Comparative effects of antihypertensives on proteinuria: angiotensin-converting enzyme inhibitor versus alpha 1-antagonist.

Control of hypertension improves the course of renal disease. We compared the renal hemodynamic and permselective responses to an angiotensin-converting enzyme inhibitor (CEI) (enalapril) and an alpha 1-antagonist (prazosin) in 14 patients with established glomerular disease. A single-blinded, randomized, cross-over design was used consisting of a 3-week baseline period followed by two 4-week treatment periods, which were separated by a 4-week washout period. During the treatment periods, the CEI or alpha 1-antagonist was added to the patients' baseline antihypertensive medications. Mean arterial pressure (MAP) was reduced to similar levels by both drugs, although the time-averaged blood pressure throughout the study was higher with the alpha 1-antagonist. Twenty-four-hour urinary protein, albumin, and IgG excretion were not significantly different at the end of the CEI and alpha 1-antagonist periods. However, compared with baseline values, significant decreases in total protein and IgG excretion occurred only during the CEI period, while albumin excretion decreased with both drugs. A 22% decrease in the fractional clearance of albumin (4.95 +/- 1.44 to 3.88 +/- 1.57 x 10(-3); P less than 0.01) and a 49% decrease in the fractional clearance of IgG (1.58 +/- 0.42 to 0.81 +/- 0.28 x 10(-3); P less than 0.001) occurred during CEI therapy with no significant changes in these parameters being seen with alpha 1-antagonist therapy (albumin: 4.95 +/- 1.44 to 4.48 +/- 1.51 x 10(-3), P = NS; IgG: 1.58 +/- 0.42 to 1.71 +/- 0.70 x 10(-3), P = NS). At the time of the fractional clearance measurements, MAP proved to be lower on the CEI. Reanalysis of the data for the subgroup of 11 patients without differences in MAP during the clearance period demonstrated a beneficial effect favoring CEI. Except for the greatest decreases in blood pressure (21 to 30 mm Hg), a greater antiproteinuric effect for a given decrease in blood pressure was seen with the CEI. Additionally, reduction in proteinuria occurred in a subset of seven patients whose baseline MAP was in the normotensive range. In conclusion, lowering MAP improves proteinuria. CEI appears to exert a more favourable effect even at similar MAP. Reductions in blood pressure, even within the accepted normal range, lessen permselective defects.     

增大剂量的福辛普利治疗慢性肾脏病轻中度蛋白尿的前瞻性研究

目的观察增大剂量的福辛普利对于慢性肾脏病患者轻、中度蛋白尿(1-3.5g/24h)的有效性和安全性。方法采用前瞻性、多中心、自身对照试验,为期24周。84例纳入研究的患者中,其中67例有肾穿刺的病理诊断,11例失访。福辛普利的剂量每8周在原有基础上增加1倍。治疗过程中检测血常规、尿常规、24h尿蛋白定量、Scr、血电解质和肝功能,并记录血压及不良反应情况。结果患者24h蛋白尿定量试验前为(2.48±1.03)g,8周时降至(1.97±0.77)g(P<0.01);16周时降至(1.43±0.34)g(P<0.01);24周时降至(0.86±0.57)g(P<0.01)。24例(32.9％)完全缓解,27例(36.9％)部分缓解。试验前血压基线水平为(135.8±3.9/83.2±4.5)mmHg;8周时降至(129.5±8.8/79.5±7.3)mmHg(P<0.01);16周时血压为(119.2±7.8/70.5±9.5)mmHg(P<0.01);24周时血压为(114.6±11.9/67.2±9.5)mmHg。24例(32.8％)在服用福辛普利40mg/d时出现低血压的不良反应。结论福辛普利可显著减少慢性肾脏病患者的蛋白尿,并呈剂量依赖性。使用20mg/d的福辛普利是较为安全的,当剂量≥40mg/d时,应注意低血压的发生。     

Effects of angiotensin-converting enzyme inhibitor during warm blood cardioplegia

BACKGROUND: Effects of captopril, an angiotensin-converting enzyme inhibitor, during warm blood cardioplegia were assessed in the blood-perfused, isolated rat heart. METHODS: The isolated hearts were arrested for 60 minutes with warm blood cardioplegia given at 20-minute intervals and were reperfused for 60 minutes. The control group (n = 10) received standard cardioplegia and the captopril group (n = 10) received cardioplegia supplemented with captopril (2 mmol/L). Cardiac function, myocardial metabolism, and cardiac release of circulating adhesion molecules were assessed before and after cardioplegic arrest. RESULTS: Left ventricular end-diastolic pressure and -dp/dt were significantly (p<0.05) lower and coronary blood flow was significantly (p<0.05) greater in the captopril group than the control group during reperfusion. The captopril group resulted in significantly (p<0.05) less cardiac release of lactate, thiobarbituric acid reactive substances during reperfusion. Cardiac release of intercellular adhesion molecule-1 was significantly (p<0.05) less in the captopril group at 60 minutes of reperfusion. CONCLUSIONS: The results suggest that supplementation of captopril during warm blood cardioplegia provides superior myocardial protection by suppressing lipid peroxidation and leukocyte-endothelial cell interaction during reperfusion.     

Nephrotic proteinuria without hypoalbuminemia: clinical characteristics and response to angiotensin-converting enzyme inhibition

Although hypoalbuminemia is a fundamental characteristic of nephrotic syndrome (NS), there are many patients with massive proteinuria that do not develop hypoalbuminemia. We have studied the clinical and biochemical characteristics of 19 patients with persistent massive proteinuria (greater than 5 g/d) and normal serum albumin (group I) in comparison with 16 patients with similar proteinuria excretion, but persistent hypoalbuminemia (group II). Most of group I patients had diagnoses suggesting glomerular hyperfiltration (focal glomerulosclerosis [FGS] associated with vesicoureteral reflux [VUR], reduction of renal mass, proteinuria associated with obesity, sclerotic phase of idiopathic crescentic glomerulonephritis [GN] in contrast with those of group II, in which membranous GN was the most frequent diagnosis. We prospectively investigated differences in the antiproteinuric effect of captopril, an antiotensin-converting enzyme inhibitor (ACEI); after 6 months of treatment, proteinuria decreased clearly in group I (7.1 +/- 1.7 to 3.7 +/- 1.7 g/d; P less than 0.001), whereas no significant changes were observed in group II (8.1 +/- 2.4 to 8.8 +/- 4 g/d). Serum creatinine (Scr) remained stable during captopril treatment in group I, whereas three patients in group II showed a worsening of renal function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Alcohol consumption and incidence of proteinuria: a retrospective cohort study

Background

Previous studies report conflicting results of a dose-dependent association between alcohol consumption and incidence of chronic kidney disease. Only a few studies have assessed the clinical impact of >?45–65 g/day of critically high alcohol consumption.

Methods

This retrospective cohort study included 88,647 males and 88,925 females with dipstick urinary protein?≤?±?and estimated glomerular filtration rate?≥?60 mL/min/1.73 m² at their first annual health examinations between April 2008 and March 2010 in Japan. The exposure was the self-reported alcohol consumption. The outcome was proteinuria defined as dipstick urinary protein?≥?1?+?or ≥?2?+.

Results

During median 1.8 years (interquartile range 1.0–2.1) of the observational period, 5416 (6.1%) males and 3262 (3.7%) females developed proteinuria defined as dipstick urinary protein?≥?1?+. In males, a U-shape association between alcohol consumption and proteinuria was observed in a multivariable-adjusted Poisson regression model [incidence rate ratio (95% confidence interval) of rare, occasional, and daily drinkers with ≤?19, 20–39, 40–59, and ≥?60 g/day: 1.00 (reference), 0.86 (0.79–0.94), 0.70 (0.64–0.78), 0.82 (0.75–0.90), 1.00 (0.90–1.11), and 1.00 (0.85–1.17), respectively], whereas a J-shape association was observed in females [1.00 (reference), 0.81 (0.75–0.87), 0.74 (0.64–0.85), 0.93 (0.78–1.11), 1.09 (0.83–1.44), and 1.45 (1.02–2.08), respectively]. Similar associations with dipstick urinary protein?≥?2?+?were shown in males and females.

Conclusions

Moderate alcohol consumption was associated with lower risk of proteinuria in both males and females. Females with ≥?60 g/day of high alcohol consumption were at higher risk of proteinuria, whereas males were not. Females were more vulnerable to high alcohol consumption, than males.

     

Dual blockade of the renin-angiotensin system compared with a 50% increase in the dose of angiotensin-converting enzyme inhibitor: effects on proteinuria and blood pressure.

BACKGROUND: Several publications in the past 2 years have demonstrated that combined angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-II receptor antagonist (AIIRA) are more effective in reducing blood pressure and proteinuria in patients with chronic renal disease than ACEI or AIIRA alone. This study compares the effect of increasing the ACEI dose by 50% with that of adding an AIIRA to a standard ACEI dose. METHODS: This study was designed as part of a previous comparison of ACEI with ACEI plus candesartan. Directly after completion of the randomized intervention periods of that study, the dose of ACEI was increased by 50% in all patients. Proteinuria and blood pressure were compared in both groups of patients in the three periods, on standard ACEI, on ACEI plus candesartan and on a dose of ACEI increased by 50%. RESULTS: No significant differences in the primary end-point proteinuria or secondary end-points were observed when the ACEI dose was increased by 50%. Proteinuria was 1.8 g in 24 h on candesartan and ACEI and 2.4 g in 24 h when the ACEI dose was increased by 50% (P<0.02). Systolic blood pressure was 126.6 mmHg on candesartan and ACEI and 134.47 mmHg when the ACEI dose was increased by 50% (P<0.002). Diastolic blood pressure, serum creatinine, urea and potassium were not different between groups. CONCLUSIONS: Standard ACEI plus candesartan is more effective in reducing systolic blood pressure and proteinuria than a 50% increase in ACEI dose. This has implications for the prevention of renal failure in chronic renal disease.     

Long-term beneficial effects of angiotensin-converting enzyme inhibition in patients with nephrotic proteinuria.

Angiotensin-converting enzyme inhibitors (ACEI) can reduce proteinuria in diabetic and nondiabetic nephropathy. However, no studies have determined whether this antiproteinuric effect modifies the progression of renal insufficiency. We studied the evolution of 46 nondiabetic patients with nephrotic proteinuria treated with captopril for a minimum of 12 months. The follow-up period before captopril treatment was 12 to 18 months. At the end of follow-up, after captopril introduction (24.4 +/- 7.6 months), proteinuria had decreased from 6.3 +/- 2.5 to 3.9 +/- 3.1 g/24 h (P less than 0.001), with a mean decrease of 45% +/- 28%. The proteinuria decrease was higher in patients with reflux nephropathy, proteinuria associated with reduction of renal mass, inactive crescentic glomerulonephritis, nephroangiosclerosis, and IgA nephropathy, whereas patients with membranous glomerulonephritis and idiopathic focal glomerulosclerosis showed a poorer response. Patients were separated according to a proteinuria reduction greater (group A, 23 patients) or lower (group B, 23 patients) than 45% of the initial value. At the end of follow-up, renal function had not significantly changed in group A with respect to values at the start of treatment: serum creatinine (SCr) was 229 +/- 167 mumol/L (2.6 +/- 1.9 mg/dL) versus 203 +/- 97 mumol/L (2.3 +/- 1.1 mg/dL), and creatinine clearance (CrCl) was 0.80 +/- 0.52 mL/s (48 +/- 31 mL/min) versus 0.87 +/- 0.47 mL/s (52 +/- 28 mL/min). The slope of the reciprocal of Scr (1/SCr) showed a significantly beneficial change after captopril introduction.(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of angiotensin-converting enzyme inhibition and dietary protein restriction in the treatment of proteinuria

Both angiotensin-converting enzyme inhibitors and dietary protein restriction have been reported to reduce urinary protein losses in patients with chronic glomerular diseases. We evaluated these two therapies in 12 such patients ingesting a constant metabolic diet containing 1.6 g protein/kg body weight per day. After a steady-state was achieved during a 3-week baseline period, patients were randomly assigned to either enalapril, titrated to reduce mean arterial pressure by 10 mm Hg, or an isocaloric 0.8 g/kg protein diet. Five patients in each group completed 3 additional weeks of observation during the treatment period. Enalapril resulted in an average reduction in urinary protein and albumin losses of 26% and 33%, respectively, without reducing creatinine clearance. Albumin synthesis was unchanged and nitrogen balance increased slightly (+142.8 +/- 85.7 mmol/d [+2.0 +/- 1.2 g/d], P = 0.075). Dietary protein restriction had no consistent effect on proteinuria or albuminuria, whereas albumin synthesis (25.9 +/- 3.4 v 21.5 +/- 2.9 g/d/1.73 m2, P less than 0.05) and nitrogen balance (-135.6 +/- 92.8 mmol/d [-1.9 +/- 1.3 g/d], P = 0.10) decreased. Both therapies resulted in a modest increase in plasma potassium concentration. Whether the maintenance of albumin synthesis in the presence of a reduction in urinary protein losses will convey a long-term advantage to treatment of proteinuric patients with angiotensin-converting enzyme inhibitors remains to be determined.     

Long-term observation of renal function on combination therapy with prostaglandin and angiotensin-converting enzyme inhibitor for chronic kidney disease

AIMS: Recently, we reported the effectiveness of PAC therapy, a combination therapy with prostaglandin (PG) and angiotensin-converting enzyme inhibitor (ACE-I), as a new tool for the prevention of chronic kidney disease. In the current study, we continually treated these patients with or without PG and analyzed the survival rate of renal function by Kaplan-Meier method and Cox regression analysis. MATERIAL AND METHODS: 52 patients (serum creatinine 2.9 A+/- 1.9 mg/dl) were followed-up for 48 months. 26 patients continued to receive ACE-I monotherapy and the remaining 26 patients were treated by PAC therapy. Primary end-point was defined as a decrease in 1/Cr by 0.2 (dl/mg), initiation of renal replacement therapy or death. RESULTS: At the end of the study, PAC therapy significantly reduced the risk for the decline in renal function compared to ACE-I monotherapy by 54%. Survival time was longer in PAC group (21.7 A+/- 2.2 and 35.1 A+/- 3.9 months, in ACE-I monotherapy and PAC therapy, p < 0.05). Cox regression analysis indicated that age, sex and blood pressure except urinary protein excretion did not relate to the risk reduction by PAC therapy. CONCLUSION: PAC therapy was proved to reduce the progression of end-stage renal failure.     

The renal functional and structural consequences of corticosteroid and angiotensin-converting enzyme inhibitor therapy in chronic puromycin aminonucleoside nephropathy

Glomerular diseases are characterized by increased urinary protein excretion. Treatment of this abnormality frequently involves administration of corticosteroids and angiotensin-converting enzyme inhibitors. There has been much recent interest in the potential impact of these drugs on progressive renal dysfunction, since they have opposing effects on intraglomerular hemodynamics. Therefore, we investigated the effect of methylprednisolone or captopril treatment on animals with chronic puromycin aminonucleoside nephropathy. In rats given a single injection of puromycin aminonucleoside, 15 mg/100 g body weight, both methylprednisolone and captopril significantly reduced proteinuria at 6 months [83±14 untreated (n=7), 34±6 with methylprednisolone (n=8), and 6±1 mg/24h with captopril (n=5),P<0.001]. Segmental glomerulosclerosis occurred with equal frequency in the untreated (7.8±2.3%) and methylprednisolone-treated rats (5.0±1.11%), but was significantly reduced by the administration of captopril (1.0±0.5%,P<0.001). We conclude that in chronic puromycin aminonucleoside nephropathy, treatment with corticosteroids reduces proteinuria without increasing the incidence of segmental glomerulosclerosis. Therapy with an angiotensin-converting enzyme inhibitor substantially decreases proteinuria and lessens the severity of glomerular scarring.     

A clinicopathological study of IgA nephropathy in renal transplant recipients: beneficial effect of angiotensin-converting enzyme inhibitor.

BACKGROUND: Prolonging the survival of transplant kidneys is a major task of modern nephrology. It has recently been shown that deteriorating renal function and substantial graft loss were observed in 55% of renal allograft recipients with recurrent IgA nephropathy (IgAN) at long-term follow-up. To gain a useful insight into the therapeutic approach towards protecting allograft kidneys from deteriorating graft function, we compared the histological characteristics of post-transplant IgAN to primary IgAN and investigated the effects of an ACE inhibitor. METHODS: Twenty-one patients with post-transplant IgAN and 63 patients with primary IgAN were included in the histopathological study. The effectiveness of angiotensin-converting enzyme (ACE) inhibitor treatment in post-transplant IgAN was also studied in 10 patients. RESULTS: The prevalence of glomeruli with adhesions and/or cellular crescents in primary IgAN was significantly greater than in post-transplant IgAN (P<0.05), but the proportion of glomeruli with segmental sclerosis was similar in both groups. The rate of global obsolescence, and the degree of interstitial fibrosis in post-transplant IgAN were significantly greater than in primary IgAN (P<0.05). The degree of glomerular obsolescence and the severity of interstitial fibrosis correlated with the severity of glomerular lesion in primary IgAN, but not in post-transplant IgAN. In primary IgAN, glomerular diameter significantly correlated with the proportions of glomerular obsolescence, but not in post-transplant IgAN, suggesting that allograft kidneys may be in a hyperfiltration state. Both the blood pressure and the urinary protein excretion significantly improved after ACE-inhibitor treatment (P<0.001). CONCLUSION: In post-transplant IgAN, histopathological lesions indicative of acute inflammatory insults were suppressed, and glomerular hypertrophy, which may relate to haemodynamic burden such as hyperfiltration, was prominent. Preliminary study of ACE-inhibitor treatment in 10 patients showed favourable effects. A future long-term follow-up study is required to establish the effectiveness of ACE inhibitors in treatment of post-transplant IgAN.     

Combination therapy with an angiotensin-converting enzyme inhibitor and a vitamin D analog suppresses the progression of renal insufficiency in uremic rats

Monotherapy with angiotensin-converting enzyme inhibitors has been shown to be beneficial in suppressing the progression of experimentally induced kidney diseases. Whether such therapy provides additional benefits when combined with vitamin D or an analog of vitamin D has not been established. Rats were made uremic by 5/6 nephrectomy and treated as follows: Uremic + vehicle (UC), uremic + enalapril (30 mg/L in drinking water; E), uremic + paricalcitol (19-nor; 0.8 microg/kg, three times a week), and uremic + enalapril + paricalcitol (E + 19-nor). A group of normal rats served as control (NC). BP was significantly elevated in the UC and 19-nor groups compared with the NC group but was indistinguishable from normal in the E and E + 19-nor groups. The decrease in creatinine clearance and the increase in the excretion of urinary protein that were observed in the UC group were ameliorated by the use of E alone or by E + 19-nor (P < 0.05 versus UC). The glomerulosclerotic index was significantly decreased in both the 19-nor (P < 0.01) and E + 19-nor groups (P < 0.01) compared with the UC group. Tubulointerstitial volume was significantly decreased in both the E (P < 0.05) and E + 19-nor groups (P < 0.01) compared with the UC group. Both macrophage infiltration (ED-1-positive cells) and production of the chemokine monocyte chemoattractant protein-1 were significantly blunted in E + 19-nor compared with E group. TGF-beta1 mRNA and protein expression were increased in the UC group (mRNA: 23.7-fold; protein: 29.1-fold versus NC). These increases were significantly blunted in the 19-nor group (mRNA: 7.1-fold; protein: 8.0-fold versus NC) and virtually normalized in the E + 19-nor group (protein: 0.8-fold versus NC). Phosphorylation of Smad2 was also elevated in the UC group (7.6-fold versus NC) but less so in the 19-nor-treated rats (5.5-fold versus NC). When rats were treated with E + 19-nor, the phosphorylation of Smad2 was normal (1.1-fold versus NC). Thus, 19-nor can suppress the progression of renal insufficiency via mediation of the TGF-beta signaling pathway, and this effect is amplified when BP is controlled via renin-angiotensin system blockade.     

Impact of blood pressure control and angiotensin-converting enzyme inhibitor therapy on new-onset microalbuminuria in type 2 diabetes: a post hoc analysis of the BENEDICT trial

For assessment of the independent renoprotective effect of BP control and angiotensin-converting enzyme inhibitor (ACEi) therapy, the relationships of baseline BP, BP reduction, and follow-up BP with the incidence of persistent microalbuminuria were evaluated in 1204 hypertensive patients who had type 2 diabetes and normoalbuminuria and were included in the BErgamo Nephrologic Diabetic Complications Trial (BENEDICT) study and were randomly assigned to 3.6 yr of treatment with the ACEi trandolapril (2 mg/d), the nondihydropyridine calcium channel blocker (ndCCB) verapamil SR (240 mg/d), their fixed combination Veratran (trandolapril 2 mg/d plus verapamil SR 180 mg/d), or placebo, plus other antihypertensive medications targeted at systolic/diastolic BP <130/80 mmHg. Follow-up (from month 3 to study end) systolic, diastolic, mean, and pulse BP and their reductions versus baseline--but not baseline BP--independently predicted (P < 0.001) the risk for microalbuminuria. In patients with follow-up BP above medians, ACEi significantly reduced the risk for microalbuminuria to levels that were observed among patients with BP below medians, regardless of ACEi treatment. The same trend was observed among patients with BP reductions below medians. ndCCB therapy did not independently affect microalbuminuria. Patients who were on Veratran had lower BP and less frequently received diuretics, beta blockers, or dihydropyridine dCCB. In hypertensive, normoalbuminuric patients with type 2 diabetes, BP reduction and ACEi therapy both independently may prevent microalbuminuria. ACEi therapy is particularly effective when BP is poorly controlled, whereas ndCCB therapy is ineffective at any level of achieved BP. As compared with trandolapril, Veratran may help with achievement of target BP with less need for concomitant antihypertensive medications.     

IgACE: a placebo-controlled, randomized trial of angiotensin-converting enzyme inhibitors in children and young people with IgA nephropathy and moderate proteinuria

This European Community Biomedicine and Health Research-supported, multicenter, randomized, placebo-controlled, double-blind trial investigated the effect of an angiotensin-converting enzyme inhibitor (ACE-I) in children and young people with IgA nephropathy (IgAN), moderate proteinuria (>1 and <3.5 g/d per 1.73 m(2)) and creatinine clearance (CrCl) >50 ml/min per 1.73 m(2). Sixty-six patients who were 20.5 yr of age (range 9 to 35 yr), were randomly assigned to Benazepril 0.2 mg/kg per d (ACE-I) or placebo and were followed for a median of 38 mo. The primary outcome was the progression of kidney disease, defined as >30% decrease of CrCl; secondary outcomes were (1) a composite end point of >30% decrease of CrCl or worsening of proteinuria until > or =3.5 g/d per 1.73 m(2) and (2) proteinuria partial remission (<0.5 g/d per 1.73 m(2)) or total remission (<160 mg/d per 1.73 m(2)) for >6 mo. Analysis was by intention to treat. A single patient (3.1%) in the ACE-I group and five (14.7%) in the placebo group showed a worsening of CrCl >30%. The composite end point of >30% decrease of CrCl or worsening of proteinuria until nephrotic range was reached by one (3.1%) of 32 patients in the ACE-I group, and nine (26.5%) of 34 in the placebo group; the difference was significant (log-rank P = 0.035). A stable, partial remission of proteinuria was observed in 13 (40.6%) of 32 patients in the ACE-I group versus three (8.8%) of 34 in the placebo group (log-rank P = 0.033), with total remission in 12.5% of ACE-I-treated patients and in none in the placebo group (log-rank P = 0.029). The multivariate Cox analysis showed that treatment with ACE-I was the independent predictor of prognosis; no influence on the composite end point was found for gender, age, baseline CrCl, systolic or diastolic BP, mean arterial pressure, or proteinuria.