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Query: UMLS:C0011881 (diabetic nephropathy)
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The attributes of Release 3.0 of the user friendly version (UFV) of the global diabetes model (GDM) are described and documented in detail. The GDM is a continuous, stochastic microsimulation model of type 2 diabetes. Suitable for predicting the medical futures of both individuals with diabetes and representative diabetic populations, the GDM predicts medical events (complications of diabetes), survival, utilities, and medical care costs. Incidence rate functions for microvascular and macrovascular complications are based on a combination of published studies and analyses of data describing diabetic members of Kaiser Permanente Northwest Region, a non-profit group-model health maintenance organization. Active risk factors include average blood glucose (HbAlc), systolic blood pressure (SBP), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), triglycerides, smoking status, and use of prophylactic aspirin. Events predicted include diabetic eye disease, diabetic nephropathy, peripheral neuropathy amputation, myocardial infarction, stroke, peripheral artery disease, congestive heart failure, coronary artery surgery, coronary angioplasty, and death.
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PMID:The global diabetes model: user friendly version 3.0. 1108 May 61

Diabetic nephropathy is a leading cause of end-stage renal disease, and its prevalence and incidence vary greatly from country to country, being highest in the United States and Japan. In the United States, diabetic nephropathy accounts for approximately 40% of patients beginning renal replacement therapy. Type 2 diabetes is the largest and fastest-growing single disease that requires dialytic therapy. Most patients succumb to cardiovascular causes, including coronary artery disease and myocardial infarction, sudden death, cardiac failure, and stroke. The survival from cardiovascular complications is relatively better in East Asian countries and to a lesser extent in Mediterranean countries compared with countries that traditionally have higher cardiovascular death rates. Peripheral vascular disease and sepsis contribute to increased morbidity and mortality. Amputation of limbs secondary to peripheral vascular disease in particular has adverse effects on rehabilitation. Asymptomatic hypoglycemia may develop in hemodialysis patients. Such hypoglycemia is not associated with a hormonal balance but is postulated to be due to blunted hormonal response to hypoglycemia. Diabetic muscle infarction is another rare complication attributable to diabetic microangiopathy; magnetic resonance imaging may help in the diagnosis. Risk factors for increased mortality include advanced age, poor glycemic control before starting dialysis, smoking, left ventricular hypertrophy, hypoalbuminemia, and neuropathy, in particular, autonomic dysfunction. In addition to adequate dialysis, it is advisable to achieve tight blood pressure control (at least <140/90 mm Hg and preferably much lower), better blood glucose control (hemoglobin A(1c), <7%), correction of nutritional status, and appropriate foot care.
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PMID:Hemodialysis in diabetic patients. 1157 54

Diabetes is a major risk factor for cardiovascular events. Indeed, people with diabetes are 2-4 times more likely to die from cardiovascular causes than individuals without diabetes. Despite evidence to suggest that the burden of cardiovascular disease may be decreasing in Western populations, this trend has not been repeated in diabetic populations. Diabetes is also the most common cause of new-onset end-stage renal disease, blindness and amputations. The growing incidence of diabetes throughout the world, particularly in developing nations, suggests that diabetes-related cardiovascular disease and other chronic cardiovascular diseases will constitute a serious global threat to health and well-being. The HOPE (Heart Outcomes Prevention Evaluation) study was designed to determine if the angiotensin converting enzyme (ACE) inhibitor, ramipril, prevents cardiovascular events in high risk patients. As people with diabetes have a high risk of such events, this group was specified for inclusion and analysis in the HOPE study. The HOPE study was designed to include up to 4,000 people with diabetes and was designed with high power to detect an 18% risk reduction in the diabetic sub group alone. A total of 3,577 individuals with diabetes were randomised to receive either 10 mg of ramipril or placebo. After a period of 4.5 years of follow-up, the group of patients receiving ramipril had a statistically and clinically significant risk reduction of 25% in the primary outcome of myocardial infarction (MI), stroke or cardiovascular (CV) death. This comprises a 37% risk reduction in CV death, a 22% risk reduction in MI, a 33% reduction in stroke and a 24% reduction in all-cause mortality. The MICRO-HOPE (Microalbuminuria, Cardiovascular, and Renal Outcomes) sub study assessed the effect of ramipril on diabetic nephropathy. This was detected by a centrally measured urine albumin:creatinine ratio and confirmed by timed urine collection. Ramipril significantly reduced the risk of overt nephropathy by 22% (P = 0.045), and overt nephropathy, laser therapy or dialysis by 15% (P = 0.05). ACE inhibition with ramipril represents a new macrovascular and microvascular preventive therapy for people with diabetes.
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PMID:Diabetes and the HOPE study: implications for macrovascular and microvascular disease. 1171 57

Platelet glycoprotein receptors play a role in the pathogenesis of chronic diabetic complications. Genetic polymorphisms of the alpha2beta1 integrin and glycoprotein IIIa (GPIIIa) have been associated with myocardial infarction, stroke, and diabetic retinopathy. To identify risk factors for their development in a cohort of patients with type 2 diabetes, we evaluated clinical variables and genetic polymorphisms in the alpha2beta1 integrin and GPIIIa genes. Two hundred thirty-four subjects with type 2 diabetes (126 patients with and 108 patients without diabetic nephropathy), as well as 217 nondiabetic healthy subjects, were recruited for this study. Clinical factors for investigation included sex, age at diagnosis, duration of diabetes, body mass index (BMI), and fasting plasma glucose, hemoglobin A(1c) (HbA(1c)), total cholesterol, and triglyceride levels. Genotypes were determined by polymerase chain reaction and restriction fragment length polymorphism analyses. No difference in the Bgl II polymorphism of the alpha2beta1 integrin gene was found between patients with type 2 diabetes with or without nephropathy (11 [8.7%], 47 [37.3%], and 68 patients [54.0%] versus 10 [9.3%], 32 [29.6%], and 66 patients [61.1%] for Bgl II+/+, Bgl II+/-, and Bgl II-/-, respectively; P = 0.271). Multiple logistic regression analyses showed that duration of diabetes, BMI, hypertension, and poor glycemic control were four independent predictors for the development of diabetic nephropathy. No contribution of the Bgl II+ allele of the alpha2beta1 integrin was found for the risk for nephropathy (odds ratio, 1.258; 95% confidence interval, 0.655 to 2.418; P = 0.490). The Pl(A2) allele genotype was not found among our studied subjects. In conclusion, age, duration of diabetes, BMI, and HbA(1c) level are strong predictors for nephropathy in patients with type 2 diabetes. However, the Bgl II polymorphism of the alpha2beta1 integrin gene and the Apa I polymorphism of the platelet GPIIIa gene do not have a major role in the development of diabetic nephropathy in our population.
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PMID:Platelet collagen receptor alpha2beta1 integrin and glycoprotein IIIa Pl(A1/A2) polymorphisms are not associated with nephropathy in type 2 diabetes. 1172 49

The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update. All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (t(max)) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals. The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin. Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and beta-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes. ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%.
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PMID:Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update. 1192 21

Recent trials have helped to clarify indications for the initial pharmacological therapy of hypertension. Both the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) and World Health Organization-international Society of Hypertension (WHO-ISH) recommendations should be revised. The more recent trials indicate that: (1) diuretics and beta-blockers appear to be as effective in reducing overall morbidity/ mortality as other agents (Swedish Trial in Old Patients with Hypertension [STOP-2], United Kingdom Prospective Diabetes Study [UKPDS], Intervention as a Goal in Hypertension Treatment [INSIGHT], Nordic diltiazem [NORDIL]); (2) the use of an a-blocker results in more cardiovascular events, especially congestive heart failure, when compared with a diuretic (Antihypertensive Therapy and Lipid Lowering Heart Attack Trial [ALLHAT]); (3)the use of an angiotensin-converting enzyme (ACE) inhibitor results in fewer myocardial infarctions and episodes of heart failure than calcium channel blockers in the elderly and in diabetic patients (Fosinopril vs. Amlodipine Cardiovascular Events Randomized Trial [FACET], Appropriate Blood Pressure Control in Diabetes [ABCD], STOP-2) - other data (Captopril Prevention Project [CAPPP]) suggest that the use of an ACE inhibitor is preferred in diabetic patients; (4) overall cardiovascular events are similar with calcium channel blockers compared with a diuretic - however, there are fewer strokes with non-dihydropyridine calcium channel blockers (NORDIL) and a trend towards an increase in heart failure and myocardial infarctions with either a dihydropyridine or non-dihydropyridine calcium channel blockers compared with a diuretic (INSIGHT, NORDIL); (5) angiotensin receptor blockers (ARBs) will decrease proteinuria and slow progression of renal disease in type 2 diabetic patients when compared with regimens that do not include an ARB or an ACE inhibitor (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan [RENAAL], Irbesartan Type II Diabetic Nephropathy Trial [IDNT], Irbesartan Type II Diabetes with Microalbuminuria [IRMA Il]). The debate over initial therapy may be moot. High-risk hypertensive patients should probably be treated initially with combination therapy, one of which should be a diuretic. The use of diuretics and beta-blockers as well as ACE-inhibitors alone or with a diuretic should be considered as initial therapy (a change from JNCVI). Alpha-blockers should be reserved for special situations, i.e. prostatic hypertrophy (in contrast to WHO-ISH recommendations). An ACE-inhibitor or ARB, usually along with a diuretic, can be considered as preferred therapy in hypertensive diabetic patients. Some data suggest equal or greater reduction in strokes with a calcium channel blocker than other medications.
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PMID:Current recommendations for the treatment of hypertension: are they still valid? 1199 97

Angiotensin II receptor antagonists (AAIIs) are the most specific inhibitors of the renin-angiotensin-aldosterone system. There are two types of angiotensin II (Ang II) receptors, the AT(1) receptor, which is responsible for all the classical physiological properties of Ang II, and the AT(2) receptor, whose function in humans remains unclear. The different AAIIs used in clinical practice vary depending on their pharmacodynamic and pharmacokinetic properties, and, for some of them, depending on their metabolism in vivo into an active metabolite. AAIIs are relatively well tolerated, and, unlike angiotensin-converting enzyme inhibitors (ACEIs), do not induce cough. AAIIs are indicated in mild, moderate and severe essential hypertension, where their efficacy has been proven in many studies. The maximal antihypertensive effect is obtained in a few days or weeks, and is somewhat retarded when compared with ACEIs. Their effect is independent of age and sex, but does depend to a certain extent on ethnic origin, since Afro-American patients are less sensitive to AAIIs than Caucasians. In general, the antihypertensive and haemodynamic response to blockers of the renin-angiotensin system is potentiated in presence of a negative salt balance and attenuated in case of a positive salt balance. This means that AAII efficiency is improved by salt depletion induced by a salt-free diet or thiazide diuretics. AAIIs induce short-term improvement of haemodynamic parameters in cardiac insufficiency. Several ongoing clinical trials have been designed to compare their efficacy in cardiac insufficiency and myocardial infarction with those of reference treatments. Valsartan has been recently shown to improve morbimortality in patients with cardiac insufficiency and receiving a conventional treatment including an ACEI. It has been convincingly shown that blockade of the renin-aldosterone system by ACEIs decreases proteinuria and slows down the progression of renal insufficiency, especially in type 2 diabetic nephropathy. Recent trials have shown that AAIIs share the same properties as ACEIs in these indications. It appears that the beneficial effect of AAIIs and ACEIs is not entirely explained by the blood pressure lowering effect of these drugs. AAII administration increases renin release and Ang II production, which may overcome Ang II blockade. On this basis, the combination of an AAII and an ACEI has been proposed to achieve a maximal renin-angiotensin system blockade. Several experimental studies in animals and preliminary clinical studies all indicate that the combination of the two drugs may be more beneficial than either drug used alone in hypertension, cardiac insufficiency and post-myocardial infarction. Clinical trials are necessary to further document the putative advantages of such a combined therapy. The future of AAIIs depends on the following: progress made in the understanding of the molecular and cellular activities of angiotensin (angiotensin receptor signalling, receptor dimerisation, presence of other angiotensin receptor subtypes, role of AT(2) receptor, etc.);a comprehensive view of the role of the local renin system in various organs (local generation and effect of Ang II on cellular proliferation, fibrosis, inflammation, angiogenesis, etc.);predictability of the response to AAII treatment (genetic predisposition to AAII treatment, in conjunction with environmental factors); andresults of the ongoing clinical trials designed to assess the long-term effects of AAIIs in cardiovascular mortality and morbidity, in comparison with reference treatments.
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PMID:[Angiotensin II receptor blockers: current status and future prospects]. 1203 89

The RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan) study is a multinational, double-blind, randomized, placebo controlled trial which was recently published. It was aimed to evaluate the effect of the angiotensin receptor blocker losartan in patients with diabetic nephropathy. The primary efficacy measure was the time to the first event of the composite end point of a doubling of serum creatinine, end-stage renal disease, or death. The conclusion was that losartan led to significant improvement in renal outcomes, that was beyond that attributable to blood pressure control in patients with type 2 diabetes and nephropathy. The perusal of the report raises concern, regarding to both the patient population as well as the outcome measures. At randomization, the placebo group included more patients with angina, myocardial infarction and lipid disorders than the losartan group. Information on glucose metabolism was disregarded, and data on antihyperglycemic therapy--which may have undesirable influences on cardiac performance--were not included in a multivariate analysis. In addition, only data on first hospitalization were reported, whilst information on total specific-cause hospitalizations was disregarded, thus potentially masking further unfavorable events. Furthermore, creatinine seems not to be a reliable surrogate end point. Based on its mechanism of action, losartan may possess favorable renoprotective properties. However, due to the methodological flaws and the incomplete data in the RENAAL study, the question of the effectiveness and safety of this drug in diabetic nephropathy remains yet unanswered.
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PMID:Losartan and diabetic nephropathy: commentaries on the RENAAL study. 1211 58

Blockade of the renin-angiotensin system by angiotensin converting enzyme (ACE) inhibitors reduces mortality and morbidity in patients post-myocardial infarction as well as in chronic heart failure and hypertension. ACE inhibitors also have a well-established place in the treatment of diabetic nephropathy. Angiotensin receptor blockers (ARBs) have been developed to produce a more complete blockade of the actions of angiotensin II as compared to other drug classes, as well as an improved side effect profile. This article provides an overview of the place of ARBs in general and of the ARB valsartan in particular, and draws comparisons to ACE inhibitors in the treatment of cardiovascular diseases.
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PMID:Role of valsartan and other angiotensin receptor blocking agents in the management of cardiovascular disease. 1222 Sep 62

Harmonic combination of efficacy and safety allowed angiotensin converting enzyme inhibitors (ACEI) to conquer popularity among physicians in the treatment of hypertension, heart failure, myocardial infarction, diabetic and non-diabetic nephropathy. This multiprofile application is determined by their action not only on systemic but also on tissue renin-angiotensin systems which augmented activity plays important role in genesis of various pathological states. One of novel and most promising directions of use of ACEI especially of those with inherent high tissue specificity and vascular selectivity (quinapril, perindopril, ramipril, trandolapril) is the treatment of atherosclerosis. Antiatherosclerotic effects of ACEI were studied in a variety of clinical trials with assessment of their effect on long term outcome. These trials demonstrated positive action of ACEI on the clinical course of cardiovascular and cerebrovascular diseases. Expediency of prescription of ACEI to patients with atherosclerosis of coronary vessels and other vascular beds irrespective of the presence of hypertension and heart failure becomes now obvious.
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PMID:[Clinical sequelae of tissue angiotensin converting enzyme inhibition: practicability of use in ischemic heart disease]. 1249 37

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