摘要:

Purpose of reviewThe emerging field of pharmacogenomics has the potential to fundamentally change the management of essential hypertension, a common, perhaps polygenic syndrome characterized by substantial inter-individual variability in drug responsiveness. As understanding of sequence diversity in the human genome progresses, the prospect grows for tailoring the prescription of antihypertensive drugs to complement common genetic variations among individual patients, allowing optimization of blood pressure control and improved avoidance of drug side effects. Some principles of pharmacogenomics are presented here, along with a review of the most recent literature on genetic determinants of antihypertensive drug responses, with a preview of likely developments to come.Recent findingsPolymorphisms at candidate pharmacodynamic loci (such as angiotensinogen, angiotensin converting enzyme, and the angiotensin II receptor) have already been shown to predict responses to such specific treatments as angiotensin converting enzyme inhibition and angiotensin II blockade. The National Institutes of Health have established a multi-institutional pharmacogenetics network and knowledge base, whose goals include understanding how common polymorphisms influence therapeutic responses to a variety of drugs, including antihypertensive agents.SummaryThe study of genetic determinants of drug responses, particularly at the pharmacodynamic (drug target/receptor and post-receptor) level, is likely to allow us to more precisely tailor therapy to the individual patient, as well as to promote the creation of novel therapies.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe two leading causes of end-stage renal disease in the United States are diabetes mellitus and hypertensive nephrosclerosis, accounting for over two-thirds of all cases. In many patients both diseases are associated with small- and large-vessel disease, commonly attributed to hypertension or accelerated atherosclerosis. Recent investigations, however, have suggested that renal large-vessel and microvascular disease may be independent contributors to progressive kidney failure.Recent findingsAlthough genes have not been definitely linked to renal vascular disease, population- and family-based epidemiology of kidney disease, segregation analysis of Pima and Caucasian families in which diabetic nephropathy is clustered, and the positional cloning of genes responsible for rare, familial glomerulosclerosis syndromes support the hypothesis that genes regulate the pathogenesis of renal disease. This review highlights developments in our current understanding of vasculopathy and its role in renal disease, and it summarizes evidence suggesting that genetic determinants for the vascular phenotype are associated with common causes of chronic renal failure.SummaryWith the application of genomics and proteomics methodologies to drug discovery, the identification of renal susceptibility genes should identify new mechanisms of progressive renal disease pathogenesis and generate novel target molecules for the treatment of kidney disease.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewAfrican-Americans are more likely than Caucasians to develop hypertension-related end-stage renal disease. Elevations in blood pressure levels clearly potentiate pre-existing renal disease and also contribute to kidney injury independently of other primary renal diseases in this cohort. Until recently, data relevant to a full examination of the issue of blood pressure levels and end-stage renal disease in African-Americans have largely been frompost-hocanalyses of clinical trials or from small, prospective, short-term studies.Recent findingsThe most recent United States Renal Data Systems data show hypertension as the primary cause of end-stage renal disease in African-Americans until 1997, diabetes now being the most prevalent etiology. Data frompost-hocanalyses of the Modification of Diet in Renal Disease study demonstrated that African-Americans with a mean arterial pressure above 98 mmHg had a higher risk of end-stage renal disease than Caucasians. The African-American Study of Kidney Disease tested the hypothesis that a blood pressure well below the usual recommended level will further reduce renal disease progression in African-Americans. The study concluded that a blood pressure lower than that needed to reduce cardiovascular events, as defined by the Sixth Joint National Committee Report on the Detection, Evaluation and Treatment of High Blood Pressure, i.e. 135-140/80-85 mmHg, will not further slow renal disease progression in African-Americans with hypertensive nephrosclerosis. Moreover, a regimen of blood pressure lowering anchored on angiotensin-converting enzyme inhibitors, antihypertensive agents that are touted as ineffective in African-Americans, was more effective than one based on either beta-blockers or dihydropyridine calcium-channel blockers in slowing the progression of renal injury.SummarySystolic blood pressure reduction in the range 130-139 mmHg is appropriate to reduce risk of nephropathy progression and cardiovascular risk in African-Americans with hypertensive nephrosclerosis. Moreover, a regimen that is initiated with an angiotensin-converting enzyme inhibitor should be the antihypertensive treatment of choice in African-Americans with kidney disease.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe pathophysiology of ischemic acute renal failure is complex, incompletely understood and there are no specific therapies. Descriptive observations in human acute renal failure, as well as mechanistic studies in animals, have demonstrated an important pathophysiological role for leukocytes and leukocyte adhesion molecules. The purpose of this review is to summarize and interpret the recent advances on the role of T cells and leukocyte adhesion molecules in ischemic acute renal failure.Recent findingsEmerging data suggest that the T cell is involved in modulating the outcome of ischemic acute renal failure, as well as ischemic injury to other organs. These new data build on the established role of inflammation in acute renal failure, and identify novel therapeutic targets. In addition, identification of the role of the T cell in the immediate injury response extends current immunological models of T cell function. Studies on leukocyte adhesion in acute renal failure have now identified the selectins and their ligands as important components of the inflammatory response to ischemic injury.SummaryThe identification of T cells and new adhesion molecule pathways as modulators of ischemic acute renal failure offers novel and feasible therapeutic opportunities for both native and transplant acute renal failure. Rigorous clinical trials are required to translate these basic findings to the bedside. In addition, mechanistic studies are needed to elucidate the molecular mechanisms by which these pathways modulate kidney injury. The identification of T cell engagement in ischemic renal injury can also help explain long-standing observations linking alloantigen-independent and alloantigen-dependent renal damage.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThere is rapidly growing appreciation that stroke morbidity and the risk of an ischaemic stroke becoming haemorrhagic can be influenced by new information about prophylaxis, rapid diagnosis and treatment.Recent findingsStrokes are strongly associated with hypertension mainly because hypertension is strongly associated with atheromatous deposits blocking or narrowing brain arteries, predisposing to local clot formation. Atheroma and its ischaemic consequences may damage cerebral arterioles and the brain tissue they supply. Cerebral infarcts are more common than spontaneous cerebral haemorrhages. High blood pressure itself cannot directly rupture cerebral blood vessels because their small size protects them and intracerebral haemorrhage usually follows previous ischaemic vascular damage. It is obvious that lowering blood pressure would reduce the risk and extent of bleeding into the brain once a break in an arteriolar wall has occurred, but it is not clear why lowering blood pressure should protect against cerebral infarction. One might expect that slowing down the rate of cerebral blood flow would give more time for local clots to form. It seems most likely that induced hypotension protects against ischaemic strokes by preventing pressure- or ischaemia-induced arteriolar spasm and by advantageous vasodilation of some of the more ischaemic territories. Added protection can be provided by coenzyme-A reductase inhibitors (statins), but probably not by antioxidants.SummaryLowering blood pressure strongly protects against ischaemic and haemorrhagic stroke. Recent work shows that more accurate and faster diagnosis of stroke pathology is urgently needed, so that appropriate treatment (e.g. with tissue plasminogen activators) can be started before local bleeding has occurred.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

摘要:

Purpose of reviewThe failure to lower systolic blood pressure at night (called non-dipping) and sleep apnea are both associated with adverse cardiovascular outcomes. Sleep apnea is a common cause of non-dipping blood pressure.Recent findingsSleep apnea increases night time blood pressure through enhanced cardiac pre-load, sleep disturbance and hypoxia. Hypoxia elicits increased levels of norepinephrine, endothelin and erythropoetin. Patients with sleep apnea tend to be elderly and obese, so they have poor endothelial nitric oxide release and blunted baroreflexes. They thus have several stimuli for high blood pressure and poor compensatory mechanisms to lower blood pressure.SummaryNon-dipping patients without sleep apnea have evidence of volume overload and correct their blood pressure pattern in response to diuretics. Individuals with sleep apnea have evidence of increased cardiac pre-load from episodes of negative intrathoracic pressure. Their daytime blood pressure responds poorly to many drugs, but beta blockers may be effective. Their night time blood pressure responds only slightly to therapy of their sleep apnea with continuous positive airway pressure, even though continuous positive airway pressure decreases their norepinephrine, erythropoetin and endothelin levels.

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID

ISSN:1062-4821    

出版商:OVID    

年代:2003

数据来源: OVID