Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies

BACKGROUND: Proteinuria predicts renal disease progression, and its reduction by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor antagonists (ARA) is renoprotective. METHODS: In this prospective, randomized, cross-over study of 24 patients with nondiabetic, chronic nephropathies, we compared the effects on proteinuria, renal hemodynamics, and glomerular permselectivity of 8 weeks with comparable blood pressure control achieved by benazepril (10 mg/day) and valsartan (80 mg/day) combined therapy with those achieved by benazepril (20 mg/day) or valsartan (160 mg/day) alone. RESULTS: Despite comparable changes in blood pressure and glomerular filtration rate (GFR), combined therapy decreased proteinuria more than benazepril (-56% vs. -45.9%, P=0.02) and valsartan (-41.5%, P=0.002). Changes in urinary protein to creatinine ratio followed the same trend. Filtration fraction and renal vascular resistances (RVR) decreased more with combined (-14.7%,-23.7%) or benazepril (-12.4%, -20.5%) than with valsartan (-2.7%, -12.5%, P < 0.05 vs. both). RVR changes, adjusted for GFR changes, were associated with those in proteinuria (P < 0.05). Changes in glomerular permeability were comparable and did not predict different changes in proteinuria in the three groups. CONCLUSION: At comparable blood pressure, combined ACEi and ARA decreased proteinuria better than ACEi and ARA. The greater antiproteinuric effect most likely depended on an ACEi-related hemodynamic effect, in addition to glomerular size selectivity amelioration. Long-term combined ACEi and ARA therapy may be more renoprotective than treatment with each agent alone.     

Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy

The benefit of angiotensin-converting enzyme (ACE) inhibitor (i) therapy in diabetic glomerulosclerosis is thought to be largely the result of attenuation of angiotensin II (AngII) effects on blood pressure, glomerular hemodynamics and hypertrophy, and tissue fibrosis. The present study was undertaken to determine whether the addition of AngII receptor antagonist therapy to ACEi therapy in diabetic nephropathy results in attenuation of AngII effects beyond that achieved by ACEi therapy alone. Seven patients were studied as inpatients on the General Clinical Research Center each for 3 consecutive weeks as follows: week 1, the patients' usual regimen which included daily oral moderate to high dose ACEi therapy; week 2, the patients' usual regimen plus oral losartan (an antagonist (a) of the angiotensin type 1 receptor, AT1) 50 mg (n = 3) or 100 mg (n = 4) daily; week 3, return to the patients' usual regimen. Diet, physical activity, and blood glucose were held as constant as possible during the three weeks of daily testing. We found that plasma renin levels increased significantly during combination therapy and then returned to baseline values with discontinuation of AT1a therapy: mean baseline renin values (week 1) 3.0 ng/ml/min +/- 1.1 SE, mean renin values during combination therapy (week 2) 7.0 ng/ml/min +/- 3.2 (p = 0.0078 by Wilcoxon rank sum test), mean renin values after discontinuation of AT1a therapy (week 3) 3.9 ng/ml/min +/- 2.0 (NS compared to baseline values). In addition, 2 patients developed transient hypotension when losartan therapy was initiated. During this short-term study, 24-hour proteinuria, serum creatinine, serum potassium, and plasma aldosterone were not changed significantly by combination therapy. We conclude that in patients with diabetic nephropathy addition of AT1a therapy to ACEi therapy attenuates AngII effects better than ACEi therapy alone. We suggest that combination therapy for the management of diabetic glomerulosclerosis merits further investigation.     

ACE inhibitor or angiotensin II receptor antagonist attenuates diabetic neuropathy in streptozotocin-induced diabetic rats

ACE inhibition and/or blocking of the angiotensin II receptor are recognized as first-line treatment for nephropathy and cardiovascular disease in diabetic patients. However, little information is available about the potential benefits of these drugs on diabetic neuropathy. We examined vascular and neural activity in streptozotocin-induced diabetic rats that were treated for 12 weeks with enalapril, an ACE inhibitor, or L-158809, an angiotensin II receptor blocker. A prevention protocol (group 1) as well as three intervention protocols (treatment was initiated after 4, 8, or 12 weeks of diabetes [groups 2, 3, and 4, respectively]) were used. Endoneurial blood flow and motor nerve conduction velocity (MNCV) were impaired in all groups of untreated diabetic rats. In group 1, treatment of diabetic rats with enalapril or L-158809 partially prevented the diabetes-induced decrease in endoneurial blood flow and MNCV. In groups 2-4, intervention with enalapril was more effective in reversing the diabetes-induced impairment in endoneurial blood flow and MNCV than L-158809. The superoxide level in the aorta and epineurial arterioles of diabetic rats was increased. Treatment of diabetic rats with enalapril or L-158809 reduced the superoxide level in the aorta in all groups but was less effective in epineurial arterioles. Acetylcholine and calcitonin gene-related peptide (CGRP) cause vasodilation in epineurial arterioles of the sciatic nerve, which was impaired by diabetes. Treatment of diabetic rats (all groups) with enalapril or L-158809 completely prevented/reversed the diabetes-induced impairment in CGRP-mediated vascular relaxation. Treatment with enalapril or L-158809 was also effective in improving impaired acetylcholine-mediated vasodilation, but the efficacy was diminished from groups 1 to 4. These studies suggest that ACE inhibitors and/or angiotensin II receptor blockers may be effective treatments for diabetes and vascular and neural dysfunction. However, the efficacy of these treatments may be dependent on when the treatment is initiated.     

ACE inhibitor and angiotensin type I receptor antagonist in combination reduce renal damage in obese Zucker rats

BACKGROUND: In this study, we evaluated whether a combination of an angiotensin-converting enzyme (ACE) inhibitor, benazepril (B), with an angiotensin type I receptor antagonist (AT1RA), irbesartan (I), is as effective or more than drugs as monotherapy in controlling renal damage in obese Zucker rats (OZR), a model of metabolic syndrome. METHODS: During six months, G1 (OZR receiving no treatment); G2 (OZR with B 10 mg/kg/day); G3 (OZR with I 50mg/kg/day); and G4 (OZR with B 5mg/kg/day + I 25 mg/kg/day). Kidneys were processed for light microscopy (LM) and immunohistochemistry, including antibodies against interstitial alpha-smooth-muscle-actin (alpha-SMA), plasminogen activator inhibitor-1 (PAI-1), transforming growth factor-beta(1)(TGF-beta 1), and collagen (COL) I, III, and IV. RESULTS: All treated groups presented similar reduction in blood pressure compared with untreated OZR. However, animals from G4 (B + I) showed better control on proteinuria together with a higher creatinine clearance. Additionally, G4 showed a significant (P < 0.05) lower kidney weight; smaller glomerular area; lower glomerulosclerosis score; lower percentage of tubular atrophy, interstitial fibrosis, and interstitial alpha-SMA; lower tubular PAI-1 score; lower percentage of COL I, III, and IV in renal interstitium; and lower wall/lumen ratio in renal vessels, when compared with the other groups. OZR treated with B and/or I showed a better outcome (P < 0.01) in the carbohydrate and lipid metabolism in comparison with untreated OZR. CONCLUSION: These results suggest that combined therapy using B and I is more effective than therapy with either drug at monotherapy for controlling renal damage in this animal model. In addition, data presented here reaffirm the benefit of interacting against renin-angiotensin-system (RAS) in the metabolic syndrome.     

Effects of the combination of an angiotensin II antagonist with an HMG-CoA reductase inhibitor in experimental diabetes

BACKGROUND: Angiotensin II type 1 (AT1) receptor antagonists and 3-hydroxy-3-methylglutaryl conenzyme A (HMG-CoA) reductase inhibitors have been shown to confer renoprotection. However, the renal effects of the combination of an AT1 receptor antagonist and an HMG-CoA reductase inhibitor in experimental diabetes are unknown. METHODS: Diabetes was induced by injection of streptozotocin in Wistar rats. Diabetic rats were randomly treated with losartan, an AT1 receptor antagonist, or simvastatin, an HMG-CoA reductase inhibitor, as well as the combination of both for eight weeks. Albumin excretion rate (AER) and plasma concentrations of blood urea nitrogen (BUN), creatinine, cholesterol, and triglycerides were measured. Renal injury was evaluated. Immunohistochemical staining of transforming growth factor beta1 (TGF beta 1) and vascular endothelial growth factor (VEGF) were performed. RESULTS: Increased AER in diabetic rats was attenuated by treatment with either losartan or simvastatin and further reduced by the combination of the two. Elevated plasma concentrations of BUN and creatinine were only reduced by the combination. There was no significant difference in plasma concentrations of cholesterol and triglycerides between control and diabetic rats and neither was influenced by losartan or simvastatin. Kidney pathologic injury was attenuated by losartan, but not simvastatin, compared to diabetic animals. Overexpression of TGF beta 1 and VEGF was observed in the glomeruli of diabetic rats and was attenuated by losartan, simvastatin, or the combination of both to a similar level. CONCLUSION: The combination of an angiotensin antagonist with an HMG-CoA reductase inhibitor confers superiority over monotherapies on renal function, as assessed by prevention of albuminuria and rise in plasma BUN and creatinine. However, no advantage of combination therapy was seen with respect to attenuating renal structural injury and renal expression of TGF beta and VEGF in experimental diabetes.     

缬沙坦与贝那普利联用治疗移植肾慢性损伤的远期效果

目的 探讨血管紧张素受体拮抗剂缬沙坦与血管紧张素转化酶抑制剂贝那普利联合应用治疗肾移植患者移植肾慢性损伤的远期效果. 方法非糖尿病患者肾移植术后尿蛋白＞0.5g/d或SCr＞177 mmol/L(＞2 mg/d)32例,随机分2组:①治疗组23例.男9例,女14例.平均40岁.病理诊断慢性移植物肾病(CAN)13例、环孢素中毒3例、肾小球疾病7例.②对照组9例.男4例,女5例.平均35岁.CAN 6例、环孢素中毒1例、肾小球疾病2例.治疗组给予缬沙坦(80mg/d)与贝那普利(20 mg,2次/d)联合治疗3年,对照组未进行此项处理.比较2组患者治疗前后SCr、24 h尿蛋白变化及移植肾生存时间.结果 随访3年后,治疗组SCr为(252.2±117.9)mmol/L,对照组为(375.3±203.0)mmol/L,2组比较差异有统计学意义(P＜0.05).治疗组CAN患者SCr为(282.4±147.3)mmol/L,对照组为(528.7±107.8)mmol/L,2组比较差异有统计学意义(P＜0.01).治疗组24 h尿蛋白为(1.0±0.6)g,对照组为(1.3±0.7)g,组问差异无统计学意义(P＞0.05).移植肾存活时间治疗组76个月,对照组为71个月,组间差异无统计学意义(P＞0.05).结论 缬沙坦与贝那普利联合应用可保护移植肾功能,对蛋白尿及移植肾远期存活的影响有待进一步观察.     

ACE inhibitor or angiotensin II receptor blocker use is a risk factor for contrast-induced nephropathy

Background: The aim of the present study was to assess the influence of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) use on the incidence of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography. Methods: A retrospective case control study was conducted on a total of 201 patients divided into 2 groups (CIN group and control group). CIN was defined as an increase in serum creatinine by more than 25% from baseline within 48 hours of radiocontrast exposure. The CIN group had 96 patients, and the control group had 105 patients. The 2 groups were matched for variables such as age, sex, weight, baseline serum creatinine, diabetes, dye load, use of diuretics, statins and preprocedure prophylactic measures for CIN. Results: The incidence of CIN was found to be 4.55%. The CIN group had 96 patients out of which 56 patients (58.3%) were on chronic ACEI or ARB, while the control group had 105 patients, but only 36 of patients (34.3%) were on ACEI or ARB (p<0.001).The odds ratio for development of CIN with respect to ACEI or ARB use was 2.68 (95% confidence interval, 1.51-4.76). Conclusion: Use of ACEI or ARB is an independent risk factor for developing CIN. It is reasonable to discontinue their use 48 hours prior to exposure to radiocontrast agents, especially in patients with multiple risk factors.     

The effect of ACE inhibitor and angiotensin II receptor antagonist therapy on serum uric acid levels and potassium homeostasis in hypertensive renal transplant recipients treated with CsA.

BACKGROUND: The angiotensin II (AT II) type I receptor antagonist losartan has been reported to increase urinary uric acid and potassium excretion. These effects might be beneficial in cyclosporin (CsA)-treated renal transplant recipients, who frequently suffer from hyperuricaemia and hyperkalaemia. METHODS: In this prospective, open, randomized, two-way cross-over study we included 13 hypertensive CsA-treated patients after renal transplantation and administered either the angiotensin-converting enzyme (ACE) inhibitors enalapril or losartan. Laboratory parameters, 24-h urinary protein excretion, and mean 24-h arterial blood pressure (MAP) were checked after 3 weeks treatment with enalapril, after a wash-out period of 2 weeks, and before and after a 3-week treatment course with losartan. RESULTS: Both drugs slightly reduced MAP (losartan from 97+/-6 to 94+/-9 and enalapril to 93+/-8 mmHg). Serum potassium levels significantly increased during enalapril therapy (from 4.3+/-0.5 to 4.8+/-0.4 mmol/l, P<0.05), as did, although not significantly, uric acid concentrations (from 7.8+/-1.9 to 8.2+/-1.8 mg/dl, P=0.5). Losartan, on the contrary, only mildly affected serum potassium (4.3+/-0.5 vs 4.5+/-0.5 mmol/l, P=0.25) and serum uric acid decreased (from 7.8+/-2.4 to 7.3+/-1.8 mg/dl, P=0.6). Serum aldosterone and urinary aldosterone excretion were significantly reduced only during ACE inhibitor treatment, which might explain the variable effects on potassium homeostasis. CONCLUSION: Losartan may be a useful agent to reduce blood pressure and serum uric acid levels in renal transplant recipients treated with CSA: Furthermore, in this high-risk population, the effects on serum potassium levels are less marked with losartan than with enalapril.     

Effects of angiotensin-converting enzyme inhibitor, angiotensin II receptor antagonist and calcium antagonist on urinary podocytes in patients with IgA nephropathy

The urinary podocyte is postulated to be a marker for estimation of the severity of active glomerular injury and a predictor of disease progression in children with glomerulonephritis. Non-dihydropyridine calcium antagonist, including verapamil, reduce proteinuria to an extent similar to that of the angiotensin-converting enzyme inhibitor (ACEI), including trandolapril, but to a greater extent than other antihypertensives. Angiotensin (Ang) II receptor antagonists, including candesartan cilexetil, show potent and long-term preventive effects against the progression of renal injury. The aim of the present study is to assess whether verapamil, trandolapril and candesartan cilexetil affect proteinuria and urinary podocytes in patients with IgA nephropathy. Thirty-two normotensive patients aged 18-54 years with biopsy-proven IgA nephropathy, nonnephrotic proteinuria (1-3 g/day), and normal renal function (creatinine clearance >80 ml/min) were studied. Twenty patients with diffuse mesangial proliferative glomerulonephritis (non-IgA PGN) and 20 healthy controls were also included in this study. The number of urinary podocytes in patients with advanced IgA nephropathy (n = 16) was significantly higher than that in patients with the disease in the mild stage (n = 16) (p < 0.01) or in patients with non-IgA PGN (p < 0.01). Urinary podocytes were not detected in healthy controls. The 32 patients with IgA nephropathy were randomly divided into four treatment groups: those treated with verapamil (120 mg/day, n = 8); those treated with trandolapril (2 mg/day, n = 8); those treated with candesartan cilexetil (8 mg/day, n = 8), and those given a placebo (n = 8). Treatment continued for 3 months. Antiproteinuric response in the trandolapril group was similar to that in the candesartan cilexetil group (-38 vs. -40%). The action of trandolapril or candesartan cilexetil was greater than that of verapamil (p < 0.01). Reduction in the number of urinary podocytes from baseline was significantly greater in patients treated with trandolapril or candesartan cilexetil than in patients treated with verapamil (p < 0.01). However, there was no difference between patients treated with trandolapril and those treated with candesartan cilexetil. Proteinuria and urinary podocytes were unaffected in the placebo group. These data suggest that urinary podocytes may be a marker of disease activity in adult patients with IgA nephropathy and that trandolapril and candesartan cilexetil are more effective than verapamil in reducing the number of podocytes.     

Additive antiproteinuric effect of angiotensin II receptor antagonist and angiotensin-converting enzyme inhibitor in patients with chronic glomerulonephritis

Angiotensin II type-1 receptor blocker (ARB) and angiotensin-converting enzyme inhibitor (ACEI) have been thought to be effective for reducing proteinuria in patients with chronic glomerulonephritis. Recently, an additive effect of these two types of angiotensin blockers has been reported in patients with IgA nephropathy, but the mechanism responsible for the effect has not yet been determined. In this study, we examined additive effect of these two drugs in chronic glomerulonephritis patients. Ten patients with biopsy-proven primary glomerulonephritis (eight IgA nephropathy patients, two membranous nephropathy patients), non-nephrotic proteinuria (protein, 0.5 to 3.5 g/day) received candesartan cilexetil (2 or 4 mg) for 8 weeks. After the 8 weeks, a combination of perindopril erbumine (1 or 2 mg) and candesartan cilexetil was administered to the patients. Perindopril was stopped after the 8-week administration of the two drugs. Candesartan alone reduced proteinuria by 13%. Combination of these two drugs induced a more remarkable reduction of proteinuria (48%; p < 0.05 vs other periods). The decrease in mean blood pressure by the combination therapy was significantly correlated with the decrease in proteinuria. The combination of drugs also reduced the amount of urinary type-IV collagen excretion. An additive effect of ACEI and ARB on proteinuria and urinary type-IV collagen excretion was recognized in patients with chronic glomerulonephritis.     

Successful treatment of combination therapy using an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker in a patient with IgA nephropathy

A 24-year-old Japanese woman with IgA nephropathy was admitted to our hospital due to the development of proteinuria and pretibial edema while on glucocorticoids and an angiotensin-converting-enzyme(ACE) inhibitor. She had been on both medications for more than 2 years. Urinary protein excretion was 2.53 g/day and renal function laboratory data were within the normal range. Plasma aldosterone concentration was high at 248 pg/ml, with normal plasma renin activity. The renal biopsy specimens showed prominent glomerular hypertrophy. Four weeks after the addition of valsartan, an angiotensin II receptor blocker(ARB), urinary protein excretion was remarkably reduced to 0.6 g/day without adversely affecting blood pressure. During the treatment period, proteinuria was maintained at less than 0.6 g/day and renal function remained normal. We propose that glomerular hypertension caused by insufficient suppression of the renin-angiotensin system was an essential factor underlying the increased urinary protein excretion in this patient. Combination therapy of an ARB and an ACE inhibitor appears to have a beneficial effect in patients with IgA nephropathy patients with persistent glomerular hypertension.     

Long-term treatment with an ACE inhibitor or an AT1 antagonist avoids hypertension-induced inflammation in the kidney

BACKGROUND: Hypertension causes an inflammatory response in the kidney. Many studies have demonstrated that activation of the renal renin-angiotensin system, and therefore an increase in local angiotensin II (AngII) production, participates in the renal inflammatory cell recruitment. Our aim was to investigate the role of AngII blockade in hypertension-induced inflammatory response. METHODS: To replicate chronic hypertension with renal disease, we used a model of spontaneously hypertensive rats with unilateral nephrectomy (UNX-SHR). These animals were studied for 48 weeks. We investigated the effect of long-term treatment with an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II type 1 (AT1 ) antagonist, 2 strategies currently used in humans, on renal proinflammatory parameters. RESULTS:UNX-SHR rats presented elevated renal inflammatory cell infiltration and up-regulation of proinflammatory factors, including activation of nuclear factor chi B (NF-chi B) and related genes. Both ACE inhibition and AT 1 blockade decreased the number of inflammatory cells as well as the up-regulation of proinflammatory factors in the kidney. CONCLUSIONS: These results suggest that either AT 1 blockade or ACE inhibition can stop the renal inflammatory process in chronic hypertension-associated inflammatory response.     

Low-dose angiotensin II receptor antagonists and angiotensin II-converting enzyme inhibitors alone or in combination for treatment of primary glomerulonephritis

OBJECTIVE: The renin-angiotensin system is thought to be involved in the progression of chronic renal diseases of both diabetic and non-diabetic origin. It has been confirmed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) reduce urinary protein excretion and attenuate the development of renal injury. Clinical data comparing the renal effects of ACEIs and ARBs, either singly or in combination, are scarce and usually concern the use of standard or high doses. MATERIAL AND METHODS: This was a prospective, randomized, 9-month study of the effects of low doses of losartan (25 mg; n = 18) versus enalapril (10 mg; n = 18) versus the combination of losartan (25 mg) and enalapril (10 mg) (n = 16) on proteinuria, kidney function and metabolic profile in 54 patients with biopsy-proven chronic glomerulonephritis, hypertension and normal or slightly impaired kidney function. The clinical evaluation and laboratory tests were performed before treatment (baseline) and after 3 and 9 months of therapy. RESULTS: After 3 months, significant decreases in proteinuria were observed in all groups: losartan, 22.6% (p = 0.02); enalapril, 43% (p = 0.012); and combined therapy, 63% (p = 0.001). This anti-proteinuric effect was even greater after 9 months of therapy: losartan, 44.2% (p = 0.02); enalapril, 49.6% (p = 0.02); and combined therapy, 51% (p = 0.003). There was no significant difference between losartan and enalapril with respect to their impact on proteinuria level. Proteinuria reduction was significantly greater in patients receiving combined therapy in comparison with losartan treatment after 3 months of therapy (p = 0.02). Creatinine clearance and serum creatinine were stable during the entire study period in all patients. No significant changes in lipids, serum uric acid or protein levels were observed. CONCLUSIONS: These results indicate that proteinuria is reduced by low doses of losartan or enalapril. The combination of these drugs seems to be beneficial and may offer an additional renoprotective effect. This needs to be confirmed in a study with a larger sample size.     

Treatment of diabetic nephropathy with angiotensin II receptor antagonist

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. Received: October 18, 2002 / Accepted: December 17, 2002 Correspondence to:E.J. Lewis