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1.
Transpl Int ; 37: 12955, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38979119

RESUMO

Cigarette smoking is a common risk factor associated with negative long-term outcomes in kidney transplant recipients. However, whether donor smoking decreases graft longevity or negatively impacts recipient survival after kidney transplantation remains unknown. Therefore, this study aims to investigate the long-term outcome in patients who received a kidney graft from a deceased smoking or non-smoking donor. A total of 580 patients were divided into two groups: patients who received a graft from a smoking donor (n = 276) and those who received a graft from a non-smoking donor (n = 304). Analysis of demographic factors showed that the non-smoking cohort was older, had more extended criteria donors and longer warm ischemia times. The primary composite endpoint of patient and graft survival was better in the smoking donor cohort when analyzed using Kaplan-Meier method but not when controlled for covariates in multivariate analyses. These findings do not support a previously reported negative impact of deceased donor smoking on kidney transplant recipients. Thus, the underlying results should not be interpreted in favor of a positive donor smoking history, but rather remind the transplant community that donor smoking should not be considered as a deciding factor in refusing an otherwise acceptable kidney graft.


Assuntos
Fumar Cigarros , Sobrevivência de Enxerto , Transplante de Rim , Doadores de Tecidos , Humanos , Transplante de Rim/efeitos adversos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Fumar Cigarros/efeitos adversos , Fatores de Risco , Resultado do Tratamento , Estimativa de Kaplan-Meier , Estudos Retrospectivos , Idoso , Fumar/efeitos adversos
2.
Int J Mol Sci ; 25(10)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38791413

RESUMO

Urinary dickkopf 3 (uDKK3) is a marker released by kidney tubular epithelial cells that is associated with the progression of chronic kidney disease (CKD) and may cause interstitial fibrosis and tubular atrophy. Recent evidence suggests that uDKK3 can also predict the loss of kidney function in CKD patients and kidney transplant recipients, regardless of their current renal function. We conducted a prospective study on 181 kidney transplant (KTx) recipients who underwent allograft biopsy to determine the cause, analyzing the relationship between uDKK3 levels in urine, histological findings, and future allograft function progression. Additionally, we studied 82 living kidney donors before unilateral nephrectomy (Nx), 1-3 days after surgery, and 1 year post-surgery to observe the effects of rapid kidney function loss. In living donors, the uDKK3/creatinine ratio significantly increased 5.3-fold 1-3 days after Nx. However, it decreased significantly to a median level of 620 pg/mg after one year, despite the absence of underlying primary kidney pathology. The estimated glomerular filtration rate (eGFR) decreased by an average of 29.3% to approximately 66.5 (±13.5) mL/min/1.73 m2 after one year, with no further decline in the subsequent years. uDKK3 levels increased in line with eGFR loss after Nx, followed by a decrease as the eGFR partially recovered within the following year. However, uDKK3 did not correlate with the eGFR at the single time points in living donors. In KTx recipients, the uDKK3/creatinine ratio was significantly elevated with a median of 1550 pg/mg compared to healthy individuals or donors after Nx. The mean eGFR in the recipient group was 35.5 mL/min/1.73 m2. The uDKK3/creatinine ratio was statistically associated with the eGFR at biopsy but was not independently associated with the eGFR one year after biopsy or allograft loss. In conclusion, uDKK3 correlates with recent and future kidney function and kidney allograft survival in the renal transplant cohort. Nevertheless, our findings indicate that the uDKK3/creatinine ratio has no prognostic influence on future renal outcome in living donors and kidney recipients beyond the eGFR, independent of the presence of acute renal graft pathology, as correlations are GFR-dependent.


Assuntos
Biomarcadores , Taxa de Filtração Glomerular , Transplante de Rim , Doadores Vivos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Adaptadoras de Transdução de Sinal , Biomarcadores/urina , Peptídeos e Proteínas de Sinalização Intercelular/urina , Rim/patologia , Rim/fisiopatologia , Transplante de Rim/efeitos adversos , Estudos Prospectivos , Insuficiência Renal Crônica/urina , Insuficiência Renal Crônica/patologia , Insuficiência Renal Crônica/etiologia , Fatores de Risco , Transplantados
3.
J Magn Reson Imaging ; 58(6): 1954-1963, 2023 12.
Artigo em Inglês | MEDLINE | ID: mdl-37026419

RESUMO

BACKGROUND: Preventing sepsis-associated acute kidney injury (S-AKI) can be challenging because it develops rapidly and is often asymptomatic. Probability assessment of disease progression for therapeutic follow-up and outcome are important to intervene and prevent further damage. PURPOSE: To establish a noninvasive multiparametric MRI (mpMRI) tool, including T1 , T2 , and perfusion mapping, for probability assessment of the outcome of S-AKI. STUDY TYPE: Preclinical randomized prospective study. ANIMAL MODEL: One hundred and forty adult female SD rats (65 control and 75 sepsis). FIELD STRENGTH/SEQUENCE: 9.4T; T1 and perfusion map (FAIR-EPI) and T2 map (multiecho RARE). ASSESSMENT: Experiment 1: To identify renal injury in relation to sepsis severity, serum creatinine levels were determined (31 control and 35 sepsis). Experiment 2: Animals underwent mpMRI (T1 , T2 , perfusion) 18 hours postsepsis. A subgroup of animals was immediately sacrificed for histology examination (nine control and seven sepsis). Result of mpMRI in follow-up subgroup (25 control and 33 sepsis) was used to predict survival outcomes at 96 hours. STATISTICAL TESTS: Mann-Whitney U test, Spearman/Pearson correlation (r), P < 0.05 was considered statistically significant. RESULTS: Severely ill septic animals exhibited significantly increased serum creatinine levels compared to controls (70 ± 30 vs. 34 ± 9 µmol/L, P < 0.0001). Cortical perfusion (480 ± 80 vs. 330 ± 140 mL/100 g tissue/min, P < 0.005), and cortical and medullary T2 relaxation time constants were significantly reduced compared to controls (41 ± 4 vs. 37 ± 5 msec in cortex, P < 0.05, 52 ± 7 vs. 45 ± 6 msec in medulla, P < 0.05). The combination of cortical T2 relaxation time constants and perfusion results at 18 hours could predict survival outcomes at 96 hours with high sensitivity (80%) and specificity (73%) (area under curve of ROC = 0.8, Jmax = 0.52). DATA CONCLUSION: This preclinical study suggests combined T2 relaxation time and perfusion mapping as first line diagnostic tool for treatment planning. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 2.


Assuntos
Injúria Renal Aguda , Sepse , Feminino , Ratos , Animais , Estudos Prospectivos , Creatinina , Ratos Sprague-Dawley , Injúria Renal Aguda/diagnóstico por imagem , Injúria Renal Aguda/patologia , Imageamento por Ressonância Magnética , Perfusão , Sepse/complicações , Sepse/diagnóstico por imagem
5.
Transpl Int ; 36: 10955, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36846605

RESUMO

Pre-clinical studies are an obligatory tool to develop and translate novel therapeutic strategies into clinical practice. Acute and chronic rejection mediated by the recipient's immune system remains an important limiting factor for the (long-term) survival of vascularized composite allografts (VCA). Furthermore, high intensity immunosuppressive (IS) protocols are needed to mitigate the immediate and long-term effects of rejection. These IS regiments can have significant side-effects such as predisposing transplant recipients to infections, organ dysfunction and malignancies. To overcome these problems, tolerance induction has been proposed as one strategy to reduce the intensity of IS protocols and to thereby mitigate long-term effects of allograft rejection. In this review article, we provide an overview about animal models and strategies that have been used to induce tolerance. The induction of donor-specific tolerance was achieved in preclinical animal models and clinical translation may help improve short and long-term outcomes in VCAs in the future.


Assuntos
Aloenxertos Compostos , Alotransplante de Tecidos Compostos Vascularizados , Animais , Rejeição de Enxerto , Alotransplante de Tecidos Compostos Vascularizados/métodos , Tolerância Imunológica , Transplante Homólogo , Imunossupressores/uso terapêutico
6.
Transpl Int ; 36: 11953, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38156296

RESUMO

Donor proteinuria (DP) is a common but rarely evaluated aspect of today's kidney transplant allocation process. While proteinuria after kidney transplantation is a risk factor for impaired graft function and survival, the long-term effects of DP in kidney transplantation have not yet been evaluated. Therefore, this study aims to investigate the impact of DP on the long-term outcome after kidney transplantation. A total of 587 patients were found to be eligible and were stratified into two groups: (1) those receiving a graft from a donor without proteinuria (DP-) and (2) those receiving a graft from a donor with proteinuria (DP+). At 36 months, there was no difference in the primary composite endpoint including graft loss and patient survival (log-rank test, p = 0.377). However, the analysis of DP+ subgroups showed a significant decrease in overall patient survival in the group with high DP (p = 0.017). DP did not adversely affect patient or graft survival over 36 months. Nevertheless, this work revealed a trend towards decreased overall survival of patients with severe proteinuria in the subgroup analysis. Therefore, the underlying results suggest caution in allocating kidneys from donors with high levels of proteinuria.


Assuntos
Transplante de Rim , Humanos , Transplante de Rim/métodos , Estudos Retrospectivos , Fatores Etários , Rim , Doadores de Tecidos , Proteinúria , Sobrevivência de Enxerto , Aloenxertos
7.
Am J Transplant ; 22(11): 2548-2559, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-35801504

RESUMO

Ischemia-reperfusion injury is a major cause of acute kidney injury. Many cytokines are involved in the pathogenesis of renal ischemia-reperfusion injury. IL24 is a member of the IL10 family and has gained importance because of its apoptosis-inducing effects in tumor disease besides its immunoregulative function. Littles is known about the role of IL24 in kidney disease. Using a mouse model, we found that IL24 is upregulated in the kidney after renal ischemia-reperfusion injury and that tubular epithelial cells and infiltrating inflammatory cells are the source of IL24. Mice lacking IL24 are protected from renal injury and inflammation. Cell culture studies showed that IL24 induces apoptosis in renal tubular epithelial cells, which is accompanied by an increased endoplasmatic reticulum stress response. Moreover, IL24 induces robust expression of endogenous IL24 in tubular cells, fostering ER-stress and apoptosis. In kidney transplant recipients with delayed graft function and patients at high risk to develop acute kidney injury after cardiac surgery IL24 is upregulated in the kidney and serum. Taken together, IL24 can serve as a biomarker, plays an important mechanistic role involving both extracellular and intracellular targets, and is a promising therapeutic target in patients at risk of or with ischemia-induced acute kidney injury.


Assuntos
Injúria Renal Aguda , Traumatismo por Reperfusão , Animais , Camundongos , Camundongos Endogâmicos C57BL , Injúria Renal Aguda/etiologia , Traumatismo por Reperfusão/metabolismo , Rim/patologia , Apoptose , Interleucinas/metabolismo , Células Epiteliais/metabolismo
8.
J Nucl Cardiol ; 29(6): 2988-2999, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-34750727

RESUMO

BACKGROUND: We aimed to compare the prognostic value of myocardial perfusion scintigraphy (MPS) and dobutamine stress echocardiography (DSE) in patients with end-stage renal disease (ESRD) without known coronary artery disease. METHODS: Two-hundred twenty-nine ESRD patients who applied for kidney transplantation at our centre were prospectively evaluated by MPS and DSE. The primary endpoint was a composite of myocardial infarction (MI) or all-cause mortality. The secondary endpoint included MI or coronary revascularization (CR) not triggered by MPS or DSE at baseline. RESULTS: MPS detected reversible ischemia in 31 patients (13.5%) and fixed perfusion defects in 13 (5.7%) patients. DSE discovered stress-induced wall motion abnormalities (WMAs) in 28 (12.2%) and at rest in 18 (7.9%) patients. MPS and DSE results agreed in 85.6% regarding reversible defects (κ = 0.358; P < .001) and in 90.8% regarding fixed defects (κ = 0.275; P < .001). Coronary angiography detected relevant stenosis > 50% in only 15 of 38 patients (39.5%) with pathological findings in MPS and/or DSE. At a median follow-up of 8 years and 10 months, the primary endpoint occurred in 70 patients (30.6%) and the secondary endpoint in 24 patients (10.5%). The adjusted Cox hazard ratios (HRs) for the primary endpoint were 1.77 (95% CI 1.02-3.08; P = .043) for perfusion defects in MPS and 1.36 (95% CI 0.78-2.37; P = ns) for WMA in DSE. The secondary endpoint was significantly correlated with the findings of both modalities, MPS (HR 3.21; 95% CI 1.35-7.61; P = .008) and DSE (HR 2.67; 95% CI 1.15-6.20; P = .022). CONCLUSION: Perfusion defects in MPS are a stronger determinant of all-cause mortality, MI and the need for future CR compared with WMAs in DSE. Given the complementary functional information provided by MPS vs DSE, results are sometimes contradictory, which may indicate differences in the underlying pathophysiology.


Assuntos
Falência Renal Crônica , Infarto do Miocárdio , Humanos , Ecocardiografia sob Estresse , Dobutamina , Prognóstico , Tomografia Computadorizada por Raios X , Infarto do Miocárdio/complicações , Perfusão , Falência Renal Crônica/diagnóstico por imagem , Falência Renal Crônica/complicações , Imagem de Perfusão
9.
J Am Soc Nephrol ; 32(8): 1933-1945, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34078665

RESUMO

BACKGROUND: In transplant medicine, clinical decision making largely relies on histology of biopsy specimens. However, histology suffers from low specificity, sensitivity, and reproducibility, leading to suboptimal stratification of patients. We developed a histology-independent immune framework of kidney graft homeostasis and rejection. METHODS: We applied tailored RNA deconvolution for leukocyte enumeration and coregulated gene network analysis to published bulk human kidney transplant RNA transcriptomes as input for unsupervised, high-dimensional phenotype clustering. We used framework-based graft survival analysis to identify a biomarker that was subsequently characterized in independent transplant biopsy specimens. RESULTS: We found seven immune phenotypes that confirm known rejection types and uncovered novel signatures. The molecular phenotypes allow for improved graft survival analysis compared with histology, and identify a high-risk group in nonrejecting transplants. Two fibrosis-related phenotypes with distinct immune features emerged with reduced graft survival. We identified lysyl oxidase-like 2 (LOXL2)-expressing peritubular CD68+ macrophages as a framework-derived biomarker of impaired allograft function. These cells precede graft fibrosis, as demonstrated in longitudinal biopsy specimens, and may be clinically useful as a biomarker for early fibrogenesis. CONCLUSIONS: This study provides a comprehensive, data-driven atlas of human kidney transplant phenotypes and demonstrates its utility to identify novel clinical biomarkers.


Assuntos
Rejeição de Enxerto/imunologia , Transplante de Rim , Rim/patologia , Rim/fisiopatologia , Fenótipo , Transcriptoma , Aloenxertos/patologia , Aloenxertos/fisiopatologia , Aminoácido Oxirredutases/metabolismo , Big Data , Biomarcadores , Biópsia , Tomada de Decisão Clínica , Bases de Dados Genéticas , Fibrose , Perfilação da Expressão Gênica , Sobrevivência de Enxerto , Humanos , Contagem de Leucócitos , Leucócitos , Macrófagos/metabolismo , RNA/análise , Máquina de Vetores de Suporte
10.
Int J Mol Sci ; 23(16)2022 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-36012395

RESUMO

Post-transplant diabetes mellitus (PTDM) after kidney transplantation induced by tacrolimus is an important issue. Fast tacrolimus metabolism, which can be estimated by concentration-to-dose (C/D) ratio, is associated with increased nephrotoxicity and unfavorable outcomes after kidney transplantation. Herein, we elucidate whether fast tacrolimus metabolism also increases the risk for PTDM. Data from 596 non-diabetic patients treated with tacrolimus-based immunosuppression at the time of kidney transplantation between 2007 and 2015 were retrospectively analyzed. The median follow-up time after kidney transplantation was 4.7 years (IQR 4.2 years). Our analysis was complemented by experimental modeling of fast and slow tacrolimus metabolism kinetics in cultured insulin-producing pancreatic cells (INS-1 cells). During the follow-up period, 117 (19.6%) patients developed PTDM. Of all patients, 210 (35.2%) were classified as fast metabolizers (C/D ratio < 1.05 ng/mL × 1/mg). Fast tacrolimus metabolizers did not have a higher incidence of PTDM than slow tacrolimus metabolizers (p = 0.496). Consistent with this, insulin secretion and the viability of tacrolimus-treated INS-1 cells exposed to 12 h of tacrolimus concentrations analogous to the serum profiles of fast or slow tacrolimus metabolizers or to continuous exposure did not differ (p = 0.286). In conclusion, fast tacrolimus metabolism is not associated with increased incidence of PTDM after kidney transplantation, either in vitro or in vivo. A short period of incubation of INS-1 cells with tacrolimus using different concentration profiles led to comparable effects on cell viability and insulin secretion in vitro. Consistent with this, in our patient, collective fast Tac metabolizers did not show a higher PTDM incidence compared to slow metabolizers.


Assuntos
Diabetes Mellitus , Transplante de Rim , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/efeitos adversos , Complicações Pós-Operatórias/tratamento farmacológico , Estudos Retrospectivos , Fatores de Risco , Tacrolimo/uso terapêutico
11.
J Nucl Cardiol ; 28(6): 2660-2670, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-32140994

RESUMO

BACKGROUND: Imaging-based measures of atherosclerosis such as coronary artery calcium score (CACS) and coronary flow reserve (CFR) as well as carotid atherosclerotic plaque burden (cPB) are predictors of cardiovascular events in the general population. The objective of this study was to correlate CACS, cPB, myocardial blood flow (MBF), and CFR in patients with end-stage renal disease (ESRD). METHODS AND RESULTS: 39 patients (mean age 53 ± 12 years) with ESRD prior to kidney transplantation were enrolled. MBF and CFR were quantified at baseline and under hyperemia by 13N-NH3-PET/CT. CACS was calculated from low-dose CT scans acquired for PET attenuation correction. cPB was assessed by 3D ultrasound. Uni- and multivariate regression analyses between these and clinical parameters were performed. Median follow-up time for clinical events was 4.4 years. Kaplan-Meier survival estimates with log-rank test were performed with regards to cardiovascular (CV) events and death of any cause. CACS and cPB were associated in ESRD patients (r = 0.48; p ≤ 0.01). While cPB correlated with age (r = 0.43; p < 0.01), CACS did not. MBFstress was negatively associated with age (r = 0.44; p < 0.01) and time on dialysis (r = 0.42; p < 0.01). There were negative correlations between MBFstress and CACS (r = - 0.62; p < 0.001) and between MBFstress and cPB (r = - 0.43; p < 0.01). Age and CACS were the strongest predictors for MBFstress. CFR was impaired (< 2.0) in eight patients who also presented with higher cPB and higher CACS compared to those with a CFR > 2.0 (p = 0.06 and p = 0.4). In contrast to MBFstress, there was neither a significant correlation between CFR and CACS (r = - 0.2; p = 0.91) nor between CFR and cPB (r = - 0.1; p = 0.55). CV event-free survival was associated with reduced CFR and MBFstress (p = 0.001 and p < 0.001) but not with cPB or CACS. CONCLUSIONS: CACS, cPB, and MBFstress are associated in patients with ESRD. Atherosclerosis is earlier detected by MBFstress than by CFR. CV event-free survival is associated with impaired CFR and MBFstress.


Assuntos
Cálcio/análise , Doenças das Artérias Carótidas/diagnóstico por imagem , Circulação Coronária , Vasos Coronários/química , Vasos Coronários/diagnóstico por imagem , Imageamento Tridimensional , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ultrassonografia de Intervenção , Adulto , Idoso , Doenças das Artérias Carótidas/complicações , Feminino , Humanos , Falência Renal Crônica/complicações , Falência Renal Crônica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/complicações , Estudos Prospectivos
12.
Kidney Blood Press Res ; 45(4): 576-588, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32575106

RESUMO

BACKGROUND/AIMS: Pulse wave analysis (PWA) and pulse wave velocity (PWV) provide information about arterial stiffness and elasticity, which is mainly used for cardiovascular risk stratification. In the presented prospective observational pilot study, we examined the hypothesis that radiocephalic fistula (RCF)-related changes of haemodynamics and blood vessel morphology including high as well as low flow can be seen in specific changes of pulse wave (PW) morphology. METHODS: Fifty-six patients with RCF underwent local ambilateral peripheral PWA and PWV measurement with the SphygmoCor® device. Given that the output parameters of the SphygmoCor® are not relevant for the study objectives, we defined new suitable parameters for PWA in direct proximity to fistulas and established an appropriate analysing algorithm. Duplex sonography served as reference method. RESULTS: Marked changes of peripheral PW morphology when considering interarm differences of slope and areas between the fistula and non-fistula arms were observed in the Arteria radialis, A. brachialis and arterialized Vena cephalica. The sum of the slope differences was found to correlate with an increased flow, while in patients with fistula failure no changes in PW morphology were seen. Moreover, PWV was significantly reduced in the fistula arm. CONCLUSION: Beside duplex sonography, ambilateral peripheral PWA and PWV measurements are potential new clinical applications to characterize and monitor RCF function, especially in terms of high and low flow.


Assuntos
Fístula Vascular/diagnóstico , Rigidez Vascular , Adulto , Idoso , Velocidade do Fluxo Sanguíneo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Estudos Prospectivos , Análise de Onda de Pulso , Fístula Vascular/fisiopatologia
13.
Unfallchirurg ; 123(3): 216-224, 2020 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-31428806

RESUMO

BACKGROUND: Needlestick injuries (NSI) are potentially infectious injuries from sharp or pointed medical instruments and through contact with blood on mucous membranes or nonintact skin. Although the European Union (EU) Council directive 2010/32/EU on the prevention of NSI was implemented in EU countries in 2013, information on the effectiveness of the measures is limited. OBJECTIVE: The aim of this study was to evaluate the effectiveness of a safety concept according to the EU Council Directive 2010/32/EU on prevention of NSI. MATERIAL AND METHODS: In 2016 the NSI safety concept at a large regional hospital was improved according to 2010/32/EU, specifically by an update of blood screening profiles and standard operating procedures (SOP), better dissemination of information to employees and complete conversion to safety cannulas and scalpels. The medical records of all NSIs from 2015-2017 were retrospectively anonymized and evaluated and a cost analysis was performed. RESULTS: The number of NSIs in 2017 was significantly reduced by 48.4% as compared to 2016 and NSIs with scalpels were completely prevented. The proportion of employees with NSIs who were adequately immunized against hepatitis B was significantly increased to 84.1% in 2017. Furthermore, identification of the index patient was significantly increased to 82.5% in 2017. The cost of avoiding NSIs increased by a total of 24.1% in 2017 as compared to 2015 before introduction of the safety concept. CONCLUSION: Implementation of the EU Council directive 2010/32/EU, resulted in an almost 50% reduction in NSIs over 1 year, including the complete prevention of NSIs due to scalpels. In addition, the anamnestic presence of immunization against hepatitis B and index patient identification were significantly increased.


Assuntos
Ferimentos Penetrantes Produzidos por Agulha , União Europeia , Hospitais , Humanos , Ferimentos Penetrantes Produzidos por Agulha/prevenção & controle , Estudos Retrospectivos , Segurança
14.
Kidney Int ; 95(5): 1091-1102, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30824181

RESUMO

Renal ischemia reperfusion injury (IRI) adversely affects clinical outcomes following kidney transplantation. Understanding the cellular mechanisms and the changes in gene/protein expression following IRI may help to improve these outcomes. Serum soluble fms-like tyrosine kinase 1 (sFlt-1), a circulating antiangiogenic protein, is increased in the first week following kidney transplantation. We evaluated the casual relationship of elevated sFlt-1 levels with renal microvascular dysfunction following IRI in a longitudinal study of 93 kidney transplant recipients and in several animal models. Transplant recipients with higher sFlt-1 levels had higher odds of delayed graft function, graft rejection, impaired graft function, and death. In a subgroup of 25 participants who underwent kidney biopsy within 4 months of kidney transplantation, peritubular capillary area was lower in those with elevated serum sFtl-1 levels. The administration of recombinant sFlt-1 into rodents resulted in significant structural and functional changes of the renal microvasculature, including reduced peritubular capillary density and intracapillary blood volume, and lead to increased expression of inflammatory genes and increased fibrosis. In a murine model of IRI, the kidney was a site of sFlt-1 production, and systemic neutralization of sFlt-1 preserved peritubular capillary density and alleviated renal fibrosis. Our data indicate that high sFlt-1 levels after IRI play an important role in the pathogenesis of microvascular dysfunction, thereby contributing to adverse clinical outcomes following kidney transplantation.


Assuntos
Falência Renal Crônica/cirurgia , Transplante de Rim/efeitos adversos , Traumatismo por Reperfusão/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Adulto , Idoso , Aloenxertos/irrigação sanguínea , Aloenxertos/patologia , Animais , Biópsia , Capilares/patologia , Linhagem Celular , Estudos de Coortes , Função Retardada do Enxerto/sangue , Função Retardada do Enxerto/etiologia , Função Retardada do Enxerto/mortalidade , Modelos Animais de Doenças , Feminino , Fibrose , Rejeição de Enxerto/sangue , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/mortalidade , Humanos , Rim/irrigação sanguínea , Rim/patologia , Falência Renal Crônica/mortalidade , Estudos Longitudinais , Masculino , Camundongos , Pessoa de Meia-Idade , Proteínas Recombinantes/administração & dosagem , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/mortalidade , Resultado do Tratamento , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/administração & dosagem
15.
Mycoses ; 62(11): 1035-1042, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31402465

RESUMO

Invasive aspergillosis (IA) is a severe complication in immunocompromised patients. Early diagnosis is crucial to decrease its high mortality, yet the diagnostic gold standard (histopathology and culture) is time-consuming and cannot offer early confirmation of IA. Detection of IA by polymerase chain reaction (PCR) shows promising potential. Various studies have analysed its diagnostic performance in different clinical settings, especially addressing optimal specimen selection. However, direct comparison of different types of specimens in individual patients though essential, is rarely reported. We systematically assessed the diagnostic performance of an Aspergillus-specific nested PCR by investigating specimens from the site of infection and comparing it with concurrent blood samples in individual patients (pts) with IA. In a retrospective multicenter analysis PCR was performed on clinical specimens (n = 138) of immunocompromised high-risk pts (n = 133) from the site of infection together with concurrent blood samples. 38 pts were classified as proven/probable, 67 as possible and 28 as no IA according to 2008 European Organization for Research and Treatment of Cancer/Mycoses Study Group consensus definitions. A considerably superior performance of PCR from the site of infection was observed particularly in pts during antifungal prophylaxis (AFP)/antifungal therapy (AFT). Besides a specificity of 85%, sensitivity varied markedly in BAL (64%), CSF (100%), tissue samples (67%) as opposed to concurrent blood samples (8%). Our results further emphasise the need for investigating clinical samples from the site of infection in case of suspected IA to further establish or rule out the diagnosis.


Assuntos
Aspergilose/diagnóstico , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/diagnóstico , Técnicas de Diagnóstico Molecular/normas , Reação em Cadeia da Polimerase/normas , Adolescente , Adulto , Idoso , Aspergilose/sangue , Aspergilose/microbiologia , Aspergillus/isolamento & purificação , Criança , Pré-Escolar , Feminino , Humanos , Infecções Fúngicas Invasivas/sangue , Infecções Fúngicas Invasivas/microbiologia , Masculino , Pessoa de Meia-Idade , Técnicas de Diagnóstico Molecular/métodos , Estudos Retrospectivos , Sensibilidade e Especificidade , Adulto Jovem
18.
Kidney Int ; 92(3): 757-764, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28709641

RESUMO

Acute cellular renal allograft rejection (AR) frequently occurs after kidney transplantations. It is a sterile T-cell mediated inflammation leading to increased local glucose metabolism. Here we demonstrate in an allogeneic model of Brown Norway rat kidneys transplanted into uninephrectomized Lewis rats the successful implementation of the recently developed glucose chemical exchange saturation transfer (glucoCEST) magnetic resonance imaging. This technique is a novel method to assess and differentiate AR. Renal allografts undergoing AR showed significantly increased glucoCEST contrast ratios of cortex to medulla of 1.61 compared to healthy controls (1.02), syngeneic Lewis kidney to Lewis rat transplants without rejection (0.92), kidneys with ischemia reperfusion injury (0.99) and kidneys affected by cyclosporine A toxicity (1.10). Receiver operating characteristic curve analysis showed an area under the curve value of 0.92, and the glucoCEST contrast ratio predicted AR with a sensitivity of 100% and a specificity of 69% at a threshold level over 1.08. In defined animal models of kidney injuries, the glucoCEST contrast ratios of cortex to medulla correlated positively with mRNA expression levels of T-cell markers (CD3, CD4, CD8a/b), but did not correlate to impaired renal perfusion. Thus, the glucoCEST parameter may be valuable for the assessment and follow up treatment of AR.


Assuntos
Aloenxertos/diagnóstico por imagem , Rejeição de Enxerto/diagnóstico por imagem , Transplante de Rim/efeitos adversos , Rim/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Traumatismo por Reperfusão/diagnóstico por imagem , Aloenxertos/imunologia , Aloenxertos/patologia , Animais , Complexo CD3/metabolismo , Antígenos CD4/metabolismo , Antígenos CD8 , Meios de Contraste , Ciclosporina/toxicidade , Modelos Animais de Doenças , Glucose/administração & dosagem , Glucose/metabolismo , Rejeição de Enxerto/induzido quimicamente , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Rim/imunologia , Rim/patologia , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos Lew , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Transplante Homólogo/efeitos adversos
20.
Transpl Int ; 30(12): 1226-1233, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28574620

RESUMO

Nonaccepted kidneys grafts enter the rescue allocation (RA) process to avoid discards. In December 2013, recipient oriented extended allocation (REAL) was introduced to improve transparency. The aim of this study was to evaluate the influence of REAL on recipients' selection and graft function compared to the formerly existing RA as well as to identify factors that influence graft outcome. Therefore, a multicenter study of 10 transplant centers in the same region in Germany was performed. All transplantations after RA or REAL from December 1, 2012, until December 31, 2014, with a follow-up time until December 31, 2015 were analyzed. 113 of 941 kidney transplantations were performed after RA or REAL (12%). With REAL, the number of refusals before transplantation had increased (12 ± 7.1 vs. 8.6 ± 8.6, P = 0.036), and cold ischemia time has decreased (13.6 ± 3.6 vs. 17.2 ± 4.8 h, P = 0.019). Recipients after REAL needed significantly more allocation points compared to RA to receive a kidney. One-year graft survival was comparable. If kidneys from the same donor were transplanted to two recipients at one center, the greater the difference in recipient age, the greater the difference in serum creatinine after 12 months (-0.019 mg/dl per year, P = 0.011) was, that is older recipients showed lower creatinine. REAL influences selection of the recipients compared to the former RA era for successful organ receipt. Graft function is comparable and seems to be influenced by recipient age.


Assuntos
Seleção do Doador/métodos , Transplante de Rim/métodos , Obtenção de Tecidos e Órgãos/métodos , Transplantados , Adulto , Fatores Etários , Idoso , Estudos de Coortes , Feminino , Alemanha , Rejeição de Enxerto , Sobrevivência de Enxerto , Humanos , Estimativa de Kaplan-Meier , Transplante de Rim/efeitos adversos , Transplante de Rim/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Medição de Risco , Estatísticas não Paramétricas , Análise de Sobrevida , Fatores de Tempo , Resultado do Tratamento
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