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International Journal of Nephrology and... 2023Anemia is prevalent among patients with chronic kidney disease (CKD), yet current evidence indicates that treatment may not adhere to Kidney Disease: Improving Global...
BACKGROUND
Anemia is prevalent among patients with chronic kidney disease (CKD), yet current evidence indicates that treatment may not adhere to Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. We aimed to document the management of patients with non-dialysis-dependent (NDD)-CKD receiving erythropoiesis-stimulating agent (ESA) therapy in Europe.
METHODS
This retrospective, observational study extracted information from medical records in Germany, Spain, and the UK. Eligible patients were adults with NDD-CKD stages 3b-5 who initiated ESA therapy for anemia between January and December 2015. Anemia was defined as hemoglobin (Hb) <13.0 g/dL (males) or <12.0 g/dL (females). Data regarding ESA treatment, treatment response, concomitant iron therapy and blood transfusions were extracted up to 24 months post-ESA initiation, and data on CKD progression until abstraction date.
RESULTS
Eight hundred and forty-eight medical records were abstracted. Approximately 40% received no iron therapy prior to ESA initiation. At ESA initiation, mean ± standard deviation Hb level was 9.8 ± 1.0 g/dL. Most patients received darbepoetin alfa, and switching between ESAs was rare (8.5% of patients). Concomitant intravenous and oral iron therapy was prescribed for 36% and 42% of patients, respectively, during initial ESA therapy. Mean Hb levels reached the target level (10-12 g/dL) within 3-6 months of ESA initiation. Hb, transferrin saturation, and ferritin levels were infrequently monitored from 3 months post-ESA initiation. Rates of blood transfusion, dialysis, and diagnosis of end-stage renal disease were 16.4%, 19.3%, and 24.6%, respectively. Rates of kidney transplant and death were 4.8% and 8.8%, respectively.
CONCLUSION
Among ESA-treated patients, ESA initiation was in accordance with KDIGO guidelines, but subsequent monitoring of Hb and iron deficiency were suboptimal.
PubMed: 37077414
DOI: 10.2147/IJNRD.S401598 -
American Journal of Nephrology 2021Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese,... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor for treating anemia of chronic kidney disease (CKD). This post hoc analysis of a Japanese, open-label, partially randomized, phase 3 study in nondialysis-dependent (NDD) CKD patients treated with traditional erythropoiesis-stimulating agents (ESAs) evaluated dosing trends of roxadustat and darbepoetin alfa (DA) required to maintain target hemoglobin concentrations in patients with risk factors associated with ESA hyporesponsiveness.
METHODS
Patients enrolled in the 1517-CL-0310 study (NCT02988973) that demonstrated noninferiority of roxadustat to DA for change in average hemoglobin levels of week 18-24 from baseline who had used human recombinant erythropoietin or DA before conversion and who were randomized to either roxadustat or DA were included. The endpoints were the average allocated dose of roxadustat and DA per administration in the last 6 weeks (AAD/6W), assessed by subgroups known to be associated with ESA hyporesponsiveness. The analysis of variance was performed by the treatment group to test the influence of subgroup factors on the AAD/6W of study drug. The ratios between the mean AAD/6W in each subgroup category and the within-arm mean AAD/6W were calculated.
RESULTS
Two hundred and sixty-two patients were randomized to either the roxadustat or DA comparative group and received treatment (roxadustat, n = 131; DA, n = 131). Higher mean (standard deviation) doses of both roxadustat (63.15 [24.84] mg) and DA (47.33 [29.79] μg) were required in the highest ESA resistance index (≥6.8) quartile (p = 0.003 and p < 0.001, respectively). Patients with adequate iron repletion had the lowest doses for both roxadustat (45.54 [18.01] mg) and DA (28.13 [20.98] μg). High-sensitivity C-reactive protein ≥28.57 nmol/L and the estimated glomerular filtration rate <15 mL/min/1.73 m2 were associated with requiring higher DA but not roxadustat doses.
DISCUSSION/CONCLUSION
The roxadustat dose required to maintain target hemoglobin in NDD patients in Japan with anemia of CKD relative to DA dose may not be impacted by low-grade inflammation. Roxadustat may be beneficial for ESA-hyporesponsive NDD CKD patients.
Topics: Aged; Aged, 80 and over; Anemia; Darbepoetin alfa; Female; Glycine; Hematinics; Humans; Isoquinolines; Japan; Male; Middle Aged; Renal Insufficiency, Chronic
PubMed: 34628408
DOI: 10.1159/000519043 -
Journal of Thoracic Oncology : Official... Feb 2020
Topics: Anemia; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Darbepoetin alfa; Double-Blind Method; Humans; Lung Neoplasms
PubMed: 32127181
DOI: 10.1016/j.jtho.2019.11.002 -
Kidney International Reports Jul 2021Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated safety and efficacy versus placebo in phase III trials in patients with...
INTRODUCTION
Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor that has demonstrated safety and efficacy versus placebo in phase III trials in patients with anemia of chronic kidney disease (CKD) who were not on dialysis (NDD).
METHODS
This was a phase III, active-controlled, multicenter, partially randomized, open-label study in Japanese patients with NDD CKD. Patients who had used recombinant human erythropoietin or darbepoetin alfa (DA) before conversion were randomized to roxadustat or DA (comparative arms). Patients who had used epoetin beta pegol before conversion were allocated to roxadustat (reference arm). The primary endpoint was change in average hemoglobin (Hb) level from baseline during the evaluation period (Weeks 18-24). Longer term efficacy and safety were evaluated in roxadustat-treated patients over 52 weeks.
RESULTS
In this study, 334 patients were randomized/allocated to receive treatment ( = 132, roxadustat [comparative]; = 131, DA [comparative]; = 71, roxadustat [reference]). The estimated difference between the roxadustat (comparative) and DA (comparative) groups in the least squares mean of change of average Hb levels of Weeks 18 to 24 from baseline was -0.07 g/dl, with the lower limit of 95% confidence interval of -0.23 g/dl, thereby confirming the noninferiority of roxadustat to DA. Common treatment-emergent adverse events (≥3% of patients in any treatment group) observed during the 24-week treatment period included nasopharyngitis, CKD, hyperkalemia, and hypertension.
CONCLUSION
Roxadustat maintained Hb within 10 to 12 g/dl in NDD CKD patients and was noninferior to DA. The safety profiles observed in this study are consistent with previous studies performed in this patient population.
PubMed: 34307976
DOI: 10.1016/j.ekir.2021.04.003 -
MBio Feb 2023Streptococcus pneumoniae colonizes the human nasopharynx and causes several diseases. Pneumococcal vaccines target the polysaccharide capsule and prevent most serious...
Streptococcus pneumoniae colonizes the human nasopharynx and causes several diseases. Pneumococcal vaccines target the polysaccharide capsule and prevent most serious disease, but there has been an increase in the prevalence of nonencapsulated S. pneumoniae (NESp). Previously, it was thought that a capsule was necessary to cause invasive disease. NESp strains expressing the oligopeptide transporters AliC and AliD have been isolated from patients with invasive disease. The AliC and AliD oligopeptide transporters regulate the expression of several genes, including choline binding protein AC (CbpAC) (a homolog of PspA), which aids in reducing C3b deposition. It is hypothesized that by altering CbpAC expression, AliC and AliD provide protection from classical complement-mediated clearance by reducing C-reactive protein (CRP) binding. Our study demonstrates that AliC and AliD regulate CbpAC expression in NESp and that AliD found in certain serotypes of encapsulated strains regulates PspA expression. C3b deposition was increased in the NESp Δ and encapsulated mutants in comparison to the wild type. NESp strains expressing AliC and AliD have a significant decrease in C1q and CRP deposition in comparison to the Δ Δ mutant. The complement protein C1q is required for NESp clearance in a murine model and increases opsonophagocytosis. By regulating CbpAC expression, NESp inhibits CRP binding to the bacterial surface and blocks classical complement activation, leading to greater systemic survival and virulence. Due to the increase in the prevalence of NESp, it is important to gain a better understanding of NESp virulence mechanisms that aid in establishing disease and persistence within a host by avoiding clearance by the immune system. Streptococcus pneumoniae (pneumococcus) can cause a range of diseases. Although there is a robust pneumococcal vaccination program that reduces invasive pneumococcal disease by targeting various polysaccharide capsules, there has been an increase in the isolation of nonvaccine serotypes and nonencapsulated S. pneumoniae (NESp) strains. While most studies of pneumococcal pathogenesis have focused on encapsulated strains, there is little understanding of how NESp causes disease. NESp lacks a protective capsule but contains novel genes, such as and , which have been shown to regulate the expression of numerous genes and to be required for NESp virulence and immune evasion. Furthermore, NESp strains have high transformation efficiencies and harbor resistance to multiple drugs. This could be deleterious to current treatment strategies employed for pneumococcal disease as NESp can be a reservoir of drug resistance genes. Therefore, deciphering how NESp survives within a host and facilitates disease is a necessity that will allow the fabrication of improved, broad-spectrum treatments and preventatives against pneumococcal disease. Our study provides a better understanding of NESp virulence mechanisms during host-pathogen interactions through the examination of genes directly regulated by the NESp proteins AliC and AliD.
Topics: Animals; Humans; Mice; Bacterial Proteins; Carrier Proteins; Choline; Complement C1q; Darbepoetin alfa; Membrane Transport Proteins; Pneumococcal Infections; Streptococcus pneumoniae
PubMed: 36625598
DOI: 10.1128/mbio.03325-22 -
Clinical Lymphoma, Myeloma & Leukemia May 2024Real-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization...
INTRODUCTION
Real-world studies of lower-risk myelodysplastic syndromes (LR-MDS) are limited. We evaluated treatment patterns, clinical outcomes, and healthcare resource utilization (HCRU) among patients with LR-MDS treated with erythropoiesis-stimulating agents (ESAs) in the United States.
PATIENTS AND METHODS
This retrospective study included patients with LR-MDS who initiated treatment with ESAs between January 1, 2016 and June 30, 2019. The primary analysis assessed patient demographic and clinical characteristics, treatment patterns, clinical outcomes (hematologic response, transfusion requirements, disease progression), and HCRU (medical encounters, laboratory tests, and medication use). Subgroup analyses of patients repeatedly treated with ESA therapy evaluated selected clinical outcomes and primary ESA failure by SF3B1 mutational status, per recently updated NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines©).
RESULTS
A total of 142 patients were included with a median follow-up time of 17 months (interquartile range [IQR], 7-33). Median age at ESA initiation was 79 years (IQR, 73-85). Patients were predominantly male (54%), overweight or obese (32% and 23%, respectively), of White race (96%) and non-Hispanic ethnicity (89%). Overall, 57% patients were initially treated with darbepoetin alfa and 43% with epoetin alfa. Clinical outcomes were poor, and there was a significant burden on both the health system and individual patients treated with ESA therapies. Hematologic improvement- erythroid was only seen in 26% of 142 patients treated with ESAs, and 65% of 82 retreated patients experienced primary ESA failure.
CONCLUSION
Our results indicate that primary ESA failure is largely unrecognized and that many patients should be considered for alternative treatments.
PubMed: 38871557
DOI: 10.1016/j.clml.2024.05.007 -
The Journal of Clinical Investigation Apr 2023Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes...
Genetic defects of GNAS, the imprinted gene encoding the stimulatory G protein α-subunit, are responsible for multiple diseases. Abnormal GNAS imprinting causes pseudohypoparathyroidism type 1B (PHP1B), a prototype of mammalian end-organ hormone resistance. Hypomethylation at the maternally methylated GNAS A/B region is the only shared defect in patients with PHP1B. In autosomal dominant (AD) PHP1B kindreds, A/B hypomethylation is associated with maternal microdeletions at either the GNAS NESP55 differentially methylated region or the STX16 gene located approximately 170 kb upstream. Functional evidence is meager regarding the causality of these microdeletions. Moreover, the mechanisms linking A/B methylation and the putative imprinting control regions (ICRs) NESP-ICR and STX16-ICR remain unknown. Here, we generated a human embryonic stem cell model of AD-PHP1B by introducing ICR deletions using CRISPR/Cas9. With this model, we showed that the NESP-ICR is required for methylation and transcriptional silencing of A/B on the maternal allele. We also found that the SXT16-ICR is a long-range enhancer of NESP55 transcription, which originates from the maternal NESP-ICR. Furthermore, we demonstrated that the STX16-ICR is an embryonic stage-specific enhancer enabled by the direct binding of pluripotency factors. Our findings uncover an essential GNAS imprinting control mechanism and advance the molecular understanding of PHP1B pathogenesis.
Topics: Animals; Humans; Darbepoetin alfa; Chromogranins; Pseudohypoparathyroidism; GTP-Binding Protein alpha Subunits, Gs; DNA Methylation; Genomic Imprinting; Mammals
PubMed: 36853809
DOI: 10.1172/JCI167953 -
International Journal of Environmental... Dec 2020The impact on health care of patients with myelodysplastic syndromes (MDS) is continuously rising. To investigate the perception of hemato-oncologists concerning the...
The impact on health care of patients with myelodysplastic syndromes (MDS) is continuously rising. To investigate the perception of hemato-oncologists concerning the recommended MDS patient care in Switzerland, we conducted a web-based survey on diagnosis, risk-stratification and treatment. 43/309 physicians (13.9%) replied to 135 questions that were based on current guidelines between 3/2017 and 2/2018. Only questions with feedback-rates >50% were further analysed and ratios >90% defined "high agreement", 70-90% "agreement", 30-70% "insufficient agreement" and <30% "disagreement". For diagnosis, we found insufficient agreement on using flow-cytometry, classifying MDS precursor conditions, performing treatment response assessment after hypomethylating agents (HMA) and evaluating patients with suspected germ-line predisposition. For risk-stratification, we identified agreement on using IPSS-R but insufficient agreement for IPSS and patient-based assessments. For treatment, we observed disagreement on performing primary infectious prophylaxis in neutropenia but agreement on using only darbepoetin alfa in anaemic, lower-risk MDS patients. For thrombopoietin receptor agonists, insufficient agreement was found for the indication, preferred agent and triggering platelet count. Insufficient agreement was also found for immunosuppressive treatment in hypoplastic MDS and HMA dose adjustments. In conclusion, we identified areas for improvement in MDS patient care, in need of further clinical trials, information, and guiding documents.
Topics: Adult; Delivery of Health Care; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Platelet Count; Switzerland
PubMed: 33371225
DOI: 10.3390/ijerph17249562 -
BMC Nephrology Aug 2021Variation in de-adoption of ineffective or unsafe treatments is not well-understood. We examined de-adoption of erythropoiesis-stimulating agents (ESA) in anemia...
BACKGROUND
Variation in de-adoption of ineffective or unsafe treatments is not well-understood. We examined de-adoption of erythropoiesis-stimulating agents (ESA) in anemia treatment among patients with chronic kidney disease (CKD) following new clinical evidence of harm and ineffectiveness (the TREAT trial) and the FDA's revision of its safety warning.
METHOD
We used a segmented regression approach to estimate changes in use of epoetin alfa (EPO) and darbepoetin alfa (DPO) in the commercial, Medicare Advantage (MA) and Medicare fee-for-service (FFS) populations. We also examined how changes in both trends and levels of use were associated with physicians' characteristics.
RESULTS
Use of DPO and EPO declined over the study period. There were no consistent changes in DPO trend across insurance groups, but the level of DPO use decreased right after the FDA revision in all groups. The decline in EPO use trend was faster after the TREAT trial for all groups. Nephrologists were largely more responsive to evidence than primary care physicians. Differences by physician's gender, and age were not consistent across insurance populations and types of ESA.
CONCLUSIONS
Physician specialty has a dominant role in prescribing decision, and that specializations with higher use of treatment (nephrologists) were more responsive to new evidence of unsafety and ineffectiveness.
Topics: Anemia; Darbepoetin alfa; Diffusion of Innovation; Epoetin Alfa; Hematinics; Humans; Practice Guidelines as Topic; Practice Patterns, Physicians'; Regression Analysis; Renal Insufficiency, Chronic; Safety-Based Drug Withdrawals; United States; United States Food and Drug Administration
PubMed: 34419007
DOI: 10.1186/s12882-021-02491-y -
Clinical Research in Cardiology :... Apr 2022We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction... (Clinical Trial)
Clinical Trial
AIMS
We aimed to assess the value of GDF-15, a stress-responsive cytokine, in predicting clinical outcomes in patients with heart failure (HF) with reduced ejection fraction (HFrEF) and anemia METHODS AND RESULTS: Serum GDF-15 was assessed in 1582 HFrEF and mild-to-moderate anemia patients who where followed for 28 months in the Reduction of Events by Darbepoetin alfa in Heart Failure (RED-HF) trial, an overall neutral RCT evaluating the effect darbepoetin alfa on clinical outcomes in patients with systolic heart failure and mild-to-moderate anemia. Association between baseline and change in GDF-15 during 6 months follow-up and the primary composite outcome of all-cause death or HF hospitalization were evaluated in multivariable Cox-models adjusted for conventional clinical and biochemical risk factors. The adjusted risk for the primary outcome increased with (i) successive tertiles of baseline GDF-15 (tertile 3 HR 1.56 [1.23-1.98] p < 0.001) as well as with (ii) a 15% increase in GDF-15 levels over 6 months of follow-up (HR 1.68 [1.38-2.06] p < 0.001). Addition of change in GDF-15 to the fully adjusted model improved the C-statistics (p < 0.001). No interaction between treatment and baseline or change in GDF-15 on outcome was observed. GDF-15 was inversely associated with several indices of anemia and correlated positively with ferritin.
CONCLUSIONS
In patients with HF and anemia, both higher baseline serum GDF-15 levels and an increase in GDF-15 during follow-up, were associated with worse clinical outcomes. GDF-15 did not identify subgroups of patients who might benefit from correction of anemia but was associated with several indices of anemia and iron status in the HF patients.
Topics: Anemia; Growth Differentiation Factor 15; Heart Failure; Heart Failure, Systolic; Humans; Prognosis; Stroke Volume
PubMed: 34611778
DOI: 10.1007/s00392-021-01944-6