Preventing microalbuminuria in type 2 diabetes.

BACKGROUND: The multicenter double-blind, randomized Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) was designed to assess whether angiotensin-converting-enzyme inhibitors and non-dihydropyridine calcium-channel blockers, alone or in combination, prevent microalbuminuria in subjects with hypertension, type 2 diabetes mellitus, and normal urinary albumin excretion. METHODS: We studied 1204 subjects, who were randomly assigned to receive at least three years of treatment with trandolapril (at a dose of 2 mg per day) plus verapamil (sustained-release formulation, 180 mg per day), trandolapril alone (2 mg per day), verapamil alone (sustained-release formulation, 240 mg per day), or placebo. The target blood pressure was 120/80 mm Hg. The primary end point was the development of persistent microalbuminuria (overnight albumin excretion, > or =20 microg per minute at two consecutive visits). RESULTS: The primary outcome was reached in 5.7 percent of the subjects receiving trandolapril plus verapamil, 6.0 percent of the subjects receiving trandolapril, 11.9 percent of the subjects receiving verapamil, and 10.0 percent of control subjects receiving placebo. The estimated acceleration factor (which quantifies the effect of one treatment relative to another in accelerating or slowing disease progression) adjusted for predefined baseline characteristics was 0.39 for the comparison between verapamil plus trandolapril and placebo (P=0.01), 0.47 for the comparison between trandolapril and placebo (P=0.01), and 0.83 for the comparison between verapamil and placebo (P=0.54). Trandolapril plus verapamil and trandolapril alone delayed the onset of microalbuminuria by factors of 2.6 and 2.1, respectively. Serious adverse events were similar in all treatment groups. CONCLUSIONS: In subjects with type 2 diabetes and hypertension but with normoalbuminuria, the use of trandolapril plus verapamil and trandolapril alone decreased the incidence of microalbuminuria to a similar extent. The effect of verapamil alone was similar to that of placebo.

Diverse effects of increasing lisinopril doses on lipid abnormalities in chronic nephropathies.

BACKGROUND: Dyslipidemia frequently complicates chronic nephropathies and increases the risk of renal and cardiovascular events. This might be ameliorated by drugs, such as angiotensin-converting enzyme inhibitors, which effectively reduce proteinuria. METHODS AND RESULTS: In this longitudinal study, we evaluated the extent to which uptitration of the ACE inhibitor lisinopril to maximum tolerated doses (median [range]: 30 [10 to 40] mg/d) ameliorated proteinuria and dyslipidemia in 28 patients with nondiabetic chronic nephropathies. Maximum lisinopril doses significantly and safely reduced proteinuria, serum total, LDL cholesterol, and triglycerides without substantially affecting serum HDL and renal hemodynamics. Proteinuria already decreased at 10 mg/d. Serum lipids progressively and dose-dependently decreased during uptitration to maximum doses. Reduction in total and LDL cholesterol correlated with increases in serum albumin/total protein concentration and oncotic pressure, peaked at lisinopril maximum doses, and persisted after treatment withdrawal. Despite less proteinuria reduction, hypercholesterolemia decreased more (and reflected the increase in serum albumin) in hypoalbuminemic than in normoalbuminemic patients who, despite more proteinuria reduction, had less decrease in cholesterol and no changes in serum albumin. Changes in serum triglycerides were independent of changes in serum proteins, were strongly correlated with lisinopril doses (r=-0.89, P=0.003) and recovered promptly after treatment withdrawal. Lisinopril was well tolerated, did not affect renal hemodynamics, and caused symptomatic, reversible hypotension in only two patients. CONCLUSIONS: In chronic nephropathies, angiotensin converting enzyme inhibitor uptitration to maximum tolerated doses safely ameliorated hypertriglyceridemia by a direct, dose-dependent effect, and hypercholesterolemia through amelioration of the nephrotic syndrome, particularly in patients with more severe hypoalbuminemia.

Single Strand Conformation Polymorphism (SSCP) as a quick and reliable method to genotype M235T polymorphism of angiotensinogen gene.

OBJECTIVES: Conflicting results on the relationship between M235T polymorphism of angiotensinogen (AGT) gene and diabetic nephropathy are reported in the literature, probably due to the small number of subjects, to different inclusion criteria and the different genotype analysis methods used. The aim of the present study was to set up a fast, cheap and reliable method to allow the genotyping of M235T polymorphism in a large number of subjects. DESIGN AND METHODS: We developed in our laboratory a new specifically designed PCR-SSCP method for M235T genotyping whose specificity was compared with that of Allele Specific PCR (ASPCR) and Mutagenically Separated PCR (MS-PCR). The exact M235T genotype was estabilished by direct sequencing. The new PCR-SSCP method was then used to genotype a population of 1171 hypertensive, normoalbuminuric type II diabetes mellitus patients. The patients were also genotyped for ACE I/D polymorphism. For comparison a group of hypertensive non diabetic patients (n = 88) were also screened. RESULTS: The PCR-SSCP method identified the M235T polymorphism with no misinterpretation at variance with ASPCR and MS-PCR methods that showed a preferential amplification of the T allele. The rare Y248C polymorphism of the AGT gene was also detected by PCR-SSCP. In diabetic hypertensive patients the prevalence of TT genotype was higher than in normotensive healthy controls and equivalent to that found in hypertensive non diabetic patients. CONCLUSIONS: The PCR-SSCP method for detection of M235T polymorphism is a powerful and sensitive tool for rapid, cheap and efficient screening of a large number of samples. The results obtained with this method demonstrate an association of the TT genotype of AGT gene with hypertension, both in diabetic and non diabetic patients.