Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diabetic nephropathy is one of the most frequent causes of end-stage renal disease (ESRD), and, in recent years, the number of diabetic patients entering renal replacement therapy has dramatically increased. The magnitude of the problem has led to numerous efforts to identify preventive and therapeutic strategies. In normoalbuminuric patients, optimal glycemic control (HbA(1c) lower than 7.5%) plays a fundamental role in the primary prevention of ESRD [weighted mean relative risk reduction (RRR) approximately 37% for metabolic control versus trivial renoprotection for intensive anti-hypertensive therapy or ACE-inhibitors (ACE-I)]. In the microalbuminuric stage, strict glycemic control probably reduces the incidence of overt nephropathy (weighted mean RRR approximately 50%), while blood pressure levels below 130/80 mmHg are recommended according to the average blood pressure levels obtained in various studies. In normotensive patients, ACE-I markedly reduce the development of overt nephropathy almost regardless of blood pressure levels; in hypertensive patients, ACE-I are less clearly active (weighted mean RRR approximately 23% versus other drugs), whereas angiotensin-receptor blockers (ARB) appear strikingly renoprotective. Once overt proteinuria appears, it is uncertain whether glycemic control affects the progression of nephropathy. In type 1 diabetes, various anti-hypertensive treatments, mainly ACE-I, are effective in slowing down the progression of nephropathy; in type 2 diabetes, two recent studies demonstrate that ARB are superior to conventional therapy or calcium channel blockers (CCB). In clinical practice, pharmacological tools are not always used to the best benefit of the patients. Therefore, clinicians and patients need to be educated regarding the renoprotection of drugs inhibiting the renin-angiotensin system (RAS) and the overwhelming importance of achieving target blood pressure.
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PMID:Treatment of diabetic nephropathy in its early stages. 1267 78

Angiotensin receptor blockers (ARBs) have gained widespread use in clinical medicine during the past decade. Several large, prospective and randomized multi-center trials have led us to reconsider the role of ARBs in the treatment of hypertension. Firstly, in view of the favorable safety and side effect profile of ARBs, we recommend their use in hypertensive subjects in whom ACE inhibitors are indicated but are unable to tolerate agents of this type due to intractable cough. Secondly, in light of the results of the RENAAL and IDNT studies, we consider ARBs as the drug of choice in diabetic subjects with hypertension and proteinuria (> 300 mg/L). Thirdly, we view ACE inhibitors and ARBs as equally adequate for the treatment of diabetic patients with hypertension and microalbuminuria and recommend the use of the maximal allowable doses of these drugs in such patients. Finally, older hypertensive individuals with left ventricular hypertrophy should receive either ACE inhibitors or ARBs, as these drug classes presently appear to provide better overall protection than beta blockers or calcium channel blockers in this particular subgroup of patients.
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PMID:[Standpoint on the use of angiotensin receptor blockers in the treatment of hypertension]. 1275 85

Combination therapy with angiotensin receptor antagonist(ARB) plus angiotensin converting enzyme inhibitor(ACE-I) (ARB/ACE-I) was efficacious in reducing proteinuria in patients with progressive renal disease. However, this therapy may be associated with the worsening of anemia and hyperkalemia. The present study addressed whether or not triple therapy with low-dose ARB, low-dose diuretic (D) and calcium channel blocker(CCB) (ARB/D/CCB) is as effective as therapy with low-dose ARB/ACE-I in retarding the progression of overt diabetic nephropathy. In the triple therapy, the patients were initially subjected to monotherapy with CCB for 24 weeks. Low-dose ARB and low-dose D were added to the treatment for an additional 24-week period. In parallel, patients undergoing double therapy were initially treated with low-dose ACE-I alone for 24 weeks, and then low-dose ARB was added for an additional 24-week period. The results were as follows: 1) In the triple therapy, blood pressure was reduced by 9 mmHg in systole and 5 mmHg in diastole (not significant) compared to monotherapy with CCB. There was a significant decline in proteinuria (3.3 +/- 1.2 g/day in the CCB-treated period vs. 2.1 +/- 1.0 g/day in the ARB/D/CCB-treated period, n = 12, p = 0.0143). Furthermore, a significant improvement in the slope of reciprocal serum creatinine concentration(1/Cr) was found in response to triple therapy(1/Cr: -0.0118 +/- 0.0009 in the CCB-treated vs. -0.0035 +/- 0.0028(I/mg/dl/month) in the ARB/D/CCB-treated period, n = 12, p < 0.001). There was neither a worsening of anemia nor an increase in the serum potassium(K) concentration. 2) In the double therapy, blood pressure was reduced by 12 mmHg in systole(p = 0.0079, n = 11) and 6 mmHg in diastole(n = 11, p = 0.0037) compared to the monotherapy with ACE-I. A significant improvement in the slope of 1/Cr was found in the double therapy(1/Cr: -0.0095 +/- 0.0052 in the ACE-I treated period vs. -0.0029 +/- 0.0028(I/mg/dl/month) in the ARB/ACE-I, n = 11, p < 0.001). In addition, there was a substantial reduction in hematocrit and increase in serum K concentration. The present result suggests that triple therapy consisting of ARB/D/CCB is as efficacious as double therapy with ARB/ACE-I in protecting the kidney from the progression in patients with diabetic overt nephropathy. The former may be expected to have less adverse effects.
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PMID:[Renoprotective effect of triple therapy with low-dose angiotensin receptor blocker, low-dose diuretic and Ca-antagonist in hypertensive type 2 diabetic patients with overt nephropathy]. 1280 73

Arterial hypertension (AH) per se is, together with diabetes mellitus, the most important cause of renal failure and of dialysis in the western world. AH is also a well known consequence of chronic renal disease, and at the same time one of the main factors which causes diabetic and/or non-diabetic chronic renal failure progression. AH is mostly registered in patients with focal segmental glomerulosclerosis and with membranoproliferative glomerulonephritis. The pathophysiology and the mechanism of AH within primary glomerular diseases are complex, including activation of the sympathetic nervous system, the renin-angiotensin system (RAS), sodium retention, volume expansion and decreased synthesis of vasodilatatory substances. As autoregulation of glomerular pressure in chronic glomerular disease is disturbed, the increment in systemic blood pressure leads to the rise in glomerular pressure. Glomerular hypertension results in glomerular capillary wall stretch, endothelial damage and a rise in protein glomerular filtration. These processes, in turn, cause changes of mesangial and proximal tubular cells, ultimately resulting in the replacement of functional by non-functional connective tissue and the development of fibrosis. One of the most important factors in the progression of chronic renal failure is activation of the RAS. Its effect is not only elevated blood pressure, but also the promotion of cell proliferation, inflammation and matrix accumulation. Many studies, first in experimental animals and later in humans, have shown that the lowering of blood pressure (and proteinuria) is associated with a slower progression of kidney disease. It seems that angiotensin-converting enzyme inhibitors (ACEIs) are more renoprotective than other antihypertensives (the protection beyond the antihypertensive effect), although some studies have also confirmed a comparatively beneficial effect of non-dihydropiridine calcium channel blockers (CCBs) and angiotensin II receptor blockers (ARBs). Moreover, it seems that a combination of antihypertensives (e.g. ACEI + CCB, ACEI + ARB) has a more effective action than either of the drugs alone. However, the effects depend first on the degree of blood pressure reduction. According to comprehensive studies, the achievement of adequate blood pressure (not higher than 130/85 mmHg) is the most important factor. An even lower blood pressure (125/75 mmHg) has been suggested as the limit value in patients with proteinuria of >1 g/24 h and in Blacks.
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PMID:The role of arterial hypertension in the progression of non-diabetic glomerular diseases. 1281 64

Outcome studies in diabetic nephropathy have focused on strategies to prevent progression of diabetic nephropathy, the leading cause of ESRD in the United States. Once diabetics develop overt nephropathy, prognosis is poor. Risk factors for diabetic nephropathy are discussed, and include hyperglycemia, hypertension, angiotensin II, proteinuria, dyslipidemia, smoking, and anemia. Major outcomes as well as outcome studies in diabetic nephropathy for patients with microalbuminuria and macroalbuminuria are reviewed. Furthermore, the role of therapy with angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, calcium channel blockers, and mineralocorticoid receptor antagonists as well as selected combination therapy are discussed. Recommendations for therapy with ace inhibitors and angiotensin II receptor blockers are made based on this evidence.
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PMID:Outcome studies in diabetic nephropathy. 1283 94

An interim analysis of the AASK trial at three years demonstrates a renoprotective effect [slower decline in glomerular filtration rate (GFR), delayed onset of significant decrease in GFR, end-stage renal disease (ESRD) or death, and a decrease in urinary protein excretion] of the angiotensin converting enzyme (ACE) inhibitor, ramipril, as compared to the dihydropyridine calcium channel blocker (DHP-CCB), amlodipine, in patients with mild-to-moderate renal insufficiency. The beneficial effect occurred in the presence of similar levels of blood pressure control and was apparent in patients with proteinuric (beyond the threshold of "dipstick positive" proteinuria, 300 mg/day) and non-proteinuric hypertensive nephrosclerosis. At the time of the interim analysis, the effectiveness of the beta-blocker metoprolol was not significantly different from that of the ACE inhibitor. The data suggest that DHP-CCBs should be used with caution in the presence of mild-to-moderate renal insufficiency.
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PMID:ACE inhibition is effective and renoprotective in hypertensive nephrosclerosis: the African American Study of Kidney Disease and Hypertension (AASK) trial. 1286 79

Temporary proteinuria occurring after exercise is a common finding, and it is explained predominantly by alterations in renal hemodynamics. In this study, we investigated whether nitric oxide (NO), which is known to have an effect on renal hemodynamics and to increase during exercise, has a role in postexercise proteinuria. In the first step of this study, the effect of acute NO synthase blockage on exercise proteinuria was evaluated. The urinary protein levels in animals that performed acute exhaustive treadmill running exercise were considerably elevated compared with the control animals. Significantly elevated urinary protein levels were also detected in animals that received Nomega-nitro-L-arginine methyl ester before exhaustion, compared with both control and exhausted groups, and mixed-type proteinuria was detected in electrophoresis, as in all exhausted animals. In the second step of the study, a NO donor (isosorbide mononitrate) was given to rats 1 h before exhaustive exercise. Mixed-type proteinuria and the elevation in urinary protein levels that occur as a consequence of exhaustive exercise were prevented by NO donor treatment. Finally, in the third step of our study, a calcium channel blocker (diltiazem), another vasodilator, was applied to the rats 1 h before exhaustive exercise. Urinary protein levels were not different in exhausted rats with or without calcium channel blocker treatment. On the other hand, in both groups, urinary protein levels were higher than in the control group. The tail-cuff blood pressure alterations caused by vasodilator drug applications before exercise were not different for NO donor and calcium channel blocker groups. These results suggest that endogenous NO might prevent the postexercise proteinuria from becoming more severe by affecting hemodynamic changes that occur during exercise.
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PMID:Effect of nitric oxide on exercise-induced proteinuria in rats. 1287 70

Several classes of drugs are used to treat hypertension but how they affect cardiovascular morbidity and mortality in high-risk patients is still under investigation. Recent outcome trials have examined the benefits associated with different levels of blood pressure control or have compared several of the 'newer' classes of antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers, with 'older' drug classes, such as diuretics and beta-blockers. Other trials have compared antihypertensive drugs with placebo. We performed a meta-regression analysis of 30 clinical trials that included a total of 149,407 patients. We based our analysis on summary statistics reported in the literature, and showed that blood pressure gradients accounted for most, if not all, of the differences in outcome in patients with hypertension or at high cardiovascular risk. We also conducted a study in older patients with isolated systolic hypertension and showed that antihypertensive drug treatment starting with the dihydropyridine calcium channel blocker, nitrendipine, reduced the risk of stroke and all cardiovascular complications. In addition, nitrendipine-based blood pressure-lowering therapy decreased the incidence of dementia. In diabetic patients, nitrendipine reduced the risk of proteinuria, decreased total mortality, and markedly improved cardiovascular prognosis. Taken together, these findings emphasize the desirability of tight blood pressure control.
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PMID:What can be expected from optimal blood pressure control? 1292 1

Type 2 diabetes is an ever-growing problem worldwide. Approximately 40% of the patients with type 2 diabetes will develop diabetic kidney disease. In the United States, diabetes has become the most common single cause of endstage renal disease defined by the need for dialysis or transplantation. Patients with type 2 diabetes and diabetic nephropathy have a dramatically increased cardiovascular risk. The Irbesartan Diabetic Nephropathy Trial was designed to determine whether the use of irbesartan or a calcium channel blocker would provide protection against the progression of nephropathy due to type 2 diabetes beyond that attributable to the lowering of blood pressure. In that study, 1715 hypertensive patients with nephropathy due to type 2 diabetes were randomly assigned to irbesartan 300 mg/day or amlodipine 10 mg/day, or placebo. All patients randomized in this trial had more than 900 mg of protein in their urine and serum creatinines between 1.0 mg/dl and 3.0 mg/dl. The target blood pressure was 135/85 mmHg or less in all groups. The primary outcome was time to a combined endpoint of doubling of their baseline serum creatinine concentration, the development of endstage renal disease, or death from any cause. The mean duration of follow-up was 2.6 years. Treatment with irbesartan was associated with a risk of the primary composite endpoint that was 20% lower than that in the placebo group ( P = 0.02) and 23% lower than that in the amlodipine group ( P = 0.006). The risk of doubling of the serum creatinine concentration was 33% lower in the irbesartan group than in the placebo group ( P = 0.003) and 37% lower in the irbesartan group than in the amlodipine group ( P < 0.001). Treatment with irbesartan was associated with a relative risk of endstage renal disease that was 23% lower than that in both other groups. These differences were not accounted for by differences in the blood pressures that were achieved. Proteinuria was reduced on average by 33% in the irbesartan group as compared with 6% in the amlodipine group and 10% in the placebo group. The angiotensin II receptor blocker irbesartan was shown to be effective in protecting against the progression of nephropathy due to type 2 diabetes. In a study done in patients with type 2 diabetes and early nephropathy as manifested by microalbuminuria, 590 hypertensive patients with type 2 diabetes and microalbuminuria were randomized to receive either irbesartan 150 mg/day or irbesartan 300 mg/day and followed for 2 years. The primary outcome in that trial was the time to the onset of diabetic nephropathy, defined by persistent albuminuria in overnight specimens, with a urinary albumin excretion rate that was more than 200 mg/min or at least 30% higher than the baseline level. The irbesartan 150 mg/day group demonstrated a 39% relative risk reduction versus the control group in the development of overt proteinuria. The irbesartan 300 mg/day group demonstrated a highly significant 70% risk reduction versus the control group ( P < 0.001). The albumin excretion rate was reduced in the two irbesartan groups throughout the study (-11% and -38% at 24 months compared with baseline in the irbesartan 150-mg and 300-mg groups, respectively). The albumin excretion rate remained unchanged in the control group. Irbesartan was demonstrated in the above study to be renoprotective, independent of its blood pressure-lowering effect, in patients with type 2 diabetes and microalbuminuria. Thus, irbesartan, an angiotensin receptor blocker, was demonstrated to be significantly renoprotective in patients with type 2 diabetes with either early nephropathy (microalbuminuria) or late nephropathy (proteinuria). The renoprotective effects of irbesartan were above and beyond the effects irbesartan had on systemic blood pressure. Patients with type 2 diabetes and either early or late diabetic nephropathy should be treated with the angiotensin II receptor blocker irbesartan.
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PMID:Treatment of diabetic nephropathy with angiotensin II receptor antagonist. 1458 37

Hypertension continues to be a major public health issue in the world. To combat this problem, many anti-hypertensive drugs have been developed and proven effective at controlling blood pressure in the last half century. In recent decades, antihypertensive drugs have been shown to have cardiovascular benefits beyond the reduction of blood pressure, and the focus has shifted to clarification of these effects. Angiotensin II receptor antagonists and calcium channel blockers are the most widely used antihypertensive drugs in Japan. However, these two classes of drugs have not yet been compared with respect to their efficacy for treating cardiovascular events. The Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial described herein is a prospective, multicenter, randomized, open-label, active-controlled, 2-arm parallel group comparison with a response-dependent dose titration and blinded assessment of endpoints in high-risk hypertensive patients treated with either an angiotensin II receptor antagonist (candesartan cilexetil) or a third-generation calcium channel blocker (amlodipine besilate). The eligibility criteria in this study were 1) age between 20 and 85 years; 2) systolic blood pressure (SBP) > or = 140 mmHg in those below 70 years of age or > or = 160 mmHg in those above 70 years of age or diastolic blood pressure (DBP) > or = 90 mmHg on two consecutive measurements at clinic; and 3) at least one of the following high risk factors for cardiovascular events: a) SBP > or = 2180 mmHg or DBP > or = 110 mmHg on two consecutive visits, b) type 2 diabetes mellitus (fasting blood glucose > or = 126 mg/dl, casual blood glucose > or = 200 mg/dl, HbA1c > or = 6.5%, 2 h blood glucose on 75 g oral glucose tolerance test (OGTT) > or = 200 mg/dl, or current treatment with hypoglycemic therapy), c) history of cerebral hemorrhage, cerebral infarction, or transient ischemic attack until 6 months prior to the screening, d) left ventricular hypertrophy on either echocardiography or ECG, angina pectoris, or history of myocardial infarction until 6 months prior to screening, e) proteinuria or serum creatinine > or = 1.3 mg/dl, and f) symptoms of arteriosclerotic artery obstruction. The therapeutic goals of blood pressure control were set as follows: SBP < 130 mmHg and DBP < 85 mmHg for patients below 60 years of age, SBP < 140 mmHg and DBP < 90 mmHg for those in their 60s, SBP < 150 mmHg and DBP < 90 mmHg for those in their 70s, and SBP < 160 mmHg and DBP < 90 mmHg for those in their 80s. A total of 3,200 patients, equally allocated to each of the two treatment arms, were required based on a two-sided alpha level 0.05 and 90% power. The CASE-J is also the first study to employ the newly developed Automatic Bar Code Data-Capturing/Allocation, Booking & Trial Coding, Data Management (ABCD) system for data collection and management. Enrollment of patients started in September 2001 and ended in December 2002. Follow-up data will be collected every 6 months until December 2005. The CASE-J trial will provide important evidence on the comparative effectiveness of candesartan cilexetil and amlodipine besilate on cardiovascular morbidity and mortality among Japanese. In addition, the use of the ABCD system is expected to contribute to the development of more efficient data management systems for large-scale clinical trials.
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PMID:Candesartan Antihypertensive Survival Evaluation in Japan (CASE-J) trial of cardiovascular events in high-risk hypertensive patients: rationale, design, and methods. 1471 41


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