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Systemic COVID-19 disease is associated with a variety of organ involvement in infected patients. A rarely reported complication is the induction of complement-mediated thrombotic microangiopathy (TMA). TMA is an extremely rare pathological condition that results in thrombosis in capillaries and small arterioles, due to an endothelial injury. It is often combined with thrombocytopenia, Coombs-negative hemolytic anemia, and end-organ damage. This case involves a patient who was admitted to our hospital for the purpose of diagnosis and treatment of acute kidney injury (AKIN 3) with severe proteinuria after a preceding SARS-CoV-2 infection. A 77-year-old male patient had COVID-19 pneumonia in January 2021 with the need of high-flow oxygen therapy in the intensive care unit. In March 2021, he was hospitalized again due to elevated serum creatinine levels and proteinuria. The patient exhibited normal vital parameters. A renal biopsy showed severe TMA. A diagnosis of COVID-19-associated TMA was made, and treatment with high-dose glucocorticoid therapy and plasma exchange was initiated. Additionally, therapy with eculizumab was established. Unfortunately, the kidney failure was initially progressive, so that hemodialysis (HD) was temporarily necessary. In May 2021, kidney function recovered to an estimated glomerular filtration rate of ~ 30 mL/min/1.73m2 corresponding to chronic kidney disease stage 3bA3 - 4A3. COVID-19-associated TMA is an extremely rare disease. TMA may be a possible long-term complication with the risk of end-stage renal disease if not properly diagnosed and treated.
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OBJECTIVE: This study was designed to demonstrate the predictive ability of quantitative indocyanine green (ICG) fluorescence angiography for the short-term postoperative outcome, the occurrence of delayed graft function (DGF), and long-term graft survival. SUMMARY BACKGROUND DATA: DGF is a relevant problem after kidney transplantation; sufficient microperfusion of the allograft is crucial for postoperative organ function. Fluorescence angiography with ICG can serve as an intraoperative quality control of microperfusion. METHODS: This prospective diagnostic study, conducted in 2 German transplantation centers from November 2015 to October 2018, included 128 consecutive kidney transplantations. Intraoperative assessment of the allograft microperfusion was performed by near-infrared fluorescence angiography with ICG; a software was used for quantitative analysis. The associations between perfusion parameters (eg, ICG Ingress) and donor, recipient, peri-procedural, and postoperative characteristics were evaluated. RESULTS: DGF occurred in 23 (24%) kidney recipients from deceased donors. ICG Ingress ( P = 0.0027), donor age ( P = 0.0452), recipient age ( P = 0.0139), and recipient body mass index ( P = 0.0017) were associated with DGF. ICG Ingress correlated significantly with recipient age (r = -0.27662, P = 0.0016), cold and warm ischemia time (r = -0.25204, P = 0.0082; r = -0.19778, P = 0.0283), operating time (r = -0.32208, P = 0.0002), eGFR on postoperative days 1 (r =+0.22674, P = 0.0104) and 7 (r = +0.33189, P = 0.0001). The cutoff value for ICG Ingress was 106.23 AU with sensitivity of 78.3% and specificity of 80.8% ( P < 0.0001) for the prediction of DGF. CONCLUSION: Fluorescence angiography with ICG allows intraoperative quantitative assessment of microperfusion during kidney transplantation. The parameter ICG Ingress reflects recipient and procedure characteristics and is able to predict the incidence of DGF. TRIAL REGISTRATION: Clinicaltrials.gov: NCT-02775838.
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Trasplante de Riñón , Funcionamiento Retardado del Injerto , Angiografía con Fluoresceína , Supervivencia de Injerto , Humanos , Verde de Indocianina , Trasplante de Riñón/métodos , Rayos Láser , Estudios Prospectivos , Factores de Riesgo , Donantes de TejidosRESUMEN
Background: Peripheral arterial disease (PAD), coronary artery disease (CAD) and carotid stenosis (CS) are robust predictors of mortality. The value of individual vascular beds in polyvascular disease (PVD) to predict mortality in patients with atherosclerotic burden is not clear. Therefore, we have examined the predictive value of PAD, CAD and CS in patients at intermediate to high risk of cardiovascular (CV) disease. Patients and methods: In our retrospective observational study we analyzed baseline data from the Ludwigshafen Risk and Cardiovascular Health (LURIC) study, a monocentric cohort study of 3316 patients referred to coronary angiography. Results: As the number of atherosclerotic vascular beds increased, the hazard ratios (HRs) for both all-cause mortality and CV mortality significantly increased in a multivariate analysis after adjusting for age, sex, body mass index, diabetes mellitus and estimated glomerular filtration rate, with HRs of 1.36 (95%CI: 1.11-1.68), 2.56 (95%CI: 2.01-3.26), 2.84 (95%CI: 1.93-4.17) and 1.56 (95%CI: 1.19-2.06), 2.70 (95%CI: 1.97-3.72), 3.50 (95%CI: 2.19-5.62), respectively. The combination of PAD with either CAD or CS was associated with higher HRs for all-cause (HR 2.81 and 7.53, respectively) and CV (HRs 2.80 and 6.03, respectively) mortality compared with the combination of CAD and CS (HRs 1.94 and 2.43, respectively). The presence of PVD was associated with higher age, systolic blood pressure, pulse pressure (PP; a marker of vascular stiffness), former smoking and inversely with lower eGFR. Conclusions: We show that as the number of atherosclerotic vascular beds increases, all-cause and CV mortality rates increase in parallel. Simultaneous prevalence of PAD is associated with significantly higher all-cause and CV mortality rates compared with CS coexistence. Furthermore, increasing atherosclerotic load may contribute to vascular stiffness and impaired renal function.
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Estenosis Carotídea , Enfermedad de la Arteria Coronaria , Enfermedad Arterial Periférica , Presión Sanguínea , Estenosis Carotídea/complicaciones , Estudios de Cohortes , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/epidemiología , Humanos , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/diagnóstico por imagen , Factores de RiesgoRESUMEN
Treatment of donation after brain death (DBD) donors with low-dose dopamine improves the outcomes after kidney and heart transplantation. This study investigates the course of liver allografts from multiorgan donors enrolled in the randomized dopamine trial between 2004 and 2007 (clinicaltrials.gov identifier: NCT00115115). There were 264 hemodynamically stable DBDs who were randomly assigned to receive low-dose dopamine. Dopamine was infused at 4 µg/kg/minute for a median duration of 6.0 hours (interquartile range, 4.4-7.5 hours). We assessed the outcomes of 212 liver transplantations (LTs) performed at 32 European centers. Donors and recipients of both groups were very similar in baseline characteristics. Pretransplant laboratory Model for End-Stage Liver Disease score was not different in recipients of a dopamine-treated versus untreated graft (18 ± 8 versus 20 ± 8; P = 0.12). Mean cold ischemia time was 10.6 ± 2.9 versus 10.1 ± 2.8 hours (P = 0.24). No differences occurred in biopsy-proven rejection episodes (14.4% versus 15.7%; P = 0.85), requirement of hemofiltration (27.9% versus 31.5%; P = 0.65), the need for early retransplantation (5.8% versus 6.5%; P > 0.99), the incidence of primary nonfunction (7.7% versus 8.3%; P > 0.99), and in-hospital mortality (15.4% versus 14.8%; P > 0.99). Graft survival was 71.2% versus 73.2% and 59.6% versus 62.0% at 2 and 3 years (log-rank P = 0.71). Patient survival was 76.0% versus 78.7% and 65.4% versus 69.4% at 1 and 3 years (log-rank P = 0.50). In conclusion, donor pretreatment with dopamine has no short-term or longterm effects on outcome after LT. Therefore, low-dose dopamine pretreatment can safely be implemented as the standard of care in hemodynamically stable DBDs.
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Dopamina/administración & dosificación , Enfermedad Hepática en Estado Terminal/cirugía , Supervivencia de Injerto/efectos de los fármacos , Trasplante de Hígado/efectos adversos , Recolección de Tejidos y Órganos/métodos , Adulto , Isquemia Fría/efectos adversos , Enfermedad Hepática en Estado Terminal/diagnóstico , Femenino , Rechazo de Injerto/prevención & control , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Índice de Severidad de la Enfermedad , Donantes de Tejidos , Resultado del TratamientoRESUMEN
Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track® CMV, a novel IFN-γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88-92% ELISpot assays were positive pre- and post-transplantation, respectively. CMV-specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track® CMV is a highly sensitive IFN-γ ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).
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Infecciones por Citomegalovirus/diagnóstico , Ensayo de Inmunoadsorción Enzimática/métodos , Inmunidad Celular , Fosfoproteínas/inmunología , Complicaciones Posoperatorias/diagnóstico , Proteínas de la Matriz Viral/inmunología , Adulto , Anciano , Citomegalovirus/inmunología , Infecciones por Citomegalovirus/inmunología , Femenino , Rechazo de Injerto/inmunología , Rechazo de Injerto/virología , Humanos , Inmunosupresores , Trasplante de Riñón , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Infecciones Oportunistas , Complicaciones Posoperatorias/inmunología , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Uncontrolled cytomegalovirus (CMV) replication in immunocompromised solid-organ transplant recipients is a clinically relevant issue and an indication of impaired CMV-specific cell-mediated immunity (CMI). Primary aim of this study was to assess the suitability of the immune monitoring tool T-Track® CMV to determine CMV-reactive CMI in a cohort of hemodialysis patients representative of patients eligible for renal transplantation. Positive and negative agreement of T-Track® CMV with CMV serology was examined in 124 hemodialysis patients, of whom 67 (54%) revealed a positive CMV serostatus. Secondary aim of the study was to evaluate T-Track® CMV performance against two unrelated CMV-specific CMI monitoring assays, QuantiFERON®-CMV and a cocktail of six class I iTAg™ MHC Tetramers. RESULTS: Positive T-Track® CMV results were obtained in 90% (60/67) of CMV-seropositive hemodialysis patients. In comparison, 73% (45/62) and 77% (40/52) positive agreement with CMV serology was achieved using QuantiFERON®-CMV and iTAg™ MHC Tetramer. Positive T-Track® CMV responses in CMV-seropositive patients were dominated by pp65-reactive cells (58/67 [87%]), while IE-1-responsive cells contributed to an improved (87% to 90%) positive agreement of T-Track® CMV with CMV serology. Interestingly, T-Track® CMV, QuantiFERON®-CMV and iTAg™ MHC Tetramers showed 79% (45/57), 87% (48/55) and 93% (42/45) negative agreement with serology, respectively, and a strong inter-assay variability. Notably, T-Track® CMV was able to detect IE-1-reactive cells in blood samples of patients with a negative CMV serology, suggesting either a previous exposure to CMV that yielded a cellular but no humoral immune response, or TCR cross-reactivity with foreign antigens, both suggesting a possible protective immunity against CMV in these patients. CONCLUSION: T-Track® CMV is a highly sensitive assay, enabling the functional assessment of CMV-responsive cells in hemodialysis patients prior to renal transplantation. T-Track® CMV thus represents a valuable immune monitoring tool to identify candidate transplant recipients potentially at increased risk for CMV-related clinical complications.
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Infecciones por Citomegalovirus/diagnóstico , Citomegalovirus/inmunología , Huésped Inmunocomprometido , Fallo Renal Crónico/diagnóstico , Diálisis Renal , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Antivirales/sangre , Células Cultivadas , Estudios de Cohortes , Infecciones por Citomegalovirus/inmunología , Femenino , Humanos , Proteínas Inmediatas-Precoces/inmunología , Inmunidad Celular , Inmunoensayo , Fallo Renal Crónico/inmunología , Fallo Renal Crónico/terapia , Trasplante de Riñón , Masculino , Persona de Mediana Edad , Monitorización Inmunológica/métodos , Variaciones Dependientes del Observador , Fosfoproteínas/inmunología , Sensibilidad y Especificidad , Proteínas de la Matriz Viral/inmunología , Listas de EsperaRESUMEN
BACKGROUND: In the Eurotransplant Kidney Allocation System (ETKAS), transplant candidates can be considered for high-urgency (HU) status in case of life-threatening inability to undergo renal replacement therapy. Data on the outcomes of HU transplantation are sparse and the benefit is controversial. METHODS: We systematically analysed data from 898 ET HU kidney transplant recipients from 61 transplant centres between 1996 and 2010 and investigated the 5-year patient and graft outcomes and differences between relevant subgroups. RESULTS: Kidney recipients with an HU status were younger (median 43 versus 55 years) and spent less time on the waiting list compared with non-HU recipients (34 versus 54 months). They received grafts with significantly more mismatches (mean 3.79 versus 2.42; P < 0.001) and the percentage of retransplantations was remarkably higher (37.5 versus 16.7%). Patient survival (P = 0.0053) and death with a functioning graft (DwFG; P < 0.0001) after HU transplantation were significantly worse than in non-HU recipients, whereas graft outcome was comparable (P = 0.094). Analysis according to the different HU indications revealed that recipients listed HU because of an imminent lack of access for dialysis had a significantly worse patient survival (P = 0.0053) and DwFG (P = 0.0462) compared with recipients with psychological problems and suicidality because of dialysis. In addition, retransplantation had a negative impact on patient and graft outcome. CONCLUSIONS: Facing organ shortages, increasing wait times and considerable mortality on dialysis, we question the current policy of HU allocation and propose more restrictive criteria with regard to individuals with vascular complications or repeated retransplantations in order to support patients on the non-HU waiting list with a much better long-term prognosis.
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Selección de Donante/normas , Rechazo de Injerto/epidemiología , Trasplante de Riñón/mortalidad , Asignación de Recursos/normas , Obtención de Tejidos y Órganos/normas , Adolescente , Adulto , Anciano , Niño , Preescolar , Europa (Continente)/epidemiología , Femenino , Rechazo de Injerto/mortalidad , Supervivencia de Injerto , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Pronóstico , Reoperación , Encuestas y Cuestionarios , Listas de Espera , Adulto JovenRESUMEN
The European Tacrolimus versus Ciclosporin-A Microemulsion (CsA-ME) Renal Transplantation Study demonstrated that tacrolimus decreased acute rejection rates at 6 months. Primary endpoints of this investigator-initiated, observational 7-year follow-up study were acute rejection rates, patient and graft survival rates, and a composite endpoint (BPAR, graft loss, and patient death). We analyzed data from the original intent-to-treat population (n = 557; 286 tacrolimus, 271 CsA-ME). A total of 237 tacrolimus and 208 CsA-ME patients provided data. At 7 years, Kaplan-Meier estimated rates of patients free from BPAR were 77.1% in the tacrolimus arm and 59.9% in the CsA-ME arm, graft survival rates amounted to 82.6% and 80.6%, and patient survival rates to 89.9% and 88.1%. Estimated combined endpoint-free survival rates were 60.2% in the tacrolimus arm and 47.0% in the CsA-ME arm (P = <0.0001). A higher number of patients from the CsA-ME arm crossed over to tacrolimus during 7 year follow-up: 19.7% vs. 7.9% (P = <0.002). More patients in the tacrolimus group stopped steroids and received immunosuppressive monotherapy. Significantly, more CsA-ME patients received lipid-lowering medication and experienced cosmetic and cardiovascular adverse events. Tacrolimus-treated renal transplant recipients had significantly higher combined endpoint-free survival rates mainly driven by lower acute rejection rates despite less immunosuppressive medication at 7 years.
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Ciclosporina/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón , Tacrolimus/uso terapéutico , Supervivencia de Injerto , Humanos , Terapia de InmunosupresiónRESUMEN
Single nucleotide polymorphisms (SNPs) have been associated with an increased incidence of invasive aspergillosis (IA) after allogeneic stem cell transplantation (allo-SCT). We analyzed 41 patients with proven/probable IA after allo-SCT for an association of SNPs, within the TLR2, TLR4, TLR5, TLR9, and NOD2/CARD15 genes, with susceptibility to IA. The control group consisted of 130 patients who had allo-SCT but did not develop IA. While no association was found for donor SNPs and the recipients' risk of IA, analysis of recipient SNPs showed a significant association between the presence of recipient TLR5-Stop SNP (1174C> T) and the incidence of IA (P = 0.004). Multivariate analysis demonstrated that the recipient TLR5-Stop SNP appeared as an independent risk factor for IA after allo-SCT. Our study suggests that TLR5 is involved in host defense against Aspergillus fumigatus, and that the recipient TLR5-Stop SNP represents a risk factor for the development of IA after allo-SCT.
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Aspergilosis/genética , Codón sin Sentido , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Trasplante de Células Madre/efectos adversos , Receptor Toll-Like 5/genética , Trasplante Homólogo/efectos adversos , Adolescente , Adulto , Anciano , Aspergilosis/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
We tested the hypothesis that increased urinary cytokine concentrations may indicate an acute kidney transplant rejection. Eight patients with an early rejection in their protocol biopsy about 14days after transplantation (group A), 9 patients with a biopsy proven rejection 2-3months after transplantation (group B) and 18 patients without acute rejection in their protocol biopsies both at 14days and 3months (group C, represents the control group) were chosen for this study. At the time of biopsy, the mean urinary concentration of interleukin 6 (IL6), soluble IL6 receptor (sIL6R), tumor necrosis factor receptor 1 (TNFR1), and soluble vascular cell adhesion molecule -1 (sVCAM-1) were significantly higher in patients with an early acute transplant rejection, i.e. in group A compared to patients in the control group (p<0.01). Additionally we found already 14days after transplantation significantly higher concentrations of urinary sIL6R and sVCAM-1 in group B patients who suffered of late acute rejection compared to patients with no acute rejection (group C, p<0.05). No significant correlation could be shown for interleukin 1 receptor antagonist (IL1ra), TNF, and TNFR2. In conclusion, elevated urinary concentrations of IL6, sIL6R, TNFR1 and sVCAM-1 clearly indicate an early acute transplant rejection. Especially sVCAM-1 may also serve as an early marker of an upcoming late rejection. However, further studies are warranted to verify the value of individual cytokine profiles to predict acute rejection episodes.
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Rechazo de Injerto/orina , Interleucina-6/orina , Trasplante de Riñón/efectos adversos , Receptores de Interleucina-6/metabolismo , Receptores Tipo I de Factores de Necrosis Tumoral/orina , Molécula 1 de Adhesión Celular Vascular/orina , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1/orina , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Receptores Tipo II del Factor de Necrosis Tumoral/orina , Solubilidad , Trasplante Homólogo , Factor de Necrosis Tumoral alfa/orinaRESUMEN
A 66-year-old female suffering from massive atherosclerosis with a long history of renal artery stenosis in the left solitary kidney was admitted to reevaluate an in-stent restenosis. Advanced peripheral arterial disease had formerly been treated by aortobifemoral bypass surgery and a highly eccentric infrarenal abdominal aortic stenosis of 70 - 80% had been treated by patch angioplasty. In this patient several percutaneous transluminal renal angioplasties after a former stent deployment had resulted in recurrent in-stent restenoses. The renal artery stenosis was reevaluated and a re-angioplasty attempt was unsuccessful due to technical failure. Blood pressure remained difficult to manage. Renal function decreased as a result of presumed acute renal failure. A further progression of the renal artery stenosis was found. Autotransplantation to the left iliac fossa was done, because aortorenal bypass was considered impossible. Renal function normalized and follow-up Doppler ultrasonography examinations revealed a newly developed ostial anastomotic stenosis of 60 - 70%. While medical therapy and percutaneous transluminal angioplasty with stent deployment are common treatment options, surgical interventions are reserved for cases of complex stenoses. Autotransplantation as a complex option in the treatment of renal artery stenosis seems to be an adequate alternative in patients with severe, generalized atherosclerosis after failure of interventional procedures and the impossibility of standard surgical techniques.
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Angioplastia , Obstrucción de la Arteria Renal/cirugía , Stents , Anciano , Femenino , Humanos , Trasplante AutólogoRESUMEN
While studies in animal models have linked Toll-like receptor (TLR) 4 signaling to kidney injury induced by ischemia and reperfusion, the relevance of TLR4 activation to allograft injury in human kidney transplants is unknown. Here we show that TLR4 is constitutively expressed within all donor kidneys but is significantly higher in deceased-, compared with living-donor organs. Tubules from deceased- but not living-donor kidneys also stained positively for high-mobility group box-1 (HMGB1), a known endogenous TLR4 ligand. In vitro stimulation of human tubular cells with HMGB1, in a TLR4-dependent system, confirmed that HMGB1 can stimulate proinflammatory responses through TLR4. To assess the functional significance of TLR4 in human kidney transplantation, we determined whether TLR4 mutations that confer diminished affinity for HMGB1 influence intragraft gene-expression profiles and immediate graft function. Compared with kidneys expressing WT alleles, kidneys with a TLR4 loss-of-function allele contained less TNFalpha, MCP-1, and more heme oxygenase 1 (HO-1), and exhibited a higher rate of immediate graft function. These results represent previously undetected evidence that donor TLR4 contributes to graft inflammation and sterile injury following cold preservation and transplantation in humans. Targeting TLR4 signaling may have value in preventing or treating postischemic acute kidney injury after transplantation.
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Trasplante de Riñón/métodos , Daño por Reperfusión/metabolismo , Donantes de Tejidos , Receptor Toll-Like 4/metabolismo , Biopsia , Regulación de la Expresión Génica , Supervivencia de Injerto , Proteína HMGB1/metabolismo , Humanos , Mutación/genética , Unión Proteica , Receptor Toll-Like 4/genética , Regulación hacia ArribaRESUMEN
BACKGROUND: At Eurotransplant (ET), kidneys are transferred to "rescue allocation" (RA), whenever the standard allocation (SA) algorithms Eurotransplant Kidney Allocation System (ETKAS) and Eurotransplant Senior Program (ESP) fail. We analyzed the outcome of RA. METHODS: Retrospective patient clinical and demographic characteristics association analyses were performed with graft outcomes for 2422 recipients of a deceased donor renal transplantation (DDRT) after RA versus 25 481 after SA from 71 centers across all ET countries from 2006 to 2018. RESULTS: Numbers of DDRTs after RA increased over the time, especially in Germany. RA played a minor role in ESP versus ETKAS (2.7% versus 10.4%). RA recipients and donors were older compared with SA recipients and donors, cold ischemia times were longer, waiting times were shorter, and the incidence of primary nonfunction was comparable. Among ETKAS recipients, HLA matching was more favorable in SA (mean 3.7 versus 2.5). In multivariate modeling, the incidence of graft loss in ETKAS recipients was reduced in RA compared with SA (subdistribution hazard ratio, 0.80; 95% confidence interval [0.70-0.91], P < 0.001), whereas other outcomes (mortality, death with functioning graft (DwFG)) were not significantly different. None of the 3 outcomes were significantly different when comparing RA with SA within the ESP program. CONCLUSIONS: Facing increased waiting times and mortality on dialysis due to donor shortage, this study reveals encouragingly positive DDRT outcomes following RA. This supports the extension of RA to more patients and as an alternative tool to enable transplantation in patients in countries with prohibitively long waiting times or at risk of deterioration.
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Trasplante de Riñón , Obtención de Tejidos y Órganos , Supervivencia de Injerto , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Donantes de Tejidos , Resultado del TratamientoAsunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Rechazo de Injerto/prevención & control , Inmunosupresores/uso terapéutico , Trasplante de Riñón/métodos , Proteínas Recombinantes de Fusión/uso terapéutico , Alemtuzumab , Basiliximab , Femenino , Humanos , MasculinoAsunto(s)
Antiinfecciosos Urinarios/administración & dosificación , Cefalosporinas/administración & dosificación , Infecciones por Bacterias Gramnegativas/tratamiento farmacológico , Infecciones por Bacterias Grampositivas/tratamiento farmacológico , Levofloxacino/administración & dosificación , Ácido Penicilánico/análogos & derivados , Infecciones Urinarias/tratamiento farmacológico , Femenino , Humanos , MasculinoRESUMEN
Although islet transplantation is an effective treatment for Type 1 diabetes, primary engraftment failure contributes to suboptimal outcomes. We tested the hypothesis that islet isolation and transplantation activate innate immunity through TLR expressed on islets. Murine islets constitutively express TLR2 and TLR4, and TLR activation with peptidoglycan or LPS upregulates islet production of cytokines and chemokines. Following transplantation into streptozotocin-induced diabetic, syngeneic mice, islets exposed to LPS or peptidoglycan had primary graft failure with intra- and peri-islet mononuclear cell inflammation. The use of knockout mice showed that recipient CD8(+) T cells caused engraftment failure and did so in the absence of islet-derived DC. To mimic physiological islet injury, islets were transplanted with exocrine debris. Transplantation of TLR2/4(-/-) islets reduced proinflammatory cytokine production and improved islet survival. Stressed islets released the alarmin high-mobility group box protein 1 (HMGB1) and recombinant HMGB1 (rHMGB1) induced NFkB activation. NFkB activation was prevented in the absence of both TLR2 and TLR4. rHMGB1 pretreatment also prevented primary engraftment through a TLR2/4-dependent pathway. Our results show that islet graft failure can be initiated by TLR2 and TLR4 signaling and suggest that HMGB1 is one likely early mediator. Subsequent downstream signaling results in intra-islet inflammation followed by T-cell-mediated graft destruction.
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Diabetes Mellitus Tipo 1/inmunología , Rechazo de Injerto/inmunología , Células Secretoras de Insulina/inmunología , Células Secretoras de Insulina/trasplante , Trasplante de Islotes Pancreáticos/inmunología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 4/inmunología , Animales , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Línea Celular , Citocinas/genética , Citocinas/inmunología , Diabetes Mellitus Tipo 1/terapia , Proteína HMGB1/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Microscopía Confocal , ARN/química , ARN/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Organismos Libres de Patógenos Específicos , Receptor Toll-Like 2/biosíntesis , Receptor Toll-Like 4/biosíntesisRESUMEN
BACKGROUND: An important role of TLR2 has been shown in various experimental models of renal ischaemia/reperfusion injury. To study the expression of TLR2 in renal allograft rejection systematically, we established an experimental rat transplantation model. METHODS: TLR2 expression was analysed in 99 human renal allograft biopsies, and in rat allografts at Day 6 and 28 after experimental renal transplantation. To discriminate whether regulation of TLR2 was following immunological processes after allogeneic transplantation or was a consequence from ischaemia/reperfusion injury, control animals subjected to syngeneic transplantation or to ischaemia/reperfusion damage were also investigated. RESULTS: TLR2 mRNA was significantly elevated in rat allografts with acute rejection on Day 6 and decreased spontaneously towards Day 28. TLR2 induction correlated with renal function and TLR2 excretion in the urine of transplanted rats. TLR2 staining was also significantly increased in human allografts with acute rejection. TLR2 protein could be localized in tubular epithelial cells and vascular endothelial cells, and in CD68- and CD4-positive infiltrating cells. CONCLUSIONS: TLR2 is markedly up-regulated in both experimental and human acute renal allograft rejection. Our data suggest a role for TLR2 during allogen-dependent graft damage after renal transplantation.
Asunto(s)
Rechazo de Injerto/metabolismo , Fallo Renal Crónico/complicaciones , Trasplante de Riñón/efectos adversos , Receptor Toll-Like 2/metabolismo , Animales , Western Blotting , Femenino , Técnica del Anticuerpo Fluorescente , Tasa de Filtración Glomerular , Rechazo de Injerto/etiología , Humanos , Técnicas para Inmunoenzimas , Fallo Renal Crónico/terapia , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Pronóstico , ARN Mensajero/genética , Ratas , Ratas Endogámicas Lew , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Riesgo , Tasa de Supervivencia , Receptor Toll-Like 2/genética , Trasplante Homólogo , Trasplante Isogénico , Regulación hacia ArribaRESUMEN
Aging of the population and improvements in diabetes therapy have led to an increased number of older pancreas transplant candidates. The aim of our retrospective study was to evaluate pancreas transplantation (PT) outcomes in patients ≥ 50 years, as limited data exist in these patients. We analyzed 398 consecutive pancreas transplant patients from June 1994 to June 2009 for different outcomes (patient/graft survival, rejection rate, and surgical complications) between the age groups ≥ 50 years (n = 69) and <50 years (n = 329). Donor and recipient characteristics were similar except for recipient age (54.0 vs. 38.8 years), BMI (24.6 vs. 22.9 kg/m(2) ), and duration of diabetes mellitus (36.0 vs. 27.7 years). One-, 5-, and 10-year patient and graft (kidney/pancreas) survival were not significantly different between the groups with patient survival rates reaching 84% and pancreas graft survival up to 67% after 10 years. Surgical complications such as relaparotomy rate (34% vs. 33%) or pancreas graft thrombosis (14% vs. 11%) as well as 1-year rejection rates (35% vs. 31%) were not significantly different. PT in selected patients aged ≥ 50 years resulted in survival comparable with that of younger patients. In conclusion, advanced age should no longer be considered as an exclusion criterion for PT. However, good medical assessment and careful patient selection are necessary.
Asunto(s)
Trasplante de Páncreas/mortalidad , Adulto , Diabetes Mellitus Tipo 1/cirugía , Femenino , Supervivencia de Injerto , Asignación de Recursos para la Atención de Salud , Humanos , Terapia de Inmunosupresión/métodos , Trasplante de Riñón/mortalidad , Masculino , Persona de Mediana Edad , Trasplante de Páncreas/efectos adversos , Selección de Paciente , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Extensive genetic variation has been described in molecules regulating innate and adaptive immunity, pharmacokinetics, coagulation, and fibrosis. However, large prospective studies need to be performed to define the clinical consequences of such variation and the potential benefits of genotyping these markers for patients. The purpose of this review is to summarize recent data describing associations of polymorphisms in both immunological and non-immunological molecules with transplant outcomes, and discuss their clinical implications and limitations.