Volume 40, Issue 3 , Pages 664-666, September 2002
High-dose ACE inhibition: Can it improve renoprotection?☆
Article Outline
Related Article, p. 458
Over the last decade, the availability of effective antihypertensive and antiproteinuric intervention has afforded considerable progress in the protection against chronic progressive renal function loss. It has become increasingly clear that, in addition to effective blood pressure control, reduction of proteinuria is a prerequisite for effective long-term renoprotection. Despite recent progress, however, interindividual differences in efficacy of renoprotective intervention remain large, with significant residual proteinuria and consequently long-term renal function loss in many patients.
Considering the prognostic impact of proteinuria reduction, it is currently assumed, albeit not proven, that titration for maximal antiproteinuric effect will have the potential to improve long-term renal prognosis. In this respect, treatment with angiotensin-converting enzyme (ACE) inhibititors or angiotensin II subtype 1 receptor antagonist (AT1-A) would be a logical first step, considering their proven antiproteinuric potential. Somewhat surprisingly, however, relatively few data are available on the appropriate dosing for optimal antiproteinuric effect, which may reflect their original introduction as antihypertensives. Usually, doses of ACE inhibitors and AT1-A are based on the dose-response for blood pressure. Yet, data on the antiproteinuric effect of nonhypotensive doses of ACE inhibitors demonstrated that responses of blood pressure and proteinuria are not necessarily concordant.1, 2 Taken together with the prognostic impact of antiproteinuric effect for long-term renoprotection, these data prompt the exploration of the specific antiproteinuric potential of doses of ACE inhibitors higher than needed for maximal blood pressure reduction. This rationale is reinforced by animal data indicating a specific protective effect against renal fibrosis of very high doses of ACE inhibitors or AT1-blockade.3 Moreover, data in heart failure patients showed that titration towards high-dose (32.5 to 35 mg/day) lisinopril resulted in a slightly better survival than did low-dose (2.5 to 5 mg/day) lisinopril.4
In this issue of the Journal, Haas et al5 explore the antiproteinuric potency of ACE inhibitor spirapril in doses exceeding the maximally effective antihypertensive dose (denoted as supra-maximal dose) in 23 hypertensive, proteinuric patients (12 of whom were transplant recipients). Titration of spirapril for blood pressure response resulted in a modest fall in median ambulatory blood pressure from 102 to 97 mmHg, with a reduction in proteinuria from 2.56 to 1.73 g/day, obtained with 3 mg/d in 11 patients, 6 mg/day in 10 patients, and 12 mg/day in 2 patients. Doubling of the doses did not further reduce proteinuria. Does this mean that it is useless to increase the dose of an ACE inhibitor once blood pressure has stabilized? As noted above, in normotensive patients ACE inhibitors can reduce glomerular protein leakage in the absence of a fall in blood pressure.1, 6 Previously, a progressive antiproteinuric effect with doses up to 20 mg/day lisinopril was reported in normotensive subjects with IgA nephropathy6 in whom the maximum reduction of blood pressure was already obtained at 5 mg/day. Recently, Laverman et al7 found a progressive reduction in proteinuria (and blood pressure) with increasing doses of 10, 20, and 40 mg/day lisinopril, in a mixed population of subjects with nondiabetic nephropathy. Taken together, these data illustrate that the relative antihypertensive and antiproteinuric potency of increasing doses of ACE inhibitors are apparently not similar across different studies and may depend on specific population characteristics, such as baseline blood pressure and proteinuria, which refutes straightforward generalizability of the present results. As to AT1-A, the relative antihypertensive and antiproteinuric potency of increasing doses is also under study. Recent data on losartan indicate that the optimal antiproteinuric effect was obtained at a higher dose than the maximal blood pressure response in nondiabetic as well as diabetic nephropathy.8, 9 In a recent uncontrolled study with candesartan, increasing the dose up to 96 (!) mg, independent of blood pressure control, was associated with a progressive reduction of proteinuria.10 Thus, whereas the data by Haas et al5 show that a supramaximal dose of ACE inhibitor does not provide a fit-for-all solution for better antiproteinuric efficacy, other studies strongly suggest that the therapeutic potential of increasing doses of ACE inhibitors and AT1-A has not yet been fully explored.
Could high-dose ACE inhibitors (or AT1-A) have the potential to overcome therapy resistance in renal patients? Obviously, a conclusive answer would require long-term data not yet available on the renoprotective effect of high-dose ACE inhibitors. However, it may be relevant to realize that between-patient differences in therapeutic efficacy of ACE inhibitors (and AT1-A) by far exceed the differences in therapy response that have been obtained so far using higher doses.11 We found that increasing the dose of enalapril from 10 to 20 mg, or of losartan from 50 to 100 mg, slightly enhanced therapy response for the patient group as a whole, but failed to turn poor responses into good responses. Moreover, the poor or good individual response persisted after switching from ACE inhibitor to AT1 or vice versa, and in another subset of patients after switching to nonsteroidal antiinflammatory drugs (NSAID). These data suggest that individual differences in responsiveness to antiproteinuric intervention are related to individual patient factors rather than to drug factors such as class of drug. An interesting, albeit retrospective, analysis in transplant recipients reported that the differences in antiproteinuric efficacy of a nonhypotensive dose fosinopril correlated to the severity of pre-existent vascular and interstitial renal lesions, providing a pathophysiological basis for individual differences in responsiveness to antiproteinuric therapy.2 It would be relevant to know whether uptitration of ACE inhibitor or AT1-A for antiproteinuric response could overcome such individual therapy resistance and whether some patients would need a higher dose for optimal reduction of proteinuria than others. No human data are available on this issue so far, but data in adriamycin nephrosis in rats indicate that neither a supramaximal dose of ACE inhibitor nor dual blockade by ACE inhibitor plus AT1-A could overcome the individual therapy resistance in animals with a poor antiproteinuric response to adequately dosed ACE inhibitors.12 Thus, at least in this normotensive experimental model, the potential of rigourous blockade of the renin-angiotensin-aldosterone system (RAAS) to overcome individual resistance to antiproteinuric therapy seems limited, and approaches combining RAAS-blockade with other modes of intervention (such as, for instance, statins13) may provide better perspectives.
For a balanced view of the potential of supramaximal doses of ACE inhibitor or AT1-A for renoprotection, further studies in different populations, also considering tolerability, would be needed. Moreover, the benefits of high-dose monotherapy ACE inhibitor or AT1-A relative to dual blockade of the RAAS would be relevant.7 In addition to blood pressure control, reduction of proteinuria is now recognized as an independent and essential treatment target for renoprotection. Considering the prognostic impact of proteinuria reduction, perhaps the most promising strategy to improve renoprotection will be to titrate for antiproteinuric effect. Dose-response data for proteinuria may be helpful for this purpose, but it is important to recollect here that several measures have already been proven to be effective to enhance the antiproteinuric effect of ACE inhibition. These include, in particular, control of volume excess by dietary sodium restriction and/or diuretic, but also dietary protein restriction (and, for selected patients, cotreatment with NSAID). It is unlikely that use of high-dose ACE inhibitors will alleviate the need for proper control of sodium status for optimal reduction of proteinuria.
Thus, for the moment, well-controlled human studies to support a specific optimal regimen, including dose recommendations, for renoprotection are lacking. Treatment targets, nevertheless, are clear and include not only effective blood pressure control, but also optimal reduction of proteinuria. To this purpose, among the measures available to improve antiproteinuric efficacy of ACE inhibitors, increasing the dose in patients in whom good pressure control has been obtained may not invariably be effective, but it is worth a try.
References
- . Enalapril reduces microalbuminuria in young normotensive type 1 (insulin-dependent) diabetic patients irrespective of its hypotensive effect. Diabetologia. 1990;33:470–476
- Antiproteinuric efficacy of fosinopril after renal transplantation is determined by the extent of vascular and tubulointerstitial damage. Clin Transplant. 1998;12:409–415
- . Targeting TGF-β overexpression in renal disease: Maximizing the antifibrotic action of angiotensin II blockade. Kidney Int. 1998;54:1570–1580
- Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation. 1999;100:2312–2318
- . Antiproteinuric versus antihypertensive effects of high-dose ACE inhibitor therapy. Am J Kidney Dis. 2002;40:458–463
- Effect of increasing doses of lisinopril on proteinuria of normotensive patients with IgA nephropathy and normal renal function. Int J Clin Pharmacol Res. 1994;14:35–43
- Laverman GD, Navis GJ, Henning RH, de Jong PE, de Zeeuw D: Combined effects of ACEi and AT1 blockade in proteinuric patients. Kidney Int (in press)
- . Optimal antiproteinuric dose of losartan in nondiabetic patients with nephrotic range proteinuria. Am J Kidney Dis. 2001;38:1381–1384
- . Optimal dose of losartan for renoprotection in diabetic nephropathy. Nephrol Dial Transplant. 2002;17:1413–1418
- . The effect of high-dose angiotensin II receptor blockade beyond maximal recommended doses in reducing urinary protein secretion. JRAAS. 2002;2(suppl 1):S196–S198
- The role of patient factors in therapy resistance to antiproteinuric intervention in non-diabetic and diabetic nephropathy. Kidney Int Suppl. 2000;75:S32–S37
- . Addition of AT1 receptor blockade fails to overcome resistance to ACE inhibition in adriamycin nephrosis. Kidney Int. 2002;61:473–480
- Effect of combining ACE inhibitor and statin in severe experimental nephropathy. Kidney Int. 2002;61:1635–1645
☆ 0272-6386/02/4003-0038$35.00/0
PII: S0272-6386(02)00096-3
doi:10.1053/ajkd.2002.36005
© 2002 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
Refers to article:
- Antiproteinuric versus antihypertensive effects of high-dose ACE inhibitor therapy
Volume 40, Issue 3 , Pages 664-666, September 2002
