RESUMEN
Describing risk factors and outcomes in kidney transplant recipients with oxalate nephropathy (ON) may help elucidate the pathogenesis and guide treatment strategies. We used a large single-center database to identify patients with ON and categorized them into delayed graft function with ON (DGF-ON) and late ON. Incidence density sampling was used to select controls. A total of 37 ON cases were diagnosed between 1/2011 and 1/2021. DGF-ON (n = 13) was diagnosed in 1.05% of the DGF population. Pancreatic atrophy on imaging (36.4% vs. 2.9%, p = 0.002) and gastric bypass history (7.7% vs. 0%; p = 0.06) were more common in DGF-ON than with controls with DGF requiring biopsy but without evidence of ON. DGF-ON was not associated with worse graft survival (p = 0.98) or death-censored graft survival (p = 0.48). Late ON (n = 24) was diagnosed after a mean of 78.2 months. Late ON patients were older (mean age 55.1 vs. 48.4 years; p = 0.02), more likely to be women (61.7% vs. 37.5%; p = 0.03), have gastric bypass history (8.3% vs. 0.8%; p = 0.02) and pancreatic atrophy on imaging (38.9% vs. 13.3%; p = 0.02). Late ON was associated with an increased risk of graft failure (HR 2.0; p = 0.07) and death-censored graft loss (HR 2.5; p = 0.10). We describe two phenotypes of ON after kidney transplantation: DGF-ON and late ON. Our study is the first to our knowledge to evaluate DGF-ON with DGF controls without ON. Although limited by small sample size, DGF-ON was not associated with adverse outcomes when compared with controls. Late ON predicted worse allograft outcomes.
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Supervivencia de Injerto , Trasplante de Riñón , Fenotipo , Complicaciones Posoperatorias , Humanos , Trasplante de Riñón/efectos adversos , Femenino , Masculino , Persona de Mediana Edad , Factores de Riesgo , Pronóstico , Estudios de Seguimiento , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/etiología , Tasa de Filtración Glomerular , Funcionamiento Retardado del Injerto/etiología , Estudios Retrospectivos , Oxalatos/metabolismo , Pruebas de Función Renal , Enfermedades Renales/etiología , Enfermedades Renales/cirugía , Fallo Renal Crónico/cirugía , Adulto , Estudios de Casos y Controles , Rechazo de Injerto/etiología , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/patología , Tasa de SupervivenciaRESUMEN
Development of a post-transplant kidney transplant tolerance induction protocol involving a novel total lymphoid irradiation (TLI) conditioning method in a rhesus macaque model is described. We examined the feasibility of acheiving tolerance to MHC 1-haplotype matched kidney transplants by establishing a mixed chimeric state with infusion of donor hematopoietic cells (HC) using TomoTherapy TLI. The chimeric state was hypothesized to permit the elimination of all immunosuppressive (IS) medications while preserving allograft function long-term without development of graft-versus-host-disease (GVHD) or rejection. An experimental group of 11 renal transplant recipients received the tolerance induction protocol and outcomes were compared to a control group (n = 7) that received the same conditioning but without donor HC infusion. Development of mixed chimerism and operational tolerance was accomplished in two recipients in the experimental group. Both recipients were withdrawn from all IS and continued to maintain normal renal allograft function for 4 years without rejection or GVHD. None of the animals in the control group achieved tolerance when IS was eliminated. This novel experimental model demonstrated the feasibility for inducing of long-term operational tolerance when mixed chimerism is achieved using a TLI post-transplant conditioning protocol in 1-haplotype matched non-human primate recipients of combined kidney and HC transplantation.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Trasplante de Riñón , Radioterapia de Intensidad Modulada , Animales , Macaca mulatta , Irradiación Linfática , Tolerancia Inmunológica , Tolerancia al Trasplante , Acondicionamiento Pretrasplante/métodos , Riñón , Quimera por TrasplanteRESUMEN
BACKGROUND: There is little published information on the natural history and the treatment of immune complex membrano-proliferative glomerulonephritis (IC-MPGN) of unknown cause in the transplanted kidney. MATERIALS AND METHODS: From 01/2004 to 12/2018, 41 patients had the diagnosis of post-transplant idiopathic IC-MPGN and were included in the study. RESULTS: The mean age of the cohort at the time of transplant was 50 ± 13 years. The most common presentation was increased proteinuria, followed by kidney dysfunction. Fewer than 50% of patients had hematuria at presentation. 25 patients (61%) had no change in their baseline immunosuppression after the diagnosis of idiopathic IC-MPGN. Eight patients (19.5%) received steroids alone, and 8 patients (19.5%) received rituximab with (7) or without (1) steroids. The patients who received rituximab had better uncensored graft survival than the patients who received no treatment (p = 0.02), but the benefit of steroids compared to no treatment did not reach statistical significance (p = 0.05). The multivariate analysis retained eGFR < 30 mL/min/1.73m2 at time of diagnosis (HR = 3.30, p = 0.02; 95% Cl 1.15 - 9.46) as a significant predictor of graft loss. In this analysis, treatment of idiopathic IC-MPGN was associated with lower graft loss (HR = 0.22, p = 0.02; 95% Cl 0.06 - 0.78). CONCLUSION: To the best of our knowledge, this is the largest clinic-pathological series of post-transplant idiopathic IC-MPGN. Treatment of idiopathic IC-MPGN may be associated with better graft outcomes.
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Glomerulonefritis Membranoproliferativa , Glomerulonefritis , Trasplante de Riñón , Adulto , Humanos , Persona de Mediana Edad , Complejo Antígeno-Anticuerpo , Glomerulonefritis/tratamiento farmacológico , Glomerulonefritis/complicaciones , Glomerulonefritis Membranoproliferativa/tratamiento farmacológico , Glomerulonefritis Membranoproliferativa/complicaciones , Riñón/patología , Rituximab/uso terapéutico , Trasplante de Riñón/efectos adversosRESUMEN
Blockade of indoleamine 2,3-dioxygenase (IDO) has been shown to alleviate lipopolysaccharide (LPS)-induced endotoxic shock and reduce sepsis mortality, but its effect on LPS-induced kidney damage has not been reported. Herein, we established a mouse kidney injury model by intraperitoneal injection of 10 mg/kg LPS and established an in vitro renal tubular epithelial cell injury model by stimulating TCMK-1 cells with 10 mg/L LPS. We found that pretreatment with 1-methyl tryptophan (1-MT), an IDO inhibitor, significantly improved LPS-induced mouse survival, and IDO knockout (KO) mice also had higher survival rates after LPS exposure than wild-type mice. At the same time, IDO KO or pretreatment with 1-MT not only reduced serum creatinine, blood urea nitrogen, renal tubular injury pathological score, but also inflammatory factors and oxidative stress status in serum or kidney of LPS-exposed mice. In vitro, blockade of IDO with 1-MT significantly inhibited LPS-induced apoptosis, inflammation and oxidative stress in TCMK-1 cells. In addition, blockade of IDO significantly inhibited LPS-activated TLR4/NF-κB signaling pathway in kidney of mice or in TCMK-1 cells. In conclusion, our results suggested that blockade of IDO attenuated kidney inflammation, apoptosis and oxidative stress to protect against LPS-induced septic kidney injury via inhibiting the TLR4/NF-κB signaling pathway.
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Lesión Renal Aguda , FN-kappa B , Ratones , Animales , FN-kappa B/metabolismo , Lipopolisacáridos/farmacología , Indolamina-Pirrol 2,3,-Dioxigenasa/genética , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismo , Transducción de Señal , Riñón , Inflamación/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/tratamiento farmacológico , Lesión Renal Aguda/prevención & controlRESUMEN
Aberrant levels of reactive oxygen species (ROS) are potential mechanisms that contribute to both cancer therapy efficacy and the side effects of cancer treatment. Upregulation of the non-canonical redox-sensitive NF-kB family member, RelB, confers radioresistance in prostate cancer (PCa). We screened FDA-approved compounds and identified betamethasone (BET) as a drug that increases hydrogen peroxide levels in vitro and protects non-PCa tissues/cells while also enhancing radiation killing of PCa tissues/cells, both in vitro and in vivo. Significantly, BET increases ROS levels and exerts different effects on RelB expression in normal cells and PCa cells. BET induces protein expression of RelB and RelB target genes, including the primary antioxidant enzyme, manganese superoxide dismutase (MnSOD), in normal cells, while it suppresses protein expression of RelB and MnSOD in LNCaP cells and PC3 cells. RNA sequencing analysis identifies B-cell linker protein (BLNK) as a novel RelB complementary partner that BET differentially regulates in normal cells and PCa cells. RelB and BLNK are upregulated and correlate with the aggressiveness of PCa in human samples. The RelB-BLNK axis translocates to the nuclear compartment to activate MnSOD protein expression. BET promotes the RelB-BLNK axis in normal cells but suppresses the RelB-BLNK axis in PCa cells. Targeted disruptions of RelB-BLNK expressions mitigate the radioprotective effect of BET on normal cells and the radiosensitizing effect of BET on PCa cells. Our study identified a novel RelB complementary partner and reveals a complex redox-mediated mechanism showing that the RelB-BLNK axis, at least in part, triggers differential responses to the redox-active agent BET by stimulating adaptive responses in normal cells but pushing PCa cells into oxidative stress overload.
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Neoplasias de la Próstata , Factor de Transcripción ReIB , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Betametasona/farmacología , Betametasona/uso terapéutico , Humanos , Masculino , Oxidación-Reducción , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/radioterapia , Tolerancia a Radiación , Especies Reactivas de Oxígeno/metabolismo , Factor de Transcripción ReIB/genética , Factor de Transcripción ReIB/metabolismoRESUMEN
Focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) are common forms of idiopathic nephrotic syndrome. The causes of these diseases are incompletely understood, but the response of patients to immunosuppressive therapies suggests that their pathogenesis is at least in part immune mediated. Preclinical and clinical research indicates that activation of the classical pathway of complement contributes to glomerular injury in FSGS. Glomerular IgM deposits are also prominent in some patients, raising the possibility that IgM is a trigger of classical pathway activation. In the present study, we examined the pattern of complement activation in the glomeruli and plasma of patients with nephrotic syndrome. We also tested whether patients with FSGS and MCD have elevated levels of natural IgM reactive with epitopes on glomerular endothelial cells and cardiolipin. We found evidence of classical pathway activation in patients with idiopathic nephrotic syndrome compared with healthy control subjects. We also detected higher levels of self-reactive IgM to both targets. Based on these results, IgM and classical pathway activation may contribute to disease pathogenesis in some patients with FSGS and MCD.NEW & NOTEWORTHY IgM is detected in biopsies from some patients with nephrotic syndrome, although this has been attributed to passive trapping of the protein. We found, however, that IgM colocalizes with complement activation fragments in some glomeruli. We also found that affected patients had higher levels of IgM reactive to glomerular endothelial cell epitopes. Thus, IgM activates the complement system in the glomeruli of some patients with nephrotic syndrome and may contribute to injury.
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Cardiolipinas/inmunología , Vía Clásica del Complemento , Proteínas del Sistema Complemento/análisis , Células Endoteliales/inmunología , Epítopos , Glomeruloesclerosis Focal y Segmentaria/inmunología , Inmunoglobulina M/análisis , Glomérulos Renales/inmunología , Nefrosis Lipoidea/inmunología , Síndrome Nefrótico/inmunología , Adulto , Anciano , Especificidad de Anticuerpos , Estudios de Casos y Controles , Vía Clásica del Complemento/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Femenino , Glomeruloesclerosis Focal y Segmentaria/sangre , Glomeruloesclerosis Focal y Segmentaria/tratamiento farmacológico , Glomeruloesclerosis Focal y Segmentaria/patología , Humanos , Inmunoglobulina M/sangre , Inmunosupresores/uso terapéutico , Glomérulos Renales/efectos de los fármacos , Glomérulos Renales/patología , Masculino , Persona de Mediana Edad , Nefrosis Lipoidea/tratamiento farmacológico , Nefrosis Lipoidea/patología , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/patología , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: Little is known aboutbiopsy findings and outcomes when kidney transplant recipients (KTRs) undergo biopsy for isolated proteinuria with stable serum creatinine (SCr). METHODS: We analyzed all KTRs who underwent biopsy for isolated proteinuria with stable SCr between January 2016 and June 2020. Patients were divided into three groups based on the biopsy findings: Active Rejection (AR), Glomerulonephritis (GN), and Other. RESULTS: A total of 130 KTRs fulfilled our selection criteria; 38 (29%) in the AR group, 26 (20%) in the GN group, and 66 (51%) in the Other group. Most baseline characteristics were similar between the groups. In multivariate analysis, higher HLA mismatch (HR per mismatch: 1.30; 95% CI:1.06-1.59; P = .01) and male gender (HR: .45; 95% CI .23-.89; P = .02) were associated with AR. There was no significant correlation between the degree of proteinuria and rejection (r = .05, P = .58) or GN (r = .07, P = .53). Graft survival was also similar between the groups. Likely due to the early diagnosis without a significant rise in SCr, outcomes were similar among all three groups. CONCLUSION: Routine monitoring for proteinuria followed by a biopsy and appropriate management may help to identify early acute graft injury and prevent graft failure.
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Rechazo de Injerto , Trasplante de Riñón , Biopsia , Creatinina , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/etiología , Supervivencia de Injerto , Humanos , Riñón , Trasplante de Riñón/efectos adversos , Masculino , Proteinuria/diagnóstico , Proteinuria/etiologíaRESUMEN
COVID-19-associated vasculitis has been reported as a defining feature of systemic disease including acute kidney injury. However, the understanding of COVID-19 kidney transplant-related injuries is still evolving. We report a case of AKI with isolated vasculitis (v2 lesion) in a new kidney transplant recipient with COVID-19 pneumonia.
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COVID-19 , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , SARS-CoV-2 , Linfocitos T , Receptores de TrasplantesRESUMEN
BACKGROUND: Data on epidemiology and outcomes of cytomegalovirus (CMV) nephritis in kidney transplant patients are limited due to the rarity of this condition. METHODS: A retrospective review of all kidney transplant recipients (KTR) (n = 6490) and biopsy-proven CMV nephritis between 1/1997 and 12/2020 was performed. RESULTS: The prevalence of CMV nephritis was low: 13/6490 (0.2%). The diagnosis was made at a median of 7.0 months (range 2.6-15.6 months) after transplant. 6 of 13 (46%) patients were CMV (D+/R-). Median CMV DNA load at biopsy was 376,000, IU/mL (range 87,000-6,460,000 IU/mL). Main biopsy features were CMV glomerulitis (n = 7/13, 54%) followed by CMV tubulointerstitial nephritis (6/13; 46%). Mean eGFR at biopsy (22.7 ± 12 mL/min/1.73 m2 ) was significantly decreased compared to baseline eGFR (38.7 ± 18.5 mL/min/1.73 m2 , p = 0.02). The vast majority, 11 of 13 (85%), experienced graft failure including 5 of 13 (38%) death-censored. 5 of 13 (38%) patients were diagnosed with acute rejection: three had concurrent acute rejection, and two had rejection within 3 months of index biopsy, respectively. Patients with tubulointerstitial CMV nephritis were significantly more likely to have rejection at the time of biopsy (50% vs. 0%, p < 0.05) compared to those with glomerular CMV nephritis. There were no significant differences between these groups in terms of eGFR at all time points, death, graft failure, immunosuppression changes or rejection after biopsy. CONCLUSION: CMV nephritis is rare but appears to be associated with poor patient/allograft outcomes. Early identification and timely treatment of CMV infection may prevent end-organ involvement and improve patient and allograft-related outcomes.
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Infecciones por Citomegalovirus , Trasplante de Riñón , Nefritis , Antivirales/uso terapéutico , Citomegalovirus , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/tratamiento farmacológico , Infecciones por Citomegalovirus/epidemiología , Rechazo de Injerto/epidemiología , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Receptores de TrasplantesRESUMEN
BACKGROUND: Published literature on predictors of polyomavirus (BKV) and cytomegalovirus (CMV) infections in simultaneous pancreas and kidney (SPK) transplant and their impact on allograft outcomes remain sparse. We hypothesize that BKV and CMV viremia infections decrease allograft survival in SPK. Identifying modifiable predictors of BKV and CMV may help tailor immunosuppression and improve allograft survival. METHODS: All SPK recipients at our institution between January 2000 and April 2016 were included (n = 757). Thirty-nine recipients had BKV only and 25 had CMV only, and infection occurred at median follow-up times of 217 and 163 days, respectively. Event density sampling was used to match recipients with BKV or CMV to up to 10 recipients without infection by age, sex, and HLA mismatch status, and these were followed for a median of 4.3 years after infection. RESULTS: Older age (HR 1.49 for each decade; 95% CI: 0.95, 2.35; P = .083) and tacrolimus use (HR 20.6; 95% CI: 2.37, 179.53; P = .006) were associated with increased incidence of BKV, but not CMV, infection. Both BKV and CMV infections were associated with increased risk of allograft failure for both pancreas (BKV [HR 2.17; 95% CI 1.47, 3.208; P = .000], CMV [HR 1.7; 95% CI 1.077, 2.687; P = .023]) and kidney (BKV [HR 2.65; 95% CI 1.765, 3.984; P = .000], CMV [HR 2.07; 95% CI 1.295, 3.308; P = .002]). CONCLUSION: Older age at time of transplant and tacrolimus may help predict BKV infection in SPK recipients.
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Infecciones por Citomegalovirus/complicaciones , Rechazo de Injerto/virología , Trasplante de Riñón/efectos adversos , Trasplante de Páncreas/efectos adversos , Infecciones por Polyomavirus/complicaciones , Adulto , Factores de Edad , Estudios de Cohortes , Femenino , Humanos , Incidencia , Masculino , Factores de Riesgo , Tacrolimus/uso terapéuticoRESUMEN
Maternal microchimerism (MMc) has been associated with development of allospecific transplant tolerance, antitumor immunity, and cross-generational reproductive fitness, but its mode of action is unknown. We found in a murine model that MMc caused exposure to the noninherited maternal antigens in all offspring, but in some, MMc magnitude was enough to cause membrane alloantigen acquisition (mAAQ; "cross-dressing") of host dendritic cells (DCs). Extracellular vesicle (EV)-enriched serum fractions from mAAQ+, but not from non-mAAQ, mice reproduced the DC cross-dressing phenomenon in vitro. In vivo, mAAQ was associated with increased expression of immune modulators PD-L1 (programmed death-ligand 1) and CD86 by myeloid DCs (mDCs) and decreased presentation of allopeptide+self-MHC complexes, along with increased PD-L1, on plasmacytoid DCs (pDCs). Remarkably, both serum EV-enriched fractions and membrane microdomains containing the acquired MHC alloantigens included CD86, but completely excluded PD-L1. In contrast, EV-enriched fractions and microdomains containing allopeptide+self-MHC did not exclude PD-L1. Adoptive transfer of allospecific transgenic CD4 T cells revealed a "split tolerance" status in mAAQ+ mice: T cells recognizing intact acquired MHC alloantigens proliferated, whereas those responding to allopeptide+self-MHC did not. Using isolated pDCs and mDCs for in vitro culture with allopeptide+self-MHC-specific CD4 T cells, we could replicate their normal activation in non-mAAQ mice, and PD-L1-dependent anergy in mAAQ+ hosts. We propose that EVs provide a physiologic link between microchimerism and split tolerance, with implications for tumor immunity, transplantation, autoimmunity, and reproductive success.
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Quimerismo , Células Dendríticas/inmunología , Vesículas Extracelulares/inmunología , Tolerancia Inmunológica , Traslado Adoptivo , Animales , Antígeno B7-2/biosíntesis , Antígeno B7-2/inmunología , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/inmunología , Linfocitos T CD4-Positivos/inmunología , Femenino , Transfusión Fetomaterna/inmunología , Antígenos H-2/genética , Antígenos H-2/inmunología , Antígeno de Histocompatibilidad H-2D/genética , Antígeno de Histocompatibilidad H-2D/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Isoantígenos/inmunología , Masculino , Intercambio Materno-Fetal/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Modelos Inmunológicos , Embarazo , Especificidad del Receptor de Antígeno de Linfocitos TRESUMEN
BACKGROUND: It has been shown that glomerulonephritis (GN) recurrence affects graft survival more than acute rejection. Thus, we assessed allograft survival after biopsy-confirmed diagnosis of acute rejection or recurrent GN in current era of immunosuppression. METHODS: Allograft survival following a biopsy diagnosis of acute rejection or recurrent GN was determined in adult kidney transplant recipients from 1994 to 2013. A total of 306 patients (35%) with IgA, 298 (35%) with FSGS, 177 (21%) with lupus nephritis, and 81 (9%) with membranous nephropathy were followed for a median of 6.3 years. RESULTS: Among the 862 transplant recipients with primary GN, allograft loss was similar following a biopsy diagnosis of acute rejection or recurrent glomerular disease (11.5 vs 14.2/100 person-years, P = .15). Differences in allograft survival emerged after 2.5 years following recurrent disease, with significantly higher graft failure in patients with FSGS, MN, or LN compared with IgA after recurrence of disease (16.7 vs 7.5/100 person-years, P = .05). The advantage in allograft survival for IgA patients did not achieve significance after acute rejection (P = .10 for IgA vs FSGS, MN, and LN). CONCLUSIONS: Allograft survival was similar after disease recurrence or acute rejection after kidney transplant in patients with ESRD due to GN.
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Glomerulonefritis Membranosa/epidemiología , Glomerulonefritis/epidemiología , Rechazo de Injerto/epidemiología , Supervivencia de Injerto , Trasplante de Riñón/efectos adversos , Complicaciones Posoperatorias/epidemiología , Adulto , Femenino , Estudios de Seguimiento , Tasa de Filtración Glomerular , Glomerulonefritis/etiología , Glomerulonefritis/patología , Glomerulonefritis Membranosa/etiología , Glomerulonefritis Membranosa/patología , Rechazo de Injerto/etiología , Rechazo de Injerto/patología , Humanos , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/patología , Prevalencia , Pronóstico , Recurrencia , Factores de Riesgo , Wisconsin/epidemiologíaRESUMEN
BACKGROUND: Risk factors for graft loss in kidney transplant recipients with g3 lesions are poorly defined. MATERIALS AND METHODS: We evaluated outcomes in 37 consecutive kidney transplant biopsies diagnosed with g3 glomerulitis based on Banff 2013 criteria in a single-center observational study. RESULTS: The diagnosis of g3 glomerulonephritis was made 6.1 ± 6.6 years after transplant. The majority of patients were Caucasian (86%), male (65%), and received basiliximab induction (54%). At the time of biopsy, all were on triple therapy with tacrolimus, mycophenolate, and prednisone. Mean serum creatinine (Scr) was 2.85 ± 2.1 mg/dL. Notably, 20 (54%) were positive for donor-specific antibodies (DSA+) and 8 (22%) were C4d+, while 24 (65%) had transplant glomerulopathy (TG). Treatment included pulse steroids/intravenous immunoglobulin (IVIG) (73%) and rituximab (51%). Patients were followed for up to 4 years after the biopsy. Eleven grafts (30%) were lost during the follow-up. Cox regression analyses determined Scr (HR = 1.63, 95% CI 1.19 - 2.24, p = 0.002), live donor status (HR = 0.18, 95% CI 0.04 - 0.90, p = 0.03), t-score (HR = 2.75, 95% CI 1.30 - 5.81, p = 0.008), and ct-score (HR = 2.19, 95% CI 1 - 4.75, p = 0.04) as significant predictors of graft loss. CONCLUSION: Severe glomerulitis was associated with a high prevalence of TG and graft loss at 4 years. Live donor status, kidney function (Scr), and tubular injury (t- and ct-scores) were independently associated with graft loss. Interventional mechanistic clinical trials are needed to better understand the pathogenesis and outcomes of g3 glomerulitis.â©.
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Glomerulonefritis/patología , Rechazo de Injerto/patología , Trasplante de Riñón , Túbulos Renales/patología , Adulto , Aloinjertos/patología , Creatina/sangre , Femenino , Glomerulonefritis/sangre , Glomerulonefritis/clasificación , Rechazo de Injerto/sangre , Supervivencia de Injerto , Humanos , Donadores Vivos , Masculino , Persona de Mediana Edad , Factores de Riesgo , Adulto JovenRESUMEN
Thyroid cancers are the most common endocrine malignancy and approximately 2% of thyroid cancers are anaplastic thyroid carcinoma (ATC), one of the most lethal and treatment resistant human cancers. Cancer stem-like cells (CSCs) may initiate tumorigenesis, induce resistance to chemotherapy and radiation therapy, have multipotent capability and may be responsible for recurrent and metastatic disease. The production of CSCs has been linked to epithelial-mesenchymal transition (EMT) and the acquisition of stemness. Exosomes are small (30-150 nm) membranous vesicles secreted by most cells that play a significant role in cell-to-cell communication. Many non-coding RNAs (ncRNA), such as long-non-coding RNAs (lncRNA), can initiate tumorigenesis and the EMT process. Exosomes carry ncRNAs to local and distant cell populations. This study examines secreted exosomes from two in vitro cell culture models; an EMT model and a CSC model. The EMT was induced in a papillary thyroid carcinoma (PTC) cell line by TGFß1 treatment. Exosomes from this model were isolated and cultured with naïve PTC cells and examined for EMT induction. In the CSC model, exosomes were isolated from a CSC clonal line, cultured with a normal thyroid cell line and examined for EMT induction. The EMT exosomes transferred the lncRNA MALAT1 and EMT effectors SLUG and SOX2; however, EMT was not induced in this model. The exosomes from the CSC model also transferred the lncRNA MALAT1 and the transcription factors SLUG and SOX2 but additionally transferred linc-ROR and induced EMT in the normal thyroid cells. Preliminary siRNA studies directed towards linc-ROR reduced invasion. We hypothesize that CSC exosomes transfer lncRNAs, importantly linc-ROR, to induce EMT and inculcate the local tumor microenvironment and the distant metastatic niche. Therapies directed towards CSCs, their exosomes and/or the lncRNAs they carry may reduce a tumor's metastatic capacity.
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Transición Epitelial-Mesenquimal/genética , Células Madre Neoplásicas/patología , ARN Largo no Codificante/genética , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Línea Celular Tumoral , Transición Epitelial-Mesenquimal/efectos de los fármacos , Exosomas/genética , Exosomas/patología , Humanos , Modelos Biológicos , Factores de Transcripción SOXB1/genética , Factores de Transcripción de la Familia Snail/genética , Esferoides Celulares/patología , Factor de Crecimiento Transformador beta/farmacologíaRESUMEN
BACKGROUND: The androgen receptor (AR) is a key oncogenic driver of prostate cancer, and has been the primary focus of prostate cancer treatment for several decades. We have previously demonstrated that the AR is also an immunological target antigen, recognized in patients with prostate cancer, and targetable by means of vaccines in rodent models with delays in prostate tumor growth. The current study was performed to determine the safety and immunological efficacy of a GMP-grade plasmid DNA vaccine encoding the ligand-binding domain (LBD) of the AR, pTVG-AR. METHODS: Groups of male mice (n = 6-10 per group) were evaluated after four or seven immunizations, using different schedules and inclusion of GM-CSF as a vaccine adjuvant. Animals were assessed for toxicity using gross observations, pathological analysis, and analysis of serum chemistries. Animals were analyzed for evidence of vaccine-augmented immunity by tetramer analysis. Survival studies using different immunization schedules and inclusion of GM-CSF were conducted in an autochthonous genetically engineered mouse model. RESULTS: No significant toxicities were observed in terms of animal weights, histopathology, hematological changes, or changes in serum chemistries, although there was a trend to lower serum glucose in animals treated with the vaccine. There was specifically no evidence of toxicity in other tissues that express AR, including liver, muscle, hematopoietic, and brain. Vaccination was found to elicit AR LBD-specific CD8+ T cells. In a subsequent study of tumor-bearing animals, animals treated with vaccine had prolonged survival compared with control-immunized mice. CONCLUSIONS: These studies demonstrate that, in immunocompetent mice expressing the target antigen, immunization with the pTVG-AR vaccine was both safe and effective in eliciting AR-specific cellular immune responses, and prolonged the survival of prostate tumor-bearing mice. These findings support the clinical evaluation of pTVG-AR in patients with recurrent prostate cancer. Prostate 77:812-821, 2017. © 2017 Wiley Periodicals, Inc.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Neoplasias de la Próstata , Receptores Androgénicos/inmunología , Vacunas de ADN , Adyuvantes Inmunológicos/administración & dosificación , Animales , Masculino , Ratones , Monitorización Inmunológica/métodos , Neoplasias de la Próstata/inmunología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Resultado del Tratamiento , Vacunas de ADN/administración & dosificación , Vacunas de ADN/efectos adversos , Vacunas de ADN/inmunologíaRESUMEN
Although glomerular immunoglobulin M (IgM) deposition occurs in a variety of glomerular diseases, the mechanism of deposition and its clinical significance remain controversial. Some have theorized IgM becomes passively trapped in areas of glomerulosclerosis. However, recent studies found that IgM specifically binds damaged glomeruli. Therefore, we tested whether natural IgM binds to neo-epitopes exposed after insults to the glomerulus and exacerbates disease in mice deficient in the complement regulatory protein factor H; a model of non-sclerotic and nonimmune-complex glomerular disease. Immunofluorescence microscopy demonstrated mesangial and capillary loop deposition of IgM, whereas ultrastructural analysis found IgM deposition on endothelial cells and subendothelial areas. Factor H-deficient mice lacking B cells were protected from renal damage, as evidenced by milder histologic lesions on light and electron microscopy. IgM, but not IgG, from wild-type mice bound to cultured murine mesangial cells. Furthermore, injection of purified IgM into mice lacking B cells bound within the glomeruli and induced proteinuria. A monoclonal natural IgM-recognizing phospholipids also bound to glomeruli in vivo and induced albuminuria. Thus, our results indicate specific IgM antibodies bind to glomerular epitopes and that IgM contributes to the progression of glomerular damage in this mouse model of non-sclerotic glomerular disease.
Asunto(s)
Activación de Complemento , Factor H de Complemento/metabolismo , Glomerulonefritis/etiología , Inmunoglobulina M/metabolismo , Glomérulos Renales/metabolismo , Albuminuria/etiología , Albuminuria/inmunología , Albuminuria/metabolismo , Animales , Especificidad de Anticuerpos , Linfocitos B/inmunología , Linfocitos B/metabolismo , Línea Celular , Factor H de Complemento/deficiencia , Factor H de Complemento/genética , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Epítopos , Glomerulonefritis/genética , Glomerulonefritis/inmunología , Glomerulonefritis/metabolismo , Glomerulonefritis/patología , Glomerulonefritis/prevención & control , Inmunoglobulina M/genética , Inmunoglobulina M/inmunología , Glomérulos Renales/inmunología , Glomérulos Renales/patología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Factores de TiempoRESUMEN
Melanoma causes more deaths than any other skin cancer, and its incidence in the US continues to rise. Current medical therapies are insufficient to control this deadly neoplasm, necessitating the development of new target-based approaches. The objective of this study was to determine the role and functional significance of the class III histone deacetylase SIRT1 in melanoma. We have found that SIRT1 is overexpressed in clinical human melanoma tissues and human melanoma cell lines (Sk-Mel-2, WM35, G361, A375, and Hs294T) compared to normal skin and normal melanocytes, respectively. In addition, treatment of melanoma cell lines A375, Hs294T, and G361 with Tenovin-1, a small molecule SIRT1 inhibitor, resulted in a significant decrease in cell growth and cell viability. Further, Tenovin-1 treatment also resulted in a marked decrease in the clonogenic survival of melanoma cells. Further experiments showed that the anti-proliferative response of Tenovin-1 was accompanied by an increase in the protein as well as activity of the tumor suppressor p53. This increase in p53 activity was substantiated by an increase in the protein level of its downstream target p21. Overall, these data suggest that small molecule inhibition of SIRT1 causes anti-proliferative effects in melanoma cells. SIRT1 appears to be acting through the activity of the tumor suppressor p53, which is not mutated in the majority of melanomas. However, future detailed studies are needed to further explore the role and mechanism of SIRT1 in melanoma development and progression and its usefulness in melanoma treatment.
Asunto(s)
Acetanilidas/farmacología , Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Melanoma/tratamiento farmacológico , Melanoma/metabolismo , Sirtuina 1/antagonistas & inhibidores , Sirtuina 1/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Tiourea/análogos & derivados , Proteína p53 Supresora de Tumor/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Inhibidor p21 de las Quinasas Dependientes de la Ciclina/metabolismo , Humanos , Melanocitos/efectos de los fármacos , Melanocitos/metabolismo , Melanoma/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , ARN Neoplásico/genética , ARN Neoplásico/metabolismo , Elementos Reguladores de la Transcripción/efectos de los fármacos , Sirtuina 1/genética , Neoplasias Cutáneas/patología , Tiourea/farmacología , Ensayo de Tumor de Célula Madre , Regulación hacia Arriba/efectos de los fármacosRESUMEN
BK polyomavirus (BKPyV) is a ubiquitous human polyomavirus and a major infection after kidney transplantation, primarily due to immunosuppression. BKPyV reactivation can manifest as viruria in 30%-40%, viremia in 10%-20%, and BK polyomavirus-associated nephropathy (BKPyVAN) in 1%-10% of recipients. BKPyVAN is an important cause of kidney graft failure. Although the first case of BKPyV was identified in 1971, progress in its management has been limited. Specifically, there is no safe and effective antiviral agent or vaccine to treat or prevent the infection. Even in the current era, the mainstay approach to BKPyV is a reduction in immunosuppression, which is also limited by safety (risk of de novo donor specific antibody and rejection) and efficacy (graft failure). However, recently BKPyV has been getting more attention in the field, and some new treatment strategies including the utilization of viral-specific T-cell therapy are emerging. Given all these challenges, the primary focus of this article is complications associated with BKPyV, as well as strategies to mitigate negative outcomes.
RESUMEN
Delayed graft function (DGF) is an early posttransplant complication predictive of adverse outcomes. This "acute kidney injury of transplantation" is often defined as allograft dysfunction requiring renal replacement within 7 d posttransplantation. DGF is an important area of study because it is emerging with efforts to expand the donor pool and address the supply-demand gap in kidney transplantation. DGF is often caused by severe kidney injury mechanisms because of multiple donors, recipients, and immunologic factors. The role of kidney biopsy, particularly in prolonged DGF, is an ongoing area of research and inquiry for clinicians and researchers alike to better define, manage, and predict outcomes of this early posttransplant event. This review aims to provide an in-depth, comprehensive summary of the literature to date on the histopathology of DGF and the role of kidney transplant biopsies in prolonged DGF.
RESUMEN
In this study, electroporation-surface-enhanced Raman scattering (SERS) was applied to rapidly measure intracellular pH. The generation of a sensitive SERS probe for measuring pH in the range of 6.0-8.0 was accomplished through the conjugation of the pH-sensitive molecule 4-mercaptobenzoic acid (4-MBA) to the surface of gold nanoparticles (Au NPs) through its thiol functional group. This bioprobe was then rapidly introduced into nasopharyngeal carcinoma CNE-1 cells by electroporation, followed by SERS scanning and the fitting of intensity ratios of each detection point's Raman peaks at 1423 cm-1 and 1072 cm-1, to create the pH distribution map of CNE-1 cells. The electroporation-SERS assay introduces pH bioprobes into a living cell in a very short time and disperses the nanoprobe throughout the cytoplasm, ultimately enabling rapid and comprehensive pH analysis of the entire cell. Our work demonstrates the potential of electroporation-SERS for the biochemical analysis of live cells.