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Combination Therapy With an Angiotensin Receptor Blocker and an ACE Inhibitor in Proteinuric Renal Disease: A Systematic Review of the Efficacy and Safety Data

  • Author Footnotes
    1 M.M. and S.S. contributed equally to this manuscript and should be considered co-first authors.
    Martin MacKinnon
    Correspondence
    Address reprint requests to Martin MacKinnon, MD, Division of Nephrology, Saint John Regional Hospital, PO Box 2100, Saint John, New Brunswick, E2L 4L2 Canada.
    Footnotes
    1 M.M. and S.S. contributed equally to this manuscript and should be considered co-first authors.
    Affiliations
    Department of Medicine, Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.

    Kidney Research Center, Ottawa, Ontario, Canada.

    Ottawa Health Research Institute, Ottawa, Ontario, Canada.
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  • Author Footnotes
    1 M.M. and S.S. contributed equally to this manuscript and should be considered co-first authors.
    Sabin Shurraw
    Footnotes
    1 M.M. and S.S. contributed equally to this manuscript and should be considered co-first authors.
    Affiliations
    Department of Medicine, Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.

    Kidney Research Center, Ottawa, Ontario, Canada.

    Ottawa Health Research Institute, Ottawa, Ontario, Canada.
    Search for articles by this author
  • Ayub Akbari
    Affiliations
    Department of Medicine, Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.

    Kidney Research Center, Ottawa, Ontario, Canada.

    Ottawa Health Research Institute, Ottawa, Ontario, Canada.
    Search for articles by this author
  • Greg A. Knoll
    Affiliations
    Department of Medicine, Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.

    Kidney Research Center, Ottawa, Ontario, Canada.

    Ottawa Health Research Institute, Ottawa, Ontario, Canada.
    Search for articles by this author
  • James Jaffey
    Affiliations
    Department of Medicine, Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.

    Kidney Research Center, Ottawa, Ontario, Canada.

    Ottawa Health Research Institute, Ottawa, Ontario, Canada.
    Search for articles by this author
  • Heather D. Clark
    Affiliations
    Department of Medicine, Division of Nephrology, University of Ottawa, Ottawa, Ontario, Canada.

    Kidney Research Center, Ottawa, Ontario, Canada.

    Ottawa Health Research Institute, Ottawa, Ontario, Canada.
    Search for articles by this author
  • Author Footnotes
    1 M.M. and S.S. contributed equally to this manuscript and should be considered co-first authors.
      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.

      Index Words

      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.
      • Lewis E.J.
      • Hunsicker L.G.
      • Bain R.P.
      • Rohde R.D.
      The Collaborative Study Group
      The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy.
      Therapy with an ACE inhibitor significantly delayed the progression of proteinuric renal disease in patients without diabetes.
      • Maschio G.
      • Alberti D.
      • Janin G.
      • et al.
      The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group
      Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.
      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.
      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.
      • Lewis E.J.
      • Hunsicker L.G.
      • Clarke W.R.
      • et al.
      Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes.
      • Brenner B.M.
      • Cooper M.E.
      • de Zeeuw D.
      • et al.
      Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
      Finally, therapy with an ACE inhibitor was shown to significantly delay the progression of proteinuric renal disease in patients without diabetes.
      • Maschio G.
      • Alberti D.
      • Janin G.
      • et al.
      The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group
      Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency.
      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.
      Recent evidence suggests that ACE inhibitors may not completely block the formation of angiotensin II.
      • Hollenberg N.K.
      • Osei S.Y.
      • Lansang M.C.
      • Price D.A.
      • Fisher N.D.
      Salt intake and non-ACE pathways for intrarenal angiotensin II generation in man.
      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.
      • Arakawa K.
      Serine protease angiotensin II systems.
      • Hanon S.
      • Vijayaraman P.
      • Sonnenblick E.H.
      • Le Jemtel T.H.
      Persistent formation of angiotensin II despite treatment with maximally recommended doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure.
      These non–ACE-dependent pathways appear to be upregulated with long-term ACE-inhibitor 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 renin-angiotensin 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 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,
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • et al.
      Assessing the quality of reports of randomized clinical trials Is blinding necessary?.
      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.
      • Deeks J.J.A.D.
      • Bradburn M.J.
      Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis.
      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 random-effects model of DerSimonian and Laird.
      • Deeks J.J.A.D.
      • Bradburn M.J.
      Statistical methods for examining heterogeneity and combining results from several studies in meta-analysis.
      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,
      • Iodice C.
      • Balletta M.M.
      • Minutolo R.
      • et al.
      Maximal suppression of renin-angiotensin system in nonproliferative glomerulonephritis.
      • Russo D.
      • Pisani A.
      • Balletta M.M.
      • et al.
      Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy.
      • Laverman G.D.
      • Navis G.
      • Henning R.H.
      • de Jong P.E.
      • de Zeeuw D.
      Dual renin-angiotensin system blockade at optimal doses for proteinuria.
      • Panos J.
      • Michelis M.F.
      • DeVita M.V.
      • Lavie R.H.
      • Wilkes B.M.
      Combined converting enzyme inhibition and angiotensin receptor blockade reduce proteinuria greater than converting enzyme inhibition alone Insights into mechanism.
      • Vogt L.
      • Navis G.
      • de Zeeuw D.
      Individual titration for maximal blockade of the renin-angiotensin system in proteinuric patients A feasible strategy?.
      • Homma K.
      • Hayashi K.
      • Kanda T.
      • et al.
      Beneficial action of candesartan cilexetil plus amlodipine or ACE inhibitors in chronic nondiabetic renal disease.
      1 study was a case report,
      • Horino T.
      • Ito H.
      • Tanimoto N.
      • et al.
      [Successful treatment of combination therapy using an angiotensin-converting enzyme inhibitor and an angiotensin II receptor blocker in a patient with IgA nephropathy].
      2 studies did not have the primary outcome measured (24-hour proteinuria),
      • Hebert L.A.
      • Falkenhain M.E.
      • Nahman Jr, N.S.
      • Cosio F.G.
      • O’Dorisio T.M.
      Combination ACE inhibitor and angiotensin II receptor antagonist therapy in diabetic nephropathy.
      • Azizi M.
      • Chatellier G.
      • Guyene T.T.
      • Murieta-Geoffroy D.
      • Menard J.
      Additive effects of combined angiotensin-converting enzyme inhibition and angiotensin II antagonism on blood pressure and renin release in sodium-depleted normotensives.
      2 studies did not allocate patients to the treatments of interest,
      • Woo K.T.
      • Lau Y.K.
      • Wong K.S.
      • Chiang G.S.
      ACEI/ATRA therapy decreases proteinuria by improving glomerular permselectivity in IgA nephritis.
      • Kuriyama S.
      • Tomonari H.
      • Tokudome G.
      • et al.
      Antiproteinuric effects of combined antihypertensive therapies in patients with overt type 2 diabetic nephropathy.
      3 studies included patients with proteinuria with protein less than 0.3 g/d at baseline,
      • Mogensen C.E.
      • Neldam S.
      • Tikkanen I.
      • et al.
      Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes The Candesartan and Lisinopril Microalbuminuria (CALM) Study.
      • Tutuncu N.B.
      • Gurlek A.
      • Gedik O.
      Efficacy of ACE inhibitors and ATII receptor blockers in patients with microalbuminuria A prospective study.
      • Scaglione R.
      • Argano C.
      • Corrao S.
      • Di Chiara T.
      • Licata A.
      • Licata G.
      Transforming growth factor beta1 and additional renoprotective effect of combination ACE inhibitor and angiotensin II receptor blocker in hypertensive subjects with minor renal abnormalities A 24-week randomized controlled trial.
      1 study reported on patients from an earlier trial,
      • Renke M.
      • Tylicki L.
      • Rutkowski P.
      • Wojnarowski K.
      • Lysiak-Szydlowska W.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system improves tubular status in non-diabetic proteinuric patients.
      and 1 study enrolled pediatric patients.
      • Yang Y.
      • Ohta K.
      • Shimizu M.
      • et al.
      Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy.
      Of 21 studies (n = 654 patients) included in this review, 16 studies (n = 373 patients) were crossover design
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      and 5 studies (n = 281 patients) were parallel-group design.
      • Nakao N.
      • Yoshimura A.
      • Morita H.
      • Takada M.
      • Kayano T.
      • Ideura T.
      Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE) A randomised controlled trial.
      • Segura J.
      • Praga M.
      • Campo C.
      • Rodicio J.L.
      • Ruilope L.M.
      Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses.
      • Luno J.
      • Barrio V.
      • Goicoechea M.A.
      • et al.
      Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies.
      • Tylicki L.
      • Rutkowski P.
      • Renke M.
      • Rutkowski B.
      Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis. Short-term observation.
      • Horita Y.
      • Tadokoro M.
      • Taura K.
      • et al.
      Low-dose combination therapy with temocapril and losartan reduces proteinuria in normotensive patients with immunoglobulin a nephropathy.
      Characteristics of parallel-group design trials are listed in Table 1, and crossover design trials are listed in Table 2, Table 3.
      Figure thumbnail gr1
      Fig 1Search results and selection of randomized trials for analysis.
      Table 1Characteristics of Parallel-Group Trials Comparing Proteinuria Decrease With ACE-Inhibitor Monotherapy and ACE-Inhibitor Plus ARB Combination Therapy
      ReferenceInclusion CriteriaACE Inhibitor Arm (n)ACE Inhibitor + ARB Arm (n)ACE Inhibitor (mg/d)ACE Inhibitor + ARB (mg/d)Treatment DurationAdverse EventsJadad Score
      Jadad score for quality assessment: low (0 to 2 points), moderate (3 to 4 points), high (5 points, maximum score).
      Nakao et al,
      • Nakao N.
      • Yoshimura A.
      • Morita H.
      • Takada M.
      • Kayano T.
      • Ideura T.
      Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE) A randomised controlled trial.
      2003
      Nondiabetic CKD; proteinuria > 0.3 g/d; calculated GFR, 20-70 mL/min8688Trandolapril, 3, + placeboTrandolapril, 3, + losartan, 100Median, 2.9 yHyperkalemia
      Hyperkalemia treated successfully with potassium binder or dietary restriction; none resulted in dropout.
      : ACE inhibitor: n = 8; ACE inhibitor + ARB: n = 7; no ARF in either group
      5
      Segura et al,
      • Segura J.
      • Praga M.
      • Campo C.
      • Rodicio J.L.
      • Ruilope L.M.
      Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses.
      2003
      CKD (unspecified cause); proteinuria > 1.5 g/d; BP > 140/90 mm Hg; CrCl > 30 mL/min1212Benazepril, 10-20
      Benazepril, 10 mg if CrCl less than 50 mL/min, 20 mg if CrCl greater than 50 mL/min.
      Benazepril, 10-20,
      Benazepril, 10 mg if CrCl less than 50 mL/min, 20 mg if CrCl greater than 50 mL/min.
      + valsartan, 80-160
      Valsartan, 80 mg, was increased to 160 mg if BP greater than 140/90 mm Hg after 4 weeks.
      6 moNo dropouts caused by hyperkalemia or ARF2
      Luno et al,
      • Luno J.
      • Barrio V.
      • Goicoechea M.A.
      • et al.
      Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies.
      2002
      Nondiabetic CKD (primary GN); proteinuria > 2 g/d; CrCl > 50 mL/min, K < 5.0 mEq/L1416Lisinopril, 10-40
      Dose of lisinopril and candesartan was doubled every 2 weeks if BP greater than 125/75 mm Hg until maximum dose achieved.
      Lisinopril, 5-20,
      Dose of lisinopril and candesartan was doubled every 2 weeks if BP greater than 125/75 mm Hg until maximum dose achieved.
      + candesartan, 4-16
      Dose of lisinopril and candesartan was doubled every 2 weeks if BP greater than 125/75 mm Hg until maximum dose achieved.
      6 moN = 2: K > 6.0 mEq/L; no dropout caused by hyperkalemia or ARF3
      Tylicki et al,
      • Tylicki L.
      • Rutkowski P.
      • Renke M.
      • Rutkowski B.
      Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis. Short-term observation.
      2002
      Nondiabetic CKD (primary GN, excluding IgA); serum creatinine < 2.3 mg/dL1715Enalapril, 10Enalapril, 10, + losartan, 253 moNo dropouts; CrCl: similar decline between groups
      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.
      ; potassium data not reported
      2
      Horita et al,
      • Horita Y.
      • Tadokoro M.
      • Taura K.
      • et al.
      Low-dose combination therapy with temocapril and losartan reduces proteinuria in normotensive patients with immunoglobulin a nephropathy.
      2004
      IgA nephropathy; proteinuria > 0.4 g/d; BP < 140/90 mm Hg; calculated GFR > 50 mL/min1011Temocapril, 1Temocapril, 1, + losartan, 12.56 moNo dropouts caused by hyperkalemia or ARF2
      NOTE. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; GFR and CrCl in mL/min to mL/s, multiply by 0.01667.
      Abbreviations: ARF, acute renal failure; CrCl, creatinine clearance; GN, glomerulonephropathy; K, serum potassium; IgA, IgA nephropathy.
      low asterisk 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.
      Table 2Patient Characteristics in Crossover Trials Comparing Proteinuria Reduction With ACE-Inhibitor Monotherapy Versus ACE-Inhibitor Plus ARB Combination Therapy
      ReferenceNo. of Patients/Sex/Mean Age (y)Cause of CKD (N)Inclusion CriteriaBaseline Proteinuria (g/d)/BP (mm Hg)/Renal Function (mL/min)
      Agarwal, 2001
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      16/14M:2F/53Diabetic nephropathy (12), GN (4)Proteinuria >1 g/d; MAP ≥97 mm Hg; CrCl > 30 mL/min, K < 5.5 mEq/L3.6/156/88
      BP measured while administered antihypertensive medication.
      /GFR, 64
      Russo et al, 2001
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      10/4M:6F/25IgA (10)Proteinuria 1–3 g/d; BP <140/90 mm Hg; CrCl > 90 mL/min1.5/128/74
      Twenty-four–hour ambulatory BP.
      /CrCl, 110
      Berger et al, 2002
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      12/6M:6F/52IgA (9), membranous (3)Proteinuria ≥1 g/d; “normotensive”; ACE-inhibitor1.8/128/79
      BP measured while administered antihypertensive medication.
      Twenty-four–hour ambulatory BP.
      /GFR, 64
      Ferrari et al, 2002
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      11/7M:4F/48Membranous (5), FSGS (4), IgA (1), MPGN (1)Proteinuria >1.5 g/d; BP >140/90 or BP medication; CrCl > 30 mL/min7.9/144/91/CrCl, 77
      Jacobsen et al, 2002
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      21/17M:4F/45DM 1 (21)Proteinuria >1 g/d
      Albuminuria.
      ; BP >135/85 mm Hg; ACE-inhibitor + diuretic GFR > 20 mL/min, K < 4.8 mEq/L
      1.9
      Albuminuria.
      /156/87
      BP measured while administered antihypertensive medication.
      /GFR, 52
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      Rossing et al, 2002
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      17/13M:4F/58DM 2 (17)Proteinuria>1 Ig/d
      Albuminuria.
      ; BP >135/85, ACE-inhibitor GFR > 25 mL/min, K < 4.6 mEq/min
      1.8
      Albuminuria.
      /159/85
      BP measured while administered antihypertensive medication.
      /GFR, 74
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      Kincaid-Smith et al, 2002
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      60/23-75Reflux (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/dL2.2, 2.4
      Prerandomization data reported separately for ACE-inhibitor alone group and ACE-inhibitor plus ARB group.
      /134/84, 139/82
      BP measured while administered antihypertensive medication.
      Prerandomization data reported separately for ACE-inhibitor alone group and ACE-inhibitor plus ARB group.
      /Cr, 2.2, 2.4 mg/dL
      Prerandomization data reported separately for ACE-inhibitor alone group and ACE-inhibitor plus ARB group.
      Jacobsen et al, 2003
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      24/17M:7F/42DM 1 (24)Proteinuria >0.3 g/d
      Albuminuria.
      ; ACE-inhibitor; GFR > 30 mL/min; K < 4.8 mEq/L
      0.52
      Albuminuria.
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      /131/74
      BP measured while administered antihypertensive medication.
      Twenty-four–hour ambulatory BP.
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      /GFR, 65
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      Jacobsen et al, 2003
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      18/13M:5F/43DM 1 (24)Proteinuria >0.3 g/d
      Albuminuria.
      ; ACE-inhibitor GFR > 30 mL/min, K < 4.8 mEq/L
      0.7
      Albuminuria.
      /141/81
      BP measured while administered antihypertensive medication.
      /GFR, 82
      Rossing et al, 2003
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      20/17M:3F/62DM 2 (20)Proteinuria >0.3 g/d
      Albuminuria.
      ; BP > 135/85 mm Hg; ACE-inhibitor GFR > 25 mL/min, K < 4.6 mEq/L
      0.7
      Albuminuria.
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      /138/72
      BP measured while administered antihypertensive medication.
      Twenty-four–hour ambulatory BP.
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      /GFR, 77
      Data after treatment with ACE inhibitor and placebo because no prerandomization data were reported.
      Kim et al, 2003
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      41/19M:22F/32DM 2 (22), IgA (19)Proteinuria >1 g/d; BP <130/80 mm Hg; ACE-inhibitor CrCl, 25-90 mL/min3.9/MAP: 92
      BP measured while administered antihypertensive medication.
      Twenty-four–hour ambulatory BP.
      /CrCl, 60
      Campbell et al, 2003
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      24/23M:1F/49IgA (11), chronic GN (4), other (4), no biopsy (5)Proteinuria >1 g/d; DBP 90-115 or BP medication; CrCl, 20-70 mL/min; K < 6.0 mEq/L3.3/140/91
      BP measured while administered antihypertensive medication.
      /CrCl, 69
      Song et al, 2003
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      34/13M:19F/34IgA (14), DM 2 (18)Proteinuria >1 g/d; BP <130/80, ACE-inhibitor CrCl, 25-90 mL/min4/MAP, 92
      BP measured while administered antihypertensive medication.
      Twenty-four–hour ambulatory BP.
      /CrCl, 60
      Rutkowski et al, 2004
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      24/12M:12F/35Mesangial GN (14), IgA (5), MPGN (4), membranous (1)Proteinuria <3.5 g/d; ACE-Inhibitor or ARB Cr <2 mg/dL2.1/134/85
      Twenty-four–hour ambulatory BP.
      /CrCl, 86
      Matos et al, 2005
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      20/5M:15F/54DM 2 (20)Proteinuria 0.5-3 g/d; SBP > 140 or BP medication; CrCl >40 mL/min; K < 5 mEq/L0.9/146/81
      BP measured while administered antihypertensive medication.
      Twenty-four–hour ambulatory BP.
      /GFR, 67
      Song et al, 2006
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      21/11M:10F/49DM 2 (21)Proteinuria >1 g/d; BP <140/90 on ACE-Inhibitor or ARB; CrCl, 30-59 mL/min; K < 5.5 mEq/L4.2/133/81
      BP measured while administered antihypertensive medication.
      Twenty-four–hour ambulatory BP.
      /CrCl, 41
      NOTE. To convert serum creatinine in mg/dL to μmol/L, multiply by 88.4; GFR and CrCl in mL/min to mL/s, multiply by 0.01667; 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.
      low asterisk 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.
      Table 3Treatment Protocol, Method Quality, and Dropouts in Crossover Trials Comparing Proteinuria Reduction With ACE-Inhibitor Monotherapy Versus ACE-Inhibitor Plus ARB Combination Therapy
      ReferenceACE-Inhibitor (mg/d)ARB (mg/d)Treatment Duration (wk)Dropouts (n) (
      Benazepril, 20 mg/d when given as monotherapy; benazepril, 10 mg/d when coadministered with ARB.
      serum K or ARF)
      Jadad Score
      Jadad score for quality assessment: low (0-2 points), moderate (3-4 points), high (5 points, maximum).
      Agarwal, 2001
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      Lisinopril, 40Losartan, 504None2
      Russo et al, 2001
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      Enalapril, 20Losartan, 1004None2
      Berger et al, 2002
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      “Low-dose” ACE-inhibitorCandesartan, 88None5
      Ferrari et al, 2002
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      Fosinopril, 20Irbesartan, 1506None3
      Jacobsen et al, 2002
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      “Recommended dose” ACE-inhibitorIrbesartan, 30081, hyperkalemia5
      Rossing et al, 2002
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      Enalapril, 20, or lisinopril, 20, or captopril, 100Candesartan, 88None5
      Kincaid-Smith et al, 2002
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      Previously prescribed ACE-inhibitor (n = 45 maximum dose)Candesartan, 8121, hyperkalemia3
      Jacobsen et al, 2003
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      Enalapril, 40Irbesartan, 3008None5
      Jacobsen et al, 2003
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      Benazepril, 20Valsartan, 808None5
      Rossing et al, 2003
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      Enalapril, 40, or lisinopril, 40, or captopril, 150Candesartan, 168None5
      Kim et al, 2003
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      Ramipril, 5.0-7.5 (previous dose)Candesartan, 4121, hyperkalemia and ARF4
      Campbell et al, 2003
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      Benazepril, 10 or 20
      Benazepril, 20 mg/d when given as monotherapy; benazepril, 10 mg/d when coadministered with ARB.
      Valsartan, 808None2
      Song et al, 2003
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      Ramipril ≥ 5Candesartan, 4 to 8, as tolerated161, hyperkalemia and ARF4
      Rutkowski et al, 2004
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      Benazepril 5 or 10
      Benazepril, 10 mg/d when given as monotherapy; benazepril, 5 mg/d when coadministered with ARB.
      Losartan, 2516None3
      Matos et al, 2005
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      Perindopril, 8Irbesartan, 300162, hyperkalemia2
      Song et al, 2006
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      Ramipril, 5 or 10
      Ramipril, 10 mg/d when given as monotherapy; ramipril, 5 mg/d when coadministered with ARB.
      Candesartan 8161 ARF3
      Abbreviations: ARF, acute renal failure; K, potassium.
      low asterisk 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.

       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.
      • Nakao N.
      • Yoshimura A.
      • Morita H.
      • Takada M.
      • Kayano T.
      • Ideura T.
      Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE) A randomised controlled trial.
      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 m2 (0.33 and 1.17 mL/s/1.73 m2). 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 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 J.
      • Praga M.
      • Campo C.
      • Rodicio J.L.
      • Ruilope L.M.
      Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses.
      • Luno J.
      • Barrio V.
      • Goicoechea M.A.
      • et al.
      Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies.
      • Tylicki L.
      • Rutkowski P.
      • Renke M.
      • Rutkowski B.
      Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis. Short-term observation.
      • Horita Y.
      • Tadokoro M.
      • Taura K.
      • et al.
      Low-dose combination therapy with temocapril and losartan reduces proteinuria in normotensive patients with immunoglobulin a nephropathy.
      Segura et al
      • Segura J.
      • Praga M.
      • Campo C.
      • Rodicio J.L.
      • Ruilope L.M.
      Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses.
      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).
      • Segura J.
      • Praga M.
      • Campo C.
      • Rodicio J.L.
      • Ruilope L.M.
      Combination is better than monotherapy with ACE inhibitor or angiotensin receptor antagonist at recommended doses.
      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 2.5 ± 1.8 g/d in the combination group versus 0.5 ± 1.7 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 significant changes in either serum potassium levels or creatinine clearances in 6 months of follow-up.
      In the study of Luno et al,
      • Luno J.
      • Barrio V.
      • Goicoechea M.A.
      • et al.
      Effects of dual blockade of the renin-angiotensin system in primary proteinuric nephropathies.
      14 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 m2 (>0.83 mL/s/1.73 m2). 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,
      • Tylicki L.
      • Rutkowski P.
      • Renke M.
      • Rutkowski B.
      Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis. Short-term observation.
      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.
      • Tylicki L.
      • Rutkowski P.
      • Renke M.
      • Rutkowski B.
      Renoprotective effect of small doses of losartan and enalapril in patients with primary glomerulonephritis. Short-term observation.
      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, 2.2 ± 2 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
      • Horita Y.
      • Tadokoro M.
      • Taura K.
      • et al.
      Low-dose combination therapy with temocapril and losartan reduces proteinuria in normotensive patients with immunoglobulin a nephropathy.
      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 m2 (>0.83 mL/s/1.73 m2) 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

      Table 2, Table 3 list the 16 crossover studies (n = 373 patients) included in this analysis. Five studies included patients with nondiabetic renal disease,
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      7 studies involved only patients with diabetes,
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      and 4 studies involved patients with both diabetic and nondiabetic renal disease.
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      Of the latter 4 studies, 2 included a separate analysis of the diabetic and nondiabetic subgroups.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      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 baseline 24-hour protein excretion varied among studies. Six studies specified a requirement of proteinuria with protein greater than 1 g/d,
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      whereas single studies specified protein greater than 0.5 g/d,
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      greater than 1.5 g/d,
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      1 to 3 g/d,
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      and greater than 3.5 g/d.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      Four trials specified albuminuria with albumin greater than 0.3 g/d,
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      and 1 trial specified albumin greater than 1 g/d
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      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.
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      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).
      Figure thumbnail gr2
      Fig 2Additional proteinuria decrease when an ARB is added to an ACE inhibitor in the treatment of proteinuric CKD.
      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,
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      195 of 199 patients had a diagnosis of diabetic nephropathy. Significant heterogeneity remained in the analysis (Q = 21.7; P = 0.01). Using the random-effects 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,
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      167 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.
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      Data for systolic and diastolic BP were not available in 2 studies because only mean arterial pressure was reported.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      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 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.
      A similar subgroup analysis for BP was performed. In 8 of 10 trials involving patients with predominantly diabetic nephropathy,
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      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,
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      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.
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      One study was excluded because serum potassium levels were not reported,
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      whereas another was excluded because only log-transformed potassium data were provided.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      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).
      Figure thumbnail gr3
      Fig 3Mean change in serum potassium levels when an ARB is added to ACE-inhibitor therapy.
      In 14 of 16 crossover studies, data for change in estimated GFR were available.
      • Agarwal R.
      Add-on angiotensin receptor blockade with maximized ACE inhibition.
      • Russo D.
      • Minutolo R.
      • Pisani A.
      • et al.
      Coadministration of losartan and enalapril exerts additive antiproteinuric effect in IgA nephropathy.
      • Berger E.D.
      • Bader B.D.
      • Ebert C.
      • Risler T.
      • Erley C.M.
      Reduction of proteinuria; combined effects of receptor blockade and low dose angiotensin-converting enzyme inhibition.
      • Ferrari P.
      • Marti H.P.
      • Pfister M.
      • Frey F.J.
      Additive antiproteinuric effect of combined ACE inhibition and angiotensin II receptor blockade.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Hansen B.V.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in type 1 patients with diabetic nephropathy.
      • Rossing K.
      • Christensen P.K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system in diabetic nephropathy A randomized double-blind crossover study.
      • Jacobsen P.
      • Andersen S.
      • Rossing K.
      • Jensen B.R.
      • Parving H.H.
      Dual blockade of the renin-angiotensin system versus maximal recommended dose of ACE inhibition in diabetic nephropathy.
      • Rossing K.
      • Jacobsen P.
      • Pietraszek L.
      • Parving H.H.
      Renoprotective effects of adding angiotensin II receptor blocker to maximal recommended doses of ACE inhibitor in diabetic nephropathy A randomized double-blind crossover trial.
      • Kim M.J.
      • Song J.H.
      • Suh J.H.
      • Lee S.W.
      • Kim G.A.
      Additive antiproteinuric effect of combination therapy with ACE inhibitor and angiotensin II receptor antagonist Differential short-term response between IgA nephropathy and diabetic nephropathy.
      • Campbell R.
      • Sangalli F.
      • Perticucci E.
      • et al.
      Effects of combined ACE inhibitor and angiotensin II antagonist treatment in human chronic nephropathies.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      • Rutkowski P.
      • Tylicki L.
      • Renke M.
      • Korejwo G.
      • Zdrojewski Z.
      • Rutkowski B.
      Low-dose dual blockade of the renin-angiotensin system in patients with primary glomerulonephritis.
      • Matos J.P.
      • de Lourdes Rodrigues M.
      • Ismerim V.L.
      • Boasquevisque E.M.
      • Genelhu V.
      • Francischetti E.A.
      Effects of dual blockade of the renin angiotensin system in hypertensive type 2 diabetic patients with nephropathy.
      • Song J.H.
      • Cha S.H.
      • Lee H.J.
      • et al.
      Effect of low-dose dual blockade of renin-angiotensin system on urinary TGF-(beta) in type 2 diabetic patients with advanced kidney disease.
      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.
      • Jacobsen P.
      • Andersen S.
      • Jensen B.R.
      • Parving H.H.
      Additive effect of ACE inhibition and angiotensin II receptor blockade in type I diabetic patients with diabetic nephropathy.
      A second study was not included because only serum creatinine values were reported.
      • Kincaid-Smith P.
      • Fairley K.
      • Packham D.
      Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria.
      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).
      Figure thumbnail gr4
      Fig 4Change in estimated GFR when an ARB is added to ACE-inhibitor therapy.

      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 disease 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 ACE-inhibitor 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 m2 [0.63 mL/s/1.73 m2]). 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
      • Juurlink D.N.
      • Mamdani M.M.
      • Lee D.S.
      • et al.
      Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.
      despite not manifesting within the original clinical trial.
      • Pitt B.
      • Zannad F.
      • Remme W.J.
      • et al.
      Randomized Aldactone Evaluation Study Investigators
      The effect of spironolactone on morbidity and mortality in patients with severe heart failure.
      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).
      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.
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      Interestingly, 2 small trials by Song et al
      • Song J.H.
      • Lee S.W.
      • Suh J.H.
      • et al.
      The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy.
      and Agarwal et al
      • Agarwal R.
      • Siva S.
      • Dunn S.R.
      • Sharma K.
      Add-on angiotensin II receptor blockade lowers urinary transforming growth factor-beta levels.
      showed decreases in urinary concentrations of transforming growth factor β, 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 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.
      • Nakao N.
      • Yoshimura A.
      • Morita H.
      • Takada M.
      • Kayano T.
      • Ideura T.
      Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE) A randomised controlled trial.
      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.

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