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The original article was published on February 15, 2024 and corrected on April 15, 2024.The revised version of the article corrects Figure 2. The changes appear in the revised online PDF copy of this article.
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Hallux , Lipoma , Humanos , Lipoma/patologia , Lipoma/diagnóstico , Hallux/patologia , Feminino , Masculino , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/diagnósticoRESUMO
Spindle cell lipomas are a rare type of lipoma usually presenting in middle-aged to older men, often located on the posterior neck or shoulder; presentation on the foot is exceptionally uncommon. We report a 24-year-old man with spindle cell lipomas on the hallux of his left foot. He experienced an uneventful recovery after excision of the mass. We discuss clinical, radiologic, and histopathologic features of spindle cell lipomas and we review the differential diagnosis at this anatomic site.
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Hallux , Lipoma , Humanos , Lipoma/patologia , Lipoma/diagnóstico , Lipoma/cirurgia , Masculino , Hallux/patologia , Adulto Jovem , Diagnóstico Diferencial , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/cirurgiaRESUMO
OBJECTIVE: Aberrant ß-catenin distribution has been theorized as a predictive biomarker for recurrence in early stage, low grade endometrioid endometrial cancer. METHODS: This retrospective single-institution cohort study reviewed 410 patients with endometrial cancer from May 2018 to May 2022. Only endometrioid histology was included. Demographic and clinicopathological data were collected from the medical records. Univariate and multivariate logistic regressions, and sensitivity analyses for early stage, low grade and no specific molecular profile (NSMP) tumors were performed. RESULTS: 297 patients were included for analysis. Most patients were over 60 years old, White, and with a BMI >30 and early stage low grade disease. Aberrant ß-catenin distribution was found in 135 patients (45.5%) and wild type membranous ß-catenin distribution in 162 (54.5%). While TP53 mutation correlated with endometrial cancer recurrence in this cohort (OR = 4.78), aberrant ß-catenin distribution did not correlate in the overall population (OR = 0.75), the early stage low grade cancers (OR = 0.84), or the NSMP group (OR = 1.41) on univariate or multivariate analysis. No correlation between ß-catenin distribution and local (OR = 0.61) or distant recurrences (OR = 0.90) was detected. CONCLUSIONS: Aberrant ß-catenin distribution did not significantly correlate with recurrence in endometrioid endometrial cancer, nor in the early stage, low grade and NSMP sub-cohorts.
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Carcinoma Endometrioide , Neoplasias do Endométrio , Feminino , Humanos , Pessoa de Meia-Idade , beta Catenina/genética , Cateninas , Estudos Retrospectivos , Estudos de Coortes , Recidiva Local de Neoplasia/patologia , Carcinoma Endometrioide/genética , Carcinoma Endometrioide/patologia , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologiaRESUMO
BACKGROUND: Sensitive and specific biomarkers are needed to provide better biologic insight into the risk of incident and progressive CKD. However, studies have been limited by sample size and design heterogeneity. METHODS: In this assessment of the prognostic value of preclinical plasma and urine biomarkers for CKD outcomes, we searched Embase (Ovid), MEDLINE ALL (Ovid), and Scopus up to November 30, 2020, for studies exploring the association between baseline kidney biomarkers and CKD outcomes (incident CKD, CKD progression, or incident ESKD). We used random-effects meta-analysis. RESULTS: After screening 26,456 abstracts and 352 full-text articles, we included 129 studies in the meta-analysis for the most frequently studied plasma biomarkers (TNFR1, FGF23, TNFR2, KIM-1, suPAR, and others) and urine biomarkers (KIM-1, NGAL, and others). For the most frequently studied plasma biomarkers, pooled RRs for CKD outcomes were 2.17 (95% confidence interval [95% CI], 1.91 to 2.47) for TNFR1 (31 studies); 1.21 (95% CI, 1.15 to 1.28) for FGF-23 (30 studies); 2.07 (95% CI, 1.82 to 2.34) for TNFR2 (23 studies); 1.51 (95% CI, 1.38 to 1.66) for KIM-1 (18 studies); and 1.42 (95% CI, 1.30 to 1.55) for suPAR (12 studies). For the most frequently studied urine biomarkers, pooled RRs were 1.10 (95% CI, 1.05 to 1.16) for KIM-1 (19 studies) and 1.12 (95% CI, 1.06 to 1.19) for NGAL (19 studies). CONCLUSIONS: Studies of preclinical biomarkers for CKD outcomes have considerable heterogeneity across study cohorts and designs, limiting comparisons of prognostic performance across studies. Plasma TNFR1, FGF23, TNFR2, KIM-1, and suPAR were among the most frequently investigated in the setting of CKD outcomes.
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Receptores Tipo I de Fatores de Necrose Tumoral , Insuficiência Renal Crônica , Humanos , Lipocalina-2 , Receptores Tipo II do Fator de Necrose Tumoral , Insuficiência Renal Crônica/diagnóstico , Receptores de Ativador de Plasminogênio Tipo Uroquinase , BiomarcadoresRESUMO
Kidney allocation trends from deceased donors with acute kidney injury (AKI) have not been characterized since initial Kidney Donor Profile Index reporting in 2012 and its use under the revised Kidney Allocation System (KAS) in 2014. We conducted a retrospective analysis of US registry data to characterize kidney procurement and discard trends in deceased donors with AKI, defined by ≥50% or ≥0.3 mg/dl (≥4.0 mg/dl or ≥200% for stage 3) increase in terminal serum creatinine from admission. From 2010 to 2020, 172 410 kidneys were procured from 93 341 deceased donors 16 years or older; 34 984 kidneys were discarded (17 559 from AKI donors). The proportion of stage 3 AKI donors doubled from 6% (412/6841) in 2010 to 12% (1365/11493) in 2020. Procurement of stage 3 AKI kidneys increased from 51% (423/824) to 80% (2183/2730). While discard of stage 3 AKI kidneys increased from 41% (175/423) in 2010 to 44% (960/2183) in 2020, this increase was not statistically significant in interrupted time-series analysis following KAS implementation (slope difference -0.41 [-3.22, 2.4], and level change 3.09 [-6.4, 12.6]). In conclusion, the absolute number of stage 3 AKI kidneys transplanted has increased. Ongoing high discard rates of these kidneys suggest opportunities for improved utilization.
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Injúria Renal Aguda , Transplante de Rim , Obtenção de Tecidos e Órgãos , Injúria Renal Aguda/etiologia , Seleção do Doador , Feminino , Sobrevivência de Enxerto , Humanos , Rim , Transplante de Rim/efeitos adversos , Masculino , Estudos Retrospectivos , Doadores de TecidosRESUMO
BACKGROUND: Allograft biopsies with lesions of Antibody-Mediated Rejection (ABMR) with Microvascular Inflammation (MVI) have shown heterogeneous etiologies and outcomes. METHODS: To examine factors associated with outcomes in biopsies that meet histologic ABMR criteria, we retrospectively evaluated for-cause biopsies at our center between 2011 and 2017. We included biopsies that met the diagnosis of ABMR by histology, along with simultaneous evaluation for anti-Human Leukocyte Antigen (HLA) donor-specific antibodies (DSA). We evaluated death-censored graft loss (DCGL) and used a principal component analysis (PCA) approach to identify key predictors of outcomes. RESULTS: Out of the histologic ABMR cohort (n = 118), 70 were DSA-positive ABMR, while 48 had no DSA. DSA(+)ABMR were younger and more often female recipients. DSA(+)ABMR occurred significantly later post-transplant than DSA(-)ABMR suggesting time-dependence. DSA(+)ABMR had higher inflammatory scores (i,t), chronicity scores (ci, ct) and tended to have higher MVI scores. Immunodominance of DQ-DSA in DSA(+)ABMR was associated with higher i+t scores. Clinical/histologic factors significantly associated with DCGL after biopsy were inputted into the PCA. Principal component-1 (PC-1), which contributed 34.8% of the variance, significantly correlated with time from transplantation to biopsy, ci/ct scores and DCGL. In the PCA analyses, i, t scores, DQ-DSA, and creatinine at biopsy retained significant correlations with GL-associated PCs. CONCLUSIONS: Time from transplantation to biopsy plays a major role in the prognosis of biopsies with histologic ABMR and MVI, likely due to ongoing chronic allograft injury over time.
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Transplante de Rim , Humanos , Feminino , Estudos Retrospectivos , Transplante de Rim/efeitos adversos , Anticorpos , Prognóstico , Inflamação , Biópsia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , IsoanticorposRESUMO
Patients undergoing cardiac surgery are placed under intense physiologic stress. Blood and urine biomarkers measured peri-operatively may help identify patients at higher risk for adverse long-term kidney outcomes.We sought to determine independent associations of various biomarkers with development or progression of chronic kidney disease (CKD) following cardiac surgery. In this sub-study of the prospective cohort -TRIBE-AKI Study, we evaluated 613 adult patients undergoing cardiac surgery in Canada in our primary analysis and tested the association of 40 blood and urinary biomarkers with the primary composite outcome of CKD incidence or progression. In those with baseline estimated glomerular filtration rate (eGFR) over 60 mL/min/1.73m2, we defined CKD incidence as a 25% reduction in eGFR and an eGFR under 60. In those with baseline eGFR under 60 mL/min/1.73m2, we defined CKD progression as a 50% reduction in eGFR or eGFR under 15. Results were evaluated in a replication cohort of 310 patients from one study site in the United States. Over a median follow-up of 5.6 years, 172 patients developed the primary outcome. Each log increase in basic fibroblast growth factor (adjusted hazard ratio 1.52 [95% confidence interval 1.19, 1.93]), Kidney Injury Molecule-1 (1.51 [0.98, 2.32]), N-terminal pro-B-type natriuretic peptide (1.19 [1.01, 1.41]), and tumor necrosis factor receptor 1 (1.75 [1.18, 2.59]) were associated with outcome after adjustment for demographic factors, serum creatinine, and albuminuria. Similar results were noted in the replication cohort. Although there was no interaction by acute kidney injury in continuous analysis, mortality was higher in the no acute kidney injury group by biomarker tertile. Thus, elevated post-operative levels of blood biomarkers following cardiac surgery were independently associated with the development of CKD. These biomarkers can provide additional value in evaluating CKD incidence and progression after cardiac surgery.
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Injúria Renal Aguda , Procedimentos Cirúrgicos Cardíacos , Insuficiência Renal Crônica , Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/etiologia , Adulto , Biomarcadores , Canadá , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Progressão da Doença , Taxa de Filtração Glomerular , Humanos , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/epidemiologia , Fatores de Risco , Estados UnidosRESUMO
The influence of patient characteristics and immunosuppression management on COVID-19 outcomes in kidney transplant recipients (KTRs) remains uncertain. We performed a single-center, retrospective review of all adult KTRs admitted to the hospital with confirmed COVID-19 between 03/15/2020 and 05/15/2020. Patients were followed from the date of admission up to 1 month following hospital discharge or study conclusion (06/15/2020). Baseline characteristics, laboratory parameters, and immunosuppression were compared between survivors and patients who died to identify predictors of mortality. 38 KTRs with a mean baseline eGFR of 52.5 ml/min/1.73 m2 were hospitalized during the review period. Maintenance immunosuppression included tacrolimus (84.2%), mycophenolate (89.5%), and corticosteroids (81.6%) in the majority of patients. Eleven patients (28.9%) died during the hospitalization. Older age (OR = 2.05; 1.04-4.04), peak D-dimer (OR = 1.20; 1.04-1.39), and peak white blood cell count (OR = 1.11; 1.02-1.21) were all associated with mortality among KTRs hospitalized for COVID-19. Increased mortality was also observed among KTRs with concomitant HIV infection (87.5% vs. 36.1%; p < .01). Conversely, immunosuppression intensity and degree of reduction following COVID-19 diagnosis were not associated with either survival or acute allograft rejection. Our findings potentially support a strategy of individualization of immunosuppression targets based on patient-specific risk factors, rather than universal immunosuppression reduction for KTRs at risk from COVID-19.
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COVID-19/mortalidade , Imunossupressores/uso terapêutico , Transplante de Rim/mortalidade , Corticosteroides/uso terapêutico , Adulto , Idoso , Feminino , Rejeição de Enxerto/epidemiologia , Infecções por HIV , Humanos , Terapia de Imunossupressão , Masculino , Pessoa de Meia-Idade , Ácido Micofenólico/uso terapêutico , Estudos Retrospectivos , Fatores de Risco , Tacrolimo/uso terapêutico , TransplantadosRESUMO
RATIONALE & OBJECTIVE: The PRESERVE trial used a 2 × 2 factorial design to compare intravenous saline solution with intravenous sodium bicarbonate solution and oral N-acetylcysteine with placebo for the prevention of 90-day major adverse kidney events and death (MAKE-D) and contrast-associated acute kidney injury (CA-AKI) among patients with chronic kidney disease undergoing angiography. In this ancillary study, we evaluated the predictive capacities of preangiography injury and repair proteins in urine and plasma for MAKE-D, CA-AKI, and their impact on trial design. STUDY DESIGN: Longitudinal analysis. SETTING & PARTICIPANTS: A subset of participants from the PRESERVE trial. EXPOSURES: Injury (KIM-1, NGAL, and IL-18) and repair (MCP-1, UMOD, and YKL-40) proteins in urine and plasma 1 to 2 hours preangiography. OUTCOMES: MAKE-D and CA-AKI. ANALYTICAL APPROACH: We analyzed the associations of preangiography biomarkers with MAKE-D and with CA-AKI. We evaluated whether the biomarker levels could enrich the MAKE-D event rate and improve future clinical trial efficiency through an online biomarker prognostic enrichment tool available at prognosticenrichment.com. RESULTS: We measured plasma biomarkers in 916 participants and urine biomarkers in 797 participants. After adjusting for urinary albumin-creatinine ratio and baseline estimated glomerular filtration rate, preangiography levels of 4 plasma (KIM-1, NGAL, UMOD, and YKL-40) and 3 urine (NGAL, IL-18, and YKL-40) biomarkers were associated with MAKE-D. Only plasma KIM-1 level was significantly associated with CA-AKI after adjustment. Biomarker levels provided modest discriminatory capacity for MAKE-D. Screening patients using the 50th percentile of preangiography plasma KIM-1 or YKL-40 levels would have reduced the required sample size by 30% (â¼2,000 participants). LIMITATIONS: Evaluation of prognostic enrichment does not account for changing trial costs, time needed to screen patients, or loss to follow-up. Most participants were male, limiting the generalizability of our findings. CONCLUSIONS: Preangiography levels of injury and repair biomarkers modestly predict the development of MAKE-D and can be used to improve the efficiency of future CA-AKI trials.
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Acetilcisteína/administração & dosagem , Injúria Renal Aguda/metabolismo , Proteínas de Fase Aguda/metabolismo , Angiografia/efeitos adversos , Meios de Contraste/efeitos adversos , Citocinas/metabolismo , Bicarbonato de Sódio/administração & dosagem , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/tratamento farmacológico , Administração Oral , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Seguimentos , Sequestradores de Radicais Livres/administração & dosagem , Taxa de Filtração Glomerular , Humanos , Infusões Intravenosas , Testes de Função Renal , Masculino , PrognósticoRESUMO
BACKGROUND: The American Diabetes Association (ADA) recommends that treatment with metformin be considered for prevention of type 2 diabetes in persons with prediabetes. However, metformin use outside the setting of diagnosed diabetes in US adults is not well characterized. OBJECTIVE: To examine trends in self-reported prediabetes and treatment with metformin. We also compared characteristics of adults self-reported prediabetes who were vs. were not taking metformin. DESIGN: Cross-sectional analysis. PARTICIPANTS: Adults ≥ 20 years of age who participated in the 2005-2014 National Health and Nutrition and Examination Survey (NHANES), n = 28,461. APPROACH: We characterized trends in self-reported prediabetes and metformin use in this population. We used multiple logistic regression models to identify predictors of metformin use among adults with self-reported prediabetes. All analyses accounted for the weighted complex survey design to generate nationally representative estimates. KEY RESULTS: The prevalence of self-reported prediabetes increased from 5.1% in 2005-2006 to 7.4% in 2013-2014 (P-for-trend < 0.001). In persons with self-reported prediabetes, metformin use increased, from 2.4 to 8.3% (P-for-trend = 0.013). Adults who were taking metformin were more likely to be obese and to report trying to lose weight in the past year. CONCLUSIONS: Self-reported prediabetes has increased in the past decade. Metformin use in the setting of prediabetes has also increased but remains relatively uncommon at 8% in adults who self-report prediabetes, despite current clinical recommendations.
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Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Metformina , Estado Pré-Diabético , Adulto , Estudos Transversais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Metformina/uso terapêutico , Inquéritos Nutricionais , Estado Pré-Diabético/diagnóstico , Estado Pré-Diabético/epidemiologia , Autorrelato , Estados Unidos/epidemiologiaRESUMO
The physical characteristics of composite materials are dictated by both the chemical composition and spatial configuration of each constituent phase. A major challenge in nanoparticle-based composites is developing methods to precisely dictate particle positions at the nanometer length scale, as this would allow complete control over nanocomposite structure-property relationships. In this work, we present a new class of building blocks called nanocomposite tectons (NCTs), which consist of inorganic nanoparticles grafted with a dense layer of polymer chains that terminate in molecular recognition units capable of programmed supramolecular bonding. By tuning various design factors, including the particle size and polymer length, we can use the supramolecular interactions between NCTs to controllably alter their assembly behavior, enabling the formation of well-ordered body-centered cubic superlattices consisting of inorganic nanoparticles surrounded by polymer chains. NCTs therefore present a modular platform that enables the construction of composite materials where the composition and three-dimensional arrangement of different constituents within the composite can be independently controlled.
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Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Inquéritos Nutricionais/tendências , Estado Pré-Diabético/epidemiologia , Comportamento de Redução do Risco , Adulto , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais/métodos , Estado Pré-Diabético/diagnóstico , Estados Unidos/epidemiologia , Adulto JovemRESUMO
PURPOSE: While there is considerable evidence supporting the relationship between job satisfaction and organizational commitment, the relationship between the antecedents of job satisfaction, organizational commitment and career commitment are not clearly understood. This study seeks to clarify whether these antecedents have an effect independent of job satisfaction on career commitment or whether these antecedents are mediated by job satisfaction. DESIGN/METHODOLOGY/APPROACH: In total, 2,799 questionnaires were mailed out to members of the American College of Healthcare Executives (ACHE). The responses received were 643 (22.9 percent) and after eliminating retirees or students, a sample of 456 respondents currently employed in the health care industry was obtained. Path analysis was conducted to test the hypothetical relationships between work situation, career experiences and career commitment. FINDINGS: It was found that job satisfaction mediated the influences of job tenure and career pattern on career commitment. Job satisfaction partially mediated the influences of perceived job security and one's satisfaction with career on career commitment. Both of these measures had a direct influence on career commitment. Career experience such as sector change was also positively associated with career commitment. RESEARCH LIMITATIONS/IMPLICATIONS: While the research offers some insights into the factors affecting the career commitment of health care executives, the sample was limited to respondents who were members of the American College of Healthcare Executives, and thus may not represent the views of all managers in the health care sector. PRACTICAL IMPLICATIONS: To retain high-valued health care workers it is important that an organization has a work environment that enhances their commitment to their occupation as well as their careers. ORIGINALITY/VALUE: This study clarifies the influence of job satisfaction on the career commitment of health care managers during a very dynamic period.
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Administradores de Instituições de Saúde/psicologia , Satisfação no Emprego , Lealdade ao Trabalho , Distribuição de Qui-Quadrado , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Estados UnidosRESUMO
Animal experimentation is key in the evaluation of cardiac efficacy and safety of novel therapeutic compounds. However, interspecies differences in the mechanisms regulating excitation-contraction coupling can limit the translation of experimental findings from animal models to human physiology and undermine the assessment of drugs' efficacy and safety. Here, we built a suite of translators for quantitatively mapping electrophysiological responses in ventricular myocytes across species. We trained these statistical operators using a broad dataset obtained by simulating populations of our biophysically detailed computational models of action potential and Ca2+ transient in mouse, rabbit, and human. We then tested our translators against experimental data describing the response to stimuli, such as ion channel block, change in beating rate, and ß-adrenergic challenge. We demonstrate that this approach is well suited to predicting the effects of perturbations across different species or experimental conditions and suggest its integration into mechanistic studies and drug development pipelines.
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BACKGROUND: Deceased-donor kidneys experience extensive injury, activating adaptive and maladaptive pathways therefore impacting graft function. We evaluated urinary donor uromodulin (UMOD) and osteopontin (OPN) in recipient graft outcomes. METHODS: Primary outcomes: all-cause graft failure (GF) and death-censored GF (dcGF). Secondary outcomes: delayed graft function (DGF) and 6-month estimated glomerular filtration rate (eGFR). We randomly divided our cohort of deceased donors and recipients into training and test datasets. We internally validated associations between donor urine UMOD and OPN at time of procurement, with our primary outcomes. The direction of association between biomarkers and GF contrasted. Subsequently, we evaluated UMOD:OPN ratio with all outcomes. To understand these mechanisms, we examined the effect of UMOD on expression of major histocompatibility complex II in mouse macrophages. RESULTS: Doubling of UMOD increased dcGF risk (adjusted hazard ratio [aHR], 1.1; 95% confidence interval [CI], 1.02-1.2), whereas OPN decreased dcGF risk (aHR, 0.94; 95% CI, 0.88-1). UMOD:OPN ratio ≤3 strengthened the association, with reduced dcGF risk (aHR, 0.57; 0.41-0.80) with similar associations for GF, and in the test dataset. A ratio ≤3 was also associated with lower DGF (aOR, 0.73; 95% CI, 0.60-0.89) and higher 6-month eGFR (adjusted ß coefficient, 3.19; 95% CI, 1.28-5.11). UMOD increased major histocompatibility complex II expression elucidating a possible mechanism behind UMOD's association with GF. CONCLUSIONS: UMOD:OPN ratio ≤3 was protective, with lower risk of DGF, higher 6-month eGFR, and improved graft survival. This ratio may supplement existing strategies for evaluating kidney quality and allocation decisions regarding deceased-donor kidney transplantation.
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Função Retardada do Enxerto/etiologia , Taxa de Filtração Glomerular , Sobrevivência de Enxerto , Transplante de Rim/efeitos adversos , Rim/cirurgia , Osteopontina/urina , Doadores de Tecidos , Uromodulina/urina , Adulto , Idoso , Animais , Biomarcadores/urina , Células Cultivadas , Função Retardada do Enxerto/mortalidade , Função Retardada do Enxerto/fisiopatologia , Feminino , Antígenos de Histocompatibilidade Classe II/metabolismo , Humanos , Rim/fisiopatologia , Transplante de Rim/mortalidade , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados UnidosRESUMO
A highly stereoselective palladium(0)-catalyzed hydrodefluorination (HDF) of tetrasubstituted gem-difluoroalkenes is developed. By using catalytic Pd(PPh3)4 (2.5-5 mol %) and hydrosilane Me2PhSiH, various trisubstituted terminal (E)-monofluoroalkenes can be synthesized with excellent E/Z selectivity (>99:1) and good functional group tolerability. The key stereocontrol should be exerted by an ester-directed C-F bond oxidative addition step in the catalytic cycle.
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Importance: The shortage of deceased donor kidneys for transplants is an ongoing concern. Prior studies support transplanting kidneys from deceased donors with acute kidney injury (AKI), but those investigations have been subject to selection bias and small sample sizes. Current allocation practices of AKI kidneys in the United States are not well characterized. Objectives: To evaluate the association of deceased donor AKI with recipient graft survival and to characterize recovery and discard practices for AKI kidneys by organ procurement organizations. Design, Setting, and Participants: Registry-based, propensity score-matched cohort study from January 1, 2010, to December 31, 2013, in the United States. The dates of analysis were March 1 to November 1, 2019. From 2010 to 2013, a total of 6832 deceased donors with AKI and 15â¯310 deceased donors without AKI had at least 1 kidney transplanted. This study used a 1:1, propensity score-matched analysis to match deceased donors with AKI to deceased donors without AKI and investigated outcomes in their corresponding kidney recipients. Exposure: Deceased donor AKI, defined as at least 50% or 0.3-mg/dL increase in terminal serum creatinine level from admission. Main Outcomes and Measures: Recipients were assessed for the time to death-censored graft failure and the following secondary outcomes: delayed graft function, primary nonfunction, and the time to all-cause graft failure. Results: Ninety-eight percent (6722 of 6832) of deceased donors with AKI were matched to deceased donors without AKI. The mean (SD) age of the 13â¯444 deceased donors was 40.4 (14.4) years, and 63% (8529 of 13â¯444) were male. A total of 25â¯323 recipients were analyzed (15â¯485 [61%] were male), and their mean (SD) age was 52.0 (14.7) years. Recipients were followed up for a median of 5 (interquartile range, 4-6) years. Deceased donor AKI status had no association with death-censored graft failure (hazard ratio, 1.01; 95% CI, 0.95-1.08) or all-cause graft failure (hazard ratio, 0.97; 95% CI, 0.93-1.02). The results were consistent after examining by AKI stage and adjusting for recipient and transplant characteristics. More recipients of AKI kidneys developed delayed graft function (29% vs 22%, P < .001). Few recipients (120 of 25â¯323 [0.5%]) developed primary nonfunction regardless of deceased donor AKI status. Recovery and transplantation of AKI kidneys varied by organ procurement organization; most (39 of 58) had high recovery and high discard of AKI kidneys. Conclusions and Relevance: Deceased donor AKI kidneys transplanted in the study period had recipient graft survival comparable to that of non-AKI kidneys. This study's findings suggest that the transplant community should evaluate whether currently discarded AKI kidneys from donors without substantial comorbidities can be used more effectively.
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Injúria Renal Aguda/fisiopatologia , Sobrevivência de Enxerto/fisiologia , Transplante de Rim/efeitos adversos , Rim/fisiopatologia , Doadores de Tecidos/estatística & dados numéricos , Transplantes/fisiopatologia , Adulto , Estudos de Coortes , Seleção do Doador , Feminino , Humanos , Transplante de Rim/métodos , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Sistema de Registros , Doadores de Tecidos/provisão & distribuição , Obtenção de Tecidos e Órgãos/métodos , Obtenção de Tecidos e Órgãos/normas , Transplantes/transplante , Estados UnidosRESUMO
BACKGROUND AND OBJECTIVES: It is unknown whether iodinated contrast causes kidney parenchymal damage. Biomarkers that are more specific to nephron injury than serum creatinine may provide insight into whether contrast-associated AKI reflects tubular damage. We assessed the association between biomarker changes after contrast angiography with contrast-associated AKI and 90-day major adverse kidney events and death. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We conducted a longitudinal analysis of participants from the biomarker substudy of the Prevention of Serious Adverse Events following Angiography trial. We measured injury (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, IL-18) and repair (monocyte chemoattractant protein-1, uromodulin, YKL-40) proteins from plasma and urine samples at baseline and 2-4 hours postangiography. We assessed the associations between absolute changes and relative ratios of biomarkers with contrast-associated AKI and 90-day major adverse kidney events and death. RESULTS: Participants (n=922) were predominately men (97%) with diabetes (82%). Mean age was 70±8 years, and eGFR was 48±13 ml/min per 1.73 m2; 73 (8%) and 60 (7%) participants experienced contrast-associated AKI and 90-day major adverse kidney events and death, respectively. No postangiography urine biomarkers were associated with contrast-associated AKI. Postangiography plasma kidney injury molecule-1 and IL-18 were significantly higher in participants with contrast-associated AKI compared with those who did not develop contrast-associated AKI: 428 (248, 745) versus 306 (179, 567) mg/dl; P=0.04 and 325 (247, 422) versus 280 (212, 366) mg/dl; P=0.009, respectively. The majority of patients did not experience an increase in urine or plasma biomarkers. Absolute changes in plasma IL-18 were comparable in participants with contrast-associated AKI (-30 [-71, -9] mg/dl) and those without contrast-associated AKI (-27 [-53, -10] mg/dl; P=0.62). Relative ratios of plasma IL-18 were also comparable in participants with contrast-associated AKI (0.91; 0.86, 0.97) and those without contrast-associated AKI (0.91; 0.85, 0.96; P=0.54). CONCLUSIONS: The lack of significant differences in the absolute changes and relative ratios of injury and repair biomarkers by contrast-associated AKI status suggests that the majority of mild contrast-associated AKI cases may be driven by hemodynamic changes at the kidney.
Assuntos
Injúria Renal Aguda/induzido quimicamente , Angiografia/efeitos adversos , Meios de Contraste/efeitos adversos , Creatinina/sangue , Injúria Renal Aguda/sangue , Injúria Renal Aguda/mortalidade , Injúria Renal Aguda/urina , Idoso , Angiografia/mortalidade , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Hemodinâmica , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Fatores de Risco , Fatores de Tempo , Regulação para CimaRESUMO
Small-molecule phosphoantigens such as (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate stimulate human Vγ9Vδ2 T cells after binding to the intracellular B30.2 domain of the immune receptor butyrophilin 3 isoform A1 (BTN3A1). To understand the ligand-target interaction in greater detail, we performed molecular docking. Based on the docking results, we synthesized the novel ligand (E)-(7-hydroxy-6-methylhept-5-en-1-yl)phosphonate and mutated proposed binding site residues. We evaluated the impact on butyrophilin binding of existing and novel ligands using a newly developed high-throughput fluorescence polarization assay. We also evaluated the ability of the compounds to stimulate proliferation and interferon-γ production of Vγ9Vδ2 T cells. Mutation of H381 fully blocked ligand binding, whereas mutations to charged surface residues impacted diphosphate interactions. Monophosphonate analogs bind similarly to BTN3A1, although they differ in their antigenicity, demonstrating that binding and efficacy are not linearly correlated. These results further define the structure-activity relationships underlying BTN3A1 ligand binding and antigenicity and support further structure-guided drug design.