Definition and Prevalence

In 1968, the World Health Organization (WHO)[i] defined anemia as blood hemoglobin levels less than 13g/dL in men and less than 12 g/dL in women.  WHO classifies anemia based on the level of hemoglobin as follows:

  •  mild anemia -- hemoglobin of 11 to 11.9 g/dL
  •  moderate anemia -- hemoglobin of 8.0 to 10.9 g/dL
  •  severe anemia -- hemoglobin below 8.0g/dL 

Anemia prevalence increases with kidney disease progression and ~90% of patients with GFR less than 25mL/min have anemia.[ii] Anemia in patients on HD may be worsened by the blood loss experienced at each dialysis treatment, which is estimated to be as high as 2 to 3 liters over a year.[iii]  The estimated usual blood lost in patients on HD is approximately:

  • Lab draws: average of 400 mL/year
  • Blood left in HD circuit after dialysis: average of 19 mL per treatment (almost 3 Liters per year)
  • Post procedure bleeding from arteriovenous access as variable: estimated as an average uncomplicated loss of 7 mL per treatment (1 Liter per year)
  • Clotted dialyzer/system which could result in about 400 mL blood loss per year

Assessment of anemia includes a complete blood count with differential (CBC), absolute reticulocyte count, serum ferritin, transferrin saturation (TSAT), and serum vitamin B12 and folate levels.  KDIGO[iv] recommends checking hemoglobin:

  • At least every 3 months in PD patients not requiring erythropoietin stimulating agents (ESA)
  • Monthly in PD patients requiring ESA
  • At least monthly in all HD patients regardless ESA requirements

Generally, the nephrology community focuses on hemoglobin level as the target for anemia management.  Hemoglobin is the iron-bearing and oxygen-carrying component of red blood cells (RBCs).  Platelets are important in the blood clotting process.  In the uremic states, platelet function is often abnormal which increases bleeding risk.  Increased bleeding has been reported in 24 to 50% of chronic HD patients with platelet dysfunction recognized as one of the causes.[v]

Iron Deficiency Anemia

Iron deficiency anemia occurs when the body lacks iron to produce the hemoglobin it needs to make RBCs.  A healthy male typically loses about 1mg of iron per day due to gastrointestinal epithelial cell loss and a menstruating female an additional 1mg a day.  A healthy diet provides about 5–15 mg of elemental iron and 1–5 mg of heme iron, of which about 1–2 mg is absorbed in the gastrointestinal (GI) tract.[vi]

Iron deficiency most commonly occurs from internal blood loss due to conditions such as:  GI problems (e.g. hemorrhoids, colon polyps, GI cancers, bleeding from esophageal varices), menorrhagia and use of nonsteroidal anti-inflammatory (NSAID) drugs.22 Impaired iron absorption can arise with celiac disease, inflammatory bowel disease, surgical duodenal bypass, and intestinal infections after GI surgeries.22 An acidic environment is needed for iron absorption; medications that suppress stomach acid (proton pump inhibitors, H2 blockers, antacids) can greatly reduce iron absorption.  In addition, iron binds to many components in the diet.  It is estimated that during every HD treatment, 5-7 mg of iron is lost.19

Iron deficiency anemia can be associated with unusual eating or cravings of food or nonfood substances such as dirt, clay or ice.  This unusual behavior is called pica, and restoring iron stores seems to decrease the pica cravings with no single explanation for the cause of pica.[vii]

Anemia of Chronic Disease

Anemia of chronic disease is a common condition associated with a wide variety of persistent inflammatory disease or chronic diseases including anemia of CKD.  It can be very severe, requiring transfusions and erythropoietin therapy.

Anemia of chronic disease[viii] is not completely understood.  However, it is known that in anemia of chronic disease, iron is not efficiently recycled, RBC survival is reduced, and response to erythropoietin is impaired.  Abnormal function and low levels of erythropoietin may be the underlying causes of anemia of chronic disease along with impaired iron utilization.

KDIGO recommends using ESAs with great caution, if at all, in all patients with CKD who have active malignancy, especially when cure is the anticipated outcome.20  The dialysis team caring for dialysis patients with active malignancy needs to coordinate anemia management care with the patient’s oncologist to verify that the patient’s cancer is appropriate to treat with ESAs and to verify the hemoglobin target and dose. 

Anemia Treatment

Iron

If the patient’s labs and diet are suggestive of low iron intake, then oral iron is often initiated as first line therapy with the patient given a trial iron supplements.20  GI side effects are common, with an estimated 50 to 70% of iron therapy not taken as prescribed due to side effects.[ix] It may take up to 6 months of treatment with oral iron to fully replete iron stores.[x]   Oral iron is most effective in CKD-ND patients. HD patients have too much blood loss in combination with impaired iron absorption (causes listed above) for oral iron supplementation to be effective.

Advise the patient that black stools are normal when taking oral iron supplements.  Patients with gastric intolerance to oral iron tablets may tolerate prescription ferrous sulfate elixir, which contains 44 mg of elemental iron per 5mL.[xi] 

Iron rich foods include all animal protein foods, beans, peas, iron-fortified cereals, breads, and pasta, dark green leafy vegetables, dried fruit, nuts, and seeds. However, many of these foods also have a high content of potassium and/or phosphate and may therefore be restricted in CKD patients.  It is important to counsel patients to avoid taking iron supplements at the same time as milk, caffeine, calcium supplements, antacids, tetracycline, penicillin, ciprofloxacin or Parkinsons drugs.[xii]

325mg oral iron supplement contains the following amounts of elemental iron: [xiii]

  • ferrous fumarate 106 mg
  • ferrous sulfate 65mg
  • ferrous gluconate 36mg

Most dialysis clinics prescribe intravenous (IV) iron during the dialysis treatment for the following reasons: 1) limited absorption of oral iron secondary to concurrent drugs and dietary components that reduce absorption, 2) increased iron demand with concurrent ESA use, 3) GI intolerance and non-adherence to oral iron.  KDIGO suggests a trial of IV iron for patients not receiving iron supplementation when not achieving hemoglobin target along with a TSAT < 30% and ferritin < 500mg/ml.20   KDIGO also recommends avoiding IV iron administration to patients with active systemic infections.20

The tables below compare IV iron formulations for dialysis dependent CKD and nondialysis dependent CKD patients (note: iron dextran was not studied in CKD, but has a general indication for iron deficiency).

Dialysis Dependent CKD – FDA Approved IV Iron Comparison Table:[xiv]

Generic name

Sodium ferric gluconatea

Iron sucroseb

Iron dextranc

low molecular weight

Ferumoxytold,e

Availability

12.5mg/mL

(62.5mg/5mL ampule or vial)

20mg/mL

(50mg/2.5mL: 100mg/5mL; 200mg/10mL vial)

25mg/mL

(50mg/2mL vial)

30mg/mL

(510mg/17mL vial)

Test dose required

No                        

No

Yes

No

Maximum single dose

125 mg

Not stated in PI but recommended

HD dose 100mg

PD dose 300mg over 1.5 hr/400mg over 2.5 hr

50mg (2mL/day)

Can be given as a 1g diluted TDI

Not stated in PI but recommended dose 510mg

How administered

Diluted-125mg over 1 hr

Undiluted-12.5mg/min

Diluted-100mg over at least 15 min

Undiluted-100mg over 2-5 min

Undiluted-50mg/min

Diluted-510mg over a minimum of 15 min, administer once blood pressure is stable and after at least 1 hr of HD, monitor for hypotension

Pre-medicate for allergies

No

No

TDI only

No-higher risk of anaphylaxis in patients with multiple drug allergies

Life threatening adverse events

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal.

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal

Anaphylactic reactions have occurred after first dose, second dose, and multiple doses

Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness

PI=package insert or product label

TDI=total dose infusion

a https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020955s013s015lbl.pdf

bhttps://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/pediatricadvisorycommittee/ucm437786.pdf

c https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/017441s171lbl.pdf

d https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022180lbl.pdf

e https://www.fda.gov/downloads/Drugs/DrugSafety/UCM440336.pdf

Nondialysis Dependent CKD – FDA Approved IV Iron Comparison Table:30

Generic name

Iron sucrosea

Ferric carboxymaltoseb

Ferumoxytolc,d

Availability

20mg/mL

(50mg/2.5mL: 100mg/5mL; 200mg/10mL vial)

50mg/mL (750mg/15mL vial)

30mg/mL

(510mg/17mL vial)

Test dose required

No

No

No

Maximum single dose

not stated in PI but recommended CKD dose 200mg

Not stated in PI but recommended CKD dose:

750mg for patients weighing >50kg

15mg/kg body weight for patients weighing <50kg

Not stated in PI but recommended dose 510mg

How administered

Diluted-200mg over 15 min

Undiluted-200mg over 2 to 5 min

Diluted-750mg over at least 15 min

Undiluted-100mg per min

Diluted-510mg over a minimum of 15 min

Pre-medicate for allergies

No

No

No-higher risk of anaphylaxis in patients with multiple drug allergies

Life threatening adverse events

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal

Serious hypersensitivity reactions, including anaphylactic-type reactions, some of which have been life-threatening and fatal

Fatal and serious hypersensitivity reactions including anaphylaxis, presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, or unresponsiveness

ahttps://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/pediatricadvisorycommittee/ucm437786.pdf

b https://www.accessdata.fda.gov/drugsatfda_docs/label/2013/203565s000lbl.pdf

c https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/022180lbl.pdf

d https://www.fda.gov/downloads/Drugs/DrugSafety/UCM440336.pdf

 

Erythropoiesis Stimulating Agents (ESAs)

Recombinant human erythropoietin was introduced in 1989, which greatly improved anemia treatment in ESRD by decreasing blood transfusions and the side effects due to these (iron overload, antibody production).  ESAs are federal drug administration (FDA) approved only for treating anemia of cancer chemotherapy or anemia of CKD.[xv]  The hemoglobin target of ESAs changed in 2007 after multiple studies were published, showing, increased cardiovascular events and increased deaths in CKD patients when ESAs were administered to normalize hemoglobin concentrations (>13 g/dl).31 In 2007, the FDA issued a “black box” warning for the labels of all ESAs, encouraging providers to use the lowest dose of all ESAs to avoid blood transfusions.[xvi]   ESAs also increase systolic blood pressures 4 to 5 mmHg when an ESA is administered.[xvii]  The epoetin alpha prescribing information insert states to not administer epoetin alpha in patients with uncontrolled blood pressure.[xviii] In situations where ESAs appear to be associated with an increase in blood pressure, the solution is to modify the antihypertensive regimen.    

KDIGO recommends starting ESA therapy when hemoglobin is between 9.0 and 10.0 g/dl and not be used to maintain hemoglobin above 11.5 g/dL.20  Importantly, KDIGO also suggests that goals should be individualized with dose adjustments of 25%. Cochrane reviewed the different ESA formulations and found insufficient evidence to suggest the superiority of any ESA formulation based on safety and efficacy data.[xix]  The drug cost, availability, and dosing frequency should drive the decision making for the ESA agent.35  All ESAs are generally considered interchangeable (see table below).[xx] 

[Insert table: ESA: Duration of Action and Dosing]

New Agents

Completed US Dialysis Based Studies

Biosimilar ESAs that have been available in Europe for several years are pursuing FDA approval having completed dialysis based studies.   

Hypoxia-inducing-factors (HIFs) in kidney cells are part of the family of oxygen-sensitive proteins that control the body’s response to hypoxia with erythropoietin regulation as managed by HIFs.   When local oxygen decreases, accumulated HIFs bind to the erythropoietin gene and activate erythropoietin.[xxi]  HIFs appear to be the master switch for hypoxic adaption responses.37 These oral agents are presently in clinical studies in CKD non-dialysis and dialysis patients.

Erythropoietin mimetic peptides (EMPS) were taken voluntarily off the market in 2013 after acute hypersensitivity reactions; 0.02% of the patients died after receiving the first IV dose of the drug.36 

Ferric pyrophosphate is a new soluble dialysate based prescriptive iron.  Ferric pyrophospate was designed as an iron maintenance product that could be delivered during dialysis to compensate for the 5mg of iron loss during each HD treatment.[xxii]

Blood Transfusions

A restrictive strategy for administering blood transfusions is now recommended:  i.e. administering less blood, waiting to transfuse at a lower hemoglobin level and targeting a lower hemoglobin level.[xxiii], [xxiv] In patients eligible for organ transplantation, KDIGO recommends avoiding, when possible, blood transfusion to minimize the risk of allosensitization.20 The American Association of Blood Banks (AABB) recommend the following blood transfusion guidelines:39, 40

Transfusions recommended for:

  • Hemoglobin 7 g/dL or less
  • Hemoglobin 7 to 8 g/dL in postoperative surgical patients with stable cardiovascular disease
  • Symptomatic patient with severe symptoms
  • Patients with acute coronary syndrome
  • Trauma patient and other patients requiring massive transfusions

Transfusions not recommended for:

  • Hemoglobin 8 to 10 g/dL with no clinical symptoms
  • Hemoglobin over 10 g/dL

ESA Hypo-responsiveness

KDIGO20 defines initial ESA hypo-responsiveness as patients who have no increase in hemoglobin from baseline after the first month of ESA therapy with appropriate weight-based dosing.  Moreover, KDIGO suggests avoiding repeated ESA dose increases beyond doubling the initial weight-based dose.  For patients that have been stabilized on an ESA dose, ESA hypo-responsiveness is defined as previous stable hemoglobin that now requires two increases in ESA doses up to 50% beyond the previous dose.  Guidelines suggest avoiding dosing escalations beyond doubling the previous dose.

Patients with ESA hypo-responsiveness should be evaluated for other underlying causes (e.g. occult bleeding, iron deficiency, advancing CKD-MBD) and treat the underlying cause.  KDIGO20 suggests individualization of ESA therapy based on the risks and benefits with goal to prevent further hemoglobin decline and blood transfusions. KDIGO does not recommend androgen therapy, vitamin C, vitamin D, vitamin E, folic acid, L-carnitine or pentoxifylline therapy as adjuvant therapy to ESA treatment. 

Pure Red Blood Cell Aplasia (PRCA)

PRCA is a rare condition that results in the bone marrow not forming red blood cells (RBCs) while white blood cells (WBCs) and platelet production remains normal.[xxv]  PRCA results in a severe anemia with a very low reticulocyte count of less than 10,000/uL (1% of RBCs) and less than 0.5% mature RBCs in the bone marrow.41 PRCA has occurred rarely in exposure to ESAs. KDIGO recommends investigating for possible PRCA when a patient receiving ESA therapy for more than 8 weeks, develops the following:20

  • Sudden rapid decrease in hemoglobin concentration at the rate of 0.5 to 1.0g/dL per week or requires transfusions at the rate of approximately 1 to 2 per week AND having
  • Normal platelet and white cell counts AND
  • Absolute reticulocyte counts less than 10,000uL. 

KDIGO20 recommends ESA therapy be stopped with PRCA. 

 

[i] World Health Organization (WHO). Haemoglobin concentrations for the diagnosis of anaemia and assessment of severity. Vitamin and Mineral Nutrition Information System. Geneva, WHO.  http://www.who.int/vmnis/indicators/haemoglobin. Published 2011. Accessed October 6 2017.

[ii] Choncol M, Chan L. Chronic kidney disease: manifestations & pathogenesis. In Schrier, RW (Ed.), Renal and Electrolyte Disorders. Philadelphia, PA: Wolters Kluwer/Lippincott Williams & Wilkins, 2010:389-425.

[iii] Sargent JA, Acchiardo SR. Iron requirements in hemodialysis.  Blood Purification, 2004;22, 112-123.

[iv] KDIGO Clinical practice guideline for anemia in chronic kidney disease. Kidney Int., Suppl. 2012;2: 279–335.

[v] Lutz J, Menke J, Sollinger D, Schinzel H, Thurmel K. Haemostasis in chronic kidney disease. Nephrol Dialysis Transpl. 2013;29, 29-40.

[vi] Zhu A, Kaneshiro M, Kaunitz JD. Evaluation and treatment of iron deficiency anemia: a gastroenterological perspective. Dig Dis Sci. 2010;55:548-559.

[vii] Khan Y, Tisman G. Pica in iron deficiency: a case series. J Med Case Rep. 2010;4:86.

[viii] Poggiali E, Migone De Amicis M, Motta I. Anemia of chronic disease: a unique defect of iron recycling for many different chronic diseases. Eur J Intern Med. 2014;25:12-17.

[x] Camaschella C. Iron-deficiency anemia. N Engl J Med. 2015;372:1832-1843.

[xi] Alleyne M, Horne MK, Miller JL. Individualized treatment for iron-deficiency anemia in adults. Am J Med. 2008;121:943-948.

[xii] Medline Plus. Taking iron supplements. https://medlineplus.gov/ency/article/007478.htm. Updated October 3 2017. Accessed October 16 2017.

[xiii] Up-To-Date. Schrier SL. Treatment of the adult with iron deficiency anemia. https://www.uptodate.com/contents/treatment-of-iron-deficiency-anemia-in-adults. Updated September 18 2017. Accessed October 16 2017.

[xiv] Veterans Administration Pharmacy Benefits Management Services, Medical Advisory Panel, and VISN Pharmacist Executives. Recommendations for use of IV iron in CKD. https://www.index.va.gov/search/va/va_search.jsp?NQ=URL%3Ahttps%3A%2F%2Fwww.pbm.va.gov%2F&QT=iv+iron&submit.x=31&submit.y=13. Published May 2014. Accessed October 16 2017.

[xv] Food and Drug Administration (FDA) (2007a).  Decision memo for erythropoietin stimulating agents (ESAs) for non-renal disease utilization (CAG – 00383N).  https://www.cms.gov/medicare-coverage-database/details/nca-decision-memo.aspx?NCAId=203&ver=12&NcaName=Erythropoiesis+Stimulating+Agents+8bc=BEAAAAAAIAAA. Published July 30 2007. Accessed October 16 2007.

[xvi] Food and Drug Administration (FDA). FDA Drug Safety Communication: Modified dosing recommendations to improve the safe use of Erythropoiesis-Stimulating Agents (ESAs) in chronic kidney disease. https://www.fda.gov/Drugs/DrugSafety/ucm259639.htm. Published October 2007. Accessed October 16 2017.

[xvii] Krapf R, Hulter HN. Arterial hypertension induced by erythropoietin and erythropoiesis stimulating agents (ESA).  Clin J Am Soc Nephrol. 2009;4:470-480.

[xviii] Amgen. Product insert. http://pi.amgen.com/united_states/epogen/epogen_pi-hcp_english.pdf. Updated September 2017. Accessed October 16 2017.

[xix] Palmer SC, Saglimbene V, Mavridis D, et al. Erythropoiesis-stimulating agents for anaemia in adults with chronic kidney disease: a network meta-analysis. Cochrane Database Syst Rev. 2014;(12):CD010590.

[xx] Jelkman, W. The ESA scenario gets complex: from biosimilars epoetins to activin traps. Neph Dial Transplant. 2015;30:553-559.

[xxi] Nangaku M, Eckardt K. Hypoxia and the HIF system in kidney disease. J Mol Med. 2007;85:1325-1330.

[xxiii] Carson JL, Kleinman S. Indications and hemoglobin thresholds for red blood cell transfusion in the adult. UpToDate.  http://www.uptodate.com/contents/indications-and-hemoglobin-thresholds-for-red-blood-cell-transfusion-in-the-adult. Updated September 8 2017. Accessed October 16 2017.

[xxiv] Carson JL, Carless PA, Hebert PC. Transfusion thresholds and other strategies for guiding allogeneic red blood cell transfusion. Cochrane Database Syst Rev. 2012;(4):CD002042.

[xxv] Means RT Jr. Pure red cell aplasia. Blood. 2016;128:2504-2509.