RESUMEN
Vertebrate cells have evolved elaborate cell-autonomous defense programs to monitor subcellular compartments for infection and to evoke counter-responses. These programs are activated by pathogen-associated pattern molecules and by various strategies intracellular pathogens employ to alter cellular microenvironments. Here, we show that, when uropathogenic E. coli (UPEC) infect bladder epithelial cells (BECs), they are targeted by autophagy but avoid degradation because of their capacity to neutralize lysosomal pH. This change is detected by mucolipin TRP channel 3 (TRPML3), a transient receptor potential cation channel localized to lysosomes. TRPML3 activation then spontaneously initiates lysosome exocytosis, resulting in expulsion of exosome-encased bacteria. These studies reveal a cellular default system for lysosome homeostasis that has been co-opted by the autonomous defense program to clear recalcitrant pathogens.
Asunto(s)
Infecciones por Escherichia coli/inmunología , Lisosomas/microbiología , Canales Catiónicos TRPC/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo , Infecciones Urinarias/inmunología , Escherichia coli Uropatógena/fisiología , Animales , Autofagia , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Exocitosis , Lisosomas/enzimología , Lisosomas/metabolismo , Ratones , Vejiga Urinaria/inmunología , Vejiga Urinaria/microbiología , Vejiga Urinaria/patología , Infecciones Urinarias/microbiología , Infecciones Urinarias/patologíaRESUMEN
Current organoid models are limited by their inability to mimic mature organ architecture and associated tissue microenvironments1,2. Here we create multilayer bladder 'assembloids' by reconstituting tissue stem cells with stromal components to represent an organized architecture with an epithelium surrounding stroma and an outer muscle layer. These assembloids exhibit characteristics of mature adult bladders in cell composition and gene expression at the single-cell transcriptome level, and recapitulate in vivo tissue dynamics of regenerative responses to injury. We also develop malignant counterpart tumour assembloids to recapitulate the in vivo pathophysiological features of urothelial carcinoma. Using the genetically manipulated tumour-assembloid platform, we identify tumoural FOXA1, induced by stromal bone morphogenetic protein (BMP), as a master pioneer factor that drives enhancer reprogramming for the determination of tumour phenotype, suggesting the importance of the FOXA1-BMP-hedgehog signalling feedback axis between tumour and stroma in the control of tumour plasticity.
Asunto(s)
Organoides/patología , Organoides/fisiología , Regeneración , Neoplasias de la Vejiga Urinaria/patología , Neoplasias de la Vejiga Urinaria/fisiopatología , Vejiga Urinaria/patología , Vejiga Urinaria/fisiología , Adulto , Animales , Proteínas Morfogenéticas Óseas/metabolismo , Femenino , Erizos/metabolismo , Factor Nuclear 3-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Organoides/fisiopatología , Análisis de la Célula Individual , Células Madre/citología , Células Madre/patología , Células Madre/fisiología , Transcriptoma , Vejiga Urinaria/citología , Infecciones Urinarias/metabolismo , Infecciones Urinarias/patologíaRESUMEN
Uromodulin, a protein exclusively produced by the kidney, is the most abundant urinary protein in physiological conditions. Already described several decades ago, uromodulin has gained the spotlight in recent years, since the discovery that mutations in its encoding gene UMOD cause a renal Mendelian disease (autosomal dominant tubulointerstitial kidney disease) and that common polymorphisms are associated with multifactorial disorders, such as chronic kidney disease, hypertension, and cardiovascular diseases. Moreover, variations in uromodulin levels in urine and/or blood reflect kidney functioning mass and are of prognostic value for renal function, cardiovascular events, and overall mortality. The clinical relevance of uromodulin reflects its multifunctional nature, playing a role in renal ion transport and immunomodulation, in protection against urinary tract infections and renal stones, and possibly as a systemic antioxidant. Here, we discuss the multifaceted roles of this protein in kidney physiology and its translational relevance.
Asunto(s)
Riñón/metabolismo , Uromodulina/metabolismo , Animales , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/patología , Humanos , Hipertensión/metabolismo , Hipertensión/patología , Riñón/patología , Cálculos Renales/metabolismo , Cálculos Renales/patología , Insuficiencia Renal Crónica/metabolismo , Insuficiencia Renal Crónica/patología , Infecciones Urinarias/metabolismo , Infecciones Urinarias/patologíaRESUMEN
Urine pH reflects the functional integrity of the body and may influence the virulence of uropathogenic Escherichia coli and Klebsiella pneumoniae, the main causes of urinary tract infections (UTIs). This study evaluated the effects of acidic pH on the pathogenicity of uropathogenic E. coli and K. pneumoniae strains, in vitro and in vivo. Four uropathogenic E. coli and four K. pneumoniae strains were used. Biofilm formation, growth competition indices, motility, and adhesion and invasion of human renal cells were analyzed in media with acidic, neutral, and alkaline pH. A murine lower UTI model was used, with urine adjusted to acidic, neutral, or alkaline pH. At acidic pH, E. coli and K. pneumoniae exhibited higher bacterial concentrations in the kidneys and systemic symptoms, including bacteremia. Alkaline urine pH did not affect bacterial concentrations of any strain. In mice with UTIs caused by E. coli Nu14 and K. pneumoniae HUVR42 and acidic urine pH, histopathological studies of the kidneys showed acute inflammation affecting the urothelium and renal parenchyma, which are traits of acute pyelonephritis. These results indicate that acidic pH could increase the pathogenicity of E. coli and K. pneumoniae in murine models of lower UTI, promoting renal infection and acute inflammation.
Asunto(s)
Escherichia coli , Riñón , Infecciones por Klebsiella , Klebsiella pneumoniae , Infecciones Urinarias , Klebsiella pneumoniae/patogenicidad , Concentración de Iones de Hidrógeno , Animales , Ratones , Infecciones Urinarias/microbiología , Infecciones Urinarias/patología , Riñón/microbiología , Riñón/patología , Humanos , Escherichia coli/patogenicidad , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/patología , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Biopelículas/crecimiento & desarrollo , Femenino , Virulencia , Modelos Animales de Enfermedad , Escherichia coli Uropatógena/patogenicidad , Pielonefritis/microbiología , Pielonefritis/patologíaRESUMEN
Proteus mirabilis is a common cause of urinary tract infection, especially in catheterized individuals. Amino acids are the predominant nutrient for bacteria during growth in urine, and our prior studies identified several amino acid import and catabolism genes as fitness factors for P. mirabilis catheter-associated urinary tract infection (CAUTI), particularly those for d- and l-serine. In this study, we sought to determine the hierarchy of amino acid utilization by P. mirabilis and to examine the relative importance of d- vs l-serine catabolism for critical steps in CAUTI development and progression. Herein, we show that P. mirabilis preferentially catabolizes l-serine during growth in human urine, followed by d-serine, threonine, tyrosine, glutamine, tryptophan, and phenylalanine. Independently disrupting catabolism of either d- or l-serine has minimal impact on in vitro phenotypes while completely disrupting both pathways decreases motility, biofilm formation, and fitness due to perturbation of membrane potential and cell wall biosynthesis. In a mouse model of CAUTI, loss of either serine catabolism system decreased fitness, but disrupting l-serine catabolism caused a greater fitness defect than disrupting d-serine catabolism. We, therefore, conclude that the hierarchical utilization of amino acids may be a critical component of P. mirabilis colonization and pathogenesis within the urinary tract.
Asunto(s)
Infecciones por Proteus , Infecciones Urinarias , Animales , Catéteres , Humanos , Ratones , Infecciones por Proteus/genética , Infecciones por Proteus/microbiología , Proteus mirabilis/metabolismo , Serina/metabolismo , Infecciones Urinarias/microbiología , Infecciones Urinarias/patologíaRESUMEN
Uropathogenic Escherichia coli (UPEC) deploy an array of virulence factors to successfully establish urinary tract infections. Hemolysin is a pore-forming toxin, and its expression correlates with the severity of UPEC infection. Two-component signaling systems (TCSs) are a major mechanism by which bacteria sense environmental cues and respond by initiating adaptive responses. Here, we began this study by characterizing a novel TCS (C3564/C3565, herein renamed orhK/orhR for oxidative resistance and hemolysis kinase/regulator) that is encoded on a UPEC pathogenicity island, using bioinformatic and biochemical approaches. A prevalence analysis indicates that orhK/orhR is highly associated with the UPEC pathotype, and it rarely occurs in other E. coli pathotypes tested. We then demonstrated that OrhK/OrhR directly activates the expression of a putative methionine sulfoxide reductase system (C3566/C3567) and hemolysin (HlyA) in response to host-derived hydrogen peroxide (H2O2) exposure. OrhK/OrhR increases UPEC resistance to H2O2 in vitro and survival in macrophages in cell culture via C3566/C3567. Additionally, OrhK/OrhR mediates hemolysin-induced renal epithelial cell and macrophage death via a pyroptosis pathway. Reducing intracellular H2O2 production by a chemical inhibitor impaired OrhK/OrhR-mediated activation of c3566-c3567 and hlyA. We also uncovered that UPEC links the two key virulence traits by cotranscribing the c3566-c3567 and hlyCABD operons. Taken together, our data suggest a paradigm in which a signal transduction system coordinates both bacterial pathogen defensive and offensive traits in the presence of host-derived signals; and this exquisite mechanism likely contributes to hemolysin-induced severe pathological outcomes.
Asunto(s)
Infecciones por Escherichia coli/patología , Proteínas Hemolisinas/metabolismo , Infecciones Urinarias/patología , Escherichia coli Uropatógena/patogenicidad , Virulencia/fisiología , Línea Celular , Infecciones por Escherichia coli/metabolismo , Humanos , Estrés Oxidativo/fisiología , Piroptosis/fisiología , Transducción de Señal/fisiología , Infecciones Urinarias/metabolismo , Escherichia coli Uropatógena/metabolismoRESUMEN
Urinary tract infections (UTIs) are among the most common outpatient infections, with a lifetime incidence of around 60% in women. We analysed urine samples from 223 patients with community-acquired UTIs and report the presence of the cleavage product released during the synthesis of colibactin, a bacterial genotoxin, in 55 of the samples examined. Uropathogenic Escherichia coli strains isolated from these patients, as well as the archetypal E. coli strain UTI89, were found to produce colibactin. In a murine model of UTI, the machinery producing colibactin was expressed during the early hours of the infection, when intracellular bacterial communities form. We observed extensive DNA damage both in umbrella and bladder progenitor cells. To the best of our knowledge this is the first report of colibactin production in UTIs in humans and its genotoxicity in bladder cells.
Asunto(s)
Daño del ADN , Infecciones por Escherichia coli/patología , Péptidos/metabolismo , Policétidos/metabolismo , Vejiga Urinaria/patología , Infecciones Urinarias/patología , Escherichia coli Uropatógena/aislamiento & purificación , Anciano , Animales , Infecciones por Escherichia coli/genética , Infecciones por Escherichia coli/microbiología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C3H , Mutágenos/metabolismo , Vejiga Urinaria/metabolismo , Vejiga Urinaria/microbiología , Infecciones Urinarias/genética , Infecciones Urinarias/microbiologíaRESUMEN
OBJECTIVE: Chronic trigonitis (CT) is usually diagnosed through cystoscopy which is invasive and expensive. Thus, an accurate non-invasive diagnostic method is necessary. The objective of this study is to determine the efficacy of transvaginal bladder ultrasound (TBU) for CT diagnosis. METHODS: Between 2012 and 2021, 114 women (17-76 years old) with recurrent urinary tract infection (RUTI) and history of antibiotic resistance were evaluated with TBU by a single ultrasonographer. As a control group, TBU was performed in 25 age-matched women with no previous history of UTI, urological or gynecological conditions. All patients with RUTI had undergone a cystoscopy with biopsy for diagnostic confirmation at the time of trigone cauterization. RESULTS: Thickening of trigone mucosa (>3 mm) was detected in all patients with RUTI and represented the most relevant criteria for trigonitis diagnosis on TBU. Other TBU findings in CT are: irregular and interrupted mucosa lining (96.4%), free debris in the urine (85.9%), increased blood flow at doppler (81.5%), mucosa shedding and tissue flaps. Biopsy showed CT with erosive pattern (58%) or non-keratinizing metaplasia (42%). Diagnostic agreement index between TBU and cystoscopy was 100%. In the control group, normal trigone mucosa is ultrasonographically regular, continuous, with thickness ≤3 mm and there is no debris in the urine. CONCLUSIONS: TBU proved to be an efficient, inexpensive and minimally invasive method to diagnose CT. To our knowledge, this is the first article that reports the use of transvaginal ultrasound as an alternative method for diagnosing trigonitis.
Asunto(s)
Cistitis , Infecciones Urinarias , Humanos , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad , Anciano , Vejiga Urinaria/patología , Infecciones Urinarias/patología , Cistoscopía , UltrasonografíaRESUMEN
Scar development in the children's renal cortex with vesicoureteral reflux (VUR) is one of the most important parameters of prognosis. It can develop regardless of the chosen treatment, even after the regression of VUR. The shape of the renal papillae, the ascending urinary tract infection, the greater than third-degree VUR, and finally the increased intra-calyceal pressure, induce the formation of renal scarring in the renal parenchyma. Renal scarring may complicate VUR independently of the therapeutic strategy (conservative or operative) and its regression. For restitution of this entity, many scientific terms have been used and the most common of them is intrarenal reflux (IRR). The effects of VUR on future renal function result from the limited ability of the affected kidney to grow (failure of renal growth) due to the existence of scars in the renal cortex, the worsening of these scars, or finally the creation of new scars. With the present study, we intend to clarify the etiology and the pathophysiology of IRR and the relation of VUR prognosis to newer biomarkers such as N-acetyl-beta-glycosaminidase, beta-2 microglobulin, Pen- traxin- 3 and Liver-type fatty-acid-binding protein.
Asunto(s)
Infecciones Urinarias , Reflujo Vesicoureteral , Niño , Humanos , Lactante , Reflujo Vesicoureteral/complicaciones , Reflujo Vesicoureteral/diagnóstico , Cicatriz/complicaciones , Riñón , Infecciones Urinarias/complicaciones , Infecciones Urinarias/patología , Pronóstico , Estudios RetrospectivosRESUMEN
Proteus mirabilis is a common cause of catheter-associated urinary tract infections (CAUTIs). In this study, we verified the effectiveness of amikacin or gentamicin and ascorbic acid (AA) co-therapy in eliminating uropathogenic cells, as well as searched for the molecular basis of AA activity by applying chromatographic and fluorescent techniques. Under simulated physiological conditions, a combined activity of the antibiotic and AA supported the growth (threefold) of the P. mirabilis C12 strain, but reduced catheter colonization (≤30%) in comparison to the drug monotherapy. Slight modifications in the phospholipid and fatty acid profiles, as well as limited (≤62%) 2',7'-dichlorofluorescein fluorescence, corresponding to the hydroxyl radical level, allowed for the exclusion of the hypothesis that the anti-biofilm effect of AA was related to membrane perturbations of the C12 strain. However, the reduced (≤20%) fluorescence intensity of propidium iodide, as a result of a decrease in membrane permeability, may be evidence of P. mirabilis cell defense against AA activity. Quantitative analyses of ascorbic acid over time with a simultaneous measurement of the pH values proved that AA can be an effective urine acidifier, provided that it is devoid of the presence of urease-positive cells. Therefore, it could be useful in a prevention of recurrent CAUTIs, rather than in their treatment.
Asunto(s)
Infecciones por Proteus , Infecciones Urinarias , Humanos , Proteus mirabilis/metabolismo , Aminoglicósidos/metabolismo , Ácido Ascórbico/farmacología , Ácido Ascórbico/metabolismo , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/prevención & control , Infecciones Urinarias/patología , Biopelículas , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antibacterianos/metabolismo , Catéteres , Infecciones por Proteus/tratamiento farmacológicoRESUMEN
The local environment forces a selection of bacteria that might invade the urinary tract, allowing only the most virulent to access the kidney. Quite similar to the diet in setting the stage for the gut microbiome, renal function determines the conditions for bacteria-host interaction in the urinary tract. In the kidney, the term local environment or microenvironment is completely justified because the environment literally changes within a few micrometers. The precise composition of the urine is a function of the epithelium lining the microdomain, and the microenvironment in the kidney shows more variation in the content of nutrients, ion composition, osmolality, and pH than any other site of bacteria-host interaction. This review will cover some of the aspects of bacterial-host interaction in this unique setting and how uropathogenic bacteria can alter the condition for bacteria-host interaction. There will be a particular focus on the recent findings regarding how bacteria specifically trigger host paracrine signaling, via release of extracellular ATP and activation of P2 purinergic receptors. These finding will be discussed from the perspective of severe urinary tract infections, including pyelonephritis and urosepsis.
Asunto(s)
Infecciones por Escherichia coli/genética , Proteínas de Escherichia coli/genética , Proteínas Hemolisinas/genética , Pielonefritis/genética , Receptores Purinérgicos P2/genética , Sepsis/genética , Infecciones Urinarias/genética , Escherichia coli Uropatógena/genética , Adenosina Trifosfato/metabolismo , Anoctamina-1/genética , Anoctamina-1/metabolismo , Infecciones por Escherichia coli/metabolismo , Infecciones por Escherichia coli/microbiología , Infecciones por Escherichia coli/patología , Proteínas de Escherichia coli/metabolismo , Regulación de la Expresión Génica , Proteínas Hemolisinas/metabolismo , Interacciones Huésped-Patógeno/genética , Humanos , Concentración de Iones de Hidrógeno , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Comunicación Paracrina , Pielonefritis/metabolismo , Pielonefritis/microbiología , Pielonefritis/patología , Receptores Purinérgicos P2/metabolismo , Sepsis/metabolismo , Sepsis/microbiología , Sepsis/patología , Transducción de Señal , Infecciones Urinarias/metabolismo , Infecciones Urinarias/microbiología , Infecciones Urinarias/patología , Escherichia coli Uropatógena/crecimiento & desarrollo , Escherichia coli Uropatógena/metabolismo , Escherichia coli Uropatógena/patogenicidadRESUMEN
BACKGROUND: Urinary tract infection (UTI) is frequently implicated as a precipitant of delirium, which refers to an acute confusional state that is associated with high mortality, increased length of stay, and long-term cognitive decline. The pathogenesis of delirium is thought to involve cytokine-mediated neuronal dysfunction of the frontal cortex and hippocampus. We hypothesized that systemic IL-6 inhibition would mitigate delirium-like phenotypes in a mouse model of UTI. METHODS: C57/BL6 mice were randomized to either: (1) non-UTI control, (2) UTI, and (3) UTI + anti-IL-6 antibody. UTI was induced by transurethral inoculation of 1 × 108 Escherichia coli. Frontal cortex and hippocampus-mediated behaviors were evaluated using functional testing and corresponding structural changes were evaluated via quantification of neuronal cleaved caspase-3 (CC3) by immunohistochemistry and western blot. IL-6 in the brain and plasma were evaluated using immunohistochemistry, ELISA, and RT-PCR. RESULTS: Compared to non-UTI control mice, mice with UTI demonstrated significantly greater impairments in frontal and hippocampus-mediated behaviors, specifically increased thigmotaxis in Open Field (p < 0.05) and reduced spontaneous alternations in Y-maze (p < 0.01), while treatment of UTI mice with systemic anti-IL-6 fully reversed these functional impairments. These behavioral impairments correlated with frontal and hippocampal neuronal CC3 changes, with significantly increased frontal and hippocampal CC3 in UTI mice compared to non-UTI controls (p < 0.0001), and full reversal of UTI-induced CC3 neuronal changes following treatment with systemic anti-IL-6 antibody (p < 0.0001). Plasma IL-6 was significantly elevated in UTI mice compared to non-UTI controls (p < 0.01) and there were positive and significant correlations between plasma IL-6 and frontal CC3 (r2 = 0.5087/p = 0.0028) and frontal IL-6 and CC3 (r2 = 0.2653, p < 0.0001). CONCLUSIONS: These data provide evidence for a role for IL-6 in mediating delirium-like phenotypes in a mouse model of UTI. These findings provide pre-clinical justification for clinical investigations of IL-6 inhibitors to treat UTI-induced delirium.
Asunto(s)
Delirio/metabolismo , Modelos Animales de Enfermedad , Interleucina-6/metabolismo , Fenotipo , Infecciones Urinarias/metabolismo , Animales , Anticuerpos Monoclonales/metabolismo , Anticuerpos Monoclonales/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Delirio/patología , Femenino , Interleucina-6/antagonistas & inhibidores , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Ratones , Ratones Endogámicos C57BL , Infecciones Urinarias/patologíaRESUMEN
BACKGROUND: Horseshoe kidney (HSK) is a congenital disorder that is usually asymptomatic, but that increases the risks of kidney stones and infectious disease. However, renal outcomes such as end-stage renal disease (ESRD) in patients with HSK remain unclear. METHODS: In total, 146 patients with HSK (age of ≥20 years) from two tertiary hospitals were included in this study. Control individuals who underwent medical check-ups were selected by matching for age, sex, serum creatinine level, hypertension and diabetes. The hazard ratios (HRs) for the risks of ESRD and all-cause mortality were calculated after adjustment for multiple variables. RESULTS: The proportions of HSK-related complications for obstruction, kidney stones, urinary tract infection and urogenital cancer were 26, 25, 19 and 4%, respectively. During the median follow-up period of 9 years (maximum 32 years), the incidence of ESRD was 2.6/10 000 person-years. The risk of ESRD in patients with HSK was higher than in control individuals [adjusted HR = 7.6; 95% confidence interval (CI) 1.14-50.47]. All-cause mortality did not differ between the two groups (adjusted HR = 0.6; 95% CI 0.08-4.29). CONCLUSIONS: Patients with HSK are at risk of ESRD, which may be attributable to the high prevalence of complications. Accordingly, these patients should be regarded as having chronic kidney disease and require regular monitoring of both kidney function and potential complications.
Asunto(s)
Riñón Fusionado/complicaciones , Cálculos Renales/etiología , Obstrucción Ureteral/etiología , Infecciones Urinarias/etiología , Neoplasias Urológicas/etiología , Adulto , Femenino , Humanos , Incidencia , Cálculos Renales/epidemiología , Cálculos Renales/patología , Masculino , Pronóstico , República de Corea/epidemiología , Tasa de Supervivencia , Obstrucción Ureteral/epidemiología , Obstrucción Ureteral/patología , Infecciones Urinarias/epidemiología , Infecciones Urinarias/patología , Neoplasias Urológicas/epidemiología , Neoplasias Urológicas/patologíaRESUMEN
BACKGROUND: Native valves infective endocarditis due to Escherichia coli is still a rare disease and a particular virulence of some E.coli isolate may be suspected. CASE PRESENTATION: A 79-year-old woman presented during the post-operative period of an orthopedic surgery a urinary tract infection following obstructive ureteral lithiasis. E. coli was isolated from a pure culture of urine and blood sampled simultaneously. After evidence of sustained E.coli septicemia, further investigations revealed acute cholecystitis with the same micro-organism in biliary drainage and a native valve mitral endocarditis. E.coli was identified as O2:K7:H6, phylogenetic group B2, ST141, and presented several putative and proven virulence genes. The present isolate can be classified as both extra-intestinal pathogenic E.coli (ExPECJJ) and uropathogenic E. coli (UPECHM). CONCLUSIONS: The relationship between the virulent factors present in ExPEC strains and some serotypes of E. coli that could facilitate the adherence to cardiac valves warrants further investigation.
Asunto(s)
Endocarditis/diagnóstico , Escherichia coli Patógena Extraintestinal/aislamiento & purificación , Anciano , Animales , Endocarditis/microbiología , Escherichia coli Patógena Extraintestinal/clasificación , Escherichia coli Patógena Extraintestinal/patogenicidad , Femenino , Humanos , Procedimientos Ortopédicos/efectos adversos , Filogenia , Periodo Posoperatorio , Infecciones Urinarias/microbiología , Infecciones Urinarias/patología , Urolitiasis/cirugía , Virulencia/genéticaRESUMEN
BACKGROUND: Complicated urinary tract infection (cUTI) is common among hospitalized patients. Though carbapenems are an effective treatment in the face of rising resistance, overuse drives carbapenem resistance (CR). We hypothesized that resistance to routinely used antimicrobials is common, and, despite frequent use of carbapenems, associated with an increased risk of inappropriate empiric treatment (IET), which in turn worsens clinical outcomes. METHODS: We conducted a retrospective cohort study of patients hospitalized with a culture-positive non-CR cUTI. Triple resistance (TR) was defined as resistance to > 3 of the following: 3rd generation cephalosporins, fluoroquinolones, trimethoprim-sulfamethoxazole, fosfomycin, and nitrofurantoin. Multivariable models quantified the impact of TR and inappropriate empiric therapy (IET) on mortality, hospital LOS, and costs. RESULTS: Among 23,331 patients with cUTI, 3040 (13.0%) had a TR pathogen. Compared to patients with non-TR, those with TR were more likely male (57.6% vs. 47.7%, p < 0.001), black (17.9% vs. 13.6%, p < 0.001), and in the South (46.3% vs. 41.5%, p < 0.001). Patients with TR had higher chronic (median [IQR] Charlson score 3 [2, 4] vs. 2 [1, 4], p < 0.001) and acute (mechanical ventilation 7.0% vs. 5.0%, p < 0.001; ICU admission 22.3% vs. 18.6%, p < 0.001) disease burden. Despite greater prevalence of empiric carbapenem exposure (43.3% vs. 16.2%, p < 0.001), patient with TR were also more likely to receive IET (19.6% vs. 5.4%, p < 0.001) than those with non-TR. Although mortality was similar between groups, TR added 0.38 (95% CI 0.18, 0.49) days to LOS, and $754 (95% CI $406, $1103) to hospital costs. Both TR and IET impacted the outcomes among cUTI patients whose UTI was not catheter-associated (CAUTI), but had no effect on outcomes in CAUTI. CONCLUSIONS: TR occurs in 1 in 8 patients hospitalized with cUTI. It is associated with an increase in the risk of IET exposure, as well as a modest attributable prolongation of LOS and increase in total costs, particularly in the setting of non-CAUTI.
Asunto(s)
Antibacterianos/uso terapéutico , Farmacorresistencia Bacteriana Múltiple , Infecciones Urinarias/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Carbapenémicos/uso terapéutico , Enfermedad Crónica , Combinación de Medicamentos , Fluoroquinolonas/uso terapéutico , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Riesgo , Sulfadoxina/uso terapéutico , Trimetoprim/uso terapéutico , Estados Unidos/epidemiología , Infecciones Urinarias/epidemiología , Infecciones Urinarias/patologíaRESUMEN
BACKGROUND: Upper urinary tract infection (UTI) or pyelonephritis may increase the pathogenesis rate and risk of severe complications in children due to kidney atrophy. OBJECTIVE: A set of clinical symptoms, laboratory markers, and ultrasound findings were assessed to achieve the early diagnosis and prognosis of pyelonephritis in hospitalized pediatrics. METHODS: A cross-sectional study with 104 Iranian children (95 girls and 9 boys) aged 1 month to 12 years with acute pyelonephritis during 2012-2018 was conducted. The ultrasound examination of kidneys and urinary tract during hospitalization, the incidence of clinical symptoms, and laboratory markers in blood and urine were monitored to identify the best predictive factors of early diagnosis of this bacterial infection. RESULTS: Three-fourth of the patients had one of the four clinical symptoms of abdominal pain, constipation, dysuria, and vomiting, while others were asymptomatic. A much frequency of pyuria (88.46%), Escherichia coli in urine (92.31%), leukocytosis (81.73%), and high ESR (> 10 mm/h, 92.30%) and CRP (> 10 mg/L, 82.82%) was observed. The kidney and urinary tract ultrasonography only in 32.7% of children revealed findings in favor of pyelonephritis (cystitis, ureteral stones, and hydronephrosis). CONCLUSION: There was a high frequency of clinical signs and laboratory markers associated with pyelonephritis. Ultrasound alone was not an efficient tool to track febrile UTI as most patients presented normal sonography.
Asunto(s)
Pielonefritis/diagnóstico , Biomarcadores/sangre , Biomarcadores/orina , Niño , Preescolar , Estudios Transversales , Femenino , Humanos , Lactante , Irán/epidemiología , Riñón/diagnóstico por imagen , Riñón/patología , Masculino , Pielonefritis/patología , Pielonefritis/fisiopatología , Estudios Retrospectivos , Ultrasonografía , Infecciones Urinarias/diagnóstico , Infecciones Urinarias/patología , Infecciones Urinarias/fisiopatologíaRESUMEN
BACKGROUND: Uropathogenic Escherichia coli (UPEC) are frequent pathogens worldwide, impacting on the morbidity and economic costs associated with antimicrobial treatment. OBJECTIVES: We report two novel mutations associated with polymyxin-B resistance in an UPEC isolate collected in 2019. METHODS: Isolate was submitted to antimicrobial susceptibility testing including broth microdilution for polymyxin B. Whole genome was sequenced and analyzed. RESULTS: Polymyxin-B total inhibition occurred at 16 mg/L (resistant). UPEC isolate was assigned to the phylogroup D, serotype O117:H4, and Sequence Type 69. mcr genes were not detected, but two novel mutations in the pmrA/basS (A80S) and pmrB/basR (D149N) genes were identified. CONCLUSIONS: The occurrence of non-mcr polymyxin resistance in E. coli from extraintestinal infections underscores the need of a continuous surveillance of this evolving pathogen.
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Proteínas Bacterianas/genética , Farmacorresistencia Bacteriana Múltiple/genética , Factores de Transcripción/genética , Escherichia coli Uropatógena/genética , Antibacterianos/farmacología , Humanos , Mutación , Filogenia , Polimixina B/farmacología , Infecciones Urinarias/microbiología , Infecciones Urinarias/patología , Escherichia coli Uropatógena/clasificación , Escherichia coli Uropatógena/efectos de los fármacos , Escherichia coli Uropatógena/aislamiento & purificaciónRESUMEN
BACKGROUND Renal parenchymal damage and scarring usually is associated with urinary tract infection (UTI), whereas the impact of vesicoureteral reflux (VUR) on the kidneys is unclear. We aimed to compare kidneys with all grades of VUR (grades Io-V) and those without VUR by using direct radionuclide cystography, voiding cystourethrography, and findings from 99mTc-DMSA scintigraphy (DMSA scan). MATERIAL AND METHODS The present analysis included 253 renal ureteral units (RUU) from 129 children with VUR and recurrent UTI and children with a single febrile UTI associated with abnormal ultrasonographic findings. The 6 grades of VUR (Io, I, II, III, IV, and V) and 35 RUUs without VUR were divided into 4 groups: 1. Non-dilated VUR (grades Io-II); 2. Mildly dilated VUR (grade III); 3. Dilated VUR (grades IV-V); and 4. The control group. RESULTS DMSA scanning showed significant differences between the groups with non-dilated VUR, grade III VUR, grades IV-V VUR, and the control group in kidney width (χ²=30.5; P<0.001); position and shape (χ²=30.6; P<0.001); intensity of activity (χ²=38.1; P<0.001); distribution of activity (χ²=34.5; P<0.001); and existence of scars (χ²=16; P<0.001). The probability of abnormalities on DMSA scans increased with the VUR grade. However, inside the groups of dilated and non-dilated VUR we found no significant statistical differences between those characteristics. CONCLUSIONS Our results indicate that kidneys without VUR or with non-dilated lateral VUR and dilated VUR on the contralateral side represent 2 different categories of parenchymal changes.
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Riñón/patología , Reflujo Vesicoureteral/diagnóstico por imagen , Niño , Preescolar , Cicatriz/diagnóstico por imagen , Cicatriz/metabolismo , Cicatriz/patología , Femenino , Humanos , Lactante , Recién Nacido , Riñón/diagnóstico por imagen , Riñón/metabolismo , Masculino , Tejido Parenquimatoso/diagnóstico por imagen , Tejido Parenquimatoso/metabolismo , Tejido Parenquimatoso/patología , Cintigrafía , Radiofármacos , Ácido Dimercaptosuccínico de Tecnecio Tc 99m , Uréter/diagnóstico por imagen , Uréter/patología , Infecciones Urinarias/diagnóstico por imagen , Infecciones Urinarias/metabolismo , Infecciones Urinarias/patología , Micción/fisiología , Reflujo Vesicoureteral/metabolismo , Reflujo Vesicoureteral/patologíaRESUMEN
BACKGROUND: Renal scarring is a serious complication in recurrent urinary tract infections (UTIs). Vitamin D deficiency has also been reported to be a risk factor for UTIs although, to date, no association between vitamin D deficiency and renal scarring has yet been identified. In the present study, it was investigated whether vitamin D deficiency may be a risk factor for renal scarring in patients with recurrent UTIs. METHODS: The study included patients between the ages of 1 and 18 years who were admitted to the pediatric nephrology department of the center between November 1, 2018 and November 1, 2019 and who were diagnosed with recurrent UTIs. The medical records of the patients were reviewed for the collection of demographic data, vitamin D levels, ultrasonography results and scintigraphic investigations with 99m-technetium dimercaptosuccinic acid (99m Tc-DMSA). The patients were divided into two groups: those with and without renal scarring, diagnosed via 99m Tc-DMSA. The vitamin D levels and other parameters of the two groups were compared. RESULTS: Vitamin D deficiency (<20 ng/mL) was observed in 73.9% of the patients without renal scarring, and in 94.1% of those with renal scarring (P = 0.015). A logistic regression analysis revealed vitamin D deficiency to be an independent risk factor for renal scarring in patients with recurrent UTIs (OR = 0.796 [0.691-0.917]). CONCLUSIONS: Vitamin D deficiency is found to be a risk factor for renal scarring in patients with recurrent UTIs. Vitamin D treatment may contribute to the prevention of renal scarring in patients with recurrent UTI.
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Infecciones Urinarias , Reflujo Vesicoureteral , Deficiencia de Vitamina D , Adolescente , Niño , Preescolar , Cicatriz/etiología , Humanos , Lactante , Riñón/patología , Recurrencia , Factores de Riesgo , Ácido Dimercaptosuccínico de Tecnecio Tc 99m , Infecciones Urinarias/complicaciones , Infecciones Urinarias/patología , Deficiencia de Vitamina D/complicacionesRESUMEN
PURPOSE: To investigate the relationship between bladder debris found on renal and bladder ultrasonography (RBUS) and the first febrile urinary tract infection (UTI) episode in children under 2 years old. METHODS: We retrospectively reviewed the data of children aged <2 years with the first febrile UTI. We recorded bladder debris on RBUS and other findings (blood test, urinalysis, and urine culture). Other RBUS findings (renal pelvis debris, renal parenchymal change, wall thickening, and renal collecting system [RCS] dilatation) were recorded. Patients were divided into the debris (D) and non-D groups. RESULTS: Of 128 patients (boys: girls = 81:47, mean age = 5.6 ± 4.2 months), 24 (18.8%) had bladder debris. The mean C-reactive protein (CRP) levels were higher in the D group (6.1 ± 4.0 vs 4.3 ± 3.5, P = .03). Twenty-one patients in the D group (87.5%) had hematuria (odds ratio = 3.706, 95% confidence interval = 1.035-13.267, P = .04). No significant differences were seen in the urine culture results between both groups. Significant associations were seen between bladder debris and other RBUS findings such as debris in renal pelvis, renal parenchymal change, and RCS wall thickening. CONCLUSION: Bladder debris on RBUS is a common finding in children aged <2 years during the first febrile UTI. Bladder debris was related to higher CRP levels, hematuria and sonographic findings, but not to urine culture results.