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OBJECTIVE: Systemic sclerosis-interstitial lung disease (SSc-ILD) is the leading cause of death in SSc, affecting around 50 % of the patients. Lung tissue of patients with early-stage SSc-ILD is characterized by a predominant inflammatory response with inconspicuous fibrosis, which may progress to honeycombing fibrosis. Hence, a better understanding of the molecular mechanisms underpinning SSc-ILD pathogenesis is needed to improve treatment options and progression prediction. This transcriptomic study aims to reveal the differential gene expression between control (ctrl) lung tissue and inflammatory, prefibrotic and fibrotic lung tissue to capture progression of early to late phase SSc-ILD. METHODS: Twelve explanted lungs from patients with SSc-ILD were used to analyze gene expression from formalin-fixed paraffin-embedded lung tissues with varying stages of ILD (n = 18) and control lung tissue (n = 6). The SSc-ILD tissues were stratified into three ROIs: inflammatory, prefibrotic, and fibrotic using histological assessments to define a longitudinal simulation of early to late phases of SSc-ILD. The nanoString (nS) nCounter Human Fibrosis Panel was used to profile the transcriptome in the regions of interest. Validation of potential targetswas performed with immunohistochemistry in the same tissues that were used for transcriptome analysis. RESULTS: To validate our simulation model, we performed subgroup analysis that showed an incremental increase in pathway scores related to the severity of fibrosis. Ctrl vs SSc-ILD comparison demonstrated 24 differentially expressed genes, two of which had the most pronounced p-values. Cyclin-dependent kinase inhibitor (cdkn2c) was overexpressed (P = 0.00052) in SSc-ILD compared to ctrl, while expression of Pellino E3 ubiquitin-protein ligase 1 (peli1) showed lower expression (P = 0.0012). Additionally, in all four groups, cdkn2c and peli1 gene expression showed an incremental increase and decrease, respectively. Immunohistochemistry of cdkn2c showed consistent results with the nS analysis. CONCLUSION: More cdkn2c and less peli1 expression were associated with more advanced stages of SSc-ILD on histologic assessment. We report the potential of the cell cycle inhibitor and senescence marker, cdkn2c (p18) to be associated with fibrosis progression.
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Solid organ transplant recipients (SOTR) frequently report tremor. Data concerning tremor-related impairment and its potential impact on health-related quality of life (HRQoL) are lacking. This cross-sectional study assesses impact of tremor on activities of daily living and HRQoL using validated questionnaires among SOTR enrolled in the TransplantLines Biobank and Cohort Study. We included 689 SOTR (38.5% female, mean [±SD] age 58 [±14] years) at median [interquartile range] 3 [1-9] years after transplantation, of which 287 (41.7%) reported mild or severe tremor. In multinomial logistic regression analyses, whole blood tacrolimus trough concentration was an independent determinant of mild tremor (OR per µg/L increase: 1.11, 95% CI: 1.02 to 1.21, p = 0.019). Furthermore, in linear regression analyses, severe tremor was strongly and independently associated with lower physical and mental HRQoL (ß = -16.10, 95% CI: -22.23 to -9.98, p < 0.001 and ß = -12.68, 95% CI: -18.23 to -7.14, p < 0.001 resp.). SOTR frequently report tremor-related impairment of activities of daily living. Tacrolimus trough concentrations appeared as a main determinant of tremor among SOTR. The strong and independent association of tremor-related impairment with lower HRQoL warrants further studies into the effects of tacrolimus on tremor. Clinical Trial Registration: ClinicalTrials.gov, Identifier NCT03272841.
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Trasplante de Órganos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Actividades Cotidianas , Estudios de Cohortes , Estudios Transversales , Calidad de Vida , Tacrolimus , Receptores de Trasplantes , TemblorRESUMEN
BACKGROUND: The role of right ventricular (RV) diastolic stiffness in pulmonary arterial hypertension (PAH) is not well established. Therefore, we investigated the presence and possible underlying mechanisms of RV diastolic stiffness in PAH patients. METHODS AND RESULTS: Single-beat RV pressure-volume analyses were performed in 21 PAH patients and 7 control subjects to study RV diastolic stiffness. Data are presented as mean ± SEM. RV diastolic stiffness (ß) was significantly increased in PAH patients (PAH, 0.050 ± 0.005 versus control, 0.029 ± 0.003; P<0.05) and was closely associated with disease severity. Subsequently, we searched for possible underlying mechanisms using RV tissue of PAH patients undergoing heart/lung transplantation and nonfailing donors. Histological analyses revealed increased cardiomyocyte cross-sectional areas (PAH, 453 ± 31 µm² versus control, 218 ± 21 µm²; P<0.001), indicating RV hypertrophy. In addition, the amount of RV fibrosis was enhanced in PAH tissue (PAH, 9.6 ± 0.7% versus control, 7.2 ± 0.6%; P<0.01). To investigate the contribution of stiffening of the sarcomere (the contractile apparatus of RV cardiomyocytes) to RV diastolic stiffness, we isolated and membrane-permeabilized single RV cardiomyocytes. Passive tension at different sarcomere lengths was significantly higher in PAH patients compared with control subjects (>200%; Pinteraction <0.001), indicating stiffening of RV sarcomeres. An important regulator of sarcomeric stiffening is the sarcomeric protein titin. Therefore, we investigated titin isoform composition and phosphorylation. No alterations were observed in titin isoform composition (N2BA/N2B ratio: PAH, 0.78 ± 0.07 versus control, 0.91 ± 0.08), but titin phosphorylation in RV tissue of PAH patients was significantly reduced (PAH, 0.16 ± 0.01 arbitrary units versus control, 0.20 ± 0.01 arbitrary units; P<0.05). CONCLUSIONS: RV diastolic stiffness is significantly increased in PAH patients, with important contributions from increased collagen and intrinsic stiffening of the RV cardiomyocyte sarcomeres.
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Diástole/fisiología , Hipertensión Pulmonar/fisiopatología , Miocardio/metabolismo , Disfunción Ventricular Derecha/metabolismo , Disfunción Ventricular Derecha/fisiopatología , Adulto , Anciano , Cateterismo Cardíaco , Volumen Cardíaco/fisiología , Colágeno/metabolismo , Conectina/metabolismo , Hipertensión Pulmonar Primaria Familiar , Femenino , Humanos , Hipertrofia Ventricular Derecha/metabolismo , Hipertrofia Ventricular Derecha/patología , Hipertrofia Ventricular Derecha/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Miocardio/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , Sarcómeros/metabolismo , Sarcómeros/patología , Disfunción Ventricular Derecha/patología , Presión Ventricular/fisiologíaRESUMEN
Gut dysbiosis has been associated with impaired outcomes in liver and kidney transplant recipients, but the gut microbiome of lung transplant recipients has not been extensively explored. We assessed the gut microbiome in 64 fecal samples from end-stage lung disease patients before transplantation and 219 samples from lung transplant recipients after transplantation using metagenomic sequencing. To identify dysbiotic microbial signatures, we analyzed 243 fecal samples from age-, sex-, and BMI-matched healthy controls. By unsupervised clustering, we identified five groups of lung transplant recipients using different combinations of immunosuppressants and antibiotics and analyzed them in relation to the gut microbiome. Finally, we investigated the gut microbiome of lung transplant recipients in different chronic lung allograft dysfunction (CLAD) stages and longitudinal gut microbiome changes after transplantation. We found 108 species (58.1%) in end-stage lung disease patients and 139 species (74.7%) in lung transplant recipients that were differentially abundant compared with healthy controls, with several species exhibiting sharp longitudinal increases from before to after transplantation. Different combinations of immunosuppressants and antibiotics were associated with specific gut microbial signatures. We found that the gut microbiome of lung transplant recipients in CLAD stage 0 was more similar to healthy controls compared to those in CLAD stage 1. Finally, the gut microbial diversity of lung transplant recipients remained lower than the average gut microbial diversity of healthy controls up to more than 20 years post-transplantation. Gut dysbiosis, already present before lung transplantation was exacerbated following lung transplantation.IMPORTANCEThis study provides extensive insights into the gut microbiome of end-stage lung disease patients and lung transplant recipients, which warrants further investigation before the gut microbiome can be used for microbiome-targeted interventions that could improve the outcome of lung transplantation.
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Disbiosis , Microbioma Gastrointestinal , Trasplante de Pulmón , Humanos , Trasplante de Pulmón/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Adulto , Disbiosis/microbiología , Enfermedades Pulmonares/microbiología , Enfermedades Pulmonares/cirugía , Inmunosupresores/uso terapéutico , Inmunosupresores/efectos adversos , Heces/microbiología , AncianoRESUMEN
BACKGROUND AND OBJECTIVE: Historically, dosing of tacrolimus is guided by therapeutic drug monitoring (TDM) of the whole blood concentration, which is strongly influenced by haematocrit. The therapeutic and adverse effects are however expected to be driven by the unbound exposure, which could be better represented by measuring plasma concentrations. OBJECTIVE: We aimed to establish plasma concentration ranges reflecting whole blood concentrations within currently used target ranges. METHODS: Plasma and whole blood tacrolimus concentrations were determined in samples of transplant recipients included in the TransplantLines Biobank and Cohort Study. Targeted whole blood trough concentrations are 4-6 ng/mL and 7-10 ng/mL for kidney and lung transplant recipients, respectively. A population pharmacokinetic model was developed using non-linear mixed-effects modelling. Simulations were performed to infer plasma concentration ranges corresponding to whole blood target ranges. RESULTS: Plasma (n = 1973) and whole blood (n = 1961) tacrolimus concentrations were determined in 1060 transplant recipients. A one-compartment model with fixed first-order absorption and estimated first-order elimination characterised observed plasma concentrations. Plasma was linked to whole blood using a saturable binding equation (maximum binding 35.7 ng/mL, 95% confidence interval (CI) 31.0-40.4 ng/mL; dissociation constant 0.24 ng/mL, 95% CI 0.19-0.29 ng/mL). Model simulations indicate that patients within the whole blood target range are expected to have plasma concentrations (95% prediction interval) of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively. CONCLUSION: Whole blood tacrolimus target ranges, currently used to guide TDM, were translated to plasma concentration ranges of 0.06-0.26 ng/mL and 0.10-0.93 ng/mL for kidney and lung transplant recipients, respectively.
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Inmunosupresores , Tacrolimus , Humanos , Tacrolimus/farmacocinética , Inmunosupresores/farmacocinética , Receptores de Trasplantes , Estudios de Cohortes , Riñón , PulmónRESUMEN
Introduction: Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are the leading causes of death in systemic sclerosis (SSc). Until now, no prospective biomarker to predict new onset of SSc-ILD or SSc-PAH in patients with SSc has reached clinical application. In homeostasis, the receptor for advanced glycation end products (RAGE) is expressed in lung tissue and involved in cell-matrix adhesion, proliferation and migration of alveolar epithelial cells, and remodeling of the pulmonary vasculature. Several studies have shown that sRAGE levels in serum and pulmonary tissue vary according to the type of lung-related complication. Therefore, we investigated levels of soluble RAGE (sRAGE) and its ligand high mobility group box 1 (HMGB1) in SSc and their abilities to predict SSc-related pulmonary complications. Methods: One hundred eighty-eight SSc patients were followed retrospectively for the development of ILD, PAH, and mortality for 8 years. Levels of sRAGE and HMGB1 were measured in serum by ELISA. Kaplan-Meier survival curves were performed to predict lung events and mortality and event rates were compared with a log-rank test. Multiple linear regression analysis was performed to examine the association between sRAGE and important clinical determinants. Results: At baseline, levels of sRAGE were significantly higher in SSc-PAH-patients (median 4099.0 pg/ml [936.3-6365.3], p = 0.011) and lower in SSc-ILD-patients (735.0 pg/ml [IQR 525.5-1988.5], p = 0.001) compared to SSc patients without pulmonary involvement (1444.5 pg/ml [966.8-2276.0]). Levels of HMGB1 were not different between groups. After adjusting for age, gender, ILD, chronic obstructive pulmonary disease, anti-centromere antibodies, the presence of puffy fingers or sclerodactyly, use of immunosuppression, antifibrotic therapy, or glucocorticoids, and use of vasodilators, higher sRAGE levels remained independently associated with PAH. After a median follow-up of 50 months (25-81) of patients without pulmonary involvement, baseline sRAGE levels in the highest quartile were predictive of development of PAH (log-rank p = 0.01) and of PAH-related mortality (p = 0.001). Conclusions: High systemic sRAGE at baseline might be used as a prospective biomarker for patients with SSc at high risk to develop new onset of PAH. Moreover, high sRAGE levels could predict lower survival rates due to PAH in patients with SSc.
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Hipertensión Arterial Pulmonar , Receptor para Productos Finales de Glicación Avanzada , Esclerodermia Sistémica , Hipertensión Arterial Pulmonar/sangre , Hipertensión Arterial Pulmonar/tratamiento farmacológico , Hipertensión Arterial Pulmonar/mortalidad , Hipertensión Arterial Pulmonar/patología , Humanos , Estudios Retrospectivos , Masculino , Femenino , Persona de Mediana Edad , Receptor para Productos Finales de Glicación Avanzada/sangre , Esclerodermia Sistémica/complicaciones , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/patología , Proteína HMGB1/sangreRESUMEN
Lung transplant (LTx) physicians are responsible for highly complex post-LTx care, including monitoring of kidney function and responding to kidney function loss. Better survival of the LTx population and changing patient characteristics, including older age and increased comorbidity, result in growing numbers of LTx patients with chronic kidney disease (CKD). CKD after LTx is correlated with worse survival, decreased quality of life and high costs. Challenges lie in different aspects of post-LTx renal care. First, serum creatinine form the basis for estimating renal function, under the assumption that patients have stable muscle mass. Low or changes in muscle mass is frequent in the LTx population and may lead to misclassification of CKD. Second, standardizing post-LTx monitoring of kidney function and renal care might contribute to slow down CKD progression. Third, new treatment options for CKD risk factors, such as diabetes mellitus, proteinuria and heart failure, have entered clinical practice. These new treatments have not been studied in LTx yet but are of interest for future use. In this review we will address the difficult aspects of post-LTx renal care and evaluate new and promising future approaches to slow down CKD progression.
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Diabetes Mellitus , Trasplante de Pulmón , Insuficiencia Renal Crónica , Humanos , Calidad de Vida , Insuficiencia Renal Crónica/cirugía , Trasplante de Pulmón/efectos adversosRESUMEN
Ex vivo lung perfusion (EVLP) is a technique for reconditioning and evaluating lungs. However, the use of EVLP for logistical reasons is still under discussion. In this retrospective study, all EVLPs performed between July 2012 and October 2019 were analyzed for ventilation and perfusion data. After transplantation, primary graft dysfunction (PGD), lung function, chronic lung allograft dysfunction (CLAD)-free survival, and overall survival were analyzed. Fifty EVLPs were performed: seventeen logistic EVLPs led to 15 lung transplantations (LT) and two rejections (LR), and 33 medical EVLPs resulted in 26 lung transplantations (MT) and seven rejections (MR). Pre-EVLP PaO2 was lower for MT than LT (p < 0.05). Dynamic lung compliance remained stable in MT and LT but decreased in MR and LR. Plateau airway pressure started at a higher level in MR (p < 0.05 MT vs. MR at T60) and increased further in LR. After transplantation, there were no differences between MT and LT in PGD, lung function, CLAD-free survival, and overall survival. In addition, the LT group was compared with a cohort group receiving standard donor lungs without EVLP (LTx). There were no significant differences between LT and LTx for PGD, CLAD-free survival, and overall survival. FVC was significantly lower in LT than in LTx after 1 year (p = 0.005). We found that LT lungs appear to perform better than MT lungs on EVLP. In turn, the outcome in the LT group was comparable with the LTx group. Overall, lung transplantation after EVLP for logistic reasons is safe and makes transplantation timing controllable.
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BACKGROUND: Concerns have been raised on the impact of coronavirus disease (COVID-19) on lung transplant (LTx) patients. The aim of this study was to evaluate the transplant function pre- and post-COVID-19 in LTx patients. METHODS: Data were retrospectively collected from LTx patients with confirmed COVID-19 from all 3 Dutch transplant centers, between February 2020 and September 2021. Spirometry results were collected pre-COVID-19, 3- and 6-months post infection. RESULTS: Seventy-four LTx patients were included. Forty-two (57%) patients were admitted, 19 (26%) to the intensive care unit (ICU). The in-hospital mortality was 20%. Twelve out of 19 ICU patients died (63%), a further 3 died on general wards. Patients with available spirometry (78% at 3 months, 65% at 6 months) showed a significant decline in mean forced expiratory volume in 1 second (FEV1) (ΔFEV1 138 ± 39 ml, p = 0.001), and forced vital capacity (FVC) (ΔFVC 233 ±74 ml, p = 0.000) 3 months post infection. Lung function improved slightly from 3 to 6 months after COVID-19 (ΔFEV1 24 ± 38 ml; ΔFVC 100 ± 46 ml), but remained significantly lower than pre-COVID-19 values (ΔFEV1 86 ml ± 36 ml, p = 0.021; ΔFVC 117 ± 35 ml, p = 0.012). FEV1/FVC was > 0.70. CONCLUSIONS: In LTx patients COVID-19 results in high mortality in hospitalized patients. Lung function declined 3 months after infection and gradually improved at 6 months, but remained significantly lower compared to pre-COVID-19 values. The more significant decline in FVC than in FEV1 and FEV1/FVC > 70%, suggested a more restrictive pattern.
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COVID-19 , Trasplante de Pulmón , Volumen Espiratorio Forzado , Humanos , Pulmón , Estudios Retrospectivos , Espirometría , Capacidad VitalRESUMEN
BACKGROUND: Evaluating and bridging patients to lung transplantation (LTx) on the intensive care unit (ICU) remains controversial, especially without a previous waitlist status. Long term outcome data after LTx from ICU remains scarce. We compared long-term survival and development of chronic lung allograft dysfunction (CLAD) in elective and LTx from ICU, with or without previous waitlist status. METHODS: Patients transplanted between 2004 and 2018 in 2 large academic Dutch institutes were included. Long-term survival and development of CLAD was compared in patients who received an elective LTx (ELTx), those bridged and transplanted from the ICU with a previous listing status (BTT), and in patients urgently evaluated and bridged on ICU (EBTT). RESULTS: A total of 582 patients underwent a LTx, 70 (12%) from ICU, 39 BTT and 31 EBTT. Patients transplanted from ICU were younger than ELTx (46 vs 51 years) and were bridged with mechanical ventilation (n = 42 (60%)), extra corporeal membrane oxygenation (n = 28 (40%)), or both (n = 21/28). Bridging success was 48% in the BTT group and 72% in the EBTT group. Patients bridged to LTx on ICU had similar 1 and 5 year survival (86.8% and 78.4%) compared to elective LTx (86.8% and 71.9%). This was not different between the BTT and EBTT group. 5 year CLAD free survival was not different in patients transplanted from ICU vs ELTx. CONCLUSION: Patients bridged to LTx on the ICU with and without prior listing status had excellent short and long-term patient and graft outcomes, and was similar to patients electively transplanted.
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Oxigenación por Membrana Extracorpórea , Trasplante de Pulmón , Oxigenación por Membrana Extracorpórea/efectos adversos , Humanos , Unidades de Cuidados Intensivos , Pulmón , Trasplante de Pulmón/efectos adversos , Estudios RetrospectivosRESUMEN
Chronic lung allograft dysfunction (CLAD) is the major long-term cause of morbidity and mortality after lung transplantation. Both bronchiolitis obliterans syndrome and restrictive lung allograft syndrome, two main types of CLAD, lead to fibrosis in either the small airways or alveoli and pleura. Pathological pathways in CLAD and other types of fibrosis, for example idiopathic pulmonary fibrosis, are assumed to overlap and therefore fibrosis biomarkers could aid in the early detection of CLAD. These biomarkers could help to differentiate between different phenotypes of CLAD and could, in comparison to biomarkers of inflammation, possibly distinguish an infectious event from CLAD when a decline in lung function is present. This review gives an overview of known CLAD specific biomarkers, describes new promising fibrosis biomarkers currently investigated in other types of fibrosis, and discusses the possible use of these fibrosis biomarkers for CLAD.
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Bronquiolitis Obliterante , Trasplante de Pulmón , Aloinjertos , Biomarcadores , Bronquiolitis Obliterante/diagnóstico , Bronquiolitis Obliterante/etiología , Fibrosis , Humanos , Pulmón , Trasplante de Pulmón/efectos adversosRESUMEN
INTRODUCTION: Direct quantification of drug concentrations allows for medication adherence monitoring (MAM) and therapeutic drug monitoring (TDM). Multiple less invasive methods have been developed in recent years: dried blood spots (DBS), saliva, and hair analyses. AIM: To provide an overview of emerging drug quantification methods for MAM and TDM, focusing on the clinical validation of methods in patients prescribed chronic drug therapies. METHODS: A scoping review was performed using a systematic search in three electronic databases covering the period 2000-2020. Screening and inclusion were performed by two independent reviewers in Rayyan. Data from the articles were aggregated in a REDCap database. The main outcome was clinical validity of methods based on study sample size, means of cross-validation, and method description. Outcomes were reported by matrix, therapeutic area and application (MAM and/or TDM). RESULTS: A total of 4590 studies were identified and 175 articles were finally included; 57 on DBS, 66 on saliva and 55 on hair analyses. Most reports were in the fields of neurological diseases (37%), infectious diseases (31%), and transplantation (14%). An overview of clinical validation was generated of all measured drugs. A total of 62 drugs assays were applied for MAM and 131 for TDM. CONCLUSION: MAM and TDM are increasingly possible without traditional invasive blood sampling: the strengths and limitations of DBS, saliva, and hair differ, but all have potential for valid and more convenient drug monitoring. To strengthen the quality and comparability of future evidence, standardisation of the clinical validation of the methods is recommended.
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Análisis Químico de la Sangre/métodos , Monitoreo de Drogas/métodos , Cabello/química , Cumplimiento de la Medicación , Saliva/química , Humanos , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND AND OBJECTIVES: Many kidney transplant recipients suffer from fatigue and poor health-related quality of life. Airflow limitation may be an underappreciated comorbidity among kidney transplant recipients, which could contribute to fatigue and lower health-related quality of life in this population. In this study, we compared the prevalence of airflow limitation between kidney transplant recipients and healthy controls and investigated associations of airflow limitation with fatigue and health-related quality of life in kidney transplant recipients. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Data from the ongoing TransplantLines Biobank and Cohort study were used. Airflow limitation was defined as forced exhaled volume in 1 second less than the fifth percentile of the general population. Fatigue and health-related quality of life were assessed using checklist individual strength 20 revised (CIS20-R) and Short Form-36 (SF-36) questionnaires. RESULTS: A total of 539 kidney transplant recipients (58% men; mean age 56±13 years) and 244 healthy controls (45% men; mean age 57±10 years) were included. Prevalence of airflow limitation was higher in kidney transplant recipients than in healthy controls (133 [25%] versus 25 [10%]). In multinomial regression models, airflow limitation was independently associated with fatigue severity (odds ratio moderate fatigue, 1.68; 95% confidence interval, 0.92 to 3.09 and odds ratio severe fatigue, 2.51; 95% confidence interval, 1.39 to 4.55; P=0.007) and lower physical health-related quality of life (-0.11 SDs; 95% confidence interval, -0.19 to -0.02; P=0.01) in kidney transplant recipients. In exploratory mediation analyses, fatigue accounted for 79% of the association of airflow limitation with physical health-related quality of life. CONCLUSIONS: Airflow limitation is common among kidney transplant recipients. Its occurrence is associated with more than two times higher risk of severe fatigue, and it is associated with lower physical health-related quality of life. Mediation analyses suggest that airflow limitation causes fatigue, which in turn, decreases physical health-related quality of life. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: TransplantLines: The Transplantation Biobank, NCT03272841 PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_11_08_CJN06600521.mp3.
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Fatiga/epidemiología , Fatiga/fisiopatología , Trasplante de Riñón , Calidad de Vida , Adulto , Anciano , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Encuestas y CuestionariosRESUMEN
AIMS: Pulmonary arterial compliance (C) is increasingly being recognized as an important contributor to right ventricular afterload, but for monitoring of treatment of pulmonary hypertension (PH) most often still only pulmonary vascular resistance (R) is used. We aimed at testing the hypothesis that R and C are coupled during treatment of PH and that substantial changes in both R and C would result in more haemodynamic improvement than changes in R alone. METHODS AND RESULTS: Data were analysed of two right-heart catheterizations of 52 patients with pulmonary arterial hypertension and 10 with chronic-thromboembolic PH. The product of R and C (= stroke volume over pulse pressure) did not change during therapy (P = 0.320), implying an inverse relationship. Changes in cardiac index correlated significantly (P < 0.001) with changes in R (R(2) = 0.37), better with changes in C (R(2) = 0.66), and best with changes in both (R(2) = 0.74). CONCLUSION: During therapy for PH, R and C remain inversely related. Therefore, changes in both R and C better explain changes in cardiac index than either of them alone. Not only resistance but also compliance plays a prominent role in PH especially in an early stage of the disease.
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Fármacos Cardiovasculares/uso terapéutico , Hemodinámica/efectos de los fármacos , Hipertensión Pulmonar/tratamiento farmacológico , Embolia Pulmonar/tratamiento farmacológico , Adulto , Anciano , Cateterismo Cardíaco , Adaptabilidad , Femenino , Humanos , Hipertensión Pulmonar/fisiopatología , Masculino , Persona de Mediana Edad , Embolia Pulmonar/fisiopatología , Resistencia Vascular/fisiologíaRESUMEN
Introduction: Azithromycin stabilises and improves lung function forced expiratory volume in one second (FEV1) in lung transplantation patients with bronchiolitis obliterans syndrome (BOS). A post hoc analysis was performed to assess the long-term effect of azithromycin on FEV1, BOS progression and survival . Methods: Eligible patients recruited for the initial randomised placebo-controlled trial received open-label azithromycin after 3 months and were followed up until 6 years after inclusion (n=45) to assess FEV1, BOS free progression and overall survival. Results: FEV1 in the placebo group improved after open-label azithromycin and was comparable with the treatment group by 6 months. FEV1 decreased after 1 and 5 years and was not different between groups. Patients (n=18) with rapid progression of BOS underwent total lymphoid irradiation (TLI). Progression-free survival (log-rank test p=0.40) and overall survival (log-rank test p=0.28) were comparable. Survival of patients with early BOS was similar to late-onset BOS (log-rank test p=0.74). Discussion: Long-term treatment with azithromycin slows down the progression of BOS, although the effect of TLI may affect the observed attenuation of FEV1 decline. BOS progression and long-term survival were not affected by randomisation to the placebo group, given the early cross-over to azithromycin and possibly due to TLI in case of further progression. Performing randomised placebo-controlled trials in lung transplantation patients with BOS with a blinded trial duration is feasible, effective and safe.
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Azitromicina/uso terapéutico , Bronquiolitis Obliterante/tratamiento farmacológico , Adulto , Azitromicina/farmacología , Bronquiolitis Obliterante/mortalidad , Bronquiolitis Obliterante/fisiopatología , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Persona de Mediana Edad , Tasa de Supervivencia , Síndrome , Factores de Tiempo , Resultado del TratamientoRESUMEN
AIMS: Decreased total compliance of the pulmonary vascular bed is associated with increased mortality in patients with pulmonary arterial hypertension (PAH). We investigated whether proximal pulmonary artery stiffness, in terms of area distensibility and noninvasively assessed relative area change (RAC), calculated as relative cross-sectional area change, predicts mortality in patients with PAH. METHODS AND RESULTS: Eighty-six subjects underwent right-heart catheterization and MRI to assess area distensibility and RAC. Patients were followed up to 48 months. Kaplan-Meier plot and Cox proportional hazards regression analyses assessed the predictive value of area distensibility and RAC. In 70 patients, the diagnosis PAH was confirmed, and 16 subjects served as control subjects. In comparison with control subjects, proximal pulmonary arteries of patients were distended (685 +/- 214 mm2 vs 411 +/- 153 mm2, p < 0.001), less distensible (area distensibility = 0.46 +/- 0.38.10(-2) mm Hg(-1) vs 3.69 +/- 1.96.10(-2) mm Hg(-1), p < 0.0001), and RAC was smaller (20 +/- 10% vs 58 +/- 21%, p < 0.0001) [mean +/- SD]. RAC showed an inverse curvilinear relation with mean pulmonary artery pressure (R2 = 0.47). Eighteen patients (26%) died because of cardiopulmonary causes. Patients with a pulmonary artery RAC
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Hipertensión Pulmonar/mortalidad , Hipertensión Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Adulto , Cateterismo Cardíaco , Estudios de Casos y Controles , Elasticidad , Femenino , Humanos , Análisis de los Mínimos Cuadrados , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos ProporcionalesRESUMEN
AIMS: This study investigated whether right ventricular (RV) diastolic function is impaired in pulmonary hypertension (PH) patients, and whether it is related to RV mass and afterload. In addition, the effects of an acute reduction of RV afterload by the oral intake of sildenafil were studied. Finally, we assessed whether diastolic function is related to cardiac parameters of disease severity. METHODS AND RESULTS: Twenty-five PH patients and 11 control subjects were studied. Right-heart catheterization and N-terminal pro-brain natriuretic peptide (NT-proBNP) sampling were performed in patients. MRI measured RV ejection fraction, mass, and diastolic function. Isovolumic relaxation time (IVRT), normalized early peak filling rate (E), atrium-induced peak filling rate (A), and E/A ratio described diastolic function. Compared to control subjects, patients had prolonged mean (+/- SD) IVRT (133.5 +/- 53.2 vs 29.3 +/- 20.8 ms, respectively; p < 0.001), decreased E (3.0 +/- 1.6 vs 6.4 +/- 2.5 s(-1), respectively; p < 0.001) and E/A ratio (1.1 +/- 0.7 vs 5.3 +/- 4.9, respectively; p < 0.001), and increased A (3.0 +/- 1.4 vs 1.5 +/- 0.9 s(-1), respectively; p = 0.001). IVRT was related to RV mass (r(25) = 0.56; p = 0.005) and pulmonary vascular resistance (r(25) = 0.74; p < 0.0001). Sildenafil therapy reduced RV afterload and improved RV diastolic and systolic function. IVRT was correlated with NT-proBNP level (r = 0.70; p < 0.001), and was inversely related to cardiac index (r = -0.70; p < 0.001) and RV ejection fraction (r = -0.69; p < 0.001). CONCLUSION: In PH patients, RV diastolic dysfunction is related to RV mass and afterload. RV diastolic function improves by reducing afterload. The correlations between diastolic function and prognostic parameters showed that diastolic function is most impaired in patients with severe disease.
Asunto(s)
Hipertensión Pulmonar/tratamiento farmacológico , Piperazinas/uso terapéutico , Sulfonas/uso terapéutico , Vasodilatadores/uso terapéutico , Disfunción Ventricular Derecha/fisiopatología , Adulto , Antihipertensivos/uso terapéutico , Circulación Sanguínea/fisiología , Presión Sanguínea/fisiología , Bosentán , Epoprostenol/uso terapéutico , Femenino , Ventrículos Cardíacos/patología , Ventrículos Cardíacos/fisiopatología , Humanos , Hipertensión Pulmonar/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Óxido Nítrico/uso terapéutico , Purinas/uso terapéutico , Índice de Severidad de la Enfermedad , Citrato de Sildenafil , Volumen Sistólico/fisiología , Sulfonamidas/uso terapéutico , Resistencia Vascular/fisiologíaRESUMEN
Several diagnostic imaging methodologies are available for the clinical evaluation of sarcoidosis, but all have their limitations. FDG PET/CT is frequently used, but this technique does not provide optimal results in all cases. Novel radiopharmaceuticals aimed at other disease targets may be helpful, particularly in cardiac sarcoidosis when FDG PET/CT has a low diagnostic accuracy, due to difficulties in preparing the patients who should use a specific diet combined with prolonged fasting. 68Ga-labeled somatostatin based receptor hybrid imaging is a potential alternative to FDG PET/CT. This short communication provides a rapid overview of initial findings concerning the application of 68Ga-labeled somatostatin based receptor hybrid imaging in the diagnosis of (cardiac) sarcoidosis activity.
RESUMEN
Heart rate (HR) at rest is an important marker of prognosis in heart failure, but has not been addressed in pulmonary arterial hypertension (PAH). To determine the prognostic value of HR at rest in patients with PAH, we retrospectively analyzed 140 consecutive patients with idiopathic PAH. Electrocardiogram (ECG)-derived HR at rest was evaluated as a potential predictor of adverse prognosis (death or lung transplantation), in addition to World Health Organization functional class, 6-minute walk distance, and hemodynamics before and approximately 1 year and 2 years after initiation of PAH treatment. During follow-up, 49 patients (35%) died, and 5 patients (4%) underwent lung transplantation. Before treatment initiation and after 1 year and 2 years of treatment, respectively, a higher HR at rest was an independent predictor of adverse prognosis (hazard ratios per 10-beats/min increase 1.76, 95% confidence interval 1.42 to 2.18, 2.31, 95% confidence interval 1.58 to 3.38, 2.1, 95% confidence interval 1.39 to 3.19, respectively, p <0.001 for all). Change in HR between the first and last ECG also independently predicted prognosis (hazard ratio per 1-beat/min increase 1.03, 95% confidence interval 1.01 to 1.06). In conclusion, a higher HR at rest and an important increase in HR at rest during follow-up signify a considerable risk of death in patients with PAH. ECG-derived HR at rest is an important marker of prognosis and should be assessed before and at frequent intervals after initiation of treatment for PAH.