NKF KDOQI GUIDELINES

KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease

III. CLINICAL PRACTICE RECOMMENDATIONS FOR ANEMIA IN CHRONIC KIDNEY DISEASE IN CHILDREN

CPR FOR PEDIATRICS 2.1: HB RANGE

Treatment thresholds in anemia management describe the intended goal of current treatment for the individual patient. The Hb treatment range represents the intended goal of ESA and iron therapy.

2.1.1 Lower limit of Hb: (FULLY APPLICABLE TO CHILDREN)
In patients with CKD, Hb level should be 11.0 g/dL or greater. (MODERATELY STRONG RECOMMENDATION)

2.1.2 Upper limit of Hb: (FULLY APPLICABLE TO CHILDREN)
In the opinion of the Work Group, there is insufficient evidence to recommend routinely maintaining Hb levels at 13.0 g/dL or greater in ESA-treated patients.

RATIONALE
Determination of Hb targets in pediatric patients resists definitive recommendation. QOL, so significant to the development of the child and life of the family, lends urgency to the consideration of higher Hb level thresholds. However, evidence lacks both quality and quantity, rendering assessment of both benefit and risk uncertain. Age-specific variation in normal Hb levels introduces further uncertainty. Finally, given key metabolic, growth, developmental, and psychological differences between children and adults, exclusive reliance on evidence in adults is inappropriate.

The Work Group presents lower and upper targets for Hb levels in children using values in adults for reference. However, we add 2 significant qualifications. The first is that both the lower and upper Hb targets serve only as opinion-based CPRs, in keeping with the lack of pediatric-specific evidence. The second is that medical decision making to set Hb targets in individual patients should be informed by available evidence that is uniquely pediatric. Consideration should be given, for example, to the potential need to make adjustments for the normal age-specific Hb distribution (Table 39 and Table 40). In weighing the potential QOL benefits of Hb targets, the available evidence in adults should be enriched by consideration of QOL issues that are crucial to children, including neurocognitive development, school attendance, exercise capacity, and family support. To assist medical decision making, the Work Group provides the following review of the literature.

Mortality
Observational evidence relating Hb level to mortality is available. Children in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database from 1992 to 2001 with an Hb level less than 9.9 g/dL compared with those with an Hb level greater than 9.9 g/dL showed an elevated risk for mortality: adjusted RR, 1.52; 95% CI, 1.03 to 2.26; P < 0.05.³⁰⁶ The relationship between Hb level and mortality, when examined at other cutoff values for Hb, appeared continuous. Patients with more severe anemia also experienced increased risk for hospitalization (17.2% ± 1.8% versus 12.3% ± 2.1%, respectively; P < 0.01).

The Heart
A single RCT provides evidence for the benefit of treatment of anemia with ESA compared with placebo. In a blinded crossover trial of 11 children aged between 2.3 and 12.3 years, undergoing HD or PD, and with a baseline Hb level between 4.3 and 8.1 g/dL, patients were assigned to either ESA therapy (Hb > 10 g/dL) or placebo for 24 weeks.¹²⁶ Seven patients completed both trial arms. ESA therapy was associated with partial correction of an elevated cardiac index by 6 months and a significant reduction in left ventricular mass by 12 months.

Two observational studies have examined the relationship between anemia and LVH in children with CKD.^307,308 In these studies, patients with severe LVH (left ventricular mass index > 51 g/m²) showed a statistically lower Hb level than those without LVH (Hb, 9.5 ± 1.8 versus 10.9 ± 2.3 g/dL; P = 0.027). Left ventricular compliance also was related to Hb level in children (r = –0.65; P = 0.02). The findings suggest that severe anemia in children with CKD stage 5 leads to chronic increases in cardiac workload and a consequent increase in both left ventricular end-diastolic volume and mass.
In this RCT, exercise capacity improved with ESA treatment (mean achieved Hb, 11.2 g/dL; range, 9.5 to 14.2 g/dL) compared with placebo control.¹²⁶ Measures of capacity significantly affected included a 2-minute walking test (n = 7) and a formal treadmill testing using the Bruce protocol, full (n = 3) or modified (n = 3). Distance walked, in meters, approached but did not reach statistical significance in the ESA arm of the crossover, P = 0.06; similar results were seen from both the regular or modified treadmill data, P = 0.07.

In a nonrandomized interventional trial, 18 children with CKD stage 5 (15 patients, on HD or PD) and a Hb level less than 9.9 g/dL were administered IV or SC ESA until Hb level was greater than 9.9 g/dL; baseline Hb level of 6.5 ± 0.8 g/dL changed to a final level of 10.0 ± 0.6 g/dL; P = 0.001.³⁰⁹ Exercise time (treadmill with a modified Bruce protocol) increased significantly (before ESA, 10.3 ± 1.9 minutes; after ESA, 11.2 ± 1.9 minutes; P = 0.01), and resting oxygen consumption decreased from 7.8 ± 1.8 to 6.9 ± 1.4 mL/min/kg; P = 0.01 with the higher Hb level. However, there was no change in stroke volume, blood pressure, or any cardiac indices after the first month at the higher Hb level.

Similarly, a small cohort (n = 7) of HD patients showed an improvement in aerobic work capacity and effort tolerance, as evidenced by statistically significant changes in the workload reached, peak oxygen uptake, and average ventilatory anaerobic threshold after treatment of anemia with ESA (baseline Hb, 6.3 ± 0.9 g/dL versus final Hb, 11.2 ± 1.2 g/dL).³¹⁰
Finally, 10 children undergoing PD were evaluated before and 18 months after limited correction of anemia with ESA (baseline Hb, 5.9 ± 0.9 g/dL versus final Hb, 8.7 ± 1.5 g/dL). Patients showed a significant slowing of heart rate, P < 0.01, but no improvement for other cardiac parameters.³¹¹

QOL and Neurocognitive Effects
The relationship between QOL and anemia has been examined in children with CKD.^126,312,313 In 2 trials,^312,313 QOL instruments were not validated in patients with CKD and were completed by parents. Only 1 study blinded parent-responders to use of ESA or placebo, although 5 of 7 parents in that study correctly identified use of ESA during the appropriate treatment.¹²⁶

In 116 children enrolled in a multicenter trial, sleep, activity (in school, at home, or in social situations), alertness, feelings, and a summary score composed of all subscores were assessed at baseline and every 6 months during ESA treatment to attain a target Hb level of 9.6 to 11.2 g/dL compared with baseline pretreatment Hb level of 6.7 g/dL (range, 3.4 to 9.5 g/dL).³¹³ Scores at 1 year after ESA increased after treatment for all aspects examined, but only the 10% increase in the summary score achieved significance (P < 0.05).

In the previously described randomized crossover trial,¹²⁶ a 25-question modified parental questionnaire used a visual analog scale to assess 5 domains: sleep, school performance, diet, psychosocial, and a physical performance/health construct. Only physical performance and general health showed a significant treatment effect (again, baseline Hb, 4.3 to 8.1 g/dL versus final Hb, 11.2 g/dL; range, 9.5 to 14.2 g/dL).

A generic health QOL questionnaire has been administered in a cross-sectional fashion to the parents of children with CKD stages 1 to 5 and transplant recipients.³¹² This instrument, which has shown internal consistency and concurrent validity and has been used in a single-center trial of children on HD therapy,³¹⁴ measures 12 aspects of health-related QOL in the domains of physical functioning; limitations in schoolwork and activities with friends, general health, bodily pain and discomfort, limitations in family activities; emotional/time impact on the parent; impact of emotional or behavior problems on school work and other daily activities; self-esteem; mental health; behavior; family cohesion; and change in health. When evaluated as a continuous variable, Hct was linked directly to measures of improved health, as seen in the single-item general health (r = 0.36; P = 0.003), general health (r = 0.29; P = 0.004), and physical functioning (r = 0.35; P = 0.0004) domains.³¹²

Further analysis of the same data, adjusting for eGFR, age, sex, race, dialysis modality, and transplantation or chronic renal insufficiency and dividing the patients into groups with Hb level greater than or less than 10.8 g/dL (defined by the investigators as anemic), showed an association between anemia and 4 domains: Parental Impact-Time, Family Activities, Role–Physical, and Physical Functioning. Further multivariate analysis done after division of the group into Hb tertiles, less than 9.9 g/dL, 9.9 to 10.8 g/dL, and greater than 10.8 g/dL, showed a strong dose-response relationship between Hb level and health-related QOL as measured by this instrument. It should be noted that differences between the mid and upper tertile of Hb levels did not reach significance, whereas those between the lowest and upper tertile in the areas of Physical Functioning (P = 0.02), Role–Emotional (P = 0.05), Role–Physical (P = 0.02), Parental Impact–Time (P = 0.004), Family Activities (P = 0.003), and Physical Summary score (P = 0.01) did. (Note: these results have been converted from Hct to Hb values.)

The neurocognitive effects of anemia also have been examined. In healthy children aged 6 to 11 years, impairment in cognition is associated with iron deficiency and an Hb level less than 11.8 g/dL.³¹⁵ Furthermore, in a multicenter single-arm interventional trial evaluating 22 children with CKD aged 4 months through 16 years, treatment of anemia was associated with a significant increase in IQ, determined by using the Weschler intelligence test, although the relative increase in Hb levels was small (Hb baseline, 9.2 ± 1.6 versus final, 9.7 ± 1.7 g/dL; P = 0.007).³¹⁶

Nutrition and Growth
No reliable studies have been published that examine the relationship between treatment of anemia and nutrition in children. The literature consists largely of subjective reports by the child or family or short small trials that fail to achieve significant treatment effects.

Treatment of anemia apparently fails to reverse growth retardation in children with CKD undergoing HD or PD.^317-318 In a US phase III, randomized, double-blinded, placebo-controlled trial of ESA therapy in children, 81 children on HD or PD therapy showed a substantial increase in Hb levels with treatment (baseline, 6.3 to 6.6 g/dL to final, 9.3 g/dL), and no effect was seen for any measured nutrition or growth parameter, including midarm circumference, triceps skin-fold thickness, weight gain, or the SD scores for growth velocity or height.³¹⁷

Hypertension
The development or worsening of hypertension during treatment with ESAs in children is of significant concern. In a study of children aged 4 months to 21 years, assignment to either high-dose (epoetin, 450 IU/kg/wk) or low-dose (150 IU/kg/wk) ESA treatment was associated with a significant increase in diastolic blood pressure by week 12 compared with baseline (88 ± 6.7 versus 68 ± 17 mm Hg; paired t-test, P = 0.01).³¹⁹ The investigators reported a nonsignificant trend between increasing Hb levels and increasing systolic and diastolic blood pressures despite stable or lower ESA dose.

Thrombotic Events
No thrombotic events, including vascular access thrombosis, were reported in either arm of the mentioned high-dose versus low-dose ESA trial.³¹⁹ However, the small number of patients, relatively short length of follow-up, and relatively few patients with HD preclude any reliable conclusions about safety. No other larger prospective trials of pediatric patients treated with ESAs to various Hb targets are available to further address the issue of clotting or access thrombosis, although it has been reported to occur intermittently in children.^318,320-323

ESA Therapy and Loss of Renal Function
In patients with ND-CKD assigned to high-dose compared with low-dose ESA treatment, no significant difference in creatinine levels was seen; in the same trial, between-group comparison showed no change in Kt/V among patients with HD-CKD.³¹⁹