Angiotensin converting enzyme inhibitors and reflux nephropathy: 2-year follow-up

 We evaluated the effect of 2 years’ therapy with an angiotensin converting enzyme inhibitor (captopril) in 16 patients who had severe reflux nephropathy and microalbuminuria. During the period of therapy, microalbuminuria decreased, glomerular filtration rate measured by diethylenetriamine pentaacetate scan, serum creatinine, and blood pressure remained stable. We suggest the captopril was useful in reducing microalbuminuria and may have slowed the progression of renal damage in our patients. Received November 12, 1996; received in revised form and accepted June 23, 1997     

Angiotensin converting enzyme in renal ontogeny: hypothesis for multiple roles

Angiotensin converting enzyme (ACE) has multiple effects both as the enzyme which cleaves angiotensin II from angiotensin I and as that which breaks down bradykinin. The present study examines ACE mRNA and protein expression in the rat kidney during development. Changes in distribution and expression during development are consistent with suggestions that the renin angiotensin system is important in growth modulation, vascular development and regulation, and protein reabsorption.     

Angiotensin converting enzyme inhibitors for reduction of proteinuria in children with steroid-resistant nephrotic syndrome

The effects of angiotensin converting enzyme inhibitors (ACEI) on proteinuria, renal function, and serum proteins were evaluated in six children with steroid-resistant nephrotic syndrome and proteinuria of 3–15 g/24h (277±47 mg/m² per hour). Following ACEI, proteinuria decreased from 7,408±2,385 (mean±SEM) to 3,746±1,395 mg/24 h (P<0.05). Creatinine clearance was 87.8±22.6 before and 96.4±23.6 ml/min per 1.73 m² after ACEI. In two patients, inulin and para-aminohippuric acid clearances were normal before and after ACEI, together with parallel reductions of urine protein of 50% and 46%. Clearance of total protein was reduced by 56% following ACEI, compared with reduction in the clearance of gamma globulin by 58% and albumin by 39.5%. No significant change was seen in blood pressure, serum albumin, or total protein following ACEI. After ACEI, diuretic doses were able to be reduced or eliminated in three patients. Reduction of proteinuria was sustained during a followup period of 11–20 months in three patients. ACEI may be of benefit in the clinical management of children with steroidresistant nephrotic syndromes, allowing reduction in diuretic requirements.     

Angiotensin converting enzyme inhibitor use soon after renal transplantation: a randomized, double-blinded placebo-controlled safety study

Activation of the renin-angiotensin system (RAS) followed by increased inflammatory cytokines may be important in the pathogenesis of chronic allograft dysfunction. As many renal transplant recipients show chronic changes on biopsy within the first year, early RAS blockade with angiotensin converting enzyme inhibitor (ACEI) could be beneficial. However, it remains unclear that early ACEI use is safe. We conducted a prospective, randomized, placebo-controlled trial to assess the safety of enalapril 5 mg during the early post-transplant period. Subjects took the study medication for six months. Primary endpoints were serum potassium (K) >5.9 mEq/L and 30% increase in baseline creatinine. A total of 53 subjects were randomized, and of them, 27 received the study drug. Twenty-nine subjects, 14 ACEI and 15 controls, completed the six-month protocol without reaching an endpoint. Patients on ACEI had higher K and higher BUN at six months. Serum creatinine, hematocrit, and urinary protein were not different. There was no difference in urinary TGF-β1. Twenty-four subjects reached study endpoints. When the common clinical endpoints of elevated creatinine and hyperkalemia were combined, ACEI group had significantly increased endpoints vs. control (10/13, 77% vs. 5/11, 45%, p < 0.05). We conclude that ACEI use in the early post-transplant period can be safe but patients must be carefully selected and monitored for elevations in serum creatinine and potassium. Whether early ACEI is beneficial in preserving allograft function requires further study.     

Angiotensin converting enzyme inhibition,CBF autoregulation,and ICP in patients with normal-pressure hydrocephalus

Summary Fourteen patients with normal pressure hydrocephalus had the autoregulation of cerebral blood flow (CBF) and intracranial pressure (ICP) investigated. In 8 of the patients the effect of Captopril on ICP and CBF was also investigated. The mean arterial blood pressure (MABP) was 109 mmHg (intra-arterially), and ICP was 11 mmHg (intraventricularly). Changes in global CBF were estimated by the arterio-venous oxygen difference method. The autoregulation of CBF was present in 13 of the patients (p < 0.01). The lower limit of CBF autoregulation was 86% of the baseline perfusion pressure. One hour after 50 mg of captopril perorally, MABP was reduced 16 mmHg, and ICP and CBF were unchanged. The autoregulation was maintained and the lower limit was decreased 19 mmHg. Thus patients would be expected to benefit from captopril treatment in hypotensive anaesthesia.     

Alterations in angiotensin converting enzyme during rodent aortic aneurysm formation

BACKGROUND: The renin-angiotensin system (RAS) has been implicated in vessel wall remodeling. This investigation tested the hypothesis that the RAS is altered during experimental rodent aneurysm formation. MATERIALS AND METHODS: Rat aortas were perfused with saline (controls, N = 45) or elastase (6 U/ml, N = 45). At 4, 7, and 14 days after aortic perfusion, aortic diameters were measured (n = 15/time point/group) and aortic wall mRNA and protein were extracted. Real time polymerase chain reation (PCR) measured RNA levels of angiotensin, angiotensin converting enzyme (ACE), angiotensin II receptor 1 (AT(1)), and angiotensin II receptor 2 (AT(2)). Western blot analysis measured ACE protein levels. Immunohistochemical studies localized ACE within the aortic wall. Statistical analyses were performed with the unpaired t-test and ANOVA. RESULTS: Elastase perfusion significantly increased aortic diameter (P < 0.01), with no significant changes in saline control aortic diameters. ACE mRNA did not become elevated in elastase-perfused aortas, yet ACE protein levels were elevated on days 4 and 7 of perfusion (P < 0.01) compared to controls, and ACE staining was noted in these aortas. This difference resolved by 14 days. In neither group were there significant alterations in AT(1), AT(2), or An mRNA levels, although ACE mRNA was elevated in controls after 7 days of perfusion compared to elastase perfused aortas (P < 0.005). CONCLUSIONS: Experimental aortic aneurysm formation may be associated with increased aortic wall ACE protein levels. The mechanisms by which these proteins contribute to, or serve as markers of, aneurysm formation in vivo requires further intervention.     

Angiotensin converting enzyme inhibition prevents development of collapsing focal segmental glomerulosclerosis in Thy-1.1 transgenic mice.

BACKGROUND: Thy-1.1 transgenic mice develop hypercellular focal and segmental glomerulosclerosis (FSGS) lesions that mimic human collapsing FSGS, in 7 days after injection with anti-Thy-1.1 antibodies. These lesions consist of proliferating parietal epithelial cells (PECs). We questioned whether the angiotensin converting enzyme inhibitor (ACE), captopril, could prevent the development of FSGS and if protection is related to the timing of drug administration. METHODS: First, we compared the effect of captopril treatment with angiotensin II-(ANGII) independent antihypertensive therapy (triple therapy). Second, we tested the effects of captopril administered over four different time intervals: days -7 to 0 (Ca-7>0), days -7 to 7 (Ca-7>7), days 0-7 (Ca0>7) and days 3-7 (Ca3>7) (day 0 being the day of injection of the antibody). RESULTS: In anti-Thy-1.1 injected control (C) mice we observed dedifferentiation and activation of podocytes, reflected by loss of ASD33 and increased expression of desmin, followed by a marked accumulation of PECs forming hypercellular lesions. PECs showed an increased expression of connective tissue growth factor (CTGF). Triple therapy or captorpil pre-treatment (Ca-7>0) had no significant effect on albuminuria or FSGS. In contrast, Ca0>7 and Ca3>7 treatment significantly lowered albuminuria and attenuated development of FSGS. The latter two treatments attenuated loss of ASD33 expression by podocytes but could not prevent increased desmin expression. In addition, these treatments reduced CTGF expression by PECs and prevented PEC proliferation. CONCLUSIONS: ACE inhibition, but not triple therapy, prevents the development of FSGS, suggesting an important role for ANGII. ACE inhibition has a protective effect even when started 3 days after the initial podocyte insult, which is probably related to the ability of ACE-inhibition to block PEC activation and proliferation.     

Influence of angiotensin converting enzyme inhibitor treatment on cardiac autonomic modulation in patients receiving haemodialysis

BACKGROUND: Cardiovascular disease mortality among patients with end stage renal disease (ESRD) exceeds that which is predicted by traditional risk factors. Sudden death accounts for up to 15-38% of patients with ESRD found dead at home. Heart rate variability (HRV) is a reliable measure of autonomic modulation and has a very strong predictive value for ventricular arrhythmias and sudden death. A lower HRV is associated with increased risk. Modifying autonomic tone pharmacologically reduces death from dysrhythmia in the general population but has not been studied in ESRD. METHODS: We examined the effect of ramipril, an angiotensin converting enzyme inhibitor (ACEI) known in the general population to increase HRV, on cardiac function and heart rate variability in patients with renal failure. Eligible subjects on haemodialysis underwent a 2-week washout period free of ACEI or beta blockers, during which time hypertension was treated with amlodipine, which has been shown not to affect HRV. Haemodynamic and HRV measurements were obtained at baseline and after subjects were treated for 4 weeks with an ACEI. RESULTS: Haemodynamics did not differ at 0 and 4 weeks. Baseline HRV values were markedly below those found in the general population, indicating pronounced predominance of sympathetic tone over vagal tone. Actual worsening of HRV with ACEI treatment was evident in several major time domains. The time domain SDNN (the standard deviation of all normal RR intervals) fell from 42.0 +/- 24.8 ms to 20.1 +/- 16.1 ms (P = 0.004) and the triangulation index fell from 178.0 +/- 94.0 to 115 +/- 59.2 (P = 0.01). A trend toward reduced HRV was seen in several other time domains. CONCLUSION: These findings suggest that, unlike the general population, treatment of ESRD patients with an angiotensin converting enzyme inhibitor may cause a deleterious shift toward increased cardiac sympathetic nervous system tone.     

Angiotensin converting enzyme inhibition and chronic cyclosporine-induced renal dysfunction in type 1 diabetes

AIM.: This study was designed to evaluate whether the angiotensinconverting enzyme inhibitor enalapril could prevent cyclosporine-inducedrenal dysfunction in diabetic patients treated with CsA in monotherapy. DESIGN.: Twenty-four recent onset insulin-dependent diabetic patientswithout prior renal involvement were randomized to receive a3 month course of either cyclosporine (CsA) alone (7.5 mg/kg.b.i.d. in olive oil) or CsA$enalapril (20 mg p.o. oad.). END POINTS.: were mean arterial pressure, plasma creatinine, GFR, renal plasmaflow, renal vascular resistance, sodium and lithium clearancesmeasured before and after 3 months of treatment. RESULTS.: Baseline values were identical in both groups except for meanarterial pressure which was slightly higher in the subjectssubsequently receiving CsA$enalapril. Three month treatmentwith CsA increased significantly mean arterial pressure andrenal vascular resistance by 9 and 24% respectively, while decreasingsignificantly glomerular filtration rate and renal plasma flowby 17 and 14% respectively. Enalapril was able to prevent thedecline in GFR and the increase in blood pressure induced byCsA. This effect was demonstrated despite a similar increasein renal vascular resistance suggesting a dissociation betweenchanges in glomerular filtration rate and renal vascular resistanceduring angiotensin converting-enzyme inhibition. CONCLUSION.: Chronic angiotensin converting-enzyme inhibition could affordsome degree of protection against CsA-induced renal dysfunction.Whether these results can be extrapolated to transplant recipientsin whom CsA is usually associated to treatment by glucocorticosteroids,deserves further evaluation.     

Invited Review Recognition and management of angiotensin converting enzyme inhibitor fetopathy

Angiotensin converting enzyme (ACE) inhibitors are extensively used for the treatment of hypertension, to decrease proteinuria, and to mitigate hyperfiltration. These drugs now have been shown to be fetotoxic causing profound fetal hypotension, renal tubular dysplasia, anuria-oligohydramnios, growth restriction, hypocalvaria, and death when used in the second and third trimesters of pregnancy. We recommend that ACE inhibitors not be used in pregnancy. However, if a child is born with ACE inhibitor fetopathy, aggressive therapy with dialysis to remove the inhibitor may mitigate the profound hypotensive effects. Therapy will depend on the specific ACE inhibitor, and care recommendations cannot be generalized for the entire class of drugs as their protein binding and volume of distribution differ substantially.     

血管紧张素转化酶基因多态性在终末期肾功能衰竭患者中的分布及其意义

目的 为了进一步阐明由于血管紧张素(ACE)基因多态性而导致的循环中ACE水平不同在肾脏疾病进展中的意义。方法 对77例终末期肾功能衰竭(ESRF)患者和150名正常人ACE基因多态性进行了分析。结果 ACE基因缺失型(DD)(15.6％VS.6.0％,P<0.01)和插入型(DI)(53.2％VS39.3％,P<0.05)在ESRF患者中的发生频率明显高于正常人,而Ⅱ型的发生频率则明显低于正常人(31.2％VS54.7％,P<0.01)。结论 ACE基因多态性与肾脏疾病病情进展及肾小球硬化的发生有一定联系。ACE基因多态性的分析,有可能成为判断肾脏疾病患者预后的一个标记物。     

Association between peri‐operative angiotensin‐converting enzyme inhibitors and angiotensin‐2 receptor blockers and acute kidney injury in major elective non‐cardiac surgery: a multicentre,prospective cohort study

The peri‐operative use of angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers is thought to be associated with an increased risk of postoperative acute kidney injury. To reduce this risk, these agents are commonly withheld during the peri‐operative period. This study aimed to investigate if withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers peri‐operatively reduces the risk of acute kidney injury following major non‐cardiac surgery. Patients undergoing elective major surgery on the gastrointestinal tract and/or the liver were eligible for inclusion in this prospective study. The primary outcome was the development of acute kidney injury within seven days of operation. Adjusted multi‐level models were used to account for centre‐level effects and propensity score matching was used to reduce the effects of selection bias between treatment groups. A total of 949 patients were included from 160 centres across the UK and Republic of Ireland. From this population, 573 (60.4%) patients had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers withheld during the peri‐operative period. One hundred and seventy‐five (18.4%) patients developed acute kidney injury; there was no difference in the incidence of acute kidney injury between patients who had their angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers continued or withheld (107 (18.7%) vs. 68 (18.1%), respectively; p = 0.914). Following propensity matching, withholding angiotensin‐converting enzyme inhibitors or angiotensin‐2 receptor blockers did not demonstrate a protective effect against the development of postoperative acute kidney injury (OR (95%CI) 0.89 (0.58–1.34); p = 0.567).     

Effect of angiotensin converting enzyme (ACE) and angiotensins on human sperm functions

Summary.  The presence of components of the renin angiotensin system (RAS) and specific receptors of angiotensin II in the female and male reproductive tract supports the hypothesis that reproductive functions may be controlled by RAS. Therefore, the present study investigated the influence of ACE and angiotensins on sperm functions and the sperm–egg interaction.
The experiments did not indicate direct effects of ACE on the capacitation process or acrosome reaction. Release of ACE from human spermatozoa during capacitation was not related to their ability to undergo acrosome reaction after stimulation with ionophore. Therefore, ACE release does not seem to be a useful clinical marker for human sperm capacitation. However, decreased binding of human spermatozoa to the oolemma of zona-free hamster oocytes after inhibition of ACE by captopril indicates that kininase II is involved in sperm–egg interactions. In contrast to other studies, incubation with captopril had no influence on sperm binding to the zona pellucida. Because effects of ACE on sperm–egg interactions but not on capacitation or acrosome reaction were observed, several experiments were performed to study the influence of substrates and products on the acrosome reaction. Angiotensin II induced the acrosome reaction dose-dependently, whereas angiotensin I had no effect on the acrosome reaction. The effect of angiotensin II on acrosome reaction seems to be calcium-dependent and mediated by protein kinases. Since a specific type 2 angiotensin II receptor inhibits the acrosome reaction induced by angiotensin II, this subtype of receptors may be present at the surface of sperm heads. Another clue for the presence of type 2 receptors on human spermatozoa is the finding that pertussis toxin did not inhibit the angiotensin II induced acrosome reaction. In contrast to type 1 angiotensin II receptors, type 2 receptors are known to be G-protein independent.     

Anaesthesia and angiotensin-converting enzyme inhibitors

The effect of enalapril pretreatment on the haemodynamic response to tracheal intubation and surgical stimulation has been studied in 22 patients. Enalapril 5 mg given 4 hours before operation was associated with a significant reduction in the pressor response associated with intubation (p less than 0.05) and surgical stimulation (p less than 0.005) compared with control. Heart rate changes were similar in the two groups. The role of the renin-angiotensin system in relation to the pressor response to sympathetic stimulation is discussed and it is concluded that angiotensin-converting enzyme inhibitors may help improve peri-operative cardiovascular stability.     

Angiotensin converting enzyme inhibitor-induced angioedema: a report of two cases

Angioedema is a rare but potentially fatal side effect of angiotensin converting enzyme (ACE) inhibitors. We report for the first time, two children with systemic lupus erythematosus who developed acute angioedema after the long-term use of enalapril. Prompt recognition and appropriate management of ACE-induced angioedema prevented life-threatening complications. This report highlights the potential risks of angioedema associated with the use of ACE inhibitors in children. Patients should be advised to seek medical treatment immediately if they experience swelling of the face, neck, or tongue, and especially if they have trouble breathing, speaking, or swallowing. Received: 12 March 1999 / Revised: 8 June 1999 / Accepted: 8 June 1999     

High flow and high dose neosynephrine are effective to maintain perfusion pressure for the patient with preoperative angiotensin converting enzyme inhibitor during cardiopulmonary bypass

Angiotensin converting enzyme inhibitors (ACEIs) are widely used in the treatment of hypertension, myocardial infarction, and congestive heart failure. They have a known adverse effect of unresponsiveness to vasoconstrictors resulting in hypotension for the patients undergoing cardiac surgery. We report a case of a 43-year-old female patient with preoperative lisinopril (2.5 mg per day for a week prior to cardiac surgery), who was diagnosed with severe mitral and tricuspid valve regurgitation. She underwent both a mitral and tricuspid valve replacement operation using cardiopulmonary bypass (CPB). To address her ACEI-associated hypotension on cardiopulmonary bypass, bypass flows were as high as cardiac index of greater than 3 (3.1 +/- .2) L/min/m2 to provide sufficient perfusion indicated by cerebral oxymetry monitoring and adequate urine on pump. In addition, due to unresponsiveness to regular concentration of neosynephrine (neo), boluses of higher concentrations up to 320 microg/mL of neo were administered to maintain the perfusion pressure on pump. The patient was weaned from CPB uneventfully and was discharged home on postoperative day 7. Additional therapeutic treatment to ACEI-associated hypotension and unresponsiveness to neo for the patients undergoing cardiac surgery using CPB is reviewed as well in this paper.     

Angiotensin converting enzyme gene polymorphism in primary vesicoureteral reflux

We studied the insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene in 78 patients with primary vesicoureteral reflux (VUR), and examined renal function by dimercaptosuccinate (DMSA) renoscintigraphy and diethylenetriaminepenta-acetic acid (DTPA) renogram in each genotype. Patients were classified into three genotypes according to the ACE gene I/D polymorphisms: 32 in II genotype, 36 in ID, and 10 in DD. The incidence of presumably congenital unilateral small kidneys was high in DD patients (70%). Glomerular filtration rate obtained from DTPA renogram was 120.7±35.7 ml/min (expressed as mean±SD) in II genotype, 111.7±33.3 in ID, and 88.0±18.0 in DD. The total quantitative DMSA tracer uptake of both kidneys was also low in patients with the D allele. This study shows that the D allele of ACE gene is closely related to small congenital kidneys with refluxing ureters in patients with primary VUR, and in accordance with previous reports, this allele is also related to the progression of reflux nephropathy. Received: 27 November 2000 / Revised: 10 April 2001 / Accepted: 10 April 2001     

Effect of combined angiotensin‐converting enzyme and aldosterone inhibition on plasma plasminogen activator inhibitor type 1 levels in chronic hypertensive patients

Aim: A possible link between the renin–angiotensin–aldosterone system (RAAS) and fibrinolysis has recently been suggested. Systemic infusion of angiotensin II results in an increase in plasminogen activator inhibitor type 1 (PAI‐1) levels and angiotensin‐converting enzyme inhibitors (ACEI) have been shown to decrease PAI‐1 levels. Moreover, recent data indicated that plasma aldosterone levels were positively correlated with plasma PAI‐1 levels. This study was designed to compare the effects of an ACEI with an ACEI in combination with an aldosterone antagonist on PAI‐1 levels in chronic hypertensive patients. Methods: Patients were randomized into two groups and were treated with either low salt diet plus fosinopril (group 1, n = 43) or low salt diet plus fosinopril plus spironolactone (group 2, n = 42). Plasma PAI‐1, tissue plasminogen activator (tPA) and plasma renin activity (PRA) levels were measured before and after 24 week treatment in both groups. Results: The mean basal PRA levels were similar in both groups. After antihypertensive therapy, the mean PRA increased significantly in both groups (P < 0.005). The mean plasma PAI‐1 levels were reduced in both treatment groups (P < 0.005). However, the reduction in group 2 was more pronounced (P < 0.05). Although after the treatment mean plasma levels of PAI‐1 significantly reduced in both groups, the reduction of PAI‐1 levels was more pronounced in group 2. Conclusion: Although the plasma levels of PAI‐1 significantly reduced after treatment in both groups, the reduction of PAI‐1 levels was more pronounced in group 2. These data indicated that administration of aldosterone antagonists in combination with ACEI had additional benefit on fibrinolysis in chronic hypertensive patients.