Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011881 (diabetic nephropathy)
 10,836 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is a rising incidence and prevalence of ESRD as a result of diabetes, with poor outcome and growing costs. Recently, two large trials, the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), showed that angiotensin receptor blockers (ARB) are more effective than traditional antihypertensive therapies at reducing progression toward ESRD in hypertensive patients with type 2 diabetes and overt nephropathy, regardless of changes in BP. The results of these two trials were used to compare the costs of ARB with those of renal replacement therapy (dialysis and renal transplantation) in an effort to establish whether ARB are cost-saving because they delay ESRD. Two different pharmacoeconomic approaches were used. With regard to the RENAAL trial, the number of ESRD days on losartan therapy as compared with the number of ESRD days on standard antihypertensive therapy was calculated, and the difference between the two was combined with the costs of ESRD. In the IDNT trial, Markov models were applied to assess the economic impact of irbesartan and to extrapolate future clinical and cost outcomes. Several economic analyses were performed in the United States and in European countries. Applying pharmacoeconomic models showed that treatment with ARB was associated with a greater improvement in life expectancy and lower total costs compared with amlodipine and standard antihypertensive therapy. Therefore, treating patients with type 2 diabetes, nephropathy, and hypertension with ARB is life- and cost-saving compared with traditional antihypertensive therapy.
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PMID:Economic evaluation of angiotensin receptor blockers in type 2 diabetes, hypertension, and nephropathy. 1656 46

The angiotensin receptor blockers (ARBs) are very effective and safe antihypertensive drugs. They exert their antihypertensive effect through blockage of the angiotensin II, type 1 receptor and quite possibly through stimulation by angiotensin II of the unoccupied type 2 receptor. Besides hypertension, the ARBs have been found recently to be of value in the treatment of heart failure and diabetic nephropathy. In addition, ARBs have emerged lately as being very effective and perhaps superior to other antihypertensive drugs in the prevention of de novo or recurrent strokes. Other actions that may account for their stroke-protective effects include their antiatherogenic, antidiabetic, antiplatelet aggregating, hypouricemic, and atrial antifibrillatory actions. All these actions make the ARBs a true pleiotropic class of drugs. Each of the foregoing effects will be discussed briefly in this concise review.
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PMID:The pleiotropic effects of angiotensin receptor blockers. 1659 29

Diabetic nephropathy occurs in 20-40% of diabetic patients, making it one of the most important causes of end-stage renal disease (ESRD). It has a large impact in terms of associated morbidity and mortality for the individual patient and in terms of costs for healthcare. Several studies have demonstrated that micro- and macroalbuminuria predict cardiovascular morbidity and mortality in patients with diabetes mellitus.Current nephroprotective therapies for diabetic nephropathy include the pursuit of normoglycemia and normotension, and a consensus is emerging that there is a necessity to also achieve as low a level of albuminuria as possible. However, the search for innovative and ancillary approaches to the prevention and treatment of this diabetic complication is warranted since strict metabolic control can be difficult, and sometimes dangerous, to achieve and even diabetic patients responding to ACE inhibitors (ACEIs) or angiotensin II receptor antagonists (angiotensin receptor blockers; ARBs) and metabolic control show progressive renal damage and eventually ESRD. A number of drugs are currently being investigated; glycosaminoglycans are particularly interesting since, in theory, they target the generalized endothelial dysfunction and metabolic defect in matrix and basement membrane synthesis which, according to the Steno hypothesis, are responsible for diabetic nephropathy and macroangiopathy.Treatment with glycosaminoglycans, and with sulodexide in particular, significantly improves albuminuria in type 1 and type 2 diabetic patients with micro- or macroalbuminuria. The albuminuria-lowering effect of sulodexide enhances the effect of ACEI/ARB therapy. Most studies have shown that the effect of sulodexide on albuminuria is sustained, strongly suggesting that favorable chemical and anatomic remodeling is induced by exogenous glycosaminoglycans in renal tisues, as observed in the experimental model.
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PMID:The role of glycosaminoglycans and sulodexide in the treatment of diabetic nephropathy. 1687

The renin-angiotensin system (RAS) plays a pivotal role in the progression of some forms of hypertension and cardiovascular disease. The development of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) has provided physicians with effective and well-tolerated inhibitors of the RAS. However, it remains open to question whether ACE inhibitors and ARBs have fully delivered the reductions in cardiovascular risk that we might have expected. There is little doubt that in conditions such as chronic and acute heart failure or diabetic nephropathy these drugs have provided significant protection. But, in patients with high-risk hypertension, for instance, the anticipated benefits of RAS blockade have been less obvious. This article provides a critical assessment of the results of clinical trials of ACE inhibitors and ARBs across a variety of clinical conditions and assesses the potential need for new methods for blocking the renin system, including the use of renin inhibitors.
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PMID:Inhibiting the renin-angiotensin system to prevent cardiovascular diseases: do we need a more comprehensive strategy? 1691 23

Intrarenally synthesized angiotensin II (Ang II) may be involved in the progression of glomerulonephritis, leading to irreversible glomerulosclerosis. There is increasing evidence that systemic angiotensin receptor blocker (ARB) treatment has beneficial effect on the prognosis of progressive glomerulonephritis and diabetic nephropathy. However, the cellular and molecular mechanisms behind this therapeutic effect of ARB remain unclear. In this study, we used a novel strategy of local ARB delivery via type-1 collagen sponge, to treat progressive glomerulonephritis that would result in irreversible glomerulosclerosis in our previously established rat model. At days 9 and 14 after disease induction, mild proteinuria, 20.7+/-4.7 and 10+/-1.3 mg/day, was found. Local ARB treatment reduced proteinuria significantly to 3.19+/-3.2 and 5.25+/-0.95 mg/day (P < 0.01), respectively. Scoring of glomerular matrix expansion and sclerotic index revealed that local ARB treatment significantly ameliorated glomerular pathology. Ang II type 1 receptor mRNA expression was remarkably enhanced in the Ang II group and ARB treatment reversed this effect at 14 days. Local delivery of ARB significantly improved glomerular blood flow levels, compared to the untreated disease control group, from 710+/-18.25 to 859.44+/-22.86 microm/s, respectively. Local delivery of ARB into the kidney affected local RAS and thus improved the renal injury and function in the potentially progressive glomerulosclerosis of rat model.
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PMID:Local delivery of angiotensin receptor blocker into the kidney ameliorates progression of experimental glomerulonephritis. 1698 12

More than a century of research on the reninangiotensin system (RAS) has uncovered the widespread involvement of angiotensin II (Ang II) in the pathophysiology of cardiovascular diseases. A number of outcomes-based mega trials utilising hard clinical endpoints have revealed beneficial effects of angiotensin receptor antagonists (AIIAs/ARBs) in patients with hypertension, heart failure, diabetic nephropathy, and post-myocardial infarction (MI). The results of these studies not only emphasise the importance of Ang II in the pathophysiology of these diseases but have provided the basis for an evidence-based approach for the use of AIIAs in clinical practice. It is hoped that the next 100 years of research into the RAS will uncover hitherto unimaginable therapeutic opportunities.
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PMID:Role of angiotensin II in cardiovascular disease therapeutic implications of more than a century of research. 1708 68

Anemia has recently been recognized as a frequent complication of diabetic nephropathy, appearing earlier than in nondiabetic renal disease and amplifying the risks of cardiovascular and microvascular complications. A major cause is an inappropriate erythropoietin response to anemia, often accompanied by iron deficiency and therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers.
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PMID:Anemia and diabetic nephropathy. 1711 31

There is clear evidence that pharmacologic blockade of the renin-angiotensin system (RAS) with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) reduces proteinuria and slows the progression of renal disease in diabetic and nondiabetic nephropathies, a beneficial effect that is not related to BP control. Some patients exhibit a significant beneficial response, whereas others do not. The absence of response may be explained by the incomplete blockade of the RAS obtained with ACEI. In the search of new alternatives that could improve the antiproteinuric and nephroprotective effects of RAS blockers, the association of ACEI and ARB might prove useful. ARB produces a complete blockade of the RAS. Several studies have shown a more marked antiproteinuric effect of the dual blockade of the RAS versus ACEI or ARB alone. A recent study also demonstrated that this more marked antiproteinuric effect is associated with less progression of renal disease in primary nondiabetic nephropathies despite a similar effect on BP. Until now, there has not been any reference to a beneficial effect on progression of the dual blockade in type 2 diabetic nephropathy, which is the most frequent cause of ESRD. A multicenter, prospective, open, active-controlled, and parallel-group trial was designed to compare the effects of an ACE inhibitor versus an ARB or its combination on renal disease progression, proteinuria, and cardiovascular events in type 2 diabetic nephropathy.
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PMID:Dual blockade of the renin-angiotensin system in the progression of renal disease: the need for more clinical trials. 1713 Feb 70

The current pandemic of diabetes mellitus will inevitably be followed by an epidemic of chronic kidney disease. It is anticipated that 25-40% of patients with type 1 diabetes and 5-40% of patients with type 2 diabetes will ultimately develop diabetic kidney disease. The control of blood pressure represents a key component for the prevention and management of diabetic nephropathy. There is a strong epidemiological connection between hypertension in diabetes and adverse outcomes in diabetes. Hypertension is closely linked to insulin resistance as part of the 'metabolic syndrome'. Diabetic nephropathy may lead to hypertension through direct actions on renal sodium handling, vascular compliance and vasomotor function. Recent clinical trials also support the utility of blood pressure reduction in the prevention of diabetic kidney disease. In patients with normoalbuminuria, transition to microalbuminuria can be prevented by blood pressure reduction. This action appears to be significant regardless of whether patients have elevated blood pressure or not. The efficacy of ACE inhibition appears to be greater than that achieved by other agents with a similar degree of blood pressure reduction; although large observational studies suggest the risk of microalbuminuria may be reduced by blood pressure reduction, regardless of modality. In patients with established microalbuminuria, ACE inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers [ARBs]) consistently reduce the risk of progression from microalbuminuria to macroalbuminuria, over and above their antihypertensive actions. The clinical utility of combining these strategies remains to be established. In patients with overt nephropathy, blood pressure reduction is associated with reduced urinary albumin excretion and, subsequently, a reduced risk of renal impairment or end stage renal disease. In addition to actions on systemic blood pressure, it is now clear that ACE inhibitors and ARBs also reduce proteinuria in patients with diabetes. This anti-proteinuric activity is distinct from other antihypertensive agents and diuretics. Although there is a clear physiological rationale for blockade of the renin angiotensin system, which is strongly supported by clinical studies, to achieve the optimal lowering of blood pressure, particularly in the setting of established diabetic renal disease, a number of different antihypertensive agents will always be needed. In the end, the choice of agents should be individualised to achieve the maximal tolerated reduction in blood pressure and albuminuria. Ultimately, no matter how it is achieved, so long as it is achieved, renal risk can be reduced by agents that lower blood pressure and albuminuria.
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PMID:Blood pressure lowering for the prevention and treatment of diabetic kidney disease. 1713 4

Despite the worldwide epidemic of chronic kidney disease complicating diabetes mellitus, current therapies directed against nephroprogression are limited to angiotensin conversion or receptor blockade. Nonetheless, additional therapeutic possibilities are slowly emerging. The diversity of therapies currently in development reflects the pathogenic complexity of diabetic nephropathy. The three most important candidate drugs currently in development include a glycosaminoglycan, a protein kinase C (PKC) inhibitor and an inhibitor of advanced glycation. In targeting primary mechanisms by which hyperglycaemia contributes to diabetic complications, these drugs could provide risk reduction complementary to the partial reduction proven for ACE inhibitors and angiotensin II receptor antagonists (angiotensin receptor blockers). Glycosaminoglycans act to restore glycoproteins present in reduced amounts in the glomerular basement membrane and mesangium of diabetic animal models. Components of the drug sulodexide prevent pathological changes and proteinuria in diabetic rats. Reductions in albuminuria, a hallmark of early diabetic kidney disease, have been reported in initial human trials. In the US, a multicentre phase II study has been completed, with an interim analysis indicating reduction in urinary albumin losses. Pivotal phase II trials have begun in patients with type 2 diabetes. A second metabolic pathway of diabetic complications is overexpression of PKC. Several activators of this family of intracellular kinases have been identified and PKC activation may result in tissue damage through a variety of mechanisms. In animal models, the inhibitor ruboxistaurin reduces albuminuria, diabetic histological changes and kidney injury. Like sulodexide, drug development of ruboxistaurin has reached completion of a phase II evaluation with mixed results. The third metabolic target is the nonenzymatic formulation of advanced glycation end-products (AGEs) through well described biochemical pathways. Multiple pathways lead to AGE accumulation in tissues in diabetes and diverse AGE products are formed. AGE deposition has been implicated in animal models of diabetic nephropathy. The leading AGE inhibitor currently in development is pyridoxamine, which has multiple actions that inhibit glycation. Pyridoxamine is an efficient AGE inhibitor in experimental diabetes. A phase II study in diabetic patients with nephropathy reported mixed efficacy results and a favourable safety profile. Phase III evaluation of pyridoxamine has not begun. These three classes of potential therapies, if successfully developed, will confirm that diabetic kidney disease has entered the era of biochemical treatments.
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PMID:New potential agents in treating diabetic kidney disease: the fourth act. 1718 72


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