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1.
Artigo em Inglês | MEDLINE | ID: mdl-31794032

RESUMO

OBJECTIVE: ANCA-associated vasculitis (AAV) is a small vessel vasculitis that commonly presents in the elderly. However, there are few long-term outcome data for these patients. Here, we assessed long-term outcomes in a single-centre cohort of elderly patients with AAV. Additionally, we tested whether a pre-morbid frailty score could aid prognosis. METHODS: Using a prospectively-compiled dataset, we investigated patients over the age of 65 who presented with AAV between 2005 and 2017 to a regional vasculitis centre. We used a Cox model to determine the factors associated with mortality. We also compared outcomes in pre-specified subgroups stratified by baseline frailty score, ANCA serotype and induction immunosuppression (with cyclophosphamide, rituximab or mycophenolate mofetil used as the main glucocorticoid-sparing agent). RESULTS: 83 patients were included in the study and were followed for a median of 1203 days. Median age was 74 years (range 65-92). Two- and five-year survival in the overall cohort were 83% (95% CI 75, 92%) and 75% (95% CI 65, 86%), respectively. The median cumulative dose of oral prednisolone was 2030 mg during the first three months. Only one patient received intravenous glucocorticoids. Age, frailty score and CRP at presentation were independently associated with mortality; all deaths occurred in patients aged over 75 at presentation. Patients treated with a cyclophosphamide-based induction regimen tended to be younger than those treated with rituximab or mycophenolate mofetil. Survival was better in the cyclophosphamide-treated group. CONCLUSION: In the contemporary era, the overall prognosis of AAV in elderly patients is good. Baseline frailty associates with disease outcomes including mortality. A low-dose glucocorticoid regimen (avoiding intravenous methylprednisolone) can be used to treat AAV effectively in elderly patients.

2.
Br J Pharmacol ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31721165

RESUMO

Phosphodiesterase type 5 inhibitors (PDE5Is), such as sildenafil, tadalafil, and vardenafil are a class of drugs used to prolong the physiological effects of nitric oxide/cGMP signalling in tissues through the inhibition of cGMP degradation. Although these agents were originally developed for the treatment of hypertension and angina, unanticipated side effects led to advances in the treatment of erectile dysfunction and, later, pulmonary arterial hypertension. In the last decade, accumulating evidence suggests that PDE5Is may confer a wider range of clinical benefits than was previously recognised. This has led to a broader interest in the cardiovascular therapeutic potential of PDE5Is, in conditions such as hypertension, myocardial infarction, stroke, peripheral arterial disease, chronic kidney disease, and diabetes mellitus. Here, we review the pharmacological properties and established licensed uses of this class of drug, along with emerging therapeutic developments and possible future indications.

3.
Arterioscler Thromb Vasc Biol ; 39(8): 1520-1541, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31189432

RESUMO

Vasculitis is a systemic disease characterized by immune-mediated injury of blood vessels. Current treatments for vasculitis, such as glucocorticoids and alkylating agents, are associated with significant side effects. Furthermore, the management of both small and large vessel vasculitis is challenging because of a lack of robust markers of disease activity. Recent research has advanced our understanding of the pathogenesis of both small and large vessel vasculitis, and this has led to the development of novel biologic therapies capable of targeting key cytokine and cellular effectors of the inflammatory cascade. In parallel, a diverse range of imaging modalities with the potential to monitor vessel inflammation are emerging. Continued expansion of combined structural and molecular imaging using positron emission tomography with computed tomography or magnetic resonance imaging may soon provide reliable longitudinal tracking of vascular inflammation. In addition, the emergence of radiotracers able to assess macrophage activation and immune checkpoint activity represents an exciting new frontier in imaging vascular inflammation. In the near future, these advances will allow more precise imaging of disease activity enabling clinicians to offer more targeted and individualized patient management.

4.
Hypertension ; 74(2): 323-330, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31177906

RESUMO

Dyslipidemia is common in chronic kidney disease (CKD). Despite statins, many patients fail to adequately lower lipids and remain at increased risk of cardiovascular disease. Selective ETA (endothelin-A) receptor antagonists reduce cardiovascular disease risk factors. Preclinical data suggest that ETA antagonism has beneficial effects on circulating lipids. We assessed the effects of selective ETA antagonism on circulating lipids and PCSK9 (proprotein convertase subtilisin/kexin type 9) in CKD. This was a secondary analysis of a fully randomized, double-blind, 3-phase crossover study. Twenty-seven subjects with predialysis CKD on optimal cardio- and renoprotective treatment were randomly assigned to receive 6 weeks dosing with placebo, the selective ETA receptor antagonist, sitaxentan, or long-acting nifedipine. We measured circulating lipids and PCSK9 at baseline and then after 3 and 6 weeks. Baseline lipids and PCSK9 did not differ before each study phase. Whereas placebo and nifedipine had no effect on lipids, 6 weeks of ETA antagonism significantly reduced total (-11±1%) and low-density lipoprotein-associated (-20±3%) cholesterol, lipoprotein (a) (-16±2%) and triglycerides (-20±4%); high-density lipoprotein-associated cholesterol increased (+14±2%), P<0.05 versus baseline for all. Additionally, ETA receptor antagonism, but neither placebo nor nifedipine, reduced circulating PCSK9 (-19±2%; P<0.001 versus baseline; P<0.05 versus nifedipine and placebo). These effects were independent of statin use and changes in blood pressure or proteinuria. Selective ETA antagonism improves lipid profiles in optimally-managed patients with CKD, effects that may occur through a reduction in circulating PCSK9. ETA receptor antagonism offers a potentially novel strategy to reduce cardiovascular disease risk in CKD. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00810732.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Antagonistas do Receptor de Endotelina A/uso terapêutico , Nifedipino/administração & dosagem , Pró-Proteína Convertase 9/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Adulto , Idoso , Análise de Variância , Doenças Cardiovasculares/etiologia , LDL-Colesterol/sangue , LDL-Colesterol/efeitos dos fármacos , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Medição de Risco , Resultado do Tratamento
6.
Kidney Int Rep ; 4(3): 484-486, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30899875
8.
Hypertension ; 70(1): 192-200, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28507171

RESUMO

Endothelin (ET) receptor antagonists are potentially novel therapeutic agents in chronic kidney disease and resistant hypertension, but their use is complicated by sodium and water retention. In animal studies, this side effect arises from ETB receptor blockade in the renal tubule. Previous attempts to determine whether this mechanism operates in humans have been confounded by the hemodynamic consequences of ET receptor stimulation/blockade. We aimed to determine the effects of ET signaling on salt transport in the human nephron by administering subpressor doses of the ET-1 precursor, big ET-1. We conducted a 2-phase randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. After sodium restriction, subjects received either intravenous placebo or big ET-1, in escalating dose (≤300 pmol/min). This increased plasma concentration and urinary excretion of ET-1. Big ET-1 reduced heart rate (≈8 beats/min) but did not otherwise affect systemic hemodynamics or glomerular filtration rate. Big ET-1 increased the fractional excretion of sodium (from 0.5 to 1.0%). It also increased free water clearance and tended to increase the abundance of the sodium-potassium-chloride cotransporter (NKCC2) in urinary extracellular vesicles. Our protocol induced modest increases in circulating and urinary ET-1. Sodium and water excretion increased in the absence of significant hemodynamic perturbation, supporting a direct action of ET-1 on the renal tubule. Our data also suggest that sodium reabsorption is stimulated by ET-1 in the thick ascending limb and suppressed in the distal renal tubule. Fluid retention associated with ET receptor antagonist therapy may be circumvented by coprescribing potassium-sparing diuretics.


Assuntos
Endotelina-1 , Insuficiência Renal Crônica , Sódio/metabolismo , Adulto , Animais , Diurese/efeitos dos fármacos , Diurese/fisiologia , Método Duplo-Cego , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/efeitos adversos , Antagonistas dos Receptores de Endotelina/farmacocinética , Endotelina-1/administração & dosagem , Endotelina-1/efeitos adversos , Endotelina-1/farmacocinética , Feminino , Taxa de Filtração Glomerular , Humanos , Túbulos Renais/metabolismo , Túbulos Renais/fisiopatologia , Masculino , Natriurese/efeitos dos fármacos , Natriurese/fisiologia , Receptores de Endotelina/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Resultado do Tratamento , Equilíbrio Hidroeletrolítico/efeitos dos fármacos
9.
Nephrol Dial Transplant ; 32(7): 1211-1216, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-27257273

RESUMO

Background: Bone fractures are an important cause of morbidity and mortality in patients on renal replacement therapy (RRT). The aim of this multicentre observational study was to quantify the incidence of radiologically proven bone fracture by anatomical site in prevalent RRT groups and study its relationship to potential risk factors. Methods: We performed a retrospective analysis of electronic records of all 2096 adults prevalent on RRT in the West of Scotland on 7 July 2010 across all hospitals (except one where inception was 1 August 2011) to identify all subsequent radiologically proven fractures during a median 3-year follow-up. Results: There were 340 fractures, with an incidence of 62.8 per 1000 patient-years. The incidences were 37.6, 99.2 and 57.6 per 1000 patient-years in the transplant, haemodialysis (HD) and peritoneal dialysis (PD) groups, respectively (P < 0.05). In the multivariable model, age and HD (relative to transplant or PD) were independently associated with increased risk of fractures, while primary glomerular disease, increasing serum albumin and taking alfacalcidol or lanthanum were associated with decreased risk. In a multivariable model of only HD patients, age was independently associated with an increased risk of fractures, while glomerular disease, high serum albumin and being on alfacalcidol and lanthanum were associated with decreased risk. In a multivariable model in transplant patients, there were no significant independent predictors of fracture. Conclusions: The risk of symptomatic bone fracture is high in RRT patients and is ∼2.5 times higher in HD than in renal transplant patients, with the increased risk being independent of baseline factors. Fracture risk increases with age and lower serum albumin and is reduced if the primary renal diagnosis is glomerular disease. The possible protective role of alfacalcidol and lanthanum in HD patients deserves further exploration.


Assuntos
Fraturas Ósseas/etiologia , Falência Renal Crônica/terapia , Terapia de Substituição Renal/efeitos adversos , Adolescente , Adulto , Idoso , Conservadores da Densidade Óssea/uso terapêutico , Feminino , Fraturas Ósseas/tratamento farmacológico , Fraturas Ósseas/epidemiologia , Humanos , Hidroxicolecalciferóis/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Diálise Renal , Estudos Retrospectivos , Fatores de Risco , Escócia/epidemiologia , Adulto Jovem
10.
Br J Clin Pharmacol ; 83(3): 584-592, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27650800

RESUMO

AIMS: microRNA-122 (miR-122) is a hepatotoxicity biomarker with utility in the management of paracetamol overdose and in drug development. Renal dysfunction and haemodialysis have been associated with a reduction in circulating microRNA. The objective of this study was to determine their effect on miR-122. METHODS: Blood samples were collected from 17 patients with end-stage renal disease (ESRD) on haemodialysis, 22 healthy controls, 30 patients with chronic kidney disease (CKD) and 15 patients post-kidney transplantation. All had normal standard liver function tests. Samples from ESRD patients were collected immediately pre- and post-haemodialysis. Serum alanine transaminase activity (ALT), miR-122 and miR-885 (liver enriched) were compared. RESULTS: Circulating miR-122 was substantially reduced in ESRD patients pre-haemodialysis compared with the other groups (19.0-fold lower than healthy controls; 21.7-fold lower than CKD). Haemodialysis increased miR-122 from a median value of 6.7 × 103 (2.3 × 103 -1.4 × 104 ) to 1.6 × 104 (5.4 × 103 -3.2 × 104 ) copies ml-1 . The increase in miR-122 did not correlate with dialysis adequacy. miR-122 was reduced in the argonaute 2 bound fraction pre-haemodialysis; this fraction was increased post-dialysis. There was no change in miR-122 associated with extracellular vesicles. miR-885 was also reduced in ESRD patients (4-fold compared to healthy subjects) and increased by haemodialysis. CONCLUSION: miR-122 is substantially lower in ESRD compared to healthy controls, patients with CKD and transplanted patients. Haemodialysis increases the concentration of miR-122. These data need to be considered when interpreting liver injury using miR-122 in patients with ESRD on dialysis, and specific reference ranges that define normal in this setting may need to be developed.


Assuntos
Falência Renal Crônica/sangue , Transplante de Rim , MicroRNAs/sangue , Diálise Renal , Adulto , Alanina Transaminase/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Curr Drug Metab ; 17(6): 550-8, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26892730

RESUMO

BACKGROUND: The management of ischemic nephropathy due to atherosclerotic renal artery stenosis has become increasingly conservative in the modern era, with current guidelines recommending optimized medical therapy as the initial step. The doubts raised by the recently published trials of revascularization strategies have led to a renewed focus on pharmacological strategies promoting blood pressure control and renal protection. It is essential to further elucidate the pathophysiological mechanisms underlying hypoperfusion induced renal microvascular dysfunction with subsequent tissue injury and fibrogenesis. The role of renin angiotensin aldosterone system as a mediator of the main pathophysiological consequences of ischemic nephropathy is well known. However, more recent experimental evidence on the adrenergic system and intrarenal tubular feedback mechanisms has stimulated new interest towards a multi-target therapeutic approach. METHODS: This review focuses on the pharmacology of the principle therapeutic drug classes currently used in the treatment of atherosclerotic renal artery stenosis with an analysis of their metabolic aspects and use in clinical practice based on evidence from clinical trials. RESULTS AND CONCLUSIONS: An optimal pharmacologic approach is crucial for a successful prevention of renal injury and cardiovascular events in this high-risk population. Antihypertensive treatment should include renin angiotensin aldosterone system blockade medication not only for their antihypertensive properties, but especially for those cardio and renoprotective.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores do Receptor Tipo 2 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Isquemia/tratamento farmacológico , Rim/efeitos dos fármacos , Obstrução da Artéria Renal/tratamento farmacológico , Insuficiência Renal Crônica/tratamento farmacológico , Sistema Renina-Angiotensina/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/efeitos adversos , Bloqueadores do Receptor Tipo 2 de Angiotensina II/efeitos adversos , Inibidores da Enzima Conversora de Angiotensina/efeitos adversos , Animais , Humanos , Isquemia/metabolismo , Isquemia/fisiopatologia , Rim/metabolismo , Rim/fisiopatologia , Obstrução da Artéria Renal/metabolismo , Obstrução da Artéria Renal/fisiopatologia , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/fisiopatologia , Renina/antagonistas & inibidores , Renina/metabolismo , Resultado do Tratamento
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