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1.
Heart Rhythm ; 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32619739

RESUMO

BACKGROUND: Central sleep apnea is common in heart failure patients. Transvenous phrenic nerve stimulation (TPNS) requires placing a lead to stimulate the phrenic nerve and activate the diaphragm. Data are lacking concerning the safety and efficacy of TPNS in patients with concomitant cardiovascular implantable electronic devices (CIEDs). OBJECTIVE: The objective is to report the safety and efficacy of TPNS in patients with concomitant CIEDs. METHODS: In the remede System Pivotal Trial, 151 patients underwent TPNS device implant. This analysis compared patients with concomitant CIEDs to those without with respect to safety, implant metrics and efficacy of TPNS. Safety was assessed using incidence of adverse events and device-device interactions. A detailed interaction protocol was followed. Implant metrics included overall TPNS implantation success. Efficacy endpoints included changes in the apnea-hypopnea index (AHI) and quality of life. RESULTS: Of 151 patients, 64 (42%) had a concomitant CIED. There were no significant differences between the groups with respect to safety. There were 4 CIED oversensing events in 3 patients leading to one inappropriate defibrillator shock and delivery of anti-tachycardia pacing. There was no difference in efficacy between the CIED and non-CIED subgroups receiving TPNS, with both having similar percentages of patients who achieved ≥ 50% reduction in AHI and quality of life improvement. CONCLUSION: Concomitant CIED and TPNS therapy is safe. The presence of a concomitant CIED did not appear to impact implant metrics, implantation success and TPNS efficacy. A detailed interaction protocol should be followed to minimize the incidence of device-device interaction.

3.
Nephrol Dial Transplant ; 35(5): 846-853, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30879076

RESUMO

BACKGROUND: Residual kidney function (RKF) is thought to exert beneficial effects through clearance of uremic toxins. However, the level of native kidney function where clearance becomes negligible is not known. METHODS: We aimed to assess whether levels of nonurea solutes differed among patients with 'clinically negligible' RKF compared with those with no RKF. The hemodialysis study excluded patients with urinary urea clearance >1.5 mL/min, below which RKF was considered to be 'clinically negligible'. We measured eight nonurea solutes from 1280 patients participating in this study and calculated the relative difference in solute levels among patients with and without RKF based on measured urinary urea clearance. RESULTS: The mean age of the participants was 57 years and 57% were female. At baseline, 34% of the included participants had clinically negligible RKF (mean 0.7 ± 0.4 mL/min) and 66% had no RKF. Seven of the eight nonurea solute levels measured were significantly lower in patients with RKF than in those without RKF, ranging from -24% [95% confidence interval (CI) -31 to -16] for hippurate, -7% (-14 to -1) for trimethylamine-N-oxide and -4% (-6 to -1) for asymmetric dimethylarginine. The effect of RKF on plasma levels was comparable or more pronounced than that achieved with a 31% higher dialysis dose (spKt/Vurea 1.7 versus 1.3). Preserved RKF at 1-year follow-up was associated with a lower risk of cardiac death and first cardiovascular event. CONCLUSIONS: Even at very low levels, RKF is not 'negligible', as it continues to provide nonurea solute clearance. Management of patients with RKF should consider these differences.

4.
Pediatr Nephrol ; 35(2): 305-312, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31728748

RESUMO

BACKGROUND: Dialysis in children as well as adults is prescribed to achieve a target spKt/Vurea, where Vurea is the volume of distribution of urea. Waste solute production may however be more closely correlated with body surface area (BSA) than Vurea which rises in proportion with body weight. Plasma levels of waste solutes may thus be higher in smaller patients when targeting spKt/Vurea since they have higher BSA relative to body weight. This study measured levels of pseudouridine (PU), a novel marker solute whose production is closely proportional to BSA, to test whether prescription of dialysis to a target spKt/Vurea results in higher plasma levels of PU in smaller children. METHODS: PU and urea nitrogen (ureaN) were measured in plasma and dialysate at the midweek hemodialysis session in 20 pediatric patients, with BSA ranging from 0.65-1.87m2. Mathematical modeling was employed to estimate solute production rates and average plasma solute levels. RESULTS: The dialytic clearance (Kd) of PU was proportional to that of ureaN (average KdPU/KdUreaN 0.69 ± 0.13, r2 0.84, p < 0.001). Production of PU rose in proportion with BSA (r2 0.57, p < 0.001). The pretreatment plasma level of PU was significantly higher in smaller children (r2 0.20, p = 0.051) while the pretreatment level of ureaN did not vary with size. CONCLUSIONS: Prescribing dialysis based on urea kinetics may leave uremic solutes at higher levels in small children. Measurement of a solute produced proportional to BSA may provide a better index of dialysis adequacy than measurement of urea.

5.
Sleep ; 42(11)2019 10 21.
Artigo em Inglês | MEDLINE | ID: mdl-31634407

RESUMO

STUDY OBJECTIVE: To evaluate long-term efficacy and safety of phrenic nerve stimulation (PNS) in patients with moderate-to-severe central sleep apnea (CSA) through 3 years of therapy. METHODS: Patients in the remede System Pivotal Trial were observed every 3 months after implant until US Food and Drug Administration approval. At the time of approval and study closure, all patients completed 24 months of follow-up; 33 patients had not reached the 36-month visit. Sleep metrics (polysomnography) and echocardiographic parameters are reported at baseline, 12, 18, and 24 months, in addition to available 36-month sleep results from polygraphy. Safety was assessed through 36 months; however, analysis focused through 24 months and available 36-month results are provided. RESULTS: Patients were assessed at 24 (n = 109) and 36 (n = 60) months. Baseline characteristics included mean age 64 years, 91% male, and mean apnea-hypopnea index 47 events per hour. Sleep metrics (apnea-hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation index, rapid eye movement sleep) remained improved through 24 and 36 months with continuous use of PNS therapy. At least 60% of patients in the treatment group achieved at least 50% reduction in AHI through 24 months. Serious adverse events (SAEs) related to the remede System implant procedure, device, or therapy through 24 months were reported by 10% of patients, no unanticipated adverse device effects or deaths, and all events resolved. No additional related SAEs were reported between 24 and 36 months. CONCLUSION: These data suggest beneficial effects of long-term PNS in patients with CSA appear to sustain through 36 months with no new safety concerns. TRIAL REGISTRATION: NCT01816776.


Assuntos
Terapia por Estimulação Elétrica/métodos , Nervo Frênico/fisiopatologia , Apneia do Sono Tipo Central/terapia , Idoso , Terapia por Estimulação Elétrica/efeitos adversos , Feminino , Seguimentos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Polissonografia , Estudos Prospectivos , Qualidade de Vida , Apneia do Sono Tipo Central/fisiopatologia , Resultado do Tratamento
6.
Am J Physiol Renal Physiol ; 317(2): F296-F302, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31141401

RESUMO

The accumulation of uremic solutes in kidney failure may impair mental function. The present study profiled the accumulation of uremic solutes in the cerebrospinal fluid (CSF) in acute renal failure. CSF and plasma ultrafiltrate were obtained from rats at 48 h after sham operation (control; n = 10) or bilateral nephrectomy (n = 10) and analyzed using an established metabolomic platform. Two hundred forty-eight solutes were identified as uremic based on their accumulation in the plasma ultrafiltrate of nephrectomized compared with control rats. CSF levels of 124 of these solutes were sufficient to allow calculation of CSF-to-plasma ultrafiltrate concentration ratios. Levels of many of the uremic solutes were normally lower in the CSF than in the plasma ultrafiltrate, indicating exclusion of these solutes from the brain. CSF levels of the great majority of the uremic solutes increased in renal failure. The increase in the CSF was, however, relatively less than in the plasma ultrafiltrate for most solutes. In particular, for the 31 uremic solutes with CSF-to-plasma ultrafiltrate ratios of <0.25 in control rats, the average CSF-to-plasma ultrafiltrate ratio decreased from 0.13 ± 0.07 in control rats to 0.09 ± 0.06 in nephrectomized rats, revealing sustained ability to exclude these solutes from the brain. In summary, levels of many uremic solutes are normally kept lower in the CSF than in the plasma ultrafiltrate by the action of the blood-brain and blood-CSF barriers. These barriers remain functional but cannot prevent accumulation of uremic solutes in the CSF when the kidneys fail.


Assuntos
Lesão Renal Aguda/líquido cefalorraquidiano , Encefalopatias/líquido cefalorraquidiano , Uremia/líquido cefalorraquidiano , Lesão Renal Aguda/sangue , Lesão Renal Aguda/complicações , Lesão Renal Aguda/fisiopatologia , Animais , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/fisiopatologia , Encefalopatias/sangue , Encefalopatias/etiologia , Encefalopatias/fisiopatologia , Cromatografia Líquida de Alta Pressão , Modelos Animais de Doenças , Progressão da Doença , Rim/metabolismo , Rim/fisiopatologia , Masculino , Metabolômica/métodos , Nefrectomia , Ratos Sprague-Dawley , Espectrometria de Massas por Ionização por Electrospray , Espectrometria de Massas em Tandem , Uremia/sangue , Uremia/etiologia , Uremia/fisiopatologia
7.
Heart Rhythm ; 16(5): 743-753, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30476543

RESUMO

BACKGROUND: Predicting a favorable cardiac resynchronization therapy (CRT) response holds great clinical importance. OBJECTIVE: The purpose of this study was to examine proteins from broad biological pathways and develop a prediction tool for response to CRT. METHODS: Plasma was collected from patients before CRT (SMART-AV [SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy] trial). A CRT response was prespecified as a ≥15-mL reduction in left ventricular end-systolic volume at 6 months, which resulted in a binary CRT response (responders 52%, nonresponders 48%; n = 758). RESULTS: Candidate proteins (n = 74) were evaluated from the inflammatory, signaling, and structural domains, which yielded 12 candidate biomarkers, but only a subset of these demonstrated predictive value for CRT response: soluble suppressor of tumorgenicity-2, soluble tumor necrosis factor receptor-II, matrix metalloproteinase-2, and C-reactive protein. These biomarkers were used in a composite categorical scoring algorithm (Biomarker CRT Score), which identified patients with a high/low probability of a response to CRT (P <.001) when adjusted for a number of clinical covariates. For example, a Biomarker CRT Score of 0 yielded 5 times higher odds of a response to CRT compared to a Biomarker CRT Score of 4 (P <.001). The Biomarker CRT Score demonstrated additive predictive value when considered against a composite of clinical variables. CONCLUSION: These unique findings demonstrate that developing a biomarker panel for predicting individual response to CRT is feasible and holds potential for point-of-care testing and integration into evaluation algorithms for patients presenting for CRT.

8.
Circ Arrhythm Electrophysiol ; 11(8): e006055, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30354310

RESUMO

BACKGROUND: Routine atrioventricular optimization (AVO) has not been shown to improve outcomes with cardiac resynchronization therapy (CRT). However, more recently subgroup analyses of multicenter CRT trials have identified electrocardiographic or lead positions associated with benefit from AVO. Therefore, the purpose of this analysis was to evaluate whether interventricular electrical delay modifies the impact of AVO on reverse remodeling with CRT. METHODS: This substudy of the SMART-AV trial (SMARTDELAY Determined AV Optimization) included 275 subjects who were randomized to either an electrogram-based AVO (SmartDelay) or nominal atrioventricular delay (120 ms). Interventricular delay was defined as the time between the peaks of the right ventricular (RV) and left ventricular (LV) electrograms (RV-LV duration). CRT response was defined prospectively as a >15% reduction in LV end-systolic volume from implant to 6 months. RESULTS: The cohort was 68% men, with a mean age of 65±11 years and LV ejection fraction of 28±8%. Longer RV-LV durations were significantly associated with CRT response ( P<0.01) for the entire cohort. Moreover, the benefit of AVO increased as RV-LV duration prolonged. At the longest quartile, there was a 4.26× greater odds of a remodeling response compared with nominal atrioventricular delays ( P=0.010). CONCLUSIONS: Baseline interventricular delay predicted CRT response. At long RV-LV durations, AVO can increase the likelihood of reverse remodeling with CRT. AVO and LV lead location optimized to maximize interventricular delay may work synergistically to increase CRT response. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00874445.


Assuntos
Nó Atrioventricular/fisiopatologia , Bloqueio de Ramo/terapia , Terapia de Ressincronização Cardíaca/métodos , Insuficiência Cardíaca/terapia , Frequência Cardíaca , Função Ventricular Esquerda , Função Ventricular Direita , Remodelação Ventricular , Potenciais de Ação , Idoso , Bloqueio de Ramo/diagnóstico , Bloqueio de Ramo/fisiopatologia , Técnicas Eletrofisiológicas Cardíacas , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento
9.
Clin J Am Soc Nephrol ; 13(9): 1398-1404, 2018 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-30087103

RESUMO

BACKGROUND AND OBJECTIVES: Colon microbial metabolism produces solutes that are normally excreted in the urine and accumulate in the plasma when the kidneys fail. This study sought to further identify and characterize human colon-derived uremic solutes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Colon-derived solutes normally excreted in the urine were identified by comparing urine from controls (n=17) and patients with total colectomies (n=12), using an established metabolomic platform. Colon-derived solutes that accumulate in kidney failure were then identified by comparing the plasma of the control patients with that of patients on dialysis (n=14). RESULTS: Ninety-one urinary solutes were classified as colon-derived on the basis of the finding of a urine excretion rate at least four-fold higher in control patients than in patients with total colectomies. Forty-six were solutes with known chemical structure, 35 of which had not previously been identified as colon-derived. Sixty of the colon-derived solutes accumulated in the plasma of patients with ESKD to a degree greater than urea and were therefore classified as uremic. The estimated urinary clearance for 27 out of the 32 colon-derived solutes for which clearance could be calculated exceeded that of creatinine, consistent with tubular secretion. Sulfatase treatment revealed that 42 out of the 91 colon-derived solutes detected were likely conjugates. CONCLUSIONS: Metabolomic analysis identified numerous colon-derived solutes that are normally excreted in human urine. Clearance by tubular secretion limits plasma levels of many colon-derived solutes.


Assuntos
Colo/metabolismo , Colo/microbiologia , Uremia/urina , Feminino , Humanos , Masculino , Metaboloma , Pessoa de Meia-Idade
10.
Diabetes ; 67(10): 2096-2106, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30065034

RESUMO

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease worldwide, but its molecular pathogenesis is not well defined, and there are no specific treatments. In humans, there is a strong genetic component determining susceptibility to DN. However, specific genes controlling DN susceptibility in humans have not been identified. In this study, we describe a mouse model combining type 1 diabetes with activation of the renin-angiotensin system (RAS), which develops robust kidney disease with features resembling human DN: heavy albuminuria, hypertension, and glomerulosclerosis. Additionally, there is a powerful effect of genetic background regulating susceptibility to nephropathy; the 129 strain is susceptible to kidney disease, whereas the C57BL/6 strain is resistant. To examine the molecular basis of this differential susceptibility, we analyzed the glomerular transcriptome of young mice early in the course of their disease. We find dramatic differences in regulation of immune and inflammatory pathways, with upregulation of proinflammatory pathways in the susceptible (129) strain and coordinate downregulation in the resistant (C57BL/6) strain. Many of these pathways are also upregulated in rat models and in humans with DN. Our studies suggest that genes controlling inflammatory responses, triggered by hyperglycemia and RAS activation, may be critical early determinants of susceptibility to DN.


Assuntos
Nefropatias Diabéticas/genética , Nefropatias Diabéticas/imunologia , Inflamação/genética , Inflamação/imunologia , Nefropatias/genética , Nefropatias/imunologia , Animais , Glicemia/genética , Glicemia/imunologia , Western Blotting , Predisposição Genética para Doença/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real
11.
Toxins (Basel) ; 10(6)2018 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-29865226

RESUMO

Uremic solutes contribute to cardiovascular disease in renal insufficiency. In this review we describe the clearance of selected uremic solutes, which have been associated with cardiovascular disease. These solutes-indoxyl sulfate (IS), p-cresol sulfate (PCS), phenylacetylglutamine (PAG), trimethylamine-n-oxide (TMAO), and kynurenine-exemplify different mechanisms of clearance. IS and PCS are protein-bound solutes efficiently cleared by the native kidney through tubular secretion. PAG and TMAO are not protein-bound but are also cleared by the native kidney through tubular secretion, while kynurenine is not normally cleared by the kidney. Increases in the plasma levels of the normally secreted solutes IS, PCS, TMAO, and PAG in chronic kidney disease (CKD) are attributable to a reduction in their renal clearances. Levels of each of these potential toxins are even higher in patients on dialysis than in those with advanced chronic kidney disease, which can be accounted for in part by a low ratio of dialytic to native kidney clearance. The rise in plasma kynurenine in CKD and dialysis patients, by contrast, remains to be explained. Our ability to detect lower levels of the potential uremic cardiovascular toxins with renal replacement therapy may be limited by the intermittency of treatment, by increases in solute production, and by the presence of non-renal clearance. Reduction in the levels of uremic cardiovascular toxins may in the future be achieved more effectively by inhibiting their production.


Assuntos
Doenças Cardiovasculares/etiologia , Toxinas Biológicas/metabolismo , Toxinas Biológicas/toxicidade , Uremia , Animais , Humanos , Diálise Renal
12.
J Am Soc Nephrol ; 29(7): 1992-1999, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29728422

RESUMO

Background Most patients on hemodialysis are treated thrice weekly even if they have residual kidney function, in part because uncertainty remains as to how residual function should be valued and incorporated into the dialysis prescription. Recent guidelines, however, have increased the weight assigned to residual function and thus reduced the treatment time required when it is present. Increasing the weight assigned to residual function may be justified by knowledge that the native kidney performs functions not replicated by dialysis, including solute removal by secretion. This study tested whether plasma concentrations of secreted solutes are as well controlled in patients with residual function on twice weekly hemodialysis as in anuric patients on thrice weekly hemodialysis.Methods We measured the plasma concentration and residual clearance, dialytic clearance, and removal rates for urea and the secreted solutes hippurate, phenylacetylglutamine, indoxyl sulfate, and p-cresol sulfate in nine patients on twice weekly hemodialysis and nine patients on thrice weekly hemodialysis.Results Compared with anuric patients on thrice weekly dialysis with the same standard Kt/Vurea, patients on twice weekly hemodialysis had lower hippurate and phenylacetylglutamine concentrations and similar indoxyl sulfate and p-cresol sulfate concentrations. Mathematical modeling revealed that residual secretory function accounted for the observed pattern of solute concentrations.Conclusions Plasma concentrations of secreted solutes can be well controlled by twice weekly hemodialysis in patients with residual kidney function. This result supports further study of residual kidney function value and the inclusion of this function in dialysis adequacy measures.


Assuntos
Falência Renal Crônica/fisiopatologia , Falência Renal Crônica/terapia , Diálise Renal/métodos , Idoso , Idoso de 80 Anos ou mais , Cresóis/sangue , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Hipuratos/sangue , Humanos , Indicã/sangue , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica , Ésteres do Ácido Sulfúrico/sangue , Ureia/sangue
14.
PLoS One ; 12(11): e0188315, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29145509

RESUMO

Many solutes have been reported to remain at higher plasma levels relative to normal than the standard index solute urea in hemodialysis patients. Untargeted mass spectrometry was employed to compare solute levels in plasma and plasma ultrafiltrate of hemodialysis patients and normal subjects. Quantitative assays were employed to check the accuracy of untargeted results for selected solutes and additional measurements were made in dialysate and urine to estimate solute clearances and production. Comparison of peak areas indicated that many solutes accumulated to high levels in hemodialysis patients, with average peak areas in plasma ultrafiltrate of dialysis patients being more than 100 times greater than those in normals for 123 features. Most of these mass spectrometric features were identified only by their mass values. Untargeted analysis correctly ranked the accumulation of 5 solutes which were quantitatively assayed but tended to overestimate its extent. Mathematical modeling showed that the elevation of plasma levels for these solutes could be accounted for by a low dialytic to native kidney clearance ratio and a high dialytic clearance relative to the volume of the accessible compartment. Numerous solutes accumulate to high levels in hemodialysis patients because dialysis does not replicate the clearance provided by the native kidney. Many of these solutes remain to be chemically identified and their pathogenic potential elucidated.


Assuntos
Espectrometria de Massas/métodos , Diálise Renal , Feminino , Humanos , Masculino
15.
Kidney Int ; 92(6): 1484-1492, 2017 12.
Artigo em Inglês | MEDLINE | ID: mdl-28739139

RESUMO

Cardiovascular disease, the leading cause of mortality in hemodialysis patients, is not fully explained by traditional risk factors. To help define non-traditional risk factors, we determined the association of predialysis total p-cresol sulfate, indoxyl sulfate, phenylacetylglutamine, and hippurate with cardiac death, sudden cardiac death, and first cardiovascular event in the 1,273 participants of the HEMO Study. The results were adjusted for potential demographic, clinical, and laboratory confounders. The mean age of the patients was 58 years, 63% were Black and 42% were male. Overall, there was no association between the solutes and outcomes. However, in sub-group analyses, among patients with lower serum albumin (under 3.6 g/dl), a twofold higher p-cresol sulfate was significantly associated with a 12% higher risk of cardiac death (hazard ratio 1.12; 95% confidence interval, 0.98-1.27) and 22% higher risk of sudden cardiac death (1.22, 1.06-1.41). Similar trends were also noted with indoxyl sulfate. Trial interventions did not modify the association between these solutes and outcomes. Routine clinical and lab data explained less than 22% of the variability in solute levels. Thus, in prevalent hemodialysis patients participating in a large U.S. hemodialysis trial, uremic solutes p-cresol sulfate, indoxyl sulfate, hippurate, and phenylacetylglutamine were not associated with cardiovascular outcomes. However, there were trends of toxicity among patients with lower serum albumin.


Assuntos
Doenças Cardiovasculares/sangue , Cresóis/sangue , Indicã/sangue , Falência Renal Crônica/terapia , Diálise Renal/efeitos adversos , Ésteres do Ácido Sulfúrico/sangue , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Feminino , Glutamina/análogos & derivados , Glutamina/sangue , Hipuratos/sangue , Humanos , Falência Renal Crônica/sangue , Falência Renal Crônica/complicações , Falência Renal Crônica/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Diálise Renal/estatística & dados numéricos , Fatores de Risco , Albumina Sérica/análise , Uremia/sangue , Uremia/complicações
16.
J Pharm Sci ; 106(9): 2551-2557, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28483424

RESUMO

Chronic kidney disease (CKD) is characterized by the accumulation of uremic solutes; however, little is known about how these solutes affect drug absorption and disposition. The goal of this study is to evaluate the effect of uremic solutes on the organic cation transporter, OCT2, which plays a key role in the renal secretion of many basic drugs. As a second goal, we reviewed the literature to determine whether there was evidence for the effect of CKD on the renal secretion of basic drugs. We first screened 72 uremic solutes as inhibitors of [14C]-labeled metformin uptake by OCT2. Seven were identified as inhibitors and 3 of them were determined to be clinically relevant. Of the 7 solutes, dimethylamine, malondialdehyde, trimethylamine, homocysteine, indoxyl-ß-d-glucuronide, and glutathione disulfide were novel OCT2 inhibitors. For 6 drugs that are known OCT2 substrates, both secretory clearance and glomerular filtration rate declined in parallel with progression of CKD from stage 2 to 4, suggesting that selective effects of uremic solutes on net tubular secretion of organic cations do not occur. Further clinical studies are warranted with a broader range of OCT2 substrates to determine whether CKD may differentially affect tubular secretion of drugs especially in patients with advanced CKD.


Assuntos
Rim/efeitos dos fármacos , Transportador 2 de Cátion Orgânico/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Toxinas Biológicas/química , Toxinas Biológicas/metabolismo , Transporte Biológico , Dimetilaminas/química , Dimetilaminas/metabolismo , Taxa de Filtração Glomerular , Glucuronatos/química , Glucuronatos/metabolismo , Dissulfeto de Glutationa/química , Dissulfeto de Glutationa/metabolismo , Células HEK293 , Homocisteína/química , Homocisteína/metabolismo , Humanos , Indóis/química , Indóis/metabolismo , Rim/metabolismo , Malondialdeído/química , Malondialdeído/metabolismo , Metformina/química , Metformina/metabolismo , Metilaminas/química , Metilaminas/metabolismo , Uremia
18.
Heart Rhythm ; 14(5): 763-782, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28161513

RESUMO

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3-5, 2015.


Assuntos
Fibrilação Atrial/terapia , Fibrilação Atrial/etiologia , Fibrilação Atrial/prevenção & controle , Ensaios Clínicos como Assunto , Humanos
19.
Medicine (Baltimore) ; 96(6): e5799, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-28178126

RESUMO

The uremic syndrome is attributed to progressive retention of compounds that, under normal conditions, are excreted by the healthy kidneys. p-cresol sulfate (PCS), a prototype protein-bound uremic retention solute, has been shown to exert toxic effects in vitro. Recent studies have identified relations between increased levels of PCS and indoxyl sulfate (IS) and adverse clinical outcomes in hemodialysis patients. We explored the relationship between free and total PCS and IS with infection-related hospitalizations (IH) and septicemia in 2 cohorts, Choices for Healthy Outcomes in Caring for end-stage renal disease (ESRD) Study (CHOICE) and Hemodialysis Study (HEMO).We measured free and total levels of PCS and IS in stored specimens in CHOICE, a cohort of 464 incident hemodialysis patients enrolled in 1995 to 1998 and followed for an average of 3.4 years and in a prevalent dialysis cohort of 495 patients enrolled in HEMO from 1995 to 2000 and followed for an average of 4.4 years. We measured free PCS and IS using mass spectroscopy. The 2 cohorts were linked to United States Renal Data System (USRDS) Medicare billing records to ascertain IH over follow-up. We examined the association of free and total levels of PCS and IS with IH and septicemia using multilevel Poisson regression models adjusted for demographics, comorbidities, clinical factors, and laboratory tests including residual kidney function. We stratified patients a priori based on gastrointestinal (GI) disease as PCS and IS are produced in colon.In CHOICE, highest tertile of free PCS in multivariable model was associated with 50% higher risk of IH [95% CI = 1.01-2.23] compared with lowest tertile in patients with no-GI disease. A significant trend was noted between greater levels of free PCS and septicemia in no-GI disease group in both cohorts, while no association was noted in GI disease group. Total PCS concentrations were not associated with either IH or septicemia in either cohort. No significant risk of IH or septicemia was noted with higher levels of free or total IS in either GI or no-GI disease group.These results suggest an association between higher concentrations of free PCS and infection-related and sepsis-related hospitalizations in hemodialysis patients. Better methods of dialysis should be developed to evaluate the utility of removing PCS and its effect on the outcome and also therapies to decrease gastrointestinal tract production of uremic solutes.


Assuntos
Cresóis/sangue , Gastroenteropatias/complicações , Indicã/sangue , Falência Renal Crônica/sangue , Sepse/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Falência Renal Crônica/complicações , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/estatística & dados numéricos , Sepse/etiologia , Adulto Jovem
20.
Kidney Int ; 91(5): 1186-1192, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28089366

RESUMO

The Frequent Hemodialysis Network Daily Trial compared conventional three-times weekly treatment to more frequent treatment with a longer weekly treatment time in patients receiving in-center hemodialysis. Evaluation at one year showed favorable effects of more intensive treatment on left ventricular mass, blood pressure, and phosphate control, but modest or no effects on physical or cognitive performance. The current study compared plasma concentrations of uremic solutes in stored samples from 53 trial patients who received three-times weekly in-center hemodialysis for an average weekly time of 10.9 hours and 30 trial patients who received six-times weekly in-center hemodialysis for an average of 14.6 hours. Metabolomic analysis revealed that increased treatment frequency and time resulted in an average reduction of only 15 percent in the levels of 107 uremic solutes. Quantitative assays confirmed that increased treatment did not significantly reduce levels of the putative uremic toxins p-cresol sulfate or indoxyl sulfate. Kinetic modeling suggested that our ability to lower solute concentrations by increasing hemodialysis frequency and duration may be limited by the presence of non-dialytic solute clearances and/or changes in solute production. Thus, failure to achieve larger reductions in uremic solute concentrations may account, in part, for the limited benefits observed with increasing frequency and weekly treatment time in Frequent Hemodialysis Daily Trial participants.


Assuntos
Cresóis/sangue , Indicã/sangue , Falência Renal Crônica/terapia , Diálise Renal/métodos , Ésteres do Ácido Sulfúrico/sangue , Uremia/sangue , Adulto , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Metabolômica , Pessoa de Meia-Idade , Fatores de Tempo
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