Continuous erythropoiesis receptor activator (CERA) for the anaemia of chronic kidney disease.
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ABSTRACT:
SUBMITTER: Saglimbene VM
PROVIDER: S-EPMC6483666 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionErythropoiesis-stimulating agents and iron are commonly used in patients with chronic kidney disease with the aim of correcting anemia and maintaining stable hemoglobin levels. We analyzed pooled data from 13 studies with similar designs included in the Umbrella Continuous Erythropoietin Receptor Activator (C.E.R.A.) program to investigate the effects of continuous erythropoiesis receptor activator in clinically relevant subgroups of patients with chronic kidney disease and to determine whether the efficacy and safety outcomes demonstrated in the overall chronic kidney disease population are maintained in specific subgroups.MethodsData from 13 Phase III trials set up with similar design were retrospectively pooled for this analysis. Patients with chronic kidney disease who had previously been receiving epoetin or darbepoetin were switched to continuous erythropoiesis receptor activator once-monthly after a 4- to 8-week screening period. Patients entered a 16-week continuous erythropoiesis receptor activator dose-titration period followed by an 8-week evaluation period. In total, 2060 patients were included in the analysis. Subgroups were defined based on: hemoglobin target range [lower (10.0-12.0 g/dL)/upper (10.5-13.0 g/dL)], gender (female/male), age (<65/≥65), baseline N-terminal pro-B-type natriuretic peptide levels (<5000/≥5000), cardiovascular risk factors (diabetes/cardiac/vascular/none).ResultsAcross all subgroups analyzed, switching from shorter-acting erythropoiesis-stimulating agents to continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin concentrations in a high proportion of patients (78%), with only moderate hemoglobin fluctuations and a low number of dose changes. The safety profile across subgroups was as expected based on pre-existing risk factors; observed increases in adverse events were attributable to underlying risk factors rather than study drug.ConclusionsThis retrospective analysis of 13 trials showed that continuous erythropoiesis receptor activator once-monthly maintained stable hemoglobin levels across a number of clinically relevant patient subgroups, including those with higher inherent cardiovascular risk. The safety profile was consistent with that previously established in the chronic kidney disease population. CLINICALTRIALS.Gov identifiersNCT00413894/NCT00545571/NCT00517413/NCT00560404/NCT00882713/NCT00550680/NCT00576303/NCT00660023/NCT00717821/NCT00642850/NCT00605293/NCT00661505/NCT00699348.FundingF. Hoffmann-La Roche Ltd, Basel, Switzerland.
| S-EPMC4846713 | biostudies-literature
Project description:AimsErythropoiesis-stimulating agents used to treat anaemia in patients with chronic kidney disease (CKD) have been associated with cardiovascular adverse events. Hepcidin production, controlled by bone morphogenic protein 6 (BMP6), regulates iron homeostasis via interactions with the iron transporter, ferroportin. High hepcidin levels are thought to contribute to increased iron sequestration and subsequent anaemia in CKD patients. To investigate alternative therapies to erythropoiesis-stimulating agents for CKD patients, monoclonal antibodies, LY3113593 and LY2928057, targeting BMP6 and ferroportin respectively, were tested in CKD patients.MethodsPreclinical in vitro/vivo data and clinical data in healthy subjects and CKD patients were used to illustrate the translation of pharmacological properties of LY3113593 and LY2928057, highlighting the novelty of targeting these nodes within the hepcidin-ferroportin pathway.ResultsLY2928057 bound ferroportin and blocked interactions with hepcidin, allowing iron efflux, leading to increased serum iron and transferrin saturation levels and increased hepcidin in monkeys and humans. In CKD patients, LY2928057 led to slower haemoglobin decline and reduction in ferritin (compared to placebo). Serum iron increase was (mean [90% confidence interval]) 1.98 [1.46-2.68] and 1.36 [1.22-1.51] fold-relative to baseline following LY2928057 600 mg and LY311593 150 mg respectively in CKD patients. LY3113593 specifically blocked BMP6 binding to its receptor and produced increases in iron and transferrin saturation and decreases in hepcidin preclinically and clinically. In CKD patients, LY3113593 produced an increase in haemoglobin and reduction in ferritin (compared to placebo).ConclusionLY3113593 and LY2928057 pharmacological effects (serum iron and ferritin) were translated from preclinical-to-clinical development. Such interventions may lead to new CKD anaemia treatments.
| S-EPMC6475730 | biostudies-literature
Project description:BackgroundChronic kidney disease (CKD) is often complicated by anaemia, which is associated with disease progression and increased hospital visits, decreased quality of life, and increased mortality.MethodsA comprehensive literature search of English language peer-reviewed articles in PubMed/MedLine published between 1998 and 2020 related to the treatment of anaemia of CKD was conducted. The United States Renal Database System and Dialysis Outcomes and Practice Patterns Study (DOPPS) data reports, the Centers for Disease Control and Prevention and the US Food and Drug Administration websites, and published congress abstracts in 2020 were surveyed for relevant information.ResultsSubgroups of patients with anaemia of CKD present a clinical challenge throughout the disease spectrum, including those with end-stage kidney disease, advanced age or resistance to or ineligibility for current standards of care (ie, oral or intravenous iron supplementation, erythropoietin-stimulating agents and red blood cell transfusions). In addition, those with an increased risk of adverse events because of comorbid conditions, such as cardiovascular diseases or diabetes, comprise special populations of patients with an unmet need for interventions to improve clinical outcomes. These comorbidities must be managed in parallel and may have a synergistic effect on overall disease severity.ConclusionsSeveral therapies provide promising opportunities to address gaps with a standard of care, including hypoxia-inducible factor prolyl hydroxylase inhibitors, which stimulate haematopoiesis through promoting modest increases in serum erythropoietin and improved iron homeostasis. The critical issues in the management of anaemia of CKD in these challenging phenotypes and the clinical utility of new therapeutic agents in development for the treatment of anaemia of CKD should be assessed and the information should be made available to healthcare providers.
| S-EPMC9285529 | biostudies-literature
Project description:BackgroundAnaemia is a known risk factor for cardiovascular disease and treating anaemia in chronic kidney disease (CKD) may improve outcomes. However, little is known about the scope to improve primary care management of anaemia in CKD.MethodsAn observational study (N = 1,099,292) with a nationally representative sample using anonymised routine primary care data from 127 Quality Improvement in CKD trial practices (ISRCTN5631023731). We explored variables associated with anaemia in CKD: eGFR, haemoglobin (Hb), mean corpuscular volume (MCV), iron status, cardiovascular comorbidities, and use of therapy which associated with gastrointestinal bleeding, oral iron and deprivation score. We developed a linear regression model to identify variables amenable to improved primary care management.ResultsThe prevalence of Stage 3-5 CKD was 6.76%. Hb was lower in CKD (13.2 g/dl) than without (13.7 g/dl). 22.2% of people with CKD had World Health Organization defined anaemia; 8.6% had Hb ? 11 g/dl; 3% Hb ? 10 g/dl; and 1% Hb ? 9 g/dl. Normocytic anaemia was present in 80.5% with Hb ? 11; 72.7% with Hb ? 10 g/dl; and 67.6% with Hb ? 9 g/dl; microcytic anaemia in 13.4% with Hb ? 11 g/dl; 20.8% with Hb ? 10 g/dl; and 24.9% where Hb ? 9 g/dl. 82.7% of people with microcytic and 58.8% with normocytic anaemia (Hb ? 11 g/dl) had a low ferritin (<100 ug/mL). Hypertension (67.2% vs. 54%) and diabetes (30.7% vs. 15.4%) were more prevalent in CKD and anaemia; 61% had been prescribed aspirin; 73% non-steroidal anti-inflammatory drugs (NSAIDs); 14.1% warfarin 12.4% clopidogrel; and 53.1% aspirin and NSAID. 56.3% of people with CKD and anaemia had been prescribed oral iron. The main limitations of the study are that routine data are inevitably incomplete and definitions of anaemia have not been standardised.ConclusionsMedication review is needed in people with CKD and anaemia prior to considering erythropoietin or parenteral iron. Iron stores may be depleted in over >60% of people with normocytic anaemia. Prescribing oral iron has not corrected anaemia.
| S-EPMC3626717 | biostudies-literature
Project description:Background Soluble urokinase-type plasminogen activator receptor (suPAR) is associated with cardiovascular risks and poor renal outcomes. However, whether elevated suPAR levels are associated with 24-hour blood pressure patterns or kidney disease progression in patients with chronic kidney disease (CKD) is unclear. Methods and Results A total of 751 patients with CKD stage 1 to 5 were recruited from CMERC-HI (Cardiovascular and Metabolic Disease Etiology Research Center-High Risk) cohort study (2013-2018). The relationship of serum suPAR levels to 24-hour blood pressure parameters and CKD progression was analyzed. The median serum suPAR level was 1439.0 (interquartile range, 1026.2-2150.1) pg/mL, and the mean estimated glomerular filtration rate was 52.8±28.5 mL/min per 1.73 m2 at baseline. Patients with higher suPAR levels had significantly higher levels of office, 24-hour, daytime, and nighttime systolic blood pressure and nighttime diastolic blood pressure than those with lower suPAR levels. The highest suPAR tertile was associated with an increased risk of a reverse dipping pattern (odds ratio, 2.93; 95% CI, 1.27-6.76; P=0.01). During a follow-up of 43.2 (interquartile range, 27.0-55.6) months, the CKD progression occurred in 271 (36.1%) patients. The highest suPAR tertile was significantly associated with higher risk of CKD progression than the lowest tertile (hazard ratio [HR], 2.09; 95% CI, 1.37-3.21; P=0.001). When the relationship was reevaluated with respect to each dipping pattern (dipper, extreme dipper, nondipper, and reverse dipper), this association was consistent only in reverse dippers in whom the risk of CKD progression increased (HR, 1.43; 95% CI, 1.02-2.01; P=0.03) with every 1-unit increase in serum suPAR levels. Conclusions Elevated suPAR levels are independently associated with CKD progression, and this association is prominent in reverse dippers.
| S-EPMC7955457 | biostudies-literature
Project description:Iron deficiency anaemia is a global health problem that manifests as fatigue and poor physical endurance. Anaemia can be caused by dietary iron deficiency, blood loss or a combination of poor iron absorption and ineffective iron mobilization in patients with chronic disease. Nephrologists caring for patients with impaired renal function understand that iron treatment is necessary to provide adequate iron for erythropoiesis during the treatment of overt anaemia. However, a less well-understood health problem is iron deficiency, which creates symptoms that overlap with those of anaemia and often occurs in concert with chronic disease. Recently, several randomized controlled clinical trials have been conducted to investigate the effects of treatment with intravenous iron in heart failure patients with iron deficiency who may or may not also have anaemia. Given that heart and kidney disease are often comorbid, these clinical trials may have implications for the way nephrologists view their patients with iron deficiency. In this article, we review several clinical studies of intravenous iron therapy for patients with iron deficiency and heart failure and discuss possible implications for the treatment of patients with kidney disease.
| S-EPMC5716152 | biostudies-literature
Project description:Relatively high plasma levels of soluble urokinase-type plasminogen activator receptor (suPAR) have been associated with focal segmental glomerulosclerosis and poor clinical outcomes in patients with various conditions. It is unknown whether elevated suPAR levels in patients with normal kidney function are associated with future decline in the estimated glomerular filtration rate (eGFR) and with incident chronic kidney disease.We measured plasma suPAR levels in 3683 persons enrolled in the Emory Cardiovascular Biobank (mean age, 63 years; 65% men; median suPAR level, 3040 pg per milliliter) and determined renal function at enrollment and at subsequent visits in 2292 persons. The relationship between suPAR levels and the eGFR at baseline, the change in the eGFR over time, and the development of chronic kidney disease (eGFR <60 ml per minute per 1.73 m(2) of body-surface area) were analyzed with the use of linear mixed models and Cox regression after adjustment for demographic and clinical variables.A higher suPAR level at baseline was associated with a greater decline in the eGFR during follow-up; the annual change in the eGFR was -0.9 ml per minute per 1.73 m(2) among participants in the lowest quartile of suPAR levels as compared with -4.2 ml per minute per 1.73 m(2) among participants in the highest quartile (P<0.001). The 921 participants with a normal eGFR (? 90 ml per minute per 1.73 m(2)) at baseline had the largest suPAR-related decline in the eGFR. In 1335 participants with a baseline eGFR of at least 60 ml per minute per 1.73 m(2), the risk of progression to chronic kidney disease in the highest quartile of suPAR levels was 3.13 times as high (95% confidence interval, 2.11 to 4.65) as that in the lowest quartile.An elevated level of suPAR was independently associated with incident chronic kidney disease and an accelerated decline in the eGFR in the groups studied. (Funded by the Abraham J. and Phyllis Katz Foundation and others.).
| S-EPMC4701036 | biostudies-literature
Project description:Background:Chronic kidney disease (CKD) has become a global public health problem with a high prevalence and mortality. There is no sensitive and effective markers for chronic kidney disease. Previous studies proposed suPAR as an early predict biomarker for chronic kidney disease, but the results are controversial. Therefore, the purpose of the current meta-analysis is to evaluate the association between suPAR and CKD. Methods:We searched the PubMed, Embase, Cochrane Library databases, and Web of Science before May 1, 2019. The search was based on the key words including suPAR and CKD. Data are extracted independently according to standard format, and quality analysis is performed. We extracted the concentration of suPAR and hazard rate (HR) values of mortality, cardiovascular disease, and end-stage renal disease. Results:There were 14 studies fulfilling the criteria. The concentration of suPAR was higher in patients with CKD than that in the control group (P < 0.001; SMD: -2.17; 95% CI: -2.71, -1.63; I 2?=?67.4%). SuPAR had a higher risk of mortality (P=0.001; HR: 1.72; 95% CI: 1.24, 2.39; I 2?=?68.0%). The higher suPAR level increased the risk of cardiovascular disease (P < 0.001; HR: 3.06; 95% CI: 2.21, 4.22; I 2?=?0.0%) and the risk of end-stage renal disease (P < 0.001; HR: 1.40; 95% CI: 1.22, 1.60; I 2?=?0.0%). Conclusions:Monitoring suPAR concentrations may be used for early diagnosis and prognosis for patients with CKD, and the higher suPAR increased the risk of mortality, cardiovascular events, and end-stage renal disease.
| S-EPMC6899318 | biostudies-literature
Project description:In a multicenter, prospective, observational study of 279 kidney transplant recipients with anemia, the efficacy and safety of once-monthly continuous erythropoietin receptor activator (C.E.R.A.) were assessed to a maximum of 15 months. The main efficacy variable was the proportion of patients achieving a hemoglobin level of 11-12 g/dL at each of visits between months 7 and 9. At study entry, 224 patients (80.3%) were receiving erythropoiesis stimulating agent (ESA) therapy including darbepoetin alfa (98), epoetin beta (61), and C.E.R.A. (45). The mean (SD) time between C.E.R.A. applications was 34.0 (11.9) days. Among 193 patients for whom efficacy data were available, mean (SD) hemoglobin was 11.1 (0.99) g/dL at study entry, 11.5 (1.1) g/dL at month 7, 11.6 (1.3) g/dL at month 9, and 11.4 (1.1) g/dL at month 15. During months 7-9, 20.7% of patients had all hemoglobin values within the range 11-12 g/dL and 64.8% were within 10-13 g/dL. Seven patients (2.5%) discontinued C.E.R.A. due to adverse events or serious adverse events. In this observational trial under real-life conditions, once-monthly C.E.R.A. therapy achieved stable hemoglobin levels in stable kidney transplant recipients with good tolerability, and with no requirement for any dose change in 43% of patients.
| S-EPMC4026977 | biostudies-literature
Project description:BackgroundHospitalized patients are at an increased risk of developing kidney disease after discharge, often despite the absence of any clinical indicators during hospitalization. Soluble urokinase plasminogen activator receptor (suPAR) is a marker of systemic chronic inflammation that can be measured from routine blood samples. We determined whether elevated suPAR during hospitalization is associated with a decline in estimated glomerular filtration rate (eGFR) after discharge.MethodsThis was a retrospective longitudinal cohort study of patients without detectable kidney disease presenting to the emergency department on two separate occasions during a 3-year period. The association between suPAR and a decline in eGFR was assessed by linear mixed models for repeated measures adjusting for age, sex, C-reactive protein, sodium, diabetes, hypertension and cardiovascular disease.ResultsIn total, 5124 patients (median age 65.9 years, 51.0% female) were included. The median suPAR was 2.9 ng/mL, the median time to readmission was 144 days and the expected rate of eGFR decline over this period was 5.1 mL/min/1.73 m2/year. Adjusting for other risk factors, patients with suPAR <3, 3-6 or ≥6 ng/mL had an expected eGFR decline of 4.3, 5.2 or 9.0 mL/min/1.73 m2/year, respectively. Similarly, patients with suPAR in the lowest (<2.4 ng/mL), middle (2.4-3.6 ng/mL) or highest (≥3.6 ng/mL) tertile had an expected eGFR decline of 4.2, 4.6 or 6.5 mL/min/1.73 m2/year, respectively. In both cases, a higher suPAR level was significantly and independently associated with a higher rate of eGFR decline (P < .001).ConclusionsA higher suPAR level was associated with accelerated eGFR decline among patients presenting to the emergency department, suggesting that routine suPAR measurements may have utility for the early detection of kidney disease.
| S-EPMC9308102 | biostudies-literature