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High-Dose ACE Inhibition: Can It Improve Renoprotection?

Related Article, p. 458

OVER THE LAST decade, the availability

of effective antihypertensive and antipro-teinuric intervention has afforded considerable

progress in the protection against chronic progres-sive renal function loss. It has become increas-

ingly clear that, in addition to effective bloodpressure control, reduction of proteinuria is a

prerequisite for effective long-term renoprotec-tion. Despite recent progress, however, interindi-

vidual differences in efficacy of renoprotectiveintervention remain large, with significant re-

sidual proteinuria and consequently long-termrenal function loss in many patients.

Considering the prognostic impact of protein-uria reduction, it is currently assumed, albeit notproven, 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) in-hibititors or angiotensin II subtype 1 receptor

antagonist (AT1-A) would be a logical first step,considering their proven antiproteinuric poten-

tial. Somewhat surprisingly, however, relativelyfew data are available on the appropriate dosing

for optimal antiproteinuric effect, which mayreflect their original introduction as antihyperten-

sives. Usually, doses of ACE inhibitors andAT1-A are based on the dose-response for blood

pressure. Yet, data on the antiproteinuric effect ofnonhypotensive doses of ACE inhibitors demon-

strated that responses of blood pressure andproteinuria are not necessarily concordant.1,2

Taken together with the prognostic impact of

antiproteinuric effect for long-term renoprotec-tion, these data prompt the exploration of the

specific antiproteinuric potential of doses of ACEinhibitors higher than needed for maximal blood

pressure reduction. This rationale is reinforcedby animal data indicating a specific protective

effect against renal fibrosis of very high doses ofACE 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 theJournal, Haas et al5 explorethe antiproteinuric potency of ACE inhibitor spi-

rapril in doses exceeding the maximally effective

antihypertensive dose (denoted as supra-maxi-

mal dose) in 23 hypertensive, proteinuric pa-

tients (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. Dou-

bling of the doses did not further reduce protein-

uria. Does this mean that it is useless to increasethe 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 antiprotein-

uric 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 pro-

gressive reduction in proteinuria (and blood pres-

sure) with increasing doses of 10, 20, and 40

mg/day lisinopril, in a mixed population of sub-

jects with nondiabetic nephropathy. Taken to-

gether, these data illustrate that the relative anti-

hypertensive and antiproteinuric potency of

increasing doses of ACE inhibitors are appar-

ently 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 antiprotein-uric 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 progres-

sive reduction of proteinuria.10 Thus, whereas

2002 by the National Kidney Foundation, Inc.0272-6386/02/4003-0038$35.00/0

doi:10.1053/ajkd.2002.36005

American Journal of Kidney Diseases,Vol 40, No 3 (September), 2002: pp 664-666664

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the data by Haas et al5 show that a supramaximaldose of ACE inhibitor does not provide a fit-

for-all solution for better antiproteinuric efficacy,other studies strongly suggest that the therapeu-

tic potential of increasing doses of ACE inhibi-tors and AT1-A has not yet been fully explored.

Could high-dose ACE inhibitors (or AT1-A)have the potential to overcome therapy resis-

tance in renal patients? Obviously, a conclusiveanswer would require long-term data not yet

available on the renoprotective effect of high-dose ACE inhibitors. However, it may be rel-

evant to realize that between-patient differencesin therapeutic efficacy of ACE inhibitors (and

AT1-A) by far exceed the differences in therapyresponse that have been obtained so far usinghigher doses.11 We found that increasing the dose

of enalapril from 10 to 20 mg, or of losartan from50 to 100 mg, slightly enhanced therapy re-

sponse for the patient group as a whole, butfailed to turn poor responses into good re-

sponses. Moreover, the poor or good individualresponse persisted after switching from ACE

inhibitor to AT1 or vice versa, and in anothersubset of patients after switching to nonsteroidal

antiinflammatory drugs (NSAID). These datasuggest that individual differences in responsive-

ness to antiproteinuric intervention are related toindividual patient factors rather than to drugfactors such as class of drug. An interesting,

albeit retrospective, analysis in transplant recipi-ents reported that the differences in antiprotein-

uric efficacy of a nonhypotensive dose fosinoprilcorrelated to the severity of pre-existent vascular

and interstitial renal lesions, providing a patho-physiological basis for individual differences in

responsiveness to antiproteinuric therapy.2 Itwould be relevant to know whether uptitration of

ACE inhibitor or AT1-A for antiproteinuric re-sponse could overcome such individual therapy

resistance and whether some patients would needa higher dose for optimal reduction of protein-

uria than others. No human data are available on

this issue so far, but data in adriamycin nephrosisin rats indicate that neither a supramaximal dose

of ACE inhibitor nor dual blockade by ACEinhibitor plus AT1-A could overcome the indi-

vidual therapy resistance in animals with a poorantiproteinuric response to adequately dosed ACE

inhibitors.12 Thus, at least in this normotensiveexperimental model, the potential of rigourous

blockade of the renin-angiotensin-aldosteronesystem (RAAS) to overcome individual resis-

tance to antiproteinuric therapy seems limited,and approaches combining RAAS-blockade with

other modes of intervention (such as, for in-stance, statins13) may provide better perspec-

tives.For a balanced view of the potential of supra-

maximal doses of ACE inhibitor or AT1-A forrenoprotection, further studies in different popu-

lations, also considering tolerability, would beneeded. Moreover, the benefits of high-dose

monotherapy ACE inhibitor or AT1-A relative todual blockade of the RAAS would be relevant. 7

In addition to blood pressure control, reduction

of proteinuria is now recognized as an indepen-dent and essential treatment target for renoprotec-

tion. Considering the prognostic impact of pro-teinuria reduction, perhaps the most promising

strategy to improve renoprotection will be totitrate for antiproteinuric effect. Dose-response

data for proteinuria may be helpful for this pur-pose, but it is important to recollect here that

several measures have already been proven to beeffective 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 pro-tein restriction (and, for selected patients, cotreat-ment with NSAID). It is unlikely that use of

high-dose ACE inhibitors will alleviate the needfor proper control of sodium status for optimal

reduction of proteinuria.Thus, for the moment, well-controlled human

studies to support a specific optimal regimen, includ-ing dose recommendations, for renoprotection are

lacking. Treatment targets, nevertheless, are clearand include not only effective blood pressure con-

trol, but also optimal reduction of proteinuria. Tothis 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 invari-

ably be effective, but it is worth a try.

Gerjan Navis, MD, PhD

Andrea B. Kramer, MDPaul E. de Jong, MD, PhD

Department of Nephrology

University HospitalGroningen, The Netherlands

EDITORIAL 665

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