Management of Anemia in Children Undergoing Dialysis

Introduction

Anemia is common and associated with adverse outcomes in children with chronic kidney disease. The management of anemia was dramatically changed due to the development of erythropoiesis-stimulating agents (ESAs) and new understandings of iron metabolism. As the adverse effects of anemia have become more apparent and concerning, there has been a push to optimize ESA and iron therapy. This chapter will review the basic management of anemia in children undergoing dialysis and should provide a practical approach to the day-to-day management of anemia in children who require renal replacement therapy.

The anemia of chronic kidney disease (CKD) is most often normocytic and normochromic. It is primarily due to the decreased production of endogenous erythropoietin (EPO) and, to a lesser degree, decreased responsiveness to the hormone, shortened red blood cell (RBC) survival, blood loss from frequent blood draws, and the hemodialysis (HD) procedure. Patients with CKD have a gradual decline in hemoglobin (Hb) over time as the level of glomerular filtration rate (GFR) declines. If left untreated, anemia of CKD has been associated not only with a multitude of adverse symptoms but also with higher morbidity, increased hospitalization days, and mortality in both adults and children.

Definition of Anemia

Anemia is defined as a decrease in RBC mass. In practice, anemia is determined by a low Hb and hematocrit (HCT) level relative to normative values based on gender and age. The World Health Organization has published Hb thresholds to classify individuals as anemic. Reference Hb concentration values have also been published using data from the U.S. National Health and Nutrition Examination Survey III (NHANES III), which included patients from age 1 year and over. The National Kidney Foundation–Kidney Disease Outcomes Quality Initiative (NKF-KDOQI) definition of anemia has been taken from the NHANES III report. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines define anemia if the Hb concentration is < 11 g/dL in children 0.5–5 years, < 11.5 g/dL in children 5–12 years, and < 12 g/dL in children 12–15 years. Hb rather than HCT is considered a more accurate indicator of anemia since it is not affected by storage of the blood sample at room temperature, is more accurate in patients with hyperglycemia, is not affected by changes in plasma water, and is more reproducible when different automated counters are used.

Prevalence of Anemia in Chronic Kidney Disease

Anemia is associated with CKD of any cause, and the severity of the anemia is related to the degree of loss of GFR. This association has been reported in both adults and children. In a single-center, cross-sectional study of 366 children and adolescents with CKD, approximately 31% of patients with stage 1 and 29% of patients with stage 2 CKD reported prevalent anemia, defined as Hb < 12 mg/dL, whereas 66% of patients with stage 3 and 93% of patients with stages 4 and 5 CKD were anemic. Among children in the 2006 End Stage Renal Disease Clinical Performance Measures Project, 98% of 801 prevalent pediatric peritoneal dialysis (PD) patients were prescribed ESA.

In the Chronic Kidney Disease in Children Prospective Cohort Study (CkiD), the investigators found a linear decline in Hb below a threshold iohexol-determined GFR of 43 mL/min per 1.73 m ² , independent of age, race, gender, and underlying diagnosis. The Hb declined by 0.3 g/dL for every 5 mL/min per 1.73 m ² decrease in GFR. Because serum creatinine-based estimated GFR may overestimate measured GFR in children, anemia might be seen even at early stages of CKD.

Other risk factors for the development of anemia include the use of angiotensin-converting enzyme (ACE) inhibitors, which may predispose to anemia by inhibiting erythropoiesis. An analysis by the International Pediatric Peritoneal Dialysis Network found an association between low urine output, low serum albumin, high serum ferritin, and the use of bioincompatible dialysate with lower Hb levels.

The Effects of Anemia

The symptoms of anemia of CKD typically manifest gradually as the decline in Hb occurs slowly. Patients may report fatigue, weakness, decreased exercise tolerance, loss of appetite, dizziness, pallor, tachycardia, tachypnea, or chest pain.

Severe anemia in children with CKD has been associated with increases in cardiac workload and left ventricular hypertrophy (LVH). In a retrospective study that included pediatric dialysis patients, 75% of the children were noted to have LVH, but those with severe LVH had a significantly lower Hb level. Diastolic dysfunction has also been reported in children with CKD and has been associated with anemia. Treatment of anemia with ESA has been reported to have beneficial effects on cardiac parameters. In a blinded, crossover study of children undergoing PD and HD, patients were assigned to ESA or placebo. ESA produced a rise in mean Hb from 6.9 g/dL to 11.5 g/dL, which was associated with a significant fall in the cardiac index. Some patients had a reduction in the thickness of the interventricular septum and left ventricular posterior wall, but this did not reach statistical significance after 24 weeks. Cardiac performance also improves with the correction of anemia. In this study, children with end-stage renal disease (ESRD) performed treadmill tests before and 1 month and 6 months after ESA administration. There was a decrease in heart rate, decrease in resting oxygen consumption, and increase in exercise time.

Anemia of CKD is associated with higher morbidity, higher risk for hospitalization, and increased mortality. In an analysis of the North American Pediatric Renal Transplant Cooperative Studies (NAPRTCS) database, which included 1942 patients, a multivariate analysis demonstrated anemia (HCT < 33%) to be associated with a 52% higher risk of death (adjusted relative risk (RR), 1.52; 95% confidence interval [CI], 1.03–2.26; p = 0.037). The presence of anemia was also associated with an increased risk for prolonged hospitalization, irrespective of dialysis modality (Warady and Ho, 2003), and was an independent risk factor for all-cause hospitalization in the pediatric predialysis CKD population.

Anemia also affects growth in children. An evaluation of the CKD registry of the NAPRTCS was used to evaluate factors associated with short stature in children with CKD. A total of 5615 patients were entered into the registry during the studied period, and investigators found that anemia (HCT below 33%) was an independent risk factor for short stature. In a retrospective study, catch-up growth was independently associated with Hb and ESA therapy. However, others have not found that correction of anemia with ESA improves the growth of children with CKD.

Anemia has been shown to cause changes in cognitive function, such as increases in reaction times and impairment in immediate and delayed memory. In another study, investigators evaluated the Wechsler intelligence score in 22 children with anemia of CKD treated with ESA. The investigators found that the Wechsler intelligence score increased in 11 children from 92 ± 16 to 97 ± 17 over the 12-month period ( p = 0.007).

Anemia of CKD has a negative impact on several aspects of health-related quality of life. In a study of adolescent patients with CKD stages 1–5, including transplantation patients, anemic patients reported greater limitations in the quality-of-life questionnaire domains relating to (1) physical functioning, (2) limitations in schoolwork or activities with friends as a result of physical health, and (3) parental impact in time and family activities when compared to children without anemia. A more recent study compared child self-reported and parent proxy-reported health-related quality of life in children with CKD. Investigators found that patients with higher Hb had a better quality of life in the physical functioning category in parent proxy reports but not in child self-reports.

Testing for Anemia

The main cause of anemia in CKD is decreased production of EPO levels. Therefore, the initial laboratory evaluation is aimed at identifying other factors that may be contributing to the anemia. In particular, if the severity of anemia is disproportionate to the degree of renal dysfunction, there is evidence of iron deficiency, or there is evidence of leukopenia or thrombocytopenia. The NKF-KDOQI Guidelines recommend the following tests in the initial assessment of anemia: a complete blood count (CBC), absolute reticulocyte count, serum ferritin, and serum transferrin saturation (TSAT), or content of Hb in reticulocytes. The KDIGO guidelines suggest the same tests plus the addition of serum vitamin B ₁₂ and folate levels.

The CBC provides information about the severity of the anemia and adequacy of bone marrow function. Hb rather than HCT should be the standard measure for assessing anemia. For HD patients, the midweek predialysis sample is optimal. For PD patients, the timing of the sample is not critical as plasma volume does not fluctuate significantly. In addition to the Hb, the RBC indices provide valuable information. The anemia of CKD is in general normocytic and normochromic. Macrocytosis may indicate folate or vitamin B ₁₂ deficiency, whereas microcytosis may indicate iron deficiency or inherited disorders of Hb formation. Leukopenia and thrombocytopenia indicate a generalized disorder of the bone marrow, such as myelodysplasia. Abnormalities of the white blood cell count and differential or platelet count are not usual in anemia of CKD and may indicate other conditions.

The reticulocyte count is used to determine effective erythropoietic activity. Erythropoietin levels are not routinely measured.