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)

The development of aliskiren, the first orally effective renin inhibitor, utilized molecular modeling based upon X-ray crystallographic analysis of renin's active site to design a potent, low molecular weight renin inhibitor with improved bioavailability (approximately 2.6%). In patients with hypertension, dose-dependent BP reduction occurs with aliskiren 75-300 mg once daily; at these doses, the safety and tolerability profile is comparable to placebo. In direct comparison studies, BP reduction with aliskiren is equivalent to commonly used antihypertensive agents including diuretics, ACE inhibitors, and ARBs. Persistent BP reduction and prolonged suppression of plasma renin activity (PRA) is observed after aliskiren withdrawal. Aliskiren suppresses PRA when given either as monotherapy or in combination with other agents. When added to an ARB, aliskiren blocks compensatory RAS activation and produces significant additional BP reduction. In patients with diabetic nephropathy, addition of aliskiren to losartan, 100 mg resulted in a 20% greater reduction in proteinuria. Ongoing studies evaluating the long-term renal protective effects of aliskiren and its effects on ventricular remodeling are currently planned or underway.
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PMID:Current concepts: renin inhibition in the treatment of hypertension. 1830 34

Hypertension is one of the leading risk factors for cardiovascular disease and represents a major health and economic burden. Most patients with high- or very high-risk hypertension have multiple cardiovascular risk factors with or without accompanying subclinical organ damage or established cardiovascular or renal disease. Patients with severe hypertension or with moderate hypertension and one to two additional risk factors have absolute 10-year risks of cardiovascular disease of 21-30% and 15-20%, respectively. Current European treatment guidelines recommend that antihypertensive therapy be initiated rapidly and aggressively in patients with high-risk hypertension. Most patients require two or more antihypertensive agents to achieve the strict blood pressure target of <130/80 mmHg. This article reviews the existing cost-effectiveness data on the use of angiotensin II receptor antagonists (blockers) [ARBs] in patients with high-risk hypertension. Aggressive ARB treatment of patients in the early (microalbuminuric) stages of diabetic nephropathy has a significant renoprotective effect, delaying the onset of overt (proteinuric) nephropathy. By slowing the progression of these patients to end-stage renal disease, substantial cost savings can be made. There is a paucity of cost-effectiveness data regarding the use of fixed-dose ARB plus thiazide diuretic combination therapies. Longitudinal cost-benefit studies of this attractive and efficacious first-line treatment option are needed.
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PMID:Economic benefits of treating high-risk hypertension with angiotensin II receptor antagonists (blockers). 1834 11

Administration of an angiotensin II receptor antagonist (ARB) during the second trimester of pregnancy is known to cause irreversible renal damage in the fetus. We report a case in which ARB was given to the mother from the first trimester until 26 weeks' gestation. The patient had diabetic nephropathy with accompanying nephrotic syndrome. At 8 weeks' gestation, she was started on candesartan cilexetil (an ARB). At 26 weeks' gestation, she was transferred to our center. Severe oligohydramnios was noted. The pregnancy was terminated, and she delivered at 27 weeks' gestation. The neonate weighed 884 g and died 1 h after birth. Autopsy revealed that the lung/bodyweight ratio was 0.0096 (>0.015) and pulmonary hypoplasia was noted. Histological examination of the kidneys showed tubular dysgenesis with poor differentiation of the proximal tubules.
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PMID:Oligohydramnios and pulmonary hypoplasia: a case in which involvement of an angiotensin II receptor antagonist was suspected. 1841 89

Several factors have been incriminated in the genesis of diabetic nephropathy. To elucidate their interplay, we have used a hypertensive, obese, diabetic rat model with nephropathy (SHR/NDmcr-cp) that mimics human type 2 diabetes. This model is characterized by hypertension, obesity with the metabolic syndrome, diabetes with insulin resistance, and intrarenal advanced glycation end product (AGE) accumulation. In order to achieve renoprotection, which was evaluated by histology and albuminuria, various therapeutic approaches were used: caloric restriction, antihypertensive agents (angiotensin II receptor blocker [ARB] and calcium channel blocker), lipid- (bezafibrate) or glucose-lowering (insulin and pioglitazone) agents, and cobalt chloride (a hypoxia-inducible factor activator). Altogether, renoprotection is not necessarily associated with blood pressure or glycemic control. By contrast, it is almost always associated with decreased AGE formation, with the exception of insulin, which induces hyperinsulinemia, eventually leading to an overproduction of transforming growth factor-beta. AGE formation is reduced directly by in vitro active compounds (e.g., ARBs) or indirectly by in vitro inactive compounds (e.g., pioglitazone and cobalt). In the latter cases, AGE reduction may reflect a decreased oxidative stress as it is concomitant with a marked reduction of oxidative stress markers. It remains to be seen whether the renoprotection offered by these various approaches may be additive.
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PMID:Inhibition of advanced glycation end products: an implicit goal in clinical medicine for the treatment of diabetic nephropathy? 1844 8

Evidence from recent studies indicates that in patients with diabetic nephropathy combined therapy with ACE inhibitors (ACEI) and AT1-receptor antagonists (ARB) results in more complete blockade of the renin-angiotensin-aldosterone system (RAS) than monotherapy, and reduces proteinuria. Most of these trials, however, had short follow-up, included a small number of patients, and were heterogeneous, so the opportunity to start this treatment in these patients remains unclear. This review summarizes the results of these studies, describing the renal effects of dual RAS blockade in both type 1 and type 2 diabetic patients.
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PMID:Renal effects of dual renin-angiotensin-aldosterone system blockade in patients with diabetic nephropathy. 1895 80

Increasing evidence suggests that circulating aldosterone per se contributes directly to renal and cardiovascular diseases. We sought to evaluate the effects of a three-month treatment with 25 mg spironolactone, an aldosterone receptor antagonist, on nephron function in 20 type II diabetic patients with persistent microalbuminuria, despite at least six months' use of an ACEi or ARB (combination group), and in eleven type II diabetic patients with persistent microalbuminuria who have never used an ACEi or an ARB (spironolactone group). In the combination group, urinary protein excretion (UPE, p = 0.015), urinary albumin excretion (UAE, p = 0.010), and the urinary albumin to creatinine ratio (ACR, p = 0.007) decreased, and serum potassium (sK(+), p = 0.004) was significantly elevated. ACR (p = 0.016) decreased significantly in the spironolactone group. In 31 patients given spironolactone (all patients group), UPE (p = 0.019), UAE (p = 0.002), and ACR (p = 0.011) decreased, and serum creatinine (sCr, p = 0.025) and sK(+) (p = 0.002) were significantly elevated. Changes in albuminuria showed a positive correlation with changes in GFR (p = 0.002) and a negative correlation with changes in sCr (p = 0.007), and changes in ACR showed a negative correlation with changes in sCr (p = 0.004) in all patient groups. In our study, we observed that spironolactone, both alone and in combination with ACEi/ARB treatment, was well tolerated, and that it slowed down the progression of diabetic nephropathy with a marked antialbuminuric effect. Our results showed that the antialbuminuric effect developed by the decrease of intraglomerular pressure, particularly in patients with persistent microalbuminuria despite long-term ACEi/ARB treatment; adding aldosterone blockers to treatment was beneficial.
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PMID:The effects of spironolactone on nephron function in patients with diabetic nephropathy. 1901 50

The intrarenal renin-angiotensin system (RAS) plays a key role in the development of diabetic nephropathy. Recently, we showed that combination therapy with an AT(1) receptor blocker (ARB) and an activated vitamin D analog produced excellent synergistic effects against diabetic nephropathy, as a result of blockade of the ARB-induced compensatory renin increase. Given the diversity of vitamin D analogs, here we used a pro-drug vitamin D analog, doxercalciferol (1alpha-hydroxyvitamin D(2)), to further test the efficacy of the combination strategy in long-term treatment. Streptozotocin-induced diabetic DBA/2J mice were treated with vehicle, losartan, doxercalciferol (0.4 and 0.6 microg/kg), or losartan and doxercalciferol combinations for 20 wk. Vehicle-treated diabetic mice developed progressive albuminuria and glomerulosclerosis. Losartan alone moderately ameliorated kidney injury, with renin being drastically upregulated. A similar therapeutic effect was seen with doxercalciferol alone, which markedly suppressed renin and angiotensinogen expression. The losartan and doxercalciferol combination most effectively prevented albuminuria, restored glomerular filtration barrier structure, and dramatically reduced glomerulosclerosis in a dose-dependent manner. These effects were accompanied by blockade of intrarenal renin upregulation and ANG II accumulation. These data demonstrate an excellent therapeutic potential for doxercalciferol in diabetic renal disease and confirm the concept that blockade of the compensatory renin increase enhances the efficacy of RAS inhibition and produces synergistic therapeutic effects in combination therapy.
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PMID:Long-term therapeutic effect of vitamin D analog doxercalciferol on diabetic nephropathy: strong synergism with AT1 receptor antagonist. 1953 71

Hypertension is a major risk factor for the development of cardiovascular disease. Numerous placebo-controlled trials have demonstrated that treatment of hypertension results in substantial reduction of hypertension-related vascular events. The benefit of specific therapies beyond their effect on blood pressure is well established. Losartan is an orally-active, selective, nonpeptide, angiotensin II type 1-receptor antagonist (ARB), and it was the first in this class to be marketed. Several large-scale clinical trials have demonstrated that losartan and other ARBs have benefits in preventing cardiovascular disease. The Losartan Intervention For End point reduction in hypertension (LIFE) study demonstrated improved outcomes with losartan as compared with atenolol-based therapies in hypertensive patients with left ventricular hypertrophy, mainly because of stroke prevention. The Reduction of End points in Non-insulin-dependent diabetes mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study demonstrated that losartan prevented the progression of diabetic nephropathy. In this review, evidence from these and other clinical trials with losartan shall be discussed. The pharmacodynamic and pharmacokinetic properties of losartan are described to explain its mechanisms of action. Among the ARB class, losartan possesses certain unique properties, which may enhance its cardiovascular protective effects. These include an increase of urinary uric acid excretion and antiatherothrombotic properties. Potential future roles for losartan and other ARBs shall be discussed, in addition to emphasizing areas in which evidence is currently lacking or indecisive, including head-to-head comparisons of ARBs and the effects of combining an ARB with angiotensin-converting-enzyme inhibitors.
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PMID:Losartan in cardiovascular disease. 1980 43

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease and a major contributor to morbidity and mortality of diabetic patients throughout the world. Albuminuria is one of the most characteristic functional changes in the early phase of DN. However, many recent studies have shown that there was no clear association between glomerulosclerosis and albuminuria in type 1 and 2 diabetes. DN is a progressive kidney disease caused by angiopathy of capillaries in the kidney glomeruli and is morphologically characterized by progressive expansion of mesangial matrix and thickening of the glomerular basement membrane. Type IV collagen (Col4) is a major component of the extracellular matrix (ECM) in the expanded mesangial matrix. Advanced glycation endproducts (AGEs) produced as the result of hyperglycemia are known to stimulate the production of ECM proteins in mesangial cells, resulting in glomerulosclerosis. Using a yeast one-hybrid screening, Smad1 was identified as a transcriptional regulator of Col4 in AGE-treated mesangial cells. Smad1 also regulated other ECM proteins, such as type I collagen and osteopontin, as well as alpha smooth muscle actin. Moreover, there was a very good correlation between urinary Smad1 levels and the development of mesangial expansion, whereas the correlation between albuminuria and mesangial expansion was not significant in experimental DN models. In addition, urinary Smad1 was revealed to be a good predictor for later onset of morphological changes and to be used to monitor the effect of ARB in DN. In conclusion, urinary Smad1 is expected to be a useful diagnostic biomarker for DN.
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PMID:[Recent progress in understanding the molecular pathogenesis of diabetic nephropathy]. 2147 4

In a meta-analysis that investigated the effects of dietary sodium restriction in diabetes nephropathy, although blood pressure fell, there were significant increases in plasma renin and aldosterone levels. In this article, we hypothesise that in diabetic nephropathy, ACE-I or ARB treatment attenuates any rise in RAS hormones that might result from dietary salt restriction and that the beneficial effects of the salt restriction such as a lower blood pressure outweigh any potentially negative consequences of RAS activation such as a rise in intraglomerular pressure because of the synergistic effects of sodium restriction and RAS antagonist therapy.
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PMID:Low dietary sodium in diabetes nephropathy. 2458 76


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