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1.
Cell Mol Life Sci ; 78(7): 3265-3283, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33507324

RESUMO

Exosomes are involved in a wide variety of biochemical processes in human body homeostasis. Exosomes also provide important information regarding communications among several organ systems. Additionally, they can serve as molecular vehicles to deliver drugs. Therefore, exosomes have received wide attention in current biomedical research for unraveling pathogenic mechanisms of diseases, searching for novel biomarkers, and discovering new drugs. This paper reviews and discusses the significance of urinary exosomes for a better understanding of human disease pathophysiology and their potential use as therapeutic targets. Isolation methods of exosomes and the latest technological advances are also discussed. Furthermore, novel urinary exosomal biomarkers are highlighted with special emphasis on their clinical applicability (particularly sensitivity, specificity, reliability, and other aspects). Finally, future trends for this field are analyzed and our perspectives are provided.


Assuntos
Biomarcadores/urina , Nefropatias Diabéticas/diagnóstico , Exossomos/metabolismo , Cardiopatias/diagnóstico , Nefropatias/diagnóstico , Nefrite Lúpica/diagnóstico , Neoplasias/diagnóstico , Animais , Nefropatias Diabéticas/urina , Cardiopatias/urina , Humanos , Nefropatias/urina , Nefrite Lúpica/urina , Neoplasias/urina
2.
Viruses ; 13(1)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33477927

RESUMO

"Definitive" biopsy proven polyomavirus nephropathy (PyVN), usually caused by BK polyomavirus (BKPyV), remains a significant infection of kidney transplants. Diagnosis depends upon an allograft biopsy and outcome depends upon early intervention. Here, we report data on a non-invasive biomarker for PyVN, the urinary PyV-Haufen test. Test results were compared to those of conventional laboratory assays targeting PyV replication, i.e., BKPy-viremia, -viruria and urinary decoy cell shedding. Of 809 kidney transplant recipients, 228 (28%) showed PyV replication with decoy cell shedding and/or BKPy-viremia by quantitative PCR; only a subset of 81/228 (36%) showed "definitive" PyVN. Sensitivity and specificity for identifying patients with PyVN was: 100% and 98%, respectively, urinary PyV-Haufen test; 50% and 54%, respectively, urinary decoy cell shedding; 97% and 32%, respectively, BKPy-viremia with cut-off of ≥250 viral copies/mL; 66% and 80%, respectively, for BKPy-viremia ≥104 viral copies/mL. The PyV-Haufen test showed a very strong correlation with the severity of PyVN (Spearman's ρ = 0.84) and the Banff PyVN disease classes (p < 0.001). In comparison, BKPy-viremia and -viruria levels by PCR displayed modest correlations with PyVN severity (Spearman's ρ = 0.35 and 0.36, respectively) and were not significantly associated with disease classes. No association was found between decoy cell shedding and PyVN severity or disease classes. Pilot data demonstrated that PyVN resolution with decreasing Banff pvl-scores was reflected by a gradual decrease in PyV-Haufen shedding; such a tight association was not noted for BKPy-viremia. In conclusion, urinary PyV-Haufen testing is a highly specific, non-invasive method to accurately diagnose patients with "definitive" PyVN and to optimize patient management. Assay specifics are discussed.


Assuntos
Nefropatias/diagnóstico , Nefropatias/etiologia , Infecções por Polyomavirus/complicações , Infecções por Polyomavirus/virologia , Polyomavirus/fisiologia , Urinálise/métodos , Biomarcadores , Biópsia , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Imuno-Histoquímica , Nefropatias/terapia , Nefropatias/urina , Transplante de Rim , Reação em Cadeia da Polimerase , Polyomavirus/ultraestrutura , Infecções por Polyomavirus/diagnóstico , Prognóstico , Sensibilidade e Especificidade , Resultado do Tratamento , Urinálise/normas , Carga Viral
4.
Environ Toxicol Pharmacol ; 83: 103587, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33460805

RESUMO

PM2.5 exposure is associated with a glomerular filtration rate (GFR) reduction, and renal tissue damage. The goal of this study was demonstrate the acute effect of PM2.5 on the kidney. Male rats were acutely exposed to PM2.5 or filtered air. Blood pressure was mesure and early kidney biomarkers were evaluated in serum and urine samples, and also IL-1ß, IL-6 and TNFα were determined. Oxidative biomarkers, angiotensin/bradykinin-related proteins, KIM-1, IL-6 and histology were determined. Blood pressure, GFR, and early kidney damage biomarkers increase together with oxidative biomarkers and angiotensin/bradykinin endocrine-related proteins increased after exposure to PM2.5. Urinary IL-6 increased after exposure to PM2.5, whereas in kidney cortex decreased. Histological changes were observed and accompanied by the induction of KIM-1. Acute exposure to PM2.5 not decline kidney function. However, it can induce early kidney damage biomarkers, oxidative stress, inflammation and angiotensin mediators, which perhabs culminates in a lose of renal function.


Assuntos
Poluentes Atmosféricos/toxicidade , Nefropatias/etiologia , Rim/efeitos dos fármacos , Material Particulado/toxicidade , Animais , Pressão Sanguínea/efeitos dos fármacos , Citocinas/imunologia , Citocinas/urina , Inflamação/etiologia , Inflamação/imunologia , Inflamação/patologia , Inflamação/fisiopatologia , Rim/patologia , Rim/fisiologia , Nefropatias/patologia , Nefropatias/fisiopatologia , Nefropatias/urina , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Masculino , Ratos Sprague-Dawley
5.
Transplant Proc ; 52(3): 823-828, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32111385

RESUMO

BACKGROUND: Human polyoma virus-associated nephropathy frequently refers to allograft failure after kidney transplant. Thus, the early detection of viral activation is extremely important for these immunocompromised patients. METHODS: Previously, urine polyoma virus-infected cells (decoy cells) were indicated as the virus action, usually screened by the routine papanicolaou cytology in renal biopsy, but these methods are complex and the positive rate is low. In this article, the direct microscopy observation method, Wright-Giemsa staining, and Sternheimer-Malbin (SM) staining were all used to screen the decoy cells in urine samples of 213 kidney transplant patients who had used immunosuppressive drugs. RESULTS: Among them, decoy cells were detected in 40 cases (18.8%) by the direct observation method, 44 cases (20.7%) by Wright-Giemsa staining and 49 cases (23.0%) by SM staining. Furthermore, the most common polyoma viruses, BK and JC viruses, were also confirmed in 41 (83.7%) cases among these 49 decoy cell-positive samples. Importantly, compared with other decoy cell detection methods, SM staining is fast, easy to operate, and has a high positive rate. CONCLUSION: Therefore, SM staining is recommended as a fast and effective method for screening urine decoy cells in kidney transplant patients.


Assuntos
DNA Viral/urina , Nefropatias/diagnóstico , Infecções por Polyomavirus/diagnóstico , Polyomavirus/genética , Complicações Pós-Operatórias/diagnóstico , Coloração e Rotulagem/métodos , Adulto , Vírus BK/genética , Feminino , Humanos , Hospedeiro Imunocomprometido , Imunossupressores/efeitos adversos , Vírus JC/genética , Nefropatias/patologia , Nefropatias/urina , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Masculino , Teste de Papanicolaou , Infecções por Polyomavirus/urina , Infecções por Polyomavirus/virologia , Complicações Pós-Operatórias/urina , Complicações Pós-Operatórias/virologia , Transplante Homólogo , Urinálise/métodos , Ativação Viral
6.
Kidney Blood Press Res ; 45(2): 263-274, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32062662

RESUMO

INTRODUCTION: The kidneys play a central role in eliminating metabolic waste products and drugs through transporter-mediated excretion along the proximal tubule. This task is mostly achieved through a variety of transporters from the solute carrier family 22 (SLC22) family of organic cation and anion transporters. Metabolic acidosis modulates metabolic and renal functions and also affects the clearance of metabolites and drugs from the body. We had previously shown that induction of metabolic acidosis in mice alters a large set of transcripts, among them also many transporters including transporters from the Slc22 family. OBJECTIVE: Here we further investigated the impact of acidosis on Slc22 family members. METHODS: Metabolic acidosis was induced for 2 or 7 days with NH4Cl, some animals also received the uricase inhibitor oxonic acid for comparison. Expression of transporters was studied by qPCR and immunoblotting. RESULTS: NH4Cl induced no significant changes in plasma or urine uric acid levels but caused downregulation of Slc22a1 (Oct1), Slc22a6 (Oat1), Slc22a19 (Oat5), and -Slc22a12 (Urat1) at mRNA level. In contrast, Slc22a4 mRNA (Octn1) was upregulated. On protein level, NH4Cl increased Octn1 (after 7 days) and Urat1 (after 2 days) abundance and decreased Oat1 (after 2 days) and Urat1 (after 7 days). Oxonic acid had no impact on protein abundance of any of the transporters tested. CONCLUSION: In summary, metabolic acidosis alters expression of several transporters involved in renal excretion of metabolic waste products and drugs. This may have implications for drug kinetics and clearance of waste metabolites.


Assuntos
Acidose/metabolismo , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/biossíntese , Nefropatias/patologia , Acidose/sangue , Acidose/patologia , Acidose/urina , Animais , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/genética , Proteínas da Membrana Plasmática de Transporte de Catecolaminas/metabolismo , Nefropatias/sangue , Nefropatias/metabolismo , Nefropatias/urina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 1 de Transcrição de Octâmero/biossíntese , Fator 1 de Transcrição de Octâmero/genética , Fator 1 de Transcrição de Octâmero/metabolismo , Transportadores de Ânions Orgânicos/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ácido Úrico/sangue , Ácido Úrico/urina
7.
Vet Clin North Am Equine Pract ; 36(1): 121-134, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32037140

RESUMO

Clinicopathologic evaluation of renal function and renal disease in sick adult horses remains grounded in detection of azotemia, assessment of serum and urine electrolyte concentrations, and evaluation of urinalysis findings, including specific gravity, reagent strip analysis, and sediment examination. Because increases in serum or plasma urea nitrogen and creatinine concentrations are insensitive indicators of a decreased glomerular filtration rate, there is considerable interest in identifying novel biomarkers of renal function or injury in blood and urine, with serum symmetric dimethylarginine concentration being the most recent addition to the commercial market.


Assuntos
Doenças dos Cavalos/patologia , Doenças dos Cavalos/urina , Nefropatias/veterinária , Animais , Biomarcadores/sangue , Biomarcadores/urina , Doenças dos Cavalos/sangue , Cavalos , Nefropatias/patologia , Nefropatias/urina , Masculino , Urinálise/veterinária
8.
J Agric Food Chem ; 68(9): 2765-2772, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32045244

RESUMO

Fatty acid esters of 3-monochloropropane 1,2-diol (3-MCPD esters) are processing-induced food toxicants, with the kidney as their major target organ. For the first time, this study treated Sprague Dawley (SD) rats with 3-MCPD 1-monooleate at 10 and 100 mg/kg BW/day and 1-monostearate at 15 and 150 mg/kg BW/day for 90 days and examined for their potential semi-long-term nephrotoxicity and the associated molecular mechanisms. No bodyweight difference was observed between groups during the study. Both 3-MCPD 1-monooleate and 1-monostearate resulted in a dose-dependent increase of serum urea creatinine, uric acid and urea nitrogen levels, and histological renal impairment. The proteomic analysis of the kidney samples showed that the 3-MCPD esters deregulated proteins involved in the pathways for ion transportation, apoptosis, the metabolism of xenobiotics, and enzymes related to endogenous biological metabolisms of carbohydrates, amino acids, nitrogen, lipids, fatty acids, and the tricarboxylic acid (TCA) cycle, providing partial explanation for the nephrotoxicity of 3-MCPD esters.


Assuntos
Nefropatias/metabolismo , Rim/efeitos dos fármacos , Estearatos/toxicidade , alfa-Cloridrina/toxicidade , Animais , Creatinina/urina , Ésteres/metabolismo , Ésteres/toxicidade , Humanos , Rim/metabolismo , Nefropatias/etiologia , Nefropatias/genética , Nefropatias/urina , Masculino , Proteômica , Ratos , Ratos Sprague-Dawley , Estearatos/química , Estearatos/metabolismo , Ácido Úrico/urina , alfa-Cloridrina/metabolismo
9.
Sci Rep ; 10(1): 1796, 2020 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-32020028

RESUMO

The PROteKT study tested the hypothesis that rosuvastatin can inhibit aminoglycoside-induced nephrotoxicity in children with Cystic Fibrosis (CF). This open label, parallel group, randomised controlled trial recruited children and young people aged 6 to 18 years with CF at 13 paediatric CF treatment centres in the UK. Participants were randomised equally to either receive oral rosuvastatin (10 mg once daily) or no intervention (control) throughout clinically indicated treatment with intravenous tobramycin. The primary outcome was the difference between the groups in mean fold-change in urinary Kidney Injury Molecule-1 (KIM-1). Fifty (rosuvastatin n = 23, control n = 27) participants were recruited between May 2015 and January 2017. Primary outcome data was available for 88% (rosuvastatin n = 20, control n = 24). The estimated mean treatment difference in the geometric mean-fold change of normalised KIM-1 was 1.08 (95% CI 0.87-1.35, p = 0.48). In total there were 12 adverse reactions, all mild, reported by five participants randomised to rosuvastatin, and one serious adverse event in each group. Whilst no protective effect of rosuvastatin was seen, there was a lower than expected level of nephrotoxicity in the cohort. Therefore, we can neither confirm nor refute the hypothesis that rosuvastatin protects against aminoglycoside nephrotoxicity.


Assuntos
Antibacterianos/efeitos adversos , Fibrose Cística/tratamento farmacológico , Nefropatias/prevenção & controle , Rosuvastatina Cálcica/uso terapêutico , Tobramicina/efeitos adversos , Adolescente , Antibacterianos/uso terapêutico , Criança , Fibrose Cística/urina , Feminino , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Humanos , Nefropatias/induzido quimicamente , Nefropatias/urina , Masculino , Tobramicina/uso terapêutico
10.
Ecotoxicol Environ Saf ; 191: 110251, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-32006870

RESUMO

Cadmium exposure is associated with renal dysfunction. However, the outcome of renal function in subjects who have had a reduction in cadmium exposure for years has not been completely clarified, particularly for individuals with normal baseline renal function. In this study, we used a nomogram model to predict renal dysfunction after a reduction in cadmium exposure in subjects with normal baseline renal function. In 1998, a survey was performed in 790 subjects living in control and cadmium-polluted areas. A total of 497 subjects was followed up in 2006. 404 subjects with normal baseline urinary ß2-microglobulin (UBMG), 373 subjects with normal baseline urinary N-acetyl-ß-d-glucosaminidase (UNAG) and 407 subjects with normal baseline urinary albumin (UALB) were included in this analysis. Cadmium in the blood (BCd) and urine (UCd) was detected using graphite-furnace atomic absorption spectrometry. A logistic regression model was used to identify potential predicting factors of renal function at follow-up. Nomograms were developed based on those predictive factors. Bootstrap self-sampling, calibration curves and receiver operating characteristic (ROC) curves were performed to quantify our modeling strategy. Adjusted and unadjusted logistic regression models both showed that age, BCd and UBMG or UNAG at baseline were independent risk factors for renal tubular dysfunction. Baseline age, sex, BCd and UNAG or UBMG or UALB were used to construct the nomogam. The internal validation showed that the C-index was 0.70-0.74 for predicting renal dysfunction. The area under the curve of the nomogram was 0.70-0.74. Decision curve analysis verified the predictive value of the nomogram. A nomogram may be a useful risk assessment tool for predicting the progress of renal function in a cadmium-exposed population with normal baseline kidney function.


Assuntos
Cádmio/sangue , Exposição Ambiental/análise , Poluentes Ambientais/sangue , Nefropatias/epidemiologia , Nomogramas , Acetilglucosaminidase/urina , Adulto , China , Exposição Ambiental/efeitos adversos , Feminino , Seguimentos , Humanos , Nefropatias/induzido quimicamente , Nefropatias/urina , Testes de Função Renal , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Microglobulina beta-2/urina
11.
PLoS One ; 15(1): e0227838, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31968011

RESUMO

Prednisolone is involved in glucose homeostasis and has been used for treatment for aristolochic acid (AA) nephropathy (AAN), but its effect on glycolysis in kidney has not yet been clarified. This study aims to investigate the effect in terms of altered proteins after prednisolone treatment in a mice model of AAN using a proteomics technique. The six-week C3H/He female mice were administrated AA (0.5 mg/kg/day) for 56 days. AA+P group mice were then given prednisolone (2 mg/kg/day) via oral gavage for the next 14 days, and AA group mice were fed water instead. The tubulointerstitial damage was improved after prednisolone treatment comparing to that of AA group. Kidney homogenates were harvested to perform the proteomics analysis with fluorogenic derivatization-liquid chromatography-tandem mass spectrometry method (FD-LC-MS/MS). On the other hand, urinary methylglyoxal and D-lactate levels were determined by high performance liquid chromatography with fluorescence detection. There were 47 altered peaks and 39 corresponding proteins on day 14 among the groups, and the glycolysis-related proteins, especially glyoxalase 1 (GLO1), fructose-bisphosphate aldolase B (aldolase B), and triosephosphate isomerase (TPI), decreased in the AA+P group. Meanwhile, prednisolone decreased the urinary amount of methylglyoxal (AA+P: 2.004 ± 0.301 µg vs. AA: 2.741 ± 0.630 µg, p < 0.05), which was accompanied with decrease in urinary amount of D-lactate (AA+P: 54.07 ± 5.45 µmol vs. AA: 86.09 ± 8.44 µmol, p < 0.05). Prednisolone thus alleviated inflammation and interstitial renal fibrosis. The renal protective mechanism might be associated with down-regulation of GLO1 via reducing the contents of methylglyoxal derived from glycolysis. With the aid of proteomics analysis and the determination of methylglyoxal and its metabolite-D-lactate, we have demonstrated for the first time the biochemical efficacy of prednisolone, and urinary methylglyoxal and its metabolite-D-lactate might be potential biomarkers for AAN.


Assuntos
Ácidos Aristolóquicos/genética , Nefropatias/tratamento farmacológico , Prednisolona/farmacologia , Proteômica , Animais , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Feminino , Fibrose/tratamento farmacológico , Fibrose/genética , Fibrose/metabolismo , Fibrose/urina , Frutose-Bifosfato Aldolase/genética , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/urina , Rim/metabolismo , Rim/patologia , Nefropatias/genética , Nefropatias/metabolismo , Nefropatias/urina , Ácido Láctico/urina , Lactoilglutationa Liase/genética , Camundongos , Aldeído Pirúvico/urina , Espectrometria de Massas em Tandem , Triose-Fosfato Isomerase/genética
12.
Cell Physiol Biochem ; 54(1): 88-109, 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31990489

RESUMO

Extracellular vesicles (EVs) are important mediators of intercellular communication. Since EVs are also released during pathological conditions, there has been considerable interest in their potential as sensitive biomarkers of cellular stress and/or injury. In the context of kidney disease, urinary EVs are promising indicators of glomerular and tubular damage. In the present review we discuss the role of urinary EVs in kidney health and disease. Our focus is to explore urinary large EVs (lEVs, often referred to as microparticles or microvesicles) as direct and noninvasive early biomarkers of renal injury. In this regard, studies have been demonstrating altered levels of urinary lEVs, especially podocyte-derived lEVs, preceding the decrease of renal function assessed by classical markers. In addition, we discuss the role of small EVs (sEVs, often referred to as exosomes) and their contents in kidney pathophysiology. Even though results concerning the production of sEVs during diseased conditions are varied, there has been a consensus on the importance of urinary sEV content assessment in kidney disease. These mediators, including EV-released miRNAs and mRNAs, are responsible for EV-mediated signaling in the regulation of renal cellular homeostasis, pathogenesis and regeneration. Finally, steps necessary for the validation of EVs as reliable markers will be discussed.


Assuntos
Vesículas Extracelulares/patologia , Nefropatias/diagnóstico , Glomérulos Renais/patologia , Túbulos Renais/patologia , Animais , Biomarcadores/análise , Biomarcadores/urina , Humanos , Nefropatias/patologia , Nefropatias/urina
13.
Toxicol Lett ; 319: 204-212, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31760061

RESUMO

Doxorubicin has been indicated to be cardiotoxic and nephrotoxic, and thus it is often used as a model drug. Possible molecular mechanisms of this toxicity have been proposed, however, the systematic investigation of time-related metabolic trajectories specific to renal toxicity has rarely been reported. The present study was designed to assess time-dependent changes in doxorubicin-induced nephropathy through urinary metabolomics and to reveal the molecular mechanism based on key pathways. Urinary metabolomics revealed that the 14th day was the critical time point for model construction. Pathway analysis results showed that 5 pathways with impact (>0.1), FDR (<0.1) and p value (<0.05) were important. Furthermore, three pathways, including butanoate metabolism, alanine, aspartate and glutamate metabolism and arginine and proline metabolism, were focused on and validated by partial least squares regression analysis (PLS-RA) and molecular docking techniques. Our findings also showed that robust metabolomics combined with PLS-RA and molecular docking techniques is promising for elucidating time-dependent changes due to doxorubicin toxicity and for clarifying mechanisms, and the results provide a research foundation for the construction of a nephropathy model.


Assuntos
Antibióticos Antineoplásicos/toxicidade , Doxorrubicina/toxicidade , Nefropatias/induzido quimicamente , Nefropatias/urina , Metaboloma/efeitos dos fármacos , Aminoácidos/metabolismo , Animais , Rim/patologia , Nefropatias/patologia , Masculino , Metabolômica , Simulação de Acoplamento Molecular , Proteinúria/induzido quimicamente , Ratos , Ratos Sprague-Dawley , Fatores de Tempo
14.
Biomed Pharmacother ; 121: 109684, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31810121

RESUMO

Nephrotoxicity is an important limitation to the clinical use of many drugs and contrast media. Drug nephrotoxicity occurs in acute, subacute and chronic manifestations ranging from glomerular, tubular, vascular and immunological phenotypes to acute kidney injury. Pre-emptive risk assessment of drug nephrotoxicity poses an urgent need of precision medicine to optimize pharmacological therapies and interventional procedures involving nephrotoxic products in a preventive and personalized manner. Biomarkers of risk have been identified in animal models, and risk scores have been proposed, whose clinical use is abated by their reduced applicability to specific etiological models or clinical circumstances. However, our present data suggest that the urinary level of transferrin may be indicative of risk of renal damage, where risk is induced by subclinical tubular alterations regardless of etiology. In fact, urinary transferrin pre-emptively correlates with the subsequent renal damage in animal models in which risk has been induced by drugs and toxins affecting the renal tubules (i.e. cisplatin, gentamicin and uranyl nitrate); whereas transferrin shows no relation with the risk posed by a drug affecting renal hemodynamics (i.e. cyclosporine A). Our experiments also show that transferrin increases in the urine in the risk state (i.e. prior to the damage) precisely as a consequence of reduced tubular reabsorption. Finally, urinary transferrin pre-emptively identifies subpopulations of oncological and cardiac patients at risk of nephrotoxicity. In perspective, urinary transferrin might be further explored as a wider biomarker of an important mechanism of predisposition to renal damage induced by insults causing subclinical tubular alterations.


Assuntos
Túbulos Renais/patologia , Transferrina/urina , Acetilglucosaminidase/urina , Animais , Biomarcadores/urina , Meios de Contraste/efeitos adversos , Creatinina/sangue , Suscetibilidade a Doenças , Feminino , Humanos , Nefropatias/induzido quimicamente , Nefropatias/urina , Lipocalina-2/urina , Masculino , Pessoa de Meia-Idade , Platina/efeitos adversos , Ratos Wistar , Fatores de Risco , Ureia/sangue
15.
Environ Pollut ; 256: 113334, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31677874

RESUMO

The goal of this study was to assess biomarkers of exposure to glyphosate and assess potential associations with renal function in children. Glyphosate is used ubiquitously in agriculture worldwide. While previous studies have indicated that glyphosate may have nephrotoxic effects, few have examined potential effects on kidney function in children. We leveraged three cohorts across different phases of child development and measured urinary levels of glyphosate. We evaluated associations of glyphosate with three biomarkers of kidney injury: albuminuria (ACR), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury marker 1 (KIM-1). Multivariable regression analyses examined associations of glyphosate with kidney injury biomarkers controlling for covariates. We identified glyphosate in 11.1% of the total participants. The herbicide was detected more frequently in the neonate population (30%). Multivariable regression models failed to identify significant associations of log-transformed glyphosate with any of the kidney injury biomarkers, controlling for covariates age, sex, and maternal education. While we confirm detectability of glyphosate in children's urine at various ages and stages of life, there is no evidence in this study for renal injury in children exposed to low levels of glyphosate. Further studies of larger sample size are indicated to better understand putative deleterious effects of the herbicide after different levels of exposure.


Assuntos
Exposição Ambiental/análise , Poluentes Ambientais/urina , Glicina/análogos & derivados , Nefropatias/urina , Biomarcadores/urina , Criança , Pré-Escolar , Estudos de Coortes , Creatinina/urina , Estudos Transversais , Feminino , Glicina/urina , Receptor Celular 1 do Vírus da Hepatite A/análise , Humanos , Lactente , Recém-Nascido , Nefropatias/epidemiologia , Lipocalina-2/urina , Estudos Longitudinais , Masculino , Prevalência , Albumina Sérica Humana/urina
16.
J Vet Intern Med ; 34(1): 176-185, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31705606

RESUMO

BACKGROUND: Urine neutrophil gelatinase-associated lipocalin (NGAL) is a promising biomarker of acute kidney injury (AKI) in dogs. OBJECTIVES: To evaluate the utility of urinary NGAL for characterizing AKI according to volume responsiveness, presence of inflammation and sepsis, and prognosis. ANIMALS: Dogs with AKI (n = 76) and healthy controls (n = 10). METHODS: Prospective study. Clinical and clinicopathologic data including absolute urine NGAL concentration (uNGAL) and NGAL normalized to urine creatinine concentration (uNGALC) were measured upon admission. Dogs were graded according to International Renal Interest Society (IRIS) AKI guidelines and compared based on AKI features: volume-responsive (VR-) AKI vs. intrinsic (I-) AKI based on IRIS criteria; VR-AKI and I-AKI based on urine chemistry; inflammatory versus noninflammatory; septic versus nonseptic; and survivors versus nonsurvivors. Nonparametric statistics were calculated, and significance set at P < .05. RESULTS: Urinary NGAL was significantly higher in dogs with AKI compared to controls, regardless of AKI grade. Urinary NGAL did not differ between dogs with VR-AKI and I-AKI based on IRIS criteria, whereas higher uNGALC was recorded in dogs with I-AKI based on urine chemistry. Urinary NGAL was significantly higher in dogs with inflammatory AKI, whereas no difference with respect to sepsis or outcome was identified. CONCLUSIONS AND CLINICAL IMPORTANCE: Urinary NGAL is a sensitive marker for AKI in dogs, but its specificity is affected by systemic inflammation. Increased urinary NGAL in both I-AKI and VR-AKI also suggests the presence of tubular damage in transient AKI. Combining urine chemistry data with IRIS criteria could facilitate AKI characterization in dogs.


Assuntos
Doenças do Cão/diagnóstico , Nefropatias/veterinária , Lipocalina-2/urina , Animais , Biomarcadores , Estudos de Casos e Controles , Doenças do Cão/urina , Cães , Feminino , Nefropatias/urina , Masculino , Estudos Prospectivos
17.
Nephrol Dial Transplant ; 35(2): 283-291, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30380100

RESUMO

BACKGROUND: Prior work has shown that urinary soluble CD163 (usCD163) displays excellent biomarker characteristics for detection of active renal vasculitis using samples that included new diagnoses with highly active renal disease. This study focused on the use of usCD163 in the detection of the more clinically relevant state of mild renal flare and compared results of usCD163 testing directly to testing of urinary monocyte chemoattractant protein-1 (uMCP-1). METHODS: Patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV, n = 88) were identified within a serially sampled, longitudinal and multicentre cohort. Creatinine-normalized usCD163 and uMCP-1 levels were measured by enzyme-linked immunosorbent assay and, both alone and in combination, were compared between times of active renal AAV and during remission and/or active non-renal AAV. RESULTS: Samples from 320 study visits included times of active renal vasculitis (n = 39), remission (n = 233) and active extrarenal vasculitis (n = 48). Median creatinine levels were 0.9 mg/dL [interquartile range (IQR) 0.8-1.2] in remission and 1.4 mg/dL (IQR 1.0-1.8) during renal flare. usCD163 levels were higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 162 ng/mmol (IQR 79-337), 44 (17-104) and 38 (7-76), respectively (P < 0.001). uMCP-1 levels were also higher in patients with active renal vasculitis compared with patients in remission and those with active extrarenal vasculitis, with median values of 10.6 pg/mmol (IQR 4.6-23.5), 4.1 (2.5-8.4) and 4.1 (1.9-6.8), respectively (P < 0.001). The proposed diagnostic cut-points for usCD163 and uMCP-1 were 72.9 ng/mmol and 10.0 pg/mmol, respectively. usCD163 and uMCP-1 levels were marginally correlated (r2 = 0.11, P < 0.001). Combining novel and existing biomarkers using recursive tree partitioning indicated that elevated usCD163 plus either elevated uMCP-1 or new/worse proteinuria improved the positive likelihood ratio (PLR) of active renal vasculitis to 19.2. CONCLUSION: A combination of usCD163 and uMCP-1 measurements appears to be useful in identifying the diagnosis of subtle renal vasculitis flare.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Anticorpos Anticitoplasma de Neutrófilos/efeitos adversos , Antígenos CD/urina , Antígenos de Diferenciação Mielomonocítica/urina , Biomarcadores/urina , Quimiocina CCL2/urina , Nefropatias/diagnóstico , Adulto , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Feminino , Humanos , Nefropatias/etiologia , Nefropatias/urina , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Receptores de Superfície Celular , Urinálise
18.
J Pharm Biomed Anal ; 177: 112889, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31568966

RESUMO

This work presents the development of a methodology for the accurate and precise quantification of the renal biomarker Cystatin C in human urine by Isotope Dilution Mass Spectrometry (IDMS). The procedure is based on the addition of a known quantity of the proteotypic peptide ALDFAVG*EYNK labelled with 13C2-glycine to the urine sample followed by protein hydrolysis using trypsin. Then, preconcentration and purification of the isotope diluted peptide was carried out by a selective monoclonal antibody bound to magnetic beads and final measurement was done after injection of the sample in a HPLC-MS/MS triple quadrupole instrument. The isotopic distribution of the isotope diluted proteotypic peptide was measured by low resolution selected reaction monitoring. Using this aquisition mode, the bandpass of the first quadrupole was widened (FWHM =13 u) so the whole isotopic clusters for both the natural abundance and the labelled peptides entered the collision cell. The proposed acquisition mode provided similar accuracy and precision than the regular SRM mode (FWHM =0.7 u) but a higher sensitivity was observed. The purification of the sample by antibody based enrichment of the target peptide was shown to remove interfering compounds more efficiently in comparison with a sample purification based on semipreparative liquid chromatography. Using 5 ng of the labelled peptide it was possible to quantify Cystatin C in human urine in patients with normal and impaired renal function. Recoveries from 100 to 104% were obtained in samples containing from 90 to 700 µg L-1 of Cystatin C with relative standard deviations from 0.5 to 6%. The stability of Cystatin C in urine samples was evaluated under different storage conditions showing that only when the urine samples were stored at room temperature during more than 10 days, a significant degradation of Cystatin C was observed.


Assuntos
Cistatina C/urina , Nefropatias/diagnóstico , Manejo de Espécimes/efeitos adversos , Espectrometria de Massas em Tandem/métodos , Biomarcadores/química , Biomarcadores/urina , Isótopos de Carbono/química , Cromatografia Líquida de Alta Pressão , Cistatina C/química , Taxa de Filtração Glomerular/fisiologia , Humanos , Técnicas de Diluição do Indicador , Rim/fisiopatologia , Nefropatias/fisiopatologia , Nefropatias/urina , Estabilidade Proteica , Manejo de Espécimes/métodos , Temperatura , Fatores de Tempo
19.
Congenit Heart Dis ; 14(6): 963-967, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31793232

RESUMO

BACKGROUND: There are significant implications for kidney disease in young adults with congenital heart disease. Prior investigations have not focused on the use of urinary tubular biomarkers for the early identification of kidney disease in this growing patient group. OBJECTIVE: Determine if young adults with congenital heart disease have differences in the baseline concentration of urinary tubular biomarkers when compared to healthy young adults. DESIGN/METHODS: In a pilot case control study, 30 patients from 18 to 35 years of age with congenital heart disease and a normal serum creatinine were recruited during a routine follow-up visit. In the same age group, 30 control subjects without history of heart or kidney disease were recruited. Urine samples were obtained to measure beta 2-microglobin, alpha 1-microglobin, N-acetyl-B-D-glucosaminidase, liver fatty acid binding protein, kidney injury molecule-1, insulin-like growth factor binding protein 7, and tissue inhibitor of metalloproteinases-2. Comparisons were done using Wilcoxon rank-sum or Fisher's exact test. RESULTS: No study participants had proteinuria on urine dipstick. Median concentrations of kidney injury molecule-1 were higher (P = .01) and concentrations of insulin-like growth factor binding protein 7 (P = .001) and tissue inhibitor of metalloproteinases-2 (P = .009) were lower in the subjects with congenital heart disease when compared to the control subjects. There were no significant differences between the groups with respect to the other biomarkers. CONCLUSION: Our data suggest that young adults with congenital heart disease may have subclinical kidney dysfunction. Lower levels of insulin-like growth factor binding protein 7 and tissue inhibitor of metalloproteinases-2 may indicate an impaired ability to respond to injury, while higher levels of kidney injury molecule-1 may reflect early tubular injury.


Assuntos
Cardiopatias Congênitas/complicações , Receptor Celular 1 do Vírus da Hepatite A/análise , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina/urina , Nefropatias/diagnóstico , Túbulos Renais/metabolismo , Inibidor Tecidual de Metaloproteinase-2/urina , Adolescente , Adulto , Doenças Assintomáticas , Biomarcadores/urina , Estudos de Casos e Controles , Feminino , Cardiopatias Congênitas/diagnóstico , Humanos , Nefropatias/etiologia , Nefropatias/urina , Masculino , Projetos Piloto , Valor Preditivo dos Testes , Prognóstico , Urinálise , Adulto Jovem
20.
BMC Vet Res ; 15(1): 439, 2019 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-31801572

RESUMO

BACKGROUND: Acute kidney injury is the most frequent complication of babesiosis in dogs and may provide a natural model for identifying early and specific markers of kidney injury in this species. There are limited data on urine proteomics in dogs, and none of the effect of babesiosis on the urine proteome. This study aimed to identify urinary proteins of dogs with kidney injury during the natural course of babesiosis caused by Babesia canis, and to compare them with proteins in a control group to reveal any potential biomarkers predicting renal injury before the presence of azotemia. Urine samples were collected from 10 dogs of various breeds and sex with naturally occurring babesiosis, and 10 healthy dogs. Pooled urine samples from both groups were separated by 2D (two-dimensional) electrophoresis, followed by protein identification using MALDI-TOF (matrix-assisted laser desorption ionization time of flight) mass spectrometry. RESULTS: In total, 176 proteins were identified in the urine samples from healthy dogs, and 403 proteins were identified in the urine samples from dogs with babesiosis. Of the 176 proteins, 146 were assigned exclusively to healthy dogs, and 373 of the 403 proteins were assigned exclusively to dogs with babesiosis; 30 proteins were common for both groups. Characteristic analysis of 373 proteins found in dogs with babesiosis led to the isolation of 8 proteins associated with 10 metabolic pathways involved in immune and inflammatory responses. CONCLUSIONS: It was hypothesized that epithelial-mesenchymal transition might play an important role in the mechanisms underlying pathological changes in renal tissue during babesiosis, as indicated by a causal relationship network built by combining 5 of the 10 selected metabolic pathways, and 4 of the 8 proteins associated with these pathways; this network included cadherins, gonadotropin releasing hormone receptors, inflammatory responses mediated by chemokine and cytokine signalling pathways, integrins, interleukins, and TGF-ß (transforming growth factor ß) pathways. Those pathways were linked by interleukin-13, bone morphogenetic protein 7, α2(1) collagen, and tyrosine protein kinase Fer, which are potential biomarkers of damage during babesiosis in dogs, that might indicate early renal injury.


Assuntos
Babesiose/urina , Doenças do Cão/urina , Nefropatias/veterinária , Proteoma , Animais , Babesiose/complicações , Babesiose/patologia , Estudos de Casos e Controles , Doenças do Cão/microbiologia , Doenças do Cão/patologia , Cães , Feminino , Nefropatias/metabolismo , Nefropatias/microbiologia , Nefropatias/urina , Masculino
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