RESUMO
Cannabis is the third most used psychoactive substance worldwide. The legal status of cannabis is changing in many Western countries, while we have very limited knowledge of the public health impact of cannabis-related harms. There is a need for a summary of the evidence of harms and risks attributed to cannabis use, in order to inform the definition of cannabis risky use. We have conducted a systematic review of systematic reviews, aiming to define cannabis-related harms. We included systematic reviews published until July 2018 from six different databases and following the PRISMA guidelines. To assess study quality we applied the AMSTAR 2 tool. A total of 44 systematic reviews, including 1,053 different studies, were eligible for inclusion. Harm was categorized in three dimensions: mental health, somatic harm and physical injury (including mortality). Evidence shows a clear association between cannabis use and psychosis, affective disorders, anxiety, sleep disorders, cognitive failures, respiratory adverse events, cancer, cardiovascular outcomes, and gastrointestinal disorders. Moreover, cannabis use is a risk factor for motor vehicle collision, suicidal behavior and partner and child violence. Cannabis use is a risk factor for several medical conditions and negative social consequences. There is still little data on the dose-dependency of these effects; evidence that is essential in order to define, from a public health perspective, what can be considered risky use of cannabis. This definition should be based on quantitative and qualitative criteria that informs and permits the evaluation of current approaches to a regulated cannabis market.
Assuntos
Cannabis/efeitos adversos , Fumar Maconha/efeitos adversos , Acidentes/estatística & dados numéricos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Humanos , Masculino , Saúde Mental , Pessoa de Meia-Idade , Revisões Sistemáticas como Assunto , Adulto JovemRESUMO
INTRODUCTION: Hard metal pneumoconiosis is a rare but serious disease of the lungs associated with inhalational exposure to tungsten or cobalt dust. Little is known about the radiologic and pathologic characteristics of this disease and the efficacy of treating with immunosuppression. OBJECTIVE: We describe the largest cohort of patients with hard metal pneumoconiosis in the literature, including radiographic and pathologic patterns as well as treatment options. METHODS: We retrospectively identified patients from the University of Pittsburgh pathology registry between the years of 1985 and 2016. Experts in chest radiology and pulmonary pathology reviewed the cases for radiologic and pathologic patterns. RESULTS: We identified 23 patients with a pathologic pattern of hard metal pneumoconiosis. The most common radiographic findings were ground glass opacities (93%) and small nodules (64%). Of 20 surgical biopsies, 17 (85%) showed features of giant cell interstitial pneumonia. Most patients received systemic corticosteroids and/or steroid-sparing immunosuppression. CONCLUSIONS: Hard metal pneumoconiosis is characterized predominately by radiographic ground glass opacities and giant cell interstitial pneumonia on histopathology. Systemic corticosteroids and steroid-sparing immunosuppression are common treatment options.
RESUMO
The authors conducted a prospective trial to assess the feasibility of real time central molecular assessment of kidney transplant biopsy samples from 10 North American or European centers. Biopsy samples taken 1 day to 34 years posttransplantation were stabilized in RNAlater, sent via courier overnight at ambient temperature to the central laboratory, and processed (29 h workflow) using microarrays to assess T cell- and antibody-mediated rejection (TCMR and ABMR, respectively). Of 538 biopsy samples submitted, 519 (96%) were sufficient for microarray analysis (average length, 3 mm). Automated reports were generated without knowledge of histology and HLA antibody, with diagnoses assigned based on Molecular Microscope Diagnostic System (MMDx) classifier algorithms and signed out by one observer. Agreement between MMDx and histology (balanced accuracy) was 77% for TCMR, 77% for ABMR, and 76% for no rejection. A classification tree derived to provide automated sign-outs predicted the observer sign-outs with >90% accuracy. In 451 biopsy samples where feedback was obtained, clinicians indicated that MMDx more frequently agreed with clinical judgment (87%) than did histology (80%) (p = 0.0042). In 81% of feedback forms, clinicians reported that MMDx increased confidence in management compared with conventional assessment alone. The authors conclude that real time central molecular assessment is feasible and offers a useful new dimension in biopsy interpretation. ClinicalTrials.gov NCT#01299168.
Assuntos
Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Rejeição de Enxerto/diagnóstico , Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Feminino , Seguimentos , Taxa de Filtração Glomerular , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Sobrevivência de Enxerto , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fatores de Risco , Adulto JovemAssuntos
Polissonografia/métodos , Síndromes da Apneia do Sono/diagnóstico , Idoso , Pressão Positiva Contínua nas Vias Aéreas , Arquitetura de Instituições de Saúde , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Monitorização Fisiológica/métodos , Atenção Primária à Saúde/métodos , Sono , Resultado do TratamentoRESUMO
In a reference set of 403 kidney transplant biopsies, we recently developed a microarray-based test that diagnoses antibody-mediated rejection (ABMR) by assigning an ABMR score. To validate the ABMR score and assess its potential impact on practice, we performed the present prospective INTERCOM study (clinicaltrials.gov NCT01299168) in 300 new biopsies (264 patients) from six centers: Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis. We assigned ABMR scores using the classifier created in the reference set and compared it to conventional assessment as documented in the pathology reports. INTERCOM documented uncertainty in conventional assessment: In 41% of biopsies where ABMR features were noted, the recorded diagnoses did not mention ABMR. The ABMR score correlated with ABMR histologic lesions and donor-specific antibodies, but not with T cell-mediated rejection lesions. The agreement between ABMR scores and conventional assessment was identical to that in the reference set (accuracy 85%). The ABMR score was more strongly associated with failure than conventional assessment, and when the ABMR score and conventional assessment disagreed, only the ABMR score was associated with early progression to failure. INTERCOM confirms the need to reduce uncertainty in the diagnosis of ABMR, and demonstrates the potential of the ABMR score to impact practice.
Assuntos
Biomarcadores/análise , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Isoanticorpos/imunologia , Falência Renal Crônica/imunologia , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias , Adolescente , Seguimentos , Perfilação da Expressão Gênica , Sobrevivência de Enxerto/imunologia , Humanos , Agências Internacionais , Falência Renal Crônica/mortalidade , Falência Renal Crônica/cirurgia , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Estudos Prospectivos , Fatores de Risco , Taxa de SobrevidaRESUMO
We previously developed a microarray-based test for T cell-mediated rejection (TCMR) in a reference set of 403 biopsies. To determine the potential impact of this test in clinical practice, we undertook INTERCOM, a prospective international study of 300 indication biopsies from 264 patients (ClinicalTrials.gov NCT01299168). Biopsies from six centers-Baltimore, Barcelona, Edmonton, Hannover, Manchester and Minneapolis-were analyzed by microarrays, assigning TCMR scores by an algorithm developed in the reference set and comparing TCMR scores to local histology assessment. The TCMR score correlated with histologic TCMR lesions-tubulitis and interstitial infiltration. The accuracy for primary histologic diagnoses (0.87) was similar to the reference set (0.89). The TCMR scores reclassified 77/300 biopsies (26%): 16 histologic TCMR were molecularly non-TCMR; 15 histologic non-TCMR were molecularly TCMR, including 6 with polyoma virus nephropathy; and all 46 "borderline" biopsies were reclassified as TCMR (8) or non-TCMR (38). Like the reference set, discrepancies were primarily in situations where histology has known limitations, for example, in biopsies with scarring and inflammation/tubulitis potentially from other diseases. Neither the TCMR score nor histologic TCMR was associated with graft loss. Thus the molecular TCMR score has potential to add new insight, particularly in situations where histology is ambiguous or potentially misleading.
Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/diagnóstico , Transplante de Rim , Análise de Sequência com Séries de Oligonucleotídeos , Linfócitos T/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Técnicas de Diagnóstico Molecular , Polyomavirus , Infecções por Polyomavirus/patologia , Estudos Prospectivos , Infecções Tumorais por Vírus/patologiaAssuntos
Rejeição de Enxerto , Nefropatias/patologia , Transplante de Rim , Feminino , Humanos , MasculinoRESUMO
Antibody-mediated rejection is the major cause of kidney transplant failure, but the histology-based diagnostic system misses most cases due to its requirement for C4d positivity. We hypothesized that gene expression data could be used to test biopsies for the presence of antibody-mediated rejection. To develop a molecular test, we prospectively assigned diagnoses, including C4d-negative antibody-mediated rejection, to 403 indication biopsies from 315 patients, based on histology (microcirculation lesions) and donor-specific HLA antibody. We then used microarray data to develop classifiers that assigned antibody-mediated rejection scores to each biopsy. The transcripts distinguishing antibody-mediated rejection from other conditions were mostly expressed in endothelial cells or NK cells, or were IFNG-inducible. The scores correlated with the presence of microcirculation lesions and donor-specific antibody. Of 45 biopsies with scores>0.5, 39 had been diagnosed as antibody-mediated rejection on the basis of histology and donor-specific antibody. High scores were also associated with unanimity among pathologists that antibody-mediated rejection was present. The molecular score also strongly predicted future graft loss in Cox regression analysis. We conclude that microarray assessment of gene expression can assign a probability of ABMR to transplant biopsies without knowledge of HLA antibody status, histology, or C4d staining, and predicts future failure.
Assuntos
Anticorpos/imunologia , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/imunologia , Transplante de Rim , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Complemento C4b/imunologia , Células Endoteliais/citologia , Feminino , Regulação da Expressão Gênica , Sobrevivência de Enxerto , Humanos , Interferon gama/metabolismo , Células Matadoras Naturais/citologia , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Fragmentos de Peptídeos/imunologia , Probabilidade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Análise de Regressão , Adulto JovemRESUMO
Histologic diagnosis of T cell-mediated rejection is flawed by subjective assessments, nonspecific lesions and arbitrary rules. This study developed a molecular test for T cell-mediated rejection. We used microarray results from 403 kidney transplant biopsies to derive a classifier assigning T cell-mediated rejection scores to all biopsies, and compared these with histologic assessments. The score correlated with histologic lesions of T cell-mediated rejection (infiltrate, tubulitis). The accuracy of the classifier for the histology diagnoses was 89%. Very high and low molecular scores corresponded with unanimity among three pathologists on the presence or absence of T cell-mediated rejection, respectively. The molecular score had low sensitivity (50%) and positive predictive value (62%) for the histology diagnoses. However, histology showed similar disagreement between pathologists--only 45-56% sensitivity of one pathologist with diagnoses of T cell-mediated rejection by another. Discrepancies between molecular scores and histology were mostly when histology was ambiguous ("borderline") or unreliable, e.g. in cases with scarring or inflammation induced by tissue injury. Vasculitis (isolated v-lesion TCMR) was particularly discrepant, with most cases exhibiting low TCMR scores. We propose new rules to integrate molecular tests and histology into a precision diagnostic system that can reduce errors, ambiguity and interpathologist disagreement.
Assuntos
Biomarcadores/metabolismo , Rejeição de Enxerto/diagnóstico , Inflamação/diagnóstico , Nefropatias/terapia , Transplante de Rim/imunologia , Linfócitos T/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Rejeição de Enxerto/classificação , Rejeição de Enxerto/genética , Sobrevivência de Enxerto , Humanos , Inflamação/classificação , Inflamação/genética , Transplante de Rim/efeitos adversos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Prognóstico , Estudos Prospectivos , Adulto JovemRESUMO
Although weaning predictors have been extensively explored in weaning research, their use is currently under debate. From all the stages of mechanical ventilation, the measurements of weaning predictors have been considered by some authors as imperative in order to progress weaning and initiate a weaning trial. However, this practice is rejected by other authors who considered that these tests are not necessary to perform a weaning trial, based in a meta-analysis study from the American College of Chest Physicians. Among all the weaning predictors, the frequency-to-tidal volume ratio (f/VT) remains the most important predictor of weaning. Other predictors have been defined, but their narrow predictive capacity or the requirement of specific technology, have limited their use. The variability of the results obtained by the efficacy of f/VT is probably explained because in most cases weaning is initiated late, when pre-test probability of weaning success is high. In order to reduce weaning duration, weaning strategies must be performed earlier, when a failed weaning trial probably is poor tolerated and the use of f/VT could have a role. New applications of weaning predictors must be clarified in future research, in order to progress in weaning in the context of new studies. Weaning is still a challenging period during mechanical ventilation.
Assuntos
Cuidados Críticos/métodos , Insuficiência Respiratória/terapia , Desmame do Respirador , Doença Aguda , Extubação , Obstrução das Vias Respiratórias/mortalidade , Tosse , Insuficiência Cardíaca/mortalidade , Frequência Cardíaca , Humanos , Hipercapnia/mortalidade , Metanálise como Assunto , Prognóstico , Insuficiência Respiratória/mortalidade , Taxa Respiratória , Fatores de Risco , Índice de Gravidade de Doença , Volume de Ventilação Pulmonar , Fatores de Tempo , Desmame do Respirador/classificaçãoRESUMO
NK cell transcripts are increased in biopsies with antibody-mediated rejection, whereas T cell transcripts are increased in T cell-mediated rejection. However, NK and T cells share many features, creating potential ambiguity. Therefore to estimate the NK- versus T cell transcript burdens separately, we defined nonoverlapping transcripts selective for NK cells (N = 4) or T cells (N = 5). We compared NK- versus T cell transcript burdens in microarrays from 403 kidney transplant biopsies (182 early, 221 late). In late biopsies, high NK-cell transcript expression was associated with antibody-mediated rejection, correlating with microvascular inflammation and donor specific HLA antibody. However, some early biopsies with T cell-mediated rejection had high NK-cell transcript expression, as well as T cell transcripts, without evidence of antibody-mediated rejection or DSA, correlating with interstitial inflammation and tubulitis. Both NK-cell and T cell transcripts were moderately increased in many kidneys with inflammation secondary to injury or atrophy scarring. These results support the distinct role of NK cells in late antibody-mediated rejection, but indicate a role for NK-transcript expressing cells (NK cells or T cells with NK features) both in T cell-mediated rejection and in inflammation associated with injury and atrophy scarring.
Assuntos
Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Rejeição de Enxerto/genética , Transplante de Rim/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos T/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Seguimentos , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto/genética , Sobrevivência de Enxerto/imunologia , Humanos , Inflamação/genética , Inflamação/imunologia , Isoanticorpos/sangue , Isoanticorpos/imunologia , Células Matadoras Naturais/imunologia , Masculino , Microcirculação/genética , Microcirculação/imunologia , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Circulação Renal/genética , Circulação Renal/imunologia , Linfócitos T/imunologia , Adulto JovemRESUMO
During the weaning process, spontaneous breathing trials (SBTs) involve cardiopulmonary stress for ventilated patients. As interleukin (IL)-6 is a major modulator of the stress response, we hypothesised that systemic IL-6 increases during a SBT and that this increase is more evident in SBT failure. 49 SBTs of 30-min duration were performed on different mechanically ventilated patients, and classified as SBT failure or success. Blood samples were drawn before and at the end of the SBT. An additional sample was drawn 24 h later in a subset of patients (n = 39). Serum IL-6 levels and other inflammatory mediators commonly associated with stress were determined. IL-6 levels increased from mechanical ventilation to spontaneous breathing in all patients (p = 0.02) and in the chronic obstructive pulmonary disease (COPD) population (p = 0.05) with SBT failure compared with success, but not in non-COPD patients (p = 0.12). After 24 h of SBT stress, IL-6 levels decreased in patients with SBT failure (under mechanical ventilation at that point) (p = 0.02) and those with weaning success (p = 0.04). No changes were observed in the remaining inflammatory mediators. Systemic IL-6 increases during a 30-min, failed SBT, especially in COPD patients. Future studies may corroborate the different IL-6 responses among different populations who initiate weaning, together with the potential clinical implications.
Assuntos
Interleucina-6/sangue , Respiração , Desmame do Respirador , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inflamação/sangue , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/terapiaRESUMO
In kidney transplantation, many inflamed biopsies with changes insufficient to be called T-cell-mediated rejection (TCMR) are labeled "borderline", leaving management uncertain. This study examined the nature of borderline biopsies as a step toward eventual elimination of this category. We compared 40 borderline, 35 TCMR and 116 nonrejection biopsies. TCMR biopsies had more inflammation than borderline but similar degrees of tubulitis and scarring. Surprisingly, recovery of function after biopsy was similar in all categories, indicating that response to treatment is unreliable for defining TCMR. We studied the molecular changes in TCMR, borderline and nonrejection using microarrays, measuring four published features: T-cell burden; a rejection classifier; a canonical TCMR classifier; and risk score. These reassigned borderline biopsies as TCMR-like 13/40 (33%) or nonrejection-like 27/40 (67%). A major reason that histology diagnosed molecularly defined TCMR as borderline was atrophy-scarring, which interfered with assessment of inflammation and tubulitis. Decision tree analysis showed that i-total >27% and tubulitis extent >3% match the molecular diagnosis of TCMR in 85% of cases. In summary, most cases designated borderline by histopathology are found to be nonrejection by molecular phenotyping. Both molecular measurements and histopathology offer opportunities for more precise assignment of these cases after clinical validation.
Assuntos
Biópsia , Rejeição de Enxerto , Transplante de Rim , Adolescente , Adulto , Idoso , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
We prospectively studied kidney transplants that progressed to failure after a biopsy for clinical indications, aiming to assign a cause to every failure. We followed 315 allograft recipients who underwent indication biopsies at 6 days to 32 years posttransplant. Sixty kidneys progressed to failure in the follow-up period (median 31.4 months). Failure was rare after T-cell-mediated rejection and acute kidney injury and common after antibody-mediated rejection or glomerulonephritis. We developed rules for using biopsy diagnoses, HLA antibody and clinical data to explain each failure. Excluding four with missing information, 56 failures were attributed to four causes: rejection 36 (64%), glomerulonephritis 10 (18%), polyoma virus nephropathy 4 (7%) and intercurrent events 6 (11%). Every rejection loss had evidence of antibody-mediated rejection by the time of failure. Among rejection losses, 17 of 36 (47%) had been independently identified as nonadherent by attending clinicians. Nonadherence was more frequent in patients who progressed to failure (32%) versus those who survived (3%). Pure T-cell-mediated rejection, acute kidney injury, drug toxicity and unexplained progressive fibrosis were not causes of loss. This prospective cohort indicates that many actual failures after indication biopsies manifest phenotypic features of antibody-mediated or mixed rejection and also underscores the major role of nonadherence.
Assuntos
Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Imunidade Humoral , Transplante de Rim/imunologia , Rim/patologia , Biópsia , Seguimentos , Rejeição de Enxerto/patologia , Humanos , Rim/imunologia , Transplante de Rim/patologia , Estudos Prospectivos , Fatores de Tempo , Transplante Homólogo , Resultado do TratamentoRESUMO
Assessment of kidney transplant biopsies relies on nonspecific inflammatory lesions: Interstitial infiltrates (i), tubulitis (t) and intimal arteritis (v). We studied the relationship between inflammation and prognosis in biopsies for clinical indications from 314 patients (median follow-up 25 months). We used a modified Banff classification, separately assessing inflammation (i-) in nonscarred (i-Banff), scarred (i-IFTA) and whole cortex (i-total), plus tubulitis and intimal arteritis. In early biopsies (<1 year), i- and t-lesions had no association with graft survival. In late (>1 year) biopsies, all i-scores correlated with progression to failure, due to the association of these infiltrates with progressive diseases: antibody-mediated rejection (ABMR) and glomerulonephritis. Tubulitis in nonscarred areas had no impact on survival. Severe tubulitis including scarred areas (tis3) was associated with worse survival, but reflected polyoma virus nephropathy or ABMR, not T-cell-mediated rejection. Intimal arteritis (v-lesions) had no association with allograft loss in early or late biopsies. In multivariate analysis, outcome was better predicted by the presence of progressive disease than by inflammation. Thus inflammation in late kidney transplants has no inherent prognostic impact, but predicts reduced survival because inflammation indicates actively progressing diseases. The most important predictor of outcome is the diagnosis of a progressive disease.
Assuntos
Rejeição de Enxerto/etiologia , Sobrevivência de Enxerto , Inflamação/etiologia , Transplante de Rim/efeitos adversos , Adolescente , Adulto , Idoso , Biópsia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Índice de Gravidade de Doença , Adulto JovemRESUMO
Microarray studies of kidney transplant biopsies provide an opportunity to define the molecular phenotype. To facilitate this process, we used experimental systems to annotate transcripts as members of pathogenesis-based transcript sets (PBTs) representing biological processes in injured or diseased tissue. Applying this annotation to microarray results revealed that changes in single molecules and PBTs reflected a large-scale coordinate disturbance, stereotyped across various diseases and injuries, without absolute specificity of individual molecules or PBTs for rejection. Nevertheless, expression of molecules and PBTs was quantitatively specific: IFNG effects for rejection; T cell and macrophage transcripts for T cell-mediated rejection; endothelial and NK transcripts for antibody-mediated rejection. Various diseases and injuries induced the same injury-repair response, undetectable by histopathology, involving epithelium, stroma and endothelium, with increased expression of developmental, cell cycle and apoptosis genes and decreased expression of differentiated epithelial features. Transcripts reflecting this injury-repair response were the best correlates of functional disturbance and risk of future graft loss. Late biopsies with atrophy-fibrosis, reflecting their cumulative burden of injury, displayed more transcripts for B cells, plasma cells and mast cells. Thus the molecular phenotype is best described in terms of three elements: specific diseases, including rejection; the injury-repair response and the cumulative burden of injury.
Assuntos
Rejeição de Enxerto/genética , Transplante de Rim/patologia , Animais , Atrofia , Biópsia , Perfilação da Expressão Gênica , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Inflamação/fisiopatologia , Interferon gama/fisiologia , Rim/patologia , Rim/fisiopatologia , Macrófagos/fisiologia , Camundongos , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Linfócitos T/fisiologiaRESUMO
Data-driven approaches to deteriorating kidney transplants, incorporating histologic, molecular and HLA antibody findings, have created a new understanding of transplant pathology and why transplants fail. Transplant dysfunction is best understood in terms of three elements: diseases, the active injury-repair response and the cumulative burden of injury. Progression to failure is mainly attributable to antibody-mediated rejection, nonadherence and glomerular disease. Antibody-mediated rejection usually develops late due to de novo HLA antibodies, particularly anti-class II, and is often C4d negative. Pure treated T cell-mediated rejection does not predispose to graft loss because it responds well, even with endothelialitis, but it may indicate nonadherence. The cumulative burden of injury results in atrophy-fibrosis (nephron loss), arterial fibrous intimal thickening and arteriolar hyalinosis, but these are not progressive without ongoing disease/injury, and do not explain progression. Calcineurin inhibitor toxicity has been overestimated because burden-of-injury lesions invite this default diagnosis when diseases such as antibody-mediated rejection are missed. Disease/injury triggers a stereotyped active injury-repair response, including de-differentiation, cell cycling and apoptosis. The active injury-repair response is the strongest correlate of organ function and future progression to failure, but should always prompt a search for the initiating injury or disease.
Assuntos
Rejeição de Enxerto/imunologia , Transplante de Rim/imunologia , Biópsia , Efeitos Psicossociais da Doença , Progressão da Doença , Fibrose , Humanos , Rim/imunologia , Rim/patologia , Cooperação do Paciente , Fenótipo , Resultado do TratamentoRESUMO
To explore the mechanisms of antibody-mediated rejection (ABMR) in kidney transplants, we studied the transcripts expressed in clinically indicated biopsies from patients with donor-specific antibody (DSA). Comparison of biopsies from DSA-positive versus DSA-negative patients revealed 132 differentially expressed transcripts: all were associated with class II DSA but none with class I DSA. Many transcripts were expressed in DSA-positive ABMR but were also expressed in T-cell-mediated rejection (TCMR), reflecting shared molecular features. Removal of shared transcripts created 23 DSA selective transcripts (DSASTs). Some DSASTs (6/23) showed selective high expression in NK cells, whereas others (8/23) were expressed in endothelium or in endothelium plus other cell types (7/23). Of 145 biopsies ranked by DSAST expression, the 25 with highest DSAST expression primarily consisted of ABMR (22/25, 88%), either C4d-positive or C4d-negative. By immunostaining, CD56+ and CD68+ cells in peritubular capillaries, but not CD3+ cells, were increased in ABMR compared to TCMR, compatible with a role for NK cells, as well as macrophages, as effectors in endothelial injury during ABMR. Thus, the strategy of using DSASTs in the biopsy to identify mechanism-related transcripts in biopsies from patients with clinical phenotypes indicates the selective involvement of NK cells in ABMR.