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1.
Eur Urol Focus ; 5(3): 329-336, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31231010

RESUMO

CONTEXT: In overactive bladder (OAB), after an initial outbreak of research, it is more consensual that biomarkers may be better used to phenotype patients. Herein, we revisit this topic, including some of the most promising biomarkers. OBJECTIVE: To provide a comprehensive analysis of the actual role of biomarkers in OAB. EVIDENCE ACQUISITION: A PubMed-based literature search was conducted, including the most relevant articles published in the last 15 yr, on nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), adenosine triphosphate (ATP), genomics, and microbiota as OAB biomarkers. Articles with no full text available or not written in English were excluded. Additional reviews were included. EVIDENCE SYNTHESIS: Urinary NGF, BDNF, and ATP are increased in many OAB patients. These biomarkers can help identify OAB phenotypes and select the ideal candidates for new therapies directed to neurotrophic and purinergic pathways. Circulating urinary miRNA may be useful for establishing the ideal moment for bladder outlet obstruction relief and will eventually lead to the development of therapeutic agents that inhibit or reverse fibrotic pathways in the bladder. Urinary microbiota seems to be related to OAB symptoms, in particular urgency urinary incontinence, and may have strong implications in the prevention, diagnosis, and treatment of OAB. CONCLUSIONS: In the future, physicians may consider the use of biomarkers to identify distinct OAB phenotypes, with distinct causal mechanisms, selecting patients for specific target therapies with expected better outcomes. PATIENT SUMMARY: Overactive bladder biomarkers can be useful for phenotype patients and for selecting more effective target therapies.


Assuntos
Bexiga Urinária Hiperativa/diagnóstico , Trifosfato de Adenosina/urina , Biomarcadores/urina , Marcadores Genéticos/genética , Humanos , Microbiota , Fatores de Crescimento Neural/urina , Bexiga Urinária Hiperativa/genética , Bexiga Urinária Hiperativa/microbiologia , Bexiga Urinária Hiperativa/urina , Sistema Urinário/microbiologia
2.
Pediatr Surg Int ; 35(9): 1027-1032, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30729304

RESUMO

PURPOSE: Based on, previously, a systematic review, urinary nerve growth factor (NGF) has emerged as one potentially noninvasive biomarker for detrusor overactivity (DO) in adults. We performed this systematic review to explore if NGF is a biomarker for DO in children. METHODS: A literature search was conducted in PubMed, Embase, Web of science, and Cochrane Library. Copies of all relevant articles were retrieved for quality assessment and data abstraction by two reviewers. Primary outcome was pooled standardized mean difference (SMD) for NGF/Cr (NGF normalized to urine creatinine) level between DO group and controls. RESULTS: Three case-control studies published from 2012 to 2016 were included with 74 patients and 70 controls. Children with DO had a significant higher baseline urinary NGF/Cr level compared to controls (SMD = 2.48, 95%CI = 0.85-4.10, P < 0.01). After treatment, the level of NGF/Cr decreased significantly compared to baseline level at 6th month time points (SMD = 0.94, 95%CI = 0.03-1.86, P = 0.04). We calculated the required information size to 99 patients for comparison of urinary NGF/Cr level between DO and controls by trail sequential analysis (TSA). CONCLUSION: Based on this systematic review, NGF/Cr may be a noninvasive biomarker for DO in children in the future. However, based on TSA, more original studies are needed to clarify the role of NGF/Cr in the biomarker effect.


Assuntos
Fatores de Crescimento Neural/urina , Bexiga Urinária Hiperativa/urina , Bexiga Urinária/inervação , Biomarcadores/urina , Estudos de Casos e Controles , Criança , Humanos , Urinálise
3.
Urologiia ; (3): 44-48, 2018 Jul.
Artigo em Russo | MEDLINE | ID: mdl-30035417

RESUMO

Lower urinary tract dysfunction is common among neurological patients. Traditionally, the basic method of diagnosis is a complex urodynamic study. In recent years, many studies have focused on the search for new non-invasive diagnostic modalities. In particular, neurotrophins are considered as potential biological markers of a neurogenic bladder. AIM: To estimate the sensitivity and specificity of the serum and urinary nerve growth factor (NGF) and brain neurotrophic factor (BDNF) in MS patients as markers of detrusor overactivity. MATERIALS AND METHODS: The study comprised 20 patients with multiple sclerosis, who complained of voiding problems. The control group consisted of 20 people without neurological diseases, lower urinary tract symptoms and detrusor overactivity estimated by filling cystometry. Apart from standard laboratory tests, diagnostic evaluation included a complex urodynamic study, ultrasound of the urinary tract, cystoscopy, testing serum and urinary NGF and BDNF using the enzyme immunoassay. The diagnostic significance of neurotrophins was evaluated using ROC analysis. RESULTS: According to the ROC analysis, the diagnostic sensitivity and specificity of serum NGF as a marker of detrusor hyperactivity was 57% and 93%, respectively (for serum NGF more or equal 26 pg/ml). The quality of the test according to the expert scale of AUC values was "very good" (AUC=0.806). Detecting NGF in patients urine was less effective. The sensitivity and specificity were 52% and 40%, respectively (for NGF more or equal 6 pg/ml). The quality of the test according to the expert scale of AUC values was "average" (AUC=0.64). The serum BDNF demonstrated high sensitivity (90%) and low specificity (23%), AUC=0.56. The urinary BDNF was more informative, (AUC=0.65). The combination of all four markers provides a sensitivity of 85.7% and a specificity of 66.7% (AUC=0.824). CONCLUSIONS: Testing serum and urinary neurotrophins in patients with multiple sclerosis can be used to diagnose detrusor overactivity. The NGF is a highly specific biomarker, while the BDNF is highly sensitive. Combined testing for serum NGF and BDNF is most informative.


Assuntos
Esclerose Múltipla/complicações , Fatores de Crescimento Neural , Bexiga Urinaria Neurogênica/sangue , Bexiga Urinaria Neurogênica/urina , Bexiga Urinária Hiperativa/sangue , Bexiga Urinária Hiperativa/urina , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Fator Neurotrófico Derivado do Encéfalo/sangue , Fator Neurotrófico Derivado do Encéfalo/urina , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/urina , Fator de Crescimento Neural/sangue , Fator de Crescimento Neural/urina , Fatores de Crescimento Neural/sangue , Fatores de Crescimento Neural/urina , Curva ROC , Sensibilidade e Especificidade , Inquéritos e Questionários , Bexiga Urinaria Neurogênica/etiologia , Bexiga Urinária Hiperativa/etiologia
4.
Clin Exp Nephrol ; 21(4): 597-607, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27530994

RESUMO

BACKGROUND: The mortality and morbidity associated with acute kidney injury (AKI) remains high, despite advances in interventions. A multifunctional heparin-binding growth factor, midkine (MK), is involved in the pathogenesis of ischemic kidney injury. However, the clinical relevance of MK has not yet been elucidated. The present study investigated whether urinary MK can serve as a novel biomarker of AKI. METHODS: We initially compared the predictive value of MK with other urinary biomarkers, including N-acetyl-ß-D-glucosaminidase (NAG), interleukin (IL)-18, and neutrophil gelatinase-associated lipocalin (NGAL), for the detection and differential diagnosis of established AKI (549 patients). Subsequently, the reliability of MK for the early detection of AKI was prospectively evaluated in 40 patients undergoing elective abdominal aortic aneurysm surgery. Urine samples were obtained at baseline, the period of aortic cross-clamping and declamping, the end of the surgery, and on post-operative day 1. RESULTS: The areas under the receiver operating characteristic curves for the diagnosis of AKI in various kidney diseases were 0.88, 0.70, 0.72, and 0.84 for MK, NAG, IL-18, and NGAL, respectively. When the optimal cutoff value of urinary MK was set at 11.5 pg/mL, the sensitivity and specificity were 0.87 and 0.85, respectively. In the second study, urinary MK peaked at the period of aortic declamping, about 1 h after cross-clamping in patients with AKI. Interestingly, the rise of MK in AKI patients was very precipitous compared with other biomarker candidates. CONCLUSION: Urinary MK was prominent in its ability to detect AKI and may allow the start of preemptive medication.


Assuntos
Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/urina , Aneurisma da Aorta Abdominal/cirurgia , Fatores de Crescimento Neural/urina , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Injúria Renal Aguda/etiologia , Adulto , Idoso , Área Sob a Curva , Biomarcadores/urina , Estudos de Casos e Controles , Estudos Transversais , Diagnóstico Diferencial , Diagnóstico Precoce , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Midkina , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Urinálise
5.
Ren Fail ; 38(6): 882-8, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27055689

RESUMO

BACKGROUND: Acute kidney injury (AKI) affects up to 60% of severely asphyxiated neonates. The diagnosis of AKI can be and is further challenged by a lack of good biomarkers. We studied the role of novel markers for AKI, neutrophil gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-18), Netrin-1 (NTN-1), and sodium hydrogen exchanger isoform 3 (NHE3) on development and early diagnosis of AKI in newborns with perinatal asphyxia (PA). METHODS: Forty-one newborns with a diagnosis of PA (15 with AKI and 26 without AKI) and 20 healthy matched controls were involved to the study. Urinary samples were obtained on postnatal days 1 and 4 for patients with PA and on postnatal day 1 for the control subjects. AKI was defined using a serum creatinine-based modification of the acute kidney injury network criteria. RESULTS: The levels of NGAL, NTN-1, NHE3, and IL-18 on the first postnatal day urine samples were higher in patients compared to controls (p < 0.001, p <0.001, p  <0.02, p  <0.001, respectively). In patients with AKI, the levels of NGAL and IL-18 were higher when compared to patients without AKI (p = 0.002, p  <0.001, respectively). The levels of NTN-1 and NHE3 were similar in both groups. For the samples obtained on postnatal day 4, only NGAL levels were significantly higher in patients with AKI (p = 0.004) compared to those without AKI. CONCLUSION: To our knowledge, this is the largest study, which evaluated the utility of urinary biomarkers in the diagnosis of AKI in newborns with PA. First day, urine NGAL and IL-18 levels have an important diagnostic power in such patients.


Assuntos
Injúria Renal Aguda/diagnóstico , Injúria Renal Aguda/urina , Asfixia/urina , Interleucina-18/urina , Lipocalina-2/urina , Fatores de Crescimento Neural/urina , Trocadores de Sódio-Hidrogênio/urina , Proteínas Supressoras de Tumor/urina , Asfixia/complicações , Biomarcadores/urina , Estudos de Casos e Controles , Creatinina/sangue , Diagnóstico Precoce , Feminino , Humanos , Recém-Nascido , Masculino , Netrina-1 , Valor Preditivo dos Testes , Estudos Prospectivos , Curva ROC , Trocador 3 de Sódio-Hidrogênio , Turquia
6.
J Clin Res Pediatr Endocrinol ; 8(3): 282-7, 2016 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-27087488

RESUMO

OBJECTIVE: Urinary netrin-1 is a new marker to demonstrate early tubular damage. The aim of this study was to determine whether urinary netrin-1 is increased in obese children. METHODS: A total of 68 normoalbuminuric and normotensive obese patients and 65 controls were included in the study. Urine samples were collected for assessment of urinary phosphorus, sodium, potassium, creatinine, albumin, and netrin-1. Blood samples were collected for measurements of fasting glucose, insulin, lipid, phosphorus, sodium, potassium, and creatinine levels. Homeostatic model assessment insulin resistance index was calculated. RESULTS: Gender and age were similar between obese and control groups (12.01±3.03 vs. 11.7±3.2 years, p=0.568 and 33 vs. 35 girls, p=0.543, respectively). Obese patients had significantly higher netrin-1 excretion than the controls (841.68±673.17 vs. 228.94±137.25 pg/mg creatinine, p=0.000). Urinary netrin-1 level was significantly higher in obese subjects with insulin resistance compared to those without insulin resistance (1142±1181 vs. 604.9±589.91 pg/mg creatinine, p=0.001). CONCLUSION: In normotensive and normoalbuminuric obese children, urinary netrin-1 level can increase before onset of albuminuria. Urinary netrin-1 excretion appears to be affected predominantly by insulin resistance and hyperinsulinemia. Urinary netrin-1 may be a new biomarker for determining early tubular injury in obese children.


Assuntos
Biomarcadores/urina , Nefropatias/urina , Fatores de Crescimento Neural/urina , Obesidade/complicações , Proteínas Supressoras de Tumor/urina , Adolescente , Análise de Variância , Biomarcadores/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Criança , Creatinina/sangue , Creatinina/urina , Estudos Transversais , Diagnóstico Precoce , Jejum/sangue , Feminino , Humanos , Insulina/sangue , Resistência à Insulina , Nefropatias/complicações , Nefropatias/diagnóstico , Masculino , Netrina-1
7.
J Am Soc Nephrol ; 27(10): 2974-2982, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26940092

RESUMO

Endoplasmic reticulum (ER) stress and disrupted proteostasis contribute to the pathogenesis of a variety of glomerular and tubular diseases. Thus, it is imperative to develop noninvasive biomarkers for detecting ER stress in podocytes or tubular cells in the incipient stage of disease, when a kidney biopsy is not yet clinically indicated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) localizes to the ER lumen and is secreted in response to ER stress in several cell types. Here, using mouse models of human nephrotic syndrome caused by mutant laminin ß2 protein-induced podocyte ER stress and AKI triggered by tunicamycin- or ischemia-reperfusion-induced tubular ER stress, we examined MANF as a potential urine biomarker for detecting ER stress in podocytes or renal tubular cells. ER stress upregulated MANF expression in podocytes and tubular cells. Notably, urinary MANF excretion concurrent with podocyte or tubular cell ER stress preceded clinical or histologic manifestations of the corresponding disease. Thus, MANF can potentially serve as a urine diagnostic or prognostic biomarker in ER stress-related kidney diseases to help stratify disease risk, predict disease progression, monitor treatment response, and identify subgroups of patients who can be treated with ER stress modulators in a highly targeted manner.


Assuntos
Estresse do Retículo Endoplasmático , Nefropatias/urina , Fatores de Crescimento Neural/urina , Animais , Biomarcadores/urina , Nefropatias/etiologia , Camundongos
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 18(1): 24-8, 2016 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-26781408

RESUMO

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.


Assuntos
Injúria Renal Aguda/diagnóstico , Asfixia Neonatal/complicações , Glicoproteínas de Membrana/urina , Fatores de Crescimento Neural/urina , Proteínas Supressoras de Tumor/urina , Injúria Renal Aguda/urina , Feminino , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Recém-Nascido , Masculino , Netrina-1 , Receptores Virais
9.
PLoS One ; 9(10): e107898, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25289643

RESUMO

Acute kidney injury (AKI) is a serious complication after liver transplantation. Currently there are no validated biomarkers available for early diagnosis of AKI. The current study was carried out to determine the usefulness of the recently identified biomarkers netrin-1 and semaphorin 3A in predicting AKI in liver transplant patients. A total of 63 patients' samples were collected and analyzed. AKI was detected at 48 hours after liver transplantation using serum creatinine as a marker. In contrast, urine netrin-1 (897.8 ± 112.4 pg/mg creatinine), semaphorin 3A (847.9 ± 93.3 pg/mg creatinine) and NGAL (2172.2 ± 378.1 ng/mg creatinine) levels were increased significantly and peaked at 2 hours after liver transplantation but were no longer significantly elevated at 6 hours after transplantation. The predictive power of netrin-1, as demonstrated by the area under the receiver-operating characteristic curve for diagnosis of AKI at 2, 6, and 24 hours after liver transplantation was 0.66, 0.57 and 0.59, respectively. The area under the curve for diagnosis of AKI was 0.63 and 0.65 for semaphorin 3A and NGAL at 2 hr respectively. Combined analysis of two or more biomarkers for simultaneous occurrence in urine did not improve the AUC for the prediction of AKI whereas the AUC was improved significantly (0.732) only when at least 1 of the 3 biomarkers in urine was positive for predicting AKI. Adjusting for BMI, all three biomarkers at 2 hours remained independent predictors of AKI with an odds ratio of 1.003 (95% confidence interval: 1.000 to 1.006; P = 0.0364). These studies demonstrate that semaphorin 3A and netrin-1 can be useful early diagnostic biomarkers of AKI after liver transplantation.


Assuntos
Injúria Renal Aguda/etiologia , Injúria Renal Aguda/metabolismo , Transplante de Fígado/efeitos adversos , Fatores de Crescimento Neural/metabolismo , Semaforina-3A/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Injúria Renal Aguda/diagnóstico , Adulto , Biomarcadores , Feminino , Humanos , Testes de Função Renal , Masculino , Pessoa de Meia-Idade , Fatores de Crescimento Neural/urina , Netrina-1 , Prognóstico , Curva ROC , Semaforina-3A/urina , Proteínas Supressoras de Tumor/urina , Adulto Jovem
10.
Ren Fail ; 36(10): 1559-63, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25154466

RESUMO

BACKGROUND: Acute kidney injury (AKI) during sepsis is associated with poor outcome. However, diagnosis of AKI with serum creatinine (SCr) level change is neither highly sensitive nor specific. Therefore, identification of novel biomarkers for early diagnosis of AKI is desirable. AIMS: To evaluate the capacity of combining urinary netrin-1 and human kidney injury molecule type 1 (KIM-1) in the early diagnosis of septic AKI. METHODS: We prospectively recruited 150 septic patients from Jun 2011 to Jun 2013 at Zhejiang Provincial People's Hospital, China. SCr, urinary netrin-1, and KIM-1 levels were recorded at 0, 1, 3, 6, 24, and 48 h of ICU admission and compared between AKI and non-AKI patients. In addition, we investigated the prognostic value of netrin-1 and KIM-1 between non-survivors and survivors in septic AKI patients. RESULTS: SCr levels started to show elevation after 24 h of ICU admission. However, netrin-1 levels increased significantly as early as 1 h, peaked at 3-6 h and remained elevated up to 48 h of ICU admission in septic AKI patients. KIM-1 increased significantly by 6 h, peaked at 24 h and remained significantly elevated until 48 h of ICU admission. Furthermore, we observed significant higher urinary KIM-1 levels at 24 h and 48 h in non-survivors compared to survivors in AKI patients. CONCLUSIONS: Our results suggest that both netrin-1 and KIM-1 are clinically useful as early biomarkers in the diagnosis of septic AKI. In addition, persistent elevation of urinary KIM-1 level may be associated with poor prognosis.


Assuntos
Injúria Renal Aguda/urina , Glicoproteínas de Membrana/urina , Fatores de Crescimento Neural/urina , Sepse/complicações , Proteínas Supressoras de Tumor/urina , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/mortalidade , Idoso , Biomarcadores/sangue , Biomarcadores/urina , China/epidemiologia , Creatinina/sangue , Feminino , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Netrina-1 , Estudos Prospectivos , Receptores Virais
11.
Cancer Res ; 74(14): 3716-26, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24812271

RESUMO

Invasion and dissemination of medulloblastoma within the central nervous system is the principal factor predicting medulloblastoma treatment failure and death. Netrin-1 is an axon guidance factor implicated in tumor and vascular biology, including in invasive behaviors. We found that exogenous netrin-1 stimulated invasion of human medulloblastoma cells and endothelial cells in contrast to VEGF-A, which promoted invasion of endothelial cells but not medulloblastoma cells. Furthermore, medulloblastoma cells expressed endogenous netrin-1 along with its receptors, neogenin and UNC5B. Blockades in endogenous netrin-1, neogenin, or UNC5B reduced medulloblastoma invasiveness. Neogenin blockade inhibited netrin-1-induced endothelial cells tube formation and recruitment of endothelial cells into Matrigel plugs, two hallmarks of angiogenesis. In patients with pediatric medulloblastoma, netrin-1 mRNA levels were increased 1.7-fold in medulloblastoma tumor specimens compared with control specimens from the same patient. Immunohistochemical analyses showed that netrin-1 was elevated in medulloblastoma tumors versus cerebellum controls. Notably, urinary levels of netrin-1 were 9-fold higher in patients with medulloblastoma compared with control individuals. Moreover, urinary netrin-1 levels were higher in patients with invasive medulloblastoma compared with patients with noninvasive medulloblastoma. Finally, we noted that urinary netrin-1 levels diminished after medulloblastoma resection in patients. Our results suggest netrin-1 is a candidate biomarker capable of detecting an invasive, disseminated phenotype in patients with medulloblastoma and predicting their disease status.


Assuntos
Meduloblastoma/genética , Meduloblastoma/patologia , Neovascularização Patológica/genética , Fatores de Crescimento Neural/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Biomarcadores/metabolismo , Biomarcadores/urina , Encéfalo/patologia , Linhagem Celular Tumoral , Criança , Células Endoteliais/metabolismo , Ativação Enzimática/efeitos dos fármacos , Expressão Gênica , Humanos , Imageamento por Ressonância Magnética , Meduloblastoma/diagnóstico , Meduloblastoma/metabolismo , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica , Neovascularização Patológica/metabolismo , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/farmacologia , Fatores de Crescimento Neural/urina , Receptores de Netrina , Netrina-1 , Prognóstico , Receptores de Superfície Celular/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/farmacologia , Proteínas Supressoras de Tumor/urina
12.
Oncotarget ; 5(10): 3350-61, 2014 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-24830820

RESUMO

BACKGROUND: To identify new epigenetic markers and further characterize Urothelial Cell Carcinoma (UCC), we tested the promoter methylation (PM) status of 19 genes previously identified as cancer specific methylated genes in other solid tumors. METHODS: We used bisulfite sequencing, methylation specific PCR and quantitative methylation specific PCR (QMSP) to test the PM status of 19 genes in urothelial cancer cell lines. RESULTS: Among the 19 genes tested, VGF was found to be completely methylated in several UCC cell lines. VGF QMSP analysis showed that methylation values of almost all the primary 19 UCC tissues were higher than the paired normal tissues (P=0.009). In another cohort, 12/35 (34.3%) of low grade UCC cases displayed VGF methylation. As a biomarker for non-invasive detection of UCC, VGF showed a significantly higher frequency of methylation in urine from UCC cases (8/20) compared to controls (1/20) (P=0.020). After treatment of cell lines with 5-Aza-2'-deoxycytidine, VGF was robustly re-expressed. Forced expression of VGF in bladder cancer cell lines inhibited cell growth. CONCLUSION: Selection of candidates from genome-wide screening approach in other solid tumors successfully identified UCC specific methylated genes.


Assuntos
Biomarcadores Tumorais/genética , Biomarcadores Tumorais/urina , Carcinoma de Células de Transição/genética , Epigênese Genética , Fatores de Crescimento Neural/genética , Neoplasias da Bexiga Urinária/genética , Carcinoma de Células de Transição/urina , Linhagem Celular Tumoral , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Humanos , Fatores de Crescimento Neural/urina , Regiões Promotoras Genéticas/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Bexiga Urinária/urina
13.
Environ Toxicol Pharmacol ; 37(3): 1028-39, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24751685

RESUMO

Acute kidney injury (AKI) occurs in a half of cisplatin (CDDP)-treated patients. Traditional biomarkers including blood urea nitrogen (BUN) and serum creatinine (SCr) are still used for detection of CDDP-induced AKI, but these biomarkers are not specific or sensitive. The aim of this study was to identify the specific and sensitive biomarkers against CDDP-induced renal injury between young (3-week-old) and old (20-week-old) rats. All animals were intraperitoneally injected once with CDDP (6 mg/kg). After 3 days, all animals were sacrificed and serum, urine, and kidney tissues were collected. Urinary and serum biomarkers as well as histological changes were measured. CDDP-induced proximal tubular damage was apparent from histopathological examination, being more severe in 3-week-old rats accompanied by increased number of TUNEL-positive apoptotic cells. This was associated with elevated urinary kidney injury molecule-1 (KIM-1), glutathione-S-transferase alpha (GST-α), vascular endothelial growth factor (VEGF), and tissue inhibitor of metalloproteinases-1 (TIMP-1). In contrast, the levels of neutrophil gelatinase-associated lipocalin (NGAL) and osteopontin were significantly increased in 20-week-old rats after CDDP treatment. These results indicate that the use of age-specific urinary biomarkers is necessary to diagnosis of CDDP-induced AKI. Especially, urinary KIM-1, GST-α, TIMP-1, and VEGF levels may help in the early diagnosis of young patients with CDDP-induced AKI.


Assuntos
Injúria Renal Aguda/urina , Envelhecimento/urina , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Envelhecimento/metabolismo , Animais , Biomarcadores/metabolismo , Moléculas de Adesão Celular/urina , Glutationa Transferase/urina , Proteína HMGB1/urina , Isoenzimas/urina , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Masculino , Fatores de Crescimento Neural/urina , Netrina-1 , Ratos Sprague-Dawley , Proteínas Supressoras de Tumor/urina , Fator A de Crescimento do Endotélio Vascular/urina
14.
J Nephrol ; 27(2): 151-7, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24510764

RESUMO

BACKGROUND: Netrin-1 was recently identified as an early diagnostic biomarker of chronic kidney disease (CKD) in an experimental animal model. However, its usefulness for early diagnosis of CKD in humans is unknown. The current study evaluated whether netrin-1 is increased in urine from human diabetic patients. METHODS: Spot urine samples from healthy volunteers, diabetes without microalbuminuria, diabetes with microalbuminuria and diabetes with macroalbuminuria were collected after receiving consent. Netrin-1 in urine was quantified by enzyme-linked immunosorbent assay and the data analyzed to determine whether urinary netrin-1 significantly correlates with disease progression. RESULTS: Urinary netrin-1 levels were significantly increased in normoalbuminuric diabetic patients compared to healthy controls, and still further elevated in patients with microalbuminuria and overt nephropathy. Urinary netrin-1 was significantly associated with albuminuria and estimated glomerular filtration rate, independently of age and sex. CONCLUSION: Netrin-1 is detectable in urine from diabetic patients and may serve as a useful early diagnostic biomarker predicting the development of CKD in diabetes.


Assuntos
Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/urina , Fatores de Crescimento Neural/urina , Insuficiência Renal Crônica/urina , Proteínas Supressoras de Tumor/urina , Adulto , Idoso , Albuminúria/complicações , Albuminúria/urina , Biomarcadores/urina , Nefropatias Diabéticas/complicações , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Túbulos Renais Proximais/patologia , Masculino , Pessoa de Meia-Idade , Netrina-1 , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/fisiopatologia , Fatores de Tempo
15.
J Pediatr ; 164(3): 607-12.e1-7, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24433829

RESUMO

OBJECTIVES: To test the hypothesis that an exploratory proteomics analysis of urine proteins with subsequent development of validated urine biomarker panels would produce molecular classifiers for both the diagnosis and prognosis of infants with necrotizing enterocolitis (NEC). STUDY DESIGN: Urine samples were collected from 119 premature infants (85 NEC, 17 sepsis, 17 control) at the time of initial clinical concern for disease. The urine from 59 infants was used for candidate biomarker discovery by liquid chromatography/mass spectrometry. The remaining 60 samples were subject to enzyme-linked immunosorbent assay for quantitative biomarker validation. RESULTS: A panel of 7 biomarkers (alpha-2-macroglobulin-like protein 1, cluster of differentiation protein 14, cystatin 3, fibrinogen alpha chain, pigment epithelium-derived factor, retinol binding protein 4, and vasolin) was identified by liquid chromatography/mass spectrometry and subsequently validated by enzyme-linked immunosorbent assay. These proteins were consistently found to be either up- or down-regulated depending on the presence, absence, or severity of disease. Biomarker panel validation resulted in a receiver-operator characteristic area under the curve of 98.2% for NEC vs sepsis and an area under the curve of 98.4% for medical NEC vs surgical NEC. CONCLUSIONS: We identified 7 urine proteins capable of providing highly accurate diagnostic and prognostic information for infants with suspected NEC. This work represents a novel approach to improving the efficiency with which we diagnose early NEC and identify those at risk for developing severe, or surgical, disease.


Assuntos
Enterocolite Necrosante/diagnóstico , Biomarcadores/urina , Estudos de Casos e Controles , Cromatografia Líquida , Cistatina C/urina , Regulação para Baixo , Ensaio de Imunoadsorção Enzimática , Proteínas do Olho/urina , Feminino , Fibrinogênio/urina , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Doenças do Prematuro/diagnóstico , Receptores de Lipopolissacarídeos/urina , Masculino , Espectrometria de Massas , Fatores de Crescimento Neural/urina , Fragmentos de Peptídeos/urina , Prognóstico , Estudos Prospectivos , Proteínas Plasmáticas de Ligação ao Retinol/urina , Sensibilidade e Especificidade , Sepse/diagnóstico , Serpinas/urina , Regulação para Cima , alfa-Macroglobulinas/urina
16.
Int Urol Nephrol ; 46(1): 1-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23673775

RESUMO

Acute kidney injury (AKI) is a very frequent and serious clinical problem, accounting for overall high morbidity and mortality. Up to date, mortality due to AKI is virtually unchanged over the past 50 years. This may partly be explained due to a delay in initiating renal protective and appropriate therapeutic measures since until now there are no reliable early-detecting biomarkers. The gold standard, serum creatinine, displays poor specificity and sensitivity with regard to identification of the incipient phase of AKI, and this is also true for cystatin C. We aimed to review novel biomarkers of AKI in urine and serum which have now progressed to the clinical phase. The main focus refers to their diagnostic and prognostic value. For this purpose, a web-based literature search using PubMed was performed comprising the following terms: renal failure, acute kidney injury and biomarkers. New molecules such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-ß-D-glucosaminidase (NAG), monocyte chemotactic peptide (MCP-1), Il-18, liver-type fatty acid-binding protein (L-FABP) and Netrin-1 are available and represent promising new markers that, however, need to be further evaluated in the clinical setting for suitability. In clinical settings with incipient AKI, not only the development and the implementation of more sensitive, practicable and accurate biomarkers are required for well-timed treatment initiation. Just as important is a substantial improvement of refined and applicable prophylactic therapeutic options in these situations. Before full adoption in clinical practice can be accomplished, adequately powered clinical trials testing a row of biomarkers are strongly warranted.


Assuntos
Injúria Renal Aguda/diagnóstico , Quimiocina CCL2/urina , Lipocalinas/sangue , Glicoproteínas de Membrana/urina , Proteínas de Neoplasias/urina , Proteínas Proto-Oncogênicas/sangue , RNA Mensageiro/urina , Injúria Renal Aguda/sangue , Injúria Renal Aguda/urina , Proteínas de Fase Aguda/urina , Biomarcadores/sangue , Biomarcadores/urina , Quimiocina CCL2/genética , Diagnóstico Precoce , Proteínas de Ligação a Ácido Graxo/urina , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Interleucina-18/urina , Lipocalina-2 , Lipocalinas/urina , Glicoproteínas de Membrana/genética , Fatores de Crescimento Neural/urina , Netrina-1 , Proteínas Proto-Oncogênicas/urina , Receptores Virais/genética , Proteínas Supressoras de Tumor/urina
17.
J Nephrol ; 26(6): 1055-64, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24052471

RESUMO

BACKGROUND: Netrin-1 was recently identified as an early diagnostic biomarker of acute kidney injury. However, its usefulness for early diagnosis of chronic kidney disease (CKD) is unknown. The current study evaluated whether these proteins are increased in urine from experimental animals with diabetes. METHODS: The current study evaluated whether netrin-1 is increased in urine from diabetic rats and mice, and whether netrin-1 correlated with development of nephropathy. RESULTS: In rats, urinary netrin-1 excretion was significantly (p<0.001) higher in the diabetic group at 4 and 10 weeks after induction of diabetes as compared with the control group. Similarly, netrin-1 was increased significantly (p<0.001) in urine from hypertensive rats at 4 weeks as compared with controls. Likewise, urinary albumin excretion rates were increased in diabetic rats at 4 and 10 weeks as compared with controls and were increased in hypertensive rats at 4 weeks. Consistent with the diabetic model in rats, netrin-1 excretion was also increased early in diabetic mice's urine, and peak levels correlated with disease severity. CONCLUSION: Netrin-1 can be detected in urine from diabetic and hypertensive rats and may serve as a useful early diagnostic biomarker for development of CKD.


Assuntos
Injúria Renal Aguda/diagnóstico , Albuminúria/urina , Diabetes Mellitus Experimental/urina , Hipertensão/urina , Fatores de Crescimento Neural/urina , Insuficiência Renal Crônica/diagnóstico , Semaforina-3A/urina , Proteínas Supressoras de Tumor/urina , Injúria Renal Aguda/sangue , Injúria Renal Aguda/urina , Animais , Biomarcadores/urina , Creatinina/sangue , Creatinina/urina , Acetato de Desoxicorticosterona , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Nefropatias Diabéticas , Hiperglicemia/induzido quimicamente , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico , Camundongos , Camundongos Endogâmicos C57BL , Netrina-1 , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/sangue , Estreptozocina , Fatores de Tempo
18.
Nat Rev Urol ; 9(11): 628-37, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23045265

RESUMO

Increased voiding frequency and urgency are among the most prevalent storage lower urinary tract symptoms (LUTS), often diagnosed as part of overactive bladder syndrome (OAB). It has been suggested that these symptoms are caused by excessive sensory activation of the neural micturition circuit. It seems likely that sensory pathway remodelling is also responsible for pain perception upon bladder filling in patients with bladder pain syndrome (BPS). Neurotrophins-including nerve growth factor (NGF), brain-derived nerve factor (BDNF), neurotrophin-3 (NT-3) and neurotrophin-4 (NT-4)-represent master modulators of neural plasticity, both in peripheral and central nervous systems. Accumulating evidence points towards a role for neurotrophins in the control of neural sensory function during micturition and indicates their involvement in the emergence of OAB-related and BPS-related LUTS. Neurotrophins could potentially be used as urinary biomarkers to improve diagnostic accuracy for OAB and BPS and monitor therapy effectiveness. Proof-of-principle clinical evidence has confirmed that NGF is a potential target for treating human bladder overactivity.


Assuntos
Sintomas do Trato Urinário Inferior/fisiopatologia , Fatores de Crescimento Neural/fisiologia , Bexiga Urinária/fisiopatologia , Micção/fisiologia , Biomarcadores/urina , Cistite Intersticial/diagnóstico , Cistite Intersticial/metabolismo , Cistite Intersticial/fisiopatologia , Humanos , Sintomas do Trato Urinário Inferior/metabolismo , Fatores de Crescimento Neural/urina , Bexiga Urinária/metabolismo , Bexiga Urinária/fisiologia , Bexiga Urinária Hiperativa/diagnóstico , Bexiga Urinária Hiperativa/metabolismo , Bexiga Urinária Hiperativa/fisiopatologia
19.
Acta Med Indones ; 44(3): 246-55, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22983082

RESUMO

The kidney has a remarkable capacity to withstand insults for an extended period of time. The sensitivities of individual renal cells to injury vary depending on their type, position in the nephron, local vascularization, and the nature of injury. The resulting kidney injury is a product of the interplay between cell dysfunction, cell death, proliferation, inflammation, and recovery. The Acute Kidney Injury Network (AKIN) defined Acute Kidney Injury (AKI) as "functional and structural disorder or signs of renal damage including any defect from blood and urine test, or tissue imaging that is less than 3 months". RIFLE (Risk, Injury, Failure, Loss, End-Stage Kidney Disease) criteria is the most frequently used system. Ideal biomarker for AKI should be affordable, quick and measurable, precise and accurate, with prognostic ability to define severity of renal dysfunction, specific for renal, increase in the early stage dysfunction, with high sensitivity and specificity. Efforts to detect AKI in the earlier stage has resulted in some promising biomarkers such as KIM-1, NGAL, IL-18, Clusterin, etc. Cystatin C is a biomarker for glomerular filtration function, while 2-microglobulin, 1-microglobulin, NAG, RBP, IL-18, NGAL, Netrin-1, KIM-1, Clusterin, Sodium Hydrogen Exchanger Isoform and Fetuin A are biomarkers for tubular reabsorption function.


Assuntos
Injúria Renal Aguda/sangue , Injúria Renal Aguda/urina , Acetilglucosaminidase/urina , Injúria Renal Aguda/diagnóstico , Proteínas de Fase Aguda/urina , alfa-Globulinas/urina , Biomarcadores/sangue , Biomarcadores/urina , Clusterina/urina , Cistatina C/sangue , Receptor Celular 1 do Vírus da Hepatite A , Humanos , Interleucina-18/urina , Lipocalina-2 , Lipocalinas/sangue , Lipocalinas/urina , Glicoproteínas de Membrana/urina , Fatores de Crescimento Neural/urina , Netrina-1 , Proteínas Proto-Oncogênicas/sangue , Proteínas Proto-Oncogênicas/urina , Receptores Virais , Proteínas de Ligação ao Retinol/urina , Índice de Gravidade de Doença , Trocador 3 de Sódio-Hidrogênio , Trocadores de Sódio-Hidrogênio/urina , Proteínas Supressoras de Tumor/urina , alfa-2-Glicoproteína-HS/urina , Microglobulina beta-2/urina
20.
J Matern Fetal Neonatal Med ; 24 Suppl 2: 15-7, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21740336

RESUMO

Neutrophil gelatinase-associated lipocalin (NGAL) and Netrin-1 have been proposed over the past years as emergent biomarkers for the early and accurate diagnosis and monitoring of acute kidney injury (AKI). During the early phases of AKI, a rapid and massive up-regulation of NGAL mRNA takes place in the thick ascending limb of Henle's loop and in the collecting ducts, and therefore, changes in urinary NGAL (uNGAL) excretion seem to be more specific than plasma NGAL in assessing early kidney injury. The availability of a new automated immunoassay for measuring uNGAL facilitates its introduction in the clinical routine, especially in an emergency setting. However, in critically ill newborns AKI often develops during sepsis, which in turn induces an up-regulation of NGAL mRNA in neutrophils. To improve the effectiveness of therapeutic treatment in septic newborns with AKI, there is the need to accurately distinguish NGAL molecular forms originating within the distal nephron from those originating from neutrophils. This concise review summarizes properties and perspectives of uNGAL and Netrin-1 for their appropriate clinical utilization.


Assuntos
Injúria Renal Aguda/terapia , Proteínas de Fase Aguda/urina , Doenças do Recém-Nascido/terapia , Lipocalinas/urina , Fatores de Crescimento Neural/urina , Proteínas Proto-Oncogênicas/urina , Sepse/terapia , Proteínas Supressoras de Tumor/urina , Injúria Renal Aguda/congênito , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/urina , Proteínas de Fase Aguda/análise , Biomarcadores/análise , Biomarcadores/urina , Humanos , Recém-Nascido , Doenças do Recém-Nascido/etiologia , Doenças do Recém-Nascido/urina , Lipocalina-2 , Lipocalinas/análise , Fatores de Crescimento Neural/análise , Netrina-1 , Valor Preditivo dos Testes , Proteínas Proto-Oncogênicas/análise , Sepse/complicações , Sepse/congênito , Sepse/urina , Resultado do Tratamento , Proteínas Supressoras de Tumor/análise , Urinálise
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