RANDOMIZED CONTROLLED trials

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1 Combination Therapy With an Angiotensin Receptor Blocker and an ACE Inhibitor in Proteinuric Renal Disease: A Systematic Review of the Efficacy and Safety Data Martin MacKinnon, MD, Sabin Shurraw, MD, Ayub Akbari, MD, Greg A. Knoll, MD, MSc, James Jaffey, MSc, and Heather D. Clark, MD, MSc Blockade of the renin-angiotensin system with either an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin receptor blocker (ARB) was shown to decrease urinary protein excretion and slow the progression of both diabetic and nondiabetic proteinuric renal disease. The safety and efficacy of combined ACE-inhibitor and ARB therapy is not well established. We conducted a systematic review and meta-analysis of randomized trials evaluating the combination of an ACE inhibitor and an ARB in patients with chronic proteinuric renal disease. Twenty-one randomized controlled studies (n 654 patients) were identified using MEDLINE, EMBASE, and Cochrane Central databases. Five trials had a parallel-group design and 16 trials used a crossover design. Combination therapy with an ACE inhibitor and an ARB resulted in a small, but significant, increase in serum potassium levels (weighted mean difference, 0.11 meq/l [0.11 mmol/l]; 95% confidence interval [CI], 0.05 to 0.17) and a nonsignificant decrease in glomerular filtration rate (weighted mean difference, 1.4 ml/min [0.02 ml/s]; 95% CI, 2.6 to 0.2). Addition of an ARB resulted in a further decrease in proteinuria (weighted mean difference, 440 mg/d; 95% CI, 289 to 591) compared with an ACE inhibitor alone. This effect was observed in patients with diabetic (210 mg/d; 95% CI, 84 to 336) and nondiabetic (582 mg/d; 95% CI, 371 to 793) renal disease. In conclusion, the combination of ACE-inhibitor and ARB therapy in patients with chronic proteinuric renal disease is safe, without clinically meaningful changes in serum potassium levels or glomerular filtration rates. Combination therapy also was associated with a significant decrease in proteinuria, at least in the short term. Additional trials with longer follow-up are needed to determine whether the decrease in proteinuria will result in significant preservation of renal function. Am J Kidney Dis 48: by the National Kidney Foundation, Inc. INDEX WORDS: Angiotensin-converting enzyme (ACE) inhibitor; angiotensin receptor blocker; proteinuria; metaanalysis; systematic review. From the Department of Medicine, Division of Nephrology, University of Ottawa; Kidney Research Center; and Ottawa Health Research Institute, Ottawa, Ontario, Canada. Received November 28, 2005; accepted in revised form April 10, Originally published online as doi: /j.ajkd on June 8, M.M. and S.S. contributed equally to this manuscript and should be considered co-first authors. Support: None. Potential conflicts of interest: None. Address reprint requests to Martin MacKinnon, MD, Division of Nephrology, Saint John Regional Hospital, PO Box 2100, Saint John, New Brunswick, E2L 4L2 Canada. mmackinnon2545@rogers.com 2006 by the National Kidney Foundation, Inc /06/ $32.00/0 doi: /j.ajkd RANDOMIZED CONTROLLED trials showed that inhibition of the renin-angiotensin system is an important factor in the treatment of patients with proteinuric renal disease. Angiotensin-converting enzyme (ACE) inhibitors are first-line therapy for patients with type 1 diabetes mellitus. 1 Therapy with an ACE inhibitor significantly delayed the progression of proteinuric renal disease in patients without diabetes. 2,3 Angiotensin receptor blockers (ARBs) were shown to reduce the composite outcome of doubling of serum creatinine level, end-stage renal disease (ESRD), or death in patients with type 2 diabetes mellitus and proteinuria. 4,5 Finally, therapy with an ACE inhibitor was shown to significantly delay the progression of proteinuric renal disease in patients without diabetes. 2,3 Recent evidence suggests that ACE inhibitors may not completely block the formation of angiotensin II. 6 Non-ACE enzymes, such as chymase, are thought to increase the conversion of angiotensin I to angiotensin II and, over time, return angiotensin II level to pretreatment values. 7,8 These non ACE-dependent pathways appear to be upregulated with long-term ACEinhibitor use, but the clinical significance of these observations is unclear. Combination therapy with an ACE inhibitor and an ARB may allow more complete blockade of the reninangiotensin system and thereby provide additional renoprotection. Although combination therapy with an ACE inhibitor and an ARB is appealing from a mechanistic point of view, risks and potential benefits 8 American Journal of Kidney Diseases, Vol 48, No 1 (July), 2006: pp 8-20

2 ANGIOTENSIN BLOCKADE IN CHRONIC KIDNEY DISEASE 9 of such a strategy have not been validated in multiple patient populations. The objective of this study is to systematically review all randomized trials involving combination therapy with an ACE inhibitor and an ARB. End points to be evaluated are change in serum potassium level, glomerular filtration rate (GFR), blood pressure (BP), and proteinuria. METHODS Search Strategy and Study Selection We searched MEDLINE (1966 to January 2006), EMBASE (1980 to 2004), and the Cochrane database of randomized controlled trials (The Cochrane Library 2006, Issue 1) for studies in which an ARB was combined with an ACE inhibitor in patients with chronic proteinuric renal disease. Proteinuria was searched as both a medical subject heading term and a text word. We then combined this search with the terms ARB, ACE inhibitor, and the names of the individual ACE-inhibitor and ARB medications. We augmented our search by reviewing reference lists of all retrieved articles, our personal files, and references suggested by local experts. Two investigators (S.S., M.M.) independently reviewed all titles and abstracts for potentially relevant studies. All potentially relevant articles were retrieved and reviewed independently by the same 2 investigators to determine eligibility. Studies that met the following criteria were considered for inclusion in the study: randomized controlled trial, study population included adult patients with either diabetic or nondiabetic chronic proteinuric renal disease (defined as proteinuria with protein 300 mg/d at initiation of the study), intervention arm included simultaneous treatment with an ACE inhibitor and an ARB, a comparator arm included treatment with an ACE inhibitor alone, and the study reported 24-hour proteinuria as one of the outcomes. Studies were excluded for the following reasons: the study population included renal transplant recipients, duration of treatment with either an ACE inhibitor or ACE inhibitor plus ARB was less than 4 weeks, or any study not published in English. Data Extraction Data were abstracted independently in duplicate by 2 investigators (S.S., M.M.). The following data were abstracted: trial design, cause of renal disease, sample size, specific medications used, duration of treatment, number of dropouts, and 24-hour protein excretion. Serum potassium level, estimation of GFR, BP data, progression to ESRD, and death also were abstracted, if reported. Differences over inclusion of studies and/or interpretation of data were resolved by consensus discussion. The 2 reviewers (S.S., M.M.) independently rated the method quality of all included studies with the validated scale by Jadad et al, 9 which measures blinding, randomization, withdrawals, and dropouts. A maximum score of 5 represents the highest quality trial. Statistical Analysis Outcomes of interest for this systematic review were changes in 24-hour proteinuria, serum potassium level, and GFR after addition of an ARB to preexisting ACE-inhibitor therapy. Secondary outcomes included change in BP, progression to ESRD, and death. Because the focus of this review is to explore the added effects of receptor-level angiotensin blockade in addition to ACE inhibition, data were not included from ARB monotherapy arms if they were part of the study design. In the published crossover trials, data generally were presented as a pooled summary posttreatment after either ACE-inhibitor or combination therapy (ie, end point data were not reported before crossover into the alternate treatment arm). Thus, crossover data could not be abstracted from the first period (approximating a parallel-group design) to combine with the parallel-group studies. From each study, mean and SD of each variable of interest were abstracted. If studies included separate data for different subgroups of interest (ie, patients with and without diabetes), data for each subgroup were entered as 2 separate studies. To calculate the mean difference and SE of the difference, correlation between results from the 2 periods is required. We assumed correlation between the initial and final period to be 0.8, which is a conservative estimate because each participant was his or her own control. Weighted mean difference was used to summarize continuous outcomes (proteinuria, GFR, serum potassium level, and BP). Several studies analyzed proteinuria data after logarithmic transformation because of the absence of normal distribution. The reported 95% confidence intervals (CIs) or interquartile ranges of these skewed proteinuria data were converted to SD to allow for a pooled analysis. Heterogeneity across studies was assessed by using Cochrane Q statistic, with P less than 0.10 considered significant. 10 In the absence of significant heterogeneity, individual study effects were pooled using a fixed-effects model by means of inverse-variance method. If there was evidence of heterogeneity, outcomes were pooled using the randomeffects model of DerSimonian and Laird. 10 All reported P are 2-tailed, and P less than 0.05 is considered statistically significant. Analysis was performed using an Excel spreadsheet (Microsoft Excel, 2000; Microsoft Corp, Redmond, WA) and SAS, version 8.1 (SAS Institute Inc, Cary, NC). RESULTS Three hundred forty-four studies were identified by our search strategy, and 37 initially met the inclusion criteria based on review of the title and abstract (Fig 1). Review of the full article led to further exclusion of 16 trials for the following reasons: 6 studies were not randomized, study was a case report, 17 2 studies did not have the primary outcome measured (24-hour proteinuria), 18,19 2 studies did not allocate patients to the treatments of interest, 20,21 3 studies included patients with proteinuria with protein less than 0.3 g/d at baseline, study reported on

3 10 MACKINNON ET AL 344 studies identified with initial search ACE-I + ARB therapy, involving proteinuria Excluded 37 Studies 307 Studies Lack of randomization (n=6) Case report (n=1) No 24-hr proteinuria data (n=2) Proteinuria <0.3 g/d at baseline(n=3) No comparison to ACEI alone (n=2) Same patients in earlier report (n=1) Pediatric patients (n=1) 21 studies included in meta-analysis & review 16 cross-over randomized controlled trials 5 parallel group randomized controlled trials Fig 1. Search results and selection of randomized trials for analysis. patients from an earlier trial, 25 and 1 study enrolled pediatric patients. 26 Of 21 studies (n 654 patients) included in this review, 16 studies (n 373 patients) were crossover design and 5 studies (n 281 patients) were parallelgroup design Characteristics of parallelgroup design trials are listed in Table 1, and crossover design trials are listed in Tables 2 and 3. Parallel-Group Design Trials Results of the 5 parallel-group trials were not pooled because significant clinical heterogeneity existed. There was marked discrepancy in duration of follow-up between the 5 studies that ranged from 3 months to nearly 3 years (Table 1). Therefore, these trials are summarized in only a qualitative manner. The Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting- Enzyme Inhibitor in Non-Diabetic Renal Disease (COOPERATE) trial was the largest of the parallel-group studies and had the highest quality and longest treatment duration. 43 Two hundred sixty-three patients with predominately immunoglobulin A (IgA) glomerulonephritis were randomly assigned to 1 of the following 3 groups: the ARB losartan (100 mg/d), the ACE inhibitor trandolapril (3 mg/d), or the combination of both drugs at the same doses. Patients were included in the trial if their calculated GFR was between 20 and 70 ml/min/1.73 m 2 (0.33 and 1.17 ml/s/ 1.73 m 2 ). There was no prespecified exclusion for the presence of hyperkalemia. Renal failure was caused by glomerular disease in 61% of patients (IgA nephropathy accounting for 80%), hypertensive nephrosclerosis (17%), polycystic kidney disease (5%), or unknown cause (13%). With a median follow-up of 2.9 years, urinary protein excretion decreased from baseline in all 3 groups, with the most marked decrease in patients treated with combination therapy. The combination-therapy group experienced a proteinuria decrease of 75.6% (interquartile range, 59.3% to 87.9%) versus only 44.3% (interquartile range, 5.6% to 54.5%) in those administered ACE-inhibitor monotherapy (P 0.01). Patients on combination therapy also had a significant decrease in the end point of doubling of serum creatinine level or ESRD compared with ACE inhibitor alone (11% versus 23%; hazard ratio, 0.38; P 0.018). Importantly, the benefit of

4 Table 1. Characteristics of Parallel-Group Trials Comparing Proteinuria Decrease With ACE-Inhibitor Monotherapy and ACE-Inhibitor Plus ARB Combination Therapy Reference Nakao et al, Segura et al, Luno et al, Tylicki et al, Horita et al, Inclusion Criteria Nondiabetic CKD; proteinuria 0.3 g/d; calculated GFR, ml/min CKD (unspecified cause); proteinuria 1.5 g/d; BP 140/90 mm Hg; CrCl 30 ml/min Nondiabetic CKD (primary GN); proteinuria 2 g/d; CrCl 50 ml/min, K 5.0 meq/l Nondiabetic CKD (primary GN, excluding IgA); serum creatinine 2.3 mg/dl IgA nephropathy; proteinuria 0.4 g/d; BP 140/90 mm Hg; calculated GFR 50 ml/min ACE Inhibitor Arm (n) ACE Inhibitor ARB Arm (n) ACE Inhibitor (mg/d) Trandolapril, 3, placebo ACE Inhibitor ARB (mg/d) Trandolapril, 3, losartan, Benazepril, Benazepril, 10-20, valsartan, Lisinopril, Lisinopril, 5-20, candesartan, Enalapril, 10 Enalapril, 10, losartan, Temocapril, 1 Temocapril, 1, losartan, 12.5 Treatment Duration Adverse Events Median, 2.9 y Hyperkalemia : ACE inhibitor: n 8; ACE inhibitor ARB: n 7; no ARF in either group 6 mo No dropouts caused by hyperkalemia or ARF 6mo N 2: K 6.0 meq/l; no dropout caused by hyperkalemia or ARF 3 mo No dropouts; CrCl: similar decline between groups ; potassium data not reported 6 mo No dropouts caused by hyperkalemia or ARF NOTE. To convert serum creatinine in mg/dl to mol/l, multiply by 88.4; GFR and CrCl in ml/min to ml/s, multiply by Abbreviations: ARF, acute renal failure; CrCl, creatinine clearance; GN, glomerulonephropathy; K, serum potassium; IgA, IgA nephropathy. *Jadad score for quality assessment: low (0 to 2 points), moderate (3 to 4 points), high (5 points, maximum score). Hyperkalemia treated successfully with potassium binder or dietary restriction; none resulted in dropout. Benazepril, 10 mg if CrCl less than 50 ml/min, 20 mg if CrCl greater than 50 ml/min. Valsartan, 80 mg, was increased to 160 mg if BP greater than 140/90 mm Hg after 4 weeks. Dose of lisinopril and candesartan was doubled every 2 weeks if BP greater than 125/75 mm Hg until maximum dose achieved. Combination group: 14% decrease in CrCl after week 1, but no difference from baseline at 3 months. ACE-inhibitor group: 15% decrease evident at 1 week persisted to 3 months. Jadad Score* ANGIOTENSIN BLOCKADE IN CHRONIC KIDNEY DISEASE 11

5 Table 2. Patient Characteristics in Crossover Trials Comparing Proteinuria Reduction With ACE-Inhibitor Monotherapy Versus ACE-Inhibitor Plus ARB Combination Therapy 12 Reference No. of Patients/ Sex/Mean Age (y) Cause of CKD (N) Inclusion Criteria Baseline Proteinuria (g/d)/bp (mm Hg)/Renal Function (ml/min) Agarwal, /14M:2F/53 Diabetic nephropathy (12), GN (4) Proteinuria 1 g/d; MAP 97 mm Hg; CrCl 30 ml/min, 3.6/156/88*/GFR, 64 K 5.5 meq/l Russo et al, /4M:6F/25 IgA (10) Proteinuria 1 3 g/d; BP 140/90 mm Hg; CrCl 1.5/128/74 /CrCl, ml/min Berger et al, /6M:6F/52 IgA (9), membranous (3) Proteinuria 1 g/d; normotensive ; ACE-inhibitor 1.8/128/79* /GFR, 64 Ferrari et al, /7M:4F/48 Membranous (5), FSGS (4), IgA (1), Proteinuria 1.5 g/d; BP 140/90 or BP medication; CrCl 7.9/144/91/CrCl, 77 MPGN (1) 30 ml/min Jacobsen et al, /17M:4F/45 DM 1 (21) Proteinuria 1 g/d ; BP 135/85 mm Hg; ACE-inhibitor 1.9 /156/87*/GFR, 52 diuretic GFR 20 ml/min, K 4.8 meq/l Rossing et al, /13M:4F/58 DM 2 (17) Proteinuria 1 Ig/d ; BP 135/85, ACE-inhibitor GFR 1.8 /159/85*/GFR, ml/min, K 4.6 meq/min Kincaid-Smith et al, /23-75 Reflux (14), IgA(12), FSGS (8), other (14), membranous (5), DM (7) Proteinuria 0.5 g/d; BP well-controlled ; ACE-inhibitor Cr 4.6 mg/dl 2.2, 2.4 /134/84, 139/82* /Cr, 2.2, 2.4 mg/dl Jacobsen et al, /17M:7F/42 DM 1 (24) Proteinuria 0.3 g/d ; ACE-inhibitor; GFR 30 ml/min; 0.52 /131/74* /GFR, 65 K 4.8 meq/l Jacobsen et al, /13M:5F/43 DM 1 (24) Proteinuria 0.3 g/d ; ACE-inhibitor GFR 30 ml/min, 0.7 /141/81*/GFR, 82 K 4.8 meq/l Rossing et al, /17M:3F/62 DM 2 (20) Proteinuria 0.3 g/d ; BP 135/85 mm Hg; ACE-inhibitor 0.7 /138/72* /GFR, 77 GFR 25 ml/min, K 4.6 meq/l Kim et al, /19M:22F/32 DM 2 (22), IgA (19) Proteinuria 1 g/d; BP 130/80 mm Hg; ACE-inhibitor 3.9/MAP: 92* /CrCl, 60 CrCl, ml/min Campbell et al, /23M:1F/49 IgA (11), chronic GN (4), other (4), Proteinuria 1 g/d; DBP or BP medication; CrCl, 3.3/140/91*/CrCl, 69 no biopsy (5) ml/min; K 6.0 meq/l Song et al, /13M:19F/34 IgA (14), DM 2 (18) Proteinuria 1 g/d; BP 130/80, ACE-inhibitor CrCl, 4/MAP, 92* /CrCl, ml/min Rutkowski et al, /12M:12F/35 Mesangial GN (14), IgA (5), MPGN Proteinuria 3.5 g/d; ACE-Inhibitor or ARB Cr 2 mg/dl 2.1/134/85 /CrCl, 86 (4), membranous (1) Matos et al, /5M:15F/54 DM 2 (20) Proteinuria g/d; SBP 140 or BP medication; CrCl 0.9/146/81* /GFR, ml/min; K 5 meq/l Song et al, /11M:10F/49 DM 2 (21) Proteinuria 1 g/d; BP 140/90 on ACE-Inhibitor or ARB; CrCl, ml/min; K 5.5 meq/l 4.2/133/81* /CrCl, 41 NOTE. To convert serum creatinine in mg/dl to mol/l, multiply by 88.4; GFR and CrCl in ml/min to ml/s, multiply by ; potassium in meq/l to mmol/l, multiply by 1. Abbreviations: Cr, serum creatinine; CrCl, creatinine clearance; DM1, type 1 diabetes mellitus; DM2, type 2 diabetes mellitus; FSGS, focal segmental glomerulosclerosis; GN, glomerulonephropathy; GFR, glomerular filtration rate (estimated by EDTA, inulin, or iothalamate clearance); K, serum potassium; MAP, mean arterial blood pressure; MPGN, membranoproliferative GN. *BP measured while administered antihypertensive medication. Twenty-four hour ambulatory BP. Albuminuria. Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported. Prerandomization data reported separately for ACE-inhibitor alone group and ACE-inhibitor plus ARB group. MACKINNON ET AL

6 ANGIOTENSIN BLOCKADE IN CHRONIC KIDNEY DISEASE 13 Table 3. Treatment Protocol, Method Quality, and Dropouts in Crossover Trials Comparing Proteinuria Reduction With ACE-Inhibitor Monotherapy Versus ACE-Inhibitor Plus ARB Combination Therapy Reference ACE-Inhibitor (mg/d) ARB (mg/d) Treatment Duration (wk) Dropouts (n) ( serum K or ARF) Jadad Score* Agarwal, Lisinopril, 40 Losartan, 50 4 None 2 Russo et al, Enalapril, 20 Losartan, None 2 Berger et al, Low-dose ACE-inhibitor Candesartan, 8 8 None 5 Ferrari et al, Fosinopril, 20 Irbesartan, None 3 Jacobsen et al, Recommended dose Irbesartan, , hyperkalemia 5 ACE-inhibitor Rossing et al, Enalapril, 20, or lisinopril, Candesartan, 8 8 None 5 20, or captopril, 100 Kincaid-Smith et al, Previously prescribed Candesartan, , hyperkalemia ACE-inhibitor (n 45 maximum dose) Jacobsen et al, Enalapril, 40 Irbesartan, None 5 Jacobsen et al, Benazepril, 20 Valsartan, 80 8 None 5 Rossing et al, Enalapril, 40, or lisinopril, Candesartan, 16 8 None 5 40, or captopril, 150 Kim et al, Ramipril, Candesartan, , hyperkalemia 4 (previous dose) and ARF Campbell et al, Benazepril, 10 or 20 Valsartan, 80 8 None 2 Song et al, Ramipril 5 Candesartan, 4 to 16 1, hyperkalemia 4 8, as tolerated and ARF Rutkowski et al, Benazepril 5 or 10 Losartan, None Matos et al, Perindopril, 8 Irbesartan, , hyperkalemia 2 Song et al, Ramipril, 5 or 10 Candesartan ARF 3 Abbreviations: ARF, acute renal failure; K, potassium. *Jadad score for quality assessment: low (0-2 points), moderate (3-4 points), high (5 points, maximum). Benazepril, 20 mg/d when given as monotherapy; benazepril, 10 mg/d when coadministered with ARB. Benazepril, 10 mg/d when given as monotherapy; benazepril, 5 mg/d when coadministered with ARB. Ramipril, 10 mg/d when given as monotherapy; ramipril, 5 mg/d when coadministered with ARB. combination therapy was shown across 3 strata of baseline urinary protein excretion: protein less than 1 g/d, 1 to 3 g/d, and greater than 3 g/d. These findings appeared to be independent of BP decrease because there was no significant difference in BPs among the 3 groups. Of 263 patients participating in the trial, 8 patients (9.3%) developed hyperkalemia in the ACE-inhibitor arm versus 7 patients (8.0%) in the combination arm. There was no acute decrease in renal function in any treatment group. The other 4 parallel-group studies were smaller than the COOPERATE study Segura et al 44 studied 36 patients, 24 of whom were randomly assigned to either the ACE-inhibitor benazepril, 20 mg/d (for patients with creatinine clearance 50 ml/min [ 0.83 ml/s]) or 10 mg/d (for patients with creatinine clearance 50 ml/min), or combination treatment (benazepril according to renal function as defined and the ARB valsartan starting at 80 mg/d and titrated to 160 mg/d as required for BP reduction). 44 The ARB-alone arm is not considered here. Each study participant had primary renal disease (which was not defined further in the report) with a baseline BP greater than 140/90 mm Hg and baseline proteinuria with greater than 1.5 g/d of protein. All patients in this study had creatinine clearance values greater than 30 ml/min ( 0.50 ml/s), with baseline average values of 72 ml/min (1.20 ml/s) in the ACE-inhibitor arm and 68 ml/min (1.13 ml/s) in the combination group. After 6 months of treatment, mean protein excretion decrease was g/d in the combination group versus g/d in the ACE-inhibitor arm (P 0.05). There was a nonsignificant trend toward greater systolic BP decrease in the combination group (mean decrease, 12 mm Hg) versus the ACE-inhibitor monotherapy group (mean decrease, 8 mm Hg). In this study, there were no

7 14 MACKINNON ET AL significant changes in either serum potassium levels or creatinine clearances in 6 months of follow-up. In the study of Luno et al, patients with nondiabetic proteinuric renal disease were treated with the ACE-inhibitor lisinopril (40 mg/d), whereas 16 patients received treatment with a combination of lisinopril (20 mg/d) and the ARB candesartan (16 mg/d). An ARB monotherapy arm is not discussed. Patients were enrolled if 24-hour protein excretion was greater than 2 g/d and creatinine clearance was greater than 50 ml/min/1.73 m 2 ( 0.83 ml/s/1.73 m 2 ). After 6 months, proteinuria decrease tended to be greater in the combination group (mean decrease, 70%) than in the ACE-inhibitor-monotherapy group (mean decrease, 50%). A statistically significant difference could be shown only at 2 months follow-up (60% decrease with combination therapy versus 33% decrease with ACE inhibitor alone; P 0.03). The BP goal in this trial was less than 125/less than 75 mm Hg and was achieved in both groups analyzed. There was no statistically significant difference between groups at study completion. The investigators reported no changes in GFRs from baseline or between the 2 study groups, and no patients had study medication discontinued secondary to hyperkalemia. However, serum potassium was measured at greater than 5.5 meq/l ( 5.5 mmol/l) in 8 instances (3% of all measurements) and greater than 6.0 meq/l ( 6.0 mmol/l) in 2 cases. The groups in which these events occurred were not reported, but all 8 cases were in patients with impaired renal function. In the parallel-group study by Tylicki et al, 46 patients with biopsy-proven primary glomerulonephritis were randomly assigned to treatment with the ACE inhibitor enalapril (10 mg/d), the ARB losartan (25 mg/d), or enalapril plus losartan in combination at the same doses. 46 There were 17 patients in the ACE-inhibitor group versus 15 patients treated with combination therapy. After 3 months, the combination-therapy group had a greater decrease in proteinuria (protein, g/d) compared with those administered enalapril (1.2 1 g/d), but the difference did not reach statistical significance. There was no statistical difference in change in systolic BP between the ACE-inhibitor and combination groups. Diastolic BP decrease was more significant (89.3 to 78.7 mm Hg [ 10.7]) in the combination group versus enalapril monotherapy (87.4 to 85.3 mm Hg [ 2.0]). A short-term decrease in creatinine clearance was observed in the enalapril group that was no longer significantly different from the combination-therapy group at study completion. There were no patient dropouts reported within the trial. Serum potassium levels pretreatment and posttreatment were not reported. Horita et al 47 studied patients with IgA nephropathy prospectively for 6 months, in which monotherapy with temocapril (1 mg/d) was compared with combination therapy with losartan (12.5 mg/d) and temocapril (1 mg/d). An ARB monotherapy arm is not discussed. Patients were included if they were normotensive (BP 140/90 mm Hg) with GFR greater than 50 ml/ min/1.73 m 2 ( 0.83 ml/s/1.73 m 2 ) and proteinuria with protein of 0.4 to 1.0 g/d. The investigators observed a more pronounced decrease in proteinuria in the combination arm (0.75 to 0.28 g/d [ 63.2%]) versus temocapril monotherapy (0.73 to 0.44 g/d [ 41.3%]). Neither GFR (estimated using the Cockcroft-Gault formula) nor serum potassium level changed significantly throughout the study. BP did not decrease significantly with low-dose temocapril therapy, but decreased with combination therapy (systolic BP, 122 to 107 mm Hg; P 0.01). Crossover Trials Tables 2 and 3 list the 16 crossover studies (n 373 patients) included in this analysis. Five studies included patients with nondiabetic renal disease, 28-30,38,40 7 studies involved only patients with diabetes, 31,32,34-36,41,42 and 4 studies involved patients with both diabetic and nondiabetic renal disease. 27,33,37,39 Of the latter 4 studies, 2 included a separate analysis of the diabetic and nondiabetic subgroups. 37,39 Average sample size in the crossover studies was 23 (range, 10 to 60). All studies were short term, with median treatment duration of only 8 weeks (range, 4 to 16 weeks). Patients generally were excluded from trial enrollment if they had a tendency toward hyperkalemia (generally with a serum potassium level approaching 5 meq/l [ 5 mmol/l]) or had chronic kidney disease (CKD) stage 3 or higher (usually excluding patients with estimated GFR 30 ml/min [ 0.50 ml/s]). Inclusion criteria for

8 ANGIOTENSIN BLOCKADE IN CHRONIC KIDNEY DISEASE 15 Fig 2. Additional proteinuria decrease when an ARB is added to an ACE inhibitor in the treatment of proteinuric CKD. baseline 24-hour protein excretion varied among studies. Six studies specified a requirement of proteinuria with protein greater than 1 g/d, 27,29,37-39,42 whereas single studies specified protein greater than 0.5 g/d, 41 greater than 1.5 g/d, 30 1 to 3 g/d, 28 and greater than 3.5 g/d. 40 Four trials specified albuminuria with albumin greater than 0.3 g/d, 31,34-36 and 1 trial specified albumin greater than 1 g/d 32 as inclusion criteria. Method quality scores of crossover studies generally were moderate to high, with only 4 studies (25%) of low method. Median Jadad score was 3.5. Effect of combination therapy on proteinuria and BP. All 16 crossover studies reported the outcome of 24-hour urine protein excretion There was significant heterogeneity for the outcome of proteinuria decrease (Q 84.9; P 0.01). Pooling of studies therefore was conducted by using a random-effects model. All studies showed a trend toward a greater decrease in proteinuria with combination therapy with an ACE inhibitor and ARB (Fig 2). The pooled estimate showed that combination therapy was associated with a significant decrease in proteinuria (weighted mean difference, 440 mg/d; 95% CI, 289 to 591; Fig 2). Subgroup analyses for proteinuria were performed based on the underlying cause of renal disease. First, an analysis was performed of trials that predominantly included patients with diabetic nephropathy. In data extracted from these 10 studies, 27,31,32,34-37,39,41, of 199 patients had a diagnosis of diabetic nephropathy. Significant heterogeneity remained in the analysis (Q 21.7; P 0.01). Using the randomeffects model, the summary estimate showed a further decrease in mean proteinuria of 210 mg/d of protein (95% CI, 84 to 336) with combination therapy compared with ACE inhibitor alone. Next, patients with primarily nondiabetic proteinuric CKD were analyzed. In data extracted from these 8 studies, 28-30,33, of 174 patients had nondiabetic proteinuric CKDs, of which the majority were primary glomerulonephritis (137 of 167). There was significant heterogeneity in the analysis (Q 19.2; P 0.01). Using the random effects, the summary estimate of mean decrease in proteinuria after an ARB was added to preexisting ACE-inhibitor therapy was 582 mg/d of protein (95% CI, 371 to 793). The effect of combination therapy on decrease in BP was ascertained in a pooled analysis of 14 studies ,38,40-42 Data for systolic and diastolic BP were not available in 2 studies because only mean arterial pressure was reported. 37,39 There was significant heterogeneity for both systolic (Q 46.7; P 0.01) or diastolic (Q 28.2; P 0.01) BP analyses. Using the random effects, the addition of an ARB to ACE-inhibitor

9 16 MACKINNON ET AL Fig 3. Mean change in serum potassium levels when an ARB is added to ACEinhibitor therapy. therapy resulted in a further decrease in systolic and diastolic BP by 4.5 mm Hg (95% CI, 2.7 to 6.4) and 2.5 mm Hg (95% CI, 1.6 to 3.5), respectively. Asimilar subgroup analysis for BP was performed. In 8 of 10 trials involving patients with predominantly diabetic nephropathy, 27,31,32,34-36,41,42 there was significant heterogeneity in both systolic (Q 27.3; P 0.01) and diastolic (Q 24.4; P 0.01) BP data. Systolic BP decrease was 4.2 mm Hg (95% CI, 1.1 to 7.2), and diastolic BP decrease was 2.8 mm Hg (95% CI, 1.2 to 4.6). In the 6 trials that included primarily patients without diabetes with proteinuric CKD, 28-30,33,38,40 there was significant heterogeneity in the systolic analysis (Q 16.5; P 0.01), but no heterogeneity in the diastolic analysis (Q 1.5; P 0.91). Decrease in BP in patients without diabetes was similar to that in patients with diabetes, with pooled mean BP decreases of 4.9 mm Hg (95% CI, 2.7 to 7.2) systolic and 2.0 mm Hg (95% CI, 1.2 to 2.9) diastolic. Serum potassium and GFR. Fourteen of 16 crossover studies were included in the pooled analysis of serum potassium data. 27,28,30-39,41,42 One study was excluded because serum potassium levels were not reported, 29 whereas another was excluded because only log-transformed potassium data were provided. 40 The pooled analysis of the remaining 14 studies indicated significant heterogeneity (Q 34.7; P 0.01), and a random-effects model was used. There was a small, but statistically significant, increase in serum potassium level with the addition of an ARB to preexisting ACE-inhibitor therapy (weighted mean difference, 0.11 meq/l [0.11 mmol/l]; 95% CI, 0.05 to 0.17; Fig 3). In 14 of 16 crossover studies, data for change in estimated GFR were available ,34,36-42 One study could not be included for statistical reasons because only the SE of change in GFR was reported as opposed to the SE of absolute GFR after each treatment arm. 35 A second study was not included because only serum creatinine values were reported. 33 There was no significant heterogeneity in the analysis of GFR (Q 4.5; P 0.99). The pooled estimate showed that combination therapy was associated with a nonsignificant decrease in GFR (weighted mean difference, 1.4 ml/min [ 0.02 ml/s]; 95% CI, 2.6 to 0.2; Fig 4). DISCUSSION This systematic review shows that combination therapy with an ACE inhibitor and an ARB is both safe and efficacious for the decrease in proteinuria in select populations of patients with proteinuric CKD. Additional proteinuria decrease was observed with the addition of an ARB to ACE-inhibitor therapy across all kidney dis-

10 ANGIOTENSIN BLOCKADE IN CHRONIC KIDNEY DISEASE 17 Fig 4. Change in estimated GFR when an ARB is added to ACE-inhibitor therapy. ease states studied in this review, including diabetic nephropathy, IgA nephropathy, and chronic glomerulonephritis. Four of the 5 parallel-group studies and the pooled analysis of crossover trials showed a statistically significant decrease in daily protein excretion compared with ACEinhibitor therapy alone. This review shows that neither hyperkalemia nor an acute decrease in estimated GFR was a major complication of combination therapy. Although the majority of parallel-design studies included patients with well-preserved GFR (average, 75 ml/min [1.25 ml/s]), patients enrolled in COOPERATE had more advanced renal insufficiency (average creatinine clearance, 38 ml/ min/1.73 m 2 [0.63 ml/s/1.73 m 2 ]). However, there was no acute GFR decrease or increased risk for hyperkalemia associated with combination therapy. Analysis of crossover designed trials showed inclusion of a more select patient population, excluding patients with an estimated GFR less than 25 ml/min ( 0.42 ml/s) or tendency toward high serum potassium level. Of 340 patients in 14 trials, there were 4 patient dropouts secondary to hyperkalemia with or without the development of acute renal failure. No deaths were reported secondary to hyperkalemia. The generalizability of these findings ultimately will require further study, including experience outside the clinical trial setting. Hyperkalemia was found to be a significant problem in everyday care when using spironolactone in patients with heart failure 48 despite not manifesting within the original clinical trial. 49 It is interesting to speculate on the significance of the subgroup analysis that suggested the benefit of combination therapy for decrease in proteinuria was greater in patients with nondiabetic compared with diabetic CKD. BP decrease did not seem to account for this difference because systolic and diastolic BP decreased to a similar extent in both nondiabetic and diabetic patient populations. It is notable that 5 of 10 crossover trials included in the diabetic renal disease subanalysis reported albuminuria as opposed to total proteinuria, which was reported in trials involving patients without diabetes. This systematic difference may be responsible in part for apparent differences between patients with diabetic versus nondiabetic nephropathy. In addition, each trial and subsequent analysis detailed absolute proteinuria decreases, thereby not accounting for differences in baseline proteinuria between trials. However, when trials were stratified on the basis of proteinuria level before the addition of an ARB (protein 2 g/d versus 2 g/d), proteinuria decrease in patients with diabetes was less than that observed in those with nondiabetic renal disease in both stratum (data not shown).

11 18 To date, there has been little experimental work attempting to determine a mechanism for a differential effect of combination therapy between patients with diabetic and nondiabetic CKD. There was speculation that local intrarenal renin-angiotensin system activation may have a more prominent role in the pathophysiologic mechanism of IgA nephropathy compared with multifactorial influences determining diabetic nephropathy. 39 Interestingly, 2 small trials by Song et al 39 and Agarwal et al 50 showed decreases in urinary concentrations of transforming growth factor, a marker of angiotensin-ii stimulated renal fibrosis, when patients with diabetic nephropathy were treated with combination therapy. This occurred despite no observed decrease in proteinuria in both study populations. The relevance of this observation is incompletely understood and may require a larger and longer trial for distinct benefits in patients with diabetes to be observed. BP decrease per se can influence proteinuria excretion. There was significant heterogeneity in degree of proteinuria decrease and BP change among studies. Although we were able to explore the heterogeneity to a limited extent (dividing studies based on degree of proteinuria, data not shown), only a more detailed analysis using summary or patient-level data for BP and proteinuria change would help determine the influence of BP decrease on proteinuria during combination therapy. Limitations to this study should be noted. With respect to the meta-analysis of crossover trials, the included trials were relatively small, with short-term follow-up. When analyzing trials with crossover design, the possibility of carry over must be considered. Because the majority of trials showed positive results, the possibility of publication bias cannot be ruled out. Furthermore, there was significant statistical heterogeneity in many pooled analyses, which reflects the clinical heterogeneity of the studies (diverse patient populations with respect to cause of renal disease, severity of proteinuria, renal function, different drugs and treatment duration, and degree of BP control). This may limit in part the generalizability of the pooled analysis to individual patients with CKD and proteinuria. In addition, measures of GFR were significantly different between studies (including estimates of MACKINNON ET AL GFR using serum creatinine and creatinine clearance calculations versus nuclear GFR determinations); therefore, the accuracy of combining these GFR determinations can be questioned. However, despite these limitations, the analysis strongly suggests that the combination was safe in a diverse population of patients. Although this study did not distinguish a specific renoprotective role of combination therapy separate from BP lowering, the demonstration that combination therapy is a safe antihypertensive strategy in these patients is as important. In conclusion, the combination of ACE-inhibitor and ARB therapy in patients with proteinuric CKD is both safe and efficacious. Given the central role of BP control and proteinuria decrease for preservation of renal function in patients with proteinuric CKD, combination therapy can be recommended as a therapeutic option for these patients. Currently, the only trial to show a decrease in rate of renal function decline associated with combination therapy is the COOPERATE study in Japanese patients with chronic glomerulonephritis. 43 However, the additive antiproteinuric efficacy of this combination appears to be found in all other types of proteinuric renal dysfunction studied to date. The antiproteinuric effects of combination therapy may be greater in patients with nondiabetic renal disease compared with patients with diabetes, but this hypothesis needs confirmation in an adequately powered randomized trial. REFERENCES 1. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 329: , Maschio G, Alberti D, Janin G, et al: Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin- Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 334: , The 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 349: , Lewis EJ, Hunsicker LG, Clarke WR, et al: Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345: , Brenner BM, Cooper ME, de Zeeuw D, et al: Effects of losartan on renal and cardiovascular outcomes in patients

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