Distinct time courses of renal protective action of angiotensin receptor antagonists and ACE inhibitors in chronic renal disease. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy. 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. ACE inhibition reduces proteinuria in normotensive patients with IgA nephropathy: a multicentre, randomized, placebo-controlled study. ACEI/ATRA therapy decreases proteinuria by improving glomerular permselectivity in IgA nephritis. Interim evidence of the renoprotective effect of the angiotensin II receptor antagonist losartan versus the calcium channel blocker amlodipine in patients with chronic kidney disease and hypertension: a report of the Japanese Losartan Therapy Intended for Global Renal Protection in Hypertensive Patients (JLIGHT) Study. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Long-term effects of spironolactone on proteinuria and kidney function in patients with chronic kidney disease. [The effects of angiotensin-converting enzyme inhibitor on IgA nephropathy and the influencing factors].
Although the angiotensin receptor antagonist (ARB) shares the angiotensin-II-blocking activity with the angiotensin-converting enzyme inhibitor (ACE-I), pharmacological mechanisms of action of these agents differ. We evaluated the temporal profiles of action of ACE-I and ARB on urinary protein excretion and nitrate/nitrate (NO(x)) excretion in hypertensive (140 and/or 90 mmHg) patients with chronic renal disease (serum creatinine < 265 (range, 44-265) micromol/l or creatinine clearance > 30 (range, 30-121) ml/min). Patients with mild (<1 g/day; range, 0.4-1.0) and moderate proteinuria (>1 g/day; range, 1.1-6.9) were randomly assigned to ACE-I- and ARB-treated groups, and were treated with ACE-I (trandolapril or perindopril) or ARB(losartan or candesartan) for 48 weeks. In all groups, treatment with ACE-I or ARB decreased blood pressure to the same level, but had no effect on creatinine clearance. In patients with mild proteinuria, neither ACE-I nor ARB altered urinary protein excretion. In patients with moderate proteinuria, ACE-I caused 44 +/- 6% reduction in proteinuria (from 2.7 +/- 0.5 to 1.5 +/- 0.4 g/day, n = 14) at 12 weeks, and this beneficial effect persisted throughout the protocol (48 weeks, 1.2 +/- 0.2 g/day). In contrast, ARB did not produce a significant decrease in proteinuria at 12 weeks (23 +/- 8%, n = 13), but a 41 +/- 6% reduction in proteinuria was observed at 48 weeks. Similarly, although early (12 weeks) increases in urinary NO(x) excretion were observed with ACE-I (from 257 +/- 70 to 1111 +/- 160 micromol/day) and ARB (from 280 +/- 82 to 723 +/- 86 micromol/day), the ARB-induced increase in NO(x) excretion was smaller than that by ACE-I (P < 0.05). In conclusion, although both ACE-I and ARB reduce blood pressure similarly, the effect of these agents on proteinuria differs in chronic renal disease with moderate proteinuria. Relatively early onset of the proteinuria-reducing effect was observed with ACE-I, which paralleled the increase in urinary NO(x) excretion. Conversely, ARB decreased proteinuria and increased urinary NO(x) excretion gradually. These time course-dependent changes in proteinuria and urinary NO(x) may reflect the pharmacological property of ACE-I and ARB, with regard to the action on bradykinin. Angiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. The purpose of this study is to ascertain whether the additive antiproteinuric effect of ACE inhibitors plus ARAs is dose dependent and related to the drug-induced reduction in systemic blood pressure. Therefore, enalapril (E; 10 mg/d) and losartan (LOS; 50 mg/d) were randomly administered alone and then in association; initial dosages were doubled when drugs were administered alone and in association. To determine the influence of the drug-dependent effect on reducing blood pressure and the reduction in urinary proteinuria, both ambulatory and office blood pressures were recorded. E and LOS administered alone reduced proteinuria by the same extent; no further reduction was observed when E and LOS alone were administered at a doubled dose. When E and LOS were coadministered, proteinuria decreased by a greater extent compared with E and LOS alone; an additional reduction in proteinuria was observed when combined therapy doses were doubled. The reduction in proteinuria was not correlated with clinical through blood pressure; however, reductions in diastolic and mean ambulatory blood pressures significantly correlated with the decrease in proteinuria, as well as with creatinine clearance. In conclusion, this study shows that combination therapy with E and LOS has an additive dose-dependent antiproteinuric effect that is likely induced by the drug-related reduction in systemic blood pressure. In normotensive proteinuric patients, it is likely that even a small reduction in systemic blood pressure may affect intraglomerular hemodynamics by a great extent because efferent arteriole regulation is hampered more completely by the coadministration of ACE inhibitors and ARAs. 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.
                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.
                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.
                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. A multicentre, randomized, placebo-controlled study was performed in 39 adult patients with biopsy-proven IgA nephropathy with the aim of comparing the effects of the ACE inhibitor fosinopril and placebo on proteinuria. All patients had normal blood pressure and normal renal function. Proteinuria ranged from 1.0 to 2.5 g/24 h. After a 3-month run-in period, fosinopril and placebo were randomly administered in two 4-month sequences separated from cross-over treatment by a 1-month interval. The mean values of creatinine clearance did not change during either the placebo or the treatment sequences. The mean values of mean arterial pressure (MAP) were significantly lower during the fosinopril sequence (90.4 +/- 9.0 mmHg) than in basal conditions (92.8 +/- 9.1 mmHg) (P = 0.034). The mean basal values of proteinuria were 1.74 +/- 0.84 g/24 h. They were unchanged during the placebo sequence (1.79 +/- 1.20) and fell to 1.37 +/- 0.98 g/24 h after 4 months of fosinopril treatment. Using a multivariate statistical analysis, the treatment effect by time on proteinuria was significantly evident only in the fosinopril sequence (Wilks test, P = 0.033). Changes in protein excretion were not correlated with changes in MAP, baseline plasma renin activity, and urinary sodium excretion. This controlled study shows that fosinopril can significantly reduce proteinuria even in normotensive patients with IgA nephropathy. Obviously, the results of treatment with ACE inhibitors on long-term renal prognosis remain to be elucidated. It has been postulated that angiotensin-converting enzyme inhibitor/angiotensin receptor antagonist (ACEI/ATRA) may decrease proteinuria in patients with glomerulonephritis by its action on the glomerular basement membrane. We therefore studied the relationship between the response of patients with IgA nephritis (IgAN) to ACEI/ATRA therapy by decreasing proteinuria and its effect on the selectivity index (SI) in these patients.
                Forty-one patients with biopsy-proven IgAN entered a control trial, with 21 in the treatment group and 20 in the control group. The entry criteria included proteinuria of 1 g or more and/or renal impairment. Patients in the treatment group received ACEI/ATRA or both with three monthly increases in dosage. In the control group, hypertension was treated with atenolol, hydrallazine, or methyldopa. The following tests were performed at three monthly intervals: serum creatinine, total urinary protein, SI, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and low molecular weight (LMW) proteinuria.
                After a mean duration of therapy of 13 +/- 5 months, in the treatment group, there was no significant change in serum creatinine, proteinuria, or SI, but in the control group, serum creatinine deteriorated from 1.8 +/- 0.8 to 2.3 +/- 1.1 mg/dL (P < 0.05). Among the 21 patients in the treatment group, 10 responded to ACEI/ATRA therapy determined as a decrease in proteinuria by 30% (responders), and the other 11 did not respond (nonresponders). Among the responders, SI improved from a mean of 0.26 +/- 0.07 to 0.18 +/- 0. 07 (P < 0.001), indicating a tendency toward selective proteinuria. This was associated with an improvement in serum creatinine from mean 1.7 +/- 0.6 to 1.5 +/- 0.6 mg/dL (P < 0.02) and a decrease in proteinuria from a mean of 2.3 +/- 1.1 to 0.7 +/- 0.5 g/day (P < 0. 001). After treatment, proteinuria in the treatment group (1.8 +/- 1. 6 g/day) was significantly less than in the control group (2.9 +/- 1. 8 g/day, P < 0.05). The post-treatment SI in the responder group (0. 18 +/- 0.07) was better than that of the nonresponder group (0.33 +/- 0.11, P < 0.002). Eight out of 21 patients in the treatment group who had documented renal impairment had improved renal function compared with two in the control group (chi2 = 4.4, P < 0. 05). Of the eight patients in the treatment group who improved their renal function, three normalized their renal function compared with one from the control group.
                Our data suggest that ACEI/ATRA therapy may be beneficial in patients with IgAN with renal impairment and nonselective proteinuria, as such patients may respond to therapy with improvement in protein selectivity, decrease in proteinuria, and improvement in renal function. ACEI/ATRA therapy probably modifies pore size distribution by reducing the radius of large unselective pores, causing the shunt pathway to become less pronounced, resulting in less leakage of protein into the urine. Insufficiency of renal function and high blood pressure influence each other and eventually result in life-threatening endstage renal disease. It has been proposed that proteinuria per se is a determinant of the progression of chronic kidney disease (CKD). The therapeutic strategy for patients with proteinuric CKD and hypertension should therefore be targeted with a view not merely toward blood pressure reduction but also toward renoprotection.
                We examined the effect of the angiotensin (AT)1 receptor antagonist losartan and the calcium channel blocker amlodipine, throughout a period of 12 months, on reduction of blood pressure and renoprotection. This was done by assessing amounts of urinary protein excretion, serum creatinine (SCr), and creatinine clearance (CCr) in patients with hypertension (systolic blood pressure [SBP] > or = 140 mmHg or diastolic blood pressure [DBP] > or = 90 mmHg) and CKD (male, body weight [BW] > or = 60 kg: 1.5 < or = SCr < 3.0 mg/dl; female or male BW < 60 kg: 1.3 < or = SCr < 3.0 mg/dl), manifesting proteinuria of 0.5 g or more/day. Losartan was administered once daily at doses of 25 to 100 mg/day, and amlodipine was given once daily at 2.5 to 5 mg/day. No antihypertensive combination therapy was allowed during the first 3-month period.
                A 3-month interim analysis revealed that, despite there being no difference in blood pressure between the two groups, there was a significant reduction in 24-h urinary protein excretion in the losartan group ( n = 43), but there was no change in the amlodipine group ( n = 43). Analysis of stratified subgroups with proteinuria of 2 g or more/day and less than 2 g/day showed that losartan lowered proteinuria by approximately 24% in both subgroups, while amlodipine lowered proteinuria by 10%, but only in the subgroup of less than 2 g/day (NS). SCr and CCr did not change throughout the period of 3 months in either group. No severe or fatal adverse event was experienced in either group during the study period.
                Losartan appeared to be efficacious for renoprotection in patients with proteinuric CKD and hypertension, with the mechanism being independent of its antihypertensive action. Chronic kidney diseases, particularly if presenting with significant proteinuria, are commonly associated with substantial alteration of serum lipid levels. Experimental evidence suggests that lipid abnormalities may contribute to the progression of kidney disease. However, studies in humans on the subject are scarce.
                In a prospective, controlled open-label study, the authors have evaluated the effects of one-year treatment with atorvastatin, a 3-hydroxy-3-methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, versus no treatment on proteinuria and progression of kidney disease in 56 patients with chronic kidney disease. Before randomization, all patients had already been treated for one year with angiotensin-converting enzyme (ACE) inhibitors or angiotensin AT1 receptor antagonists (ARBs) and other antihypertensive drugs.
                By the end of one-year treatment, urine protein excretion decreased from 2.2 +/- 0.1 to 1.2 +/- 1.0 g every 24 hours (P < 0.01) in patients treated with atorvastatin in addition to ACE inhibitor and ARBs. By contrast, urinary protein excretion decreased only from 2.0 +/- 0.1 to 1.8 +/- 0.1 g every 24 hours (P value not significant) in patients who did not receive atorvastatin in addition to ACE inhibitor or ARBs. During this time, creatinine clearance decreased only slightly and not significantly (from 51 +/- 1.8 to 49.8 +/- 1.7) in patients treated with atorvastatin. By contrast, during the same period of observation, creatinine clearance decreased from 50 +/- 1.9 to 44.2 +/- 1.6 mL/min (P < 0.01) in patients who did not receive atorvastatin.
                This study has shown that treatment with atorvastatin in addition to a regimen with ACE inhibitors or ARBs may reduce proteinuria and the rate of progression of kidney disease in patients with chronic kidney disease, proteinuria, and hypercholesterolemia. The benefits appear to occur in addition to those of treatment with ACE inhibitor and ARBs.
                Copyright 2003 by the National Kidney Foundation, Inc. Experimental evidence suggests that aldosterone contributes to progressive kidney disease. Angiotensin-converting enzyme inhibitors and angiotensin type 1 receptor antagonists suppress the renin-angiotensin system but they do not effectively reduce plasma aldosterone. Hence, administration of aldosterone receptor antagonists may provide additional renal protection. In the present prospective randomized open-label study, we evaluated the effects of spironolactone (25 mg/day for 1 year) on proteinuria and estimated glomerular filtration rate in 83 patients with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists. Eighty-two patients were treated with angiotensin-converting enzyme inhibitors and/or angiotensin type 1 receptor antagonists alone and served as controls. After 1 year of therapy, proteinuria decreased from 2.1+/-0.08 to 0.89+/-0.06 g/g creatinine (P<0.001) in patients treated with spironolactone, but it did not change in control patients. Baseline aldosterone levels were significantly correlated with proteinuria (r=0.76, P<0.0001), and predicted the degree of reduction in proteinuria with spironolactone (r=0.42, P<0.0002). Baseline estimated glomerular filtration rate was similar in patients treated with spironolactone and controls (62.4+/-2.4 and 62.2+/-2.1 ml/min/1.73 m(2), respectively). After 1 month of therapy with spironolactone, estimated glomerular filtration rate decreased more in patients treated with spironolactone than in controls. However, by the end of 1 year the monthly rate of decrease in estimated glomerular filtration rate from baseline was lower in patients treated with spironolactone than in controls (0.323+/-0.044 vs 0.474+/-0.037 ml/min/1.73 m(2), P<0.01). Spironolactone caused a significant rise in serum potassium levels (from 4.2+/-0.04 at baseline to 5.0+/-0.05 mEq/l after 12 months of treatment, P<0.001). In conclusion, this study has shown that spironolactone may reduce proteinuria and retard renal progression in chronic kidney disease patients. OBJECTIVE To investigate the effects of angiotensin-converting enzyme inhibitor (ACEI) on IgA nephropathy(IgAN) and the factors influencing the therapeutic effects. METHODS 131 cases with IgAN diagnosed by renal biopsy were randomly divided into two groups: ACEI group (benazepril 10 mg/d) and non-ACEI group as control. The pathological changes in the kidney were analyzed using Lee SMK. RESULTS After 1 month treatment of ACEI, the levels of proteinuria and serum cholesterol decreased significantly, meanwhile those of serum albumin and total protein increased obviously in patients with IgAN(P < 0.05). The proteinuria level at the 3rd month after treatment was lower than that at the 1st month, but was same as that at the 18th month. While in the control group the proteinuria level increased and the clearance of creatinine decreased continuously during the observation (P < 0.05). The effects correlated positively with mesangial proliferation and negatively with course of the disease glomerular sclerosis in glomerulus and changes of small arterioles in the kidney. Normal blood pressare normal renal function I approximately II degree of Lee SMK I degee of interstitial changes minimal changes of small arterioles and mild glomerular sclerosis predicted better response to ACEI treatment than hypertension renal insufficiency V degree of Lee SMK IV degee of interstitial changes severe changes of small arterioles and massive glomerular sclerosis. CONCLUSIONS It is suggested that benezepril could definitely reduce the excretion of urinary protein and protect renal function of patients with IgAN and should be used as earlier as possible. Mesangial prolife ration glomerular sclerosis in glomerulus changes of small arterioles in kidney and course of the disease are the major influencing factors of ACEI treatment on IgAN.
Aldosterone antagonists contribute to reduction of proteinuria in patients with CKD who are already on ACEi and ARB but increase the risk of hyperkalaemia. Available studies are small and have short follow-up. Long-term effects on renal outcomes, mortality and safety are unknown.