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Anemic control in patients with chronic kidney disease: a controversial issue.

Anemia exists when the hemoglobin (Hgb) concentration is less than 12 g/dL in women and less than 13 g/dL in men (Kidney Disease: Improving Global Outcomes Anemia Workgroup (KDIGO), 2012). Factors that can affect Hgb values include age and sex, smoking, pregnancy, and altitude habituation (World Health Organization, 2014). Anemia is a public health concern in patients with chronic kidney disease (CKD), with an estimated prevalence of 15.4% in comparison to 7.6% in the general population (Stauffer & Fan, 2014). In addition, more than 10% of the population in the United States has CKD in varying degrees of severity (Centers for Disease Control and Prevention, 2014).

Erythropoiesis, the process of forming red blood cells, is different in patients with CKD compared to healthy individuals. Erythropoiesis usually is stimulated by blood loss, a decrease in oxygen, or increase in oxygen affinity. In healthy individuals, these phenomena cause a rapid increase in erythropoietin (EPO) production. In patients with CKD however, the response is ineffective as EPO remains at normal or even below normal values. Anemia of CKD is due mainly to decreased production of EPO by the kidneys, rendering the level insufficient for adequate red blood cell production. It also can be caused by nutritional deficiency, oxidative stress, inflammation, shortened red blood cell lifespan due to uremic toxins, and use of angiotensin-converting enzyme inhibitor medications (Stauffer & Fan, 2014). Anemia usually becomes more marked as kidney function worsens (glomerular filtration rate <70 ml/minute in males or 50 ml/minute in females) (Taliercio, 2010).

Significance of Anemia of CKD

Anemia of CKD doubles the relative risk of death in patients and, when present along with cardiovascular disease, triples the relative risk of death (Taliercio, 2010). Chronic hypoxia present in anemia is a causative factor for worsening cardiovascular health in patients with CKD. This hypoxia leads to the release of free radicals that cause an inflammatory process, which then damages endothelial tissue and vascular tone. These events stimulate the renin angiotensin aldosterone and sympathetic nervous systems, eventually causing tachycardia, increased sodium and water retention, ventricular dilation secondary to increased preload, and increased cardiac workload (Tomey & Winston, 2014). This explains the association between CKD anemia and left ventricular hypertrophy (LVH), congestive heart failure (CHF), myocardial infarction, ischemic heart disease, and increased mortality (Taliercio, 2010). Clinical manifestations of anemia include fatigue, decreased stamina, sexual dysfunction, impaired cognitive function, decreased quality of life, and increased occurrence of hospitalization (Szromba, 2009).

CKD-related anemia places a notable financial burden on health care institutions because of its contribution to the cost of CKD treatment, which represents $45.5 billion of Medicare finances (National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases [NIDDKD], 2013). Anemia also affects hospitalization rates directly because of its many associated co-morbidities and the related need for blood transfusions as a life-saving treatment. Only 22.8% of patients with CKD reported being treated for their anemia, suggesting quality of care and patient outcomes concerns (Stauffer & Fan, 2014).

Guidelines for Management of Anemia

For diagnosis of CKD-related anemia, a blood smear will show normocytic normochromic red blood cells. In addition, a complete blood count, iron binding capacity, ferritin, serum iron, reticulocyte count, vitamin [B.sub.12], and folate are obtained; hemolysis, folate and vitamin [B.sub.12] deficiency, and iron deficiency are very common causes for anemia of CKD and should be excluded in diagnosis (Murphy, Bennett, & Jenkins, 2010). Many patients with CKD-related anemia also have iron deficiency because they are in a pro-inflammatory state and thus unable to use iron stores adequately. Diagnosis of absolute iron deficiency is based on serum ferritin values lower than or equal to 500 ng/ml and transferrin saturation (TSAT) less than or equal to 30% (KDIGO, 2012).

When the patient is believed to have CKD-related anemia, appropriate diagnostics should be completed so findings can guide the next course of action. For example, if a patient displays signs consistent with iron deficiency based on serum ferritin results and transferrin saturation, occult gastrointestinal malignancy should be excluded before initiation of iron therapy. When iron stores are replenished and Hgb is less than or equal to 10 g/dL, erythropoietin-stimulating agent (ESA) therapy may be initiated with frequent monitoring of iron stores. Patients who have signs consistent with vitamin [B.sub.12] or folate deficiency also should be supplemented with [B.sub.12] and folate before initiation of ESA therapy. If no signs of iron, [B.sub.12], or folate deficiency exist and the patient has Hgb less than or equal to 10 g/dL, ESA may be initiated immediately with frequent iron stores testing (Taliercio, 2010).

In summary, treatment for anemia should not be initiated before testing for underlying causes. When any identified causes are treated or eliminated and the patient continues to maintain Hgb less than or equal to 10 g/dL, ESAs should be used to maintain Hgb at 11.5 g/dl. Erythropoietin-stimulating agents should not be used intentionally to increase Hgb levels to greater than 13 g/dl (KDIGO, 2012).

Treatment of Iron Deficiency

Patients who do not receive dialysis can be given oral or intravenous (IV) iron after assessment of intravenous access and gastrointestinal status, cost, previous response to iron, and patient adherence trends (KDIGO, 2012). Oral iron can cause severe gastrointestinal upset and could affect patient adherence to treatment. Thus, each patient should be assessed individually before prescription of oral or IV iron (Murphy et al., 2010).

Treatment for iron deficiency can be started with oral elemental iron 200 mg divided into three doses per day for 3 months; this treatment depends on if the patient tolerates oral iron. If iron deficiency is not reversed after 3 months or the patient is intolerant of oral iron, intravenous iron can be considered (Taliercio, 2010). In patients found to be inappropriate for oral iron use, IV iron can be initiated directly. Patients should receive a trial of IV iron, with close assessment continued for 60 minutes after the trial transfusion, before IV maintenance treatment is initiated; the patient thus can be monitored for iron toxicity or anaphylaxis (KDIGO, 2012). Finding an appropriate maintenance dose of iron is essential in maintaining good anemia management in patients with CKD, and helps in decreasing needed ESA doses and improving Hgb levels (Nguyen & Wells, 2011).

The most common intravenous iron products include iron dextran (Cosmofer[R]), ferric carboxymaltose (Ferinject[R]), and iron sucrose (Venofer[R]) (Murphy et al., 2010). A recent randomized control trial found ferric carboxymaltose to be superior to oral iron in its efficacy (MacDougall et al., 2014). Assessment of patients with iron deficiency anemia and non-dialysis-dependent CKD showed those receiving IV ferric carboxymaltose to a target ferritin level of 400-600 ug/L had a significantly faster increase of 1 g/dL of Hgb when compared to the oral iron group (p=0.014), with no significant difference in adverse effects between the groups. In addition, patients receiving the IV iron had a delayed or decreased need for ESAs and other anemia management therapy.

Treatment of iron deficiency is usually conservative. Each medication dose is followed by assessment of iron need and clinical status, ferritin and TSAT values, and response to iron therapy. In patients receiving ESA therapy, ESA responsiveness and dose also are assessed (KDIGO, 2012).

Erythropoietin Stimulating Agents

Erythropoietin stimulating agents have improved quality of life for patients with CKD and decreased patients' need for frequent transfusions. These medications also decrease mortality and morbidity for patients with CKD because of their effective treatment of anemia (Szromba, 2009). However, controversy exists about how much correction of anemia to seek with ESA therapy. Two major trials were completed to address this issue: the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) and the CREATE (Cardiovascular Risk Reduction by Early Anemia Treatment) trials.

The CHOIR trial (Inrig et al., 2012) was undertaken to determine if targeting high hemoglobin levels would improve kidney outcomes. Epoeitin alpha was given subcutaneously to two groups. However, the study was stopped early because it showed a trend toward increased hospitalization and CHF exacerbations in the group targeted to have a hemoglobin of 13.5 g/dl vs. another targeted at 11.3 g/dl. Furthermore, a secondary analysis of this study found targeting higher Hgb levels led to faster CKD progression. The CREATE trial (Drueke et al., 2006) found no significant difference in decreased cardiovascular complications in patients targeted to have normal Hgb (13-15 g/dl) vs. those targeted to have lower values of 10.5-11.5 g/dl.

Another pivotal trial for ESA use for anemia management was the Trial to Reduce Cardiovascular Events with Aranesp Therapy (TREAT) (Goldsmith & Covic, 2010). It compared two groups: one receiving darbapoeitin alpha (Aranesp[R]) to achieve Hgb levels above 13 g/dl, and a placebo group allowed to have Hgb as low as 9 g/dl without treatment (with an emergency plan to elevate Hgb). Patients receiving ESA to a target Hgb of 13 g/dL were almost twice as likely to have a stroke as patients receiving the placebo who were targeted to have a lower Hgb. In addition, no overall cardiovascular or renal improvement was witnessed with early anemia correction. A secondary analysis of the TREAT trial suggests ESA therapy be used sparingly in cases of moderate anemia in patients with CKDs. However, ESAs remain beneficial in treating symptomatic anemia alongside iron therapy and possible transfusions. This controversy makes clinicians weigh risks vs. benefits very carefully before targeting high hemoglobin; this is why the KDIGO 2012 guidelines recommend targeting Hgb of 11.5 g/dl.

Erythropoietin stimulating agents in general have the same mechanism of action as endogenous EPO, but each agent differs slightly in pharmacodynamic and pharmacokinetic properties. Agents used are epoeitin alpha (Epogen[R], Procrit[R]), darbepoeitin alpha, and peginesatide (Omontys[R]) (Dutka, 2012). During the initiation phase of ESA management, Hgb should be monitored at least once monthly, and later once every 3 months. The initial dose of ESA should be based on individual Hgb values as well as patient's weight and clinical status. General recommendations indicate transfusions should be avoided due to their associated risks; however, transfusions may be necessary in patients who have not been responsive to ESA therapy or cannot receive ESAs (e.g., persons with history of malignancy, stroke). Moreover, transfusions are the preferred treatment of anemia in emergency situations to raise Hgb rapidly, such as in hemorrhage (KDIGO, 2012).

Special Patient Populations

Erythropoietin stimulating agents may have several side effects in specific patient populations. For example, they need to be used in caution in patients with high blood pressure and stroke because they tend to exacerbate hypertension and increase the risk for stroke (Palmer et al., 2010). Erythropoietin-stimulating agent therapy in persons with cancer has contributed to shortened survival as well as progression of tumor cells in head, neck, breast, cervical, and non-small cell lung cancer. Therefore, ESAs are not indicated for use in oncology patients with CKD who are receiving myelosuppressive therapy if the intent is to cure the patient. If the intent is palliative, then the minimal dose of ESAs should be used only to avoid using blood transfusions to treat the anemia (Bennett, Becker, Kraut, Samaras, & West, 2009).

Due to the prevalence of anemia of CKD, its effect on public health population, and the financial burden it imposes on health care institutions (NIDDKD, 2013), nurses should be prepared to manage this disease alongside other health care providers. Ensuring good outcomes and patient adherence will decrease the disease burden and improve quality of life (Szromba, 2009).

Role of the Clinical Nurse Specialist

The clinical nurse specialist (CNS) plays a major role in the management of patients with CKD, as well as in the maintenance of their well-being. As an expert clinician, the CNS performs a thorough assessment of the patient for any signs of co-morbidities such as anemia. The nephrology CNS also may assess patient response to treatment through blood tests for Hgb and iron stores, and recommend dosage adjustments for prescribed medications. The CNS is an expert resource on CKD-related anemia for other nurses. Moreover, the CNS collaborates with other members of the multidisciplinary team, and acts as a facilitator between the patient and other health care providers. This fortifies the provision of multidisciplinary care, ensures comprehensive disease management for the patient, and allows the patient to make health-related decisions more effectively (Harrison & Watson, 2011).

As an educator, the CNS helps clinical care nurses develop competence in working with anemic patients with CKD. For example, the CNS may develop formal educational programs concerning diagnosis guidelines, anemia management guidelines, appropriate protocols for followup, and special considerations in patients with cancer or hypertension. Moreover, the CNS has a major role in educating patients about their disease process, symptom management, nutritional status, and medication regimen (Murphy et al., 2010). The CNS may provide disease and treatment updates to medical and nursing staff. In collaboration with the multidisciplinary team, the CNS can create protocols for the management of anemia, and develop or participate in revision of guidelines and policies (Wickham, 2014). This increases the uniformity of patient management, expands evidence-based practice, and improves patient outcomes and treatment adherence. The use of these protocols may improve patients' Hgb values and decrease ineffective response to treatment (Murphy et al., 2010).

A randomized controlled trial assessed the efficacy of a nurse-led CKD management program (Wong, Chow, & Chan, 2010). Participants included CNSs and generalist nurses. Findings indicated significant improvement in patient adherence and several measures of quality of life, along with overall improvement in patient satisfaction, as a result of nurse involvement.


The treatment of CKD-related anemia can improve the patient's quality of life and decrease the risk of related death. However, care must be taken about the extent of treatment based on Hgb values in order to avoid serious complications, such as LVH, CHF, stroke, and ischemic heart disease. Possible reasons for the anemia should be assessed consistently, and iron deficiency or vitamin [B.sub.12] or folate deficiency corrected before initiating ESA therapy (Taliercio, 2010). Care should be taken in the management of specific patients, such as those with hypertension or cancer diagnoses, because of concerns related to ESA therapy in these groups (Bennett et al., 2009). Finally, the CNS plays a pivotal role in continued nurse and patient education as well as evidence-based protocol creation for increased quality of care. Involvement of the CNS can improve patient adherence to treatment for better outcomes (Murphy et al., 2010; Sherwood & Zomorodi, 2014; Wong et al., 2010).


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Rachele Bejjani, MSN, RN, is Registered Nurse, Intensive Care Unit, American University of Beirut Medical Center, Beirut, Lebanon.
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Title Annotation:Advanced Practice
Author:Bejjani, Rachele
Publication:MedSurg Nursing
Date:Jan 1, 2015
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