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We evaluated the long-term changes on overt proteinuria induced by dual blockade of the renin–angiotensin system (RAS). Dual blockade was produced by adding an angiotensin II receptor blocker (ARB) to treatment with maximal recommended doses of an angiotensin converting enzyme (ACE) inhibitor in proteinuric patients. A total of 28 patients (19 men and 9 women) with proteinuria higher than 1 g/24 h were enrolled in this trial of treatment with the ARB candesartan (from 4 up to 32 mg daily) added to existing treatment with an ACE inhibitor. At 6, 12, 24, and 36 months, we evaluated proteinuria in 24-h urinary collections, office blood pressure (BP), plasmatic creatinine (Cr), serum potassium (K), and 24 h urine collection creatinine clearance (CrC). During monoblockade of the RAS by ACE inhibitor treatment, albuminuria was 2.94 ± 1.92 mg/24 h; BP was 137/76 mmHg; K+ was 4.8 ± 0.5 mmol/l, Cr was 1.76 ± 0.67 mg/dL, and CrC was 62 ± 31.9 mL/min. After 6 months, dual blockade of the RAS albuminuria was 2.18 ± 2.29 mg/24 h ( P < 0.01 vs. baseline) and BP was 133/75 mmHg (not significant). At 36 months, albuminuria was 2.21 ± 2.20 mg/24 h ( P < 0.05 vs. baseline); BP was 133/73 mmHg (not significant). CrC was not changed along the follow up. A small increment of Cr was detected at 24 months (2.11 ± 1.06 mg/mL, P < 0.05). The antiproteinuric effect of dual renin–angiotensin system blockade combining candesartan and ACE inhibitors remain after 36 months without losing its initial effect. Blood pressure changes seem not to explain this long-term antiproteinuric effect. [ABSTRACT FROM AUTHOR]

Dual blockade of the renin–angiotensin system (RAS) has increased antiproteinuric effects and so a higher incidence of secondary effects can be expected when this kind of treatment is administered. The aim of this study was to assess the safety of dual blockade of RAS. Seventy-five (54 men and 21 women) patients has been treated in our unit with dual RAS blockade due to proteinuria higher than 1 g/24 h. Mean age was 57.1 ± 14.0 years. Fifty-three patients had chronic renal failure (CRF) at baseline. Analytical data of 6 months visit and last follow-up visit were recorded. A small reduction of systolic blood pressure and diastolic blood pressure was observed in both treatment groups throughout the study. Neither the CRF patients nor those with normal renal function showed any reduction in mean plasma haemoglobin levels, but differences between groups were significant at the second and third visits (anova). No change was detected in haematocrit. Mean K+ significantly increase at the second visit in the CRF group (from 4.80 ± 0.64 to 5.23 ± 0.81 mmol/l, p < 0.001, Student's t-test). There were no changes in normal kidney function group (4.58 ± 0.37 vs. 4.63 ± 0.44). At baseline plasmatic creatinine was higher in the CRF group (2.09 ± 0.60 0.20 mg/dl vs. 0.99 ± 0.20 mg/dl, p < 0.001, Student's t-test) and creatinine clearance was lower (48.6 ± 20.7 ml/min vs. 107.0 ± 0.30 ml/min, p < 0.001, Student's t-test). There was a small increase in creatinine along the follow-up when compared with the normal renal function group (p < 0.001,anova). Conversely, creatinine clearance remain unchanged in the normal renal function group, and there was a decrease in creatinine in CRF patients (p < 0.001). Dual RAS blockade seems to be safe in renal patients even when mild to moderate renal failure is present. Severe hyperkalaemia is uncommon. Small increments in plasmatic creatinine can be seen but they are hardly dangerous. Combined treatment does not significantly influence erythropoiesis. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy is a major cause of diabetes related morbidity and mortality. The first part of the current review was published in the last issue of this journal and discussed the impotant role of the renin-angiotensin system (RAS) in diabetic nephropathy and the genetic influence on development of end-stage renal disease (ESRD) in diabetic patients. This second part of the review focus on the potential improvement of the current treatment strategy to slow down the loss of kidney function using dual blockade of the RAS with both ACE-inhibitors (ACE-I) and angiotensin II receptor blockers (ARBs). Substantial evidence from short-term studies using surrogate endpoints indicates a beneficial impact of dual blockade of the RAS, not obtainable with single agent blockade alone, both in diabetic and non-diabetic renal disease. This conclusion has been confirmed and extended in a longterm trial with regard to prevention of ESRD in non-diabetic renal disease. Results indicate that dual blockade of the RAS may further slow down, but not arrest progressive loss of renal function. However, studies defining the optimal dose of ACE-I / ARBs without additional adverse effects are essential to ensure relevant comparison with dual blockade therapy. Trials using primary renal endpoints in diabetic nephropathy are still needed, and will finally establish the role of dual blockade of the RAS in a clinical setting. [ABSTRACT FROM PUBLISHER]