Introduction
Anemia is a universal problem among children with chronic kidney disease (CKD). Lower levels of glomerular filtration rate (GFR) are associated with lower levels of hemoglobin, and in adults the latter is most pronounced when the GFR falls below 60 mL/min per 1.73 m
2 [
1]. In children, the relationship between GFR and anemia is less clear. However, treatment of anemia in both adults and children has improved dramatically with the advent of regular erythropoietin (EPO) and iron therapy, and it has become possible to avoid routine transfusions to maintain a patient’s hemoglobin. As well, the many studies performed in adults and relatively fewer studies carried out in children have demonstrated that improved hemoglobin levels are associated with benefits in quality of life, cognitive function, exercise capacity and cardiovascular function [
2‐
4].
Despite the wide availability of erythropoietic stimulating agents and supplemental iron preparations, anemia remains highly prevalent in the pediatric CKD population. Using data from the United States Renal Data System, Chavers et al. demonstrated that the hemoglobin values in pediatric chronic hemodialysis (HD) and peritoneal dialysis (PD) patients treated with recombinant human EPO were still lower than those of adult patients. These researchers found that mean annual hemoglobin values of less than 11 g/dL were present in 54.1% patient years among pediatric HD patients compared to 39.8% patient years in their adult counterparts. For PD patients, anemia was present in 69.5% patient years among pediatric patients and 55.1% among adult patients [
5]. A recent Canadian study investigated the prevalence of complications according to stage of CKD in children. Overall, anemia was present in 36.6% of all patients with kidney disease. Anemia was defined as all those who were treated with iron or darbepoetin and those with a hemoglobin count of <120 g/L. The prevalence of anemia increased from 31% in those with stage 1 CKD to 93.3% among those with CKD stages 4 plus 5 [
6].
Management guidelines for anemia in pediatric CKD patients have been developed from reported studies in both adults and children, from clinical experience and from expert opinion. The revised National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) clinical practice guidelines for the management of anemia specifically for children have been recently published [
7]. The objective of this article is to provide a review of the diagnosis, etiology, investigations, patient outcomes and treatment of anemia in children with CKD.
Diagnosis
According to the classical definition of anemia in Nelson’s
Textbook of Pediatrics, ‘anemia is defined as a reduction of the red blood cell volume or hemoglobin below the range of values for healthy persons’ [
8]. However, a great deal of controversy surrounds the definition of normal values of hemoglobin in children with CKD. Normal values adopted for children with CKD are based on observations of values in healthy children, the ranges of which are 120 g/L (range: 95–145 g/L) in 3-month-old children, 120 g/L (range: 105–140 g/L) in 6-month-old to 6-year-old children and 130 g/L (range: 110–160 g/L) in children aged 7–12 years [
8]. Some studies also cite the World Health Organization definition of anemia where children aged 6 months to 6 years are anemic if the hemoglobin count is less than 110 g/L and children aged 6–14 years are considered anemic if it is less than 120 g/L [
9]. The new NKF-KDOQI clinical practice guidelines use NHANES-III reference data to cite normative values in children [
7]. NHANES-III is the third U.S. National Health and Nutrition Examination Survey database, and the report on hematological and iron-related indices provides means, standard errors and percentile distributions for laboratory values of hematological and iron indices for the United States population in 1988–1994 [
10] (Tables
1,
2). The NKF-KDOQI guidelines recommend the initiation of a work-up for anemia if the hemoglobin value is less than the fifth percentile for age and sex [
7].
Table 1
Hemoglobin levels from NHANES-III for boys of all race/ethnic groups according to age [
10]
1 and over | 146.7 | 13.9 | 121.0 |
1–2 | 120.1 | 8.2 | 107.0 |
3–5 | 123.5 | 7.7 | 111.5 |
6–8 | 128.8 | 8.0 | 115.1 |
9–11 | 132.8 | 8.4 | 119.6 |
12–14 | 141.4 | 10.8 | 124.1 |
15–19 | 150.7 | 10.3 | 134.6 |
Table 2
Hemoglobin levels from NHANES-III for girls of all race/ethnic groups according to age [
10]
1 and over | 131.9 | 11.0 | 114.0 |
1–2 | 120.2 | 8.0 | 108.0 |
3–5 | 123.9 | 7.7 | 111.1 |
6–8 | 128.2 | 7.7 | 115.0 |
9–11 | 131.0 | 7.8 | 118.5 |
12–14 | 132.9 | 10.0 | 117.0 |
15–19 | 131.5 | 10.0 | 114.6 |
Earlier NKF-KDOQI guidelines suggested threshold values for hematocrit as well as hemoglobin to guide the initiation of work-up for anemia. However, a patient’s hematocrit is highly vulnerable to volume status, hyperglycemia and the timing of sampling and, therefore, it has become a less useful measure of anemia. It is also affected by the technological approach used at different laboratories.
Etiology
There are several causes of anemia in patients with CKD. EPO deficiency and iron deficiency are the leading causes regardless of dialysis status. Other causes contributing to anemia in CKD patients are inflammation, chronic blood loss, hyperparathyroidism, aluminum toxicity, hemoglobinopathies, vitamin deficiencies (B12 and folate), hemolysis and adverse effects of cytotoxic or immunosuppressive drugs and angiotensin converting enzyme inhibitors.
Lack of erythropoietin
The major cause of anemia in patients with CKD is lack of EPO synthesis in the diseased kidneys [
11,
12]. EPO is a 30.4-kDa glycoprotein containing 40% carbohydrate that is encoded by a gene identified and cloned in 1985 [
13,
14]. The liver is the primary source of EPO production in the fetus, but after birth, a group of peritubular interstitial cells in the kidney take over this function, becoming the major sites of EPO production [
15,
16]. In response to reduced oxygen supply, EPO production is increased by a hypoxia-inducible factor transcription factor that controls the EPO gene [
15]. A reduced GFR may cause decreased sodium re-absorption in the tubules and because sodium re-absorption is the main determinant of energy consumption in the nephron, this may lead to a relative excess of oxygen, signaling a decrease in EPO production [
17]. The protein portion of EPO binds to an erythroid progenitor cell surface receptor to regulate bone marrow erythroid cell proliferation, differentiation and survival [
15]. As might be expected, in renal failure the control of EPO is deranged, becoming the single largest factor contributing to the anemia of chronic renal disease. In 1987, therapy with recombinant human EPO was shown to correct the anemia resulting from chronic renal failure in dialysis patients [
12].
Iron deficiency
The second major cause of anemia in kidney disease is iron deficiency. There is an ‘absolute’ and ‘functional’ iron deficiency that can be corrected with aggressive iron replacement therapy in CKD. Absolute iron deficiency occurs when iron stores are depleted as a result of loss or decreased intake; however, functional deficiency occurs when there is a need for a greater amount of iron to support hemoglobin synthesis than can be released from iron stores [
18].
Iron deficiency is common in HD patients due to chronic blood loss from repeated blood sampling, surgical interventions, blood loss through the use of dialyzers and tubing and shortened red blood cell lifespan [
19]. Daily blood loss in pre-dialysis pediatric CKD patients is approximately 6 mL/m
2. In contrast, HD patients have gastrointestinal blood losses estimated to be 11 mL/m
2 daily, and there is a further HD-associated blood loss of 8 mL/m
2 per treatment [
20]. Treatment with EPO also demands more iron for hemoglobin synthesis, and iron supplementation can decrease the required dose of EPO in both adults and children [
21,
22].
Iron is absorbed mainly in the duodenum, but it is also recycled from old red blood cells. It circulates in the plasma bound to transferrin. In the body, iron is mostly bound to hemoglobin and cells of the reticuloendothelial system and hepatocytes. A small amount is also stored in muscle fibers and other tissues. Transferrin with iron binds to erythroid cells and is endocytosed into the red cells for the production of heme. In non-red blood cells iron is stored as ferritin or hemosiderin [
23]. Patients with CKD present with disturbances in the iron metabolic pathway. As transferrin levels are reduced to one half or one third that of normal levels in patients with kidney disease, iron transport to the bone marrow for the production of red cells is decreased [
18]. In addition, there is an impaired release of stored iron from macrophages and hepatocytes to transferrin in patients with kidney disease. This will manifest clinically as high ferritin levels due to the impaired release of stored iron [
18].
Other causes
There are numerous other causes of anemia among CKD patients, some of which may cause hyporesponsiveness to EPO and iron. For example, the presence of inflammation contributes to anemia [
24] also, ferritin levels tend to be increased in the presence of inflammation, thereby complicating the diagnosis of iron deficiency. Inflammatory mediators such as interleukin-6, interleukin-1 and tumor necrosis factor-α interfere with the maturation of red cell precursors in patients with CKD [
25]. In addition, severe secondary hyperparathyroidism is known to cause myelofibrosis that may obliterate bone marrow, leading to anemia [
26]. In addition, aluminum toxicity due to chronic hemodialysis is associated with a microcytic anemia in HD patients [
27]. One must also look for coexisting hemoglobinopathies, such as sickle cell disease and β-thalassemia, depending on the ethnic background of the patient as these microcytic anemias can also complicate the diagnosis of iron deficiency [
28,
29]. Furthermore, poor nutritional intake will lead to vitamin B12 and folate deficiencies. Finally, the use of cytotoxic and immunosuppressive drugs, such as cyclophosphamide and mycophenolate mofetil as well as angiotensin converting enzyme inhibitors, especially prior to initiation of dialysis, can also contribute to anemia [
30].
Investigations for anemia
The diagnosis of anemia and the determination of etiology should be made using a systematic approach utilizing both clinical and laboratory investigations (Table
3). A detailed history and physical examination including a family history, is invaluable for all patients. In terms of laboratory investigations, the NKF-DOQI guidelines recommend the following tests: complete blood count, including serum hemoglobin, mean corpuscular hemoglobin, mean corpuscular volume, mean corpuscular hemoglobin concentration, white blood cell count, differential count and platelet count [
7]. Red blood cell indices on peripheral blood smears, especially mean corpuscular volume, can be useful in determining the etiology of anemia. Hypochromic microcytic erthryocytes with pencil cells is the classic presentation of iron deficiency anemia on a blood smear. However, CKD patients may have a normochromic and normocytic anemia [
31]. NKF-KDOQI guidelines also recommend that reticulocyte counts should be obtained to measure the bone marrow response to anemia [
7]. Furthermore, hemoglobin electrophoresis can detect the presence of concomitant hemoglobinopathies. A bone marrow examination is indicated when the etiology of the anemia cannot be determined after the clinician has performed a careful history, physical examination and a thorough analytical investigation of a peripheral blood sample. In HD patients, additional tests, including stool occult blood, serum aluminum and investigations for hemolysis, may be useful for delineating the cause of the anemia [
19,
27].
Table 3
The clinical and laboratory investigations recommended for evaluating anemia in pediatric patients with chronic kidney disease (CKD)
Clinical |
Review of medical history, including family history |
Physical examination |
Review of medication list |
Determination of compliance with treatment |
Initial investigations |
Hemoglobin |
Hematocrit |
White blood cell count |
-Differential count |
Platelet count |
Red blood cell indices |
-Mean corpuscular hemoglobin |
-Mean corpuscular volume |
-Mean corpuscular hemoglobin concentration |
Absolute reticulocyte count |
Serum iron, ferritin and transferrin |
Additional Investigations as indicated: |
Hemoglobin electrophoresis |
Assessment of occult blood loss |
Serum folate, vitamin B12 |
Serum parathyroid hormone |
Assessment of hemolysis |
Serum aluminum |
Bone marrow examination |
Hematocrit is less reliable clinically, and this measure is affected by body temperature, body water, hyperglycemia and storage time prior to analysis [
32,
33]. For hemoglobin measurements, the timing of measurements is also important. For example, in HD patients, although pre-dialysis hemoglobin levels are commonly used, it is not certain whether a pre-dialysis sample is appropriate when the patients have relative water excess. Post-dialysis samples usually demonstrate higher hemoglobin values that may be exaggerated if an inadequate time interval has been allotted for equilibration of fluid compartments post-dialysis.
The assessment of iron stores is essential to an evaluation of anemia. A number of laboratory measures are used to assess absolute and functional iron deficiency, including serum iron, ferritin and transferrin. NKF-KDOQI guidelines for the evaluation of anemia in children with CKD recommend measurements of serum ferritin and serum transferrin saturation (TSAT) [
7].
The ideal iron measures will ensure that the treatment will provide consistent hemoglobin levels while avoiding excessive doses of iron and EPO. Serum iron is used as a measure of the amount of transferrin-bound iron in circulation [
10]. Serum transferrin, a protein-based receptor for circulating iron, is an indicator of total iron binding capacity, but there is a diurnal fluctuation in its level and it is affected by nutritional status [
34]. Serum ferritin indicates the level of stored iron; however, ferritin is an acute phase reactant and its level is less reliable in CKD patients. Therefore, no single measure accurately measures iron deficiency. Fishbane et al. studied 47 adult patients with baseline serum ferritin levels of less than 600 ng/mL who were treated with intravenous (IV) iron dextran. Patients whose hematocrit increased by 5% or who had a 10% decrease in their EPO dose over 2 months were classified as having an iron deficiency. These researchers found that serum ferritin levels of less than 150 ng/mL had a sensitivity and specificity of 71 and 69%, respectively, and that transferrin saturations of less than 21% had a sensitivity and specificity of 81 and 63%, respectively [
35].
The most accepted method of determining iron status in pediatric patients is the TSAT, which is calculated by dividing serum iron by total iron binding capacity and multiplying by 100. Total iron binding capacity is an indirect measure of the concentration of transferrin and is derived by multiplying the serum transferrin value by 1.4 [
36]. A pediatric study of 160 patients on HD suggested that a TSAT of less than 20% is a significant predictor of iron deficiency [
37].
There are several new methods available for assessing iron stores. These assays are important analytical tools in the presence of a functional iron deficiency where there is an adequate amount of stored iron but an impairment exists in the release of iron from these body stores. The percentage of circulating hypochromic red blood cells (PHRC) and the reticulocyte hemoglobin content (CHr) are two such measures [
36]. Many institutions may lack the necessary technology to measure PHRC. In terms of CHr, there is no clear consensus on precisely what is the proper cut-off, and this measure is not used routinely in clinical practice. Additional tests described in the literature but not recommended for use are the measurement of zinc protoporphyrin (ZPP) and the serum soluble transferrin receptor assays [
36]. Zinc replaces iron in protoporphyrin IX to form ZPP under conditions of iron deficiency [
38]. ZPP is a measure of iron availability and stores; however, it is considered to be an inferior measure. The soluble transferrin receptor assay indicates the number of erythroblasts in the bone marrow and total erythroid activity. It has not been shown to be useful in CKD patients and is more costly [
39,
40]. All of these tests have not been examined fully in the pediatric CKD population and are limited to the research realm.
Clinical outcomes and benefits of therapy
Anemia is associated with significant morbidity and mortality in patients with CKD. Complications related to anemia include kidney disease progression, cardiovascular disease, hospitalization, mortality, and an impaired quality of life.
Summary
In summary, the etiology and management of anemia is complex in children with CKD, with current management and therapeutic decisions guided by results of both adult and pediatric studies. EPO and IV iron therapy have revolutionized the treatment of anemia in children; however, anemia continues to be a very prevalent problem among pediatric CKD patients. Pediatric nephrologists are encouraged to use current clinical practice guidelines and best evidence in conjunction with their clinical experience to optimally manage patients with anemia.
Questions: (answers will appear following the reference list)
1.
Reported side effects of erythropoietin therapy include:
2.
Iron supplements should not be taken together with:
a.
Calcium containing binders
3.
Pure red cell aplasia is more common in what form of erythropoietin administration:
4.
Correction of anemia in children with chronic kidney disease has been associated with:
a.
Improved exercise tolerance
5.
Severe hyperparathyroidism can cause anemia in chronic kidney disease due to:
Answers:
1. d. All of the above
2. a. Calcium containing binders
3. b. Subcutaneous
4. d. All of the above
5. c. Myelofibrosis