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1.
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
2.
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
3.
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
4.
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
5.
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 Ambiente , Fatores de Tempo
6.
Molecules ; 24(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618977

RESUMO

p-Cresyl sulfate is one of the bound uremic toxins whose level increases in the sera of patients with the severity of chronic kidney disease and is therefore used as a standard for clinical investigations. Our first attempts to obtain p-cresyl sulfate led exclusively to the product of sulfonation of the aromatic ring instead of sulfation on the OH moiety. Nevertheless, this initial discouraging result allowed us to handle both p-cresyl sulfate and 2-hydroxy-5-methylbenzenesulfonic acid obtained by different synthetic pathways. Interestingly, the comparison between the two isomers pointed out that the two molecules show the same fragmentation pattern and are indistinguishable by mass spectrometry. They cannot be separated on several commercially available columns. The only difference between the two compounds is a 10-fold higher ionization yield under negative ion electrospray ionization. NMR spectral studies definitely confirmed the different molecular structures. We present here an unambiguous biomimetic synthetic route for p-cresyl sulfate and the spectroscopic characterization of both the compounds by nuclear magnetic resonance and mass spectrometry.


Assuntos
Biomarcadores , Cresóis/metabolismo , Cardiopatias/metabolismo , Nefropatias/metabolismo , Ésteres do Ácido Sulfúrico/metabolismo , Toxinas Biológicas/metabolismo , Cromatografia Líquida , Cresóis/sangue , Cresóis/química , Cardiopatias/sangue , Cardiopatias/urina , Humanos , Nefropatias/sangue , Nefropatias/urina , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Ésteres do Ácido Sulfúrico/sangue , Ésteres do Ácido Sulfúrico/química , Espectrometria de Massas em Tandem , Toxinas Biológicas/sangue , Toxinas Biológicas/química
7.
Int J Mol Sci ; 20(18)2019 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-31505904

RESUMO

: Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of kidney disease in adults and children. However, it is uncertain whether this association is influenced by major NAFLD susceptibility genes. In a sample of 230 overweight/obese children, 105 with NAFLD (hepatic fat fraction ≥5% by magnetic resonance imaging) and 125 without NAFLD, rs738409 in PNPLA3, rs58542926 in TM6SF2, rs1260326 in GCKR, and rs641738 in MBOAT7 were genotyped. Abnormal kidney function was defined as estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 and/or the presence of microalbuminuria (24 h urinary albumin excretion between 30 and 300 mg). In comparison with children without NAFLD, those with NAFLD showed increased prevalence of reduced eGFR (13.3% vs. 1.6%; p < 0.001) and microalbuminuria (8.6% vs. 3.4%, p = 0.025). TM6SF2, GCKR, and MBOAT7 risk alleles did not show any impact on kidney function, while the PNPLA3 G allele was associated with lower eGFR, but only in children with NAFLD (p = 0.003). After adjustment for confounders, NAFLD (OR, 4.7; 95% CI, 1.5-14.8; padj = 0.007), but not the PNPLA3 gene variant, emerged as the main independent predictor of renal dysfunction. Overall, our findings suggest that NAFLD remains the main determinant of decline in kidney function in overweight/obese children, while the PNPLA3 rs738409 prosteatogenic variant has a small impact, if any.


Assuntos
Albuminúria , Variação Genética , Nefropatias , Lipase/genética , Proteínas de Membrana/genética , Hepatopatia Gordurosa não Alcoólica , Obesidade Pediátrica , Adolescente , Albuminúria/genética , Albuminúria/urina , Criança , Estudos Transversais , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/genética , Nefropatias/urina , Masculino , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/urina , Obesidade Pediátrica/genética , Obesidade Pediátrica/urina
8.
Int J Mol Sci ; 20(18)2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31500276

RESUMO

In various models of chronic kidney disease, the amount and localization of Cx43 in the nephron is known to increase, but the intracellular pathways that regulate these changes have not been identified. Therefore, we proposed that: "In the model of renal damage induced by infusion of angiotensin II (AngII), a RhoA/ROCK-dependent pathway, is activated and regulates the abundance of renal Cx43". In rats, we evaluated: 1) the time-point where the renal damage induced by AngII is no longer reversible; and 2) the involvement of a RhoA/ROCK-dependent pathway and its relationship with the amount of Cx43 in this irreversible stage. Systolic blood pressure (SBP) and renal function (urinary protein/urinary creatinine: Uprot/UCrea) were evaluated as systemic and organ outcomes, respectively. In kidney tissue, we also evaluated: 1) oxidative stress (amount of thiobarbituric acid reactive species), 2) inflammation (immunoperoxidase detection of the inflammatory markers ED-1 and IL-1ß), 3) fibrosis (immune detection of type III collagen; Col III) and 4) activity of RhoA/ROCK (amount of phosphorylated MYPT1; p-MYPT1). The ratio Uprot/UCrea, SBP, oxidative stress, inflammation, amount of Cx43 and p-MYPT1 remained high 2 weeks after suspending AngII treatment in rats treated for 4 weeks with AngII. These responses were not observed in rats treated with AngII for less than 4 weeks, in which all measurements returned spontaneously close to the control values after suspending AngII treatment. Rats treated with AngII for 6 weeks and co-treated for the last 4 weeks with Fasudil, an inhibitor of ROCK, showed high SBP but did not present renal damage or increased amount of renal Cx43. Therefore, renal damage induced by AngII correlates with the activation of RhoA/ROCK and the increase in Cx43 amounts and can be prevented by inhibitors of this pathway.


Assuntos
Angiotensina II/efeitos adversos , Conexina 43/metabolismo , Nefropatias/metabolismo , Quinases Associadas a rho/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/farmacologia , Animais , Creatinina/urina , Modelos Animais de Doenças , Regulação da Expressão Gênica , Nefropatias/induzido quimicamente , Nefropatias/tratamento farmacológico , Nefropatias/urina , Masculino , Estresse Oxidativo , Ratos , Transdução de Sinais , Fatores de Tempo
9.
Adv Exp Med Biol ; 1165: 607-623, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399987

RESUMO

Renal fibrosis is the common pathological pathway of progressive CKD. The commonly used biomarkers in clinical practice are not optimal to detect injury or predict prognosis. Therefore, it is crucial to develop novel biomarkers to allow prompt intervention. Urine serves as a valuable resource of biomarker discovery for kidney diseases. Owing to the rapid development of omics platforms and bioinformatics, research on novel urinary biomarkers for renal fibrosis has proliferated in recent years. In this chapter, we discuss the current status and provide basic knowledge in this field. We present novel promising biomarkers including tubular injury markers, proteins related to activated inflammation/fibrosis pathways, CKD273, transcriptomic biomarkers, as well as metabolomic biomarkers. Furthermore, considering the complex nature of the pathogenesis of renal fibrosis, we also highlight the combination of biomarkers to further improve the diagnostic and prognostic performance.


Assuntos
Biomarcadores/urina , Nefropatias/urina , Rim/patologia , Fibrose , Humanos
10.
Ann Biol Clin (Paris) ; 77(4): 381-389, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31418699

RESUMO

The SFBC working group aimed to deal with biological tests outside the french nomenclature that may be useful in the context of urinary exploration of metabolism. This section will be divides into three parts: 1) nutritional assessment using urinary urea; 2) metabolic assessment of urolithiasis; 3) exploration of tubulopathies. National and international recommendations support the evaluation of nutritional status from urea measurements in urine and dialysate with the following indications: primary metabolic evaluation of urolithiasis patients, monitoring of protein intake in chronic renal failure stage 3 or stage 5D with residual diuresis. For the management of the urolithiasis disease, biomedical tests recommended by the national and international guidelines are the measurement of the urinary density using refractometry in the primary metabolic evaluation as well as the determination of oxalemia in the diagnosis (patients with GFR< 30 mL/min/1.73 m2) and follow-up (patients with GFR< 60 mL/min/1.73 m2) of primary hyperoxaluria. The determination of the bicarbonaturia is retained for the in depth exploration of urolithiasis and tubular acidosis. The measure of chlore in urine is used to evaluate the volume status during metabolic alkalosis and to calculate the urinary anionic gap during metabolic acidosis.


Assuntos
Metabolismo Energético/fisiologia , Nefropatias/diagnóstico , Avaliação Nutricional , Urinálise/métodos , Urolitíase/diagnóstico , Humanos , Nefropatias/patologia , Nefropatias/urina , Túbulos Renais/patologia , Padrões de Referência , Refratometria/métodos , Refratometria/normas , Urinálise/normas , Urolitíase/urina
11.
Saudi J Kidney Dis Transpl ; 30(4): 832-842, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31464240

RESUMO

Microalbuminuria (MA) has been recognized as a sensitive marker of early glomerular injury and a predictor of kidney dysfunction in patients with sickle cell disease (SCD). Limited data are available about MA in SCD children in the Arab countries and none from Yemen. The aim of this study is to determine the prevalence and correlates of MA among 101 children aged 1-16 years, with SCD at their steady state. Children were recruited during their routine health-care visits to the pediatric outpatient clinic in Al-Sadaqa general teaching hospital, Aden, Yemen, between September 2014 and February 2015. A random spot urine sample for each child was screened for MA using Micral-Test strips method. Data on clinical history, anthropometry, blood pressure (BP), and laboratory investigations were obtained. The overall prevalence of MA in this sample was 30.7%, with male predominance (80.6%) (P <0.05). The mean age of children with MA was 7.5 ± 3.2 years, and 10% of them were under five years of age. MA was correlated to both hemoglobin and hematocrit levels, which found to have protective effect against MA (Odds ratio = 0.17 and 0.59, respectively, P <0.05). No correlations were found between MA with age, height, weight, body mass index, recurrent clinical events (painful crises, blood transfusions, and hospitalizations), or fetal hemoglobin levels. BP measurements for all individuals were within the normal ranges, but systolic and diastolic BP were significantly higher in those with MA than without. This study demonstrated a high prevalence of MA in Yemeni children with SCD, and affecting young children as early as 2.5 years of age. Screening for MA as one of the early renal injury markers in children with SCD may help in the prevention of permanent loss of renal function and subsequent renal insufficiency in adulthood.


Assuntos
Albuminúria/epidemiologia , Anemia Falciforme/epidemiologia , Nefropatias/epidemiologia , Adolescente , Fatores Etários , Albuminúria/diagnóstico , Albuminúria/urina , Anemia Falciforme/sangue , Anemia Falciforme/diagnóstico , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Lactente , Nefropatias/diagnóstico , Nefropatias/urina , Masculino , Prevalência , Fatores de Risco , Fatores Sexuais , Iêmen/epidemiologia
12.
Urology ; 133: 199-203, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31454657

RESUMO

OBJECTIVE: To investigate the role of albuminuria as a clinical marker of early renal disease in children with neurogenic bladder (NGB) in association with commonly used predictors of renal risk. METHODS: Catheterized urine was obtained from 40 patients with NGB at a tertiary pediatric hospital. Albumin-to-creatinine ratio (ACR) was analyzed for associations with estimated glomerular filtration rate, vesicoureteral reflux, hydronephrosis, bladder dynamics, and renal scarring. RESULTS: About 32% (13/40) of NGB patients had elevated ACR (≥30 mg/g. Elevated ACR was associated with Caucasian race, clean intermittent catheterization, hydronephrosis, and vesicoureteral reflux on univariate analysis. In multivariable analysis, presence of vesicoureteral reflux and use of anticholinergic medication were significant predictors of ACR elevation. CONCLUSION: Albuminuria is an established clinical predictor of renal disease and risk for progression to renal failure. The presence of albuminuria in NGB patients with urinary tract abnormalities suggests these patients may be at increased risk for progressive renal disease. This supports the clinical utility of adding ACR to the evaluation of renal risk in pediatric NGB.


Assuntos
Albuminúria/etiologia , Nefropatias/diagnóstico , Nefropatias/etiologia , Bexiga Urinaria Neurogênica/complicações , Adolescente , Albuminúria/urina , Biomarcadores/urina , Criança , Pré-Escolar , Estudos Transversais , Diagnóstico Precoce , Feminino , Humanos , Nefropatias/urina , Masculino , Bexiga Urinaria Neurogênica/urina
13.
Clin Lab ; 65(6)2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31232037

RESUMO

BACKGROUND: Urinary levels of EGF may be a noninvasive biomarker of the degree of interstitial fibrosis. However, all the available data are based on studies that examined the EGF/creatinine ratio in spot urine samples. The agreement between EGF/creatinine ratio and 24-hours EGF excretion has not been analyzed, neither has it been established which of these two measurements is a better predictor of the degree of interstitial fibrosis. To investigate whether the EGF/creatinine ratio can predict 24-hours EGF, and which of these two measures is a better predictor of interstitial fibrosis in patients with IgA nephropathy (IgAN). METHODS: This is a cross-sectional study including 80 patients with IgAN. EGF levels were measured by ELISA in spot second-morning and 24-hours urine samples. We analyzed the concordance between these two measures and their respective ability to predict interstitial kidney fibrosis. RESULTS: The intraclass correlation coefficient between 24-hours and spot EGF/creatinine was 0.63 (95% CI: 0.54 - 0.70), bias was 2.7 µg/mL (95% CI: 2.1 - 7.5). Passing-Bablok regression did not show a significant deviation from linearity (p = 0.72). Bland-Altman showed a systematic and proportional error between both EGF measures. Spot EGF/creatinine ratios overestimated the 24-hours EGF at low excretion values and underestimated it at high excretion values. In univariate analyses, 24-hours excretion of EGF was a better predictor of interstitial fibrosis than spot EGF/creatinine ratio (R2: 0.43 vs. 0.30, p = 0.000). In multivariate analyses, the 24-hours excretion of EGF plus GFR, significantly improved the prediction of interstitial fibrosis when compared with GFR alone (R2: 0.52 vs. 0.39, p = 0.000). When spot-urine EGF was introduced instead of the 24-hours excretion, the model was statistically significant but had a lower predictive capacity (R2: 0.46 spot EGF/creatinine vs. R2: 0.52 24-hours EGF excretion, p = 0.000). CONCLUSIONS: The 24-hours excretion of EGF should be considered as the first-choice measure to estimate the interstitial fibrosis. The EGF/creatinine ratio cannot accurately estimate the total EGF excretion of but it also improves the estimation of the fibrosis surface, and, consequently, could be an alternative whenever 24-hours urine samples cannot be obtained.


Assuntos
Biomarcadores/urina , Creatinina/urina , Fator de Crescimento Epidérmico/urina , Glomerulonefrite por IGA/urina , Adulto , Idoso , Estudos Transversais , Feminino , Fibrose , Taxa de Filtração Glomerular , Glomerulonefrite por IGA/diagnóstico , Humanos , Nefropatias/diagnóstico , Nefropatias/urina , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Sensibilidade e Especificidade
14.
Transplant Proc ; 51(5): 1331-1336, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31076148

RESUMO

BACKGROUND: The albumin to creatinine ratio (ACR) has been shown to be an important prognostic marker in kidney disease. The ACR has been shown to predict graft failure and patient death after kidney transplant. METHODS: From March 1, 2011, to December 31, 2013, we checked the urine ACR and blood for highly sensitive C-reactive protein in 93 kidney recipients who regularly follow up at out institute. We tested the linear correlations of these parameters with estimated glomerular filtration rate. Furthermore, we used multivariate linear regression to examine its value in predicting graft function. Finally, we used receiver operating characteristic curve analysis to validate their predictive value on creatinine clearance > 45 mL/min. RESULTS: With multivariate linear regression, the latest estimated glomerular filtration rate has a strong linear relationship with initial ACR (B = -0.032; P = .02), suggesting each unit rise in ACR with a decrease in creatinine clearance by 0.032 mL/min. To investigate their value in predicting good functional graft defined as creatinine clearance >45 mL/min, a receiver operating characteristic curve analysis was applied on these parameters. The area under curve for age is 0.496, for body weight is 0.539, and for highly sensitive C-reactive protein is 0.582, which are all around the chance of 0.5 by flipping coins. The area under ACR curve is 0.825, better than above parameters, and only second to serum creatinine level. CONCLUSIONS: Urine ACR is a simple and effective measure to predict graft function after a kidney transplant. It has similar independent strong correlations to creatinine clearance comparing with serum creatinine without requirement of a blood draw.


Assuntos
Albuminúria/urina , Creatinina/urina , Sobrevivência de Enxerto , Testes de Função Renal/métodos , Transplante de Rim , Adulto , Feminino , Taxa de Filtração Glomerular , Humanos , Nefropatias/urina , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Curva ROC , Urinálise
15.
Toxicol Lett ; 312: 148-156, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31100493

RESUMO

Cadmium (Cd), lead (Pb) and mercury (Hg) are known nephrotoxicants that have been associated with the risk of developing type-2 diabetes (T2D). The aim of this pilot study was to explore relations between biomarkers of Cd, Pb and Hg exposure, early urinary biomarkers of renal dysfunction (kidney-injured molecule-1 (KIM-1), N-acetylglucosaminidase and retinol-binding protein (RBP)) and plasma biomarkers deemed predictive of the risk of developing T2D (adiponectin, leptin, branched-chain and aromatic amino acids), among 70 participants (age range: (46-87 yrs)) from the Canadian Longitudinal Study on Aging (CLSA) with normal glycemic control (glycated haemoglobin ≤ 6.5%) in all but four of them. Significant (p < 0.05) Spearman correlation coefficients were obtained between: plasma adiponectin and RBP (r = 0.42), urinary Cd (r = 0.32), blood Cd (r = 0.36); KIM-1 and CdU (r = 0.33) as well as HgU (r = 0.37); RBP and isoleucine (r = -0.28), leucine (r = -0.33), tyrosine (r = -0.3) and valine (r = -0.44); CdU and isoleucine and valine (r = -0.27 for both). Multiple linear regression analyses showed that some T2D-related biomarkers are confounders of associations between RBP and Hg or Cd biomarkers. Path analyses support a mediating effect of adiponectin on the relation between urinary Cd and RBP. Concluding, this pilot study originally investigated a comprehensive set of biomarkers on complex interactions between toxic metal exposure, renal function and T2D in a group of aging Canadians. Its findings warrant further investigation of longitudinal data in a greater number of participants.


Assuntos
Cádmio , Diabetes Mellitus Tipo 2/sangue , Nefropatias/urina , Chumbo , Mercúrio , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Canadá , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/patologia , Exposição Ambiental , Feminino , Humanos , Nefropatias/etiologia , Nefropatias/patologia , Masculino , Pessoa de Meia-Idade , Projetos Piloto
16.
Kidney Blood Press Res ; 44(2): 245-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31071709

RESUMO

BACKGROUND/AIMS: Diabetic nephropathy (DN) is a leading cause of end-stage renal disease. Microalbuminuria (MA) is widely used to predict early progressive renal function decline (ERFD) of DN in type 2 diabetes mellitus (T2D) patients, but the sensitivity and specificity of MA have been questioned. Here, we determined the urine metabolites differences between T2D patients with MA who maintained stable renal function and those who progressed to ERFD in order to identify specific biomarkers of the progression of renal dysfunction. METHODS: A total of 102 T2D patients with MA and normal renal function at baseline were followed up for 5-6 years. Of these, 52 patients were selected and classified into two groups according to the later renal function; 25 patients who experienced ERFD were regarded as the progressive group, while 27 patients who maintained stable renal function were considered as the stable group. In the pilot study, untargeted, broad-spectrum urine metabolomics was performed on the urine of 12 subjects from the progressive group (5 patients as "progressors") and stable group (7 patients as "non-progressors") to discover candidate markers. We then used a targeted metabolomics analysis to identify the selected markers in the urine of an additional 40 patients (20 from the progressive group as cases, and 20 from the stable group as controls) in the validation study. RESULTS: A total of 318 known metabolites were detected in the pilot study and 6 metabolites with significant difference between progressors and non-progressors were identified. The levels of 4 metabolites, including azelaic acid, adipic acid, 5-hydroxyhexanoic acid, and L-tryptophan decreased significantly, while levels of L-pyroglutamic acid and D-norvaline increased observably in the progressors compared with non-progressors. Furthermore, in the validation study, 6 metabolites were confirmed by quantitative measurements and their concentrations were consistent with the changes in the pilot study. Concentrations of L-pyroglutamic acid and D-norvaline still increased in the cases, but were not statistically significant. Of the 4 metabolites with decreased concentrations among the cases, only 5-hydroxyhexanoic acid remained statistically significant while the other 3 metabolites did not differ between cases and controls. CONCLUSION: We have identified urine metabolites and shown that 5-hydroxyhexanoic acid can be used as a predictor of progression of ERFD in T2D patients with MA. This finding provides the new perspective that 5-hydroxyhexanoic acid may be useful to identify T2D patients with MA who are at risk of ERFD.


Assuntos
Albuminúria/urina , Caproatos/urina , Diabetes Mellitus Tipo 2/urina , Nefropatias Diabéticas/urina , Progressão da Doença , Hidroxiácidos/urina , Adulto , Biomarcadores/urina , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/complicações , Feminino , Seguimentos , Humanos , Nefropatias/urina , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade
17.
Chemosphere ; 228: 149-158, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31029960

RESUMO

1,4-Dioxane (dioxane), an industrial solvent widely detected in environmental and biological matrices, has potential nephrotoxicity. However, the underlying mechanism by which dioxane induces kidney damage remains unclear. In this study, we used an integrated approach, combining kidney transcriptomics and urine metabolomics, to explore the mechanism for the toxic effects of dioxane on the mouse kidney. Transcriptomics profiling showed that exposure to 0.5 mg/L dioxane induced perturbations of multiple signaling pathways in kidneys, such as MAPK and Wnt, although no changes in oxidative stress indicators or anatomical pathology were observed. Exposure to 500 mg/L dioxane significantly disrupted various metabolic pathways, concomitantly with observed renal tissue damage and stimulated oxidant defense system. Urine metabolomic analysis using NMR indicated that exposure to dioxane gradually altered the metabolic profile of urine. Within the full range of altered metabolites, the metabolic pathway containing glycine, serine and threonine was the most significantly altered pathway at the early stage of exposure (3 weeks) in both 0.5 and 500 mg/L dioxane-treated groups. However, with prolonged exposure (9 and 12 weeks), the level of taurine significantly decreased after treatment of 0.5 mg/L dioxane, while exposure to 500 mg/L dioxane significantly increased glutathione levels in urine and decreased arginine metabolism. Furthermore, integrated omics analysis showed that 500 mg/L dioxane exposure induced arginine deficiency by perturbing several genes involved in renal arginine metabolism. Shortage of arginine coupled with increased oxidative stress could lead to renal dysfunction. These findings offer novel insights into the toxicity of dioxane.


Assuntos
Dioxanos/toxicidade , Rim/lesões , Redes e Vias Metabólicas , Animais , Arginina/deficiência , Perfilação da Expressão Gênica/métodos , Rim/efeitos dos fármacos , Nefropatias/induzido quimicamente , Nefropatias/genética , Nefropatias/urina , Masculino , Metaboloma/efeitos dos fármacos , Metabolômica/métodos , Camundongos , Solventes/toxicidade , Urina/química
18.
Clin Nephrol ; 91(6): 344-352, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30935460

RESUMO

AIMS: We attempted to classify 115 consecutive nonedematous hyponatremic patients according to their history and saline responsiveness. We hereby describe 6 out of them presenting a transient renal salt wasting (TRSW) state of unknown origin. MATERIALS AND METHODS: Six patients with an initial SNa of 126 ± 3 mEq/L were included in the study. They were treated with 2 L isotonic saline infusion over 24 hours. The evolution of the biochemical data of 5 patients were compared to 6 patients with syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH), 6 hyponatremias following the use of thiazides, and to 5 salt-depleted hyponatremic patients of similar age and body weight, treated in the same way. RESULTS: The mean values of FEurea and FEuric acid in the 6 described patients, together with a clearly inappropriate natriuresis suggested SIADH. However, the high mean fractional potassium excretion (FEK = 34 ± 15%) was not observed in SIADH (13 ± 3%) (p < 0.01). Plasma sodium levels improved quickly after saline infusion in most of these patients, while fractional solute excretions and diuresis decreased. Calciuria is increased in patients with renal salt waisting (RSW), while low calciuria values are observed in the thiazide group. Four of the 6 hyponatremic patients were admitted for syncopal malaise or fall. CONCLUSION: We observed in 6 out of 115 consecutive hyponatremic patients a TRSW. RSW as a diagnosis has to be considered when in hyponatremia with excessive natriuresis, high FEK and an intake of diuretics is ruled out. This hyponatremia is saline-responsive, but relapse can be frequently observed.


Assuntos
Hiponatremia/sangue , Hiponatremia/etiologia , Nefropatias/sangue , Sódio/sangue , Idoso , Idoso de 80 Anos ou mais , Cálcio/urina , Diurese , Diuréticos/efeitos adversos , Feminino , Hidratação , Humanos , Hiponatremia/terapia , Hiponatremia/urina , Síndrome de Secreção Inadequada de HAD/sangue , Síndrome de Secreção Inadequada de HAD/complicações , Síndrome de Secreção Inadequada de HAD/urina , Soluções Isotônicas , Nefropatias/complicações , Nefropatias/urina , Potássio/urina , Solução Salina/uso terapêutico , Tiazidas/efeitos adversos , Ureia/urina , Ácido Úrico/urina
19.
Clin Lab ; 65(4)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30969091

RESUMO

BACKGROUND: Urinary extracellular vesicles (UEVs) carry rich markers of their parent cells, so they can serve as possible biomarkers of kidney diseases. METHODS: In this study, we isolated urinary extracellular vesicles from five individuals using a simple, clinically applicable method called hydrostatic filtration dialysis (HFD) and compared it to the gold-standard ultracentrifuga-tion (UC) with transmission electron microscopy (TEM). We also employed a proteomic approach using pooled human urine samples from the same five individuals to profile the protein composition of UEVs to evaluate the effectiveness of these two methods. RESULTS: Notably, using TEM, we found that all isolations contained 0 - 400 nm vesicles with the traditionally reported morphology, although the TEM results showed that the UEVs isolated from HFD compared to those from UC are larger and more extensive. We obtained a total of 2,564 UEV proteins in the two methods. We showed a large overlap (2,185 > 85%) between the proteins identified by both isolation methods. The result also showed that the obtained proteins in extracellular vesicles, which are isolated with these methods, are consistent with the results in currently available databases. However, in the associated gene ontologies, the enriched proteins found by the two methods showed some differences. CONCLUSIONS: The HFD method is clinically feasible and allows large-scale protein profiling of UEV biomarkers. The results of this study also provide valuable UEV protein data from the methodological comparison, which might be valuable to other researchers.


Assuntos
Vesículas Extracelulares/metabolismo , Perfilação da Expressão Gênica , Nefropatias/urina , Proteômica/métodos , Ultracentrifugação/métodos , Urinálise/normas , Adulto , Biomarcadores/metabolismo , Feminino , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Diálise Renal , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Urinálise/métodos , Adulto Jovem
20.
J Infect Dis ; 220(3): 370-376, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-30869132

RESUMO

BACKGROUND: BK virus (BKV) is a significant cause of nephropathy in kidney transplantation. The goal of this study was to characterize the course and source of BKV in kidney transplant recipients. METHODS: We prospectively collected pretransplant plasma and urine samples from living and deceased kidney donors and performed BKV polymerase chain reaction (PCR) and immunoglobulin G (IgG) testing on pretransplant and serially collected posttransplant samples in kidney transplant recipients. RESULTS: Among deceased donors, 8.1% (17/208) had detectable BKV DNA in urine prior to organ procurement. BK viruria was observed in 15.4% (6/39) of living donors and 8.5% (4/47) of deceased donors of recipients at our institution (P = .50). BKV VP1 sequencing revealed identical virus between donor-recipient pairs to suggest donor transmission of virus. Recipients of BK viruric donors were more likely to develop BK viruria (66.6% vs 7.8%; P < .001) and viremia (66.6% vs 8.9%; P < .001) with a shorter time to onset (log-rank test, P < .001). Though donor BKV IgG titers were higher in recipients who developed BK viremia, pretransplant donor, recipient, and combined donor/recipient serology status was not associated with BK viremia (P = .31, P = .75, and P = .51, respectively). CONCLUSIONS: Donor BK viruria is associated with early BK viruria and viremia in kidney transplant recipients. BKV PCR testing of donor urine may be useful in identifying recipients at risk for BKV complications.


Assuntos
Vírus BK/isolamento & purificação , Nefropatias/virologia , Transplante de Rim/efeitos adversos , Infecções por Polyomavirus/virologia , Infecções Tumorais por Vírus/virologia , Adulto , Feminino , Humanos , Imunoglobulina G/sangue , Rim/virologia , Nefropatias/sangue , Nefropatias/urina , Doadores Vivos , Masculino , Pessoa de Meia-Idade , Infecções por Polyomavirus/sangue , Infecções por Polyomavirus/urina , Estudos Prospectivos , Transplantados , Infecções Tumorais por Vírus/sangue , Infecções Tumorais por Vírus/urina , Viremia/sangue , Viremia/urina , Viremia/virologia
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