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Diabetic nephropathy has become the single most important cause of end-stage renal disease in the USA, Europe and Japan. The earliest marker of incipient diabetic nephropathy is the transition of normoalbuminuria to microalbuminuria at an albumin excretion rate of 20 microg/min. Human studies in patients both with and without diabetic kidney diseases have shown that the severity of baseline proteinuria is an important predictor of the rate of loss of renal function. Moreover, the reduction in protein excretion rate when patients with nephropathies are being treated with antihypertensive agents predicts the efficacy of subsequent renoprotection. Experimental and clinical observations provide the rationale for targeting the renin-angiotensin system as a renoprotective approach in diabetic and nondiabetic proteinuric nephropathies. Losartan (Cozaar, Merck Sharpe and Dohme) is a potent, orally active and highly specific angiotensin-type 1 receptor blocker. In addition to its antihypertensive efficacy, losartan decreases the left ventricular mass index in patients with hypertension, left ventricular end-diastolic and end-systolic volume in subjects with heart failure and prevents cardiovascular morbidity and death, predominantly stroke, independent of blood pressure reduction. Short-term studies in Type 1 diabetic patients with overt nephropathy have demonstrated that losartan and angiotensin-converting enzyme inhibitors have similar beneficial effects on albumin excretion rate, blood pressure and renal hemodynamics. Losartan also lowered albumin excretion rate in microalbuminuric patients with Type 2 diabetes mellitus. Moreover, the large multicenter Reduction of End points in Noninsulin dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial has shown that blockade of angiotensin-type 1 receptor with losartan is superior to conventional antihypertensive therapy in slowing the progression of overt Type 2 diabetic nephropathy. Together, data from clinical trials demonstrate the beneficial effect of angiotensin-type 1 receptor blockers, including losartan, in the primary and secondary prevention of renal disease progression in diabetic patients. Nevertheless, it can be expected that the positive results achieved so far with this class of drugs may be further implemented by including angiotensin-type 1 receptor antagonists as a part of the multidrug approach that may hold more promise for the future of renoprotection in diabetic patients with chronic nephropathy.
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PMID:Losartan in diabetic nephropathy. 1522 8

This study aimed to assess the distribution of cardiovascular risk factors among subjects with type 2 clinical diabetic nephropathy, since in diabetic subjects, the excess mortality in cardiovascular events is primarily related to nephropathy. The study group consisted of 162 subjects with type 2 diabetes mellitus and persistent proteinuria, and the control group was 80 type 2 diabetic subjects without nephropathy. In the study group there were 81 male and 81 female subjects whose mean age was 53.4 +/- 6.3 years. There was no significant consumption of alcohol and cigarette use in the population. The mean waist-hip ratio (WHR) was 0.97 and 0.96 in male and female subjects, respectively. The mean body mass index (BMI) of the subjects was 25.5 +/- 5.2 (males: 24.4 +/- 4.3, females: 27.2 +/- 5.5). A total of 106 subjects, made up of 45 male (27.8%) and 61 female (37.7%) subjects, were hypertensive as compared with 16 controls (20%). There was a significant difference in systolic blood pressure (p < 0.05) between the obese and non-obese subjects. One hundred and thirty three subjects (82.1%) had serum total cholesterol below 200 mg% as compared with 74 (92.5% ) in the control. Seventy-eight subjects (48.1%) had left ventricular hypertrophy. Males had a higher tendency of developing left ventricular hypertrophy (p = 0.04). Stroke and peripheral vascular disease respectively occurred more commonly in type 2 diabetes mellitus subjects with nephropathy [7 (4%) and 44 (27.2%)] compared to type 2 diabetic subjects without nephropathy [0 (0% ) and 9 (11.3% )] (p < 0.05). We found that there is a high prevalence of cardiovascular risk factors among Nigerian subjects with clinical diabetic nephropathy.
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PMID:Cardiovascular risk factors in type 2 diabetic Nigerians with clinical diabetic nephropathy. 1525 22

In the present study, we evaluated the clinical course and outcome of chronic peritoneal dialysis (PD) in a group of elderly patients. We enrolled 60 elderly patients (37 men, 23 women) starting PD over a 4-year study period and assessed outcomes. The mean age of our patients was 61 +/- 7 years; mean PD duration was 16 months (range: 3 - 40 months). Primary diseases were mainly diabetic nephropathy (54%) and glomerulonephritis (20%). In most patients, the PD modality was chosen because of cardiac instability. Complications during PD included peritonitis (1 episode per 9 patient-months) and exit-site infection (1 episode per 26 patient-months). Technique survival was 89% at 1 year. Patient survival was 83% and 32% at 1 and 4 years respectively. The most frequent causes of death were cerebrovascular accident, cardiac complications, and sepsis. We also compared predialysis parameters to final parameters for 20 deceased patients. Mean age in this group was 62 +/- 8 years, and mean PD duration was 13 +/- 8 months. Body mass index (BMI) was 23 +/- 3 kg/m2 predialysis versus 22 +/- 3 kg/m2 at the end of dialysis (p < 0.01); residual renal creatinine clearance was 4.4 +/- 2 mL/min versus 2.3 +/- 2 mL/min (p < 0.003), and weekly total Kt/V was 2.1 +/- 0.3 versus 1.8 +/- 0.3 (p < 0.002). Albumin showed positive correlations with BMI (r = 0.40, p < 0.02) and with creatinine (r = 0.40, p < 0.01). We conclude that survival of elderly patients on continuous ambulatory peritoneal dialysis is reasonable in the first year, and that further improvement may be achieved by initiating dialysis early, by increasing the dialysis dose, and by improving the patients' nutrition status.
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PMID:Outcome of continuous ambulatory peritoneal dialysis in a group of elderly patients from Bangladesh. 1538 6

Diabetes mellitus is increasing, and in some countries is the single most important cause, for end-stage renal disease. In general, primarily elderly patients on renal replacement therapy, are not only affected by diabetes-related long-term complications, but also frequently with a wide range of co-morbidities. Apart from cardiac complications, the patients are subject to a wide range of vascular (i.e. peripheral vascular disease, stroke) and infectious complications. In the past this has been reflected by a relatively poor survival rate on dialysis, and minimized chances to obtain renal transplantation. Today, several renal replacement strategies are available, including the main 3: hemodialysis, peritoneal dialysis or kidney transplantation. For patients with diabetes mellitus, hemodialysis is the most commonly used therapy. Each dialysis unit should achieve an optimal dialysis adequacy represented by a single pool Kt/V of at least 1.2. The most important independent predictor of patient survival with hemodialysis treatment is age. Other factors related to complications are left ventricular hypertrophy, arterial hypertension, hypervolaemia and chronic anemia. Moreover, medial arterial calcification, malnutrition, gastrointestinal disorders and dialysis against low potassium dialysate are related to increased morbidity and mortality as well. An integral part of treatment is the availability of good vascular access. The survival rates of fistulas show a nearly twofold higher rate of failure for synthetic grafts compared with arteriovenous fistulas. The role of peritoneal dialysis in renal replacement therapy in patients with diabetic nephropathy is well established and used world-wide. Most patients with residual renal function start with continuous ambulatory peritoneal dialysis (CAPD), but automated peritoneal dialysis can also be used. An unresolved problem associated with CAPD is the glucose absorption and caloric intake. The optimum adjustment of blood glucose values is made more difficult. Death rates of diabetic patients on peritoneal dialysis remain higher than in non-diabetics. The changes in peritoneal membrane thickness and vascular alterations in relationship to the duration of dialysis are caused mainly by glucose and glucose degradation products, such as advanced glycation endproduct (AGEs). Therefore, new peritoneal dialysis solutions are needed to reduce the complications and to delay a long-time function of the peritoneal membrane. Peritonitis remains still the major cause of discontinuation of dialysis but there is no increased risk in diabetic patients. Nevertheless, an integrative care of end-stage renal disease patients with diabetic nephropathy should be offered to the patient, starting on peritoneal dialysis and switch to hemodialysis if problems arise. During the whole time patients should be kept on the renal transplantation waiting list.
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PMID:Diabetes mellitus and dialysis. 1546 7

Individuals with type 2 diabetes and nephropathy represent a particularly high-risk group for both adverse cardiac as well as renal events. Using the Irbesartan in Diabetic Nephropathy Trial (IDNT) cohort, our objective was to determine baseline characteristics of individuals with type 2 diabetic nephropathy and hypertension predictive for cardiac events. IDNT identified 1715 individuals with type 2 diabetic nephropathy and hypertension having serum creatinine of 1.0 to 3.0 mg/dL and urinary albumin excretion rates > or = 900 mg/day. A cardiovascular (CV) composite was used consisting of CV death, nonfatal MI, hospitalization for heart failure, stroke, amputation, and coronary and peripheral revascularization. Using multivariable Cox regression analysis, 41 baseline characteristics determined a priori were analyzed for their potential relationship to risk of experiencing a CV event. Of the 1715 individuals, 518 (30.2%) had at least one of the CV composite end points. Older age, male gender, longer duration of diabetes, history of cardiovascular disease, history of CHF, high urinary albumin:creatinine ratio, and low serum albumin were strong predictors for CV events; of these, prior history of CVD (RR 2.00, 95% CI 1.63-2.45; P < 0.0001) and high urinary albumin:creatinine ratio (RR 1.29 per natural log unit, 95% CI 1.13-1.48; P = 0.0002) at baseline were highly predictive for cardiovascular events. In conclusion, among individuals with hypertension and diabetic nephropathy, both the degree of albuminuria and lower serum albumin levels provide additional prognostic information concerning cardiovascular risk, in addition to traditional coronary risk factors.
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PMID:Predictors of cardiovascular events in patients with type 2 diabetic nephropathy and hypertension: a case for albuminuria. 1548 18

Hypertension is a major cardiovascular risk factor, but most patients remain asymptomatic for many years. Successful therapy not only needs to be effective, it also needs to be well tolerated. Angiotensin receptor blockers have emerged as a major therapeutic class because they meet both of these requirements. Numerous studies indicate that all approved angiotensin receptor blockers are highly selective for angiotensin-1 receptors, lower blood pressure as monotherapies, and work well in combination with other drugs - particularly diuretics. The side-effect profile of angiotensin receptor blockers is similar to that of placebo and they have not been associated with known side effects of angiotensin-converting enzyme inhibitors such as cough and angioneurotic edema. Candesartan cilexetil is an angiotensin receptor blocker with insurmountable binding properties to the angiotensin-1 receptor, long duration of action and improved efficacy. In patients with hypertension, candesartan monotherapy has been shown to be safe and effective. Comparative data have shown similar or better results to other monotherapies in blood-pressure control, and in combination with hydrochlorothiazide it has been shown to have additive or synergistic effects. More recent data demonstrate that candesartan cilexetil is useful in the treatment of patients with heart failure and may protect against diabetic nephropathy. Studies have also shown protection from stroke, particularly in patients with isolated systolic hypertension.
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PMID:Candesartan cilexetil in cardiovascular disease. 1550 Apr 28

Calcium antagonists were introduced for the treatment of hypertension in the 1980s. Their use was subsequently expanded to additional disorders, such as angina pectoris, paroxysmal supraventricular tachycardias, hypertrophic cardiomyopathy, Raynaud phenomenon, pulmonary hypertension, diffuse esophageal spasms, and migraine. Calcium antagonists as a group are heterogeneous and include 3 main classes--phenylalkylamines, benzothiazepines, and dihydropyridines--that differ in their molecular structure, sites and modes of action, and effects on various other cardiovascular functions. Calcium antagonists lower blood pressure mainly through vasodilation and reduction of peripheral resistance. They maintain blood flow to vital organs, and are safe in patients with renal impairment. Unlike diuretics and beta-blockers, calcium antagonists do not impair glucose metabolism or lipid profile and may even attenuate the development of arteriosclerotic lesions. In long-term follow-up, patients treated with calcium antagonists had development of less overt diabetes mellitus than those who were treated with diuretics and beta-blockers. Moreover, calcium antagonists are able to reduce left ventricular mass and are effective in improving anginal pain. Recent prospective randomized studies attested to the beneficial effects of calcium antagonists in hypertensive patients. In comparison with placebo, calcium antagonist-based therapy reduced major cardiovascular events and cardiovascular death significantly in elderly hypertensive patients and in diabetic patients. In several comparative studies in hypertensive patients, treatment with calcium antagonists was equally effective as treatment with diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors. From these studies, it seems that a calcium antagonist-based regimen is superior to other regimens in preventing stroke, equivalent in preventing ischemic heart disease, and inferior in preventing congestive heart failure. Calcium antagonists are also safe and effective as first-line or add-on therapy in diabetic hypertensive patients. Heart rate-lowering calcium antagonists (verapamil, diltiazem) may have an edge over the dihydropyridines in post-myocardial infarction patients and in diabetic nephropathy. Thus, calcium antagonists may be safely used in the management of hypertension and angina pectoris.
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PMID:Calcium antagonists. 1551 14

Randomised clinical trials completed over the past 8 to 10 years have provided much new evidence regarding the cardiovascular risks and benefits of treatment with newer blood pressure lowering drugs, particularly ACE inhibitors and calcium channel blockers (CCB). Trials of active treatment against placebo have now established that ACE inhibitors and CCBs reduce the risk of coronary heat disease and stroke in subjects with elevated blood pressure and that ACE inhibitors reduce the risk of heart failure but calcium antagonists do not. Clinical trials comparing active treatment regimens based on different blood pressure lowering drug classes, have provided convincing evidence that ACE inhibitors, CCBs, and "conventional treatment" with diuretics/beta-blockers are equally effective in the primary prevention of coronary heart disease, but that minor differences of the order of 5-12% favouring calcium antagonists may exist. The one area with a major difference is again for the primary prevention of heart failure where calcium antagonists are clearly inferior to diuretics/ beta-blockers and to ACE inhibitors. There is now convincing evidence that blood pressure lowering is effective in the secondary prevention of cardiovascular outcomes in subjects with established coronary heart disease, cerebrovascular disease, diabetes and chronic kidney disease, especially diabetic nephropathy. Clinical trial evidence comprising regimens based on different drug classes for the secondary prevention of cardiovascular outcomes is still very limited. It is possible that longer differences will be found between the efficacy and safety of drugs in secondary prevention than have been reported so far in primary prevention.
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PMID:Comparison of various blood pressure lowering treatments on the primary prevention of cardiovascular outcomes in recent randomised clinical trials. 1570 25

Macro- and microvascular disease are the most common causes of morbidity and mortality in patients with diabetes mellitus. Diabetic cardiovascular dysfunction represents a problem of great clinical importance underlying the development of various severe complications including retinopathy, nephropathy, neuropathy and increase the risk of stroke, hypertension and myocardial infarction. Hyperglycemic episodes, which complicate even well-controlled cases of diabetes, are closely associated with increased oxidative and nitrosative stress, which can trigger the development of diabetic complications. Hyperglycemia stimulates the production of advanced glycosylated end products, activates protein kinase C, and enhances the polyol pathway leading to increased superoxide anion formation. Superoxide anion interacts with nitric oxide, forming the potent cytotoxin peroxynitrite, which attacks various biomolecules in the vascular endothelium, vascular smooth muscle and myocardium, leading to cardiovascular dysfunction. The pathogenetic role of nitrosative stress and peroxynitrite, and downstream mechanisms including poly(ADP-ribose) polymerase (PARP) activation, is not limited to the diabetes-induced cardiovascular dysfunction, but also contributes to the development and progression of diabetic nephropathy, retinopathy and neuropathy. Accordingly, neutralization of peroxynitrite or pharmacological inhibition of PARP is a promising new approach in the therapy and prevention of diabetic complications. This review focuses on the role of nitrosative stress and downstream mechanisms including activation of PARP in diabetic complications and on novel emerging therapeutical strategies offered by neutralization of peroxynitrite and inhibition of PARP.
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PMID:Role of nitrosative stress and peroxynitrite in the pathogenesis of diabetic complications. Emerging new therapeutical strategies. 1572 18

The introduction of Angiotensin II receptor blockers (ARB) in 1995 was another milestone in the pharmacological management of hypertension. Due to the manifold effects on several target organs Angiotensin II is one of the most important mediator in the pathogenesis of hypertension. The blockade of the Angiotensin II receptor type 1 is a crucial cornerstone in interrupting the pathophysiological pathways in hypertension. Furthermore ARB have an excellent tolerability comparable with placebo. In the last decade large placebo-controlled trials could prove the efficiency of ARB in terms of morbidity and mortality. Patients after acute myocardial infarction and patients with chronic heart failure benefit from treatment with ARB equally compared to treatment with ACE inhibitors. Combining ARB and ACE inhibitors in patient after myocardial infarction increases the rate of adverse events without improving survival. Increase of microalbuminuria and worsening of diabetic nephropathy is reduced by ARB in patients with diabetes type 2, but an advantage over ACE inhibitors could not be documented. Hypertensive patients with electrocardiographically left ventricular hypertrophy treated with ARB seem to have an additional benefit in terms of morbidity and mortality compared to treatment with beta-blockers. In the early treatment of stroke patients treated with ARB have a lower 12-mounth mortality than patients receiving placebo. In conclusion, Angiotensin II receptor blockers are due to their well proved efficiency, the cardio- and renoprotective qualities and the excellent tolerability profile a useful therapeutic option in the management of patients with hypertension.
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PMID:[Angiotensin II receptor blockers--evidence along the cardiovascular continuum]. 1588 24


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