Abstract

RATIONALE & OBJECTIVE Prespecified analyses of the PRO(2)TECT trials comparing the safety of the oral hypoxia-inducible factor prolyl hydroxylase inhibitor vadadustat with darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) found no difference in major adverse cardiovascular events (MACE; death from any cause or nonfatal myocardial infarction or stroke) among US patients and a higher risk among patients treated with vadadustat outside the United States. We investigated regional differences in MACE in the PRO(2)TECT trial that enrolled 1,751 patients previously untreated with erythropoiesis-stimulating agents. STUDY DESIGN Phase 3, global, open-label, randomized, active-controlled clinical trial. SETTING AND PARTICIPANTS Erythropoiesis-stimulating agent-untreated patients with anemia and NDD-CKD. INTERVENTION Eligible patients were randomized 1:1 to receive vadadustat or darbepoetin alfa. OUTCOMES The primary safety end point was time to first MACE. Secondary safety end points included time to first expanded MACE (MACE plus hospitalization for heart failure or thromboembolic event, excluding vascular access thrombosis). RESULTS In the non-US/non-Europe region, there was a higher proportion of patients with baseline estimated glomerular filtration rate (eGFR) level of ≤10 mL/min/1.73 m(2) in the vadadustat group [96 (34.7%)] than in the darbepoetin alfa group [66 (24.0%)]. In this region, there were 21 excess MACEs reported in the vadadustat group [78 events (n=276)] versus the darbepoetin alfa [57 events (n=275)], including 13 excess noncardiovascular deaths, largely from kidney failure. Noncardiovascular deaths were concentrated in Brazil and South Africa, which enrolled higher proportions of patients with an eGFR of ≤10 mL/min/1.73 m(2) and who may not have had access to dialysis. LIMITATIONS Different regional treatment patterns of patients with NDD-CKD. CONCLUSIONS The higher MACE rate in the non-US/non-Europe vadadustat group may have been partly because of imbalances in the baseline eGFR level in countries where dialysis was not uniformly available resulting in many kidney-related deaths.

Abstract

Modern intravenous iron compounds (e.g., ferric carboxymaltose [FCM] and ferric derisomaltose [FDI]) are utilized in the treatment of iron deficiency anemia in non-dialysis-dependent chronic kidney disease (ND-CKD). Product-specific alterations in the metabolism of fibroblast growth factor 23 (FGF-23) leading to hypophosphatemia have been described for certain intravenous iron compounds, such as FCM, with potential effects on bone and cardiovascular health and quality of life. No prior head-to-head comparison between FCM and FDI exists in ND-CKD. This single-center exploratory double-blind randomized controlled trial primarily aimed to investigate the differential impact of FCM and FDI on FGF-23 and phosphate in patients with iron deficiency +/- anemia and ND-CKD (stages 3a-5 - serum ferritin <200 μg/L or serum ferritin 200-299 μg/L and transferrin saturation <20%). Patients were randomized (1:1) to receive either FCM or FDI over two infusions (1 month apart). Follow-up was 3 months. Measurements of serum intact FGF-23, phosphate, vitamin D metabolites, parathyroid hormone, other bone metabolism, cardiovascular, and quality of life markers were monitored. 168 patients were prescreened. Thirty-five patients were screened; 26 patients were randomized. The mean (standard deviation) age was 67.9 (12.4) years and 17 participants were male. Most participants had stage 4 CKD (median [interquartile range] estimated glomerular filtration rate [eGFR]: 18.0 [11.3] mL/min/1.73 m2). A higher than normal median (interquartile range) level of intact FGF-23 (212.1 [116.4] pg/mL) was noted. Serum phosphate was within normal range, while parathyroid hormone was higher and 1,25 (OH)2 vitamin D lower than the normal range. The "Iron and Phosphaturia - ExplorIRON-CKD" trial will provide important information regarding the differential effect of intravenous iron products in terms of FGF-23, phosphate, and other markers of bone and cardiovascular metabolism, alongside patient-reported outcome measures in patients with ND-CKD.

Abstract

OBJECTIVE To compare the effects of five hypoxia-inducible factor-prolyl hydroxylase domain inhibitors (HIF-PHIs), two erythropoiesis-stimulating agents (ESAs), and placebo on iron metabolism in renal anemia patients with non-dialysis-dependent chronic kidney disease (NDD-CKD). METHOD Five electronic databases were searched for studies. Randomized controlled clinical trials comparing HIF-PHIs, ESAs, and placebo in NDD-CKD patients were selected. The statistical program used for network meta-analysis was Stata/SE 15.1. The main outcomes were the change in hepcidin and hemoglobin (Hb) levels. The merits of intervention measures were predicted by the surface under the cumulative ranking curve method. RESULTS Of 1,589 original titles screened, data were extracted from 15 trials (3,228 participants). All HIF-PHIs and ESAs showed greater Hb level-raising ability than placebo. Among them, desidustat demonstrated the highest probability of increasing Hb (95.6%). Hepcidin [mean deviation (MD) = -43.42, 95%CI: -47.08 to -39.76], ferritin (MD= -48.56, 95%CI: -55.21 to -41.96), and transferrin saturation (MD = -4.73, 95%CI: -5.52 to -3.94) were decreased, while transferrin (MD = 0.09, 95%CI: 0.01 to 0.18) and total iron-binding capacity (MD = 6.34, 95%CI: 5.71 to 6.96) was increased in HIF-PHIs versus those in ESAs. In addition, this study observed heterogeneity in the ability of HIF-PHIs to decrease hepcidin. Compared with darbepoetin, only daprodustat (MD = -49.09, 95% CI: -98.13 to -0.05) could significantly reduce hepcidin levels. Meanwhile, daprodustat also showed the highest hepcidin-lowering efficacy (84.0%), while placebo was the lowest (8.2%). CONCLUSION For NDD-CKD patients, HIF-PHIs could ameliorate functional iron deficiency by promoting iron transport and utilization, which may be achieved by decreasing hepcidin levels. Interestingly, HIF-PHIs had heterogeneous effects on iron metabolism. SYSTEMATIC REVIEW REGISTRATION https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=242777, Identifier CRD42021242777.

Abstract

BACKGROUND Hemodialysis patients are common to have renal anemia in the nephrology practice. For the renal anemia, the high-dose iron from the intravenous route is an important treatment option. We can understand the treatment effects and cardiovascular events of high-dose intravenous iron reviewing the randomized clinical trials. METHODS We compared the high-dose and low-dose iron treatments to find if the high-dose intravenous iron can influence the hematological parameters more significantly than the low-dose iron. The cardiovascular events were also analyzed for the high-dose iron treatment. Six studies with a total of 2422 renal anemia patients under hemodialysis were enrolled. We focused the outcomes of hemoglobin, transferrin saturation percentage, ferritin, erythropoietin dose, and cardiovascular events. RESULTS The high-dose intravenous iron might be associated with a greater number of ferritin, transferrin saturation percentage, and hemoglobin. In addition, the erythropoietin dose was less needed to maintain the ideal hemoglobin range in the high-dose intravenous iron group. CONCLUSIONS In current meta-analysis, the high-dose intravenous iron might show the superior effects on the ferritin, transferrin saturation percentage, and hemoglobin levels and needed dose of erythropoietin when compared to low-dose iron treatment.

Abstract

BACKGROUND Renal anemia, a common complication and threat factor of chronic kidney disease (CKD), has long been treated with injectable erythropoietin-stimulating agents (ESAs). As concerns regarding cardiovascular safety and erythropoietin resistance to ESAs have emerged, alternative therapies are urgently needed. Hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), an oral agent, has been proven to be effective in improving renal anemia. However, the effects of HIF-PHIs on nondialysis-dependent CKD (NDD-CKD) have yet to be supported by updated meta-analyses. METHODS A meta-analysis of clinical randomized controlled trials (RCTs) on HIF-PHI treatment of NDD-CKD patients based on PubMed, EMBASE, and Cochrane databases as of July 16th, 2023, was conducted. The primary outcomes were the level of hemoglobin (Hb) postintervention and the ratio of Hb responses. Most of the analysis was conducted via RevMan 5.3 software using a random-effects model. Stata (version 15.0) was used to analyze the publication bias. RESULTS Twenty-two studies with a total of 7178 subjects in the HIF-PHI group, 3501 subjects in the ESA group and 2533 subjects in the placebo group were enrolled. HIF-PHIs increased the level of Hb and improved iron metabolism but were not inferior to ESAs in terms of safety. CONCLUSIONS HIF-PHIs may be a convenient and safe alternative to ESAs in patients with NDD-CKD and anemia.

Abstract

PURPOSE This study was conducted to evaluate whether the efficacy and safety profile of recombinant human erythropoietin (rhEPO) manufactured by Daewoong Pharmaceutical Co., Ltd was similar to biological products approved by the drug safety regulatory authority. PATIENTS AND METHODS It was an open-label, randomized, comparative, parallel, multi-center study in hemodialysis patients with anemia. The reference product at an individualized dose 3 times a week was given in 4-8 weeks of titration period and hemoglobin (Hb) level was controlled to reach the range of 10-12 g/dL. Then, the subjects were randomly administered with reference or test product with the same dose regimen. The primary endpoints were to demonstrate the Hb level change between baseline and evaluation period in both treatment groups, while the secondary endpoints were the mean change in weekly dosage per kg body weight and the instability rate of Hb level during maintenance and evaluation period. The safety was evaluated based on the adverse events incidence. RESULTS There was no statistical difference in the change of Hb between test and reference (0.14 g/dL and 0.75 g/dL respectively, with p>0.05), also for the mean changes of weekly dosage between groups (1091.40 IU and 570.15 IU respectively, with p>0.05). The instability rate of Hb in both test and reference was not statistically significantly different as well (26 and 15% respectively, with p>0.05). CONCLUSION This study proves that the efficacy indicated by the change instability of Hb and safety indicated by adverse event incidence of Epodion and the reference product on chronic kidney disease were similar.

Abstract

Intravenous iron is commonly used to treat iron deficiency anemia in non-dialysis chronic kidney disease (ND-CKD). There is a paucity of information on the potential impact of intravenous iron on patient reported outcome measures, functional status and markers of cardiovascular health. As part of the secondary analysis of this double-blind exploratory randomized controlled trial focusing on patients with iron deficiency (+ /- anemia) and ND-CKD (serum ferritin < 200 µg/L or transferrin saturation ≤ 20% and serum ferritin 200-299 µg/L; CKD stages: 3a-5), 26 patients were randomized in a 1:1 ratio to receive ferric derisomaltose or ferric carboxymaltose. Participants received 1000 mg at baseline and 500-1000 mg at one month to achieve iron repletion. Quality of life and fatigue status were assessed using the Short-Form (36) questionnaire and the fatigue severity scale. Functional status was evaluated using the Duke Activity Status Index and the 1-min-sit-to-stand test. Cardiac markers such as NT-proBNP, Troponin T and pulse wave velocity were monitored. Intravenous iron was associated with similar improvements in most domains of the Short-Form (36) questionnaire, fatigue status, and 1-min-sit-to-stand ability increased significantly by the end of the trial in both groups (p < 0.001). Markers of cardiac function remained stable, with no arterial stiffness impact. Longer term studies are required to further evaluate the impact of intravenous iron on quality of life and cardiac safety in patients with ND-CKD.

Abstract

BACKGROUND Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anaemia in people with chronic kidney disease (CKD). However, their use has been associated with cardiovascular events. This is an update of a Cochrane review first published in 2014. OBJECTIVES To compare the efficacy and safety of ESAs (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, and biosimilar ESAs against each other, placebo, or no treatment) to treat anaemia in adults with CKD. SEARCH METHODS In this update, we searched the Cochrane Kidney and Transplant Register of Studies up to 29 April 2022 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 Randomised controlled trials (RCTs) that included a comparison of an ESA (epoetin alfa, epoetin beta, darbepoetin alfa, methoxy polyethylene glycol-epoetin beta, a biosimilar epoetin or a biosimilar darbepoetin alfa) with another ESA, placebo or no treatment in adults with CKD were considered for inclusion. DATA COLLECTION AND ANALYSIS Two independent authors screened the search results and extracted data. Data synthesis was performed using random-effects pairwise meta-analysis (expressed as odds ratios (OR) and their 95% confidence intervals (CI)) and network meta-analysis. We assessed for heterogeneity and inconsistency within meta-analyses using standard techniques and planned subgroup and meta-regression to explore sources of heterogeneity or inconsistency. We assessed certainty in treatment estimates for the primary outcomes (preventing blood transfusions and death (any cause)) using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. MAIN RESULTS Sixty-two new studies (9237 participants) were included in this update, so the review now includes 117 studies with 25,237 participants. Most studies were at high or unclear risk of bias in most methodological domains. Overall, results remain similar in this update compared to our previous review in 2014. For preventing blood transfusion, epoetin alfa (OR 0.28, 95% CI 0.13 to 0.61; low certainty evidence) and epoetin beta (OR 0.19, 95% CI 0.08 to 0.47; low certainty evidence) may be superior to placebo, and darbepoetin alfa was probably superior to placebo (OR 0.27, 95% CI 0.11 to 0.67; moderate certainty evidence). Methoxy polyethylene glycol-epoetin beta (OR 0.33, 95% CI 0.11 to 1.02; very low certainty evidence), a biosimilar epoetin (OR 0.34, 95% CI 0.11 to 1.03; very low certainty evidence) and a biosimilar darbepoetin alfa (OR 0.37, 95% CI 0.07 to 1.91; very low certainty evidence) had uncertain effects on preventing blood transfusion compared to placebo. The comparative effects of ESAs compared with another ESA on preventing blood transfusions were uncertain, in low to very low certainty evidence. Effects on death (any cause) were uncertain for epoetin alfa (OR 0.79, 95% CI 0.51 to 1.22; low certainty evidence), epoetin beta (OR 0.69, 95% CI 0.40 to 1.20; low certainty evidence), methoxy polyethylene glycol-epoetin beta (OR 1.07, 95% CI 0.67 to 1.71; very low certainty evidence), a biosimilar epoetin (OR 0.80, 95% CI 0.47 to 1.36; low certainty evidence) and a biosimilar darbepoetin alfa (OR 1.63, 95% CI 0.51 to 5.23; very low certainty evidence) compared to placebo. There was probably no difference between darbepoetin alfa and placebo on the odds of death (any cause) (OR 0.99, 95% CI 0.81 to 1.21; moderate certainty evidence). The comparative effects of ESAs compared with another ESA on death (any cause) were uncertain in low to very low certainty evidence. Epoetin beta probably increased the odds of hypertension when compared to placebo (OR 2.17, 95% CI 1.17 to 4.00; moderate certainty evidence). Compared to placebo, epoetin alfa (OR 2.10, 95% CI 1.22 to 3.59; very low certainty evidence), darbepoetin alfa (OR 1.88, 95% CI 1.12 to 3.14; low certainty evidence) and methoxy polyethylene glycol-epoetin beta (OR 1.98, 95% CI 1.05 to 3.74; low certainty evidence) may increase the odds of hypertension, but a biosimilar epoetin (OR 1.88, 95% CI 0.96 to 3.67; low certainty evidence) and biosimilar darbepoetin alfa (OR 1.98, 95% CI 0.84 to 4.66; low certainty evidence) had uncertain effects on hypertension. The comparative effects of all ESAs compared with another ESA, placebo or no treatment on cardiovascular death, myocardial infarction, stroke, vascular access thrombosis, kidney failure, and breathlessness were uncertain. Network analysis for fatigue was not possible due to sparse data.  AUTHORS' CONCLUSIONS The comparative effects of different ESAs on blood transfusions, death (any cause and cardiovascular), major cardiovascular events, myocardial infarction, stroke, vascular access thrombosis, kidney failure, fatigue and breathlessness were uncertain.

Abstract

BACKGROUND In the primary analysis of the PREDICT trial, a higher hemoglobin target (11-13 g/dl) with darbepoetin alfa did not improve renal outcomes compared with a lower hemoglobin target (9-11 g/dl) in advanced chronic kidney disease (CKD) without diabetes. Prespecified secondary analyses were performed to further study the effects of targeting higher hemoglobin levels on renal outcomes. METHODS Patients with an estimated glomerular filtration rate (eGFR) 8-20 ml/min/1.73 m(2) without diabetes were randomly assigned 1:1 to the high- and low-hemoglobin groups. The differences between the groups were evaluated for the following endpoints and cohort sets: eGFR and proteinuria slopes, assessed using a mixed-effects model in the full analysis set and the per-protocol set that excluded patients with off-target hemoglobin levels; the primary endpoint of composite renal outcome, evaluated in the per-protocol set using the Cox model. RESULTS In the full analysis set (high hemoglobin, n = 239; low hemoglobin, n = 240), eGFR and proteinuria slopes were not significantly different between the groups. In the per-protocol set (high hemoglobin, n = 136; low hemoglobin, n = 171), the high-hemoglobin group was associated with reduced composite renal outcome (adjusted hazard ratio: 0.64; 95% confidence interval: 0.43-0.96) and an improved eGFR slope (coefficient: + 1.00 ml/min/1.73 m(2)/year; 95% confidence interval: 0.38-1.63), while the proteinuria slope did not differ between the groups. CONCLUSIONS In the per-protocol set, the high-hemoglobin group demonstrated better kidney outcomes than the low-hemoglobin group, suggesting a potential benefit of maintaining higher hemoglobin levels in patients with advanced CKD without diabetes. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov (identifier: NCT01581073).

Abstract

INTRODUCTION Hyporesponsiveness to erythropoiesis-stimulating agents (ESA) has been associated with increased mortality and cardiovascular events in patients with chronic kidney disease. We hypothesized that the prediction of ESA resistance when ESA administration would be very useful in deciding on a treatment plan. METHODS Patients enrolled in a randomized controlled trial to evaluate renal prognosis in anemic patients with non-dialysis-dependent chronic kidney disease with hyporesponsiveness to ESA were included; the patients had different target hemoglobin levels. A landmark analysis was performed at 3 months into the study. To construct a predictive model for the severe ESA hypo-responder group, in which there was no increase in hemoglobin even with active treatment, background factors and serum test items that affect anemia at study entry were included in a logistic regression model, the area under the curve (AUC) and 95% confidence intervals (CI) were estimated, and sensitivity and specificity were calculated. This study was a post-hoc sub-analysis of a randomized controlled trial. RESULTS The AUC for the 19 existing risk factors as predictors was 0.783 (95% CI; 0.711-0.855). Among the 19 risk factors, the combination of six factors (hemoglobin level, systolic blood pressure, weight, gender, smoking status and hypertensive retinopathy) with the largest χ-square statistics were selected by multiple logistics regression. The AUC for these 6 predictors was 0.716 (95% CI: 0.634-0.799). To the six existing risk factors, five serum test items that affecting anemia (vitamin B12, vitamin B6, folic acid, parathyroid hormone, and 25-hydroxyvitamin D) were added, for a total of 11 risk factors, with a similar AUC of 0.736 (95% CI; 0.655-0.817), sufficient to predict ESA resistance. CONCLUSIONS Our results suggest that existing risk factors and serum test items can be used to predict ESA resistance in patients with non-dialysis-dependent chronic kidney disease on ESA.