RESUMO
AIM: To characterize the clinical context for the decision to order red blood cell (RBC) transfusions in dialysis patients. MATERIALS AND METHODS: Retrospective review of medical records from three integrated health systems serving chronic dialysis patients. Subjects were randomly selected from all patients who received at least one transfusion between January 2009 and December 2013. Data abstracted included transfusion setting, prescribing clinician type, patient demographics and hemoglobin (Hb) concentration prior to transfusion, and cataloguing and prioritizing of clinical factors for their contribution to the decision to transfuse. Data from one system were stratified between transfusions before and after the 2011 dialysis payment reform and anemia drug label changes. RESULTS: Charts for 590 patients were reviewed. The primary reason for transfusion was low Hb (51%), medical conditions (22%), symptoms of anemia (18%), surgery-related (6%), and undetermined (3%). In 93% of cases, multiple factors were cited as contributors to the transfusion decision. Mean Hb prior to transfusion was 7.2 g/dL in patients where low Hb was the primary reason for transfusion (range: 4.0 - 9.9 g/dL). CONCLUSIONS: The decision to transfuse dialysis patients is influenced by multiple patient factors and medical conditions, of which low Hb is the main contributor to this decision about half of the time.â©.
Assuntos
Anemia/terapia , Transfusão de Eritrócitos/estatística & dados numéricos , Falência Renal Crônica/terapia , Diálise Renal , Idoso , Anemia/complicações , Anemia/metabolismo , Tomada de Decisão Clínica , Feminino , Hemoglobinas , Hemorragia/complicações , Hemorragia/terapia , Humanos , Cuidados Intraoperatórios , Falência Renal Crônica/complicações , Falência Renal Crônica/metabolismo , Masculino , Cuidados Pós-Operatórios , Estudos RetrospectivosRESUMO
BACKGROUND: Patient engagement in end-stage renal disease (ESRD) is expected to result in a more patient-centered approach to care that aligns with patients' values, preferences, and goals for treatment. Nevertheless, no previous studies of which we are aware have evaluated patients' benefit-risk preferences for the management of anemia associated with ESRD. The primary objective of this study was to quantify the tradeoffs patients are willing to make between cardiovascular risks associated with some anemia medicines and red blood cell (RBC) transfusions. A secondary objective was to quantify the importance of avoiding transfusion-related risks. METHODS: A survey instrument was developed from the clinical literature, clinician input, patient-education resources, and a patient focus group. The survey instrument was qualitatively pretested before its administration to a broader sample of patients. The National Kidney Foundation invited individuals in the United States to participate in the survey. In a discrete-choice experiment (DCE), respondents chose between two hypothetical anemia medications in a series of questions. Each medication was defined by symptom relief, frequency of transfusions, cardiovascular risk, mode of administration, and out-of-pocket cost. The survey also included a best-worst scaling (BWS) exercise to quantify the importance of avoiding attributes of blood transfusions. Results from the DCE were used to estimate relative importance and marginal willingness to pay. Results from the BWS were converted to relative importance weights. RESULTS: A total of 200 individuals completed the survey. Patients were willing to accept a 6% medication-related risk of heart attack to avoid having two RBC transfusions per month. Symptom relief and mode of administration were of moderate importance. The most important transfusion-related risk to avoid was transfusion-related lung injury. CONCLUSIONS: Patients with ESRD and anemia have measurable treatment preferences and are willing to accept risks associated with anemia medications to avoid transfusions.
Assuntos
Anemia/terapia , Gerenciamento Clínico , Falência Renal Crônica/terapia , Preferência do Paciente , Diálise Renal/métodos , Adulto , Idoso , Anemia/diagnóstico , Anemia/etiologia , Transfusão de Eritrócitos/métodos , Feminino , Humanos , Falência Renal Crônica/diagnóstico , Masculino , Pessoa de Meia-Idade , Diálise Renal/efeitos adversos , Medição de Risco/métodos , Inquéritos e QuestionáriosRESUMO
Erythropoiesis-stimulating agents (ESAs) are commonly used to treat anemia in patients with CKD, including those receiving dialysis, although clinical trials have identified risks associated with ESA use. We evaluated the effects of changes in dialysis payment policies and product labeling instituted in 2011 on mortality and major cardiovascular events across the United States dialysis population in an open cohort study of patients on dialysis from January 1, 2005, through December 31, 2012, with Medicare as primary payer. We compared observed rates of death and major cardiovascular events in 2011 and 2012 with expected rates calculated on the basis of rates in 2005-2010, accounting for differences in patient characteristics and influenza virulence. An abrupt decline in erythropoietin dosing and hemoglobin concentration began in late 2010. Observed rates of all-cause mortality, cardiovascular mortality, and myocardial infarction in 2011 and 2012 were consistent with expected rates. During 2012, observed rates of stroke, venous thromboembolic disease (VTE), and heart failure were lower than expected (absolute deviation from trend per 100 patient-years [95% confidence interval]: -0.24 [-0.08 to -0.37] for stroke, -2.43 [-1.35 to -3.70] for VTE, and -0.77 [-0.28 to -1.27] for heart failure), although non-ESA-related changes in practice and Medicare payment penalties for rehospitalization may have confounded the results. This initial evidence suggests that action taken to mitigate risks associated with ESA use and changes in payment policy did not result in a relative increase in death or major cardiovascular events and may reflect improvements in stroke, VTE, and heart failure.
Assuntos
Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Mecanismo de Reembolso , Diálise Renal , Doenças Cardiovasculares/mortalidade , Estudos de Coortes , Prescrições de Medicamentos/normas , Feminino , Humanos , Masculino , Medicare , Pessoa de Meia-Idade , Padrões de Prática Médica , Estados UnidosRESUMO
U.S. regulations require biosimilars to be highly similar to their reference product and demonstrate no clinically meaningful differences in safety, purity, or potency. For biosimilars of erythropoiesis-stimulating agents (ESAs), this standard is challenging--structural differences are likely, and their effect on safety and efficacy cannot be predicted from analytical studies. Thus, clinical trials should compare hemoglobin, dose, and immunogenicity endpoints.
Assuntos
Medicamentos Biossimilares , Ensaios Clínicos como Assunto/métodos , Hematínicos , Guias como Assunto , Humanos , Projetos de PesquisaRESUMO
YB-1 is a member of the cold shock domain family, with complex roles in DNA structure, gene transcription and translation. YB-1 promotes chromosomal instability, and mammary gland transgenic expression induces tumors with 100% penetrance. YB-1 is linked to poor prognosis in breast carcinoma and is a strong predictor of relapse and disease-specific survival. Survival is directly tied to the extent of local invasion and distal metastasis, processes dependent upon the activity of the membrane type I-matrix metalloproteinase, MT1-MMP. Non-invasive MCF-7 breast adenocarcinoma cells were transfected with YB-1/EGFP. YB-1 protein was detected in the invadopodia of cells with a migratory phenotype. There was increased expression of MT1-MMP protein concentrated at the leading edges of motile cells, which were highly invasive in collagen three-dimensional culture. The rates of MT1-MMP protein endocytosis and recycling to the cell surface were elevated in clones expressing higher levels of YB-1 protein. Control MCF-7 cells formed nonfatal, non-invasive, differentiated adenocarcinomas in vivo. MCF-7 cells expressing a twofold increase in YB-1 formed highly anaplastic tumors with local invasion, pulmonary metastases and high lethality. We conclude that YB-1 contributes to the development of an invasive, metastatic breast carcinoma phenotype by enhanced presentation of MT1-MMP at the sites of cellular invasion.
Assuntos
Adenocarcinoma/patologia , Neoplasias da Mama/patologia , Proteínas de Ligação a DNA/metabolismo , Metaloproteinase 14 da Matriz/metabolismo , Proteínas Nucleares/metabolismo , Adenocarcinoma/enzimologia , Animais , Neoplasias da Mama/enzimologia , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/genética , Feminino , Humanos , Metaloproteinase 14 da Matriz/genética , Camundongos , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Proteínas Nucleares/genética , Transporte Proteico , Proteína 1 de Ligação a Y-BoxRESUMO
Comparability studies used to assess a proposed manufacturing change for a biological product include sensitive analytical studies to confirm there are no significant differences in structural or functional attributes that may contribute to clinically meaningful changes in efficacy or safety. When a proposed change is relatively complex or when clinically relevant differences between the product before and after the change cannot be ruled out based on analytical studies, nonclinical and clinical bridging studies are generally required to confirm overall comparability. In this study, we report findings from a comparability assessment of epoetin alfa before and after a proposed manufacturing process change. Although differences in glycosylation attributes were observed, these were initially believed to be irrelevant to the product's pharmacology. This assumption was initially supported via nonclinical and clinical pharmacology studies, but a clinically meaningful difference in potency was ultimately observed in a phase 3 clinical study conducted in a sensitive patient population using a sensitive study design. These results indicate that the nonclinical assessments of structure-function relationships were insufficiently sensitive to identify clinically relevant differences resulting from differences in the glycosylation profile. This case study highlights important findings that may be relevant in the development of biosimilar epoetin alfa products.
Assuntos
Anemia/tratamento farmacológico , Epoetina alfa/uso terapêutico , Hematínicos/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Anemia/complicações , Animais , Medicamentos Biossimilares/química , Medicamentos Biossimilares/farmacocinética , Medicamentos Biossimilares/farmacologia , Medicamentos Biossimilares/uso terapêutico , Aprovação de Drogas , Epoetina alfa/química , Epoetina alfa/farmacocinética , Epoetina alfa/farmacologia , Glicosilação , Hematínicos/química , Hematínicos/farmacocinética , Hematínicos/farmacologia , Humanos , Camundongos , Camundongos SCID , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/farmacologia , Proteínas Recombinantes/uso terapêutico , Insuficiência Renal Crônica/complicações , Projetos de Pesquisa , Relação Estrutura-AtividadeRESUMO
Chronic kidney disease (CKD) and failure are problems of increasing importance. Regardless of the primary etiology, CKD is characterized by tubular atrophy, interstitial fibrosis, and glomerulosclerosis. It has been assumed that diminished matrix metalloproteinase (MMP) activity is responsible for the accumulation of the extracellular matrix (ECM) proteins and collagens that typify the fibrotic kidney. Here we demonstrate that transgenic renal proximal tubular epithelial expression of a specific enzyme, MMP-2, is sufficient to generate the entire spectrum of pathological and functional changes characteristic of human CKD. At the earliest point, MMP-2 leads to structural alterations in the tubular basement membrane, a process that triggers tubular epithelial-mesenchymal transition, with resultant tubular atrophy, fibrosis and renal failure. Inhibition of MMP-2, specifically in the early, prefibrotic stages of disease may offer an additional approach for treatment of these disabling disorders.
Assuntos
Membrana Basal/fisiologia , Nefropatias/fisiopatologia , Falência Renal Crônica/fisiopatologia , Metaloproteinase 2 da Matriz/metabolismo , Animais , Atrofia , Sequência de Bases , Membrana Basal/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/genética , Colágeno Tipo I/genética , Progressão da Doença , Proteínas de Choque Térmico HSP47/genética , Humanos , Túbulos Renais/patologia , Metaloproteinase 2 da Matriz/genética , Inibidores de Metaloproteinases de Matriz , Camundongos , Camundongos Endogâmicos , Camundongos Transgênicos , Dados de Sequência Molecular , Ratos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteína A4 de Ligação a Cálcio da Família S100 , Proteínas S100 , Vimentina/genéticaRESUMO
Renal tubular epithelial cells in all nephron segments express a distinct member of the metalloprotease-disintegrin family, ADAM9 (a disintegrin and metalloprotease 9), in a punctate basolateral distribution co-localized to the beta1 integrin chain [Mahimkar, Baricos, Visaya, Pollock and Lovett (2000) J. Am. Soc. Nephrol. 11, 595-603]. Discrete segments of the nephron express several defined beta1 integrins, suggesting that ADAM9 interacts with multiple renal integrins and thereby regulates epithelial cell-matrix interactions. Intact ADAM9 and a series of deletion constructs sequentially lacking the metalloprotease domain and the disintegrin domain were assembled as chimaeras with a C-terminal GFP (green fluorescent protein) tag. Stable expression of the ADAM9/GFP protein on the surface of HEK-293 cells (human embryonic kidney 293 cells) significantly decreased adhesion to types I and IV collagen, vitronectin and laminin, but had little effect on adhesion to fibronectin. Expression of the disintegrin/cysteine-rich/GFP construct yielded a similar, but more marked pattern of decreased adhesion. Expression of the cysteine-rich/GFP construct had no effect on adhesion, indicating that the disintegrin domain was responsible for the competitive inhibition of cell-matrix binding. To define the specific renal tubular beta1 integrins interacting with the ADAM9 disintegrin domain, a recombinant GST (glutathione S-transferase)-disintegrin protein was used as a substrate in adhesion assays in the presence or absence of specific integrin-blocking antibodies. Inclusion of antibodies to alpha1, alpha3, alpha6, alphav and beta1 blocked adhesion of HEK-293 cells to GST-disintegrin protein. Immobilized GST-disintegrin domain perfused with renal cortical lysates specifically recovered the alpha3, alpha6, alphav and beta1 integrin chains by Western analysis. It is concluded that ADAM9 is a polyvalent ligand, through its disintegrin domain, for multiple renal integrins of the beta1 class.
Assuntos
Desintegrinas/química , Desintegrinas/metabolismo , Integrina beta1/metabolismo , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Proteínas ADAM , Animais , Linhagem Celular , Linhagem Celular Tumoral , Junções Célula-Matriz/fisiologia , Desintegrinas/fisiologia , Glutationa Transferase , Humanos , Cadeias beta de Integrinas/metabolismo , Rim/química , Rim/citologia , Rim/embriologia , Rim/metabolismo , Ligantes , Melanoma/química , Melanoma/metabolismo , Melanoma/patologia , Proteínas de Membrana/fisiologia , Metaloendopeptidases/fisiologia , Peptídeos/fisiologia , Estrutura Terciária de Proteína , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes de FusãoRESUMO
Interleukin 1alpha (IL-1alpha), a 33 kDa precursor, is cleaved releasing the 17 kDa carboxyl-terminal cytokine IL-1alpha to which all of the biological properties of IL-1alpha have been attributed. We investigated the potential independent properties of the remaining 16 kDa IL-1alpha amino-terminal propiece by expression in human tumor and primary human cell lines. The IL-1alpha propiece produced apoptosis in malignant but not normal cell lines. A minimal fragment comprised of amino acids 55-108 was required for apoptosis. Deletion and mutation studies identified an extended nuclear localization sequence required for nuclear localization, induction of apoptosis and concentration of the IL-1alpha propiece in interchromatin granule clusters, concentrations of proteins in the RNA splicing and processing pathways. The IL-1alpha propiece interacted with five known components of the RNA splicing/processing pathway, suggesting that the mechanism of action may involve changes in RNA splicing or processing. Expression of the IL-1alpha propiece caused a shift in the ratio of Bcl-Xl/Bcl-Xs toward the apoptotic direction. Our findings indicate that the IL-1alpha propiece induces apoptosis in a range of tumor cells and likely operates through a mechanism involving the RNA processing apparatus and the alternate splicing of apoptosis regulatory proteins.
Assuntos
Apoptose , Interleucina-1/metabolismo , Processamento Pós-Transcricional do RNA , Sequência de Aminoácidos , Sítios de Ligação , Linhagem Celular , Núcleo Celular/metabolismo , Proteínas de Fluorescência Verde , Células HL-60 , Células HeLa , Humanos , Imuno-Histoquímica , Interleucina-1/genética , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Dados de Sequência Molecular , Mutação , Ligação Proteica , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Homologia de Sequência de Aminoácidos , Transfecção , Células Tumorais Cultivadas , Proteína bcl-XRESUMO
The complex interactions of glomerular and tubular epithelial cells with the basal laminae play a critical role in renal function. Disruption of these interactions has been widely implicated in glomerular diseases and acute renal failure. MDC are a large family of membrane-bound proteins containing metalloprotease, disintegrin (integrin interaction sites), and cysteine-rich domains. Little information is available concerning the presence of MDC in the kidney or their role in renal pathophysiology. Using degenerate PCR primers for the conserved metalloprotease and disintegrin domains of this protein family, cDNA templates from tubules, whole glomeruli, and glomerular epithelial cells (GEC) yielded a single, 195-bp product, which on sequence analysis corresponded to a region in the disintegrin domain of MDC9. Northern analysis of poly(A)+ RNA from tubules, whole glomeruli, and GEC revealed a 3.9-kb transcript, identical to that of mouse MDC9. Using antibodies generated against a 21-amino acid peptide present in the metalloprotease domain of MDC9, Western analysis of concanavalin A-enriched glomerular microsomal extracts demonstrated both processed (76 kD) and unprocessed (116 kD) forms of MDC9, which upon reduction changed to the corresponding 84- and 124-kD forms. Histochemical studies revealed a basolateral localization of intrinsic MDC9 protein in renal cortical tubule cells and glomerular visceral epithelial cells, which colocalized with the beta1 integrin chain. Expression of green fluorescence protein MDC9 chimeric constructs in GEC or polarized Madin-Darby canine kidney epithelial cells revealed a similar punctate basolateral surface localization. Transient overexpression of the soluble disintegrin domain-green fluorescence protein chimera in GEC led to dramatic changes in cellular morphology with rounding and detachment from cell monolayers. These studies document the presence of MDC9 in renal epithelial cells and suggest an important role for MDC9 in renal epithelial cellular interactions with the basal lamina and adjoining cells.