Optimizing ACE-Inhibitor Therapy for Chronic Kidney Disease
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《新英格兰医药杂志》
In this issue of the Journal, Hou and colleagues1 present data indicating that the use of benazepril, an angiotensin-converting–enzyme (ACE) inhibitor, is feasible and beneficial in patients with advanced chronic kidney disease, a point that has been much debated. This clinical trial in China, which confirms pilot data from the same group,2 provides some clarity, demonstrating that ACE inhibitors can be administered in generous doses, even in patients with stage 4 chronic kidney disease, as defined by a glomerular filtration rate (GFR) of 15 to 29 ml per minute per 1.73 m2 and a serum creatinine level of approximately 3.0 to 5.0 mg per deciliter (265 to 442 μmol per liter). Their findings also indicate that ACE inhibitors may provide renal benefit even if a patient's serum creatinine level continues to increase. Their conclusions may come as news to the many clinicians who avoid or abandon the use of ACE inhibitors or angiotensin-receptor blockers in their patients with stage 4 chronic kidney disease, fearing that this approach merely increases risk (especially of hyperkalemia) without providing benefit (e.g., slowing the decline in GFR). Although their results indicate that it may be time to change our practice, a number of caveats should be considered before we do so.
Hou et al. used a daily dose of 20 mg of benazepril, half the maximal recommended dose for patients with chronic kidney disease. This choice is remarkable because almost all studies that have demonstrated a renal-protective effect of ACE inhibitors used about 15 to 25 percent of the maximal recommended dose,3 and the patients in those studies had GFRs that were 50 to 100 percent higher than the rates in the patients studied by Hou et al.4,5 Another important difference is that Hou et al. used a twice-daily dose, a regimen that provides little opportunity for nocturnal recovery from any hyperkalemia that might have developed during the day as a result of dietary intake. Thus, it is surprising that serious hyperkalemia was not a major problem in the study. The study patients were divided into two groups on the basis of their creatinine levels: group 1 had a serum creatinine level of 1.5 to 3.0 mg per deciliter (133 to 265 μmol per liter), and group 2 had a level of 3.1 to 5.0 mg per deciliter (274 to 442 μmol per liter).
The absence of serious hyperkalemia might be explained by three factors. First, during the eight-week run-in period, about 5 percent of the patients in group 2 were excluded because of the development of hyperkalemia or an inordinate increase in serum creatinine levels or because of an adherence rate of less than 80 percent. Second, potassium intake in these Chinese patients may have been substantially lower than that of most Western patients, a fact suggested by the low baseline protein intake in the study subjects — about 0.5 g per kilogram of body weight per day, estimated from 24-hour urea excretion and the body-mass index, as compared with about 1.0 to 1.5 g per kilogram per day in Western patients with chronic kidney disease.4,5 Third, more than 80 percent of the patients in group 2 received a diuretic during follow-up. In contrast, in the Modification of Diet in Renal Disease study, only about 40 percent of patients received diuretic therapy.5 Diuretic use protects against hyperkalemia by shifting sodium reabsorption to the distal nephron, where increased sodium–potassium exchange occurs, resulting in increased renal potassium excretion. Also noteworthy is that group 2 had a low salt intake (approximately 100 meq daily), which, by itself, promotes hyperkalemia. Thus, the use of a diuretic in the great majority of the patients in group 2 was likely an important hedge against hyperkalemia.
In the light of these observations and the conditions of the study, applying the results more widely would have certain implications, particularly with respect to the use of "generous" doses of ACE inhibitors in patients with stage 4 chronic kidney disease. Before ACE-inhibitor therapy is initiated, it is important to assess a patient's dietary potassium intake by determining 24-hour urinary potassium excretion, ideally on at least two representative days. If the potassium content of a 24-hour urine collection is 40 meq per day or less, it is impractical to lower dietary potassium intake further.3 In such a patient, concomitant therapy with sodium bicarbonate and furosemide may be a consideration if hyperkalemia develops.4,5
The initial dose of an ACE inhibitor should be conservative — for instance, 15 to 25 percent of the maximal recommended dose. Furthermore, the dose should be increased only if the initial dose is well tolerated, and then only with caution. Once-daily morning dosing should potentially be considered, since it is likely to result in reduced ACE inhibition in the evening hours and thus permit increased nocturnal excretion of renal potassium to avoid hyperkalemia.
The results of Hou et al. suggest that it is worthwhile to continue ACE-inhibitor therapy in patients with chronic kidney disease even if their serum creatinine level continues to climb. The benefit of such an approach is revealed by extrapolating the creatinine clearance trend lines in Figure 3 of the article. Doing so indicates that end-stage renal disease might take twice as long to develop in the group given benazepril as in the control cohort: 7 years instead of 3.5 years.
Whether other types of ACE inhibitors can achieve the results reported by Hou et al. with benazepril is not clear. ACE inhibitors have potentially important differences in plasma protein binding, their affinity for ACE, and pharmacokinetics.5 However, there is no convincing evidence that generic long-acting ACE inhibitors (such as lisinopril and enalapril) are inferior to brand-name ACE inhibitors.4,5 Captopril, however, would not be recommended over benazepril, because its shorter half-life necessitates thrice-daily dosing, increasing the likelihood of missed doses and undertreatment.6
Other evidence-based measures that might improve the efficacy of ACE-inhibitor therapy in patients with chronic kidney disease should be considered. One such measure is achieving a target systolic blood pressure, measured while a patient is seated, of 120 mm Hg or less, if tolerated.4,5,7 Furthermore, controlling dietary salt intake is important during therapy with an ACE inhibitor or an angiotensin-receptor blocker, because a high-salt diet can override the antiproteinuric effects of these agents.4,5 For the bulk of patients with chronic kidney disease, the recommended salt intake (documented by periodic 24-hour urine testing) is approximately 90 to 120 meq per day (approximately 2 to 3 g of sodium per day).4,5 To achieve this level of salt intake without sacrificing taste, the patient should prepare a low-salt meal (2 g of sodium, or 88 meq), and then add salt to each portion just before eating it, so that the salt is on the surface of the food, permitting direct contact with the taste buds.4 An appropriate daily allotment of surface salt is one third of a teaspoon (28 meq of sodium)
Adding an angiotensin-receptor blocker to an ACE inhibitor appears to be beneficial in patients with stage 3 chronic kidney disease (as defined by a GFR of 30 to 59 ml per minute per 1.73 m2). For example, in the Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting–Enzyme Inhibitor in Non-diabetic Renal Disease study, in which the mean baseline GFR was about 38 ml per minute per 1.73 m2, this combination slowed the progression of kidney disease more than did either drug alone.8 However, it is not yet clear whether patients with stage 4 chronic kidney disease will benefit from this approach, since similar studies have yet to be performed in this population.9
Another point to consider is that there is evidence that controlling hypertension by adding a dihydropyridine calcium-channel blocker (DHCCB) to ACE-inhibitor therapy may not reduce proteinuria or slow the decline in GFR. Thus, arguably, this approach should be avoided unless it is required to achieve the blood-pressure goal. The rationale for this viewpoint comes from the recent Ramipril Efficacy in Nephropathy 2 (REIN-2) study, which added DHCCB to ramipril therapy in patients with chronic kidney disease and proteinuria to achieve a blood-pressure level below the usual goal. Paradoxically, achieving the low blood-pressure goal neither reduced proteinuria nor slowed the decline in GFR as compared with the results in the control group.10 This implies that DHCCB therapy sustained glomerular hypertension even though the systemic blood pressure had decreased substantially. Other options to achieve the goal blood pressure and reduce proteinuria have been discussed elsewhere.5
Finally, the use of medications to treat other conditions that arise in patients with chronic kidney disease may also help slow the progression of the renal failure itself. For example, there are some data indicating that adding a statin to an ACE inhibitor may enhance the antiproteinuric and renal-protective effects of ACE inhibitors.11
The study by Hou et al. does not clarify when in the course of advancing chronic kidney disease should treatment with an ACE inhibitor be stopped. However, common sense mandates that an ACE inhibitor (or an angiotensin-receptor blocker) should certainly be discontinued in the presence of uncontrollable hyperkalemia. Such agents should also be halted to see whether an increase in GFR will ensue, possibly averting the need for dialysis until vascular access is adequate or preemptive kidney transplantation can be performed. By demonstrating that ACE inhibitors can be used successfully in patients with advanced chronic kidney disease, Hou et al. suggest that abandoning treatment with an ACE inhibitor (or angiotensin-receptor blocker) when chronic kidney disease progresses to stage 3 or 4 is not necessary and hastens the onset of end-stage renal disease.
No potential conflict of interest relevant to this article was reported.
Source Information
From Ohio State University Medical Center, Columbus.
References
Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131-140.
Zhang GH, Hou FF, Zhang X, Liu QF. Can angiotensin-converting enzyme inhibitor be used in chronic kidney disease patients with serum creatinine level greater than 266 micromol/L? Zhonghua Nei Ke Za Zhi 2005;44:592-596.
Hebert LA. Target blood pressure for antihypertensive therapy in patients with proteinuric renal disease. Curr Hypertens Rep 1999;1:454-460.
Hebert LA, Wilmer WA, Falkenhain ME, Ladson-Wofford SE, Nahman NS Jr, Rovin BH. Renoprotection: one or many therapies? Kidney Int 2001;59:1211-1226.
Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert LA. Management of glomerular proteinuria: a commentary. J Am Soc Nephrol 2003;14:3217-3232.
Hebert LA, Rovin BH, Hebert CJ. Response to Dr. Brenner's comments. J Am Soc Nephrol 2004;15:1356-1357.
Hebert CJ, Shidham G, Hebert LA. Should the target for blood pressure control specify both a systolic and a diastolic component? Curr Hypertens Rep 2005;7:360-362.
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361:117-124.
Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 2005;67:799-812.
Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005;365:939-946.
Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003;41:565-570.(Lee A. Hebert, M.D.)
Hou et al. used a daily dose of 20 mg of benazepril, half the maximal recommended dose for patients with chronic kidney disease. This choice is remarkable because almost all studies that have demonstrated a renal-protective effect of ACE inhibitors used about 15 to 25 percent of the maximal recommended dose,3 and the patients in those studies had GFRs that were 50 to 100 percent higher than the rates in the patients studied by Hou et al.4,5 Another important difference is that Hou et al. used a twice-daily dose, a regimen that provides little opportunity for nocturnal recovery from any hyperkalemia that might have developed during the day as a result of dietary intake. Thus, it is surprising that serious hyperkalemia was not a major problem in the study. The study patients were divided into two groups on the basis of their creatinine levels: group 1 had a serum creatinine level of 1.5 to 3.0 mg per deciliter (133 to 265 μmol per liter), and group 2 had a level of 3.1 to 5.0 mg per deciliter (274 to 442 μmol per liter).
The absence of serious hyperkalemia might be explained by three factors. First, during the eight-week run-in period, about 5 percent of the patients in group 2 were excluded because of the development of hyperkalemia or an inordinate increase in serum creatinine levels or because of an adherence rate of less than 80 percent. Second, potassium intake in these Chinese patients may have been substantially lower than that of most Western patients, a fact suggested by the low baseline protein intake in the study subjects — about 0.5 g per kilogram of body weight per day, estimated from 24-hour urea excretion and the body-mass index, as compared with about 1.0 to 1.5 g per kilogram per day in Western patients with chronic kidney disease.4,5 Third, more than 80 percent of the patients in group 2 received a diuretic during follow-up. In contrast, in the Modification of Diet in Renal Disease study, only about 40 percent of patients received diuretic therapy.5 Diuretic use protects against hyperkalemia by shifting sodium reabsorption to the distal nephron, where increased sodium–potassium exchange occurs, resulting in increased renal potassium excretion. Also noteworthy is that group 2 had a low salt intake (approximately 100 meq daily), which, by itself, promotes hyperkalemia. Thus, the use of a diuretic in the great majority of the patients in group 2 was likely an important hedge against hyperkalemia.
In the light of these observations and the conditions of the study, applying the results more widely would have certain implications, particularly with respect to the use of "generous" doses of ACE inhibitors in patients with stage 4 chronic kidney disease. Before ACE-inhibitor therapy is initiated, it is important to assess a patient's dietary potassium intake by determining 24-hour urinary potassium excretion, ideally on at least two representative days. If the potassium content of a 24-hour urine collection is 40 meq per day or less, it is impractical to lower dietary potassium intake further.3 In such a patient, concomitant therapy with sodium bicarbonate and furosemide may be a consideration if hyperkalemia develops.4,5
The initial dose of an ACE inhibitor should be conservative — for instance, 15 to 25 percent of the maximal recommended dose. Furthermore, the dose should be increased only if the initial dose is well tolerated, and then only with caution. Once-daily morning dosing should potentially be considered, since it is likely to result in reduced ACE inhibition in the evening hours and thus permit increased nocturnal excretion of renal potassium to avoid hyperkalemia.
The results of Hou et al. suggest that it is worthwhile to continue ACE-inhibitor therapy in patients with chronic kidney disease even if their serum creatinine level continues to climb. The benefit of such an approach is revealed by extrapolating the creatinine clearance trend lines in Figure 3 of the article. Doing so indicates that end-stage renal disease might take twice as long to develop in the group given benazepril as in the control cohort: 7 years instead of 3.5 years.
Whether other types of ACE inhibitors can achieve the results reported by Hou et al. with benazepril is not clear. ACE inhibitors have potentially important differences in plasma protein binding, their affinity for ACE, and pharmacokinetics.5 However, there is no convincing evidence that generic long-acting ACE inhibitors (such as lisinopril and enalapril) are inferior to brand-name ACE inhibitors.4,5 Captopril, however, would not be recommended over benazepril, because its shorter half-life necessitates thrice-daily dosing, increasing the likelihood of missed doses and undertreatment.6
Other evidence-based measures that might improve the efficacy of ACE-inhibitor therapy in patients with chronic kidney disease should be considered. One such measure is achieving a target systolic blood pressure, measured while a patient is seated, of 120 mm Hg or less, if tolerated.4,5,7 Furthermore, controlling dietary salt intake is important during therapy with an ACE inhibitor or an angiotensin-receptor blocker, because a high-salt diet can override the antiproteinuric effects of these agents.4,5 For the bulk of patients with chronic kidney disease, the recommended salt intake (documented by periodic 24-hour urine testing) is approximately 90 to 120 meq per day (approximately 2 to 3 g of sodium per day).4,5 To achieve this level of salt intake without sacrificing taste, the patient should prepare a low-salt meal (2 g of sodium, or 88 meq), and then add salt to each portion just before eating it, so that the salt is on the surface of the food, permitting direct contact with the taste buds.4 An appropriate daily allotment of surface salt is one third of a teaspoon (28 meq of sodium)
Adding an angiotensin-receptor blocker to an ACE inhibitor appears to be beneficial in patients with stage 3 chronic kidney disease (as defined by a GFR of 30 to 59 ml per minute per 1.73 m2). For example, in the Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting–Enzyme Inhibitor in Non-diabetic Renal Disease study, in which the mean baseline GFR was about 38 ml per minute per 1.73 m2, this combination slowed the progression of kidney disease more than did either drug alone.8 However, it is not yet clear whether patients with stage 4 chronic kidney disease will benefit from this approach, since similar studies have yet to be performed in this population.9
Another point to consider is that there is evidence that controlling hypertension by adding a dihydropyridine calcium-channel blocker (DHCCB) to ACE-inhibitor therapy may not reduce proteinuria or slow the decline in GFR. Thus, arguably, this approach should be avoided unless it is required to achieve the blood-pressure goal. The rationale for this viewpoint comes from the recent Ramipril Efficacy in Nephropathy 2 (REIN-2) study, which added DHCCB to ramipril therapy in patients with chronic kidney disease and proteinuria to achieve a blood-pressure level below the usual goal. Paradoxically, achieving the low blood-pressure goal neither reduced proteinuria nor slowed the decline in GFR as compared with the results in the control group.10 This implies that DHCCB therapy sustained glomerular hypertension even though the systemic blood pressure had decreased substantially. Other options to achieve the goal blood pressure and reduce proteinuria have been discussed elsewhere.5
Finally, the use of medications to treat other conditions that arise in patients with chronic kidney disease may also help slow the progression of the renal failure itself. For example, there are some data indicating that adding a statin to an ACE inhibitor may enhance the antiproteinuric and renal-protective effects of ACE inhibitors.11
The study by Hou et al. does not clarify when in the course of advancing chronic kidney disease should treatment with an ACE inhibitor be stopped. However, common sense mandates that an ACE inhibitor (or an angiotensin-receptor blocker) should certainly be discontinued in the presence of uncontrollable hyperkalemia. Such agents should also be halted to see whether an increase in GFR will ensue, possibly averting the need for dialysis until vascular access is adequate or preemptive kidney transplantation can be performed. By demonstrating that ACE inhibitors can be used successfully in patients with advanced chronic kidney disease, Hou et al. suggest that abandoning treatment with an ACE inhibitor (or angiotensin-receptor blocker) when chronic kidney disease progresses to stage 3 or 4 is not necessary and hastens the onset of end-stage renal disease.
No potential conflict of interest relevant to this article was reported.
Source Information
From Ohio State University Medical Center, Columbus.
References
Hou FF, Zhang X, Zhang GH, et al. Efficacy and safety of benazepril for advanced chronic renal insufficiency. N Engl J Med 2006;354:131-140.
Zhang GH, Hou FF, Zhang X, Liu QF. Can angiotensin-converting enzyme inhibitor be used in chronic kidney disease patients with serum creatinine level greater than 266 micromol/L? Zhonghua Nei Ke Za Zhi 2005;44:592-596.
Hebert LA. Target blood pressure for antihypertensive therapy in patients with proteinuric renal disease. Curr Hypertens Rep 1999;1:454-460.
Hebert LA, Wilmer WA, Falkenhain ME, Ladson-Wofford SE, Nahman NS Jr, Rovin BH. Renoprotection: one or many therapies? Kidney Int 2001;59:1211-1226.
Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert LA. Management of glomerular proteinuria: a commentary. J Am Soc Nephrol 2003;14:3217-3232.
Hebert LA, Rovin BH, Hebert CJ. Response to Dr. Brenner's comments. J Am Soc Nephrol 2004;15:1356-1357.
Hebert CJ, Shidham G, Hebert LA. Should the target for blood pressure control specify both a systolic and a diastolic component? Curr Hypertens Rep 2005;7:360-362.
Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361:117-124.
Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 2005;67:799-812.
Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005;365:939-946.
Bianchi S, Bigazzi R, Caiazza A, Campese VM. A controlled, prospective study of the effects of atorvastatin on proteinuria and progression of kidney disease. Am J Kidney Dis 2003;41:565-570.(Lee A. Hebert, M.D.)