IgA nephropathy inhibitors of the renin angiotensin system: Is reduction in proteinuria adequate proof of efficacy?
2001; Elsevier BV; Volume: 38; Issue: 1 Linguagem: Inglês
10.1053/ajkd.2001.26330
ISSN1523-6838
AutoresDonal Reddan, William F. Owen,
Tópico(s)Chronic Kidney Disease and Diabetes
ResumoRelated Article, p. 18 In this issue of the Journal, Russo et al1Russo D Minutolo R Pisani A Esposito R Signoriello G Andreucci M Balletta MM Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.Am J Kidney Dis. 2001; 38: 18-25Abstract Full Text Full Text PDF PubMed Scopus (225) Google Scholar present findings from a small, randomized controlled study suggesting that the combination angiotensin II receptor blocker and angiotensin-converting enzyme (ACE) inhibitor therapy has a greater antiproteinuric effect than higher dose therapy with either agent alone when used in the treatment of immunoglobulin A (IgA) nephropathy. IgA nephropathy is the most common form of idiopathic glomerulopathy and in general has a good prognosis.2D'Amico G The commonest glomerulonephritis in the world: IgA nephropathy.Q J Med. 1987; 64: 709-727PubMed Google Scholar However, the clinical course is not always benign and up to 30% of patients may progress to end-stage renal disease (ESRD) within 10 years.3Rychlik I Andrassy K Waldherr R Zuna I Tesar V Jancova E Stejskalova A Ritz E Clinical features and natural history of IgA nephropathy.Ann Med Interne. 1999; 150: 117-126PubMed Google Scholar, 4D'Amico G Natural history of idiopathic IgA nephropathy: Role of clinical and histological prognostic factors.Am J Kidney Dis. 2000; 36: 227-237Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 5Ibels LS Gyory AZ Caterson RJ Pollock CA Mahony JF Waugh DA Roger SD Coulshed S Primary IgA nephropathy: Natural history and factors of importance in the progression of renal impairment.Kidney Int. 1997; 61: S67-S70Google Scholar Proteinuria, hypertension, and persistent microscopic hematuria have all been associated with deterioration in renal function in IgA nephropathy,4D'Amico G Natural history of idiopathic IgA nephropathy: Role of clinical and histological prognostic factors.Am J Kidney Dis. 2000; 36: 227-237Abstract Full Text Full Text PDF PubMed Scopus (449) Google Scholar, 6Alamartine E Sabatier JC Guerin C Berliet JM Berthoux F Prognostic factors in mesangial IgA glomerulo-nephritis: An extensive study with univariate and multivariate analyses.Am J Kidney Dis. 1991; 18: 12-19Abstract Full Text PDF PubMed Scopus (270) Google Scholar, 7Johnston PA Brown JS Braumholtz DA Davison AM Clinico-pathological correlations and long-term follow-up of 253 United Kingdom patients with IgA nephropathy. A report from the MRC Glomerulonephritis Registry.Q J Med. 1992; 84: 619-627PubMed Google Scholar and recent evidence suggests that the onset of progressive renal insufficiency is preceded by the development of proteinuria and hypertension.8Szeto C Lai FM To K Yuk-Hwa Wong T Chow K Cheung-Lung Choi P Lui S Kam-Tao Li P The natural history of immunoglobulin A nephropathy among patients with hematuria and minimal proteinuria.Am J Med. 2001; 110: 434-437Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar Antihypertensive therapy has been demonstrated to delay progression of chronic kidney disease in both proteinuric and nonproteinuric nephropathies. Lewis et al9Lewis EJ Hunsicker LG Bain RP Rohde RD The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329 (The Collaborative Study Group): 1456-1462Crossref PubMed Scopus (5056) Google Scholar demonstrated that in type 1 diabetics with similar levels of blood pressure control across treatment groups, captopril therapy slowed renal deterioration more than conventional non-ACE inhibitor antihypertensive therapy. The Ramipril Efficacy in Nephropathy (REIN) study investigators reported that in nondiabetics with proteinuria ≥3 g/24 hours, treatment with ramipril resulted in a significantly lower level of decline in glomerular filtration rate (GFR) than treatment with conventional therapy without a significant blood pressure difference between groups.10The GISEN Group Gruppo Italiano di Studi Epidemiologici in Nefrologia Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy.Lancet. 1997; 349: 1857-1863Abstract Full Text Full Text PDF PubMed Scopus (1750) Google Scholar In patients with IgA nephropathy, antihypertensive therapy with ACE inhibitors has also been shown to be associated with slower decline in renal function than therapy with beta-blockers.11Rekola S Bergstrand A Bucht H Deterioration rate in hypertensive IgA nephropathy: Comparison of a converting enzyme inhibitor and beta-blocking agents.Nephron. 1991; 59: 57-60Crossref PubMed Scopus (75) Google Scholar Increased protein trafficking has been associated with deteriorating renal function in many animal models.12Ruggenenti P Remuzzi G The role of protein traffic in the progression of renal diseases.Annu Rev Med. 2000; 51: 315-327Crossref PubMed Scopus (64) Google Scholar The effectiveness of ACE inhibitors and angiotensin II receptor blockers in reducing progression of renal dysfunction is posited to be a consequence of their antiproteinuric effects, rather than attributable to their blood pressure lowering effect alone.13Remuzzi A Perico N Sangalli F Vendramin G Moriggi M Ruggenenti P Remuzzi G ACE inhibition and ANG II receptor blockade improve glomerular size-selectivity in IgA nephropathy.Am J Physiol. 1999; 276: F457-F466PubMed Google Scholar, 14Perico N Remuzzi A Sangalli F Azzollini N Mister M Ruggenenti P Remuzzi G The antiproteinuric effect of angiotensin antagonism in human IgA nephropathy is potentiated by indomethacin.J Am Soc Nephrol. 1998; 9: 2308-2317PubMed Google Scholar Indifferent to the benefits of altering abnormal protein trafficking or reducing blood pressure abnormalities, angiotensin II is perceived to be a provocateur. Therefore, the ability of ACE inhibitors and angiotensin receptor blocking agents to attenuate angiotensin II production and action, respectively, offers a rationale for the selection of one or both in proteinuric renal diseases. The intervention trial described in this issue of the Journal is a randomized crossover study of 19 normotensive patients with non-nephrotic range proteinuria. The study is analyzed using an as-treated design, rather than the more conventional intention-to-treat strategy used to determine clinical efficacy. In terms of external validity, it is also noteworthy that 8 of 19 patients were excluded from analysis because of protocol violations, nonadherence, or side effects. Had this study been analyzed on an intention-to-treat basis, it is likely that the null hypothesis would not have been rejected. The blood pressure and antiproteinuric effect of 6 intervention therapies were compared: enalapril at 10 mg/day, enalapril at 20 mg/day, losartan at 50 mg/day, losartan at 100 mg/day, and combination therapy consisting of enalapril at 10 mg/day and losartan at 50 mg/day or consisting of enalapril at 20 mg/day and losartan at 100 mg/day. All 6 interventions resulted in significant reductions in both proteinuria and ambulatory blood pressure from baseline measurements. Moreover, the combination therapies were more effective for both endpoints. The intervention trial presented herein is reported primarily in the context of an antiproteinuric strategy. The trial design does not permit an analysis of the effect of progression of kidney disease as either reduction in GFR or development of ESRD. In this respect clinical efficacy is defined based on a putative clinical surrogate (ie, proteinuria). The suggestion is made that less proteinuria results in better outcomes. Two major queries are raised: (1) does proteinuria reduction always result in a clinical benefit, and (2) if a clinical benefit occurs, is it a consequence of proteinuria reduction alone? The burden of proof for these two integrated queries should be met before the reader routinely embraces the findings offered herein in clinical practice. Towards addressing the first issue, the reader is reminded that proteinuria remains a provocative but unproven surrogate outcome for future deterioration in renal function. Although a sound pathobiologic chain of logic exists, and substantial associations exist as primary and secondary outcomes from several clinical trials,9Lewis EJ Hunsicker LG Bain RP Rohde RD The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329 (The Collaborative Study Group): 1456-1462Crossref PubMed Scopus (5056) Google Scholar, 15Ruggenenti P Pagano E Tammuzzo L Benini R Garattini L Remuzzi G Ramipril prolongs life and is cost effective in chronic proteinuric nephropathies.Kidney Int. 2001; 59: 286-294Crossref PubMed Scopus (44) Google Scholar, 16Maschio G Alberti D Janin G Locatelli F Mann JF Motolese M Ponticelli C Ritz E Zucchelli P Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996; 334: 939-945Crossref PubMed Scopus (1704) Google Scholar the burden of proof for a surrogate outcome has not yet been met. Reduction in proteinuria has been found to correlate with slowing in renal deterioration,9Lewis EJ Hunsicker LG Bain RP Rohde RD The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.N Engl J Med. 1993; 329 (The Collaborative Study Group): 1456-1462Crossref PubMed Scopus (5056) Google Scholar but in this area long-term outcome studies that establish a clear pathobiologic pathway have not yet been performed. For example, it is unclear what threshold of proteinuria corresponds to an increased risk of progressive kidney disease. So, is more necessarily better in proteinuria reduction? Increased medications are likely associated with increased side effects—so, does a better surrogate outcome justify an increased risk exposure? These two questions have not been definitely answered; therefore, equipoise exists. Surrogate response variables, such as proteinuria reduction in this case, are often selected as trial indicators, because as continuous variables they lend to smaller sample size and therefore less expense than trials with clinical endpoints.17Friedman L Furberg CD DeMets DL Fundamentals of Clinical Trials.ed 3. New York, Springer, 1998Crossref Google Scholar However, the use of such surrogate endpoints has led to a number of misleading results and interpretations in the past. Perhaps the most oft-quoted example is the Cardiac Arrhythmia Suppression Trial (CAST) that demonstrated that effective suppression of ventricular arrhythmias as the surrogate outcome was associated with increased mortality.18The Cardiac Arrhythmia Suppression Trial CAST Investigators Preliminary report: Effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction.N Engl J Med. 1989; 321: 406-412Crossref PubMed Scopus (3114) Google Scholar Another example is the use of CD4 lymphocytes as an indicator of disease status in patients with HIV.19Choi S Lagakos SW Schooley RT Volberding PA CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine.Ann Intern Med. 1993; 118: 674-680Crossref PubMed Scopus (172) Google Scholar The ideal surrogate outcome should be easy and accurate to measure, acceptable to the subject, and relatively inexpensive. Proteinuria meets these criteria. However, for a surrogate outcome to be clinically meaningful, it must truly represent the relationship between the treatment and the true clinical end-point for which it is purported to be a surrogate.17Friedman L Furberg CD DeMets DL Fundamentals of Clinical Trials.ed 3. New York, Springer, 1998Crossref Google Scholar, 20Fleming TR DeMets DL Surrogate end points in clinical trials: Are we being misled?.Ann Intern Med. 1996; 125: 605-613Crossref PubMed Scopus (1361) Google Scholar Although proteinuria has been shown to correlate with renal outcome, interventions that cause reduction in proteinuria may have other unrecognized undesirable clinical effects that are not apparent when results are described in the context of the surrogate but would be apparent if clinical outcomes were all that were considered.17Friedman L Furberg CD DeMets DL Fundamentals of Clinical Trials.ed 3. New York, Springer, 1998Crossref Google Scholar Reduction in proteinuria may not necessarily “capture”21Prentice RL Surrogate endpoints in clinical trials: Definition and operational criteria.Stat Med. 1989; 8: 431-440Crossref PubMed Scopus (1521) Google Scholar the clinically relevant effect of the intervention.21Prentice RL Surrogate endpoints in clinical trials: Definition and operational criteria.Stat Med. 1989; 8: 431-440Crossref PubMed Scopus (1521) Google Scholar As this study does not demonstrate a blood pressure-independent reduction in proteinuria, the combination therapy offered has not been proven to be any more antiproteinuric than a combination of ACE inhibitor or angiotensin receptor blocker and any other antihypertensive agent. Unsurprisingly, the renal protective effect of ACE inhibitor therapy has been difficult to separate from the blood pressure lowering effect in previous studies.16Maschio G Alberti D Janin G Locatelli F Mann JF Motolese M Ponticelli C Ritz E Zucchelli P Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.N Engl J Med. 1996; 334: 939-945Crossref PubMed Scopus (1704) Google Scholar The effect of blood pressure reduction of even a quantitatively modest extent on clinical outcomes is also often underestimated. The Hypertension Optimal Treatment (HOT) trial is an example of how small changes in blood pressure can affect outcomes. An achieved diastolic blood pressure difference of only 2 mmHg between groups was associated with a significant reduction in risk of cardiovascular events.22Hansson L Zanchetti A Carruthers SG Dahlof B Elmfeldt D Julius S Menard J Rahn KH Wedel H Westerling S Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomised trial.Lancet. 1998; 351: 1755-1762Abstract Full Text Full Text PDF PubMed Scopus (5455) Google Scholar The recent Heart Outcomes Prevention Evaluation (HOPE) trial23Yusuf S Sleight P Pogue J Bosch J Davies R Dagenais G Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.N Engl J Med. 2000; 34: 145-153Google Scholar demonstrated reductions in the rates of death, myocardial infarction, and stroke in high-risk patients with ramipril use. It is notable that there was a small but significant difference in blood pressure levels when treatment and placebo groups were compared.23Yusuf S Sleight P Pogue J Bosch J Davies R Dagenais G Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators.N Engl J Med. 2000; 34: 145-153Google Scholar It seems unlikely that the kidney is not similarly affected by seemingly insignificant alterations in blood pressure. Therefore, some of the effect typically ascribed to antiproteinuric antihypertensive medications may be a consequence of previously disregarded modest alterations in blood pressure. In patients who adhered to therapy and did not suffer side effects that mandated discontinuation from the trial, proteinuria associated with IgA nephropathy was reduced to a greater extent with treatment using the combination of losartan and enalapril compared with either agent alone. The reduction in proteinuria did not occur independently of blood pressure. A more definitive evaluation of such combination therapy in nondiabetic nephropathies such as IgA nephropathy should be based on clinically meaningful endpoints. The inclusion of secondary outcome measures like proteinuria will permit their validation as safe and reliable surrogate endpoints. These are required before such therapy should be recommended for all patients with IgA nephropathy. The same cautionary note is offered for the use of all putative surrogate outcomes in renal medicine. Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathyAmerican Journal of Kidney DiseasesVol. 38Issue 1PreviewAngiotensin-converting enzyme (ACE) inhibitors and AT1-receptor antagonists (ARAs) are widely administered to reduce urinary protein loss and slow the progression of proteinuric nephropathy to end-stage renal failure. Our group recently observed that the combination of ACE inhibitors and ARAs may have an additive antiproteinuric effect, which may occur because ACE inhibitors do not completely reduce angiotensin II (Ang II) production. Ang II is also produced by chymase. Thus, combination therapy better antagonizes the effects of Ang II. Full-Text PDF
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