In general, angiotensin-converting enzyme (ACE)

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1 AJH 1999;12:195S 203S Are Drugs That Block the Renin-Angiotensin System Effective and Safe in Patients With Renal Insufficiency? Matthew R. Weir Extensive clinical experience with angiotensinconverting enzyme (ACE) inhibitors in patients with renal disease has demonstrated efficacy in reducing blood pressure, proteinuria, and the rate of progression of renal disease. This is evident in both diabetic and nondiabetic nephropathy, particularly that associated with proteinuria. The ability of ACE inhibitors to stabilize renal function is not attenuated by more severe renal insufficiency, but greater caution with these drugs is necessary, as there may be drug accumulation and a greater propensity for an increase in serum potassium and creatinine levels. Both of these effects are selflimited and rarely require discontinuation of the drug. Increases in creatinine up to 20% are expected; greater increases are indicative of volume depletion or anatomic renal artery disease. Angiotensin II receptor blockers reduce blood pressure to a degree comparable to that achieved with ACE inhibitors, and like ACE inhibitors, they reduce proteinuria to an extent greater than what would be expected by blood pressure reduction alone. Angiotensin II receptor blockers are currently being evaluated in comparison with other therapies in two large clinical trials of non insulindependent diabetic nephropathy with proteinuria to assess impact on the rate of progression of renal disease. Because of their antihypertensive/ antiproteinuric properties, it is likely they will provide some advantages over conventional drugs in protecting renal function. Early clinical experience with these drugs in patients with renal disease suggests that there might be a lesser incidence of functional renal insufficiency and hyperkalemia compared with ACE inhibitors. Am J Hypertens 1999;12:195S 203S 1999 American Journal of Hypertension, Ltd. KEY WORDS: ACE inhibitor, angiotensin receptor blocker, creatinine, potassium. In general, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers reduce blood pressure and proteinuria to a similar extent, although some differences may exist between the drug classes once comparative studies are performed in different demographic subgroups and with varying amounts of dietary salt consumption. 1 3 Both drug classes reduce proteinuria to a greater extent than would be expected with blood pressure reduction alone. Extensive clinical experience with ACE inhibitors in patients with renal disease has demonstrated efficacy in reducing blood pressure and proteinuria and the rate of progression of renal disease. 4,5 This is evident in both diabetic and nondiabetic ne- From the Division of Nephrology, Department of Medicine, and Clinical Research Unit, University of Maryland School of Medicine, Baltimore, Maryland. Address correspondence and reprint requests to Matthew R. Weir, MD, Division of Nephrology, University of Maryland Hospital, 22 S. Greene Street, Baltimore, MD 21201; mweir@ umppal.ab.umd.edu 1999 by the American Journal of Hypertension, Ltd /99/$20.00 Published by Elsevier Science, Inc. PII S (99)

2 196S WEIR AJH DECEMBER 1999 VOL. 12, NO. 12, PART 3 TABLE 1. BENEFITS TO RENAL FUNCTIONS OF DRUGS THAT BLOCK THE RENIN-ANGIOTENSIN SYSTEM Reduction in blood pressure Reduction in glomerular capillary pressure Stimulation of extracellular matrix degradation Reduction of proteinuria Attenuation of macrophage/monocyte infiltration phropathy, particularly that associated with proteinuria. 6 8 Similar data with the angiotensin II receptor blockers are not yet available, although two large international clinical trials are assessing the effects of angiotensin II receptor blockers versus other agents in patients with non insulin-dependent diabetes mellitus and nephropathy. Drugs that block the renin-angiotensin system have multiple mechanisms by which they stabilize renal function, including reduction of blood pressure, reduction of glomerular capillary pressure, stimulation of extracellular matrix degradation, reduction of proteinuria, and attenuation of macrophage/monocyte infiltration of the glomerulus (Table 1) Clinical studies have demonstrated that ACE inhibitors and angiotensin II receptor blockers provide similar levels of systemic blood pressure reduction. 1 3 Experimental and clinical studies suggest that ACE inhibitors cause glomerular capillary pressure reduction because of dilation of the efferent glomerular arteriole due to the effects of diminished angiotensin II synthesis and inhibition of bradykinin degradation, whereas angiotensin II receptor blockers reduce glomerular pressure primarily because of systemic blood pressure reduction and inhibition of angiotensin II effects. The greater reduction in glomerular capillary pressure with augmented bradykinin by ACE inhibitors may predispose volume-depleted subjects to functional renal insufficiency. Both ACE inhibitors and angiotensin II receptor blockers stimulate extracellular matrix degradation. 15,19 ACE inhibitors may have a theoretical advantage over angiotensin II receptor blockers because they augment bradykinin-mediated activation of plasminogen conversion to plasmin, which facilitates active metalloproteinase production and extracellular matrix degradation. 15 However, experimental studies show similar abilities of both classes of drugs in attenuating interstitial renal fibrosis. 15,20 ACE inhibitors and angiotensin II receptor blockers reduce proteinuria to a similar degree when administered longterm in human subjects. 5 With short-term dosing in experimental studies, proteinuria reduction occurs more quickly with an ACE inhibitor. 21 Both classes of FIGURE 1. Comparative effects of angiotensin-converting enzyme (ACE) inhibition v angiotensin II type 1 (AT 1 ) receptor antagonism on the rate of progression of renal disease. Predictive values for both classes of drugs are based on experimental data, and for ACE inhibitors, on human data as well. 15 GFR, glomerular filtration rate. drugs attenuate macrophage/monocyte infiltration in the glomerulus, thus limiting glomerulosclerotic damage. 15 Consequently, the experimental and clinical data suggest that although the two drug classes are mechanistically similar, some subtle differences exist. It is likely that despite these differences they will provide similar abilities in delaying progression of renal disease. However, clinical studies must confirm these theories (Figure 1). Despite the known ability of drugs that block the renin angiotensin system to lower blood pressure and stabilize renal function, physicians stop the use of these drugs once the serum creatinine level becomes abnormal. The ability of ACE inhibitors to stabilize renal function is not attenuated by more severe renal insufficiency. 6 However, greater caution when using these drugs is necessary because many of them are primarily excreted by the kidney, and drug accumulation may result in toxicity. It is for this reason that dosage adjustment should be made, and drugs that have a balanced excretory route between the liver and the kidneys should be preferentially used in patients with renal disease. One should expect an increase in serum creatinine level of up to 20% with the use of a drug that blocks the renin angiotensin system. This change should remain stable If the serum creatinine continues to rise, it indicates that the patient has either diminished effective arterial blood volume (usually due to the use of a diuretic) or anatomic renal artery stenosis. Consequently, appropriate therapeutic decisions can be made. Theoretically, angiotensin II receptor blockers may be less likely than ACE inhibitors to induce functional renal insufficiency and hyperkalemia, as they do not effect bradykinin metabolism. Bradykinin di-

3 AJH DECEMBER 1999 VOL. 12, NO. 12, PART 3 SAFETY, EFFICACY OF RENIN-ANGIOTENSIN INHIBITORS 197S FIGURE 2. Mechanism of action of angiotensin-converting enzyme (ACE) inhibitors: inhibition of angiotensin synthesis and bradykinin degradation. There is no effect on alternate pathways of angiotensin II synthesis. AT 1, angiotensin type 1; AT 2, angiotensin type 2. lates the efferent glomerular arteriole and this may further reduce glomerular filtration rate and alter potassium handling by the kidney. The purpose of this review is to explore the benefitrisk ratio of these two classes of drugs that inhibit the renin angiotensin system in patients with or without renal insufficiency, and to assess the means of optimizing their therapeutic index. MECHANISM OF ACTION OF ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS ACE inhibitors inhibit the angiotensin-converting enzyme that is necessary to catalyze the conversion of angiotensin I to angiotensin II. This blockade limits the production of angiotensin II and thus diminishes its likelihood to bind to its high-affinity type 1 receptor site, exert the actions of vasoconstriction, and increase extracellular fluid volume (Figure 2). Because angiotensin II has such a pervasive effect on the regulation of systemic arterial pressure, it is not surprising that this simple blockade results in substantial hemodynamic effects. Clinical studies demonstrate that the inhibition of angiotensin II formation is not attenuated with time. 26 However, the blockade is not complete in that serum angiotensin II levels remain about 20% of normal after long-term treatment with ACE inhibitors in human hypertensives. 27 ACE inhibitors do not affect enzymatic pathways leading to angiotensin II synthesis that do not involve the angiotensin-converting enzyme. In addition, ACE inhibitors inactivate kininase II, a kinin-degrading enzyme, which results in an accumulation of bradykinin, a vasodilatory peptide. Bradykinin likely enhances the vasodilatory effect of the ACE inhibitor, 28,29 although there is substantial debate as to the importance of this effect in contributing to the overall antihypertensive activity of ACE inhibitors. As will be discussed later, bradykinin causes dilatation of the efferent glomerular arteriole, which may be important not only in the development of functional renal insufficiency, but perhaps also in renal protection. FIGURE 3. Mechanism of action of angiotensin II type 1 (AT 1 ) receptor blockers: interruption of the binding of angiotensin II to its high-affinity receptor site. A subsequent increase in angiotensin II levels results in binding to other angiotensin binding sites, which may counteract type 1 receptor stimulation. On the other hand, angiotensin II receptor blockers, unlike ACE inhibitors, do not affect the angiotensinconverting enzyme. Instead, they occupy the highaffinity type 1 receptor site for angiotensin II (AT 1 ), thus limiting its binding and interfering with its effects (Figure 3). 30,31 Angiotensin II levels do accumulate in response to AT 1 receptor inhibition. Experimental studies suggest that other, lower-affinity receptor sites for angiotensin II may subsequently be occupied. 32 For example, the angiotensin type 2 (AT 2 ) receptor site is expressed not only during fetal development, but also in injured tissues, cardiac hypertrophy, or post myocardial infarction. 33,34 The AT 2 receptor site, when stimulated, results in diametrically opposite effects compared with the AT 1 receptor when stimulated. In experimental models, AT 2 receptor stimulation results in vasodilation, natriuresis, and attenuation of restructuring and remodeling. 34 It is possible that AT 2 receptor stimulation in some tissues may be important in the hypotensive response to angiotensin II receptor blockers. Because the angiotensin II receptor blocker does not affect kininase II, there is no effect on bradykinin production and thus no hemodynamic component from this vasoactive peptide. BLOOD PRESSURE REDUCTION In comparative clinical trials in hypertensive patients, ACE inhibitors and angiotensin II receptor blockers provide similar antihypertensive responses across their full dosing range. 1 3 However, none of these clinical studies have evaluated this efficacy in relationship to dietary salt consumption, blood pressure salt sensitivity of the clinical trial participants, or racial or gender demographics. Consequently, these issues need to be examined more carefully in future clinical trials. One reason for interest in this regard stems from clinical trials evaluating the differential effects of these drugs on renal blood flow. Angiotensin II receptor blockers appear to have a more substantial ability to

4 198S WEIR AJH DECEMBER 1999 VOL. 12, NO. 12, PART 3 FIGURE 4. A meta-analysis of human clinical studies comparing the renal blood flow responses to various types of drugs that block the renin-angiotensin system. 37 ACE, angiotensin-converting enzyme; RPF, renal plasma flow. improve renal blood flow in hypertensive patients than do ACE inhibitors (Figure 4) This increase in renal blood flow may facilitate natriuresis and be necessary for blood pressure reduction, particularly in the face of higher dietary salt consumption. Moreover, in lower-renin, more salt-sensitive patients, such as African-Americans, in whom intrarenal vasoconstriction is a substantial component of the clinical problem, more effective renal vasodilators may be of significant utility in blood pressure reduction. It is also possible that the more potent renal vasodilatory properties of the angiotensin II receptor blocker may lessen the likelihood of functional renal insufficiency in the clinical setting of diminished effective arterial blood volume. The reason for the renal blood flow response differences between the two drug classes is not known. PROTEINURIA REDUCTION Short-term clinical studies have compared the effects of ACE inhibitors and angiotensin II receptor blockers on proteinuria. 5 ACE inhibitors appear to induce a more rapid reduction in proteinuria, but within a few weeks both classes of drugs provide comparable antiproteinuric effects regardless of the level of renal insufficiency. 6 8,39 An additional area of clinical interest not yet studied is whether the angiotensin II receptor blocker will be more or less immune to the effects of salt in increasing proteinuria. This is an important issue, as clinical studies demonstrate that increasing dietary salt in the normal dietary range can substantially attenuate the antiproteinuric effects of ACE inhibitors. 38,40 Both classes of drugs provide similar systemic and intrarenal hemodynamic responses that would likely provide an important advantage to protecting kidney function. However, long-term clinical trials addressing the impact of angiotensin II receptor blockers in patients with both diabetic and nondiabetic nephropathy need to be evaluated to assess possible differences, compared with the proven renoprotective entities, the ACE inhibitors. Experimental studies have failed to show any convincing differences between these two classes of drugs in experimental renal disease. 15 Thus, it is likely that both classes of drugs will have broadly similar effects on stabilizing renal function, given similar degrees of blood pressure reduction. RISK OF FUNCTIONAL RENAL INSUFFICIENCY Because drugs that block the renin-angiotensin system reduce glomerular capillary pressure and systemic blood pressure, it is not surprising that there should be a fall in glomerular filtration rate (GFR) and glomerular filtration fraction (GFR/renal blood flow). It is not uncommon to see an up to 20% increase in serum creatinine level with the use of drugs that block the renin-angiotensin system. This increase is usually selflimiting and stabilizes within 20% of baseline On the other hand, if the serum creatinine level continues to rise, this is indicative of either diminished effective arterial blood volume (as might occur with excessive diuretic administration) or evidence of anatomic renal arterial disease. Thus, the use of a drug that blocks the renin-angiotensin system can be both therapeutic (by lowering systemic and glomerular capillary pressure, reducing proteinuria, and delaying progression of renal disease) and diagnostic (by providing the clinician evidence of functional renal insufficiency, which would require subsequent evaluation and treatment). Clinical studies have demonstrated that in patients with known anatomic atherosclerotic renal vascular disease, ACE inhibitors induce a reproducible increase in serum creatinine within 1 to 2 weeks in the majority of cases, and in the remainder of patients, only after diuretics have been administered. 41 In this type of selected population, a greater than 20% increase in serum creatinine level with ACE inhibition is highly sensitive for the detection of renal vascular disease and correlates quite well with the degree of stenosis of the artery of the largest kidney (Figure 5). 41 SAFETY CONCERNS ABOUT RENAL FUNCTION v REALITY Despite both the therapeutic and diagnostic benefits of using drugs that block the renin-angiotensin system in patients with kidney disease, physicians are reluctant to use these drugs, particularly if there are subtle changes in serum creatinine levels or potassium homeostasis. The results of numerous clinical trials have

5 AJH DECEMBER 1999 VOL. 12, NO. 12, PART 3 SAFETY, EFFICACY OF RENIN-ANGIOTENSIN INHIBITORS 199S TABLE 2. PERCENT REDUCTION IN OVERALL RISK OF PROGRESSION OF DIABETIC NEPHROPATHY WITH CAPTOPRIL TREATMENT ACCORDING TO BASELINE SERUM CREATININE CONCENTRATION Percent Reduction in Risk (95% Confidence Interval) Event Unadjusted for Mean Arterial Pressure Adjusted for Mean Arterial Pressure FIGURE 5. This figure shows the relationship between renal stenosis grade (the best renal artery) and serum creatinine in patients with bilateral renal artery stenosis receiving an angiotensin-converting enzyme (ACE) inhibitor. 41 BP, blood pressure. demonstrated that the presence of renal insufficiency does not attenuate the benefit of ACE inhibitors in delaying the progression of renal disease. 6 8 If anything, the greater the serum creatinine level or the prevalence of proteinuria, the greater the risk reduction for progressive renal insufficiency. 6 8 In the collaborative diabetic nephropathy study, 6 in which captopril was compared with placebo in addition to other antihypertensive medications for blood pressure control, patients treated with captopril who had a baseline serum creatinine concentration of 2.0 mg/dl had a 74% risk reduction in doubling of baseline serum creatinine and a 75% risk reduction in the incidence of death, dialysis, or transplantation, compared with patients receiving placebo (Table 2). On the other hand, patients with a baseline serum creatinine of 1.0 mg/dl had a 4% risk reduction in doubling of baseline serum creatinine and a 4% risk reduction in the incidence of death, dialysis, or transplantation. 6 Similarly, in the Ramipril Efficacy in Nephropathy Trial, 8 there was clear evidence that the greater the baseline urinary protein excretion, the greater the benefit derived from the ACE inhibitor compared with placebo in slowing GFR decline and reducing the percentage of patients reaching kidney failure (Figure 6). Thus, physician avoidance of ACE inhibitors in patients with renal disease is strictly to the patients disadvantage. Drugs that block the renin-angiotensin system have also been noted to provide substantial hemodynamic and survival benefits in patients with systolic heart failure, or post myocardial infarction These patients are also susceptible to functional renal insufficiency because of their low cardiac output syndrome and diminished effective arterial blood volume. In addition, they are commonly taking diuretics. Thus, optimizing hemodynamics and volume status in these Doubling of baseline serum creatinine All patients 48 (16 69) 43 (6 65) Baseline serum creatinine 1.0 mg/dl 17 ( 97 65) 4 ( ) 1.5 mg/dl 55 (25 73) 50 (16 70) 2.0 mg/dl 76 (55 87) 74 (52 86) Death, dialysis, or transplantation All patients 50 (18 70) 46 (10 68) Baseline serum creatinine 1.0 mg/dl 7 ( ) 4 ( ) 1.5 mg/dl 54 (22 73) 51 (16 71) 2.0 mg/dl 78 (57 89) 75 (51 87) Adapted from Lewis EJ et al. 6 patients is critical, to reduce the likelihood of both hypotension and functional renal insufficiency. Again, one should not avoid drugs that block the reninangiotensin system in this setting, because they are disease-modifying drugs and provide survival benefit. Reducing the dose of diuretics or changing from loop to thiazide diuretics may be an important therapeutic decision made to avoid volume compromise. One has to remember that drugs that block the renin-angiotensin system have natriuretic properties. 46 TABLE 3. INDEPENDENT RISK FACTORS PREDICTING HYPERKALEMIA Factor Odds Ratio (95% Confidence Interval) Serum urea nitrogen level 6.4 mmol/l (18 mg/dl) 2.5 ( ) Creatinine level mol/l ( mg/dl) 1.5 ( ) 137 mol/l ( 1.6 mg/dl) 4.6 ( ) Use of long-acting ACE inhibitor 2.8 ( ) Congestive heart failure 2.6 ( ) Use of loop diuretic agent 0.4 ( ) Use of thiazide diuretic agent 0.4 ( ) Adapted from Reardon and Macpherson. 47

6 200S WEIR AJH DECEMBER 1999 VOL. 12, NO. 12, PART 3 FIGURE 6. Effect of the ACE inhibitor ramipril v placebo on the progression of renal disease in 166 patients (ramipril, n 78; placebo, n 88) with mild nondiabetic renal insufficiency and macroproteinuria ( 3 g/24 h). GFR, glomerular filtration rate. 8 HYPERKALEMIA WITH DRUGS THAT BLOCK THE RENIN-ANGIOTENSIN SYSTEM: FACT v FICTION An increase in serum potassium is a known effect of drugs that inhibit the renin-angiotensin system, as there is a reduction in serum aldosterone and a mild reduction in GFR. The incidence of hyperkalemia is quite low in patients with normal renal function; however, it becomes increasingly common in those with renal insufficiency. Physicians are frequently concerned about subtle ( meq/l) increases in serum potassium, particularly in patients with mild renal insufficiency. Despite physician concern, the likelihood of development of hyperkalemia significant enough to necessitate discontinuation of the drug is uncommon. A recent case-control clinical trial was conducted in 1818 outpatients receiving ACE inhibitors at a large Veterans Affairs medical center general medicine clinic to assess the risk factors for development of hyperkalemia. 47 Abnormal renal function, congestive heart failure, and use of long-acting ACE inhibitors were independently associated with an increase in serum potassium (Table 3). Of the hyperkalemic ( 5.1 meq/l) patients continuing to take ACE inhibitors after 1 year of follow-up, only 10% developed what the authors described as severe hyperkalemia (a potassium level 6.0 meq/l). Renal insufficiency and age 70 years were independently associated with risk for this increase in serum potassium. Thus, only 15 of 1818 patients (fewer than 1%) required discontinuation of the ACE inhibitor. These demographic observations facilitate our understanding of which patients need to be more carefully monitored with laboratory testing. Numerous clinical trials in patients with renal disease demonstrate stable increases in serum potassium of 0.5 meq/l or less with an ACE inhibitor or angiotensin II receptor blocker, but rarely an increase to a level that justifies drug removal. 7 The kidney develops potassium homeostasis adaptation, which is mediated by an increase in sodium potassium ATPase activity in the potassium secretory cells in the cortical collecting duct. 48,49 Enhanced pumping of potassium into these cells increases the size of the intracellular potassium secretory pool. Thus, renal insufficiency has to be quite severe to substantially impair urinary potassium excretion. This is why drugs that block the reninangiotensin system can be safely employed in patients with renal disease. Only rarely does the risk for severe potassium intoxication increase to the point at which the use of ACE inhibitors or angiotensin II receptor blockers should be precluded. This could occur, for example, in clinical situations such as type 4 renal tubular acidosis, in which there is effective hypoaldosteronism, or with the concomitant use of nonsteroidal anti-inflammatory drugs, potassium-sparing diuretics, or ingestion of large amounts of potassium salts, such as with salt substitutes. The diminished efficiency of potassium excretion with hypoaldosteronism does not prevent the reattainment of steady state, in which intake and excretion are roughly equal. However, a higher than normal plasma potassium concentration is required to counteract the decreased availability of aldosterone. Clinical trials using ACE inhibitors in patients with renal disease have not demonstrated substantial risk of hyperkalemia. In the collaborative diabetic nephropathy study, only three of 207 patients receiving

7 AJH DECEMBER 1999 VOL. 12, NO. 12, PART 3 SAFETY, EFFICACY OF RENIN-ANGIOTENSIN INHIBITORS 201S captopril were discontinued because of hyperkalemia. 6 In the Ramipril Efficacy in Nephropathy Trial, only two of 166 patients were dropouts due to hyperkalemia (one patient was taking ramipril and the other was taking placebo). 8 In the Angiotensin-Converting Enzyme Inhibition in Progressive Renal Insufficiency study, employing benazepril, only five of 300 patients taking benazepril therapy were withdrawn because of hyperkalemia, as opposed to three of 283 patients receiving placebo. 7 A recent evaluation of the use of the angiotensin II receptor blocker losartan in patients with renal insufficiency noted that only one of 112 patients developed hyperkalemia that required discontinuation of the drug, and only 18% of patients had a stable increase of potassium 0.5 meq/l. 39 Thus, the data in clinical trials in patients with renal insufficiency due to either diabetes or nondiabetic nephropathy indicate the likelihood of hyperkalemia severe enough to require withdrawal of therapy to be on the order of 1% to 2%. COMPARABLE SAFETY OF ACE INHIBITORS AND ANGIOTENSIN II RECEPTOR BLOCKERS On the basis of the mechanistic differences between these two classes of drugs and their different effects on bradykinin metabolism, angiotensin II receptor blockers might be less likely than ACE inhibitors to induce functional renal insufficiency and hyperkalemia. Only one clinical trial (ELITE: The Evaluation of Losartan in the Elderly) 50 has assessed this possible difference. The study was conducted in elderly patients with systolic heart failure and compared the safety of the ACE inhibitor captopril with the angiotensin II receptor blocker losartan. Based on the patients age (mean, 73 to 74 years), systolic heart failure and serum creatinine level (106 mol/l), one can assume that creatinine clearance was subnormal (probably 60 ml/ min) in most of the patients. The results of the study demonstrated fewer overall adverse events in the losartan group, 12.2% versus 20.8% for captopril, but a comparable incidence of persisting increase in creatinine level in each group (10.5%). Fewer than 2% of all patients required discontinuation of either the ACE inhibitor or the angiotensin II receptor blocker because of renal dysfunction. Similarly, there was such a low incidence of hyperkalemia (two of 352 in the losartan group, five of 370 in the captopril group), that no apparent differences were noted. Consequently, in this clinical trial of systolic heart failure, with careful clinical evaluation of volume status and judicious use of diuretics, the incidence of hypercreatinemia and hyperkalemia was too low to indicate any potential differences between the drug classes. Unfortunately, no head-to-head comparison trials with ACE inhibitors or angiotensin II receptor blockers have been conducted in patients with renal insufficiency. CONCLUSIONS ACE inhibitors and angiotensin II receptor blockers provide similar efficacy in reducing blood pressure and proteinuria, although definitive studies comparing these drugs in different demographic groups and under varying dietary salt conditions have not been performed. ACE inhibitors have proven ability to protect against deterioration of renal function in diabetic and nondiabetic nephropathy, particularly in proteinuric patients. It is likely that angiotensin II receptor blockers will provide similar benefits based on comparable hemodynamics and antiproteinuric effects. Drugs that block the renin-angiotensin system are safe in patients with renal disease and should be employed routinely to protect renal function. Alterations in serum creatinine and potassium are predictable, and drug discontinuation is almost always avoidable. Although not universal, dosage adjustment of these drugs is necessary, and use of agents with balanced hepatic and renal excretion is preferred. 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