Is Proteinuria Reduction by Angiotensin-Converting Enzyme Inhibition Enough to Prove Its Role in Renal Protection in IgA Nephropathy?
Daniel C. Cattran
University Health Network, Toronto General Hospital, Toronto, Ontario, Canada
Address correspondence to: Dr. Daniel C. Cattran, University Health Network NCSB 11–1256, 585 University Avenue, Toronto, Ontario M5G 2N2, Canada. Phone: 416-340-4181; Fax: 416-340-3714; E-mail: daniel.cattran{at}uhn.on.ca
IgA nephropathy (IgAN) is the most common biopsy-proven typeof glomerulonephritis globally, including children (1). In theUnited States alone, it is estimated that as many as 30% ofchildren with IgAN are likely to progress to ESRD (2). Mostpediatric studies that deal with treatment, prognostic markers,and outcome indicators that are used in clinical trials in IgANmust rely on surrogate measures, such as changes in proteinuria,serum creatinine, or creatinine clearance, rather than renalsurvival because the disease has such a slow progression rate(3–6). The problem of establishing outcome targets withina reasonable trial time frame, especially ones that are valuedby the clinician and not just of statistical importance, isillustrated in the study by Coppo et al. (7) in this issue.This randomized, controlled trial (RCT), conducted in 23 centersin five European countries over 6 yr, was designed to test therenal protective effect of the angiotensin-converting enzymeinhibitor (ACE-I) benazepril in 57 children and young adultswith this disease. Coppo et al. tried to account for appropriatemaintenance of equality of BP between the groups, an importantpotential confounder, based on pediatric standards by adjustingthe limits according to patient height and gender. Althoughnot statistically different, both the diastolic BP in childrenand the mean arterial pressure in adults was higher in the placebogroup in the last 1 to 2 yr of the trial. Although this mayhave contributed to the differences that were found betweenthe ACE-I–treated and placebo groups, its effect was likelyto be small given that these differences were not seen duringthe first 3 yr of the trial. In support of their trial effortsto maintain BP control and its equality, we can only add limitedRCT evidence has been devoted specifically to a target BP inIgAN that is necessary to preserve renal function. The bestevidence is a recent 3-yr RCT of 49 patients with IgAN, in whichan achieved mean BP of 129/70 stabilized GFR during the study,whereas patients with an achieved mean BP of 136/76 had an averagedecline in GFR of 13 ml/min during the same timeframe (8). Coppo'sstudy means were within these boundaries. No RCT in childrenregarding effects of target differences in BP alone has beendone.
The trial's primary end point, time to a 30% decrease from initialcreatinine clearance value, was not significantly differentbetween their ACE-I–treated and placebo groups even thoughthe expected event rate of 3.3% in the placebo group and 0.83%in the active drug group was achieved. Part of the problem maylie in the marked difference between their estimated samplesize (n = 122) and the number of patients who actually wererandomly assigned (n = 66).
The significant differences between the ACE-I–treatedand placebo patients in this RCT were limited to the secondaryend points and largely involved changes in proteinuria. Thelevel of evidence that supports the importance of outcome changesin proteinuria in IgAN therefore becomes critical in assessingthe clinical value of the article by Coppo et al. These authorsfound that presenting proteinuria was not significant as anindependent prognostic value in their trial when examined bymultivariate survival analysis using a Cox regression model.This is not radically different from the literature. Althoughthe severity of the presenting proteinuria in some early studieswas found to correlate with outcome (9), more recently, especiallyin more mild cases, the presenting proteinuria has not beenfound to be a significant long-term predictor (10). More recently,approaches to predicting outcome have incorporated sequentialinformation on proteinuria and BP. This type of algorithm, althoughnot perfect, has significantly improved our capacity to predictthe risk for progression and underlined the importance of changeover time in these parameters on outcome (11–14). Certainlyin other proteinuric glomerular diseases, the magnitude of theantiproteinuric effect of antihypertensive treatment has beenshown to correlate closely and predict the renal protectivebenefits and, in addition, that the class of drug (i.e., thosethat block the renin-angiotensin system) is also relevant. Dataspecific to IgAN dates back more than a decade, when it wasshown that patients who had IgAN and were treated with an ACE-Ihad a significantly lower rate of annual loss of renal functionthan patients who were treated with alternative antihypertensiveagents despite equivalent BP control (14). Recently, a predictivealgorithm in adult patients with IgAN found that only lowerBP and lower levels of proteinuria measured over time and notthe values at presentation predicted outcome (12). An RCT ofadult patients with IgAN recently confirmed an independent renalprotective effect of ACE inhibition (enalapril) and confirmedby multivariate analysis the independent value of proteinuriareduction over the course of the trial (but not the presentingproteinuria) (15). The importance of renin-angiotensin-aldosteronesystem blockade on proteinuria, although not on GFR, is alsosupported by the results of a recent RCT in Asian patients withIgA using the angiotensin II receptor blocker valsartan (16).
These studies help place in context the importance of the trialof Coppo et al. Both of their secondary end points were positive.The first one was a composite of a 30% reduction from baselinein creatinine clearance and/or an increase in proteinuria tothe nephrotic range (>3.5 g/d). A significant differencewas found largely because a greater number reached this levelof proteinuria in the placebo group (n = 4) versus in the ACE-Igroup (n = 0; P = 0.034). In addition, their other secondaryend point, partial remission in proteinuria (<0.5 g/d), hada greater number (13 [40.6%] of 32) and was reached earlier(after 20 mo) compared with the placebo group (3 [8.9%] of 34;after 32 mo; P = 0.0002). In addition, complete remission ofproteinuria (<0.16 g/d) occurred in four (12.5%) cases inthe ACE-I group and in 0% in the placebo group.
Multivariate analysis showed that ACE-I treatment was an independentpredictor of prognosis in their trial. The authors found noinfluence on the composite end point for gender, age, baselinecreatinine clearance, systolic or diastolic BP, mean arterialpressure, or presenting proteinuria. Given the data discussedhere, this is not a surprise and confirms earlier work by anumber of adult studies in IgAN that it is the change, not thepresenting BP or proteinuria, that is important in slowing progressionof the disease.
This study by Coppo et al. is an important one and raises thelevel of evidence of the specific renal protective effect ofACE-I therapy in IgAN in this age group to a higher grade. Italso raises some interesting questions about the mechanism ofaction of ACE inhibition in IgAN and what the proteinuria targetlevel should be for clinicians, given the complete remissionthat was observed in some cases. Furthermore, given that thestudy population was largely children and young adults, it providesimportant support for the use of this agent in this particularlyvulnerable age group whose whole life, both personal and professional,stretches before them.
Published online ahead of print. Publication date availableat www.jasn.org.
See the related article, "IgACE: A Placebo-Controlled, RandomizedTrial of Angiotensin-Converting Enzyme Inhibitors in Childrenand Young People with IgA Nephropathy and Moderate Proteinuria,"on pages 1880–1888.
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Related Article
IgACE: A Placebo-Controlled, Randomized Trial of Angiotensin-Converting Enzyme Inhibitors in Children and Young People with IgA Nephropathy and Moderate Proteinuria
Rosanna Coppo, Licia Peruzzi, Alessandro Amore, Antonio Piccoli, Pierre Cochat, Rosario Stone, Martin Kirschstein, Tommy Linné on behalf of the EC Biomed Concerted Action Project BMH4-97-2487(DG 12-SSMI) and IgACE European Collaborative Group
J. Am. Soc. Nephrol. 2007 18: 1880-1888.
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