双重肾素-血管紧张素系统抑制策略在心肾血管疾病中的应用价值

肾素-血管紧张素系统(renin-angiotensin system,RAS)的抑制剂包括血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitor,ACEIs)、血管紧张素Ⅱ受体拮抗剂(angiotensinⅡreceptor blocker,ARBs)和肾素抑制剂,都是心肾血管疾病的重要治疗药物。从药理机制上分析,联用上述药物(即双重RAS抑制的策略)对于心肾血管疾病的治疗可能有协同作用,并减少各自的不良反应。但前期一些临床研究报道显示双重RAS抑制方案对于很多心肾血管疾病的患者观察未发现显著受益,反而使高血钾、低血压和肾功能损伤的风险有所增加。因此欧洲和美国药品监督管理机构警告临床应慎重使用,但此警告对个体化用药保留了肯定,特别强调心力衰竭患者联合使用ACEI类和ARB类药物可能是有效的,联用的前提是密切监测患者的肾功能、电解质以及血压。基于上述原因,目前心血管疾病的临床指南往往对ACEIs和ARBs的联用持不推荐的态度。然而,临床上也确有证据显示低剂量的ACEsⅠ和ARBs联合使用可以获得更为有效的RAS阻断,且不良反应极少,尤其是在合并有蛋白尿的慢性肾脏病患者。

Lipid abnormalities in kidney disease and management strategies

Patients with kidney diseases continue to experience significant cardiovascular disease(CVD) morbidity and mortality. Although there are many important risk factors playing a role in the pathogenesis of CVD in chronic kidney disease(CKD) patients, dyslipidemia(elevated triglycerides, elevated oxidized low-densitylipoprotein and low/dysfunctional low high-density) represents one of the modifiable risk factors. Renal failure patients have unique lipid abnormalities which not only have complex role in pathogenesis of CVD but also cause relative resistance to usual interventions. Most of the randomized trials have been in hemodialysis population and data from CKD non-dialysis, peritoneal dialysis and renal transplant populations is extremely limited. Compared to general population, evidence of mortality benefit of lipid lowering medications in CKD population is scarce. Future research should be directed towards establishing long term benefits and side effects of lipid lowering medications, through randomized trials, in CKD population.

Central blood pressure and chronic kidney disease

In this review, we focused on the relationship between central blood pressure and chronic kidney diseases(CKD). Wave reflection is a major mechanism that determines central blood pressure in patients with CKD. Recent medical technology advances have enabled non-invasive central blood pressure measurements. Clinical trials have demonstrated that compared with brachial blood pressure, central blood pressure is a stronger risk factor for cardiovascular(CV) and renal diseases. CKD is characterized by a diminished renal autoregulatory ability, an augmented direct transmission of systemic blood pressure to glomeruli, and an increase in proteinuria. Any elevation in central blood pressure accelerates CKD progression. In the kidney, interstitial inflammation induces oxidative stress to handle proteinuria. Oxidative stress facilitates atherogenesis, increases arterial stiffness and central blood pressure, and worsens the CV prognosis in patients with CKD. A vicious cycle exists between CKD and central blood pressure. To stop this cycle, vasodilator antihypertensive drugs and statins can reduce central blood pressure and oxidative stress. Even in early-stage CKD, mineral and bone disorders(MBD) may develop. MBD promotes oxidative stress, arteriosclerosis, and elevated central blood pressure in patients with CKD. Early intervention or prevention seems necessary to maintain vascular health in patients with CKD.

Use of percutaneous nephrostomy and ureteral stenting in management of ureteral obstruction

The management options for ureteral obstruction are diverse, including retrograde ureteral stent insertion or antegrade nephrostomy placement, with or without eventual antegrade stent insertion. There is currently no consensus on the ideal treatment or treatment pathway for ureteral obstruction owing, in part, to the varied etiologies of obstruction and diversity of institutional practices. Additionally, different clinicians such as internists, urologists, oncologists and radiologists are often involved in the care of patients with ureteral obstruction and may have differing opinions concerning the best management strategy. The purpose of this manuscript was to review available literature that compares percutaneous nephrostomy placement vs ureteral stenting in the management of ureteral obstruction from both benign and malignant etiologies.

Major comorbid disease processes associated with increased incidence of acute kidney injury

Acute kidney injury （AKI） is commonly seen amongst critically ill and hospitalized patients. Individuals with certain co-morbid diseases have an increased risk of developing AKI. Thus, recognizing the co-morbidities that predispose patients to AKI is important in AKI prevention and treatment. Some of the most common co-morbid disease processes that increase the risk of AKI are diabetes, cancer, cardiac surgery and human immunodefciency virus （HIV） acquired immune defciency syndrome （AIDS）. This review article identifies the increased risk of acquiring AKI with given co-morbid diseases. Furthermore, the pathophysiological mechanisms underlying AKI in relation to co-morbid diseases are discussed to understand how the risk of acquiring AKI is increased. This paper reviews the effects of various co-morbid diseases including： Diabetes, cancer, cardiovascular disease and HIV AIDS, which all exhibit a significant increased risk of developing AKI. Amongst these co-morbid diseases, inflammation, the use of nephrotoxic agents, and hypoperfusion to the kidneys have been shown to be major pathological processes that predisposes individuals to AKI. The pathogenesis of kidney injury is complex, however, effective treatment of the co-morbid disease processes may reduce its risk. Therefore, improved management of co-morbid diseases may prevent some of the underlying pathology that contributes to the increased risk of developing AKI.

Cardiovascular co-morbidity in chronic kidney disease:Current knowledge and future research needs

Chronic kidney disease(CKD) is recognised as a health concern globally and leads to high rates of morbidity,mortality and healthcare expenditure.CKD is itself an independent risk factor for unfavorable health outcomes that include cardiovascular disease(CVD).Coronary artery disease is the primary type of CVD in CKD patients and a significant cause of death among renal transplant patients.Traditional and non-traditional risk factors for CVD exist in patients with CKD.Traditional factors include smoking,hypertension,dyslipidemia and diabetes which are highly prevalent in CKD patients.Non-traditional risk factors of CKD are mainly uraemiaspecific and increase in prevalence as kidney function declines.Some examples of uraemia-specific risk factors that have been well documented include low levels of haemoglobin,albuminuria,and abnormal bone and mineral metabolism.Therapeutic interventions targeted at more traditional risk factors which contribute to CVD,have not had the desired effect on lowering CVD events and mortality in those suffering with CKD.Future research is warranted to delineate clear evidence to the benefit of modifying non-traditional risk factors.

Why do young people with chronic kidney disease die early?

Cardiovascular disease poses the greatest risk of premature death seen among patients with chronic kidney disease(CKD).Up to 50% of mortality risk in the dialysis population is attributable to cardiovascular disease and the largest relative excess mortality is observed in younger patients.In early CKD,occlusive thrombotic coronary disease is common,but those who survive to reach end-stage renal failure requiring dialysis are more prone to sudden death attributable mostly to sudden arrhythmic events and heart failure related to left ventricular hypertrophy,coronary vascular calcification and electrolyte disturbances.In this review,we discuss the basis of the interaction of traditional risk factors for cardiovascular disease with various pathological processes such as endothelial dysfunction,oxidative stress,low grade chronic inflammation,neurohormonal changes and vascular calcification and stiffness which account for the structural and functional cardiac changes that predispose to excess morbidity and mortality in young people with CKD.

Baroreflex dysfunction in chronic kidney disease

Chronic kidney disease （CKD） patients have high cardiovascular mortality and morbidity. The presence of traditional and CKD related risk factors results in exaggerated vascular calcification in these patients. Vascular calcification is associated with reduced large arterial compliance and thus impaired barorefex sensi-tivity （BRS） resulting in augmented blood pressure （BP） variability and hampered BP regulation. Barorefex plays a vital role in short term regulation of BP. This review discusses the normal barorefex physiology, methods to assess baroreflex function, its determinants along with the prognostic significance of assessing BRS in CKD patients, available literature on BRS in CKD patients and the probable patho-physiology of barorefex dysfunction in CKD.

Podocyturia: Potential applications and current limitations

Chronic kidney disease is a prevalent condition that affects millions of people worldwide and is a major risk factor of cardiovascular morbidity and mortality. The main diseases that lead to chronic kidney disease are frequent entities as diabetes mellitus, hypertension and glomerulopathies. One of the clinical markers of kidney disease progression is proteinuria. Moreover, the histological hallmark of kidney disease is sclerosis, located both in the glomerular and in the interstitial compartments. Glomerulosclerosis underscores an irreversible lesion that is clinically accompanied by proteinuria. In this regard, proteinuria and glomerular sclerosis are linked by the cell that has been conserved phylogenetically not only to prevent the loss of proteins in the urine, but also to maintain the health of the glomerular fltration barrier： The podocyte. It can then be concluded that the link between proteinuria, kidney disease progression and chronic kidney disease is mainly related to the podocyte. What is this situation due to？ The podocyte is unable to proliferate under normal conditions, and a complex molecular machinery exists to avoid its detachment and eventual loss. When the loss of podocytes in the urine, or podocyturia, is taking place and its glomerular absolute number decreased, glomerulosclerosis is the predominant histological feature in a kidney biopsy. Therefore, tissular podocyte shortage is the cause of proteinuria and chronic kidney disease. In this regard, podocyturia has been demonstrated to precede proteinuria, showing that the clinical mana-gement of proteinuria cannot be considered an early intervention. The identifcation of urinary podocytes could be an additional tool to be considered by nephrologists to assess the activity of glomerulopathies, for follow-up purposes and also to unravel the pathophysiology of podocyte detachment in order to tailor the therapy of glomerular diseases more appropriately.

Hepatitis C comorbidities affecting the course and response to therapy

Several studies have demonstrated that the outcome of chronic hepatitis C (CHC) infection is profoundly influenced by a variety of comorbidities. Many of these comorbidities have a significant influence on the response to antiviral therapy. These comorbidities negatively affect the course and outcome of liver disease, often reducing the chance of achieving a sustained virological response with PEGylated interferon and ribavirin treatments. Comorbidities affecting response to antiviral therapy reduce compliance and adherence to inadequate doses of therapy. The most important comorbidities affecting the course of CHC include hepatitis B virus coinfection, metabolic syndrome, and intestinal bacterial overgrowth. Comorbidities affecting the course and response to therapy include schistosomiasis, iron overload, alcohol abuse, and excessive smoking. Comorbidities affecting response to antiviral therapy include depression, anemia, cardiovascular disease, and renal failure.

Arterial stiffness, vascular calcification and bone metabolism in chronic kidney disease

Patients with chronic kidney disease （CKD） have an extremely poor cardiovascular outcome. Arterial stiff-ness, a strong independent predictor of survival in CKD, is connected to arterial media calcification. A huge number of different factors contribute to the increased arterial calcification and stiffening in CKD, a process which is in parallel with impaired bone metabolism. This coincidence was demonstrated to be part of the direct inhibition of calcifcation in the vessels, which is a counterbalancing effect but also leads to low bone turnover. Due to the growing evidence, the defnition of “CKD mineral bone disorder” was created recently, un-derlining the strong connection of the two phenomena. In this review, we aim to demonstrate the mechanisms leading to increased arterial stiffness and the up-to date data of the bone-vascular axis in CKD. We over-view a list of the different factors, including inhibitors of bone metabolism like osteoprotegerin, fetuin-A, pyro-phosphates, matrix Gla protein, osteopontin, fbroblast growth factor 23 and bone morphogenic protein, which seem to play role in the progression of vascular calcif-cation and we evaluate their connection to impaired ar-terial stiffness in the mirror of recent scientifc results.

Nonalcoholic fatty liver disease-A multisystem disease?

Non-alcoholic fatty liver disease(NAFLD) is one of the most common comorbidities associated with overweight and metabolic syndrome(Met S). Importantly, NAFLD is one of its most dangerous complications because it can lead to severe liver pathologies, including fibrosis, cirrhosis and hepatic cellular carcinoma. Given the increasing worldwide prevalence of obesity, NAFLD has become the most common cause of chronic liver disease and therefore is a major global health problem. Currently, NAFLD is predominantly regarded as a hepatic manifestation of Met S. However, accumulating evidence indicates that the effects of NAFLD extend beyond the liver and are negatively associated with a range of chronic diseases, most notably cardiovascular disease(CVD), diabetes mellitus type 2(T2DM) and chronic kidney disease(CKD). It is becoming increasingly clear that these diseases are the result of the same underlying pathophysiological processes associated with Met S, such as insulin resistance, chronic systemic inflammation and dyslipidemia. As a result, they have been shown to be independent reciprocal risk factors. In addition, recent data have shown that NAFLD actively contributes to aggravation of the pathophysiology of CVD, T2 DM, and CKD, as well as several other pathologies. Thus, NAFLD is a direct cause of many chronic diseases associated with MetS, and better detection and treatment of fatty liver disease is therefore urgently needed. As non-invasive screening methods for liver disease become increasingly available, detection and treatment of NAFLD in patients with MetS should therefore be considered by both(sub-) specialists and primary care physicians.

Diabetes onset before or after the age of 65 does it affect the progression of renal and cardiovascular diseases in the elderly patient？

Type 2 diabetes （T2D） is common in the elderly and more than half of the people with diabetes are over 65 years old. Elderly diabetic patients have a higher frequency of hypertension, coronary artery disease and chronic kidney disease than non-diabetic elderly patients and the risk of these complications increases with patient age, duration of the dia- betes and glycated hemoglobin values. Besides the known classical factors of renal disease progression,

Cell cycle regulator geminin is dispensable for the proliferation of vascular smooth muscle cells

The proliferation of vascular smooth muscle cells(VSMCs) plays a major role in the pathogenesis of many cardiovascular diseases.Geminin regulates DNA replication and cell cycle progression and plays a key role in the proliferation of cancer cells.We therefore hypothesized that geminin regulates the proliferation of VSMCs.The present study demonstrates that the level of geminin expression was low in quiescent VSMCs(approximately 90% and 10% of cells in the G1 and in S/G2/M phases of the cell cycle,respectively),increased as more cells entered in S/G2/M,and then decreased as cells exited S/G2/M.Further,angiotensin II and norepinephrine stimulated expression of geminin in VSMCs.However,the DNA content,nuclear morphology,percentage of cells at different stages of the cell cycle,and rate of proliferation of VSMCs from which geminin was either depleted or overexpressed were all similar.These findings indicate geminin functions differently in VSMCs than it does in cancer cell lines and that it may provide a target for treating cancers without affecting normal cells.