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1.
PLoS Negl Trop Dis ; 14(9): e0008712, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970687

RESUMO

BACKGROUND: Several studies addressed changes on the insect vector behavior due to parasite infection, but little is known for triatomine bugs, vectors of Trypanosoma cruzi, the etiological agent of Chagas disease. We assessed infection rates and metacyclogenesis of T. cruzi (TcVI) in fifth-instar nymphs of Triatoma rubrovaria comparing with the primary vector Triatoma infestans. Also, biological parameters related to feeding-excretion behavior were evaluated aiming to identify which variables are most influenced by T. cruzi infection. METHODOLOGY/PRINCIPAL FINDINGS: Fifth-instar nymphs of T. rubrovaria and T. infestans were fed on mice infected with T. cruzi (TcVI). We compared the presence and the number of parasite evolutive forms in excreta of both triatomine species at 30, 60 and 90 days post-infection (dpi) with traditional statistical analyses. Moreover, both species were analyzed through generalized linear models and multinomial logistic regression hypotheses for seven behavioral parameters related to host-seeking and feeding-excretion. Triatoma rubrovaria and T. infestans had similar overall infection and metacyclogenesis rates of T. cruzi TcVI in laboratory conditions. Regarding vector behavior, we confirmed that the triatomine's tendency is to move away from the bite region after a blood meal, probably to avoid being noticed by the vertebrate host. Interspecific differences were observed on the volume of blood ingested and on the proportion of individuals that excreted after the blood meal, revealing the higher feeding efficiency and dejection rates of T. infestans. The amount of ingested blood and the bite behavior of T. rubrovaria seems to be influenced by TcVI infection. Infected specimens tended to ingest ~25% more blood and to bite more the head of the host. Noteworthy, in two occasions, kleptohematophagy and coprophagy behaviors were also observed in T. rubrovaria. CONCLUSIONS/SIGNIFICANCE: Laboratory infections revealed similar rate of T. cruzi TcVI trypomatigotes in excreta of T. rubrovaria and T. infestans, one of the most epidemiological important vectors of T. cruzi. Therefore, TcVI DTU was able to complete its life cycle in T. rubrovaria under laboratory conditions, and this infection changed the feeding behavior of T. rubrovaria. Considering these results, T. rubrovaria must be kept under constant entomological surveillance in Rio Grande do Sul, Brazil.


Assuntos
Comportamento Alimentar , Insetos Vetores/fisiologia , Insetos Vetores/parasitologia , Triatoma/fisiologia , Triatoma/parasitologia , Trypanosoma cruzi/fisiologia , Animais , Brasil , Doença de Chagas/transmissão , Modelos Animais de Doenças , Interações Hospedeiro-Parasita , Mordeduras e Picadas de Insetos , Modelos Logísticos , Camundongos , Ninfa , Eliminação Renal , Trypanosoma cruzi/patogenicidade
3.
Vasc Health Risk Manag ; 16: 167-180, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32494148

RESUMO

Vascular calcification (VC) is a life-threatening state in chronic kidney disease (CKD). High cardiovascular mortality and morbidity of CKD cases may root from medial VC promoted by hyperphosphatemia. Vascular calcification is an active, highly regulated, and complex biological process that is mediated by genetics, epigenetics, dysregulated form of matrix mineral metabolism, hormones, and the activation of cellular signaling pathways. Moreover, gut microbiome as a source of uremic toxins (eg, phosphate, advanced glycation end products and indoxyl-sulfate) can be regarded as a potential contributor to VC in CKD. Here, an update on different cellular and molecular processes involved in VC in CKD is discussed to elucidate the probable therapeutic pathways in the future.


Assuntos
Vasos Sanguíneos/metabolismo , Rim/metabolismo , Eliminação Renal , Insuficiência Renal Crônica/complicações , Calcificação Vascular/etiologia , Remodelação Vascular , Animais , Vasos Sanguíneos/patologia , Vasos Sanguíneos/fisiopatologia , Humanos , Rim/fisiopatologia , Prognóstico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/fisiopatologia , Fatores de Risco , Calcificação Vascular/metabolismo , Calcificação Vascular/mortalidade , Calcificação Vascular/fisiopatologia
4.
PLoS One ; 15(6): e0233925, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32530952

RESUMO

It is important to calculate the drug removal by hemodialysis (HD) for drug dosing regimens in HD patients. However, there are limited and inconsistent information about the dialyzability of drugs by HD. Therefore, the aim of our study is to evaluate drug removal by utilizing a rat model of HD (HD rat) and to extrapolate this result to the drug removal rate in HD patients. HD rats received bilateral nephrectomy and HD for 2 h. The dialysis removal of 6 drugs was evaluated in HD rats. Dialysis efficiency, plasma protein binding rate (PBR) and distribution volume (Vd) of drugs were also measured. Furthermore, we examined the correlation between the dialyzability of drug in HD rats and humans and constructed the prediction formula of the drug dialyzability in HD patients. The clearance of urea and creatinine and normalized dialysis dose in HD rats were 0.83 ± 0.07 mL/min, 0.70 ± 0.08 mL/min, and 0.13 ± 0.06, respectively. The drug dialyzability in HD rats was similar to reported clinical data except for doripenem. A higher correlation was observed between drug dialyzability in reported clinical data and HD rats which were adjusted for PBR (r2 = 0.936; p < 0.001) compared to unadjusted (r2 = 0.812; p = 0.009). Therefore, we constructed the prediction formula of the drug dialyzability in HD patients by utilizing the HD rat model and PBR. This study is useful for evaluating the dialyzability of high-risk drugs in a clinical setting and might provide appropriate preclinical dialyzability data for new drug.


Assuntos
Preparações Farmacêuticas/sangue , Diálise Renal/métodos , Eliminação Renal , Animais , Creatina/sangue , Humanos , Masculino , Taxa de Depuração Metabólica , Modelos Animais , Farmacocinética , Ratos , Ratos Wistar , Ureia/sangue
5.
Cardiovasc Ther ; 2020: 2478781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32426035

RESUMO

It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α 2-adrenoceptors (α 2-ARs) in skin-lightening experiments in the frog. Now α 2-ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α 2-AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α 2-ARs. In this model system and in the setting of furosemide-induced sodium excretion, α 2-AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α 2-AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α 2-ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α 2-ARs activate prohypertensive biochemical systems. While investigating the role of α 1-adrenoceptors (α 1-ARs) versus α 2-ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α 1-ARs suppress the postjunctional expression of α 2-ARs. Here, we describe how this finding relates to a broader understanding of the role of α 2-ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α 2-AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.


Assuntos
Pressão Sanguínea , Hipertensão Essencial/metabolismo , Rim/metabolismo , Receptores Adrenérgicos alfa 2/metabolismo , Acidentes por Quedas , Antagonistas de Receptores Adrenérgicos alfa 2/uso terapêutico , Animais , Anti-Hipertensivos/uso terapêutico , Ansiedade/metabolismo , Ansiedade/fisiopatologia , Ansiedade/psicologia , Denervação Autônoma , Pressão Sanguínea/efeitos dos fármacos , Diuréticos/uso terapêutico , Hipertensão Essencial/fisiopatologia , Hipertensão Essencial/terapia , Humanos , Hipotensão Ortostática/metabolismo , Hipotensão Ortostática/fisiopatologia , Rim/efeitos dos fármacos , Rim/fisiopatologia , Receptores Adrenérgicos alfa 1/metabolismo , Receptores Adrenérgicos alfa 2/efeitos dos fármacos , Eliminação Renal , Reabsorção Renal , Transdução de Sinais , Sódio/metabolismo , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/psicologia
6.
BMC Cardiovasc Disord ; 20(1): 251, 2020 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-32460763

RESUMO

BACKGROUND: This study examined the effect of serum uric acid (SUA) level and urinary sodium excretion on blood pressure as well as their combined effect on prehypertension in a Korean population. METHOD: Data from the 7th Korea National Health and Nutrition Examination Survey for adults (≥ 19 years of age) were used. The participants were classified into two groups, normotension and prehypertension, according to the JNC-7 definition. Logistic regression was carried out and adjusted for traditionally regarded confounders of blood pressure. All analyses considered a complex sampling design. A multivariate analysis was performed on subgroups defined according to their SUA level and urinary sodium excretion. RESULTS: The 4200 participants were divided into normotension (n = 2646) and prehypertension (n = 1554) groups. In the univariate analysis, patient age, male sex, concurrent comorbidity (diabetes mellitus, cardiovascular disease, stroke, dyslipidemia, and chronic kidney disease), uric acid, and urinary sodium excretion were associated with prehypertension. After adjusting for baseline covariates, both the SUA level and urinary sodium excretion were significant predictors of incident prehypertension (SUA, per 1 mg/dL increase, odds ratio [OR] 1.216, 95% confidence interval [95% CI] 1.131-1.309; urinary sodium excretion, per 1 g/day increase, OR 1.067, 95% CI 1.019-1.117). Additionally, simultaneously higher tertiles of SUA and urinary sodium excretion resulted in higher ORs for prehypertension. CONCLUSION: Increased SUA is a significant risk marker for the development of prehypertension in normotensives. Simultaneously high SUA and urinary sodium excretion amplified the effect on the development of prehypertension. Our findings suggest that lowering SUA levels and reducing sodium intake will contribute to preventing hypertension.


Assuntos
Pressão Sanguínea , Natriurese , Pré-Hipertensão/fisiopatologia , Eliminação Renal , Sódio na Dieta/urina , Ácido Úrico/sangue , Adulto , Biomarcadores/sangue , Biomarcadores/urina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Pré-Hipertensão/sangue , Pré-Hipertensão/epidemiologia , Pré-Hipertensão/urina , República da Coreia/epidemiologia , Medição de Risco , Fatores de Risco , Sódio na Dieta/efeitos adversos
8.
Nutr Metab Cardiovasc Dis ; 30(6): 1005-1013, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32265100

RESUMO

BACKGROUND AND AIMS: Potassium-wasting (loop diuretics [LD]) and potassium-sparing (spironolactone) medications used for heart failure (HF) may alter renal potassium handling and confound the use of twenty-four-hour (24-h) urine collections as a surrogate marker for potassium intake, an effect that has been observed with dietary sodium assessment. The objective was to determine the strength of association between 24-h urine collections and weighed food records in assessing potassium intake in HF patients stratified by LD usage and spironolactone usage. METHODS AND RESULTS: Stable outpatients with HF simultaneously completed two 24-h urine collections and two weighed food records on consecutive days. Analyses compared patients stratified by LD and/or spironolactone use. Pearson's correlation and the Bland-Altman method of agreement assessed the relationship between the techniques. Overall, 109 patients (61 ± 11 yrs, 74% male) were included. The mean difference in dietary potassium estimated between 24-h urine collections and food records was -353 ± 1043 mg (p < 0.01) for all patients, with no differences between measures among subgroups. The association between the two methods was r = 0.551 (95% CI, 0.373 to 0.852, p < 0.001) for LD users; r = 0.287 (95% CI, 0.01 to 0.570, p = 0.050) for LD non-users; r = 0.321 (95% CI, 0.13 to 0.798, p = 0.043) for spironolactone users, and; r = 0.534 (95% CI, 0.331 to 0.747, p < 0.001) for spironolactone non-users. There were no significant mean biases identified as part of the Bland-Altman analysis. CONCLUSION: Among HF patients, potassium-wasting and potassium-sparing medications do not influence the agreement between the two methods in the assessment of potassium intake.


Assuntos
Registros de Dieta , Insuficiência Cardíaca/tratamento farmacológico , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Avaliação Nutricional , Potássio na Dieta/administração & dosagem , Inibidores de Simportadores de Cloreto de Sódio e Potássio/uso terapêutico , Espironolactona/uso terapêutico , Idoso , Feminino , Absorção Gastrointestinal/efeitos dos fármacos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/urina , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/efeitos adversos , Potássio na Dieta/urina , Valor Preditivo dos Testes , Eliminação Renal/efeitos dos fármacos , Reprodutibilidade dos Testes , Inibidores de Simportadores de Cloreto de Sódio e Potássio/efeitos adversos , Espironolactona/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Urinálise , Equilíbrio Hidroeletrolítico/efeitos dos fármacos
9.
Am J Physiol Renal Physiol ; 318(5): F1100-F1112, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32116018

RESUMO

In the early proximal tubule, Na+-glucose cotransporter 2 (SGLT2) mediates the bulk of renal glucose reabsorption. Gene deletion in mice (Sglt2-/-) was used to determine the role of SGLT2 in acute kidney injury induced by bilateral ischemia-reperfusion (IR). In Sglt2-/- and littermate wild-type mice, plasma creatinine increased similarly on day 1 after IR. This was associated with an equal increase in both genotypes in the urinary kidney injury molecule-1-to-creatinine ratio, a tubular injury marker, and similarly reduced urine osmolality and increased plasma osmolality, indicating impaired urine concentration. In both IR groups, FITC-sinistrin glomerular filtration rate was equally reduced on day 14, and plasma creatinine was similarly and incompletely restored on day 23. In Sglt2-/- mice subjected to IR, fractional urinary glucose excretion was increased on day 1 but reduced and associated with normal renal Na+-glucose cotransporter 1 (Sglt1) mRNA expression on day 23, suggesting temporary SGLT1 suppression. In wild-type mice subjected to IR, renal Sglt1 mRNA was likewise normal on day 23, whereas Sglt2 mRNA was reduced by 57%. In both genotypes, IR equally reduced urine osmolality and renal mRNA expression of the Na+-K+-2Cl- cotransporter and renin on day 23, suggesting thick ascending limb dysfunction, and similarly increased renal mRNA expression of markers of injury, inflammation, oxidative stress, and fibrosis (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, transforming growth factor-ß1, NADPH oxidase-2, and collagen type 1). This was associated with equal increases in kidney histological damage scores and similar degree of capillary loss in both genotypes. The data indicate that genetic deletion of SGLT2 did not protect the kidneys in the initial injury phase or the subsequent recovery phase in a mouse model of IR-induced acute kidney injury.


Assuntos
Lesão Renal Aguda/metabolismo , Glicemia/metabolismo , Rim/metabolismo , Traumatismo por Reperfusão/metabolismo , Transportador 2 de Glucose-Sódio/deficiência , Lesão Renal Aguda/genética , Lesão Renal Aguda/patologia , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Modelos Animais de Doenças , Taxa de Filtração Glomerular , Rim/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Eliminação Renal , Reabsorção Renal , Traumatismo por Reperfusão/genética , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/fisiopatologia , Transportador 2 de Glucose-Sódio/genética , Fatores de Tempo
10.
Am J Physiol Renal Physiol ; 318(4): F922-F935, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32116019

RESUMO

There are substantial sex differences in renal structure and ammonia metabolism that correlate with differences in expression of proteins involved in ammonia generation and transport. This study determined the role of testis-derived testosterone in these differences. We studied 4-mo-old male C57BL/6 mice 4 and 8 wk after either bilateral orchiectomy (ORCH) or sham-operated control surgery and determined the effect of testosterone replacement to reverse the effects of ORCH. Finally, we determined the cellular expression of androgen receptor (AR), testosterone's canonical target receptor. ORCH decreased kidney and proximal tubule size, and testosterone replacement reversed this effect. ORCH increased ammonia excretion in a testosterone-dependent fashion; this occurred despite similar food intake, which is the primary component of endogenous acid production. ORCH increased expression of both phosphoenolpyruvate, a major ammonia-generating protein, and Na+-K+-2Cl- cotransporter, which mediates thick ascending limb ammonia reabsorption; these changes were reversed with testosterone replacement. Orchiectomy also decreased expression of Na+/H+ exchanger isoform 3, which mediates proximal tubule ammonia secretion, in a testosterone-dependent pattern. Finally, ARs are expressed throughout the proximal tubule in both the male and female kidney. Testosterone, possibly acting through ARs, has dramatic effects on kidney and proximal tubule size and decreases ammonia excretion through its effects on several key proteins involved in ammonia metabolism.


Assuntos
Amônia/metabolismo , Terapia de Reposição Hormonal , Rim/efeitos dos fármacos , Eliminação Renal/efeitos dos fármacos , Testosterona/administração & dosagem , Animais , Feminino , Rim/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Orquiectomia , Fosfoenolpiruvato Carboxiquinase (ATP)/genética , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Receptores Androgênicos/efeitos dos fármacos , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Fatores Sexuais , Simportadores de Sódio-Bicarbonato/genética , Simportadores de Sódio-Bicarbonato/metabolismo , Trocador 3 de Sódio-Hidrogênio/genética , Trocador 3 de Sódio-Hidrogênio/metabolismo , Membro 1 da Família 12 de Carreador de Soluto/genética , Membro 1 da Família 12 de Carreador de Soluto/metabolismo , Testosterona/deficiência
11.
J Pharmacol Exp Ther ; 373(3): 488-501, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32198137

RESUMO

The effect of urine pH on renal excretion and systemic disposition has been observed for many drugs and metabolites. When urine pH is altered, tubular ionization, passive reabsorption, renal clearance, and systemic exposure of drugs and metabolites may all change dramatically, raising clinically significant concerns. Surprisingly, the urine pH effect on drug disposition is not routinely explored in humans, and regulatory agencies have neither developed guidance on this issue nor required industry to conduct pertinent human trials. In this study, we hypothesized that physiologically based pharmacokinetic (PBPK) modeling could be used as a cost-effective method to examine potential urine pH effect on drug and metabolite disposition. Our previously developed and verified mechanistic kidney model was integrated with a full-body PBPK model to simulate renal clearance and area under the plasma concentration-time curve (AUC) with varying urine pH statuses using methamphetamine and amphetamine as model compounds. We first developed and verified drug models for methamphetamine and amphetamine under normal urine pH condition [absolute average fold error (AAFE) < 1.25 at study level]. Then, acidic and alkaline urine scenarios were simulated. Our simulation results show that the renal excretion and plasma concentration-time profiles for methamphetamine and amphetamine could be recapitulated under different urine pH (AAFE < 2 at individual level). The methamphetamine-amphetamine parent-metabolite full-body PBPK model also successfully simulated amphetamine plasma concentration-time profiles (AAFE < 1.25 at study level) and amphetamine/methamphetamine urinary concentration ratios (AAFE < 2 at individual level) after dosing methamphetamine. This demonstrates that our mechanistic PBPK model can predict urine pH effect on systemic and urinary disposition of drugs and metabolites. SIGNIFICANCE STATEMENT: Our study shows that integrating mechanistic kidney model with full-body physiologically based pharmacokinetic model can predict the magnitude of alteration in renal excretion and area under the plasma concentration-time curve (AUC) of drugs and metabolites when urine pH is changed. This provides a cost-effective method to evaluate the likelihood of renal and systemic disposition changes due to varying urine pH. This is important because multiple drugs and diseases can alter urine pH, leading to quantitatively and clinically significant changes in drug and metabolite disposition that may require adjustment of therapy.


Assuntos
Anfetamina/farmacocinética , Rim/metabolismo , Metanfetamina/farmacocinética , Área Sob a Curva , Humanos , Concentração de Íons de Hidrogênio , Modelos Biológicos , Eliminação Renal/fisiologia
12.
High Blood Press Cardiovasc Prev ; 27(2): 151-156, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32215878

RESUMO

INTRODUCTION: Dabigatran is effective and widely used to prevent ischemic stroke and systemic embolism (SE) in patients with atrial fibrillation (AF). Chronic kidney disease (CKD) also has implications for choice of any medications, as it alters pharmacokinetic parameters of drugs. AIM: To evaluate trough plasma dabigatran concentration (DTPC) and to analyse potential factors affecting these values in patients with AF and CKD. METHODS: Patients with AF and stage 3 CKD were treated with dabigatran 110 mg or 150 mg have been included in the study and allocated into D110 or D150 group. DTPC was evaluated with high-performance liquid chromatography. A plasma trough concentration/dose (C/D) ratio was used as a pharmacokinetic index. Factors affecting the DTPC were investigated. RESULTS: A total of 60 patients, aged 51-89 years, were evaluated. Compared with patients given 150 mg twice a day, those given 110 mg twice a day were older (79 vs 67.5, p < 0.0001) and had lower creatinine clearance (CrCl) (50.5 vs 60.5 mL/min/1.73 m2, p = 0.015). During the median follow up of 9.5 months there were 11 bleedings in 9 patients. The C/D ratio was higher in patients aged > 75 years (p = 0.024) and was also affected by CrCl (CrCl < 50 mL/min, p = 0.02). Individuals with CKD 3B had higher concentration of dabigatran were compared with those with 3A stage (488.7 vs 332 pg/ml: mg/day, p = 0.02). However, there was also negative correlation between C/D and CrCl (r = - 0.4, p = 0.0015). Co-prescribed medications did not influence DTPC. In addition, patients with bleeding events were additionally evaluated for C/D and no significant differences were found. CONCLUSION: Patients on dabigatran treatment showed highly variable trough plasma concentrations. C/D values were significantly higher in patients with CKD 3B stage and were influenced by elder age and comorbidities.


Assuntos
Antitrombinas/sangue , Fibrilação Atrial/tratamento farmacológico , Dabigatrana/sangue , Rim/fisiopatologia , Eliminação Renal , Insuficiência Renal Crônica/fisiopatologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antitrombinas/efeitos adversos , Antitrombinas/farmacocinética , Fibrilação Atrial/sangue , Fibrilação Atrial/diagnóstico , Comorbidade , Dabigatrana/efeitos adversos , Dabigatrana/farmacocinética , Monitoramento de Medicamentos , Feminino , Hemorragia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/diagnóstico , Fatores de Risco , Resultado do Tratamento
13.
Proc Natl Acad Sci U S A ; 117(11): 6086-6091, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32123080

RESUMO

Recombinant immunotoxins (RITs) are chimeric proteins composed of an Fv and a protein toxin being developed for cancer treatment. The Fv brings the toxin to the cancer cell, but most of the RITs do not reach the tumor and are removed by other organs. To identify cells responsible for RIT removal, and the pathway by which RITs reach these cells, we studied SS1P, a 63-kDa RIT that targets mesothelin-expressing tumors and has a short serum half-life. The major organs that remove RIT were identified by live mouse imaging of RIT labeled with FNIR-Z-759. Cells responsible for SS1P removal were identified by immunohistochemistry and intravital two-photon microscopy of kidneys of rats. The primary organ of SS1P removal is kidney followed by liver. In the kidney, SS1P passes through the glomerulus, is taken up by proximal tubular cells, and transferred to lysosomes. In the liver, macrophages are involved in removal. The short half-life of SS1P is due to its very rapid filtration by the kidney followed by degradation in proximal tubular cells of the kidney. In mice treated with SS1P, proximal tubular cells are damaged and albumin in the urine is increased. SS1P uptake by kidney is reduced by coadministration of l-lysine. Our data suggests that l-lysine administration to humans might prevent SS1P-mediated kidney damage, reduce albumin loss in urine, and alleviate capillary leak syndrome.


Assuntos
Albuminúria/patologia , Anticorpos Monoclonais/farmacocinética , Síndrome de Vazamento Capilar/patologia , Imunotoxinas/farmacocinética , Túbulos Renais Proximais/efeitos dos fármacos , Albuminúria/induzido quimicamente , Albuminúria/prevenção & controle , Albuminúria/urina , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/química , Anticorpos Monoclonais/toxicidade , Síndrome de Vazamento Capilar/induzido quimicamente , Síndrome de Vazamento Capilar/prevenção & controle , Síndrome de Vazamento Capilar/urina , Modelos Animais de Doenças , Feminino , Corantes Fluorescentes/química , Meia-Vida , Humanos , Imunotoxinas/administração & dosagem , Imunotoxinas/química , Imunotoxinas/toxicidade , Microscopia Intravital , Glomérulos Renais/metabolismo , Túbulos Renais Proximais/diagnóstico por imagem , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Lisina/administração & dosagem , Camundongos , Microscopia de Fluorescência , Neoplasias/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/toxicidade , Eliminação Renal/efeitos dos fármacos , Albumina Sérica/análise , Albumina Sérica/metabolismo , Coloração e Rotulagem
14.
J Am Soc Nephrol ; 31(4): 817-827, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32205410

RESUMO

BACKGROUND: The secretion of organic solutes by the proximal tubules is an essential intrinsic kidney function. However, the clinical significance of the kidney's clearance of tubular secretory solutes is uncertain. METHODS: In this prospective cohort study, we evaluated 3416 participants with CKD from the Chronic Renal Insufficiency Cohort (CRIC) study. We measured plasma and 24-hour urine concentrations of endogenous candidate secretory solutes at baseline, using targeted liquid chromatography-tandem mass spectrometry. The study defined CKD progression by a ≥50% decline in the eGFR, initiation of maintenance dialysis, or kidney transplantation. We used Cox proportional hazards regression to test associations of secretory-solute clearances with CKD progression and mortality, adjusting for eGFR, albuminuria, and other confounding characteristics. RESULTS: Participants in this ancillary study had a mean age of 58 years and 41% were black; the median eGFR was 43 ml/min per 1.73 m2. After adjustment, lower kidney clearances of six solutes-kynurenic acid, pyridoxic acid, indoxyl sulfate, xanthosine, isovalerylglycine, and cinnamoylglycine-were associated with significantly greater risks of CKD progression, with clearance of kynurenic acid, a highly protein-bound solute, having the strongest association. Lower clearances of isovalerylglycine, tiglylglycine, hippurate, and trimethyluric acid were significantly associated with all-cause mortality after adjustment. CONCLUSIONS: We found lower kidney clearances of endogenous secretory solutes to be associated with CKD progression and all-cause mortality, independent of eGFR and albuminuria. This suggests that tubular clearance of secretory solutes provides additional information about kidney health beyond measurements of glomerular function alone.


Assuntos
Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Taxa de Filtração Glomerular , Humanos , Testes de Função Renal , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Masculino , Pessoa de Meia-Idade , Eliminação Renal , Insuficiência Renal Crônica/mortalidade , Sensibilidade e Especificidade , Taxa de Sobrevida
15.
PLoS One ; 15(3): e0229756, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32126132

RESUMO

The aim of this work was to study the effect of a high sodium (HS) diet on blood pressure and renal function in male adult rats that have been treated with a dual Endothelin receptor antagonist (ERA) during their early postnatal period (day 1 to 20 of life). Male Sprague-Dawley rats were divided in four groups: CNS: control rats with normosodic diet; ERANS: ERA-treated rats with normosodic diet; CHS: control rats with high sodium diet; ERAHS: ERA-treated rats with HS diet. Systolic blood pressure (SBP) was recorded before and after the diet and 24-hour metabolic cage studies were performed. AQP2 and α-ENac expressions were measured by western blot and real time PCR in the renal medulla. Vasopressin (AVP) pathway was evaluated by measuring V2 receptor and adenylyl cyclase 6 (AC6) expression and cAMP production in the renal medulla. Pre-pro ET-1mRNA was also evaluated in the renal medulla. Only rats that had been treated with an ERA during their postnatal period increased their SBP after consumption of a HS diet, showing an impaired capacity to excrete sodium and water, i.e. developing salt sensitivity. This salt sensitivity would be mediated by an increase in renomedullary expression and activity of AQP2 and α-ENaC as a consequence of increased AC6 expression and cAMP production and/or a decreased ET-1 production in the renal medulla. The knowledge of the molecular mechanisms underlying the perinatal programming of salt sensitive hypertension will allow the development of reprogramming strategies in order to avoid this pathology.


Assuntos
Endotelinas/metabolismo , Hipertensão/etiologia , Medula Renal/crescimento & desenvolvimento , Receptores de Endotelina/metabolismo , Transdução de Sinais/fisiologia , Adulto , Animais , Animais Recém-Nascidos , Aquaporina 2/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelinas/antagonistas & inibidores , Canais Epiteliais de Sódio/metabolismo , Humanos , Hipertensão/fisiopatologia , Recém-Nascido , Medula Renal/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Eliminação Renal/efeitos dos fármacos , Eliminação Renal/fisiologia , Transdução de Sinais/efeitos dos fármacos , Cloreto de Sódio na Dieta/efeitos adversos , Cloreto de Sódio na Dieta/metabolismo , Vasopressinas/metabolismo
16.
Am J Kidney Dis ; 75(6): 847-856, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31955921

RESUMO

RATIONALE & OBJECTIVE: Patients with chronic kidney disease (CKD) are particularly sensitive to dietary sodium. We evaluated a self-management approach for dietary sodium restriction in patients with CKD. STUDY DESIGN: Randomized controlled trial. SETTING & PARTICIPANTS: Nephrology outpatient clinics in 4 Dutch hospitals. 99 adults with CKD stages 1 to 4 or a functioning (estimated glomerular filtration rate≥25mL/min/1.73m2) kidney transplant, hypertension, and sodium intake>130mmol/d. INTERVENTION: Routine care was compared with routine care plus a web-based self-management intervention including individual e-coaching and group meetings implemented over a 3-month intervention period, followed by e-coaching over a 6-month maintenance period. OUTCOMES: Primary outcomes were sodium excretion after the 3-month intervention and after the 6-month maintenance period. Secondary outcomes were blood pressure, proteinuria, costs, quality of life, self-management skills, and barriers and facilitators for implementation. RESULTS: Baseline estimated glomerular filtration rate was 55.0±22.0mL/min/1.73m2. During the intervention period, sodium excretion decreased in the intervention group from 188±8 (SE) to 148±8mmol/d (P<0.001), but did not change significantly in the control group. At 3 months, mean sodium excretion was 24.8 (95% CI, 0.1-49.6) mmol/d lower in the intervention group (P=0.049). At 3 months, systolic blood pressure (SBP) decreased in the intervention group from 140±3 to 132±3mm Hg (P<0.001), but was unchanged in the control group. Mean difference in SBP across groups was-4.7 (95% CI, -10.7 to 1.3) mm Hg (P=0.1). During the maintenance phase, sodium excretion increased in the intervention group, but remained lower than at baseline at 160±8mmol/d (P=0.01), while it decreased in the control group from 174±9 at the end of the intervention period to 154±9mmol/d (P=0.001). Consequently, no difference in sodium excretion between groups was observed after the maintenance phase. There was no difference in SBP between groups after the maintenance phase. LIMITATIONS: Limited power, postrandomization loss to follow-up, Hawthorne effect, lack of dietary data, short-term follow-up. CONCLUSIONS: A coaching intervention reduced sodium intake at 3 months. Efficacy during the maintenance phase was diminished, possibly due to inadvertent adoption of the intervention by the control group. FUNDING: Grant funding from the Netherlands Organization for Health Research and Development and the Dutch Kidney Foundation. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT02132013.


Assuntos
Dieta Hipossódica/métodos , Educação a Distância/métodos , Eliminação Renal , Autogestão , Cloreto de Sódio na Dieta/metabolismo , Adulto , Feminino , Taxa de Filtração Glomerular/efeitos dos fármacos , Processos Grupais , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Gravidade do Paciente , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/dietoterapia , Insuficiência Renal Crônica/urina , Autogestão/educação , Autogestão/métodos
17.
Am J Physiol Regul Integr Comp Physiol ; 318(2): R418-R427, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913682

RESUMO

Genes for the epithelial sodium channel (ENaC) subunits are expressed in a circadian manner, but whether this results in time-of-day differences in activity is not known. Recent data show that protein expression of ENaC subunits is higher in kidneys from female rats, yet females are more efficient in excreting an acute salt load. Thus, our in vivo study determined whether there is a time-of-day difference as well as a sex difference in the response to ENaC inhibition by benzamil. Our results showed that the natriuretic and diuretic responses to a single dose of benzamil were significantly greater in male compared with female rats whether given at the beginning of the inactive period [Zeitgeber time 0 (ZT0), 7 AM] or active period (ZT12, 7 PM). However, the response to benzamil was not significantly different between ZT0 and ZT12 dosing in either male or female rats. There was no difference in renal cortical α-ENaC protein abundance between ZT0 and ZT12 or males and females. Given previous reports of flow-induced stimulation of endothelin-1 (ET-1) production and sex differences in the renal endothelin system, we measured urinary ET-1 excretion to assess the effects of increased urine flow on intrarenal ET-1. ET-1 excretion was significantly increased following benzamil administration in both sexes, but this increase was significantly greater in females. These results support the hypothesis that ENaC activity is less prominent in maintaining Na+ balance in females independent of renal ET-1. Because ENaC subunit genes and protein expression vary by time of day and are greater in female rat kidneys, this suggests a clear disconnect between ENaC expression and channel activity.


Assuntos
Amilorida/análogos & derivados , Bloqueadores do Canal de Sódio Epitelial/farmacologia , Canais Epiteliais de Sódio/efeitos dos fármacos , Rim/efeitos dos fármacos , Natriurese/efeitos dos fármacos , Ciclos de Atividade , Amilorida/farmacologia , Animais , Endotelina-1/urina , Canais Epiteliais de Sódio/metabolismo , Feminino , Rim/metabolismo , Masculino , Ovariectomia , Ratos Sprague-Dawley , Eliminação Renal/efeitos dos fármacos , Fatores Sexuais , Fatores de Tempo , Urodinâmica/efeitos dos fármacos
18.
AJNR Am J Neuroradiol ; 41(2): 351-356, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31974082

RESUMO

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the sensitivity and specificity of renal/ureteric opacification on postmyelographic CT as a sign of CSF leak. MATERIALS AND METHODS: We performed a retrospective review of postmyelographic CT scans from 49 consecutive patients seen between January 2008 and August 2018 with imaging and/or clinical findings related to intracranial hypotension. Each scan was evaluated by both a neuroradiology fellow and a board-certified neuroradiologist for the presence of contrast in the renal excretory system. A similar assessment was also performed on 90 consecutive control subjects who underwent CT myelography for alternative indications. RESULTS: Among the 49 patients with suspected CSF leak, 21 (43%) had an overt CSF leak on postmyelographic CT (group 1) and 28 (57%) did not (group 2). Overall, renal contrast was identified in 7/49 patients (14.3%): 5 (24%) patients in group 1, and 2 (7%) patients in group 2. Renal contrast was not seen in any of the 90 controls on postmyelographic CT. CONCLUSIONS: Renal contrast was exclusively seen in patients with a clinically or radiographically suspected CSF leak. Given its 100% specificity, identification of this finding should prompt a second look for subtle myelographic contrast extravasation or an underlying CSF-venous fistula. Our results suggest that this sign may be considered an additional diagnostic criterion for CSF leak in the absence of an identifiable leak.


Assuntos
Vazamento de Líquido Cefalorraquidiano/diagnóstico por imagem , Meios de Contraste/metabolismo , Extravasamento de Materiais Terapêuticos e Diagnósticos/diagnóstico por imagem , Mielografia/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Eliminação Renal , Estudos Retrospectivos , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X/métodos
19.
Xenobiotica ; 50(5): 588-592, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31448977

RESUMO

Indoxyl sulfate (IS), a highly protein-bound nephro-cardiovascular toxin, was poorly removed by hemodialysis. IS exists as anions in the body and the renal excretion is mediated by organic anion transporter 1 (OAT1) and OAT3. Acidic antibiotics such as cephalosporins and fluoroquinolones were putative substrates/inhibitors of OATs. We hypothesized that cephalosporins and fluoroquinolones might compete with IS for OAT1- and/or OAT3-mediated renal excretions.This study investigated the effects of ciprofloxacin, cefuroxime, cefotaxime, cefazolin and ofloxacin on the intravenous pharmacokinetics of IS in rats. IS was intravenously injected with and without each individual antibiotics, and the concentrations of IS in serum and lysate were determined by HPLC.The results showed that ciprofloxacin significantly increased AUC0-t and T1/2 of IS by 272% and 491%, respectively, and decreased the clearance by 71%. However, ofloxacin, cefuroxime, cefotaxime and cefazolin did not alter the pharmacokinetics of IS. Furthermore, cell line study showed that ciprofloxacin inhibited the OAT3-mediated transport of IS.This study indicates 30 mg/kg of ciprofloxacin decreased the clearance of IS through inhibition on the OAT3-mediated transport, whereas 50 mg/kg of ofloxacin, cefuroxime, cefotaxime and cefazolin did not show significant influence.


Assuntos
Antibacterianos/farmacologia , Indicã/metabolismo , Animais , Sistema Cardiovascular , Humanos , Indicã/toxicidade , Rim , Ratos , Eliminação Renal
20.
Obes Surg ; 30(1): 102-110, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31515727

RESUMO

INTRODUCTION: Bariatric surgery has been shown to be effective in reducing weight and has benefits, such as lowering blood pressure. An increase in urinary sodium excretion has been suggested as a possible mechanism. This study explored changes in sodium excretion and their correlation with blood pressure after Roux-en-Y gastric bypass. MATERIALS AND METHODS: This study was conducted on 28 obese participants with body mass index (BMI) of 44.54 ± 7.81 kg/m2 who underwent gastric bypass. Before surgery and at the third and sixth months after gastric bypass, blood pressure, urinary sodium concentration, 24-hour (24-h) urinary sodium excretion, and fractional excretion of sodium were evaluated. In addition, serum sodium and potassium levels were determined. Nonparametric tests were used to analyze the data. RESULTS: Blood pressure decreased after surgery and remained at low levels over the 3- and 6-month periods. The urinary sodium concentration increased at 3 months after surgery; however, the 24-h urinary sodium excretion and urine volume decreased. Interestingly, although some associations between variables were observed, significant correlations between the 24-h urinary sodium excretion and the systolic, diastolic, and mean blood pressures were found. In addition, the urine volume was higher in the sixth month than in the third month following surgery. CONCLUSIONS: In the months immediately following surgery, a low-salt and low-volume diet favors decreases in urine volume and 24-h urinary sodium excretion. In addition, in the sixth month after surgery, an association between blood pressure and 24-h urinary sodium excretion was observed.


Assuntos
Pressão Sanguínea/fisiologia , Derivação Gástrica , Obesidade Mórbida/cirurgia , Eliminação Renal/fisiologia , Sódio/metabolismo , Adulto , Índice de Massa Corporal , Feminino , Seguimentos , Derivação Gástrica/métodos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade Mórbida/metabolismo , Obesidade Mórbida/fisiopatologia , Obesidade Mórbida/urina , Período Pós-Operatório , Potássio/sangue , Sódio/sangue , Sódio/urina , Fatores de Tempo , Perda de Peso/fisiologia
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