Parenteral versus oral iron therapy for adults and children with chronic kidney disease
The Cochrane database of systematic reviews. 2019;2:Cd007857
BACKGROUND The anaemia seen in chronic kidney disease (CKD) may be exacerbated by iron deficiency. Iron can be provided through different routes, with advantages and drawbacks of each route. It remains unclear whether the potential harms and additional costs of intravenous (IV) compared with oral iron are justified. This is an update of a review first published in 2012. OBJECTIVES To determine the benefits and harms of IV iron supplementation compared with oral iron for anaemia in adults and children with CKD, including participants on dialysis, with kidney transplants and CKD not requiring dialysis. SEARCH METHODS We searched the Cochrane Kidney and Transplant Register of Studies up to 7 December 2018 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA We included randomised controlled trials (RCTs) and quasi-RCTs in which IV and oral routes of iron administration were compared in adults and children with CKD. DATA COLLECTION AND ANALYSIS Two authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes the mean difference (MD) was used or standardised mean difference (SMD) if different scales had been used. Statistical analyses were performed using the random-effects model. Subgroup analysis and univariate meta-regression were performed to investigate between study differences. The certainty of the evidence was assessed using GRADE. MAIN RESULTS We included 39 studies (3852 participants), 11 of which were added in this update. A low risk of bias was attributed to 20 (51%) studies for sequence generation, 14 (36%) studies for allocation concealment, 22 (56%) studies for attrition bias and 20 (51%) for selective outcome reporting. All studies were at a high risk of performance bias. However, all studies were considered at low risk of detection bias because the primary outcome in all studies was laboratory-based and unlikely to be influenced by lack of blinding.There is insufficient evidence to suggest that IV iron compared with oral iron makes any difference to death (all causes) (11 studies, 1952 participants: RR 1.12, 95% CI 0.64, 1.94) (absolute effect: 33 participants per 1000 with IV iron versus 31 per 1000 with oral iron), the number of participants needing to start dialysis (4 studies, 743 participants: RR 0.81, 95% CI 0.41, 1.61) or the number needing blood transfusions (5 studies, 774 participants: RR 0.86, 95% CI 0.55, 1.34) (absolute effect: 87 per 1,000 with IV iron versus 101 per 1,000 with oral iron). These analyses were assessed as having low certainty evidence. It is uncertain whether IV iron compared with oral iron reduces cardiovascular death because the certainty of this evidence was very low (3 studies, 206 participants: RR 1.71, 95% CI 0.41 to 7.18). Quality of life was reported in five studies with four reporting no difference between treatment groups and one reporting improvement in participants treated with IV iron.IV iron compared with oral iron may increase the numbers of participants, who experience allergic reactions or hypotension (15 studies, 2607 participants: RR 3.56, 95% CI 1.88 to 6.74) (absolute harm: 24 per 1000 with IV iron versus 7 per 1000) but may reduce the number of participants with all gastrointestinal adverse effects (14 studies, 1986 participants: RR 0.47, 95% CI 0.33 to 0.66) (absolute benefit: 150 per 1000 with IV iron versus 319 per 1000). These analyses were assessed as having low certainty evidence.IV iron compared with oral iron may increase the number of participants who achieve target haemoglobin (13 studies, 2206 participants: RR 1.71, 95% CI 1.43 to 2.04) (absolute benefit: 542 participants per 1,000 with IV iron versus 317 per 1000 with oral iron), increased haemoglobin (31 studies, 3373 participants: MD 0.72 g/dL, 95% CI 0.39 to 1.05); ferritin (33 studies, 3389 participants: MD 224.84 microg/L, 95% CI 165.85 to 283.83) and transferrin saturation (27 studies, 3089 participants: MD 7.69%, 95% CI 5.10 to 10.28), and may reduce the dose required of erythropoietin-stimulating agents (ESAs) (11 studies, 522 participants: SMD -0.72, 95% CI -1.12 to -0.31) while making little or no difference to glomerular filtration rate (8 studies, 1052 participants: 0.83 mL/min, 95% CI -0.79 to 2.44). All analyses were assessed as having low certainty evidence. There were moderate to high degrees of heterogeneity in these analyses but in meta-regression, definite reasons for this could not be determined. AUTHORS' CONCLUSIONS The included studies provide low certainty evidence that IV iron compared with oral iron increases haemoglobin, ferritin and transferrin levels in CKD participants, increases the number of participants who achieve target haemoglobin and reduces ESA requirements. However, there is insufficient evidence to determine whether IV iron compared with oral iron influences death (all causes), cardiovascular death and quality of life though most studies reported only short periods of follow-up. Adverse effects were reported in only 50% of included studies. We therefore suggest that further studies that focus on patient-centred outcomes with longer follow-up periods are needed to determine if the use of IV iron is justified on the basis of reductions in ESA dose and cost, improvements in patient quality of life, and with few serious adverse effects.
De novo weekly and biweekly darbepoetin alfa dosing in pediatric patients with chronic kidney disease
Pediatric Nephrology (Berlin, Germany). 2017;33((1):):125-137
BACKGROUND Darbepoetin alfa is a commonly prescribed erythropoiesis-stimulating agent (ESA) for correcting anemia in pediatric chronic kidney disease (CKD) patients. However, little information exists on its use in ESA-naive patients. This study evaluated the efficacy and safety of darbepoetin alfa in pediatric patients initiating ESA therapy. METHODS One-hundred sixteen pediatric ESA-naive subjects (aged 1-18 years) with CKD stages 3-5D and hemoglobin (Hb) <10 g/dl from 43 centers in the US, Europe, and Mexico were randomized by age (three groups) and dialysis status (yes vs. no) to receive darbepoetin alfa once weekly (QW) or every 2 weeks (Q2W) subcutaneously (not on dialysis and peritoneal dialysis subjects) and intravenously (hemodialysis subjects). The drug was titrated to achieve Hb levels of 10.0-12.0 g/dl over 25 weeks. Patient- and parent-reported health-related outcomes were measured by the Pediatric Quality of Life Inventory (PedsQL) in children ≥2 years. RESULTS In both groups, mean Hb concentrations increased to ≥11.0 g/dl over the first 3 months of treatment and remained stable within the 10.0-12.0 g/dl target range. The median time to achieve hemoglobin ≥10 g/dl was slightly longer for subjects <12 years (QW and Q2W, both 28 days) vs. those ≥12 years (23 and 22 days, respectively). Adverse event profiles were similar between groups, with QW, four (7%) and Q2W, five (9%). PedsQL scores showed modest increases. CONCLUSIONS Darbepoetin alfa can be safely administered either QW or Q2W to ESA-naive pediatric patients with CKD-related anemia to achieve Hb targets of 10.0-12.0 g/dl.
Early erythropoietin reduced the need for red blood cell transfusion in childhood hemolytic uremic syndrome: a randomized prospective pilot trial
Pediatric Nephrology (Berlin, Germany). 2009;24((5):):1061-4.
Childhood hemolytic uremic syndrome (HUS) is most often caused by enterohemorrhagic Escherichia coli (EHEC). Due to severe hemolysis, red blood cell (RBC) transfusions are often necessary, and anemia is aggravated by low erythropoietin (EPO) levels caused by acute renal failure. In a single center, prospective study, we randomized ten children with EHEC-positive HUS into two therapeutic groups: one receiving EPO treatment (median age 2 years, age range 1-3 years) and the other receiving standard therapy (median age 2 years, age range 1-6 years). Red blood cell transfusions were performed when the hemoglobin level (Hb) fell below 5 mg/dl. The number of RBC transfusions was compared in both groups. The Hb level at admission was comparable between both groups (6. 4 vs. 8. 1 mg/dl, P > 0. 05, t-test). However, children in the EPO group required a significantly lower mean number of RBCs than those in the non-EPO group (0. 2 vs. 1. 4, P < 0. 04, t-test). Based on these results, we suggest that the early administration of EPO at the time of hemolytic anemia and beginning renal failure may attenuate renal anemia in children with EHEC-induced HUS and thereby reduce the number of RBC transfusions required. The results of this pilot study will have to be confirmed in a larger multicenter trial.
Randomized cross-over trial comparing albumin and frusemide infusions in nephrotic syndrome
Pediatric Nephrology (Berlin, Germany). 2009;24((4):):775-82.
The contribution of hypoalbuminemia to impaired diuretic responsiveness can be overcome by administering larger doses of loop diuretics. However, the clinical efficacy of the combination of loop-acting diuretics with human albumin remains controversial. In the study reported here, 16 children with nephrotic syndrome and refractory edema were randomized in a cross-over trial to receive either the combination of 20% human albumin and frusemide infusion (HA+FU infusion group) or frusemide infusion alone (FU infusion group). At the end of study, median urine volume was 3. 27 [95% confidence interval (CI) 2. 04-4. 50] ml/kg per hour in the HA+FU infusion group and 1. 33 (95% CI 0. 79-1. 88) ml/kg per hour in the FU infusion group (P = 0. 01); the median daily sodium excretion was 58 (95% CI 30-366) mEq and 30 (95% CI 10-122) mEq (P = 0. 08), respectively The changes in other variables included weight loss [HA+FU 5. 2% (95% CI 3. 1-8. 8); FU 0. 8% (95% CI -1. 9 to 4. 1); P = 0. 006]; urine osmolality [HA+FU 315 (95% CI 220-426) mOsm/kg; FU 368 (95% CI 318-446) mOsm/kg; P = 0. 13]; osmolal clearance [HA+FU 1600 (95% CI 916-4140) ml/day; FU 880 (95% CI 510-2105) ml/day; P = 0. 01; free water clearance [HA+FU -190 (95% CI -960 to 280) ml/day; FU -162 (95% CI -446 to -70) ml/day; P = 0. 18]. The findings from this study suggest that the co-administration of albumin and frusemide infusions is more effective than the administration of frusemide infusion alone in inducing diuresis and natriuresis in patients with nephrotic syndrome.
Population pharmacokinetic modeling of epoetin delta in pediatric patients with chronic kidney disease
Journal of Clinical Pharmacology. 2008;48((7):):837-48.
This analysis quantifies the population pharmacokinetics of subcutaneous and intravenous epoetin delta, an epoetin produced in a human cell line, in pediatric patients with chronic kidney disease and estimates the effects of covariate factors on epoetin delta and epoetin alfa pharmacokinetic parameters. Erythropoietin serum concentration data, taken from a phase III study conducted in 60 patients aged 1 to 17 years, were best described by a 1-compartment model with first-order absorption and elimination. The typical point estimates were clearance (0. 268 L/h), central volume of distribution (1. 03 L), absorption rate constant (0. 0554 h(-1)), and bioavailability (0. 708) for a 35-kg male < or = 10 years who was predialysis and on subcutaneous epoetin delta treatment. Erythropoietin pharmacokinetic parameters were similar in pediatric patients as compared with adults when scaled by weight. The subcutaneous administration of epoetin alfa exhibited lower systemic bioavailability than subcutaneous administration of epoetin delta.
Increased injection pain with darbepoetin-alpha compared to epoetin-beta in paediatric dialysis patients
Nephrology, Dialysis, Transplantation. 2006;21((12):):3520-4.
BACKGROUND Darbepoetin-alpha is applicable at longer injection intervals. Our early experience in children on peritoneal dialysis suggested increased injection pain compared to epoetin-beta, possibly due to technical differences or patient anxiety. METHODS To verify a possible difference in the painfulness of the injected fluids per se, we performed a prospective, randomized, double-blind trial in 13 paediatric end-stage renal disease patients. They received three injections of equivalent doses of darbepoetin-alpha or epoetin-beta in 0. 6 ml saline, using neutral syringes and 27G needles, at 4 week intervals. Pain perception was recorded immediately and after 30 min on a visual analogue scale (VAS, 0 = no pain, 10 = maximal pain; complemented by 5 faces for young children). RESULTS The patients perceived more intense immediate injection pain with darbepoetin-alpha than with epoetin-beta (5. 4 +/- 1 vs 2. 3 +/- 0. 6, P < 0. 05). This was confirmed by the impression of the parents (5. 3 +/- 1 vs 2. 0 +/- 0. 9, P < 0. 05) and the nurses (4. 4 +/- 1 vs 2. 2 +/- 0. 6, P < 0. 05). General injection pain was inversely related to patient age (R = -0. 77, P = 0. 001). Six patients perceived no or a mild difference in injection pain, whereas 7 subjects reported a markedly higher pain score (> or =4 VAS points) with darbepoetin-alpha. After 30 min, the injection site was largely painless with both drugs. No significant local reactions occurred with either medication (0. 3 +/- 0. 1 vs 0. 3 +/- 0. 1 on a 5-score scale). CONCLUSIONS Subcutaneous injections of darbepoetin-alpha are more painful than those of epoetin-beta in the majority of paediatric patients. The observed difference in painfulness is related to the nature of the injected compounds and may limit the subcutaneous applicability of darbepoetin-alpha in children.
Darbepoetin alfa for the treatment of anemia in pediatric patients with chronic kidney disease
Pediatric Nephrology (Berlin, Germany). 2006;21((8):):1144-52.
Darbepoetin alfa, an erythropoiesis-stimulating glycoprotein, has proved efficacious in the treatment of anemia of chronic kidney disease (CKD) in adult subjects. However, little information is available from pediatric populations. We conducted an open-label, non-inferiority, 28-week study comparing the efficacy of darbepoetin alfa with that of recombinant human erythropoietin (rHuEpo) in pediatric subjects with CKD. Subjects, aged 1-18, who were receiving stable rHuEpo treatment (n=124) were randomized (1:2) to either continue receiving rHuEpo or convert to darbepoetin alfa, with doses titrated to achieve and maintain hemoglobin (Hb) levels between 10. 0 and 12. 5 g/dl. Darbepoetin alfa was considered to be non-inferior to rHuEpo if the lower limit of the two-sided 95% confidence interval (CI) for the difference in the mean change in Hb between the two treatment groups was above -1. 0 g/dl. The adjusted mean change in Hb between the baseline and the evaluation period for the rHuEpo and darbepoetin alfa groups was -0. 16 g/dl and 0. 15 g/dl, respectively, with a difference of 0. 31 g/dl (95% CI: -0. 45, 1. 07) between the means. These results, and the comparable safety profiles, demonstrate that darbepoetin alfa is non-inferior to rHuEpo in the treatment of anemia in pediatric patients with CKD.
Sodium ferric gluconate complex therapy in anemic children on hemodialysis
Pediatric Nephrology (Berlin, Germany). 2005;20((9):):1320-7.
Pediatric patients with end-stage renal disease undergoing hemodialysis (HD) frequently develop anemia. Administration of recombinant human erythropoietin (rHuEPO) is effective in managing this anemia, although the additional demand for iron often results in iron deficiency. In adult patients undergoing HD, intravenous (IV) iron administration is known to replenish iron stores more effectively than oral iron administration. Nevertheless, IV iron supplementation is underutilized in pediatric patients, possibly because of unproved safety in this population. This international, multicenter study investigated the safety and efficacy of two dosing regimens (1. 5 mg kg(-1) and 3. 0 mg kg(-1)) of sodium ferric gluconate complex (SFGC) therapy, during eight consecutive HD sessions, in iron-deficient pediatric HD patients receiving concomitant rHuEPO therapy. Safety was evaluated in 66 patients and efficacy was evaluated in 56 patients. Significant increases from baseline were observed in both treatment groups 2 and 4 weeks after cessation of SFGC dosing for mean hemoglobin, hematocrit, transferrin saturation, serum ferritin, and reticulocyte hemoglobin content. Efficacy and safety profiles were comparable for 1. 5 mg kg(-1) and 3. 0 mg kg(-1) SFGC with no unexpected adverse events with either dose. Administration of SFGC was safe and efficacious in the pediatric HD population. Given the equivalent efficacy of the two doses, an initial dosing regimen of 1. 5 mg kg(-1) is recommended for pediatric HD patients.
Intermittent versus maintenance iron therapy in children on hemodialysis: a randomized study
Pediatric Nephrology (Berlin, Germany). 2004;19((1):):77-81.
In patients with renal anemia, iron therapy can be administered intermittently or regularly at a low dose. We performed a randomized clinical trial in pediatric patients with end-stage renal failure on hemodialysis and absolute or functional iron deficiency. The study group received maintenance iron therapy according to the ferritin serum levels and the control group received intermittent 10-weekly doses. Success was defined as stabilization of ferritin levels between 100 and 800 microg/l and transferrin saturation (TSAT) between 20% and 50%, in addition to an increase in the hemoglobin level. The major reason for exclusion was iron overload. The study group received 6 mg/kg per month of parenteral iron [95% confidence interval (CI) 3. 3-8. 8] and the control group 14. 4 mg/kg per month (95% CI 12-16. 8) ( P<0. 001). After 4 months of treatment, ferritin levels increased to 66 microg/l (95% CI 69-200) in the study group and to 334 microg/l (95% CI 145-522) in the control group ( P=0. 009). Maintenance therapy and intermittent weekly doses were successful in 73% and 38%, respectively. After 3 months of treatment, hemoglobin levels increased to 10 g/dl, with no difference between the groups. However, in the control group the increase in hemoglobin levels was unsustained, and 3 patients needed transfusion. Patients in the control group had a higher risk of iron overload than patients in the study group (70% vs. 19%). Thus, the regimen based on assessment of serum ferritin levels was more efficient than the intermittent regimen because it increased and maintained the hemoglobin levels with lower iron doses and a lower risk of iron overload.
Fibrin glue is useful in preventing early dialysate leakage in children on chronic peritoneal dialysis
Peritoneal Dialysis International : Journal of the International Society for Peritoneal Dialysis. 2004;24((2):):186-90.
OBJECTIVE To assess if application of fibrin glue sealant to the peritoneal cuff suture is useful in the prevention of early dialysate leakage in children with end-stage renal disease on chronic peritoneal dialysis (CPD). DESIGN Single-center, open-label, prospective randomized study. SETTING University Pediatric Hospital. METHODS 52 catheters were implanted in 45 children (mean age 6. 2 +/- 4. 5 years). Catheters were randomly assigned to either the control group or the sealant group. In the latter group, 1 mL of fibrin glue sealant was applied to the peritoneal cuff suture. 18 catheters were used for the first time within 5 days after implantation (early-used catheters). Leakage, exit-site or tunnel infection, peritonitis, and adverse secondary effects were evaluated during the initial 60 days after implantation. RESULTS No adverse secondary effects were seen after the application of the fibrin glue sealant. The incidence of exit/tunnel infection and peritonitis was similar in the two groups. The incidence of leakage was significantly lower in the sealant group (p < 0. 02). In the early-used catheters, leakage was detected in 9% of the catheters in the sealant group and in 57% of the control group (p < 0. 05). CONCLUSIONS The application of 1 mL of fibrin glue to the peritoneal cuff suture prevented early dialysate leakage without secondary adverse effects in children on CPD.