RESUMEN
BACKGROUND: Infection with multiple cytomegalovirus (CMV) strains (mixed infection) was reported in a variety of hosts. As the virus genetic diversity in primary CMV infection and the changes over time remain incompletely defined, we examined CMV diversity and changes in diversity over time in healthy adolescent females who participated in a phase 2 CMV gB/MF59 vaccine trial. METHODS: CMV genetic diversity was determined by genotyping of 5 genes-gB (UL55), gH (UL75), gN (UL73), US28, and UL144-in urine, saliva, and plasma samples from 15 study subjects. RESULTS: At the time of primary infection, 5 of 12 (42%) urine samples had multiple virus strains, and 50% of vaccine recipients were infected with gB1 genotype (vaccine strain). Mixed infection was documented in all 15 subjects within 3 months after primary infection, and the majority had different CMV genotypes in different compartments. Changes in genotypes over time were observed in all subjects. CONCLUSIONS: Infection with multiple CMV genotypes was common during primary infection and further diversification occurred over time. Infection with gB1 genotype in vaccine recipients suggests a lack of strain-specific protection from the vaccine. As only 5 polymorphic genes were assessed, this study likely underestimated the true genetic diversity in primary CMV infection.
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Infecciones por Citomegalovirus/prevención & control , Vacunas contra Citomegalovirus/uso terapéutico , Citomegalovirus/genética , Polimorfismo Genético , Vacunación , Adolescente , Coinfección/diagnóstico , Coinfección/virología , Infecciones por Citomegalovirus/diagnóstico , Infecciones por Citomegalovirus/virología , Método Doble Ciego , Femenino , Genotipo , Humanos , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/orina , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Quimiocina/sangre , Receptores de Quimiocina/genética , Saliva/virología , Proteínas del Envoltorio Viral/sangre , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/orina , Carga Viral , Proteínas Virales/sangre , Proteínas Virales/genética , Proteínas Virales/orinaRESUMEN
Ischemia-reperfusion injury represents one of the most common causes of acute kidney injury, a serious and often deadly condition that affects up to 20% of all hospitalized patients in the United States. However, the current standard assay used universally for the diagnosis of acute kidney injury, serum creatinine, does not detect renal damage early in its course. Serendipitously, we found that the immunofluorescent signal of the constitutive podocyte marker podoplanin fades in the glomerulus and intensifies in the tubulointerstitial compartment of the kidney shortly after ischemia-reperfusion injury in 8- to 10-wk-old male C57Bl/6j mice. Therefore, we sought to define the appearance and course of the podoplanin-positive signal in the kidney after ischemia-reperfusion injury. The tubulointerstitial podoplanin-positive signal increased as early as 2 h but persisted for 7 days after ischemia-reperfusion injury. In addition, the strength of this tubulointerstitial signal was directly proportional to the severity of ischemia, and its location shifted from the tubules to interstitial cells over time. Finally, we detected podoplanin in the urine of mice after ischemia, and we observed that an increase in the urine podoplanin-to-creatinine ratio correlated strongly with the onset of renal ischemia-reperfusion injury. Our findings indicate that the measurement of urine podoplanin harbors promising potential for use as a novel biomarker for the early detection of ischemia-reperfusion injury of the kidney.
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Lesión Renal Aguda/orina , Glicoproteínas de Membrana/orina , Podocitos/metabolismo , Daño por Reperfusión/orina , Lesión Renal Aguda/patología , Animales , Biomarcadores/orina , Creatinina/orina , Modelos Animales de Enfermedad , Masculino , Ratones Endogámicos C57BL , Podocitos/patología , Daño por Reperfusión/patología , Índice de Severidad de la Enfermedad , Factores de Tiempo , Regulación hacia ArribaRESUMEN
Podocyte loss and changes to the complex morphology are major causes of chronic kidney disease (CKD). As the incidence is continuously increasing over the last decades without sufficient treatment, it is important to find predicting biomarkers. Therefore, we measured urinary mRNA levels of podocyte genes NPHS1, NPHS2, PODXL and BDNF, KIM-1, CTSL by qRT-PCR of 120 CKD patients. We showed a strong correlation between BDNF and the kidney injury marker KIM-1, which were also correlated with NPHS1, suggesting podocytes as a contributing source. In human biopsies, BDNF was localized in the cell body and major processes of podocytes. In glomeruli of diabetic nephropathy patients, we found a strong BDNF signal in the remaining podocytes. An inhibition of the BDNF receptor TrkB resulted in enhanced podocyte dedifferentiation. The knockdown of the orthologue resulted in pericardial oedema formation and lowered viability of zebrafish larvae. We found an enlarged Bowman's space, dilated glomerular capillaries, podocyte loss and an impaired glomerular filtration. We demonstrated that BDNF is essential for glomerular development, morphology and function and the expression of BDNF and KIM-1 is highly correlated in urine cells of CKD patients. Therefore, BDNF mRNA in urine cells could serve as a potential CKD biomarker.
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Factor Neurotrófico Derivado del Encéfalo/genética , Nefropatías Diabéticas/genética , Receptor Celular 1 del Virus de la Hepatitis A/genética , Glicoproteínas de Membrana/genética , Receptor trkB/genética , Insuficiencia Renal Crónica/genética , Anciano , Animales , Factor Neurotrófico Derivado del Encéfalo/orina , Nefropatías Diabéticas/patología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica/genética , Humanos , Riñón/metabolismo , Riñón/patología , Glomérulos Renales/metabolismo , Glomérulos Renales/patología , Masculino , Glicoproteínas de Membrana/orina , Persona de Mediana Edad , Podocitos/metabolismo , Podocitos/patología , Proteinuria/genética , Proteinuria/patología , ARN Mensajero/genética , Receptor trkB/orina , Insuficiencia Renal Crónica/patología , Insuficiencia Renal Crónica/orina , Pez Cebra/genéticaRESUMEN
BACKGROUND: Reflux nephropathy is the most serious complication of vesicoureteral reflux (VUR). The aim of this study was to assess the role of urinary levels of neutrophil-gelatinase-associated lipocalin (NGAL),kidney injury molecule-1 (KIM-1), and liver-type fatty-acid-binding protein (L-FABP) in the early diagnosis of reflux nephropathy in patients with VUR. METHODS: This study assessed 123 patients with primary VUR and 30 healthy children as a control group. The children were divided into five groups: Group A, patients with VUR and renal parenchymal scarring (RPS); Group B, patients with VUR and without RPS; Group C, patients with RPS and resolved VUR; Group D, patients with resolved VUR and without RPS; Group E, healthy reference group. RESULTS: Median urinary NGAL (uNGAL)/Creatinine (Cr) was significantly higher in patients with than those without RPS and the control group (p = 0.0001). Median uKIM-1/Cr was similar in all groups (p = 0.417). Median uL-FABP/Cr was significantly higher in patients with RPS than in the reference group (p < 0.05). CONCLUSIONS: Urinary NGAL levels may be used as a noninvasive diagnostic marker for predicting renal scarring in reflux nephropathy.
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Proteínas de Fase Aguda/orina , Cicatriz/etiología , Proteínas de Unión a Ácidos Grasos/orina , Enfermedades Renales/etiología , Lipocalinas/orina , Glicoproteínas de Membrana/orina , Proteínas Proto-Oncogénicas/orina , Reflujo Vesicoureteral/orina , Adolescente , Área Bajo la Curva , Biomarcadores/orina , Estudios de Casos y Controles , Niño , Preescolar , Cicatriz/patología , Creatinina/orina , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Enfermedades Renales/patología , Lipocalina 2 , Masculino , Valor Predictivo de las Pruebas , Estudios Prospectivos , Curva ROC , Receptores Virales , Factores de Riesgo , Urinálisis , Reflujo Vesicoureteral/complicaciones , Reflujo Vesicoureteral/diagnósticoRESUMEN
Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.
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Lesión Renal Aguda/orina , Biomarcadores/orina , Diuréticos , Furosemida , Lesión Renal Aguda/sangre , Lesión Renal Aguda/mortalidad , Proteínas de Fase Aguda/orina , Anciano , Albuminuria/orina , Biomarcadores/sangre , Creatinina/orina , Progresión de la Enfermedad , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Proteínas de Unión a Factor de Crecimiento Similar a la Insulina/orina , Interleucina-18/orina , Lipocalina 2 , Lipocalinas/sangre , Lipocalinas/orina , Masculino , Glicoproteínas de Membrana/orina , Persona de Mediana Edad , Proteínas Proto-Oncogénicas/sangre , Proteínas Proto-Oncogénicas/orina , Receptores Virales , Índice de Severidad de la Enfermedad , Sodio/sangre , Sodio/orina , Inhibidor Tisular de Metaloproteinasa-2/orina , Uromodulina/orinaRESUMEN
OBJECTIVE: We evaluated whether urinary excretion of tubular injury markers could be useful for early detection of gentamicin (GM)-induced renal damage in neonates. STUDY DESIGN: We conducted a prospective, observational trial in neonates admitted to the neonatal intensive care unit (26 GM treated, 20 control). Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-ß-D-glucosaminidase (NAG), and π- and α-glutathione-S-transferase (GSTP1-1 and GSTA1-1) were measured every 2 hours during admission and compared with serum creatinine (sCr) and urine output. RESULTS: Nine neonates developed AKI during the course of the study. The peak in excretion of urinary biomarkers preceded the peak in sCr (p < 0.0001). GM administration resulted in a more pronounced increase of sCr compared with control (13 [12-28] vs. 10 µmol/L [8.5-17]; p < 0.05). The urinary excretion of NAG (178 [104-698] vs. 32 ng/mol Cr [9-82]; p < 0.001) and NGAL (569 [168-1,681] vs. 222 ng/mol Cr [90-497]; p < 0.05) was higher in the GM group compared with control and preceded the peak of sCr and urine output decrease. CONCLUSION: GM administration to neonates is associated with renal damage reflected by a more pronounced increase in sCr preceded by urinary excretion of biomarkers. Urinary biomarkers may be useful for earlier identification of renal injury in neonates.
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Lesión Renal Aguda/metabolismo , Antibacterianos/efectos adversos , Gentamicinas/efectos adversos , Edad Gestacional , Acetilglucosaminidasa/orina , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/diagnóstico , Proteínas de Fase Aguda/orina , Asfixia Neonatal , Biomarcadores/sangre , Biomarcadores/orina , Estudios de Cohortes , Anomalías Congénitas , Creatinina/sangre , Femenino , Gutatión-S-Transferasa pi/orina , Glutatión Transferasa/orina , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Recién Nacido , Recien Nacido Prematuro , Unidades de Cuidado Intensivo Neonatal , Lipocalina 2 , Lipocalinas/orina , Masculino , Glicoproteínas de Membrana/orina , Estudios Prospectivos , Proteínas Proto-Oncogénicas/orina , Receptores ViralesRESUMEN
On the basis of scientific literature, there is growing evidence that KIM-1 and NGAL are interesting and promising biomarkers not only in acute and chronic inflammatory processes but also in oncogenesis. There are a number of studies which investigate their possible use in diagnosis, treatment and monitoring of therapy effectiveness. The results of recent research suggests that they may play an important role in standard oncology practice. Simultaneous measurement of KIM-1 and NGAL in urine can play a crucial role in carcinogenesis assessment and cancer progression. In the future, they can become rapid diagnostic indicators, which allow one to determine cancer subtype leading to biopsy replacement and therapy improvement. In the present work, beside biochemical characteristics of KIM-1 and NGAL, we will also discuss their role in the diagnosis and assessment of development of cancer.
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Proteínas de Fase Aguda/orina , Lipocalinas/orina , Glicoproteínas de Membrana/orina , Neoplasias/diagnóstico , Proteínas Proto-Oncogénicas/orina , Proteínas de Fase Aguda/metabolismo , Biomarcadores/orina , Progresión de la Enfermedad , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Lipocalina 2 , Lipocalinas/metabolismo , Glicoproteínas de Membrana/metabolismo , Neoplasias/orina , Proteínas Proto-Oncogénicas/metabolismo , Receptores Virales/metabolismo , Toma de Muestras de OrinaRESUMEN
AIM: To estimate the urinary excretion of KIM-1 in groups of patients with varying clinical activity of chronic glomerulonephritis (CGN) and to determine the possibility of using the urinary KIM-1 concentration as a criterion for predicting the course of CGN. SUBJECTS AND METHODS: A total of 47 patients with CGN were examined. Group 1 included 10 patients with nephrotic syndrome (NS) and decreased glomerular filtration rate (GFR); Group 2 consisted of 16 patients with NS and normal GFR; Group 3 comprised 10 patients with partial remission of NS; Group 4 included 11 patients with CGN, hematuria, moderate proteinuria, and normal GFR. A control group consisted of 9 healthy individuals. In the examined groups, urinary KIM-1 concentrations were estimated using an indirect immunoassay. RESULTS: The urinary KIM-1 excretion in the patients with CGN was higher than that in the healthy individuals (p <0.0001), at the same time, in the average the KIM-1 excretion was statistically significantly higher in the patients with proteinuria than in those with hematuria (p=0.01). The highest levels were registered in Group 1; Group 2 was intermediate in the level of KIM-1 excretion and the difference between Groups 3 and 4 proved to be statistically insignificant. The lowest levels were noted in Group 4 and in the controls; the differences between the groups were statistically insignificant. In the patients with CGN, the level of KIM-1 excretion was established to correlate with all indicators of NS severity. The value of the determination of KIM-1 as a risk factor of persistent/refractory NS was estimated. The results of constructing the ROC-curve indicate that KIM-1 levels higher than 2.34 ng/ml could predict NS persistence in CGN patients with a high sensitivity and specificity. CONCLUSION: Urinary KIM-1 levels may be used to estimate the activity of CGN with NS and to evaluate the efficiency of treatment. The results of the study substantiate the search for ways of pharmacological blockade of KIM-1 production in the kidney in order to optimize the methods that impact on the pathogenesis of CGN progression.
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Glomerulonefritis , Glicoproteínas de Membrana/orina , Síndrome Nefrótico , Adulto , Biomarcadores/orina , Enfermedad Crónica , Progresión de la Enfermedad , Femenino , Glomerulonefritis/complicaciones , Glomerulonefritis/diagnóstico , Glomerulonefritis/fisiopatología , Glomerulonefritis/orina , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Masculino , Persona de Mediana Edad , Síndrome Nefrótico/diagnóstico , Síndrome Nefrótico/etiología , Gravedad del Paciente , Pronóstico , Receptores Virales , Eliminación Renal/fisiología , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To investigate the values of urinary netrin-1 and kidney injury molecule-1 (KIM-1) in the early diagnosis of acute kidney injury (AKI) induced by neonatal asphyxia. METHODS: A total of 80 full-term neonates with asphyxia were enrolled (mild asphyxia: 34 neonates; severe asphyxia: 46 neonates). Forty normal full-term neonates were selected as the control group. Urinary samples were collected from the neonates in the three groups within 12 hours and 13-48 hours after birth. ELISA was applied to measure urinary levels of netrin-1 and KIM-1. Peripheral venous blood samples were also collected to measure serum creatinine (Scr) level. RESULTS: Compared with the control group, the asphyxia group had significantly higher urinary levels of netrin-1 and KIM-1 within 48 hours after birth and a significantly higher Scr level within 13-48 hours after birth (P<0.05). The neonates in the AKI group had significantly higher urinary levels of netrin-1 and KIM-1 and Scr level within 48 hours after birth than those in the non-AKI group (P<0.05). The areas under the receiver operating characteristic curve for urinary netrin-1 and KIM-1 levels within 12 hours after birth to predict AKI after asphyxia were 0.878 (95% CI: 0.775-0.981; P<0.01) and 0.899 (95% CI: 0.829-0.969; P<0.01), respectively. Any two indicators of urinary netrin-1 level, urinary KIM-1 level, and Scr level within 12 hours after neonatal asphyxia had a positive correlation (P<0.05). CONCLUSIONS: Urinary netrin-1 and KIM-1 levels increase significantly when neonates with asphyxia develop AKI. Urinary netrin-1 and KIM-1 can be used as indicators for the early diagnosis of AKI after asphyxia.
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Lesión Renal Aguda/diagnóstico , Asfixia Neonatal/complicaciones , Glicoproteínas de Membrana/orina , Factores de Crecimiento Nervioso/orina , Proteínas Supresoras de Tumor/orina , Lesión Renal Aguda/orina , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Recién Nacido , Masculino , Netrina-1 , Receptores ViralesRESUMEN
AIMS/HYPOTHESIS: Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-ß-D-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes. METHODS: Biomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP. RESULTS: During follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p < 0.001 for KIM-1/Cr, NAG/Cr and L-FABP; p = 0.006 for NGAL/Cr). After multivariable adjustment, NGAL/Cr was positively associated with ESRD (HR 1.59, 95% CI 1.20, 2.11) and mortality (HR 1.39, 95% CI 1.06, 1.82); L-FABP/Cr was inversely associated with ESRD (HR [for highest vs lowest tertile] 0.40, 95% CI 0.19, 0.83). Addition of NGAL/Cr to models that included albuminuria and glomerular filtration rate increased the c-statistic for predicting ESRD from 0.828 to 0.833 (p = 0.001) and for death from 0.710 to 0.722 (p = 0.018). Addition of L-FABP/Cr increased the c-statistic for ESRD from 0.828 to 0.832 (p = 0.042). CONCLUSIONS/INTERPRETATION: In Pima Indians with type 2 diabetes, urinary concentrations of NGAL and L-FABP are associated with important health outcomes, but they are unlikely to add to risk prediction with standard markers in a clinically meaningful way given the small increase in the c-statistic.
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Diabetes Mellitus Tipo 2/mortalidad , Diabetes Mellitus Tipo 2/orina , Nefropatías Diabéticas/mortalidad , Nefropatías Diabéticas/orina , Indígenas Norteamericanos , Fallo Renal Crónico/mortalidad , Fallo Renal Crónico/orina , Proteínas de Fase Aguda/orina , Adolescente , Adulto , Anciano , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/etnología , Nefropatías Diabéticas/etnología , Proteínas de Unión a Ácidos Grasos/orina , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Incidencia , Indígenas Norteamericanos/estadística & datos numéricos , Fallo Renal Crónico/etnología , Lipocalina 2 , Lipocalinas/orina , Masculino , Glicoproteínas de Membrana/orina , Persona de Mediana Edad , Proteínas de Neoplasias/orina , Proteínas Proto-Oncogénicas/orina , Receptores Virales , Adulto JovenRESUMEN
Biomarker studies for early detection of acute kidney injury (AKI) have been limited by nonselective testing and uncertainties in using small changes in serum creatinine as a reference standard. Here we examine the ability of urine L-type fatty acid-binding protein (L-FABP), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), and kidney injury molecule-1 (KIM-1) to predict injury progression, dialysis, or death within 7 days in critically ill adults with early AKI. Of 152 patients with known baseline creatinine examined, 36 experienced the composite outcome. Urine L-FABP demonstrated an area under the receiver-operating characteristic curve (AUC-ROC) of 0.79 (95% confidence interval 0.70-0.86), which improved to 0.82 (95% confidence interval 0.75-0.90) when added to the clinical model (AUC-ROC of 0.74). Urine NGAL, IL-18, and KIM-1 had AUC-ROCs of 0.65, 0.64, and 0.62, respectively, but did not significantly improve discrimination of the clinical model. The category-free net reclassification index improved with urine L-FABP (total net reclassification index for nonevents 31.0%) and urine NGAL (total net reclassification index for events 33.3%). However, only urine L-FABP significantly improved the integrated discrimination index. Thus, modest early changes in serum creatinine can help target biomarker measurement for determining prognosis with urine L-FABP, providing independent and additive prognostic information when combined with clinical predictors.
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Lesión Renal Aguda/orina , Proteínas de Unión a Ácidos Grasos/orina , APACHE , Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/terapia , Proteínas de Fase Aguda/orina , Anciano , Área Bajo la Curva , Biomarcadores/sangre , Biomarcadores/orina , Creatinina/sangre , Enfermedad Crítica , Progresión de la Enfermedad , Diagnóstico Precoz , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Interleucina-18/orina , Lipocalina 2 , Lipocalinas/orina , Masculino , Glicoproteínas de Membrana/orina , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Proteínas Proto-Oncogénicas/orina , Curva ROC , Receptores Virales , Diálisis RenalRESUMEN
UNLABELLED: The UL128 complex of human cytomegalovirus (CMV) is a major determinant of viral entry into epithelial and endothelial cells and a target for vaccine development. The UL/b' region of rhesus CMV contains several open reading frames, including orthologs of the UL128 complex. We recently showed that the coding content of the rhesus CMV (RhCMV) UL/b' region predicts acute endothelial tropism and long-term shedding in vivo in the rhesus macaque model of CMV infection. The laboratory-passaged RhCMV 180.92 strain has a truncated UL/b' region but an intact UL128 complex. To investigate whether the presence of the UL128 complex alone was sufficient to confer endothelial and epithelial tropism in vivo, we investigated tissue dissemination and viral excretion following experimental RhCMV 180.92 inoculation of RhCMV-seronegative rhesus macaques. We show the presence of at least two virus variants in the RhCMV 180.92 infectious virus stock. A rare variant noted for a nontruncated wild-type-virus-like UL/b' region, rapidly emerged during in vivo replication and showed high-level replication in blood and tissues and excretion in urine and saliva, features similar to those previously reported in naturally occurring wild-type RhCMV infection. In contrast, the predominant truncated version of RhCMV 180.92 showed significantly lower plasma DNAemia and limited tissue dissemination and viral shedding. These data demonstrate that the truncated RhCMV 180.92 variant is attenuated in vivo and suggest that additional UL/b' genes, besides the UL128 complex, are required for optimal in vivo CMV replication and dissemination. IMPORTANCE: An effective vaccine against human CMV infection will need to target genes that are essential for virus propagation and transmission. The human CMV UL128 complex represents one such candidate antigen since it is essential for endothelial and epithelial cell tropism, and is a target for neutralizing antibodies in CMV-infected individuals. In this study, we used the rhesus macaque animal model of CMV infection to investigate the in vivo function of the UL128 complex. Using experimental infection of rhesus macaques with a rhesus CMV virus variant that contained an intact UL128 complex but was missing several other genes, we show that the presence of the UL128 complex alone is not sufficient for widespread tissue dissemination and virus excretion. These data highlight the importance of in vivo studies in evaluating human CMV gene function and suggest that additional UL/b' genes are required for optimal CMV dissemination and transmission.
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Citomegalovirus/genética , Citomegalovirus/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/metabolismo , Proteínas Virales/genética , Proteínas Virales/metabolismo , Esparcimiento de Virus/genética , Animales , Línea Celular , Infecciones por Citomegalovirus/virología , Modelos Animales de Enfermedad , Endotelio/virología , Epitelio/virología , Fibroblastos/virología , Humanos , Macaca mulatta/virología , Glicoproteínas de Membrana/orina , Sistemas de Lectura Abierta , Proteínas del Envoltorio Viral/orina , Proteínas Virales/orina , Tropismo Viral/genética , Replicación Viral/genéticaRESUMEN
PURPOSE OF REVIEW: Although recovery of kidney function following acute kidney injury (AKI) is not uncommon, it is often incomplete and associated with the development of chronic kidney disease (CKD). In order to improve AKI management, there is a critical need to develop a series of tests and biomarkers to detect renal function recovery and identify patients with progressive kidney disease. This article examines the current body of literature in the field. RECENT FINDINGS: The recently established consensus definition for AKI has resulted in significant advances in pathophysiologic understanding, patient identification, and disease prognostication. Unfortunately, the definition for renal recovery following AKI remains inconsistent. Proteinuria and microalbuminuria - classical markers of CKD progression - have been used and validated for the progression of AKI to CKD. Data on the performance of other biomarkers of kidney repair and the progression toward CKD are very limited. Specifically, the role of novel biomarkers including neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, and nephronectin (NPNT) in the recovery process has been studied, but it has not reached the point of widespread clinical implementation. SUMMARY: There is a critical need for translational and clinical investigations to verify the performance of potential kidney injury repair and progression biomarker candidates in the clinical setting.
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Lesión Renal Aguda/orina , Proteínas de Fase Aguda/orina , Proteínas de la Matriz Extracelular/análisis , Lipocalinas/orina , Glicoproteínas de Membrana/orina , Proteínas Proto-Oncogénicas/orina , Lesión Renal Aguda/fisiopatología , Animales , Biomarcadores/orina , Progresión de la Enfermedad , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Necrosis Tubular Aguda/metabolismo , Túbulos Renales/química , Lipocalina 2 , Receptores Virales , Recuperación de la FunciónRESUMEN
UNLABELLED: Acute kidney injury (AKI) is common in patients with cirrhosis and associated with significant mortality. The most common etiologies of AKI in this setting are prerenal azotemia (PRA), acute tubular necrosis (ATN), and hepatorenal syndrome (HRS). Accurately distinguishing the etiology of AKI is critical, as treatments differ markedly. However, establishing an accurate differential diagnosis is extremely challenging. Urinary biomarkers of kidney injury distinguish structural from functional causes of AKI and may facilitate more accurate and rapid diagnoses. We conducted a multicenter, prospective cohort study of patients with cirrhosis and AKI assessing multiple biomarkers for differential diagnosis of clinically adjudicated AKI. Patients (n = 36) whose creatinine returned to within 25% of their baseline within 48 hours were diagnosed with PRA. In addition, 76 patients with progressive AKI were diagnosed by way of blinded retrospective adjudication. Of these progressors, 39 (53%) patients were diagnosed with ATN, 19 (26%) with PRA, and 16 (22%) with HRS. Median values for neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and albumin differed between etiologies and were significantly higher in patients adjudicated with ATN. The fractional excretion of sodium (FENa) was lowest in patients with HRS, 0.10%, but did not differ between those with PRA, 0.27%, or ATN, 0.31%, P = 0.54. The likelihood of being diagnosed with ATN increased step-wise with the number of biomarkers above optimal diagnostic cutoffs. CONCLUSION: Urinary biomarkers of kidney injury are elevated in patients with cirrhosis and AKI due to ATN. Incorporating biomarkers into clinical decision making has the potential to more accurately guide treatment by establishing which patients have structural injury underlying their AKI. Further research is required to document biomarkers specific to HRS.
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Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/metabolismo , Proteínas de Fase Aguda/orina , Proteínas de Unión a Ácidos Grasos/orina , Interleucina-18/orina , Lipocalinas/orina , Glicoproteínas de Membrana/orina , Proteínas Proto-Oncogénicas/orina , Adulto , Anciano , Albuminuria/diagnóstico , Albuminuria/orina , Biomarcadores/orina , Creatinina/orina , Diagnóstico Diferencial , Femenino , Tasa de Filtración Glomerular/fisiología , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Riñón/metabolismo , Lipocalina 2 , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/metabolismo , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Receptores Virales , Sodio/orinaRESUMEN
Cytomegalovirus (CMV) is the most common cause of congenital infection. This pathogen exhibits extensive genetic variability in the genes that encode structural envelope glycoproteins, regulatory proteins, and proteins that contribute to immune evasion. However, the role of specific viral strains in the outcome of congenital CMV infection is unclear. Variation in the UL55 gene encoding glycoprotein B (gB), the UL144 gene encoding TNF α-like receptor, and the US28 gene encoding ß-chemokine receptor was determined in 60 newborn infants with congenital CMV infection and 90 infants with postnatal or undefined CMV infection. CMV polymorphisms were studied in relation to disease outcome and viral load. Genotyping was performed by a sequencing analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. The results demonstrated that (1) the UL55 and US28 genotype distributions were similar among the group of congenital and postnatal CMV infection; (2) the UL144 B1 genotype was more prevalent in congenital than in postnatal infection and was detected in 70% of newborns with asymptomatic congenital infection; and (3) none of the examined genotype was significantly linked with symptomatic CMV infection. No relationship was observed between genotype and viral load. The results revealed that UL55, UL144, and US28 polymorphisms are not associated with the outcome of CMV infection in infants, but the presence of UL144 B1 genotype might be virological marker of asymptomatic infection at birth.
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Infecciones por Citomegalovirus/congénito , Infecciones por Citomegalovirus/virología , Citomegalovirus/genética , Glicoproteínas de Membrana/genética , Receptores de Quimiocina/genética , Proteínas Virales/genética , Secuencia de Aminoácidos , Infecciones Asintomáticas/epidemiología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/química , Biomarcadores/orina , Infecciones por Citomegalovirus/epidemiología , Genotipo , Humanos , Lactante , Recién Nacido , Glicoproteínas de Membrana/sangre , Glicoproteínas de Membrana/líquido cefalorraquídeo , Glicoproteínas de Membrana/orina , Filogenia , Polimorfismo Genético , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores de Quimiocina/sangre , Alineación de Secuencia , Análisis de Secuencia , Factores de Tiempo , Proteínas del Envoltorio Viral , Carga Viral , Proteínas Virales/sangre , Proteínas Virales/líquido cefalorraquídeo , Proteínas Virales/orinaRESUMEN
Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoL1 is involved in cell-free hemoglobin scavenging through association with haptoglobin-related protein. APOL1 G1/G2 variants are the strongest genetic predictors of kidney disease in the general African-American population. A single report associated APOL1 G1/G2 with sickle cell nephropathy. In 221 patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOL1 G1/G2 with proteinuria, specifically with urine albumin concentration (ß=1.1, P=0.003), observed an even stronger association with hemoglobinuria (OR=2.5, P=4.3×10(-6)), and also replicated the finding of an association with hemoglobinuria in 487 patients from the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy study (OR=2.6, P=0.003). In 25 University of Illinois sickle cell disease patients, concentrations of urine kidney injury molecule-1 correlated with urine cell-free hemoglobin concentrations (r=0.59, P=0.002). Exposing human proximal tubular cells to increasing cell-free hemoglobin led to increasing concentrations of supernatant kidney injury molecule-1 (P=0.01), reduced viability (P=0.01) and induction of HMOX1 and SOD2. HMOX1 rs743811 associated with chronic kidney disease stage (OR=3.0, P=0.0001) in the University of Illinois cohort and end-stage renal disease (OR=10.0, P=0.0003) in the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy cohort. Longer HMOX1 GT-tandem repeats (>25) were associated with lower estimated glomerular filtration rate in the University of Illinois cohort (P=0.01). Our findings point to an association of APOL1 G1/G2 with kidney disease in sickle cell disease, possibly through increased risk of hemoglobinuria, and associations of HMOX1 variants with kidney disease, possibly through reduced protection of the kidney from hemoglobin-mediated toxicity.
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Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Variación Genética , Hemoglobinas/genética , Hemoglobinas/metabolismo , Enfermedades Renales/etiología , Enfermedades Renales/metabolismo , Adulto , Apolipoproteína L1 , Apolipoproteínas/genética , Línea Celular , Estudios de Cohortes , Femenino , Expresión Génica , Predisposición Genética a la Enfermedad , Genotipo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Hemoglobinuria , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Túbulos Renales Proximales/metabolismo , Lipoproteínas HDL/genética , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/orina , Persona de Mediana Edad , Receptores Virales/genéticaRESUMEN
BACKGROUND: The new urinary and serum biomarkers are discovered and are being investigated. With them we can diagnose acute kidney injury (AKI) faster and more precisely and they also have a significant role in the outcome prediction. METHODS: The study included 22 extremely low-birth-weight neonates who were hospitalized in the neonatal intensive care units. They were divided into two groups based on serum creatinine (SCr) level-with and without AKI. Detection and quantification of urinary kidney injury molecule-1 (uKIM-1) was done on the third day of life, using commercially available KIM-1 rapid test. Subsequently, measurements were repeated only in subjects who were diagnosed with AKI, at different values of SCr. RESULTS: Logistic regression analysis showed that AKI is an independent risk factor for mortality. In a group of neonates with AKI, 50% of neonates administered the KIM-1 rapid test showed positive findings. KIM-1 rapid test was positive in patients with a wide range of SCr levels (range of 78.73-385 µmol/l), but all subjects had oliguria and died in the next 24 h. CONCLUSION: KIM-1 is a significant predictor of death. On the other hand, our study failed to prove that KIM-1 rapid test has any significance for early prediction of AKI.
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Lesión Renal Aguda/diagnóstico , Lesión Renal Aguda/orina , Recien Nacido con Peso al Nacer Extremadamente Bajo , Glicoproteínas de Membrana/orina , Lesión Renal Aguda/etiología , Lesión Renal Aguda/mortalidad , Biomarcadores/sangre , Biomarcadores/orina , Peso al Nacer , Creatinina/sangre , Femenino , Edad Gestacional , Receptor Celular 1 del Virus de la Hepatitis A , Mortalidad Hospitalaria , Humanos , Recien Nacido Extremadamente Prematuro , Recién Nacido , Unidades de Cuidado Intensivo Neonatal , Modelos Lineales , Modelos Logísticos , Oportunidad Relativa , Mortalidad Perinatal , Valor Predictivo de las Pruebas , Embarazo , Pronóstico , Estudios Prospectivos , Receptores Virales , Factores de Riesgo , UrinálisisRESUMEN
OBJECTIVES: To analyze kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (N-GAL) excretion post-intravenous contrast enhanced-CT (CE-CT) in patients with chronic kidney disease (CKD). METHODS: Patients were enrolled in a trial on hydration regimes to prevent contrast-induced acute kidney injury (CI-AKI). Blood and urine samples were taken at baseline, 4 - 6, and 48 - 96 h post CE-CT. Urinary KIM-1 and N-GAL values were normalized for urinary creatinine levels, presented as medians with 2.5 - 97.5 percentiles. RESULTS: Of the enrolled 511 patients, 10 (2%) were lost to follow-up. CI-AKI occurred in 3.9% of patients (20/501). Median KIM-1 values were 1.2 (0.1 - 7.7) at baseline, 1.3 (0.1 - 8.6) at 4 - 6 h, and 1.3 ng/mg (0.1 - 8.1) at 48 - 96 h post CE-CT (P = 0.39). Median N-GAL values were 41.0 (4.4 - 3,174.4), 48.9 (5.7 - 3,406.1), and 37.8 µg/mg (3.5 - 3,200.4), respectively (P = 0.07). The amount of KIM-1 and N-GAL excretion in follow-up was similar for patients with and without CI-AKI (P-value KIM-1 0.08, P-value N-GAL 0.73). Neither patient characteristics at baseline including severe CKD, medication use, nor contrast dose were associated with increased excretion of KIM-1 or N-GAL during follow-up. CONCLUSION: KIM-1 and N-GAL excretion were unaffected by CE-CT both in patients with and without CI-AKI, suggesting that CI-AKI was not accompanied by tubular injury. KEY POINTS: ⢠KIM-1 and N-GAL excretion were unaffected by intravenous contrast-enhanced CT (CE-CT). ⢠Patient or procedure characteristics were not associated with increased KIM-1 or N-GAL excretion. ⢠Performance of CE-CT in CKD patients is likely to be safe.
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Lesión Renal Aguda/orina , Proteínas de Fase Aguda/orina , Medios de Contraste/efectos adversos , Compuestos de Yodo/efectos adversos , Lipocalinas/orina , Glicoproteínas de Membrana/orina , Proteínas Proto-Oncogénicas/orina , Lesión Renal Aguda/sangre , Lesión Renal Aguda/inducido químicamente , Anciano , Biomarcadores/sangre , Biomarcadores/orina , Creatinina/orina , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Lipocalina 2 , Lipocalinas/sangre , Masculino , Glicoproteínas de Membrana/sangre , Proteínas Proto-Oncogénicas/sangre , Receptores Virales/sangre , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/complicaciones , Insuficiencia Renal Crónica/orina , Tomografía Computarizada por Rayos X/métodosRESUMEN
As the beginning of living-donor kidney transplantation, physicians have expressed concern about the possibility that unilateral nephrectomy can be harmful to a healthy individual. To investigate whether the elevated intra-abdominal pressure (IAP) during laparoscopic donor nephrectomy causes early damage to the remaining kidney, we evaluated urine biomarkers after laparoscopic donor nephrectomy. We measured albumin and alpha-1-microglobulin (α-1-MGB) in urine samples collected during and after open and laparoscopic donor nephrectomy and laparoscopic cholecystectomy and colectomy. Additionally, kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) were measured in urine samples collected during and after laparoscopic donor nephrectomy and colectomy. The same biomarkers were studied in patients randomly assigned to standard or low IAP during laparoscopic donor nephrectomy. We observed a peak in urinary albumin excretion during all procedures. Urine α-1-MGB rose in the postoperative period with a peak on the third postoperative day after donor nephrectomy. Urine α-1-MGB did not increase after laparoscopic cholecystectomy and colectomy. After laparoscopic nephrectomy, we observed slight increases in urine KIM-1 during surgery and in urine NGAL at day 2-3 after the procedure. After laparoscopic colectomy, both KIM-1 and NGAL were increased in the postoperative period. There were no differences between the high- and low-pressure procedure. Elevated urinary α-1-MGB suggests kidney damage after donor nephrectomy, occurring irrespective of IAP during the laparoscopic procedure.
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alfa-Globulinas/orina , Biomarcadores/orina , Nefrectomía , Proteínas de Fase Aguda/orina , Adulto , Anciano , Albúminas/química , Colecistectomía Laparoscópica , Colectomía , Creatinina/sangre , Método Doble Ciego , Femenino , Receptor Celular 1 del Virus de la Hepatitis A , Humanos , Riñón/cirugía , Laparoscopía , Lipocalina 2 , Lipocalinas/orina , Donadores Vivos , Masculino , Glicoproteínas de Membrana/orina , Persona de Mediana Edad , Periodo Posoperatorio , Presión , Proteínas Proto-Oncogénicas/orina , Receptores Virales , Factores de Tiempo , Resultado del Tratamiento , Catéteres UrinariosRESUMEN
INTRODUCTION: Children admitted to a pediatric intensive care unit (ICU) are at high risk of developing acute kidney injury (AKI). Although serum creatinine (SCr) levels are used in clinical practice, they are insensitive for early diagnosis of AKI. Urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury molecule-1 (KIM-1) are novel AKI biomarkers whose performance in pediatric ICU patients is largely unknown. In this study, we aimed to characterize uNGAL and KIM-1 patterns in children following ICU admission and to assess their properties in relation to identifying children at risk for AKI development. METHODS: From June 2010 until January 2014, we conducted a prospective observational cohort study of term-born children ages 1 day to 1 year on mechanical ventilation. Blood and urine samples were obtained every 6 to 12 hours up to 72 hours post-admission. Blood samples were assayed for SCr, and urine samples were assayed for uNGAL and KIM-1. The RIFLE (risk, injury, failure, loss, end-stage renal disease) classification as 150%, 200% or 300% of median SCr reference values was used to define AKI. RESULTS: A total of 100 children were included (80 survived). Their median age at admission was 27.7 days (interquartile range (IQR), 1.5 to 85.5). The median duration of mechanical ventilation was 5.8 days (IQR, 3.1 to 11.4). Thirty-five patients had evidence of AKI within the first 48 hours post-admission, of whom 24 (69%) already had AKI when they entered the ICU. uNGAL and KIM-1 concentrations in AKI peaked between 6 to 12 hours and between 12 to 24 hours post-admission, respectively. The maximal area under the receiver operating characteristic curve (AUC) for uNGAL was 0.815 (95% confidence interval (CI), 0.685 to 0.945, P < 0.001) at 0 to 6 hours post-admission. The discriminative ability of KIM-1 was moderate, with a largest AUC of 0.737 (95% CI, 0.628 to 0.847; P < 0.001) at 12 to 24 hours post-admission. At the optimal cutoff point (126 ng/ml), uNGAL concentration predicted AKI development correctly in 16 (84%) of 19 children, up to 24 hours before a rise in SCr became apparent. CONCLUSIONS: Levels of uNGAL and KIM-1 increase in patients with AKI following ICU admission and peak at 6 to 12 hours and 12 to 24 hours post-admission, respectively. uNGAL seems to be a reliable marker for identifying children who will develop AKI 24 hours later.