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Anemia associated with ACE inhibitors is rare but it may cause problems especially in patients with renal disease. This study assessed the acute effect of trandolapril, an ACE inhibitor, on serum erythropoietin (EPO) levels in uremic and hypertensive patients. Trandolapril 2 mg/day was given orally for three days and blood samples were collected on the first and third day. Trandolapril led to a significant decrease in serum EPO in patients with chronic renal failure. Although the drug lowered serum EPO in hypertensive patients, this effect was not statistically significant. This drop in serum EPO levels may be one of the mechanisms by which ACE inhibitors cause anemia, or worsen anemia, in uremic patients and further studies are needed to clarify this point.     

Renal effects of angiotensin converting enzyme inhibitors in heart failure: a clinician's guide to minimizing azotemia and diuretic-induced electrolyte imbalances

Angiotensin converting enzyme (ACE) inhibitors have proved to be valuable, life-saving medications in the management of heart failure. While reducing myocardial oxygen consumption, they increase cardiac output and thus renal plasma flow. Despite reports in the literature of adverse effects of these drugs on renal function, the risks of functional deterioration are predictable in patient populations and remediable. Patients at greatest risk of declining renal function during therapy with ACE inhibitors are those in whom maintenance of renal function is dependent on angiotensin II. Reducing the dose of the concomitant diuretic, liberalizing the dietary intake of sodium, and increasing the dose of the ACE inhibitor usually restores renal function to baseline. In patients with severe renal insufficiency, reducing the dose of the ACE inhibitor might be necessary to preserve the glomerular filtration rate.     

Pharmacologic, pharmacokinetic, and therapeutic differences among ACE inhibitors

Angiotensin-converting enzyme (ACE) inhibitors are a heterogeneous group of agents, and important pharmacologic, pharmacokinetic, and therapeutic differences among them must be understood to obtain optimal therapy. For patients with severe liver disease, lisinopril and captopril are not prodrugs (e.g., do not require hepatic activation), and lisinopril has almost solely renal elimination. Enalaprilat, the intravenous formulation of enalapril, is the only intravenously available ACE inhibitor and can be given to patients with severe liver dysfunction as it is also not a prodrug. Fosinopril is the only drug with compensatory dual routes of elimination, and it does not require dosage adjustment in patients with reduced renal function, as other ACE inhibitors do. Captopril and moexipril have potential drug-food interactions and are the only agents that should be spaced from meals. The ACE inhibitors also differ in their dialyzability, half-life, lipophilicity, trough:peak ratios, approved indications, and therapeutic information available for many indications.     

ACE inhibitors and proteinuria

This review discusses the clinical consequences of urinary protein loss and the effects of inhibitors of the angiotensin converting enzyme (ACE) on this clinical finding. Proteinuria appears to be an important risk factor for renal function deterioration and for cardiovascular mortality. ACE inhibitors have been shown to reduce proteinuria more effectively than other antihypertensives. Their antiproteinuric effect seems to be independent of the underlying renal disease, and is mediated by a specific, not yet fully elucidated mechanism. Urinary protein loss related phenomena, such as hypoalbuminemia and aberrant lipoprotein profile, tend to improve also during ACE inhibitor treatment. Furthermore, ACE inhibition has been shown to prevent the renal function deterioration that is frequently observed in patients with renal disease. Interestingly, it has recently been shown that in proteinuric patients with renal disease the initial proteinuria lowering response to ACE inhibition predicts long-term renal function outcome during this treatment the more proteinuna is lowered during the first months, the better renal function will be preserved over the following years. Because of these favorable effects ACE inhibitors have become a widely used class of agents in nephrology. They are not only prescribed for lowering blood pressure in the hypertensive renal patient, but also as symptomatic treatment of patients with proteinuria, and to prevent renal function loss in patients with both diabetic and non-diabetic renal disease.     

Angiotensin receptor antagonists and ACE inhibitors

BACKGROUND: ACE inhibitors are valuable and effective drugs in the treatment of hypertension, heart failure, myocardial infarction and nephropathy. Angiotensin receptor antagonists, which have recently been introduced into clinical practice, have the potential to replace ACE inhibitor therapy in many patients. OBJECTIVE: To review the mechanisms of action, indications and side effects of ACE inhibitors and angiotensin receptor antagonists and to highlight similarities and differences between the two drug classes. DISCUSSION: Angiotensin receptor antagonists have the theoretical advantage of being more effective in blocking the effects of angiotensin II at angiotensin type I receptors. The potential disadvantage of not potentiating bradykinin may be compensated by the unopposed action of angiotensin II on vascular angiotensin type II receptors, which appear to mediate similar beneficial cardiovascular effects to bradykinin. Angiotensin II receptor antagonists have a lower incidence of adverse effects than ACE inhibitors as they do not produce cough and appear much less likely to produce angioedema. Although ACE inhibitors are the most commonly prescribed antihypertensive drug class in Australia, they are underused for the treatment of heart failure and left ventricular dysfunction following myocardial infarction. Angiotensin receptor antagonists may become alternative therapies to ACE inhibitors in these disorders. However, at present they are only indicated for the treatment of hypertension.     

Angiotensin-converting enzyme inhibitors

ACE inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease. ACE inhibitors alter the balance between the vasoconstrictive, salt-retentive, and hypertrophic properties of angiotensin II (Ang II) and the vasodilatory and natriuretic properties of bradykinin and alter the metabolism of a number of other vasoactive substances. ACE inhibitors differ in the chemical structure of their active moieties, in potency, in bioavailability, in plasma half-life, in route of elimination, in their distribution and affinity for tissue-bound ACE, and in whether they are administered as prodrugs. Thus, the side effects of ACE inhibitors can be divided into those that are class specific and those that relate to specific agents. ACE inhibitors decrease systemic vascular resistance without increasing heart rate and promote natriuresis. They have proved effective in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction, and they delay the progression of diabetic nephropathy. Ongoing studies will elucidate the effect of ACE inhibitors on cardiovascular mortality in essential hypertension, the role of ACE inhibitors in patients without ventricular dysfunction after myocardial infarction, and the role of ACE inhibitors compared with newly available angiotensin AT1 receptor antagonists.     

Therapeutic interventions for nephropathy in type I diabetes mellitus

Diabetic nephropathy is the single most common cause of end-stage renal disease in the United States. Recently, several major therapeutic interventions have been developed and shown to slow or halt the progression of renal failure in patients with diabetes and diabetic kidney disease. Studies have shown that in patients with insulin-dependent diabetes and proteinuria, lowering systemic blood pressure slows the rate of decline in renal function and improves patients' survival. In the recently completed trial of angiotensin converting enzyme (ACE) inhibition in diabetic nephropathy, ACE inhibitors were specifically shown to decrease dramatically the risk of doubling of serum creatinine or reaching a combined outcome of end-stage renal disease or death independent of their effect on systemic blood pressure. In studies with small numbers of patients, dietary protein restriction has also been shown to slow the rate of decline of renal function. New potential interventions currently undergoing study include treatment with aldose reductase inhibitors, treatment with inhibitors of the formation of advanced glycosylation end-products, treatment of dyslipidemia, and a variety of other less well-studied interventions.     

Renal protection and angiotensin converting enzyme inhibition in microalbuminuric type I and type II diabetic patients

BACKGROUND: Many studies have emphasized the role of antihypertensive drugs and in particular angiotension converting enzyme (ACE) inhibitors in the retardation of diabetic nephropathy. Although these studies have focused predominantly on patients with overt proteinuria, more recently a number of investigators have explored the role of ACE inhibitors in both type I and type II diabetic patients with an earlier phase of diabetic renal disease known as microalbuminuria. These agents are now being considered as renoprotective agents not only in hypertensive patients but also in those with 'normal' blood pressure. Initially, studies in type I diabetic patients showed that ACE inhibition was effective in retarding the increase in albuminuria which was observed in placebo treated groups. More recently, several multi-centre placebo controlled studies have been performed suggesting that prolonged treatment not only reduced albuminuria but also preserved renal function. The role of ACE inhibition in microalbuminuric type II diabetic patients is less well characterised although several studies have recently described beneficial effects of ACE inhibition on albuminuria and possibly on renal function. REVIEW: Although ACE inhibitors have been clearly shown to reduce urinary albumin excretion in diabetic patients, the issue as to whether they confer a specific benefit over other classes of antihypertensive agents remains controversial. Several meta-analyses have suggested that ACE inhibitors are more potent at decreasing albuminuria or proteinuria than other antihypertensive agents, for a given reduction in blood pressure. The Melbourne Diabetic Nephropathy Study Group has instituted a study which is placebo-controlled and is confined to normotensive type I and type II diabetic patients. The ACE inhibitor perindopril has been compared not only with placebo but also with the dihydropyridine calcium channel blocker, nifedipine. Preliminary analysis reveals that after 12 and 24 months of treatment, perindopril is more effective in reducing albuminuria than placebo or nifedipine. CONCLUSION: ACE inhibitors are a promising class of antihypertensive agents in diabetic patients with microalbuminuria. These drugs should be considered as first line agents in such patients, even in the absence of systemic hypertension.     

Effect of angiotensin-converting enzyme inhibitors on the progression of nondiabetic renal disease: a meta-analysis of randomized trials. Angiotensin-Converting-Enzyme Inhibition and Progressive Renal Disease Study Group

BACKGROUND: The effect of angiotensin-converting enzyme (ACE) inhibitors in slowing the decline in renal function in nondiabetic renal disease varies among studies. PURPOSE: To use meta-analysis to assess the effect of ACE inhibitors on the development of end-stage renal disease caused by factors other than diabetes. DATA SOURCES: The English-language medical literature, identified by a MEDLINE search and unpublished studies. STUDY SELECTION: All randomized studies that compared ACE inhibitors with other antihypertensive agents and had at least 1 year of planned follow-up were selected. Studies of diabetic renal disease and renal transplants were excluded. A total of 1594 patients in 10 studies was included. DATA EXTRACTION: Data on end-stage renal disease, death, drop out, and blood pressure were extracted. Study investigators confirmed results and provided additional data. DATA SYNTHESIS: Among 806 patients receiving ACE inhibitors, 52 (6.4%) developed end-stage renal disease and 17 (2.1%) died; in the 788 controls, the respective values were 72 (9.1%) and 12 (1.5%). The pooled relative risks were 0.70 (95% CI, 0.51 to 0.97) for end-stage renal disease and 1.24 (CI, 0.55 to 2.83) for death; the studies were not significantly heterogeneous. The decreases in weighted mean systolic and diastolic blood pressures during follow-up were 4.9 and 1.2 mm Hg greater, respectively, in the patients who received ACE inhibitors. CONCLUSIONS: Angiotensin-converting enzyme inhibitors are more effective than other antihypertensive agents in reducing the development of end-stage nondiabetic renal disease, and they do not increase mortality. It could not be determined whether this beneficial effect is due to the greater decline in blood pressure or to other effects of ACE inhibition.     

The significance of converting enzyme inhibitor angiotensin I to angiotensin II in treatment of patients with coronary disease]

Angiotensin-converting enzyme (ACE) inhibitors are now established drugs in the treatment of hypertension and heart failure. The renin-angiotensin-aldosterone system is complex and acts as a circulating hormonal system, a local endogenous tissue system and neuromodular. Current experimental evidence suggests that ACE inhibitors reduce the risk associated with atherosclerotic cardiovascular disease. The antiatherogenic action of ACE inhibitors is related to complex effects mediated by these agent, including an antiproliferative and antimitotic action, beneficial effects on endothelial function, plaque-stabilizing effects and the action of these agents on the sympathetic nervous system. The role of ACE inhibitors in preventing the clinical sequale of atherosclerotic cardiac disease has been evaluated in various patient populations. Several small trial assess the effects of ACE inhibitors in severity of angina pectoris have reported conflicting results, with benefit is some patients and no benefit or even exacerbation of angina in others, indicating that ACE inhibitors do not have consistent antianginal effects in short-term study. ACE inhibitors have the theoretical potential to prevent restenosis after PTCA but they do not prevent restenosis and has no effect on overall clinical outcome. New data suggest that ACE inhibitors may be effective therapy fir patients following acute myocardial infarction. The renin-angiotensin system, is activated during new myocardial infarction and has an impact on the process of remodeling of the left ventricle which causes ist dysfunction and heart failure. In most of the large mortality trials the rationale for early treatment with ACE inhibitors after myocardial infarction was stated. ACE inhibitors have a positive effect in preventing the ventricular dilatation and they reduce the rate of reinfarctions and the mortality rate.     

Calcium antagonists and renal protection: emerging perspectives

During the past two decades, major investigative interest has focused on the determinants of chronic renal disease and interventions that retard the inexorable progression to end-stage renal disease. Recent studies have provided a theoretic framework for anticipating that angiotensin-converting enzyme (ACE) inhibitors, and possibly calcium antagonists, may preferentially retard the progression of renal disease. Whereas the majority of available clinical trials have assessed the effects of ACE inhibitors in patients with insulin-dependent diabetes mellitus, relatively few long-term studies have evaluated the renoprotective effects of ACE inhibitors and calcium antagonists in patients with nondiabetic renal disease. Recent observations suggest that the two classes of drugs act in a complementary manner to countervail pathogenetic mechanisms at the level of the mesangium. Such observations recently prompted randomized prospective studies that compare the renoprotective effects of calcium antagonist versus ACE inhibitor monotherapy in both diabetic patients and patients with nondiabetic renal disease.     

Drug administration in patients with renal insufficiency. Minimising renal and extrarenal toxicity

Renal insufficiency has been associated with an increased risk of adverse effects with many classes of medications. The risk of some, but not all, adverse effects has been linked to the patient's degree of residual renal function. This may be the result of inappropriate individualisation of those agents that are primarily eliminated by the kidney, or an alteration in the pharmacodynamic response as a result of renal insufficiency. The pathophysiological mechanism responsible for alterations in drug disposition, especially metabolism and renal excretion, is the accumulation of uraemic toxins that may modulate cytochrome P450 enzyme activity and decrease glomerular filtration as well as tubular secretion. The general principles to enhance the safety of drug therapy in patients with renal insufficiency include knowledge of the potential toxicities and interactions of the therapeutic agent, consideration of possible alternatives therapies and individualisation of drug therapy based on patient level of renal function. Although optimisation of the desired therapeutic outcomes are of paramount importance, additional pharmacotherapeutic issues for patients with reduced renal function are the prevention or minimisation of future acute or chronic nephrotoxic insults, as well as the severity and occurrence of adverse effects on other organ systems. Risk factors for the development of nephrotoxicity for selected high-risk therapies (e.g. aminoglycosides, nonsteroidal anti-inflammatory drugs, ACE inhibitors and radiographic contrast media) are quite similar and include pre-existing renal insufficiency, concomitant administration of other nephrotoxins, volume depletion and concomitant hepatic disease or congestive heart failure. Investigations of prophylactic approaches to enhance the safety of these agents in patients with renal insufficiency have yielded inconsistent outcomes. Hydration with saline prior to drug exposure has given the most consistent benefit, while sodium loading and use of pharmacological interventions [e.g. furosemide (frusemide) dopomine/dobutamine, calcium antagonists and mannitol] have resulted in limited success. The mechanisms responsible for altered dynamic responses of some agents (benzodiazepines, theophylline, digoxin and loop diuretics) in renally compromised patients include enhanced receptor sensitivity secondary to the accumulation of endogenous uraemic toxins and competition for secretion to the renal tubular site of action. Application of the pharmacotherapeutic principles discussed into clinical practice will hopefully enhance the safety of these agents and optimise patient outcomes.     

Benefits and cost of antihypertensive treatment in incipient and overt diabetic nephropathy

PREVALENCE: The prevalence of abnormally elevated urinary albumin excretion rate (> 30 mg/24 h) is approximately 40% in insulin-dependent and in non-insulin-dependent diabetic patients. Diabetes has become the leading cause of end-stage renal failure in Europe, USA and Japan. Approximately 90% of the direct and indirect costs of caring for diabetic patients are spent on the complications of diabetes. RISK FACTORS: Identification of patients at high risk of developing diabetic nephropathy is possible by screening for microalbuminuria (30-300 mg/24 h). Additional risk factors/ markers for development of nephropathy are male sex, genetic predisposition, ethnic conditions, early onset of diabetes, poor metabolic control, hyperfiltration, elevated prorenin and smoking. Elevated urinary albumin excretion rate indicates a substantially increased cardiovascular morbidity and mortality risk in diabetic patients. PREVENTION OF NEPHROPATHY: Randomized controlled trials in normotensive insulin-dependent and in non-insulin-dependent diabetic patients with persistent microalbuminuria indicate that angiotensin converting enzyme (ACE) inhibitors diminish urinary albumin excretion rate, and postpone and may even prevent progression to clinical overt nephropathy. These findings indicate that screening and intervention programs could probably save lives and lead to considerable economic savings. TREATMENT OF NEPHROPATHY: Systemic blood pressure elevation to a hypertensive level is an early and frequent phenomenon in diabetic nephropathy. Furthermore, nocturnal blood pressure elevation (non-dippers) occurs more frequently in patients with nephropathy. Systemic blood pressure elevation, hyperglycaemia, albuminuria and the D polymorphism in the ACE gene accelerate the progression of diabetic nephropathy. Studies of the impact of other potential progression promoters (i.e. smoking, hyperlipidaemia and protein intake) have yielded conflicting results. Effective blood pressure reduction using ACE inhibitors or drugs of other classes, or both, frequently in combination with diuretics reduces albuminuria, delays the progression of nephropathy, postpones renal failure and improves survival in patients with diabetic nephropathy. Antihypertensive treatment for diabetic nephropathy extends life and saves money.     

Serum angiotensin converting enzyme activity in patients with untreated essential arterial hypertension

The serum angiotensin converting enzyme (ACE) in 30 patients with untreated essential arterial hypertension, 30 patients with chronic renal failure accompanied with arterial hypertension and 30 healthy individuals was measured. The subjects of both sexes have been old 35-60 years. The serum ACE activity was determined by the spectrophotometric method, using Hip-Gly-Gly as a substrate. The serum ACE activity significantly increased in patients with arterial hypertension (32.48 +/- 2.02; X +/- SEM) and patients with chronical renal failure accompanied with arterial hypertension (37.10 +/- 1.45) when compared to the healthy individuals (20.83 +/- 1.33). Possible mechanisms of increasing ACE activity with the patients suffering of arterial hypertension are discussed.     

The effect of ionic conditions on the conformations of supercoiled DNA. I. Sedimentation analysis

Valsartan competitively and selectively inhibits the actions of angiotensin II at the AT1 receptor subtype which is responsible for most of the known effects of angiotensin II. In clinical trials in patients with mild to moderate essential hypertension valsartan was as effective as losartan, lisinopril, enalapril, amlodipine and hydrochlorothiazide. Addition of the latter reduced blood pressure in patients who did not respond sufficiently to valsartan monotherapy. Preliminary data also suggest valsartan may be effective in patients with severe essential hypertension. The drug was as effective as lisinopril as treatment for mild to moderate essential hypertension in patients with renal insufficiency and did not worsen renal function. Headache, dizziness and fatigue were the most common adverse events in placebo-controlled studies; the incidence of these adverse events was not significantly different between placebo and valsartan recipients. Compared with ACE inhibitors, valsartan was associated with a significantly lower incidence of dry cough. Thus, valsartan is an effective treatment for mild to moderate essential hypertension and may be particularly useful in patients who experience persistent cough during ACE inhibitor therapy.     

Effects of ACE inhibitor therapy on quality of life in patients with heart failure

In addition to effects on survival, hemodynamics, and exercise capacity, quality of life has become an important outcome of therapy for chronic heart failure. A large clinical trial of the angiotensin-converting enzyme (ACE) inhibitor enalapril reports that certain domains of health-related quality of life (HRQL) have a long-term impact on survival in patients with reduced left ventricular systolic function, regardless of symptoms of heart failure at diagnosis. Results of large-scale clinical trials that measured the impact of several different ACE inhibitors on quality of life in these patients suggest benefits of the drugs, but data are confounded by a definite placebo effect. Studies are further confounded by high noncompletion rates for sicker patients, particularly beyond 1 year. Because measurement tools varied and different quality of life domains were evaluated, direct comparison of studies is problematic. Typically, HRQL measurements in patients receiving ACE inhibitors showed small improvement or did not differ significantly from those in placebo-treated patients with long-term follow-up, although short-term trials (< 6 mo) showed some benefit. Moreover, multicenter trials such as SOLVD, V-HeFT II, and ramipril studies indicated that ACE inhibitors do not compromise and may actually improve certain components of quality of life in a large number of patients with chronic heart failure secondary to reduced left ventricular systolic function while having favorable effects on survival, exercise capacity, hemodynamics, or symptoms.     

Current therapy of chronic renal failure

The course of chronic renal failure is generally progressive and mediated by several factors that operate in combination. Several extrarenal events which may cause transient or permanent deterioration of renal function, are important, because their correction may slow the progression of renal disease e.g. volume disorders, infection, nephrotoxic agents. In progression of chronic renal disease leading factors are hypertension, proteinuria and high protein/phosphorus intake. Number of evidence suggests that ameliorating hypertension, reducing proteinuria slow the progression of chronic renal failure. Clinical studies in diabetic nephropathy demonstrated that the renoprotective effect of ACE inhibitors was independent of their effect of systemic blood pressure. In ESRD patients access for renal replacement therapy should be obtained as early as possible. An A-V fistula may take several weeks to mature especially in diabetic or elderly patients. Early dialysis has been advocated in diabetic patients. In general, patients can start ESRD therapy when residual kidney function drops to 5-10% of normal value. High quality of dialysis should be provided to the uremic patient with respect of successful renal transplantation.     

The antiproteinuric action of angiotensin-converting enzyme inhibitors in chronic glomerulonephritis and diabetic nephropathy

Antiproteinuria effects of angiotensin-converting enzyme (ACE) inhibitors was studied in 23 patients with chronic nephritis (CN) and 32 patients with diabetic nephropathy (DN). CN patients received Capoten, DN patients were given enalapril. The drugs were also examined for the action on systemic arterial pressure, renal function and intrarenal hemodynamics. Significantly decreased urinary excretion of protein occurred in DN patients on the treatment month 1, in CN subjects on month 3. In both groups ACE inhibitors produced marked hypotensive effect, did not affect renal function, noticeably improved intraglomerular hemodynamics. Hypotensive and antiproteinuria activity of the drugs were unrelated. The mechanism of antiproteinuria action of ACE inhibitors works via normalization of intrarenal hemodynamics. Systemic arterial hypertension seems to be an additional factor aggravating disturbances of intrarenal circulation and provoking proteinuria.     

The effect of angiotensin-converting enzyme inhibitors on proteinuria in chronic glomerulonephritis

The effect of two angiotensin-converting enzyme (ACE) inhibitors, lisinopril and captopril, on proteinuria and renal haemodynamics was investigated in 11 hypertensives (9 men, 2 women; mean age 46 +/- 16 years) with proteinuria (> 1.5 g/24 h) due to chronic glomerulonephritis and impaired renal function (glomerular filtration rate < 75 ml/min). In a randomized and double-blind cross-over trial the patients received, each time for six weeks, either lisinopril (5 mg/d, sometimes increased to 10 mg/d after 3 weeks) or captopril (twice daily 12.5 mg, sometimes increased to twice 25 mg after 3 weeks). Initially and between the individual treatment phases they were on a placebo phase for 4 weeks. The following were measured: protein excretion, including fractional clearance of albumin and IgG, plasma-renin activity and renal haemodynamics. Protein excretion was not significantly reduced by either drug (placebo: 7.1 +/- 4.0 g/d; lisinopril: 5.1 +/- 2.8 g/d; captopril: 5.4 +/- 3.0 g/d). Albumin excretion and fractional albumin clearance were significantly decreased only by lisinopril (P < 0.05), not by captopril. Plasma-renin activity was increased more by lisinopril than captopril (Placebo: 1.0 +/- 0.9 ng/ml.h; lisinopril: 5.2 +/- 2.8 ng/ml.h [P < 0.05]; captopril: 1.8 +/- 1.3 ng/ml.h [P < 0.05]). The renal haemodynamics was only slightly influenced by either drug, but captopril significantly decreased the filtration fraction in the presence of chronic glomerulonephritis and renal failure. - Resulting from their influence on the renin-angiotensin-aldosterone system, ACE inhibitors have, in addition to their known action on renal haemodynamics, an independent effect on the loading barrier of the basal membrane of the kidney.