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Query: UMLS:C0033687 (proteinuria)
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This study was undertaken to determine whether angiotensin receptor blockers are as renoprotective as angiotensin-converting enzyme inhibitors in an experimental model of chronic interstitial renal disease. Groups of rats received one of the following treatments for 1 week: (1) enalapril, (2) diltiazem, (3) a cocktail of hydralazine, reserpine, and hydrochlorothiazide, or (4) irbesartan (an AT1 antagonist). The animals were injected with bromoethylamine (200 mg/kg), and antihypertensive treatment continued for 1 month. All drugs were effective in lowering the mean arterial pressure. The bromoethylamine-treated rats developed albuminuria and sustained a 40-50% decrease in creatinine clearance. Enalapril and irbesartan reduced albuminuria, but only enalapril partially prevented the decline in creatinine clearance and lowered the number of ED-1-positive cells. Diltiazem and cocktail had no effect on proteinuria, creatinine clearance, or ED-1 cells. In this experimental model, the effects of enalapril and irbesartan were not identical. Both drugs reduced proteinuria, but enalapril was more effective in protecting the renal function. The fact that the AT1 antagonist protected against albuminuria but did not affect the clearance of creatinine implies that the results seen with angiotensin-converting enzyme inhibition may be in part due to an effect on angiotensin II via AT2 receptor blockade or through an effect on bradykinin.
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PMID:Differential effects of enalapril and irbesartan in experimental papillary necrosis. 1117 5

Hypertension plays a critical role in causing a high rate of cardiovascular events in patients with diabetes mellitus. Large trials show that lowering blood pressure in the patient with diabetes who has hypertension has profoundly favorable effects. This review discusses recent trials to answer the question of how low patients' blood pressure should go and which agents should be used to achieve this goal. The National Institutes of Health's guidelines, published in the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, call for a blood pressure goal of <130/85 mmHg in patients with diabetes. Based on data from the recent trials, an even lower blood pressure of <130/80 mmHg in patients with diabetes and hypertension appears to be appropriate. Observational studies show that the lowest cardiovascular event rate is observed in patients with diabetes whose systolic blood pressure is <120 mmHg. Thus, goal blood pressure in patients with diabetes who have hypertension may need to be revised lower, to <120/80 mmHg. In patients with overt proteinuria of 1 g/d or more, mean arterial pressure of <92 mmHg is recommended. Available evidence justifies the use of angiotensin-converting enzyme (ACE) inhibitors as first-line agents and angiotensin receptor blockers in those patients who are intolerant to ACE inhibitors. Because the blood pressure goal is lower in patients with diabetes who are hypertensive, these patients require the use of multiple agents. Diuretics or long-acting calcium channel blockers are logical second choices because of their synergistic blood pressure reduction effect observed with ACE inhibitors. Alpha-blockers should be used with caution, however. In patients with renal disease, loop diuretics may be required to reduce sodium and volume overload and to improve blood pressure control.
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PMID:Treatment of hypertension in patients with diabetes: lessons from recent trials. 1117 14

Hypertensive nephrosclerosis is a leading cause of end-stage renal disease; therefore, strategies to prevent the development of renal disease require close study. Here it is demonstrated that transient treatment of prepubescent rats with angiotensin inhibitors attenuated their susceptibility to the development of hypertensive nephrosclerosis after maturation. Stroke-prone spontaneously hypertensive Izumo strain rats were divided into four groups, treated with vehicle, the angiotensin-converting enzyme inhibitor (ACEI) delapril (40 mg/kg per d), the angiotensin receptor antagonist (AT1R-Ant) candesartan cilexetil (1 mg/kg per d), or the vasodilator hydralazine (25 mg/kg per d) from weaning to puberty (3 to 10 wk of age), and then monitored without treatment for 6 mo. BP in the ACEI- and AT1R-Ant-treated groups remained significantly decreased, compared with the untreated and hydralazine-treated groups. Moreover, marked proteinuria and nephrosclerosis developed in the untreated and hydralazine-treated groups at 30 wk but were suppressed in the ACEI- and AT1R-Ant-treated groups. Of interest, plasma renin activity, plasma angiotensin II concentrations, and renal renin mRNA levels were reduced by >50% in the ACEI- and AT1R-Ant-treated rats, suggesting that the treatments may have attenuated the development of nephrosclerosis by overcoming the susceptibility of stroke-prone spontaneously hypertensive rats to overactivation of the renin-angiotensin system.
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PMID:Temporary treatment of prepubescent rats with angiotensin inhibitors suppresses the development of hypertensive nephrosclerosis. 1127 26

Hypertension is found among 1 to 6% of young women. Treatment aims to decrease cardiovascular risk, the magnitude of which is less dependent on the absolute level of blood pressure (BP) than on associated cardiovascular risk factors, hypertension-related target organ damage and/or concomitant disease. Lifestyle modifications are recommended for all hypertensive individuals. The threshold of BP at which antihypertensive therapy should be initiated is based on absolute cardiovascular risk. Most young women are at low risk and not in need of antihypertensive therapy. All antihypertensive agents appear to be equally efficacious; choice depends on personal preference, social circumstances and an agent's effect on cardiovascular risk factors, target organ damage and/or concomitant disease. Although most agents are appropriate for, and tolerated well by, young women, another consideration remains that of pregnancy, 50% of which are unplanned. A clinician must be aware of a woman's method of contraception and the potential of an antihypertensive agent to cause birth defects following inadvertent exposure in early pregnancy. Conversely, if an oral contraceptive is effective and well tolerated, but the woman's BP becomes mildly elevated, continuing the contraceptive and initiating antihypertensive treatment may not be contraindicated, especially if the ability to plan pregnancy is important (e.g. in type 1 diabetes mellitus). No commonly used antihypertensive is known to be teratogenic, although ACE inhibitors and angiotensin receptor antagonists should be discontinued, and any antihypertensive drugs should be continued in pregnancy only if anticipated benefits outweigh potential reproductive risk(s). The hypertensive disorders of pregnancy complicate 5 to 10% of pregnancies and are a leading cause of maternal and perinatal mortality and morbidity. Treatment aims to improve pregnancy outcome. There is consensus that severe maternal hypertension (systolic BP > or = 170mm Hg and/or diastolic BP > or = 110mm Hg) should be treated immediately to avoid maternal stroke, death and, possibly, eclampsia. Parenteral hydralazine may be associated with a higher risk of maternal hypotension, and intravenous labetalol with neonatal bradycardia. There is no consensus as to whether mild-to-moderate hypertension in pregnancy should be treated: the risks of transient severe hypertension, antenatal hospitalisation, proteinuria at delivery and neonatal respiratory distress syndrome may be decreased by therapy, but intrauterine fetal growth may also be impaired, particularly by atenolol. Methyldopa and other beta-blockers have been used most extensively. Reporting bias and the uncertainty of outcomes as defined warrant cautious interpretation of these findings and preclude treatment recommendations.
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PMID:Treating hypertension in women of child-bearing age and during pregnancy. 1136 52

Microalbuminuria (MA) is defined as persistent elevation of albumin in the urine, of 30-300 mg/day (20-200 microg/min). These values are less than the values detected by routine urine dipstick testing, which does not become positive until protein excretion exceeds 300-500 mg/day. Use of the albumin-to-creatinine ratio is recommended as the preferred screening strategy for all diabetic patients. MA is measured in spot morning urine obtained from the patient in the office and sent for measurement of both albumin and creatinine. A value above 0.03 mg/mg suggests that albumin excretion is above 30 mg/day and therefore MA is present. MA should be checked annually in everyone, and every 6 months within the first year of treatment to assess the impact in patients started on antihypertensive therapy. MA is an established risk factor for renal disease progression in type 1 diabetes and its presence is the earliest clinical sign of diabetic nephropathy. In addition, a number of studies suggest that MA is an important risk factor for cardiovascular disease and defines a group at high risk for early cardiovascular mortality in both type 2 diabetes and essential hypertension. MA also signifies abnormal vascular permeability and the presence of atherosclerosis. Among nondiabetic patients with essential hypertension, MA is associated with higher blood pressures, increased serum total cholesterol, and reduced serum high-density lipoprotein cholesterol. Thus, taken together these data support the concept that the presence of MA is the kidney's notice to the physician/patient that there is a problem with the vasculature. MA can be reduced, and progression to overt proteinuria prevented, by aggressive blood pressure reduction. The National Kidney Foundation recommends that blood pressure levels be maintained at or below 130/80 mm Hg in anyone with diabetes or renal disease. This should be accomplished with antihypertensive agents that prevent the rise in MA and hence prevent development of proteinuria. Such agents are angiotensin-converting enzyme inhibitors, angiotensin receptor blockers and, to a lesser extent, Beta blockers, non-dihydropyridine calcium antagonists, and diuretics. In summary, the presence of MA is a marker of endothelial dysfunction and a harbinger of markedly enhanced cardiovascular risk. All patients with diabetes and/or hypertension should be screened for the presence of microalbuminuria with use of spot morning urine. To maximize prevention of MA development, the following goals should be instituted: 1) blood pressure should be maintained at less than 130/80 mm Hg and a low-salt, moderate-potassium diet instituted; 2) in diabetics, HbA1c should be kept at less than 7%; 3) in obese patients, a weight loss program should be implemented, with a goal BMI of less than 30; and 4) the physician and patient, working together, should maintain low-density lipoprotein cholesterol at less than 120 mg/dL, and less than 100 mg/dL if diabetes is present. (c)2001 by Le Jacq Communications, Inc.
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PMID:Microalbuminuria: what is it? Why is it important? What should be done about it? 1141 91

The use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor antagonists, or aldosterone antagonists can have important beneficial effects on the progression of renal disease associated with glomerular and interstitial fibrosis, especially if the adverse side effects (eg, hyperkalemia) can be minimized. Because it appears that chronic renal insufficiency and proteinuria may well be cardiovascular risk factors, it is exciting to note that recent large scale epidemiologic studies (Heart Outcomes and Prevention Evaluation [HOPE]) have shown both cardioprotective and renoprotective effects of ACE inhibition. It appears paradoxic that such renoprotective effects are clearly evident in diabetes mellitus in which the plasma renin activity may be suppressed. Even in this setting, it appears that there is activation of the renal angiotensin system(s), and inhibitions of these intrarenal systems are involved in the renoprotective effects of these agents. Recent studies have identified nearly all of the components needed to generate angiotensin II in the renal luminal compartment, and suggest that there may be a direct effect through AT(1) receptors on NaCl transport in the distal nephron. The possibility that the components of this intraluminal renin-angiotensin system may be acutely regulated by variations in dietary salt intake provides an opportunity to better understand the normal maintenance of salt balance. Whether or not inhibition of these pathways is involved in the renoprotective effects of ACE inhibitors and angiotensin receptor antagonists is an important issue to be addressed.
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PMID:Prevention, protection, and the intrarenal renin-angiotensin systems. 1170 7

Type II diabetes and hypertension are two pathologies which are frequently associated in adults, especially in developed countries. All the more so when patients are also obese: obesity is today, and will be in the next future, a true epidemic in these countries. These three pathologies imply a risk for cardiovascular complications much higher than that due to an isolated arterial hypertension. This increased risk is probably due to many factors: hyperglycemia, a dismetabolic syndrome (hyperlipemia, hyperuricemia, thrombophilia, altered Na(+)-H+ membrane exchanges = syndrome X) and hyperinsulinemia which favor atherosclerosis and clinical events. Consequently non-pharmacological and aggressive pharmacological therapy is necessary. Even if the trials done in the last years are questionable and not totally convincing, all researchers agree that lowering blood pressure to normality is the best way to improve prognosis of these patients. Usually for this purpose we need a therapy with more than one drug. Among the antihypertensive drugs, ACE-inhibitors (and perhaps also angiotensin receptor blockers) are preferred, especially in those hypertensives with diabetes who have also microalbuminuria or a frank proteinuria.
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PMID:[Diabetes and arterial hypertension]. 1177 8

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

Type 2 diabetes is the most common cause of end-stage renal disease in the United States, and type 2 diabetes has been shown to be a myocardial infarction equivalent in regard to risk of death from a cardiovascular event. Proteinuria is a surrogate marker for renal disease progression, and although data favor both the angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in reducing proteinuria, data for renal outcomes, such as time to dialysis, only exist for the ARBs, which clearly increase the duration to dialysis. Conversely, ACE inhibitors have overwhelming data that show substantial risk reduction from cardiovascular events and death in people with type 2 diabetes. Similar data on cardiovascular risk reduction are not yet available with ARBs, although two trials of renal disease progression did have cardiovascular endpoints as secondary outcomes. There were no significant differences between the ARB and control group except for first hospitalization with heart failure, where losartan reduced the risk by 32%, but there was a trend, albeit not significant, toward reduction of myocardial infarction. The first information regarding ARB effects on cardiovascular events as primary outcomes will come from the Losartan Intervention for Endpoint (LIFE) Reduction in Hypertension study. Therefore, as of this writing, all patients with type 2 diabetes and no evidence of nephropathy, ie, proteinuria and an elevated creatinine > 1.5 mg/dL, should be placed on an ACE inhibitor for cardiovascular risk reduction. If nephropathy is present, the evidence would support an ARB for therapy in concert with a b-blocker for cardiovascular risk reduction and renoprotection.
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PMID:Angiotensin converting enzyme inhibitors or angiotensin receptor blockers in nephropathy from type 2 diabetes. 1200 99

The treatment of hypertension is proven to reduce cardiovascular and renal risk. Combination drug therapy is becoming recognized as a necessity in most patients with hypertension and kidney disease. Allegations about the safe use of calcium antagonists in patients with kidney disease have led to questions and confusion about their use in this common condition. This article reviews the cardiovascular and renal safety of the long-acting calcium antagonists from studies comparing calcium antagonists with placebo and with angiotensin converting enzyme inhibitors or angiotensin receptor blockers in patients with kidney disease and hypertension. Patients with proteinuria and kidney disease should have their blood pressure brought as close to target (< 130/80 mm Hg) as possible for cardiovascular and renal protection. Lowering blood pressure in this setting will require an average of three antihypertensive agents. In patients with hypertension and proteinuria, angiotensin converting enzyme inhibitors or angiotensin receptor blockers must be part of the regimen, and calcium antagonists are safe and effective in this condition when used with them in combination.
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PMID:The use of calcium antagonists in the treatment of hypertensive persons with kidney disease. 1200

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