Continuing Education Activity

Anemia of chronic renal disease, also known as anemia of chronic kidney disease (CKD), is a form of normocytic, normochromic, hypoproliferative anemia. It is frequently associated with poor outcomes in chronic kidney disease and confers an increased mortality risk. Treatment is directed toward improving renal function, when possible, and increasing red blood cell production. Erythropoiesis-stimulating agents, together with iron supplementation, constitute the treatment of choice for anemia of chronic renal disease. This activity reviews the evaluation and management of the anemia of chronic renal disease and highlights the role of the interprofessional team in the care of individuals affected by this condition.

Objectives:

• Explain the pathophysiology of anemia of chronic renal disease.
• Explain how to diagnose anemia of chronic renal disease.
• Explain the management of anemia of chronic renal disease.
• Explain the interprofessional team strategies for improving coordination and communication to enhance the management of patients with anemia of chronic renal disease.

Introduction

Anemia is generally defined as hemoglobin of less than 13.0 g/dL in men and less than 12.0 g/dL in premenopausal women.[1] Anemia of chronic kidney disease (CKD) is a form of normocytic normochromic, hypoproliferative anemia. Among other complications of CKD, it is frequently associated with poor outcomes in CKD and increases mortality.[2][3]

The disorder starts to develop when the glomerular filtration rate drops to below 60 mg/ml. The anemia is rare when the GFR is above 80 mg/ml. As the GFR worsens, the anemia gets more severe.

Etiology

Anemia in chronic renal disease is a multifactorial condition, the widely accepted etiology being decreased renal production of erythropoietin, the hormone that is responsible for the stimulation of red blood cells production. Decreased erythropoietin has recently linked with downregulation of hypoxia-inducible factor (HIF), a transcription factor that regulates gene expression of erythropoietin.[4][5] Other mechanisms include uremia (leading to RBC deformity responsible for hemolysis), folate and vitamin B12 deficiency, iron deficiency, bleeding due to dysfunctional platelets, and rarely blood loss from hemodialysis.[6] RBC fragmentation by injured renovascular endothelium in selected conditions such as glomerulopathy and malignant hypertension exacerbates the anemia, which explains why anemia can be particularly severe in renal glomerulopathies, including glomerulonephritis, diabetic nephropathy, for the degree of excretory failure.

Epidemiology

The condition usually starts to develop following a greater than 50 percent loss of the kidney function, typically when the glomerular filtration rate (GFR) decreases to less than 60 mL/min.[7] The severity of anemia tends to worsen as chronic kidney disease (CKD) progresses. The deficiency in renal production of erythropoietin and the severity of anemia do not always tend to correlate with the severity of renal dysfunction. At least 90% of patients who end up on dialysis will eventually develop anemia of chronic disease.

History and Physical

Clinical presentation of anemia of renal disease is not different from that of anemia due to other causes. Common symptoms include:

• Dyspnea (shortness of breath)
• Fatigue
• Generalized weakness
• Headaches
• Decreased concentration
• Dizziness
• Reduced exercise tolerance.

Commonly observable signs include:

• Skin and conjunctival pallor
• Respiratory distress
• Tachycardia
• Chest pain (mostly with severe anemia)
• Heart failure (usually with chronic severe anemia)

Evaluation

Common workup required to diagnose the condition include,

• CBC with differential
• Peripheral smear
• Iron indices (iron, ferritin, TIBC, transferrin saturation)
• Iron, vitamin B, and folate levels (included in initial workup to rule out other reversible causes of anemia)
• Thyroid function tests (rule out alternate etiology of hypoproliferative normocytic anemia).

Normocytic normochromic anemia and peripheral reticulocytopenia are observable on CBC with a peripheral smear. 

Unfortunately, due to high serum ferritin levels secondary to chronic inflammation in CKD, serum iron indices are not accurately indicative of the degree of iron deficiency in dialysis patients, thus raising the standard cutoffs of iron responsiveness.[8][9] The Dialysis Patients’ Response to IV Iron With Elevated Ferritin (DRIVE) study demonstrated that intravenous iron is beneficial in dialysis patients even in the setting of ferritin as high as 1200 ng/mL if the transferrin saturation is less than 30%.[10]

Measuring serum erythropoietin levels are discouraged in CKD, and is not usable as an indicator of a renal source of the anemia, because, in kidney disease, there is 'relative erythropoietin deficiency,' that is, an inappropriate rise in erythropoietin levels for the severity of anemia.[11][12]

Bone marrow may show erythroid hypoplasia, which correlates to the reports of resistance of bone marrow to erythropoietin.

Treatment / Management

Treatment directs toward improving renal function (when possible) and measures aimed at increasing red blood cells production. ESAs, together with iron supplementation, is the treatment of choice in anemia of CKD.

Treatment of anemia in CKD has come a long way. Before the advanced treatment options that are available today, the main treatment option used to be blood transfusions, which came with numerous complications including infections, hemosiderosis, fluid overload, transfusion reactions, etc. It started with the use of androgens in the 1970s to avoid transfusion in patients with CKD.[13][14] After that, in the 1980s, the development of recombinant EPO followed by erythropoiesis-stimulating agents (ESAs) revolutionized the management of anemia in CKD.[15] Although initially instituted to avoid transfusions, they were soon known to have various positive effects, including improved survival and quality of life, improved cardiac function and mortality associated with it,[16] lower hospitalizations,[17] and lower costs.[18] 

Recombinant human erythropoietin and darbepoetin alfa are the two ESAs generally used in the management of anemia in CKD. They are fairly similar in efficacy and side effect profile, except for the longer half-life of darbepoetin alfa, thus allowing for less frequent dosing.[19][20]

As per KIDGO guidelines, in patients with CKD who are not on dialysis, ESAs are typically considered when hemoglobin level drops below 10 g/dl, but is individualized depending on various factors, including symptoms related to anemia, dependence on transfusions, the rate of drop in hemoglobin concentration, and response to iron therapy. In these patients, erythropoietin (50 to 100 units/kg IV or SC) is usually given every 1 to 2 weeks, and darbepoetin alfa dosing is every 2 to 4 weeks.

In patients who are on dialysis, ESAs are usually avoided unless the hemoglobin level is between 9 and 10 g/dL. In this subset, erythropoietin is given with every dialysis, i.e., three times a week, whereas darbepoetin alfa is dosed to once a week.

Generally, the peak rise in RBCs in response to ESAs occurs at 8 to 12 weeks. However, in around 10% to 20% of cases, anemia can be resistant to ESAs. Common adverse effects of ESAs include seizures, the progression of hypertension, clotting of dialysis access, the progression of malignancy and higher mortality in cancer patients.[21][15] 

In all patients with CKD, regardless of the need for dialysis, goal hemoglobin with the use of ESAs is less than 11.5 g/dL. Multiple trials were done to assess the superiority of target hemoglobin to 'high normal' versus lower range. These trials, including CHOIR, NHCT and TREAT trials demonstrated higher mortality, thrombosis, adverse cerebrovascular and cardiovascular events due to higher levels of ESAs when used for target hemoglobin greater than 11 g/dl.[22][23][24] These events are likely related to the effect of ESAs on vascular remodeling and causing vasoconstriction.[25] CHOIR trial also showed that patients requiring higher levels of ESAs to achieve target hemoglobin had worse outcomes.[22] The discovery of stated side effects of ESAs, when used to target high normal hemoglobin levels, raised questions about the benefits of ESAs beside avoidance of transfusions, which has led to growing interest in looking for alternative etiologies and thus, management for anemia of CKD.

Patients with CKD have increased risk of iron deficiency, due to impaired dietary iron absorption, chronic bleeding due to platelet dysfunction from uremia, frequent phlebotomy, and blood trapping in the dialysis apparatus. This deficiency, in addition to depletion of the circulating iron pool by stimulation of erythropoiesis by ESAs, makes iron supplementation the core of treatment of anemia in CKD. Due to decreased absorption of oral iron, intravenous iron is preferable in hemodialysis patients.[26][27]

KIDGO recommends target transferrin saturation between 20 to 30% and ferritin level 100 to 500 ng/mL in patients with CKD who are not on dialysis. In patients with ESRD on dialysis receiving intravenous iron, goal transferrin saturation of 30 to 50% and ferritin higher than 200 ng/mL.[28] Iron has correlations with a risk of acute toxicity and infection, which should be weighed against the benefits in individual patients.

Unlike the general population, high serum ferritin levels are not predictive of hemoglobin responsiveness in renal failure patients. Finally, there is no level of erythropietin that can be considered adequate for defining renal anemia. Thus, erythropoietin levels should not regularly be measured in the evaluation of patients with renal anemia.

Differential Diagnosis

• Acute Kidney Injury
• Adrenal Crisis
• Alcohol abuse
• Aplastic anemia
• Anal fistulas and fissures
• Coccidioidomycosis
• Cushing syndrome
• Dengue fever
• Dialysis complications
• Disseminated intravascular coagulation
• Diverticulitis
• Dysfunctional uterine bleeding
• Dysmenorrhea
• Hemophilia type A
• Hemophilia type B
• Hemorrhoids
• Henoch-Schoenlein purpura
• Hypothyroidism
• Inflammatory bowel disease
• Malaria
• Methemoglobinemia
• Mononucleosis
• Mycoplasma pneumonia
• Myxedema Coma
• Rheumatoid arthritis
• Sarcoidosis
• Sickle cell anemia
• Systemic lupus erythematosus
• Tuberculosis (TB)

Prognosis

There are many patients with renal failure who will not respond to erythropoiein and this is important as it is an important predictor of adverse cardiac events. Two factors that lead to unresponsiveness include iron deficiency and inflammation. High levels of CRP predict resistance to erythropoietin in dialysis patients. To enhance responsiveness to erythropoietin, iron supplements are recommended.

Complications

Anemia of renal disease is an independent risk factor for death. It has been shown to promote faster progression of left ventricular hypertrophy, peripheral oxygen demand and worsening of cardiac outcomes. More important anemia of renal failure leads to depression, fatigue, stroke, reduced exercise tolerance and increased rate of re-admissions.

Long term treatment with erythropoietin can cause hypertension, vasoconstriction, and seizures.

Deterrence and Patient Education

Eat a healthy diet

Take iron and multivitamin supplements

Pearls and Other Issues

1. Anemia of renal disease is common and is chiefly due to a decrease in erythropoietin production
2. It is necessary to investigate other treatable causes of anemia in renal failure patients
3. Anemia of renal disease is associated with adverse cardiac events, heart failure, MI and death.
4. Erythropoietin levels are not indicative of anemia in renal failure patients. One should target a hemoglobin level of no more than 11.5 g/dl.

Enhancing Healthcare Team Outcomes

The management of the anemia of CKD is complex because it is not a simple matter of giving patients more blood transfusions or erythropoietin. Both these products have serious adverse effects when given chronically. One should never assume that anemia of renal disease is solely due to lack of erythropoietin, it may be due to poor nutrition or chronic illness- so a thorough workup is essential to determine the cause.

To manage patients on dialysis with anemia requires an integrated approach by an interprofessional team consisting of the nephrologist, PCP including the nurse practitioner, physician assistant, physician, nursing, pharmacy, and occasionally also a hematologist may be necessary to help achieve the best possible outcomes. The dialysis nurse should always monitor vital signs and obtain total blood counts to determine the level of anemia. The pharmacists should educate the patient about the importance of iron supplements because without iron, many patients develop resistance to erythropoietin. 

Further, anemia of renal disease is also associated with adverse cardiac outcomes and hence the patient's cardiopulmonary status has to be monitored for life.

Finally, the involvement of a nutritionist is essential for avoidance and/or treatment of the deficiency of vitamins that can exacerbate the anemia of kidney disease.

Outcomes

The outcomes for patients with anemia of renal disease are guarded. Many develop adverse cardiac events that lead to a high mortality rate. Too much iron from blood transfusions also affects outcomes. Finally, chronic use of erythropoietin has been associated with severe hypertension, stroke and heart failure. AN interprofessional team approach will maximize positive outcomes and minimize adverse events. [Level 5]