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 renin-angiotensin system has two roles in clinical hypertension: its vasoconstrictor properties directly govern blood pressure, and its actions on arterial smooth muscle, connective tissue, and endothelial integrity affect cardiovascular prognosis. Additionally, the direct actions of angiotensin II on the function and structure of the heart and renal vasculature influence clinical events. Angiotensin-converting enzyme (ACE) inhibitors have produced functional and clinical outcome benefits in clinical trials of patients with congestive heart failure, systolic dysfunction after myocardial infarction, and diabetic nephropathy. Similar favorable trends have been noted in observational studies in hypertension. Because such enzymes as chymase can substitute for ACE, the ACE inhibitors may not completely block angiotensin II formation, although they enhance bradykinin accumulation and secondarily stimulate nitric oxide and vasodilatory prostaglandins. Angiotensin II receptor blockers (ARB) selectively block the angiotensin II type 1 (AT1) receptor that not only mediates the known effects of angiotensin II but, according to recent reports, might be responsible for sequestering angiotensin II molecules in renal and cardiac cells. Moreover, by increasing plasma concentrations of angiotensin II, the ARB stimulate the unblocked angiotensin II type 2 (AT2) receptors, which-if they exist in meaningful numbers in human hypertension-mediate additional vasodilatory and antiproliferative effects. The contrasting actions of these two classes of drugs might be clinically relevant. For example, they may have additive antihypertensive efficacy; they have differing effects on renal plasma flow; and in a small pilot study of patients with congestive heart failure, the ARB demonstrated an apparent advantage in survival. Ongoing clinical trials will try to determine whether the effects of ARB can equal or even exceed the beneficial effects of ACE inhibitors on cardiovascular prognosis.
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PMID:Interrupting the renin-angiotensin system: the role of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists in the treatment of hypertension. 1061 71

Angiotensin-converting enzyme inhibitors (ACEi) are a class of antihypertensive agents that decrease mortality in congestive heart failure and have established efficacy in the treatment of hypertension and the slowing of established diabetic nephropathy and other proteinuria-associated glomerulonephritides. These drugs have not gained wide acceptance in the treatment of hypertension in renal transplant recipients (RTRs) because of a potential for decreased renal blood flow and glomerular filtration rate associated with a single kidney and concomitant cyclosporine use. Experimental animal models suggest that ACEi may be of benefit in slowing the progression of chronic renal allograft rejection. We undertook a retrospective chart analysis of all RTRs in our institution who had been treated with an ACEi or an angiotensin II (AT II) antagonist, with the objectives of determining the safety, efficacy, and side effect profile of these medications. The minimum follow-up period was 6 months. One hundred seventy-seven of 642 RTRs were prescribed an ACEi or AT II antagonist. Forty-seven patients discontinued therapy, with the most common causes of discontinuation being cough (8 patients) and hyperkalemia (6 patients). The mean arterial blood pressure at each follow-up period was lower than that at the time of initiation of ACEi or AT II antagonist therapy, with a decrease from 92 +/- 12 mm Hg to 86 +/- 9 mm Hg (P < 0.05) after 3 years of treatment. The serum creatinine concentrations did not change throughout the follow-up period. There was a nonsustained increase from the baseline serum potassium of 4.4 +/- 0.5 to 4.6 +/- 0.6 mEq/L at 3 months (P < 0.05), but no further increases in potassium beyond this time. The mean hemoglobin concentration for the cohort did not change, but 13 RTRs given an ACEi for posttransplantation erythrocytosis (PTE) had a decrease in hemoglobin from 17.1 +/- 1.0 g/dL at the start of ACEi therapy to 14.8 +/- 2.2 g/dL at 3 years (P < 0.05). ACEi and AT II antagonists were generally effective antihypertensives, and were safe and well-tolerated agents in this cohort of RTRs. ACEi were also effective in the treatment of PTE.
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PMID:ACE inhibitors and angiotensin II antagonists in renal transplantation: an analysis of safety and efficacy. 1062 May 59

Angiotensin II is the most active hormone of the renin-angiotensin system. In humans, two angiotensin receptors have been identified: AT(1) and AT(2). In adults, most of the effects of angiotensin II are mediated by the AT(1) receptor; the function of the AT(2) receptor is not yet well established. Angiotensin II has both systemic and local paracrine effects. Increased activity of angiotensin II and stimulation of the AT(1) receptor have been linked to the development of several cardiovascular and renal diseases, including hypertension, heart failure, left ventricular hypertrophy, and diabetic nephropathy. Over the past two decades, angiotensin-converting enzymes have been used to manage these diseases. However, the side effects and less-than- maximum therapeutic effects of angiotensin-converting enzyme inhibitors, particularly in the decrease of mortality associated with congestive heart failure, have led to the development of AT(1)-receptor blockers.
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PMID:Mechanism of action of angiotensin-receptor blocking agents. 1098 Oct 80

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

Cyclooxygenase-2 (COX-2) is constitutively expressed in the macula densa of several laboratory animal species where it is considered to play a physiologic role in the regulation of basal renal function. Pertubations to normal homeostasis is shown to be associated with the upregulation of COX-2 in the macula densa of rats and dogs. In contrast, COX-2 has not been detected in the macula densa of normal adult human and non-human primate kidneys, suggesting a less prominent role of this isoform in normal renal function in these species. In this study, we characterized COX-2 expression in human kidneys collected from subjects with a clinical history indicative of compromised renal function associated with diabetic nephropathy (DN), hypertension, and congestive heart failure (CHF). COX-2 expression was evaluated by immunohistochemistry using isoform-specific antibodies and in situ hybridization. No COX-2 protein or mRNA was observed in the macula densa of normal kidneys (n= 11), whereas slight to moderate COX-2 expression was present in the macula densa of 7/15 subjects (46%) with DN, 5/11 (46%) subjects with hypertension, and 3/10 subjects (30%) with CHF. These results indicate that COX-2 is variably induced in the macula densa of the human kidney in compromised renal conditions and that COX-2-mediated prostaglandins may be involved in maintaining adequate renal functions in some patients with DN, hypertension, and CHF. This variability may be related to individual clinical status or synthesis of vasodilatory prostaglandins by cyclooxygenase-1 (COX-1).
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PMID:Expression of cyclooxygenase-2 in the macula densa of human kidney in hypertension, congestive heart failure, and diabetic nephropathy. 1149 48

Familial aggregation of end-stage renal disease (ESRD) is frequently observed in the common causes of kidney failure. It is unknown whether the clinical course of nephropathy differs based on an individual's family history of ESRD. The ESRD Network 6 Family History of ESRD database was analyzed to compare dialytic survival among patients with first- or second-degree relatives on dialysis therapy (positive family history) with those lacking relatives with ESRD (negative family history). Study participants included 3,442 adult, black or white, incident patients with ESRD who initiated dialysis therapy in ESRD Network 6 facilities in 1995 and participated in the Network-sponsored Family History of ESRD study. All deaths were reported to the Network and used to calculate mortality rates. The relative risk for death was used to compare rates between levels of patient characteristics. Multivariate analyses used proportional hazards regression. Overall, 730 patients (21.2%) had a positive family history of ESRD. Black patients, those who were younger at the onset of ESRD, patients with greater degrees of functional status, and women were more likely to have a positive family history. During 9,000 patient-years of follow-up, 1,599 patients died (17.8 deaths/100 dialysis-years). Univariate analyses showed that patients with a positive family history of ESRD had 20% lower mortality than those with a negative family history of ESRD (relative risk, 0.80; 95% confidence interval, 0.7 to 0.9; P = 0.001). Older age, white race, diabetic nephropathy, lower functional status, lower serum albumin level, congestive heart failure, and ischemic heart disease also were associated with greater mortality rates. Multivariate analyses showed that only older age at onset of ESRD, white race, low functional status, ESRD caused by diabetes, and congestive heart failure were associated with increased mortality. A family history of ESRD in either first- or second-degree relatives was no longer a significant determinant of survival. We conclude that familial clustering of ESRD does not significantly impact on dialytic survival after controlling for the competing effects of patient race, age of ESRD onset, and the presence of diabetes mellitus.
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PMID:Family history of end-stage renal disease does not predict dialytic survival. 1153 87

A prospective, randomized, three-armed, double-blind, placebo-controlled clinical trial has been completed in 210 sites worldwide to determine whether the angiotensin II receptor blocker irbesartan or the calcium channel blocker amlodipine has a renoprotective effect in patients with overt type 2 diabetic nephropathy. A total of 1,715 subjects randomized during a 3-year period were followed a minimum of 2 years. The goal for all treatment groups was to achieve equivalent blood pressure control, with the blinded study drug (irbesartan, amlodipine, or placebo) as primary therapy with additional antihypertensive drugs, excluding angiotensin-converting enzyme inhibitors, calcium antagonists, and angiotensin II receptor antagonists, to achieve seated systolic blood pressure less than 135 mm Hg and diastolic blood pressure less than 85 mm Hg. The primary outcome was the combined endpoint of time to doubling of entry serum creatinine, end-stage renal disease, or death. Secondary outcomes included fatal and nonfatal cardiovascular events. A Clinical Management Committee monitored the conduct of the study. An Outcome Confirmation Committee classified all study outcome events in blinded fashion. An external Data Safety Monitoring Committee monitored unblinded data for interim safety and efficacy analyses of the study. Eligibility criteria included informed consent, age 30 to 70 years, adult-onset diabetes, hypertension, urine protein excretion greater than 900 mg/24 hours, and serum creatinine values of 90 to 265 micromol/L in women and 110 to 265 micromol/L in men. Baseline characteristics were age, 59 +/- 8 years; body mass index, 31 +/- 7 kg/m(2); 67% male; 73% white, 14% black, and 13% other; duration of diabetes, 15 +/- 9 years; retinopathy, 66%; neuropathy, 48%; congestive heart failure, 7.5%; screening seated systolic blood pressure, 156 +/- 18 mm Hg, and diastolic blood pressure, 85 +/- 11 mm Hg; urine protein excretion, 4.0 +/- 3.5 g/24 hours; serum creatinine, 150 +/- 53 micromol/L; serum potassium, 4.6 +/- 0.5 mEq/L; total cholesterol, 229 +/- 58 mg/dL; and hemoglobin A(1c), 8.1 +/- 1.7%. This large-scale international trial should help define the clinical course and standards of care for hypertensive adults with type 2 diabetes mellitus and nephropathy. Results available on May 19, 2001, will help in defining the current controversy of the risks and benefits of blockade of the renin-angiotensin system versus calcium channel blockade versus standard antihypertensive therapy in this large patient population.
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PMID:A clinical trial in type 2 diabetic nephropathy. 1157 53

SR121463 is a selective, orally active, non-peptide antagonist of vasopressin (AVP) V(2) receptors with powerful aquaretic properties in various animal species and humans. SR121463 belongs to a new class of drugs, called aquaretics, which are capable of inducing free-water excretion without affecting electrolyte balance. SR121463 displays high affinity for animal and human V(2) receptors and exhibits a remarkably selective V(2) receptor profile. SR121463 and [(3)H]SR121463 are used, therefore, as selective probes for characterization and labeling of V(2) receptors. In various functional studies in vitro, SR121463 behaves as a potent antagonist. It inhibits AVP-stimulated human renal adenylyl cyclase and dDAVP (1-desamino, 8-D arginine-vasopressin)-induced relaxation of rat aorta. SR121463 also behaves as an inverse agonist in cells expressing a constitutively activated human V(2) receptor mutant. In vitro, SR121463 rescued misfolded V(2) AVP receptor mutants by increasing cell surface expression and restoring V(2) function. In normally hydrated conscious rats, dogs and monkeys, SR121463, by either i.v. or p.o. administration, induced a dose-dependent aquaresis with no major changes in urinary Na+ and K+ excretion (unlike classical diuretics). In cirrhotic rats with ascites and impaired renal function, a 10-day treatment with SR121463 totally corrected hyponatremia and restored normal urine excretion. In a model of diabetic nephropathy in rats, SR121463 strongly reduced albumin excretion. SR121463 was also effective at extrarenal V(2) (or V(2)-like) receptors involved in vascular relaxation or clotting factor release in vitro and in vivo. In the rabbit model of ocular hypertension, SR121463 by either single or repeated instillation, decreased intraocular pressure. After acute and chronic administration to rats, dogs or healthy human volunteers, SR121463 was well absorbed and well tolerated. In all species studied the drug produced pronounced aquaresis without any agonist effect. Thus, SR121463 is a potent, orally active and selective antagonist at V(2) receptors with powerful aquaretic properties. It is a useful tool for further exploration of function of renal or extrarenal V(2) receptors. Pure V(2) receptor antagonists are likely to be therapeutically useful in several water-retaining diseases such as hyponatremia, Syndrome of Inappropriate Antidiuretic Hormone secretion (SIADH), congestive heart failure, liver cirrhosis, and other disorders possibly mediated by V(2) receptors (e.g., glaucoma).
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PMID:An overview of SR121463, a selective non-peptide vasopressin V(2) receptor antagonist. 1160 38

The rising incidence of stroke, congestive heart failure (CHF) and end stage renal disease (ESRD) has signalled a need to increase awareness, treatment and control of hypertension. There continues to be a need for effective antihypertensive medications since hypertension is a major precursor to various forms of cardiovascular disease. The renin-angiotensin (AT) aldosterone system (RAAS) is a key component to the development of hypertension and can be one target of drug therapy. Angotensin II (ATII) receptor blockers (ARBs) are the most recent class of agents available to treat hypertension, which work by by inhibiting ATII at the receptor level. Currently, national consensus guidelines recommend that ARBs should be reserved for hypertensive patients who cannot tolerate angiotensin converting enzyme (ACE) inhibitors (ACEIs). ARBs, however, are moving to the forefront of therapy with a promising role in the area of renoprotection and CHF. Recent trials such as the The Renoprotective Effect of the Angiotensin-Receptor Antagonist Irbesartan in Patients with Nephropathy Due to Type 2 Diabetes Trial (IDNT), the Effect of Irbesartan on the Development of Diabetic Nephropathy in Patients with Type 2 Diabetes (IRMA2), and The Effects of Losartan on Renal and Cardiovascular Outcomes in Patients with Type 2 Diabetes and Nephropathy (RENAAL) study have demonstrated the renoprotective effects of ARBs in patients with Type 2 diabetes. The Valsartan Heart Failure Trial (Val-HeFT) adds to the growing body of evidence that ARBs may improve morbidity and mortality in CHF patients. As a class, ARBs are well tolerated and have a lower incidence of cough and angioedema compared to ACEIs. This article reviews the differences among the ARBs, existing efficacy data in hypertension, and explores the role of ARBs in CHF and renal disease.
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PMID:Angiotensin II receptor blockers for the treatment of hypertension. 1182 17

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


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