RESUMEN
Clinical trials in nephrology often use composite end points comprising clinical events, such as onset of ESKD and initiation of kidney function replacement therapy, along with a sustained large ( e.g. , ≥50%) decrease in GFR. Such events typically occur late in the disease course, resulting in large trials in which most participants do not contribute clinical events. In addition, components of the end point are considered of equal importance; however, their clinical significance varies. For example, kidney function replacement therapy initiation is likely to be clinically more meaningful than GFR decline of ≥50%. By contrast, hierarchical composite end points (HCEs) combine multiple outcomes and prioritize each patient's most clinically relevant outcome for inclusion in analysis. In this review, we consider the use of HCEs in clinical trials of CKD progression, emphasizing the potential to combine dichotomous clinical events such as those typically used in CKD progression trials, with the continuous variable of GFR over time, while ranking all components according to clinical significance. We consider maraca plots to visualize overall treatment effects and the contributions of individual components, discuss the application of win odds in kidney HCE trials, and review general design considerations for clinical trials for CKD progression with kidney HCE as an efficacy end point.
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Insuficiencia Renal Crónica , Humanos , Tasa de Filtración Glomerular , Riñón , Progresión de la EnfermedadRESUMEN
SIGNIFICANCE STATEMENT: The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR but does not weigh the relative clinical importance of the end point components. By contrast, a hierarchical composite end point (HCE) accounts for the clinical importance of the end point components. The authors developed and validated a kidney HCE that combines clinical kidney outcomes with longitudinal GFR changes (GFR slope). They demonstrate that in seven major placebo-controlled kidney outcome trials with different medications, treatment effect estimates on the HCE were consistently in similar directions and of similar magnitudes compared with treatment effects on the established kidney end point. The HCE's prioritization of clinical outcomes and ability to combine dichotomous outcomes with GFR slope make it an attractive alternative to the established kidney end point. BACKGROUND: The established composite kidney end point in clinical trials combines clinical events with sustained large changes in GFR. However, the statistical method does not weigh the relative clinical importance of the end point components. A HCE accounts for the clinical importance of the end point components and enables combining dichotomous outcomes with continuous measures. METHODS: We developed and validated a new HCE for kidney disease progression, performing post hoc analyses of seven major Phase 3 placebo-controlled trials that assessed the effects of canagliflozin, dapagliflozin, finerenone, atrasentan, losartan, irbesartan, and aliskiren in patients with CKD. We calculated the win odds (WOs) for treatment effects on a kidney HCE, defined as a hierarchical composite of all-cause mortality; kidney failure; sustained 57%, 50%, and 40% GFR declines from baseline; and GFR slope. The WO describes the odds of a more favorable outcome for receiving the active compared with the control. We compared the WO with the hazard ratio (HR) of the primary kidney outcome of the original trials. RESULTS: In all trials, treatment effects calculated with the WO reflected a similar direction and magnitude of the treatment effect compared with the HR. Clinical trials incorporating the HCE would achieve increased statistical power compared with the established composite end point at equivalent sample sizes. CONCLUSIONS: In seven major kidney clinical trials, the WO and HR provided similar direction of treatment effect estimates with smaller HRs associated with larger WOs. The prioritization of clinical outcomes and inclusion of broader composite end points makes the HCE an attractive alternative to the established kidney end point.
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Insuficiencia Renal Crónica , Humanos , Insuficiencia Renal Crónica/tratamiento farmacológico , Tasa de Filtración Glomerular , Riñón , Progresión de la EnfermedadRESUMEN
AKI after cardiac surgery is associated with mortality, prolonged hospital length of stay, use of dialysis, and subsequent CKD. We evaluated the effects of THR-184, a bone morphogenetic protein-7 agonist, in patients at high risk for AKI after cardiac surgery. We conducted a randomized, double-blind, placebo-controlled, multidose comparison of the safety and efficacy of perioperative THR-184 using a two-stage seamless adaptive design in 452 patients between 18 and 85 years of age who were scheduled for nonemergent cardiac surgery requiring cardiopulmonary bypass and had recognized risk factors for AKI. The primary efficacy end point was the proportion of patients who developed AKI according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. The proportion of patients who developed AKI within 7 days of surgery was similar in THR-184 treatment groups and placebo groups (range, 74%-79%; P=0.43). Prespecified secondary end point analysis did not show significant differences in the severity of AKI stage (P=0.53) or the total duration of AKI (P=0.44). A composite of death, dialysis, or sustained impaired renal function by day 30 after surgery did not differ between groups (range, 11%-20%; P=0.46). Safety-related outcomes were similar across all treatment groups. In conclusion, compared with placebo, administration of perioperative THR-184 through a range of dose exposures failed to reduce the incidence, severity, or duration of AKI after cardiac surgery in high-risk patients.
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Lesión Renal Aguda/etiología , Lesión Renal Aguda/prevención & control , Proteína Morfogenética Ósea 7/agonistas , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Oligopéptidos/administración & dosificación , Lesión Renal Aguda/fisiopatología , Anciano , Anciano de 80 o más Años , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oligopéptidos/farmacología , Periodo Perioperatorio , Índice de Severidad de la Enfermedad , Insuficiencia del TratamientoRESUMEN
In order to change the current state of chronic kidney disease knowledge and therapeutics, a fundamental improvement in the understanding of genetic and environmental causes of chronic kidney disease is essential. This article first provides an overview of the existing knowledge gaps in our understanding of the genetic and environmental causes of chronic kidney disease, as well as their interactions. The second part of the article formulates goals that should be achieved in order to close these gaps, along with suggested timelines and stakeholders that are to be involved. A better understanding of genetic and environmental factors and their interactions that influence kidney function in healthy and diseased conditions can provide novel insights into renal physiology and pathophysiology and result in the identification of novel therapeutic or preventive targets to tackle the global public health care problem of chronic kidney disease.
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The focus of this article is to define goals and resulting action plans that can be collectively embraced by interested stakeholders to facilitate new therapeutic approaches to mitigate chronic kidney disease progression. The specific goals include identifying druggable targets, increasing the capacity for preclinical and early clinical development, broadening the availability of new therapeutic approaches, and increasing investment in the development of new therapies to limit chronic kidney disease. Key deliverables include the establishment of new regional, national, and global consortia; development of clinical trial networks; and creation of programs to support the temporary mutual movement of scientists between academia and the biotechnology and pharmaceutical sector. Other deliverables include cataloging and maintaining up-to-date records to collate progress in renal research and development, inventorying the capacity of research and clinical networks, and describing methods to ensure novel drug development.
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Reliable identification of features distinguishing biological groups of interest in urinary metabolite fingerprints requires the control of total metabolite abundance, which may vary significantly as the kidneys adjust the excretion of water and solutes to meet the homeostatic needs of the body. Failure to account for such variation may lead to misclassification and accumulation of missing data in case of less concentrated urine specimens. Here, different pre- and post-acquisition methods of normalization were compared systematically for their ability to recover features from liquid chromatography-mass spectrometry metabolite fingerprints of urine that allow distinction between patients with chronic kidney disease and healthy controls. Methods of normalization that were employed prior to analysis included dilution of urine specimens to either a fixed creatinine concentration or osmolality value. Post-acquisition normalization methods applied to chromatograms of 1:4 diluted urine specimens comprised normalization to creatinine, osmolality, and sum of all integrals. Dilution of urine specimens to a fixed creatinine concentration resulted not only in the least number of missing values, but it was also the only method allowing the unambiguous classification of urine specimens from healthy and diseased individuals. The robustness of classification could be confirmed for two independent patient cohorts of chronic kidney disease patients and yielded a shared set of 49 discriminant metabolite features. Graphical Abstract Dilution to a uniform creatinine concentration across urine specimens yields more comparable urinary metabolite fingerprints.
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Biomarcadores/orina , Creatinina/análisis , Metabolómica/normas , Urinálisis/métodos , Anemia/orina , Estudios de Cohortes , Diabetes Mellitus Tipo 2/orina , Voluntarios Sanos , Humanos , Metabolómica/métodos , Concentración Osmolar , Insuficiencia Renal Crónica/orina , Manejo de Especímenes , Urinálisis/normasRESUMEN
OBJECTIVE: Retinopathy is an established microvascular complication of type 2 diabetes mellitus (T2DM), but its independent relationship with macrovascular and other microvascular complications is less well defined across the spectrum of kidney disease in T2DM. We examined the prognostic value of retinopathy in assessing the risk of developing end-stage renal disease (ESRD), cardiovascular morbidity or death among patients in the Trial to Reduce cardiovascular Events with Aranesp Therapy (TREAT). DESIGN: TREAT enrolled 4038 patients with T2DM, chronic kidney disease (CKD) and moderate anemia. Patients were grouped by baseline history of retinopathy. Proportional hazards regression models were utilized to assess the association between retinopathy and subsequent ESRD, cardiovascular morbidity or death over an average of 2.4â years. RESULTS: Although younger, the 1895 (47%) patients with retinopathy had longer duration of diabetes, lower estimated glomerular filtration rate, more proteinuria, and more microvascular complications. In univariate analysis, retinopathy was associated with a higher rate of ESRD, but not with cardiovascular events or mortality. After adjustment, retinopathy was no longer statistically significant for the prediction of ESRD or any clinical endpoint. CONCLUSIONS: In a large cohort of patients with T2DM, CKD, and anemia, retinopathy was common but not independently associated with a higher risk of renal or cardiovascular morbidity or death. TRIAL REGISTRATION NUMBER: NCT00093015.
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BACKGROUND: Glomerular filtration rate (GFR) estimating equations using the combination of creatinine and cystatin C (eGFRcr-cys) are more accurate than equations using either alone (eGFRcr or eGFRcys). New guidelines suggest measuring cystatin C as a confirmatory test when eGFRcr may be inaccurate, but do not specify demographic or clinical conditions in which eGFRcys or eGFRcr-cys are more accurate than eGFRcr nor which estimate to use in such circumstances. METHODS: We compared the performance of the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations in 1119 subjects in the CKD-EPI cystatin C external validation dataset. Subgroups were defined by eGFRcr, age, sex, diabetes status and body mass index (BMI). The reference test was GFR measured using urinary or plasma clearance of exogenous filtration markers. Cystatin C and creatinine assays were traceable to primary reference materials. Accuracy was defined as the absolute difference in eGFR compared with mGFR. RESULTS: The mean mGFR was 70 ± 41 (SD) mL/min/1.73 m(2). eGFRcys was more accurate than eGFRcr at lower BMI and less accurate at higher BMI, especially at higher levels of eGFRcr. There were small differences in accuracy in people according to the diabetes status. eGFRcr-cys was as accurate or more accurate than eGFRcr or eGFRcys in these and all other subgroups. CONCLUSIONS: eGFRcr-cys, but not eGFRcys, is more accurate than eGFRcr in most subgroups we studied, suggesting preferential use of eGFRcr-cys when serum cystatin C is measured as a confirmatory test to obtain more accurate eGFR. Further studies are necessary to evaluate diagnostic strategies for using eGFRcys and eGFRcr-cys.
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Creatinina/sangre , Cistatina C/sangre , Tasa de Filtración Glomerular/fisiología , Insuficiencia Renal Crónica/fisiopatología , Adulto , Anciano , Biomarcadores/sangre , Índice de Masa Corporal , Estudios Transversales , Diabetes Mellitus/metabolismo , Femenino , Humanos , Pruebas de Función Renal/normas , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Insuficiencia Renal Crónica/sangreRESUMEN
BACKGROUND: Most studies of HLA sensitization after red blood cell transfusion in transplant candidates were done before widespread use of leuko reduced blood and based on relatively insensitive, nonspecific antibody assays. We evaluated the effect of transfusion on the breadth and magnitude of HLA antibody formation using current, sensitive, HLA-specific immunoassays. METHODS: Serial HLA antibody data were merged with transfusion data from the US Renal Data System for 1324 patients on the kidney transplant wait list (2004-2010). Two study groups were identified: a matched cohort consisting of 89 patients who received transfusion and 251 patients who did not receive transfusion and a crossover cohort consisting of 69 patients. Changes in antibody levels and calculated panel-reactive antibody (CPRA) were compared using χ and Sign tests, respectively. Logistic regression was used to estimate the relative risk of antibody responses. RESULTS: Among the matched cohort, 20% of those who received transfusion compared to 3% of those who did not receive transfusion exhibited an antibody response (P=0.001), whereas in the crossover cohort, 19% exhibited a response in those who received transfusion compared to 1% of those who did not receive transfusion (P=0.0001). Moreover, 26.3% of those who received transfusion had increased CPRA compared to 5.8% of those who did not receive transfusion . These effects were greater in women and blacks compared to men and whites, respectively. Importantly, patients who received transfusion were at an increased risk of a potentially crossmatch positive response (odds ratio=9.6, 95% confidence interval=3.0-30.7). CONCLUSIONS: Sensitization from transfusion can occur in up to 20% of transplant candidates, resulting in higher antibody levels and CPRA values that adversely impact access to transplantation. These results support transfusion avoidance whenever possible.
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Formación de Anticuerpos/inmunología , Transfusión de Eritrocitos/efectos adversos , Inmunización/efectos adversos , Fallo Renal Crónico/inmunología , Trasplante de Riñón , Listas de Espera , Adulto , Anciano , Anticuerpos/sangre , Anticuerpos/inmunología , Estudios de Casos y Controles , Estudios de Cohortes , Estudios Cruzados , Femenino , Antígenos HLA/inmunología , Humanos , Inmunoensayo , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/cirugía , Modelos Logísticos , Masculino , Persona de Mediana Edad , Factores de RiesgoRESUMEN
Antibody-mediated pure red cell aplasia (PRCA) has been primarily observed in patients with chronic kidney disease treated with an erythropoiesis-stimulating agent (ESA); only a few anecdotal cases have been reported in other patient populations. We searched the Amgen Global Safety Adverse Event Database and identified 14 patients with hepatitis C who developed severe anemia, anti-erythropoietin antibodies, and bone marrow biopsy-proven PRCA, while receiving interferon therapy (with or without ribavirin) and an ESA. During the follow-up period and after ESA treatment stopped, 11 patients no longer required transfusions and 3 did. Analysis of antibody isotypes showed that, contrary to reports of patients with chronic kidney disease, immunoglobulin G1 was the predominant isotype rather than immunoglobulin G4 (immunoglobulin G4 was detected in only 1 of 6 patients). Epitope mapping showed the anti-erythropoietin antibodies bound domains required for receptor binding. Therefore, the potential benefits of ESA therapy must be weighed against the risk for PRCA in patients with hepatitis C who are receiving treatment with interferon and ribavirin.
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Hematínicos/efectos adversos , Hepatitis C/complicaciones , Hepatitis C/tratamiento farmacológico , Aplasia Pura de Células Rojas/complicaciones , Adulto , Anciano , Anticuerpos/sangre , Antivirales/uso terapéutico , Mapeo Epitopo , Eritropoyetina/inmunología , Humanos , Inmunoglobulina G/análisis , Persona de Mediana Edad , Aplasia Pura de Células Rojas/inmunologíaRESUMEN
BACKGROUND: Sensitization to human leukocyte antigen (HLA) from red blood cell (RBC) transfusion is poorly quantified and is based on outdated, insensitive methods. The objective was to evaluate the effect of transfusion on the breadth, magnitude and specificity of HLA antibody formation using sensitive and specific methods. METHODS: Transfusion, demographic and clinical data from the US Renal Data System were obtained for patients on dialysis awaiting primary kidney transplant who had ≥ 2 HLA antibody measurements using the Luminex single-antigen bead assay. One cohort included patients with a transfusion (n = 50) between two antibody measurements matched with up to four nontransfused patients (n = 155) by age, sex, race and vintage (time on dialysis). A second crossover cohort (n = 25) included patients with multiple antibody measurements before and after transfusion. We studied changes in HLA antibody mean fluorescence intensity (MFI) and calculated panel reactive antibody (cPRA). RESULTS: In the matched cohort, 10 of 50 (20%) transfused versus 6 of 155 (4%) nontransfused patients had a ≥ 10 HLA antibodies increase of >3000 MFI (P = 0.0006); 6 of 50 (12%) transfused patients had a ≥ 30 antibodies increase (P = 0.0007). In the crossover cohort, the number of HLA antibodies increasing >1000 and >3000 MFI was higher in the transfused versus the control period, P = 0.03 and P = 0.008, respectively. Using a ≥ 3000 MFI threshold, cPRA significantly increased in both matched (P = 0.01) and crossover (P = 0.002) transfused patients. CONCLUSIONS: Among prospective primary kidney transplant recipients, RBC transfusion results in clinically significant increases in HLA antibody strength and breadth, which adversely affect the opportunity for future transplant.
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Anticuerpos/sangre , Formación de Anticuerpos/inmunología , Transfusión Sanguínea , Antígenos HLA/inmunología , Fallo Renal Crónico/inmunología , Trasplante de Riñón , Anticuerpos/inmunología , Estudios Cruzados , Femenino , Humanos , Fallo Renal Crónico/sangre , Fallo Renal Crónico/cirugía , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Diálisis Renal , Listas de EsperaRESUMEN
BACKGROUND: Sparse data are available about the natural history of hemoglobin (Hb) level trends in contemporary patients with anemia, chronic kidney disease (CKD), and type 2 diabetes mellitus. We intended to describe Hb level trends over time with no or minimal administration of erythropoiesis-stimulating agents. STUDY DESIGN: Prospective clinical trial cohort. SETTING & PARTICIPANTS: 2,019 individuals with type 2 diabetes, moderate anemia, and CKD from the placebo arm of the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT) followed up for 2.3 years with an average of 32 monthly Hb level determinations per patient. Darbepoetin alfa was administered only if Hb level decreased to <9 g/dL. OUTCOMES & MEASUREMENTS: Number of protocol-directed doses of darbepoetin alfa received due to an Hb level decrease to <9 g/dL. RESULTS: 1,106 (55%) placebo patients consistently maintained an Hb level ≥9 g/dL and received no protocol-directed darbepoetin alfa. The other patients received 1 (16%), 2-4 (16%), or 5 or more (13%) doses of darbepoetin alfa. Those who received no darbepoetin alfa doses had higher baseline Hb levels, higher estimated glomerular filtration rates (eGFRs), less proteinuria, and lower ferritin and transferrin saturation values. On average, Hb levels were stable or increased in all groups. Compared with individuals who received no darbepoetin alfa, those who received 5 or more doses were more likely to receive intravenous iron therapy and blood transfusions and progress to renal replacement therapy, but were not at higher risk of death. The strongest predictors of requiring 5 or more doses of darbepoetin alfa were lower baseline Hb level, lower eGFR, and higher proteinuria level. LIMITATIONS: Post hoc analysis of a clinical trial of a specific population with diabetes, anemia, and non-dialysis-dependent CKD. CONCLUSIONS: In the TREAT placebo arm, Hb levels were stable with no or minimal protocol-directed darbepoetin alfa during 2.3 years of follow-up. Most patients with moderate anemia, non-dialysis-dependent CKD, and type 2 diabetes are able to maintain a stable Hb level without implementing long-term erythropoiesis-stimulating agent therapy.
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Anemia/sangre , Anemia/tratamiento farmacológico , Diabetes Mellitus Tipo 2/sangre , Eritropoyetina/análogos & derivados , Hematínicos/farmacología , Hematínicos/uso terapéutico , Hemoglobinas/análisis , Insuficiencia Renal Crónica/sangre , Anciano , Darbepoetina alfa , Método Doble Ciego , Eritropoyetina/farmacología , Eritropoyetina/uso terapéutico , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
The molecules involved in vertebrate tendon formation during development remain largely unknown. To date, only two DNA-binding proteins have been identified as being involved in vertebrate tendon formation, the basic helix-loop-helix transcription factor Scleraxis and, recently, the Mohawk homeobox gene. We investigated the involvement of the early growth response transcription factors Egr1 and Egr2 in vertebrate tendon formation. We established that Egr1 and Egr2 expression in tendon cells was correlated with the increase of collagen expression during tendon cell differentiation in embryonic limbs. Vertebrate tendon differentiation relies on a muscle-derived FGF (fibroblast growth factor) signal. FGF4 was able to activate the expression of Egr genes and that of the tendon-associated collagens in chick limbs. Egr gene misexpression experiments using the chick model allowed us to establish that either Egr gene has the ability to induce de novo expression of the reference tendon marker scleraxis, the main tendon collagen Col1a1, and other tendon-associated collagens Col3a1, Col5a1, Col12a1, and Col14a1. Mouse mutants for Egr1 or Egr2 displayed reduced amounts of Col1a1 transcripts and a decrease in the number of collagen fibrils in embryonic tendons. Moreover, EGR1 and EGR2 trans-activated the mouse Col1a1 proximal promoter and were recruited to the tendon regulatory regions of this promoter. These results identify EGRs as novel DNA-binding proteins involved in vertebrate tendon differentiation by regulating type I collagen production.
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Diferenciación Celular/fisiología , Proteína 1 de la Respuesta de Crecimiento Precoz/metabolismo , Proteína 2 de la Respuesta de Crecimiento Precoz/metabolismo , Embrión de Mamíferos/embriología , Tendones/embriología , Animales , Proteínas Aviares/biosíntesis , Proteínas Aviares/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/biosíntesis , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Embrión de Pollo , Pollos , Colágeno/biosíntesis , Colágeno/genética , Proteína 1 de la Respuesta de Crecimiento Precoz/genética , Proteína 2 de la Respuesta de Crecimiento Precoz/genética , Embrión de Mamíferos/citología , Factor 4 de Crecimiento de Fibroblastos/genética , Factor 4 de Crecimiento de Fibroblastos/metabolismo , Ratones , Ratones Noqueados , Tendones/citologíaRESUMEN
BACKGROUND: Nonplacebo-controlled trials of erythropoiesis-stimulating agents (ESAs) comparing lower and higher hemoglobin targets in patients with chronic kidney disease indicate that targeting of a lower hemoglobin range may avoid ESA-associated risks. However, target-based strategies are confounded by each patient's individual hematopoietic response. METHODS: We assessed the relationship among the initial hemoglobin response to darbepoetin alfa after two weight-based doses, the hemoglobin level achieved after 4 weeks, the subsequent darbepoetin alfa dose, and outcomes in 1872 patients with chronic kidney disease and type 2 diabetes mellitus who were not receiving dialysis. We defined a poor initial response to darbepoetin alfa (which occurred in 471 patients) as the lowest quartile of percent change in hemoglobin level (<2%) after the first two standardized doses of the drug. RESULTS: Patients who had a poor initial response to darbepoetin alfa had a lower average hemoglobin level at 12 weeks and during follow-up than did patients with a better hemoglobin response (a change in hemoglobin level ranging from 2 to 15% or more) (P<0.001 for both comparisons), despite receiving higher doses of darbepoetin alfa (median dose, 232 µg vs. 167 µg; P<0.001). Patients with a poor response, as compared with those with a better response, had higher rates of the composite cardiovascular end point (adjusted hazard ratio, 1.31; 95% confidence interval [CI], 1.09 to 1.59) or death (adjusted hazard ratio, 1.41; 95% CI, 1.12 to 1.78). CONCLUSIONS: A poor initial hematopoietic response to darbepoetin alfa was associated with an increased subsequent risk of death or cardiovascular events as doses were escalated to meet target hemoglobin levels. Although the mechanism of this differential effect is not known, these findings raise concern about current target-based strategies for treating anemia in patients with chronic kidney disease. (Funded by Amgen; ClinicalTrials.gov number, NCT00093015.)
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Anemia/tratamiento farmacológico , Diabetes Mellitus Tipo 2/complicaciones , Eritropoyetina/análogos & derivados , Hematínicos/uso terapéutico , Hemoglobinas/metabolismo , Fallo Renal Crónico/complicaciones , Anciano , Anemia/etiología , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/prevención & control , Distribución de Chi-Cuadrado , Darbepoetina alfa , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/mortalidad , Método Doble Ciego , Eritropoyetina/uso terapéutico , Femenino , Humanos , Inyecciones Subcutáneas , Fallo Renal Crónico/sangre , Fallo Renal Crónico/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Riesgo , Accidente Cerebrovascular/epidemiologíaRESUMEN
The present work identifies a new mouse model of inductible acute glomerular injury leading to focal segmental glomerulonephritis. We take advantage of the suicide gene/prodrug nitroreductase/CB1954 combination, in which nitroreductase converts CB1954, a monofunctional alkylating agent, into its toxic form. We generate two lines of transgenic mice in which the nitroreductase gene was placed under the control of the podocyte-specific gene podocin. The functional analysis of transgenic mice lines showed that CB1954 treatment induced a severe but transitory proteinuria. Sequential histopathological analysis was performed on serial kidney biopsies. Injured glomeruli showed acute lesions with early podocyte vacuolization and detachment, podocyte apoptosis, and cellular proliferation leading to a marked hypercellularity of the urinary space that was associated with collapsing of the glomerular tuft. After 1 month, progressive scarring lead to focal segmental glomerulosclerosis with fibrous capsular adhesion, hyalinosis, and podocytosis associated with interstitial fibrosis. The phenotype of podocytes was changed exhibiting dedifferentiation characterized by the loss of podocyte specific proteins/transcription factor and the expression of injury markers. Bowman's capsule cells were also involved in the cellular changes in a manner suggesting epithelial to mesenchymal transition. This model of podocyte injury in transgenic mice provides new insights into the cellular mechanisms of podocytopathies and their progression to scarring.
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Glomeruloesclerosis Focal y Segmentaria/fisiopatología , Péptidos y Proteínas de Señalización Intracelular/genética , Glomérulos Renales/metabolismo , Proteínas de la Membrana/genética , Nitrorreductasas/genética , Animales , Aziridinas/metabolismo , Modelos Animales de Enfermedad , Femenino , Glomeruloesclerosis Focal y Segmentaria/inducido químicamente , Glomeruloesclerosis Focal y Segmentaria/patología , Ratones , Ratones Transgénicos , Podocitos/patología , Regiones Promotoras Genéticas/fisiologíaRESUMEN
Among 1121 patients (90% Caucasian) infected by the human immunodeficiency virus (HIV), the glomerular filtration rate increased (+0.72 mL/min/1.73 m(2)/month) from treatment initiation to month 16 (the rate increase was lower among men and those with low body mass index, AIDS, or receipt of indinavir), then remained stable up to 7 years. Kidney function should be monitored in patients previously exposed to indinavir.
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Fármacos Anti-VIH/administración & dosificación , Infecciones por VIH/tratamiento farmacológico , Riñón/fisiopatología , Adolescente , Adulto , Anciano , Recuento de Linfocito CD4 , Estudios de Cohortes , Quimioterapia Combinada , Femenino , Tasa de Filtración Glomerular , Infecciones por VIH/fisiopatología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: We investigated whether a novel, synthetic, peptide-based erythropoietin-receptor agonist (Hematide, Affymax) can stimulate erythropoiesis in patients with anemia that is caused by antierythropoietin antibodies. METHODS: In this open-label, single-group trial, we enrolled patients with chronic kidney disease who had pure red-cell aplasia or hypoplasia due to antierythropoietin antibodies and treated them with a synthetic peptide-based erythropoietin-receptor agonist. The agonist was administered by subcutaneous injection at an initial dose of 0.05 mg per kilogram of body weight every 4 weeks. The primary end point was a hemoglobin concentration above 11 g per deciliter without the need for transfusions. RESULTS: We treated 14 patients with the peptide agonist for a median of 28 months. The median hemoglobin concentration increased from 9.0 g per deciliter (with transfusion support in the case of 12 patients) before treatment to 11.4 g per deciliter at the time of the last administration of the agonist; transfusion requirements diminished within 12 weeks after the first dose, after which 13 of the 14 patients no longer required regular transfusions. Peak reticulocyte counts increased from a median of 10x10(9) per liter before treatment to peak counts of greater than 100x10(9) per liter. The level of antierythropoietin antibodies declined over the course of the study and became undetectable in six patients. One patient who initially responded to treatment had a diminished hematologic response a few months later despite increased doses of the agonist and required transfusions again; this patient was found to have antibodies against the agonist. One patient died 4 months after the last dose of the agonist, and a grade 3 or 4 adverse event occurred in seven other patients during the study period. CONCLUSIONS: This novel agonist of the erythropoietin receptor can correct anemia in patients with pure red-cell aplasia caused by antierythropoietin antibodies. (ClinicalTrials.gov number, NCT00314795.).
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Receptores de Eritropoyetina/agonistas , Aplasia Pura de Células Rojas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Autoanticuerpos/sangre , Transfusión de Eritrocitos/estadística & datos numéricos , Eritropoyetina/efectos adversos , Eritropoyetina/inmunología , Femenino , Hemoglobinas/análisis , Humanos , Masculino , Persona de Mediana Edad , Proteínas Recombinantes , Aplasia Pura de Células Rojas/etiología , Aplasia Pura de Células Rojas/terapia , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/inmunologíaRESUMEN
Chronic kidney disease (CKD) guidelines recommend evaluating patients with GFR <60 ml/min per 1.73 m(2) for complications, but little evidence supports the use of a single GFR threshold for all metabolic disorders. We used data from the NephroTest cohort, including 1038 adult patients who had stages 2 through 5 CKD and were not on dialysis, to study the occurrence of metabolic complications. GFR was measured using renal clearance of (51)Cr-EDTA (mGFR) and estimated using two equations derived from the Modification of Diet in Renal Disease study. As mGFR decreased from 60 to 90 to <20 ml/min per 1.73 m(2), the prevalence of hyperparathyroidism increased from 17 to 85%, anemia from 8 to 41%, hyperphosphatemia from 1 to 30%, metabolic acidosis from 2 to 39%, and hyperkalemia from 2 to 42%. Factors most strongly associated with metabolic complications, independent of mGFR, were younger age for acidosis and hyperphosphatemia, presence of diabetes for acidosis, diabetic kidney disease for anemia, and both male gender and the use of inhibitors of the renin-angiotensin system for hyperkalemia. mGFR thresholds for detecting complications with 90% sensitivity were 50, 44, 40, 39, and 37 ml/min per 1.73 m(2) for hyperparathyroidism, anemia, acidosis, hyperkalemia, and hyperphosphatemia, respectively. Analysis using estimated GFR produced similar results. In summary, this study describes the onset of CKD-related complications at different levels of GFR; anemia and hyperparathyroidism occur earlier than acidosis, hyperkalemia, and hyperphosphatemia.
Asunto(s)
Enfermedades Renales/complicaciones , Enfermedades Renales/metabolismo , Acidosis/epidemiología , Adulto , Anciano , Anemia/epidemiología , Enfermedad Crónica , Femenino , Tasa de Filtración Glomerular , Humanos , Hiperpotasemia/epidemiología , Hiperparatiroidismo/epidemiología , Hiperfosfatemia/epidemiología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Prevalencia , Factores de TiempoRESUMEN
BACKGROUND: Since 1988, millions of patients have received epoetin products intravenously (IV) and subcutaneously. In 1998, epoetin-associated pure red cell aplasia (PRCA) was first reported and causation was attributed to formulations without human serum albumin (HSA), subcutaneous administration, and uncoated rubber stoppers. STUDY DESIGN AND METHODS: Data on erythropoietin (EPO)-associated PRCA were obtained from the Food and Drug Administration (FDA), regulatory authorities in other countries, and the manufacturers of epoetin alfa, epoetin beta, and darbepoetin. The data included information on numbers of PRCA cases and estimated exposure-adjusted incidence rates by EPO product, anemia etiology, administration route, country of PRCA identification, and date reported. RESULTS: In 1999, academicians in Paris identified 12 EPO-treated patients with antibody-mediated PRCA; 11 of these patients were on hemodialysis and had received subcutaneous Eprex (Johnson & Johnson). In 2002, authorities in Europe, Australia, Singapore, and Canada mandated Eprex by IV route to hemodialysis patients, and the relevant manufacturers added Teflon coating to prefilled syringes of Eprex; PRCA cases subsequently decreased by 90 percent. By 2003, 180 Eprex-associated PRCA cases were identified in Europe, Canada, Australia, and Asia, despite improvements in handling. Since 2002, FDA safety databases include information on 59 new cases of antibody-associated PRCA, primarily associated with subcutaneous epoetin alfa and darbepoetin that does not contain HSA. CONCLUSION: Independent actions by regulatory authorities, manufacturers, and academic researchers identified significant numbers of PRCA cases between 1998 and 2003 and characterized the probable etiology. Today, antibody-mediated PRCA is an infrequent class toxicity occurring among some hemodialysis patients on EPOs.
Asunto(s)
Anemia/tratamiento farmacológico , Eritropoyetina/efectos adversos , Hematínicos/efectos adversos , Aplasia Pura de Células Rojas/inducido químicamente , Anemia/epidemiología , Etiquetado de Medicamentos , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Epoetina alfa , Humanos , Proteínas Recombinantes , Aplasia Pura de Células Rojas/epidemiologíaRESUMEN
Disorders of mineral and bone metabolism are prevalent in patients with chronic kidney disease (CKD). The recent National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines recommend that blood calcium (Ca) be regularly measured in patients with stages 3 to 5 CKD. The Kidney Disease: Improving Global Outcomes (KDIGO) position states that the measurement of ionized Ca (iCa) is preferred and that if total Ca (tCa) concentration is used instead, then it should be adjusted in the setting of hypoalbuminemia. In 691 consecutive patients with stages 3 to 5 CKD, we compared the ability of noncorrected and albumin-corrected tCa concentration to identify low, normal, or high iCa concentration. The agreement between noncorrected or albumin-corrected tCa and iCa was only fair. The risk for underestimating ionized calcium was independently increased by a low total CO(2) concentration when either noncorrected or albumin-corrected Ca was used and by a low albumin concentration only when noncorrected tCa was used. The risk for overestimating iCa was increased by a low albumin concentration only when albumin-corrected Ca was used. In conclusion, albumin-corrected tCa does not predict iCa better than noncorrected tCa. Moreover, both noncorrected and albumin-corrected tCa concentrations poorly predict hypo- or hypercalcemia in patients with CKD.