By definition, anemia refers to an absolute reduction of the total number of circulating red blood cells (RBCs). For practical purposes, anemia is considered when one or more of the following are decreased: hemoglobin, hematocrit, or red blood cell (RBC) count. This condition is a laboratory finding that signifies the presence of illness or disease; anemia should not be considered a diagnosis.
Anemia usually is grouped into three etiologic categories: decreased RBC production, increased RBC destruction, and blood loss. Anemia of chronic illness and anemia of chronic kidney disease(CKD) both fall under the category of decreased RBC production. When the classification of anemia is based on the morphology of the RBCs, both anemia of chronic illness and chronic kidney disease usually fall under the classification of normochromic, normocytic anemia.
Mechanism of Anemia of Chronic Disease
Anemia of chronic illness traditionally encompassed any inflammatory, infectious, or malignant disease of a long-standing nature. The modern definition includes rheumatoid arthritis, severe trauma, heart disease, and diabetes mellitus. In these conditions, there is primarily a decreased availability of iron, relatively decreased levels of erythropoietin, and a mild decrease in the lifespan of RBCs to 70-80 days (normally 120 days). 
Relatively recently, hepcidin, an endogenous antimicrobial peptide secreted by the liver, has been identified [2, 3, 4] as controlling the level of plasma iron by regulating the intestinal absorption of dietary iron, as well as the release of iron from macrophages and the transfer of iron stored in the hepatocytes. Increase in hepcidin level in the course of inflammatory disease may be a significant mediator of the accompanying anemia. [2, 3, 4]
Another proposed mechanism for anemia of chronic illness deals with cytokines, such as interleukins (IL-1 and IL-6), and tumor necrosis factor (TNF-alpha), which are believed to cause the destruction of RBC precursors and decrease the number of erythropoietin receptors on progenitor cells. [5, 6, 7]
Whereas hypoxia in the individual with normal functioning kidneys leads to erythropoietin gene transcription, and hence increased RBC production, in those with anemia of chronic kidney disease, there is primary deficiency of erythropoietin production by the interstitial fibroblasts, also known as type I interstitial cells, thereby leading to anemia. The anemia that develops is directly related to the amount of residual renal function.  The kidneys are responsible for approximately 90% of erythropoietin production in an individual.
Prevalence of Anemia of Chronic Disease and CKD
In general, anemia is more common in women, in particular, those in their childbearing years. In the latter decades of life, anemia tends to occur without any particular sex predilection. However, in anemia of chronic kidney disease, males have a 30% greater risk of developing anemia as compared to their female counterparts. Although males have higher hemoglobin values, they also have higher rates of advanced chronic kidney disease. There has been a lower prevalence of anemia in current smokers, which has been attributed to secondary erythrocytosis.
Anemia is common in patients with chronic kidney disease. The landmark study by Obrador et al showed that among predialysis patients, 68% of those with advanced chronic kidney disease who required renal replacement therapy had a hematocrit less than 30 mg/dL; of these, 51% of patients had a hematocrit less than 28 mg/dL.  Furthermore, although anemia is not as common in earlier stages of chronic kidney disease, patients with stage III disease have a prevalence of concurrent anemia of 5.2%, whereas those with stage IV disease have a prevalence of concurrent anemia of 44.1%. 
There is also a greater prevalence of anemia of chronic kidney disease in those older than 60 years, as compared to those aged between 46 and 60 years (see Anemia in Elderly Persons). This is probably secondary to the greater rate of chronic kidney disease in older individuals, as well as the lower estimated glomerular filtration rates (GFRs) that are associated with aging.
Black individuals have not only a 4-fold increased risk of developing chronic kidney disease relative to white persons  but also an increased prevalence of anemia.
The morbidity and mortality depend greatly on the underlying etiology of the patient's anemia as well as the stage of the disease, whether early or advanced. In fact, in individuals with advanced stages of chronic kidney disease, the etiology of anemia tends to be multifactorial (eg, decreased RBC production due to lack of erythropoietin, increased RBC destruction due to hemolysis [intravascular or extravascular], as well as increased blood loss due to multiple venipunctures for an array of indications).
Evaluation of Anemia and CKD
Symptoms and physical findings
Although the diseases that lead to anemia, such as malignancy or chronic kidney disease, may cause obvious symptoms, the anemia itself tends to cause quite nonspecific symptoms. Clinicians must be wary of the tendency to dismiss these symptoms as insignificant—for example, as being due to old age—when in fact they should serve as alarming signals of disease or pathology.
Patients with anemia of chronic disease or CKD may present with the following symptoms:
Generalized weakness or malaise, easy fatigability
Generalized body aches, or myalgias
Orthostatic symptoms (eg, lightheadedness, dizziness)
Syncope or near-syncope
Decreased exercise tolerance
Inability to concentrate
Loss of appetite
The following physical findings may be noted:
Skin - Pallor
Neurovascular - Decreased cognitive ability
Eyes - Pale conjunctivae
Cardiovascular - Orthostatic hypotension, tachyarrhythmias
Pulmonary - Tachypnea
Abdomen - Ascites, hepatosplenomegaly
Other causes of normochromic, normocytic anemia and decreased RBC production (hypoproliferative) should be noted, and conditions involving the bone marrow and secondary conditions involving the liver and endocrine system should be assessed.
Diseases primarily involving the bone marrow
The following diseases should be included in the differential diagnosis:
Myelophthisic anemia (see the image below)This blood film at 1000X magnification demonstrates a leukoerythroblastic blood picture with the presence of precursor cells of the myeloid and erythroid lineage. In addition, anisocytosis, poikilocytosis, and polychromasia can be seen. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Myeloid metaplasia (see the image below)Peripheral smear from a patient with agnogenic myeloid metaplasia. This image shows the presence of teardrop red blood cells (RBCs) and a leukoerythroblastic picture with the presence of nucleated RBC precursors and immature myeloid cells. Courtesy of Wei Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.
The following conditions should also be evaluated:
Liver disease – Cirrhosis
Other causes of normochromic, normocytic anemia and decreased RBC production (hypoproliferative) should be noted.
The following four laboratory tests are vital in the evaluation of anemia of chronic illness or chronic kidney disease:
Peripheral blood smear
Bone marrow biopsy (optional in most cases)
Laboratory tests that may help eliminate other common causes of anemia include the following:
Iron panel – serum iron, ferritin, total iron-binding capacity (TIBC), iron saturation (see Role of iron under Management of Anemia of CKD)
Serum vitamin B12 and folic acid
Serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT)
Thyroid-stimulating hormone (TSH)
Electrophoretic studies of serum and urine
Serum levels of heavy metals (eg, lead, arsenic)
A low reticulocyte count usually points to decreased RBC production as the primary mechanism responsible for anemia, whereas an elevated reticulocyte count points to increased RBC destruction or hemolysis as the most likely cause.
Although decreased RBC production is the main mechanism in both anemia of chronic illness and anemia of chronic kidney disease, oftentimes the anemia is due to a combination of events, including concomitant blood loss. Therefore, a reticulocyte count should always be interpreted with caution.
Serum Erythropoietin Levels
Measurement of serum erythropoietin levels is of no current diagnostic utility in patients with chronic kidney disease, as it is expected to be low. Neither does it influence the starting dose or any adjustment in dosing of erythropoiesis-stimulating agents (ESAs) in such patients; these agents may have some use, however, in patients with anemia secondary to chronic illness. In addition, regression of left ventricular hypertrophy (LVH) is a known-benefit of initiation of treatment with ESAs.
In general, patients with anemia of chronic illness or chronic kidney disease can be treated on an outpatient basis. Confounding factors that need to be addressed in both diseases include concomitant blood loss, iron deficiency, or deficiencies of vitamin B12 and/or folic acid.
The preferred initial form of therapy for anemia of chronic illness is treatment of the underlying disease. Use of erythropoiesis-stimulating agents (ESAs) and blood transfusion are reserved for severe and symptomatic cases. Administration of ESAs is usually best done under the auspices of a hematologist or nephrologist, who may be more adept regarding the latest guidelines on the uses of such agents, as well as for insurance policy coverages.
Hemoglobin target levels
What are the appropriate target levels for the correction of anemia? This issue has received much recognition in connection with published literature in which it was demonstrated that targeting higher hemoglobin levels may relate positively with higher rates of death and cardiovascular disease death, as well as positively with an increased risk of death, overall. Two of the trials relating to patients with cardiovascular disease will be discussed here.
Two landmark trials tried to address the controversial issue of the upper limit to target hemoglobin concentration, namely, the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE)  and the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR)  studies. As a result of the CREATE and CHOIR studies, in March 2007, the US Food and Drug Administration (FDA) issued a black box warning to the labeling of epoetin alfa (Procrit) and darbepoetin alfa (Aranesp) to emphasize that use of these ESAs may increase the risk of serious cardiovascular events and death when they are dosed to achieve a target hemoglobin of greater than 12 g/dL.
This warning was again updated in November 2007, at which time, the FDA stated that "ESAs should be used to maintain a hemoglobin level between 10 g/dL to 12 g/dL. Maintaining higher hemoglobin levels in patients with chronic kidney failure increases the risk for death and for serious cardiovascular reactions such as stroke, heart attack or heart failure." 
The FDA further recommends that hemoglobin be measured twice per week for 2-6 weeks after a dose adjustment, the purpose of which is to ascertain that the hemoglobin has had enough time to stabilize in response to the dose adjustment. Moreover, the FDA recommends withholding the dose of the ESA if the hemoglobin is greater than 12 g/dL or increases by 1 g/dL over a 2-week period. The latter recommendation is in stark contrast to what has been done in most clinical practices until recently.
With these latest developments, the current clinical management of anemia in chronic kidney disease will certainly be significantly affected.
Likewise, the 2007 National Kidney Foundation update of the target hemoglobin recommendation stated that, although the lower limit of the target hemoglobin range remains 11 g/dL, the target range is 11–12 g/dL, and patients who have already or are currently receiving an ESA should maintain a hemoglobin target of less than 13 g/dL. 
To examine the impact of target hemoglobin level on progression of kidney disease in the CHOIR (Correction of Hemoglobin and Outcomes in Renal Insufficiency) trial, a post-hoc analysis was performed which showed that a high hemoglobin target may be associated with a greater risk of progression of CKD, which is apparently augmented by concurrent smoking.
Participants randomly assigned to higher hemoglobin targets experienced shorter time to progression of kidney disease in both univariate and multivariable models and these differences were attributable to higher rates of renal replacement therapy and death for participants in the high hemoglobin arm. Hemoglobin target did not interact with estimated glomerular filtration rate, proteinuria, diabetes, or heart failure. In the multivariable model, hemoglobin target interacted with tobacco use such that the higher target had a greater risk of CKD progression for participants who currently smoked, which was not present for those who did not currently smoke. 
Management of Anemia of CKD
The preferred initial form of therapy for anemia of chronic kidney disease is the use of erythropoiesis-stimulating agents (ESAs). ESAs available in the United States include epoetin alfa (Epogen) and darbepoetin alfa (Aranesp). The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-DOQI) guidelines recommend a target hemoglobin in the range of 11 to 12 g/dL, and the hemoglobin should not exceed 13 g/dL.  These goals are associated with lower mortality and less frequent hospitalization rates.
Several trials have been conducted to provide more information regarding the use of ESAs and hemoglobin targets. The Trial to Reduce Cardiovascular Events With Aranesp® Therapy (TREAT) resulted in two reports raising concern about the current use of target-based strategies in managing anemia of chronic kidney disease. The initial report indicated an increased risk of stroke and no reduction in the risk of death or a cardiovascular or renal event with darbepoetin alfa. 
The second report noted that when doses of darbepoetin alfa were increased to meet target hemoglobin levels in patients with a poor initial hematopoietic response, the subsequent risk of death or cardiovascular invents increased.  (See Cardiovascular disease under Complications of Anemia of Chronic Disease and CKD, as well as Hemoglobin target levels under Treatment Considerations.)
The STIMULATE Study was intended to study health-related quality of life outcomes in elderly patients with anemia of chronic kidney disease who were treated with an ESA. However, the study was terminated due to difficulty with recruitment and timely enrollment.
The NEPHRODIAB2 Prospective Randomized Controlled Open-Labelled Trial Comparing Effect of Two Haemoglobin levels, which was conducted in patients with type 2 diabetes mellitus and stage 3-4 CKD, found that raising hemoglobin to the normal range (130-140 g/L) with ESA treatment was safe but did not significantly slow renal function decline and increased treatment cost. 
Methoxy polyethylene glycol-epoetin beta (Mircera) is a third-generation, pegylated epoetin (PEG-EPO) beta under the new category of a continuous erythropoietin receptor activator (CERA) that was approved by the FDA in 2007 for the treatment of anemia of chronic kidney disease. In Phase 3 trials, methoxy polyethylene glycol-epoetin beta was given every 2 or 4 weeks, with both regimens achieving hemoglobin targets. Disadvantages of this agent include concerns about possibility of PRCA. In addition, in 2009, the FDA upheld a 2008 injunction against the marketing of methoxy polyethylene glycol-epoetin beta by Roche due to infringement of several Amgen patents.
Peginesatide (Hematide) is a pegylated, peptidic ESA (also called an erythropoietin mimetic [EPO mimetic]) that was approved in the United States in March 2012 for treatment of anemia of chronic kidney disease, but was discontinued in February 2013 following postmarketing reports of severe hypersensitivity, including fatalities.  This agent binds to the erythropoietin receptor, thereby activating intracellular signaling pathways. The advantages of peginesatide include low immunogenicity and no structural homology to endogenous or exogenously administered ESAs.
The EMERALD study found that the effectiveness of peginesatide was not inferior to epoetin for patients receiving dialysis.  Similarly, the PEARL study found peginesatide was not inferior to darbepoetin for patients with chronic kidney disease who were not receiving dialysis.  However, safety endpoints (ie, cardiovascular events and death) were worse for peginesatide than for darbepoetin in the PEARL study.
In kidney transplant recipients, the Correction of Anaemia and Progression of Renal Failure on Transplanted Patients found that correction of hemoglobin values to 13 g/dL or higher reduces progression of chronic allograft nephropathy. No increase in cardiovascular events was noted. 
Adverse effects of ESAs
Long-term treatment with ESAs has been associated with increased systemic blood pressure and occurrence of seizures; hypertension has been documented to be a common side effect of intravenous use of ESAs. For this reason, blood pressure should always be closely monitored in patients administered with such agents. The postulated mechanism is believed to be an imbalance between endothelin and proendothelin that leads to hyperresponsiveness to the effects of norepinephrine (vasoconstriction) and hyporesponsiveness to the effects of nitric oxide (vasodilatation).
Reports of neutralizing "anti-epoetin antibodies" have been linked to the unusual occurrence of pure red cell aplasia (PRCA) in European cohorts, but this finding has been attributed to the difference in immunogenicity of the ESAs marketed between the US and Europe.
The working definition of ESA resistance is the requirement for greater than 150 units/kg of ESA at least 3 times per week or the sudden response refractoriness to a previous stable maintenance dose, such that hemoglobin levels fall below target levels.
The most common cause of ESA resistance is iron deficiency. Therefore, it is imperative that iron stores are adequate during ESA treatment. The second most common cause of ESA resistance is a chronic infection/inflammatory state, and such resistance is attributed to inflammatory cytokines (eg, IL-1).
Other less common causes of ESA resistance include hyperparathyroidism (the mechanism appears to be related to bone marrow fibrosis), as well as severe malnutrition.
Role of iron
As noted above, iron deficiency is the most common identifiable cause of ESA resistance. The 2 most important tests to order to assess iron deficiency are transferrin saturation and serum ferritin.
The importance of these tests lie in the fact that even the diagnosis of iron deficiency anemia is not truly straightforward. In anemia of chronic kidney disease, there is primarily an imbalance between the iron required for erythropoiesis versus the amount released by the reticuloendothelial tissues. This is referred to as functional iron deficiency, which is characterized by a transferrin saturation (TSAT) less than 20% and a ferritin level less than 100 ng/mL.
However, clinicians must be aware that ferritin is an acute phase reactant that can be elevated in states of chronic infection or inflammation. Therefore, an elevated ferritin does not necessarily imply iron store adequacy or overload. Current guidelines recommend against use of iron products when ferritin is 500 ng/mL or greater.
At present, various new potential markers of iron status are being developed and experiments are under way, identifying each and every minute component that may be involved in the mobilization of iron throughout the body. One of these markers is an endogenous antimicrobial peptide, hepcidin. The possible central role of hepcidin in the pathogenesis of anemia of chronic disease is an interesting one that has been the subject of numerous publications. [2, 3, 4]
There are some newer agents that may aid in the treatment of anemia in chronic illness or chronic kidney disease.  Some of these have been approved and others are experimental.
In January 2015, the FDA approved ferric pyrophosphate (Triferic), a soluble iron replacement therapy, which is added to the hemodialysate solution. Approval was based on the PRIME study that showed soluble ferric pyrophosphate to be erythropoiesis-stimulator agent (ESA) sparing. Patients (n=103) were randomized to receive ferric pyrophosphate in dialysate or standard dialysate. The researchers found that ferric pyrophosphate was able to maintain hemoglobin and not increase ferritin, while significantly reducing the use of ESAs by 37.1% compared with regular dialysate. 
Examples of intravenous iron replacement therapies include the following:
Iron dextran complex (Dexferrum, INFeD)
Iron sucrose (Venofer)
Ferric carboxymaltose (Injectafer)
Ferric fluconate (Ferrlecit)
Hypoxia inducible factor (HIF) is a key regulator of erythropoietic gene expression, iron absorption, energy metabolism, pH, and angiogenesis; as its name implies, HIF is induced by hypoxia. HIF stabilizers drive endogenous erythropoietin production by the kidney (or by extrarenal sources [eg, liver]) Advantages of these agents include the fact that they are orally active, and some mechanistic and in vitro data suggest their role in inducing or increasing vascular reactivity.
FG-2216 is a first-generation inhibitor of a family of prolyl hydroxylases that facilitate the degradation of HIF. This agent currently remains investigational in the treatment of anemia.
Complications of Anemia of Chronic Disease and CKD
Hypoxia is the most potent stimulus to the production of erythropoietin by the kidneys. In the healthy individual, erythropoietin exerts its effects in the bone marrow to help in the production of RBCs, thereby improving oxygen concentration in the blood, relieving the hypoxia.
Another complication that commonly occurs in those with chronic kidney disease is that of secondary hyperparathyroidism and the development of renal osteodystrophy. In these patients, the bone marrow tends to be fibrotic and, hence, less responsive to the effects of erythropoietin.
Cardiorenal anemia syndrome
Silverberg et al described the "cardiorenal syndrome," which refers to a vicious cycle, whereby decreased kidney function, as seen in chronic kidney disease, leads to decreased erythropoietin production and, thence, anemia. 
Anemia, if severe, leads to a compensatory left ventricular hypertrophy (LVH). Such compensatory LVH eventually leads to precipitation of congestive heart failure (CHF), which causes a decline in blood perfusion to the kidneys, resulting in further kidney damage. Levin et al estimated that for every 1-g decrease in hemoglobin concentration, there is an increased 6% risk of LVH in patients with chronic kidney disease.  Foley et al estimated that such a 1-g decrease in hemoglobin concentration also translated into a 42% increase in left ventricular dilatation in patients with stage 5 chronic kidney disease. 
As an individual ages, the risk of death from cardiovascular disease also increases. The impact of anemia in cardiovascular disease and chronic kidney disease in this elderly population cannot be understated. Cardiovascular disease remains the most common cause of mortality in this patient population, much higher than in the general population.  Anemia has been shown to be an independent risk factor for increased cardiovascular morbidity and mortality.
The Dialysis Outcomes Practice Pattern Study (DOPPS) involved several countries and showed that as hemoglobin concentrations decreased to less than 11 g/dL, there was a corresponding increase in the rates of hospitalization and mortality in patients with chronic kidney disease.  Ofsthun et al analyzed the databases from Fresenius Medical Care of North America (FMCNA) (selection restricted to patients in the census for 6 consecutive months from July 1, 1998, through June 30, 2000) and showed that the longer it took for these patients with stage 5 chronic kidney resolve their hemoglobin concentrations from less than 11 g/dL, the more dramatic an increase in their mortality hazard ratio.  The investigators further added that lower hemoglobin concentrations clearly correlated positively with adverse events in these patients.
In summary, one can derive that if hemoglobin levels are maintained at the recommended target goals, these translate into decreased LVH, decreased hospitalizations related to cardiovascular disease, and decreased mortality from cardiovascular disease. Aside from these findings, however, higher quality of life (QOL) scores are also obtained: less easy fatigability and fatigue symptoms, improved physical well-being and exercise tolerance, and improved functional well-being.