Nephrology Hypertension

Anemia of Chronic Kidney Disease

Patients with anemia from chronic kidney disease (CKD) may be symptomatic or asymptomatic from their anemia depending on the age of the patient, the presence of co-morbid conditions, and the severity of the anemia. Most patients with anemia of CKD start to become symptomatic when their hemoglobin (Hb) concentration falls below 9 g/dL, although some are symptomatic when less than 10 g/dL especially with comorbid conditions.

Symptoms include:

  • Easy fatigue and loss of energy

  • Dyspnea particularly with exercise

  • Difficulty concentrating

  • Dizziness

The most common sign of anemia is the presence of pale mucous membranes. However, patients with more severe anemia may additionally manifest with evidence of heart failure (elevated jugular venous pressure, lung rales, and peripheral edema), a resting tachycardia, and more chronically changes in the nails - koilonychia (or spoon nails) - a manifestation of iron deficiency anemia.

Diagnosis

Kidney Disease Improving Global Outcomes (KDIGO) Guidelines recommend Hb testing be performed at least annually for all CKD 3 patients, semiannually for stage 4 and non-HD stage 5, and at least every 3 months for dialysis patients. They recommend that anemia work-up should be started when the adult Hb concentration falls below 13.0 g/dL in males and <12.0 g/dL in females. The European Best Practice Guidelines for management of anemia in patients with CKD define anemia as an Hb concentration <11.5 g/dL in women and <13.5 g/dL in men ≤ 70 years of age and <12 g/dL in men >70 years of age.

The clinical evaluation of the patient is key in working up the anemia. Clues in the history include:

  • Evidence suggestive of reduced iron and vitamin intake ("tea-and-toast" diet)

  • Evidence for blood loss (for example, history of vomiting coffee ground like material, rectal bleeding)

  • Underlying history suggesting an inflammatory focus (for example, a failed allograft, a skin ulcer in a diabetic patient, sacral sore in an elderly, bed-ridden patient, or an active autoimmune process like rheumatoid arthritis).

The physical examination can also provide important clues. For example, patients with an iron deficiency may chew or suck ice (pagophagia). Occasionally, they may complain of dysphasia, brittle fingernails, relative impotence, fatigue, and cramps in the calves on climbing stairs out of proportion to their anemia.

In vitamin B-12 deficiency, early graying of the hair, a burning sensation in the tongue, and a loss of proprioception are common. Patients with folate deficiency may have a sore tongue, cheilosis, and symptoms associated with steatorrhea. Color, bulk, frequency, and odor of stools and whether the feces float or sink can be helpful in detecting malabsorption.

The differential diagnosis of anemia of CKD is long and includes:

  • erythropoietin deficiency

  • iron deficiency

  • anemia of chronic disease (chronic inflammation)

  • B12 or folate deficiency

  • hemoglobinopathy

It is always very tempting to assume that patient's with CKD who are anemic have erythropoietin deficiency. However, studies have demonstrated that iron deficiency anemia is present in approximately 40% of patients and that inflammatory causes may also be an important reason for the patient to be anemic.

What tests should be performed?

A complete blood count (CBC):

  • Hb concentration

  • Red blood cell indices (mean corpuscular hemoglobin [MCH], mean corpuscular volume [MCV], mean corpuscular hemoglobin concentration [MCHC]), white blood cell count, and differential

  • Platelet count.

Additional tests include:

  • Absolute reticulocyte count to assess the hematological response to the anemia.

  • Measures of iron stores: serum ferritin, serum iron and total iron binding capacity (TIBC) to calculate the transferring saturation or TSAT (TSAT=serum iron/total iron binding capacity), and B12 and folate to evaluate for nutritional deficiency.

  • Checking the stool for occult blood

In general measurement of an erythropoietin level is not necessary in the work-up of a CKD patient with anemia unless a hematological cause is suspected, as even a “normal” erythropoietin level may be inappropriately low for the degree of anemia.

Other considerations in the anemia work-up include:

  • Imaging studies: these are not useful in the work-up for chronic anemia unless a neoplastic etiology is suggested.

  • If GI bleeding is suspected then endoscopy and radiographic studies should be considered in order to identify the bleeding site. However, the source of GI bleeding may be from an angiodysplastic lesion, which is more common in CKD patients and may be very difficult to detect. GI bleeding also may be exacerbated by the effect of uremia on platelet function, where it can prolong the bleeding time.

  • Bone marrow aspirates and biopsy findings are particularly useful in establishing the etiology of anemia in patients with decreased production of red blood cells (RBCs). A bone marrow biopsy will help in the work of various hematological problems including aplasia, megaloblastic hyperplasia, infiltration of marrow with neoplasia, myelodysplasia, and myelofibrosis. In addition, a bone marrow biopsy may be useful in the diagnosis of leukemias, lymphomas, myelomas, and metastatic carcinomas.

  • Assessment of Iron deficiency. While Prussian blue staining of the bone marrow aspirate can be used to document the existence of iron deficiency anemia, this test is not routinely performed.

There continues to be controversy about the best way to diagnose iron deficiency anemia. Doubts have been raised about the predictive value of serum ferritin, TSAT, reticulocyte Hb concentration or percent hypochromic red cells. However, the two most common measures of iron deficiency used in clinical practice are serum ferritin and the TSAT.

The serum ferritin is the cellular storage protein for iron in tissues found in the intestines, liver and spleen. A ferritin level <100 ng/ml is considered compatible with iron deficiency, and the NKF KDOQI guidelines suggest that a ferritin of <200 ng/ml in hemodialysis patients should be used as an indicator of iron deficiency.

The TSAT is a measure of iron that is saturating transferrin (i.e., the level of circulating iron). A TSAT of <20% is considered suggestive of iron deficiency.

While the serum ferritin is the best measure of iron stores it also functions as an acute phase reactant. In the presence of infection or inflammation, serum ferritin is frequently falsely elevated.

How should patients with anemia from chronic kidney disease be managed?

ESA THERAPY

The treatment of anemia in CKD patients is controversial. The most recent guidelines were published in 2012 by KDIGO, and the FDA has also played an influential role in guiding the management of anemia of CKD.

The FDA guidelines state:

1. Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular events and has not been shown to provide additional patient benefit.

2. No clinical trial to date has identified a hemoglobin target level, erythropoiesis stimulating agents (ESA) dose, or dosing strategy that does not increase these risks.

3. The lowest ESA dose sufficient to reduce the need for red blood cell transfusions should be used.

For patients with CKD not on dialysis, the FDA recommends:

1. Consider initiating ESA treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply: The rate of hemoglobin decline indicates the likelihood of requiring a red blood cell transfusion; and reducing the risk of alloimmunization and/or other red blood cell transfusion-related risks is a goal.

2. If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of ESA and use the lowest dose of ESA sufficient to reduce the need for red blood cell transfusions.

KDIGO recommendations for these patients are that those with a Hb <10 g/dl should be initiated on ESA therapy on an individualized basis based on the rate of fall of hemoglobin, response to iron therapy, the risk of needing a transfusion, the risks related to ESA therapy and the presence of anemia symptoms.

For patients with CKD on dialysis, the FDA recommends:

  • Initiate ESA treatment when the hemoglobin level is less than 10 g/dL.

  • If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of ESA.When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly.

  • For patients who do not respond adequately over a 12-week escalation period, increasing the ESA dose further is unlikely to improve response and may increase risks.

KDIGO recommends in these patients to use ESA therapy to avoid Hb less than 9.g/dl so to start when between 9-10 g/dl.

One approach is to individualize anemia management by identifying “the hemoglobin trigger” for each patient and considering the "risk-reward" for the patient. However, being cognizant of the Hb target in treating patients is recommended.

The hemoglobin trigger is defined as the Hb concentration at which patients become symptomatic. The intervention could be an ESA, iron, red blood cell transfusion, or a combination thereof. As a result, some patients who become symptomatic at 10 g/dL would require treatment, whereas others who are asymptomatic at lower Hb concentrations will need no intervention. Additionally, patients who might be symptomatic at 11.5 g/dL would still be treated, but their treatment would be tailored to their symptoms.

Key strategies in treatment are as follows:

1. For CKD patients both pre-dialysis and those on dialysis, ESA treatment is recommended for:

  • Iron replete status is defined as ferritin>100 ng/ml and/or TSAT>20% although KDIGO suggests to try iron first as long as TSAT is <30% and ferritin is <500 ng/ml

  • Symptomatic patients

  • Candidates for kidney transplantation with a Hb<10 g/dL

The starting dose should be weight-based. The dose can be titrated up or down to maintain the patient above their Hb trigger.

Using the lowest possible ESA dose in managing the anemia is important. The TREAT study, as well as the randomized controlled trials preceding it such as CHOIR, CREATE, and the Normal Hematocrit study, and a recent meta-analysis have demonstrated that targeting a higher Hb concentration with high ESA dosage is associated with increased risk.

Observational studies and secondary analyses of the anemia trials have raised the possibility of several factors accounting for this increased risk observed in the trials. However, accumulating evidence suggests that exposure to high ESA dose is the most likely explanation for this increased risk.

The types of ESAs available in the US market currently are epoetin-alfa and darbepoetin alfa as well as a long-acting erythropoetin receptor activator known as Mircera (methoxy polyethylene glycol-epoietin beta). Darbepoetin alfa has a longer half life (~ 25 h on i.v administration and ~ 48 h when administered subcutaneously) than epoetin-alfa enabling a lesser frequency of dosing about once a week or once every other week, and Mircera has an even longer half life of up to 135 hours. Subcutaneous dosing is recommended for all non-dialysis CKD patients.

Hyporesponsiveness to ESA therapy is a major challenge in CKD patients and is defined as having no increase in hemoglobin concentration from baseline on the first month of a weight-appropriate ESA treatment. Causes include, iron deficiency, underlying acute or chronic infections, diabetes, longstanding hyperparathyroidism, malignancy, uremia, pure red cell aplasia, vitamin and/or mineral deficiency, chronic blood loss (frequent clotting of dialyzer, excessive post-dialysis bleeding), aluminum toxicity and acute blood loss. Treating the underlying cause of ESA hyporesponsiveness should be pursued rather than progressively increasing the dose of ESA.

Optimization of metabolic parameters results in reduced ESA utilization. Evidence demonstrates that folic acid deficiency can result in ESA hyporesponsiveness, especially in elderly hemodialysis patients with poor dietary folate intake without regular oral supplementation. But folic acid deficiency can be easily detected by the presence of macrocytosis and measurement of folate levels.

Optimizing dialysis adequacy and/or reverting to nocturnal dialysis or peritoneal dialysis is effective in lowering ESA utilization. There is good evidence that hyperparathyroidism is an important factor in ESA hyporesponsiveness. L-carnitine therapy may also lower ESA utilization; however, its use in dialysis patients remains controversial.

IRON DEFICIENCY

Iron can be supplemented either in oral or parenteral form. The important objectives to be considered when administering iron agents are to avoid depletion of storage iron, prevention of functional iron deficiency (iron deficient erythropoiesis) and to achieve and maintain target Hb levels.

Intravenous iron administration is more effective than oral iron supplementation in HD-CKD patients and in adult patients with chronic kidney disease (CKD). The 2006 KDOQI guidelines and 2012 KDIGO guidelines recommend that for patients not on hemodialysis, the route of administration can be either intravenous (IV) or oral; for hemodialysis patients, the preferred route of administration is IV.

Oral iron therapy, the traditional method of supplementation, has not proven to be effective in adequately repleting iron stores in dialysis dependant (CKD-D) and non-dialysis dependant patients (CKD-ND). In CKD-ND patients, oral iron can be tried first. Oral iron is best absorbed when given without food and/or with vitamin C to help with absorption although vitamin C intake should be limited in general with CKD. Low efficacy, poor compliance, gastrointestinal disturbances, poor intestinal absorption and medication costs were the major drawbacks in administering oral iron for therapy in CKD-ND patients.

The recommended adult dosage of oral iron to be administered is ≥200 mg/day of elemental iron. Flatulence, diarrhea or constipation, nausea, and abdominal pain are the common side effects of oral iron therapy. One 300 mg tablet (containing 60 mg elemental iron) of ferrous sulfate three to four times daily is the preferred adult dose or one 500 mg ferrous sulfate tablet at nightly at bedtime may be effective.

Intravenous iron therapy is used to treat anemia in CKD-D patients as an adjunct to achieve target Hb levels in patients receiving ESAs. Although intravenous iron therapy is considered efficacious, toxic effects of labile iron and immunogenicity are serious concerns. Adverse reactions from intravenous iron can range from mild allergy to life threatening anaphylactic reactions.

The intravenous iron preparations most commonly used are iron dextran, iron sucrose, sodium ferric gluconate complex, ferric carboxymaltose and ferumoxytol. Intravenous iron therapy in the CKD-D population involves 1 gm of elemental iron being administered intravenously over 8-10 dialysis sittings if iron deficient and then maintenance dosing if no sign of iron overload. In peritoneal dialysis patients and CKD-ND patients who have not responded favorably to oral iron, 1 gram of elemental iron is administered over 3-4 infusions, spread 2 weeks apart.

The Extent of the Problem

Anemia attributed to kidney disease is observed in 40 to 95% of the patients with stages 3 to 5 CKD and is ubiquitous in ESRD patients. According to the Centers for Disease Control and Prevention (CDC), more than 20 million people aged ≥20 years in the United States have CKD. The data analysis reports from two major community studies, National Health and Nutrition Examination Survey (NHANES III) and NKF’s Kidney Early Evaluation Program (KEEP) reported that in patients age ≥ 61 years with stage 3 CKD or higher (GFR <60 mL/min/1.73 m2) there was an increased prevalence in anemia (Hb <12 g/dL). NHANES III data analysis revealed that approximately one third of anemia in people age ≥ 65 years is caused by either inflammation or renal insufficiency; approximately one-third by nutritional deficiency and the other one-third by non-nutritional and other causes that could not be explained.

Anemia is a powerful risk factor for mortality, cardiovascular complications, heart failure, and hospitalizations. However, correction of anemia with ESA in randomized trials has not been associated with improvement in outcomes. There is ongoing research to help determine the best approach to this very prevalent and important issue.

How to utilize team care?

Nurses who monitor and administer ESA and intravenous iron are key members of the healthcare team.

Are there clinical practice guidelines to inform decision making?

The KDIGO 2012 anemia guidelines are the most updated guidelines.

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