - An increase in oxygen affinity

Erythropoiesis is stimulated by:

RBC

Erythropoietin is essential to the production of ___

- growth - pregnancy - lactation - blood loss - consumption of food low in iron - impaired absorption of iron - abnormal transferrin function

Etiology of Iron Deficiency Anemia:

Intestinal malabsorption: - Spure (Celiac disease) - Drugs: (methotrexate, phenytoin) - Crohn disease - HIV-related enteropathy Drugs: - Ethanol - Sulfa drugs - barbiturates Defective cellular uptake of folic acid (rare)

Etiology of folic acid deficiency:

- ferric ammonium citrate - iron polysaccharide - ferric hydroxide polymaltose complex.

Ferric salt examples:

33%

Ferrous fumigate have ___ of elemental iron

20%

Ferrous salts have ___ of elemental iron

12%

Ferrous succinate have ___ of elemental iron

19%

Ferrous sulfate have ___ of elemental iron

- oral folic

Folic acid deficiency Tx:

Folic acid precursor - the active coenzyme forms of folic acid are derivatives of tetrahydrofolate. Tetrahydrofolate acts as a methyl donor for purine and pyrimidine synthesis. Converts deoxyuridine monophosphate to deoxythymidine monophosphate for DNA synthesis. Folic acid is absorbed in the small intestine. From the small intestine it makes its way to the serum, where most of the folic acid is free or loosely and nonspecifically bound to serum proteins. In most tissues other than the liver, folic acid enters and remains within the cell throughout its life span. Stored folic acid in liver can be released into the biliary circulation. Biliary drainage results in a dramatic decrease in serum folate levels.

Folic acid metabolism summary:

Folvite Folitab

Folic acid types:

Fecovorin

Folinic acid types:

33%

Hb has ___ of iron

adults

In ___, 200mg of elemental iron administered in 2-3 divided doses after meal

children

In ___, 3-5mg/kg in 3 divided doses. 325mg tablets of ferrous sulfate, thrice a day

elevated; normal

In folic acid deficiency there is a low serum folic acid level, characterized by ___ serum homocysteine levels and ___ methylmalonic acid levels.

hypoxia

In healthy persons detection of ___ by the kidney can result in a 1000-fold increase in EPO production

hypoxemia-inducible factor (HIF)

In presence of anemia/hypoxemia, ___ increases transcription of EPO gene

cell survival

In the later stages of erythrocyte differentiation, the receptor for erythropoietin is downregulated and the hormone no longer necessary for ___

active

Iron absorbs by ___ transport across intestinal mucosa.

Apoprotein-iron complex (ferritin) is released on demand. The absorption depends on apoprotein to ferritin ratio. Transferrin binds with free Fe2+ or Fe3+ from ferritin and carries to bone marrow

Iron absorption and transport:

functional

Iron deficiency can be "___" iron deficiency with adequate or increased body/bone marrow stores that are sequestered in reticuloendothelial cells and not available for erythropoiesis

true

Iron deficiency can be "___" iron deficiency with inadequate total body and bone marrow iron

to replenish the patient's total body stores of B12 by administering B12 via an effective route.

What is the goal of treatment of B12 deficiency?

oral iron replacement

What is the therapy of choice for iron deficiency anemia?

anemia

___ in CKD often goes undetected b/c of its hidden/ slick onset

true

___ iron deficiency usually associated with TSAT < 20% and serum ferritin < 100-200 ng/ml

functional

___ iron deficiency usually associated with infection and/or inflammation - mediated by various inflammatory cytokines and abnormality in iron regulatory protein hepcidin

functional

___ iron deficiency, TSAT typically 15-25% and serum ferritin > 300-500 ng/ml

EPO

___ is a 165 AA glycoprotein

iron-dextran

___ is a stable complex of ferric hydroxide and low-molecular-weight Dextran. - IM or IV - IV administration eliminates the local pain and tissue staining

Darbepoetin alfa (Aranesp)

___ is a super-sialylated analog of rHuEPO - 5 N-linked carbohydrate chains - 5 amino acid substitutions to EPO peptide backbone distant from receptor binding domain - Binds to EPO-receptor with same mechanism of action

iron

___ is needed to for adequate erythropoiesis and hemoglobin synthesis

erythropoietin

___ is produced by recombinant technology - Available as epoeitin α and β. - 25-100 IU/kg, s.c. or i.v. 3 times a week.

erythropoietin (EPO)

___ is required for survival, proliferation, and differentiationof erythroid progenitor cells in the bone marrow.

parenteral iron therapy

___ is reserved for patients with documented iron deficiency who are unable to tolerate or absorb oral iron.

Haemosiderin granules

___ is seen with iron overload & gives rise to haemosiderosis or bronze diabetes.

CKD

___ leads to relative EPO deficiency

anemia

___ of CKD is one of the first signs of kidney dysfunction

hemodialysis

___ patients are also more likely to have infection/inflammation and functional iron deficiency—especially with tunneled dialysis catheter

folates

___ regulate DNA synthesis

- iron deficiency - inflammation - folate deficiency - vitamin B12 deficiency

Other contributors to anemia:

iron-dextran

Owing to the risk of a hypersensitivity reaction, a small test dose of ___ should always be given before full intramuscular or intravenous doses.

- Iron-dextran - Iron sucrose complex - Iron-sodium gluconate - Iron-sorbitol-citrate (IM only)

Parental Iron drugs:

- Postgastrectomy conditions - Previous small bowel resection - Inflammatory bowel disease - Malabsorption syndrome

Parenteral Iron Therapy for patients with extensive chronic blood loss who cannot be maintained with oral iron alone:

erythropoietin (EPO)

Patients develop anemia of CKD because failing kidneys produce less ___ than the body requires for the production of red blood cells.

erythropoietin (EPO)

Patients with CKD due to impaired kidneys, EPO levels remain normal or below normal even when challenged by lack of oxygen

LVH (left ventricular hypertrophy)

People with stages 2 to 4 CKD reported anemia to be an independent risk factor for the development of ___

hypoxemia/ anemia

Renal EPO synthesis is stimulated by ___

iron

20-50% of patients with CKD/ESRD may have some degree of ___ deficiency

2/3

About ___ of pts in the early stages of kidney failure tend to be anemic - hemoglobin levels are <11 g/ dL

- EPO gene cloned 1985; initial clinical trials with epoetin alfa reported in 1986-1989. Approved by US FDA in 1989. - Human gene expressed in Chinese Hamster Ovary system - Same amino acid structure and biological activity as native EPO - Contains 3 N-linked carbohydrate chains required for biological activity - In US, marketed as Epogen® and Procrit

Recombinant human erythropoietin (rHuEPO, epoetin alfa):

gradually

Anemia develops ___ as kidney function declines

increase

Anemia in CKD blood levels are often in "normal" range but do not ___ to levels seen in most other anemias

GFR drops to 50 mL/min

Anemia in females:

GFR drops to 70 mL/min

Anemia in males:

Anemia (characterized by low RBC conc) means low oxygen carrying capacity of blood and decreased tissue oxygenation. This get to the kidneys which increase the secretion of EPO. Increased EPO stimulates the production of RBC. It reaches normal RBC conc levels.

Anemia, Kidney, and Inc RBC conc:

double

Anemic patients ___ their relative risk of death when CKD is present

triple

Anemic patients ___ their risk if they have anemia, CKD, and cardiovascular disease

- Oxygen-carrying capacity of the blood - Change in whole blood volume - LFH - changes in the hemoglobin-oxygen dissociation curve - manifestations of the underlying illness that caused the anemia

Clinical manifestations of anemia:

Cyanocobalamine (Redisol, Macrabin) Hydroxocobalamine (Redisol-H, Macrabin-H) Methylcobalamine (Methylcobal, Neurokind-OD)

Cobalamin examples:

- dialysis-related blood loss - blood tests - vascular access surgery - GI tract blood losses

Hemodialysis patients are particularly likely to have true iron deficiency due to:

hypoxemia-inducible factor (HIF)

Hypoxemia stabilizes ___ complex that is degraded at higher oxygen levels

- MI - stroke - death

If hemoglobin <13 g/dL in males and <12 g/dL in females, in stage 3 and 4 CKD patients with anemia, the results showed an increase in composite outcomes of:

Fe3+

Iron is covered Fe2+ to ___

- HA - light-headedness - fever - arthralgias - nausea - vomiting - back pain - flushing - anaphylaxis - death - hypersensitivity rxns (delayed for 48-72 hrs after administration)

Iron-dextran AEs:

iron-dextran

Iron-sucrose complex and iron sodium gluconate complex appear to be much less likely to cause hypersensitivity reactions when compared to ___

alternative

Iron-sucrose complex and iron sodium gluconate complex are ___ preparations.

IV

Iron-sucrose complex and iron sodium gluconate complex are both administered ___

- iron - vit b12 - folic acid - vit b2 - vit b6 - nicotinic acid - vit C - vit A - vit E - proteins, AAs, calories - Copper - cobalt

Nutritional needs for erythropoeisis:

- ferrous salts of sulfate - Fumerate - Gluconate - Lactate - succinate and glycine sulfate etc.

Oral Iron therapy drugs:

dose-related

Oral iron therapy AEs are usually ___ and can often be overcome by lowering the daily dose of iron or by taking the tablets immediately after or with meals

- Nausea - epigastric discomfort - abdominal cramps - Constipation - diarrhea

Oral iron therapy common AEs:

- All women contemplating pregnancy to prevent neural tube defects - Pregnant or lactating women - Patients with chronic hemolysis and increased erythropoiesis - Folic acid supplementation decreases homocysteine levels

Prophylactic folic acid should be given to:

1

Stage ___ iron-deficiency anemia: Decrease in iron stores --> dec ferritin

2

Stage ___ iron-deficiency anemia: biochemical indicators of low iron stores --> dec transferrin saturation and inc erythrocyte protoporphyrin

3

Stage ___ iron-deficiency anemia: iron-deficiency anemia --> dec hemoglobin

- A serum creatinine ≥2 mg/dL when the hemoglobin is <12 g/dLin adult males and postmenopausal females - <11 g/dL in premenopausal females

The NKF KDOQI guidelines recommend that the evaluation of anemia of CKD begin in patients with:

- Reversion of megaloblastic (the clinical manifestation of B12 deficiency) hematopoiesis to normal hematopoiesis - Reticulocyte counts - Methylmalonic acid and homocysteine levels return to normal - RBC count, hemoglobin and hematocrit normalization

The results of B12 treatment can be monitored:

serum ferritin; transferrinsaturation with iron (TSAT)

Traditional iron tests like ___ and ___ are not reliable markers of bone marrow iron stores or responsiveness to IV iron infusion

- B12 is given parenterally in the form of cyanocobalamin, intramuscularly (IM) - Oral replacement of B12 and/or oral administration of pancreatic extract

Treatment of Cobalamin (B12) deficiency:

Oral iron replacement is the therapy of choice: - Ferrous sulfate - Other iron salts or preparations

Treatment of iron deficiency anemia:

3-4 months

Treatment with oral iron should be continued for ___ after correction of the cause of the iron loss. This corrects the anemia and replenishes iron stores.

- Iron deficiency anemia - Cobalamin (B12) deficiency - Folic acid deficiency - Megaloblastic anemia

Types of nutritional anemias:

Anemia due to: - Chronic renal failure - Cancer chemotherapy - AIDS - Premature infants - Blood transfusion

When to use Erythropoietin?

hemolytic

___ anemia is caused by RBC destruction

hemorrhagic

___ anemia is caused by loss of blood

aplastic

___ anemia is complete cessation (cause unknown_

ferrous salts

___ are better absorbed than ferric salts

hypoxemia-inducible factor (HIF)

___ complex is an EPO gene transcription factor