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Background. As the incidences of type 2 diabetes (non-insulin dependent diabetes mellitus; NIDDM) and associated nephropathy increase worldwide at epidemic rates, the occurrence of serious renal outcomes such as end-stage renal disease has become a critical burden to patients and health care systems. Methods. The Irbesartan Diabetic Nephropathy Trial (IDNT), Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL), and Losartan Intervention For Endpoint reduction in hypertension (LIFE) trials are reviewed. Results. In the IDNT trial, treatment with irbesartan significantly reduced the composite primary endpoint [doubling of serum creatinine (SCr), end-stage renal disease (ESRD; dialysis, transplantation, or SCr ≥ 6 mg/dl), or death] by 20% compared with placebo ( P = 0.02), and by 23% compared with amlodipine ( P = 0.006). In the RENAAL study, treatment with losartan resulted in a significant risk reduction of 16% in the primary composite endpoint [doubling of SCr, ESRD (dialysis or transplantation), or death]; P = 0.02. In the diabetic subgroup of LIFE, losartan reduced the risk of the primary composite endpoint of cardiovascular morbidity and mortality by 24% ( P = 0.031). The risk of cardiovascular mortality was 37% lower in the losartan group than in the atenolol group ( P = 0.028). These benefits in IDNT, RENAAL, and LIFE appeared to be beyond the blood pressure effect. Conclusions. The findings from recent clinical trials support the use of angiotensin receptor antagonists in patients with nephropathy due to type 2 diabetes, and have shown a significant reduction in the progression towards ESRD (losartan) and proteinuria (losartan, irbesartan), effects that were independent of blood pressure lowering achieved with these agents. Reduction in cardiovascular morbidity and mortality have also been shown in a trial with losartan in diabetics. Collectively, these studies will have worldwide beneficial impact on the treatment of this devastating disease. [ABSTRACT FROM AUTHOR]

Objective: To compare the low-density lipoprotein (LDL) cholesterol-lowering efficacy of low-dose combinations of cholestyramine and fluvastatin.Design: Randomized, double-blind, parallel group, placebo-controlled trial with a 24-week double-blind treatment period divided into three phases.Setting: Office-based clinics.Patients: Hypercholesterolemic, with LDL cholesterol of 4.14 mmol/L or greater (> or = 160 mg/dL) and plasma triglycerides of 3.39 mmol/L or less (< or = 300 mg/dL). Four hundred sixty patients were screened; 224 patients were randomized into a double-blind treatment period; 203 completed the study; 6 dropped out because of adverse events.Intervention: Patients were treated with 10 mg or 20 mg of fluvastatin alone, 8 g or 16 g of cholestyramine alone, or combinations of these fluvastatin and cholestyramine dosages (six treatment groups).Measurements: Changes in lipid variables, particularly LDL cholesterol.Results: The 10-mg and 20-mg fluvastatin monotherapy groups showed considerable reductions in LDL cholesterol initially (-20.1% [SD, 8.8%] and -20.2% [SD, 10.1%], respectively); these reductions were maintained. Reductions in LDL cholesterol that resulted from the addition of cholestyramine, 8 g/d, to 10 mg of fluvastatin and 20 mg of fluvastatin were greater than those observed with monotherapy (10-mg fluvastatin--[10-mg fluvastatin plus cholestyramine], 9.1%; 95% CI, 3.8% to 14.4%) and 20-mg fluvastatin--[20-mg fluvastatin plus cholestyramine], 11.6%; CI, 6.5% to 16.8%). The increase in cholestyramine dose to 16 g/d in the three combination groups provided only a modest additional response.Conclusions: Low-density lipoprotein cholesterol reductions of about 25% to 30% can be achieved with low-dose combination therapy with fluvastatin and cholestyramine. The addition of low-dose resin appears to produce greater overall cholesterol reduction than does a simple doubling of the fluvastatin dosage. The low-dose combination treatment was highly successful in achieving the goals of the National Cholesterol Education Program guidelines. [ABSTRACT FROM AUTHOR]

Objective: To assess the relative effect of different antihypertensive agents on proteinuria and renal function in patients with diabetes.Data Sources: We used MEDLINE and bibliographies in recent articles to identify studies of the effects of antihypertensive agents on renal function in patients with diabetes.Study Selection: We selected 100 controlled and uncontrolled studies that provided data on renal function, proteinuria, or both, before and after treatment with an antihypertensive agent.Data Extraction: Data on blood pressure, renal function, proteinuria, patient characteristics (for example, age, sex, and type of diabetes), and study design (for example, random allocation and the use of a placebo) were extracted from selected studies.Data Synthesis: Multiple linear regression analysis indicated that angiotensin-converting enzyme (ACE) inhibitors decreased proteinuria independent of changes in blood pressure, treatment duration, and the type of diabetes or stage of nephropathy, as well as study design (P < 0.0001). Reductions in proteinuria from other antihypertensive agents could be entirely explained by changes in blood pressure. Blood pressure reduction in itself was associated with a relative increase in glomerular filtration rate (regression coefficient [+/- SE], 3.70 +/- .92 mL/min for each reduction of 10 mm Hg in mean arterial pressure; P = 0.0002); however, compared with other agents, ACE inhibitors had an additional favorable effect on glomerular filtration rate that was independent of blood pressure changes (3.41 +/- 1.71 mL/min; P = 0.05).Conclusion: Angiotensin-converting enzyme inhibitors can decrease proteinuria and preserve glomerular filtration rate in patients with diabetes. These effects occur independent of changes in systemic blood pressure. [ABSTRACT FROM AUTHOR]

Study Objective: To review the rationale for using angiotensin converting enzyme (ACE) inhibitors in progressive renal disease, and to evaluate the experience with these agents in patients with hypertension and renal insufficiency.Data Identification: Experimental and clinical studies published from January 1977 to November 1988 were identified by searching the literature and by extensive hand searching of bibliographies of identified articles.Study Selection: Experimental studies of glomerular function during therapy with ACE inhibitors or other antihypertensive regimens were reviewed. Series using ACE inhibitors for treating hypertensive patients with renal disease were evaluated and reports of adverse events were studied.Results Of Data Synthesis: Experimentally, ACE inhibitors seem to decrease glomerular injury by reducing both systemic and glomerular hypertension. Clinically, ACE inhibitors reduce systemic blood pressure in hypertensive patients with diabetic and nondiabetic renal disease without causing dramatic changes in glomerular filtration rate or renal blood flow. Most studies of nondiabetic renal insufficiency suggest that proteinuria is reduced in most patients. However, no long-term controlled study on the effect of ACE inhibitors on the progression rate of nondiabetic renal disease has been completed. ACE inhibitors have not yet been approved by the Food and Drug Administration (FDA) for treating or preventing progressive renal disease. Such use would therefore be considered "innovative" therapy.Conclusions: ACE inhibitors are tolerated by azotemic patients, although transient reductions in renal function can occur. Patients with bilateral renal insufficiency or low cardiac output are at increased risk for developing reversible acute renal insufficiency. Hyperkalemia may occur, particularly in patients with diabetes or severe renal insufficiency. In many patients with renal disease, ACE inhibitors dramatically reduce proteinuria, but whether they also reduce the rate of progression of renal disease remains unproved. [ABSTRACT FROM AUTHOR]

Legionella pnewnophila has previously been shown to require serum factors for efficient uptake by phagocytic cells. In this investigation, the roles of specific antibody and complement in phagocytosis of L. pneumophila by human polymorphonuclear leucocytes (PMN) and tissue macrophages were deter- mined. Opsonization was assessed by quantitating the uptake of [³H]-label led Legionellae. Compared to other Gram-negative and to Gram-positive bacterial species, L. pneumophila was highly resistant to the opsonic activity of normal pooled human serum (PHS). Of 12 donor sera tested, only four promoted significant L. pneumophila uptake when used at full strength. Experiments with immune antibody, and with human sera deficient in immunoglobulins, or the complement components C2, C3, or C5, revealed that L. pneumophila opsonization was dependent on antibody-mediated activation of the classical complement pathway; activation of the alternative pathway could not be detected. At high concentrations, immune antibody alone could adequately opsonize L. pneumophila. Human alveolar and peritoneal macrophages required very similar amounts and types of opsonins for L. pneumophila phagocytosis as did human PMN. Heating L. pneumophila to temperatures ≧ 80° abolished its resistance to opsonization by diluted PHS; however, activation of complement via the alternative pathway or via other antibody-independent routes remained undetectable. These studies show that, in addition to immune antibody, the classical pathway of complement plays an important role in the opsonization of L. pneumophila. The limited ability of these bacteria to interact with human complement provides a likely explanation for their resistance to opsonization and may be partly based on heat-sensitive structures on the surface of L. pneumophila. [ABSTRACT FROM AUTHOR]