Abstract

BACKGROUND

Although dual blockade of the renin–angiotensin–aldosterone system (RAAS) has gained popularity for the treatment of kidney disease, its benefits and potential risks have not been fully elucidated. We conducted a meta-analysis of all randomized controlled trials comparing the efficacy and safety of combined vs. single RAAS blockade therapy in chronic kidney disease (CKD).

METHODS

We performed a literature search using MEDLINE, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, scientific abstracts from meetings, and bibliographies of retrieved articles. We used random-effects models to compute net changes and rate differences in variables.

RESULTS

Fifty-nine (25 crossover and 34 parallel-arm) randomized controlled trials (RCTs) comparing the efficacy and safety of combined vs. single RAAS blockade therapy in CKD were identified (4,975 patients). Combined RAAS blockade therapy was associated with a significant net decrease in glomerular filtration rate (GFR) (–1.8ml/min or ml/min/1.73 m2; P = 0.005), albuminuria (–90mg/g of creatinine; P = 0.001 or –32mg/day; P = 0.03), and proteinuria (–291mg/g; P = 0.003 or –363mg/day; P < 0.001). Combined RAAS blockade therapy was associated with a 9.4% higher rate of regression to normoalbuminuria and a 5% higher rate of achieving the blood pressure (BP) goal (as defined in individual trials). However, combined RAAS blockade therapy was associated with a significant net increase in serum potassium level, a 3.4% higher rate of hyperkalemia, and a 4.6% higher rate of hypotension. There was no effect on doubling of the serum creatinine level, hospitalization, or mortality.

CONCLUSIONS

Although combined RAAS blockade therapy in CKD is associated with a decrease in albuminuria and proteinuria, it is associated with a decrease in GFR and a higher incidence of hyperkalemia and hypotension relative to monotherapy. The potential long-term kidney benefits of combined RAAS blockade therapy require further study.

The prevalence of chronic kidney disease (CKD) is rising throughout the world, partly as the result of an aging population and an increasing prevalence of hypertension, obesity, diabetes, and cardiovascular disease.1,2 Chronic kidney disease is associated with increased morbidity and mortality,3 including significant consumption of resources and healthcare expenditures.4 Hypertension and proteinuria are well-known predictors of the progression of CKD.5 For the same decrease in systemic blood pressure (BP), agents that block the renin–angiotensin–aldosterone system (RAAS) exert a stronger antiproteinuric effect than other antihypertensive drugs such as calcium-channel blockers.6–8 Because of this, current clinical-practice guidelines recommend using blockers of the RAAS as preferred agents for treating kidney disease.9,10 Although prior meta-analyses have demonstrated a beneficial effect of dual RAAS blockade therapy with an angiotensin-converting enzyme inhibitor (ACEI) and an angiotensin-II type-2 receptor blocker (ARB) in reducing proteinuria in patients with kidney disease, no discernible effect of this drug combination was noted on kidney function.11–13 Other combination therapies, including that of an ACEI, ARB, or both with an aldosterone receptor antagonist (ARA) and, most recently, an ACEI or ARB with a direct renin inhibitor (DRI), have also been shown to further reduce urinary protein excretion in kidney disease beyond that achieved with single RAAS blockade,14,15 leading to a more widespread clinical use of combination therapies in treating CKD.

The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET),16 the largest trial of dual vs. single RAAS blockade therapy in patients with coronary, peripheral, or cerebrovascular disease or diabetes with end-organ damage, has called into question the trend in clinical practice toward using combination therapies for RAAS blockade. Indeed, in that trial, the use of an ACEI and ARB was associated with a higher rate of syncope and kidney dysfunction than monotherapy, without benefit on the composite endpoint of fatal and nonfatal cardiovascular outcomes.16 In a subsequent ONTARGET analysis of kidney-related endpoints, doubling of serum creatinine or dialysis was more frequent in the combination-therapy group.17 Several cautionary notes on dual RAAS blockade therapy have since appeared in the literature.18–20 The Canadian Heart and Stroke Foundation clinical guidelines now recommend that combined RAAS blockade therapy be discontinued for the treatment of hypertension.21 In light of scarce data on the potentially deleterious effect of combined RAAS blockade therapy on kidney-related endpoints in patients with CKD, we conducted a meta-analysis of all randomized controlled trials (RCTs) comparing the efficacy and safety of combined vs. single RAAS blockade therapy in patients with CKD.

METHODS

Data sources and searches.

We performed a MEDLINE literature search beginning in August 2011 to identify eligible studies using the Medical Subject Headings (MeSH) database search terms “diabetic nephropathy,” “hypertensive nephropathy,” “glomerular disease,” “proteinuric kidney disease,” “renal insufficiency,” “kidney disease,” “chronic renal failure,” “chronic kidney disease,” “dual therapy,” “dual blockade,” “renin–angiotensin system,” “angiotensin-converting enzyme inhibitor,” “angiotensin-receptor blocker,” “aldosterone blockade,” “selective aldosterone blockade,” “renin inhibitor,” or “direct renin inhibitor.” The search was limited to human studies. We also searched the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov for completed studies using similar search terms, and reviewed the American Society of Nephrology scientific abstracts (2003–2011 meetings), as well as the bibliographies of retrieved articles.

Study selection.

We included randomized, controlled crossover and parallel-arm trials examining the effect of combined vs. single RAAS blockade therapy on kidney-related endpoints, BP parameters, and other outcomes of interest in patients with proteinuria or low GFR (< 60ml/min or ml/min/1.73 m2). There were no restrictions on language, sample size, or study duration. Two authors (PS and KS) independently screened the titles and abstracts of all electronic citations, and full-text articles were retrieved for comprehensive review and independently re-screened.

Data extraction and quality assessment.

The following data were extracted for the RCTs examined in the study: country of origin, year of publication, study design, sample size, duration of intervention, percentage of men, mean age of subjects, serum creatinine, GFR, urine albumin or protein excretion, systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP), and in studies of patients with diabetes, the duration of diabetes and mean concentration of hemoglobin A1C (HbA1C). For each RCT included in the meta-analysis, we also tabulated the exclusion criteria pertaining to the level of kidney function and serum potassium.

For assessment of kidney function, we extracted data on methods of measuring GFR that included measured, estimated, or calculated GFR. We extracted data on the urine albumin and protein specimen collection methods used in each study, including the use of random or timed (24-hour) samples.

When indicated, we used the G3data graph analyzer ( version 1.5.3; GNU General Public License, www.frantz.fi/software/g3data.php) to extract data from graphs. Disagreements were resolved through consensus and arbitration by a third author (BLJ). Study quality was assessed with a modified version of the Jadad scale, which assesses randomization adequacy, blinding, and attrition, with higher scores reflecting better quality.22,23

Data synthesis and analysis.

We used random-effects model meta-analyses to assess absolute and standardized net changes in continuous outcomes. The standardized net change was computed to overcome the use of different units of measurement, and allowed us to include trials that reported only net changes among study groups. The standardized effect size is derived by dividing the mean change in the continuous outcome level of a particular variable by the standard deviation of the mean change in the variable. The variance of the standardized effect size is estimated through the inverse of the sample size. Binary outcomes were examined through random-effects model meta-analyses that assessed rate differences, as well as through Peto fixed-effect model meta-analyses that assessed odds ratios (ORs). The latter approach was used because of the small number of observed events. All pooled estimates are displayed with a 95% confidence interval (CI).

Existence of heterogeneity among effect sizes estimated by individual studies was described with the I2 index and the chi-square test. An I2 index ≥ 50% was used to indicate medium-to-high heterogeneity.24 We investigated sources of heterogeneity for the outcomes of interest by performing random-effects model meta-regression analyses based on a priori selected study characteristics, including trial design (crossover vs. parallel-arm), population setting (diabetic, nondiabetic, or mixed populations), status of hypertension control at enrollment (poorly vs. well-controlled), urine albumin or protein excretion rate (microalbuminuria (30–300mg/day or mg/g of creatinine, macroalbuminuria (> 300mg/day or mg/g of creatinine) vs. overt proteinuria (> 500mg/day or mg/g of creatinine)), baseline GFR (≥ 60ml/min or ml/min/1.73 m2 vs. < 60ml/min or ml/min/1.73 m2), duration of follow up (1–6 months, 7–12 months, or >12 months), type of combination therapy (ACEI and ARB, ACEI or ARB and ARA, ACEI or ARB and DRI vs. ACEI and ARB and ARA), GFR, and albuminuria/proteinuria specimen collection method (random vs. timed), and study quality. Student’s t-test was used to compare subgroups. Publication bias was formally assessed using funnel plots and the Egger test, a test that assesses asymmetry of the funnel plot, whereby a value of P < 0.05 indicates publication bias.25 The meta-analyses were performed with Comprehensive Meta-Analysis version 2.0 (www.meta-analysis.com; Biostat, Englewood, NJ), and OpenMeta (http://tuftscaes.org/open_meta/ download. html). The subgroup analysis figures were generated with the R system software version 2.13.0 (cran.rproject.org/bin/windows/base/old/2.13.0).

RESULTS

Characteristics and quality of the studies.

A total of 12,118 potentially relevant citations were identified and screened; 183 articles were retrieved for detailed evaluation, of which 59, consisting of 25 crossover and 34 parallel-arm randomized controlled trials, fulfilled the eligibility criteria for inclusion in the meta-analysis (Fig. 1).14,15,2682 Twenty-seven trials had two single-therapy groups that included an ACEI or ARB,29,32,34,35,38,4043,4851,54,56,58,59,62,66,67,6971,73,75,80,82 each of which were each compared to the combination-therapy group. Two trials tested different doses of RAAS blockade combination therapies14,65, which was compared with the single-therapy group. In addition, one trial tested different doses of single therapies,33 each of which was compared with the combination-therapy group, and one trial tested double and triple combination therapies,72 each of which was compared with the single-therapy group. In terms of combined RAAS blockade therapy, 74 study arms used an ACEI and ARB, 10 study arms used an ACEI or ARB and an ARA, 5 study arms used an ACEI or ARB and a DRI, and 2 study arms used a combination of an ACEI, ARB, and ARA (Fig. 2).

Figure 1.

Flow diagram for selection of studies of combined vs. single-agent blockade of the renin–angiotensin–aldosterone system (RAAS) included in the meta-analysis.

Figure 1.

Flow diagram for selection of studies of combined vs. single-agent blockade of the renin–angiotensin–aldosterone system (RAAS) included in the meta-analysis.

Figure 2.

Distribution of combined renin–angiotensin–aldosterone system (RAAS) blockade therapies. Abbreviations: ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor type-2 blocker; ARA, aldosterone receptor antagonist; DRI, direct renin inhibitor.

Figure 2.

Distribution of combined renin–angiotensin–aldosterone system (RAAS) blockade therapies. Abbreviations: ACEI, Angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor type-2 blocker; ARA, aldosterone receptor antagonist; DRI, direct renin inhibitor.

Characteristics of the individual trials are displayed in Table 1. The trials spanned more than 10 years, varied in sample size (10–599 patients), and involved three types of populations, consisting of diabetics, nondiabetics, or a mixture of the two populations. The mean age of the subjects of the trials ranged from 25 to 66 years, and the duration of follow up ranged from 1–49 months. Thirty-one (52.5%) studies enrolled patients with preserved kidney function (GFR ≥ 60ml/min or ml/min/1.73 m2) and 7 studies enrolled patients with a low GFR (< 60ml/min or ml/min/1.73 m2). Twenty-one studies did not report the subjects’ baseline kidney function. At enrollment, the subjects’ hypertension was well controlled in 13 studies and poorly controlled in 46 studies. The GFR was assessed in a total of 44 studies, in which it was measured in 12 studies, estimated in 14 studies, and calculated in 18 studies. Urine albumin or protein excretion was measured on random samples in 17 studies and on timed samples in 40 studies. At enrollment, the patients in 10 studies had microalbuminuria, those in 9 studies had macroalbuminuria, and those in 38 studies had overt proteinuria. Thirty-four studies were of fair quality (score 1–3) and 25 were of good quality (score 4–5).

Table 1.

Characteristics of randomized controlled trials included in this meta-analysis of trials of single-agent vs. combined therapy for blockade of the renin–angiotensin–aldosterone system

    Renin–angiotensin–aldosterone system blockade             Exclusion criteria  
Author Year Country Study design Combined therapy Single therapy Number of patients Duration of follow up (months) Mean age (years) Men (%) Mean serum creatinine (mg/dl) Mean glomerular filtration rate (ml/min or ml/min /1.73 m2Mean albuminuria or proteinuria (g/g or g/day) Mean systolic blood pressure (mm Hg) Mean diastolic blood pressure (mm Hg) Population settings Diabetes duration (years) Mean hemoglobin A1C (%) Kidney function Serum potassium (mEq/l) Jadad score 
Ruilope65 2000 Multinational Parallel-arm Benazepril + valsartan Valsartan 64 1.25 57 71 NR NR 1.8 NR NR Nondiabetic Cr clearance < 20ml/min NR 
   Parallel-arm Benazepril + valsartan (varying dosing regimens) Valsartan 66 1.25 58 68 NR NR 1.7 NR NR Nondiabetic Cr clearance < 20ml/min NR 
Agarwal44 2001 USA Crossover Lisinopril + losartan Lisinopril 16 53 88 2.0 NR 3.6 156 88 Mixed NR NR eGFR < 30ml/min > 5.5 
Russo38 2001 Italy Crossover Enalapril + losartan Enalapril 19 25 40 NR 110 1.5 119 76 Nondiabetic eGFR < 90ml/min/1.73 m2 NR 
   Crossover Enalapril + losartan Losartan 19 25 40 NR 110 1.5 119 76 Nondiabetic eGFR < 90ml/min/1.73 m2 NR 
Tutuncu51 2001 Turkey Parallel-arm Enalapril + losartan Enalapril 22 12 54 NR NR NR 0.1a 117 75 Diabetic 8.1 7.6 Renal impairment NR 
   Parallel-arm Enalapril + losartan Losartan 22 12 58 NR NR NR 0.1 a 117 78 Diabetic 7.6 7.6 Renal impairment NR 
Kincaid-Smith45 2002 Australia Crossover Any ACEI + candesartan Any ACEI 65 NR NR 2.0 NR 2.3 139 82 Mixed NR NR sCr > 3.96mg/dl NR 
Berger39 2002 Germany Crossover ACEI + candesartan ACEI + placebo 12 52 50 1.1 NR NR NR Nondiabetic NR NR 
Ferrari40 2002 Switzerland Crossover Fosinopril + irbesartan Fosinopril 11 1.5 48 64 1.5 77 7.9 143 91 Nondiabetic eGFR < 30ml/min NR 
   Crossover Fosinopril + irbesartan Irbesartan 11 1.5 48 64 1.5 77 7.9 143 91 Nondiabetic eGFR < 30ml/min NR 
Jacobsen26 2002 Denmark Crossover Any ACEI + irbesartan Any ACEI 21 45 81 NR NR 1.9* 156 87 Diabetic 29 NR eGFR < 20ml/min > 4.8 
Rossing27 2002 Denmark Crossover Any ACEI + candesartan Any ACEI 18 58 77 NR NR 1.8* 159 85 Diabetic 13 NR eGFR < 25ml/min > 4.6 
Kuriyama60 2002 Japan Parallel-arm Temocapril + candesartan Candesartan+ amdopidine 17 53 53 2.3 29 4.2 153 91 Diabetic NR 7.7 sCr > 4.0mg/dl NR 
Tylicki66 2002 Poland Parallel-arm Enalapril + losartan Enalapril 32 41 72 1.2 95 2.9 137 88 Nondiabetic sCr > 2.0mg/dl NR 
   Parallel-arm Enalapril + losartan Losartan 32 39 56 1.1 93 2.7 139 89 Nondiabetic sCr > 2.0mg/dl NR 
Luno67 2002 Spain Parallel-arm Lisinopril + candesartan Lisinopril 30 46 70 1.2 90 3.7 135 82 Non-diabetic eGFR < 50ml/min/1.73 m2 > 5.0 
   Parallel-arm Lisinopril + candesartan Candesartan 31 44 61 1.1 100 3.9 134 82 Nondiabetic eGFR < 50ml/min/1.73 m2 > 5.0 
Jacobsen28 2003 Denmark Crossover Enalapril + irbesartan Enalapril 24 42 71 NR NR NR NR NR Diabetic 31 NR eGFR < 30ml/min > 4.8 
Jacobsen29 2003 Denmark Crossover Benazepril + valsartan Benazepril 20 43 72 NR NR 0.4 a 141 81 Diabetic 30 NR eGFR < 30ml/min > 4.8 
   Crossover Benazepril + valsartan Valsartan 20 43 72 NR NR 0.4 a 141 81 Diabetic 30 NR eGFR < 30ml/min > 4.8 
Rossing30 2003 Denmark Crossover Any ACEI + candesartan Any ACEI 20 62 85 NR NR NR NR NR Diabetic 15 NR eGFR < 25ml/min > 4.6 
Kim46 2003 Korea Crossover Ramipril + candesartan Ramipril 43 34 46 NR 60 3.9 NR NR Mixed NR NR eGFR < 25ml/min/1.73 m2 NR 
Song47 2003 Korea Crossover Ramipril + candesartan Ramipril +placebo 34 34 41 NR NR 4.1 NR NR Mixed NR NR eGFR < 25ml/min/1.73 m2 NR 
Campbell41 2003 Italy Crossover Benazepril + valsartan Benazepril 24 49 96 1.7 69 3.3 140 91 Nondiabetic eGFR < 20ml/min/1.73 m2 K > 6 
   Crossover Benazepril + valsartan Valsartan 24 49 96 1.7 69 3.3 140 91 Nondiabetic eGFR < 20ml/min/1.73 m2 K > 6 
Shoji68 2003 Japan Parallel-arm Enalapril + losartan Enalapril 16 12 NR NR NR 79 2.0 NR NR Nondiabetic NR NR 
Segura69 2003 Spain Parallel-arm Benazepril + valsartan Benazepril 24 49 79 NR 70 4.0 152 91 Nondiabetic eGFR < 30ml/min > 5.0 
   Parallel-arm Benazepril + valsartan Valsartan 24 49 79 NR 71 4.4 151 88 Nondiabetic eGFR < 30ml/min > 5.0 
Rutkowski42 2004 Poland Crossover Benazepril + losartan Benazepril 30 36 50 1.2 86 2.1 140 91 Nondiabetic sCr > 2.0mg/dl NR 
   Crossover Benazepril + losartan Losartan 30 36 50 1.2 86 2.1 140 91 Nondiabetic sCr > 2.0mg/dl NR 
Cetinkaya33 2004 Turkey Crossover Enalapril + losartan Enalapril 10 55 55 NR 65 4.8 151 93 Diabetic NR 6.9 NR NR 
   Crossover Enalapril + losartan Losartan 10 55 55 NR 65 4.8 151 93 Diabetic NR 6.9 NR NR 
   Crossover Enalapril + losartan Double-dose monotherapy 10 55 55 NR 65 4.8 151 93 Diabetic NR 6.9 NR NR 
Renke70 2004 Poland Parallel-arm Enalapril + losartan Enalapril 36 41 68 1.2 94 2.9 137 89 Nondiabetic sCr > 2.0mg/dl NR 
   Parallel-arm Enalapril + losartan Losartan 36 39 54 1.1 94 2.7 139 90 Nondiabetic sCr > 2.0mg/dl NR 
Scaglione71 2005 Italy Parallel-arm Ramipril + losartan Ramipril 34 56 52 1.0 72 0.5 161 96 Non-diabetic sCr > 1.3mg/dl (women), sCr > 1.4mg/dl (men) NR 
   Parallel-arm Ramipril + losartan Losartan 34 57 52 1.0 70 0.4 163 93 No-diabetic sCr > 1.3mg/dl (women), sCr > 1.4mg/dl (men) NR 
Matos34 2005 Brazil Crossover Peridopril + irbesartan Peridopril 20 54 25 NR NR 0.9 NR NR Diabetic 11 NR eGFR < 40ml/min/1.73 m2 > 5.0 
   Crossover Peridopril + irbesartan Irbesartan 20 54 25 NR NR 0.9 NR NR Diabetic 11 NR eGFR < 40ml/min/1.73 m2 > 5.0 
Schjoedt31 2005 Denmark Crossover ACEI or ARB + spinolactone ACEI or ARB 22 45 75 NR NR NR NR NR Diabetic 33 NR eGFR < 30ml/min/1.73 m2 > 4.5 
Esnault48 2005 France Crossover Ramipril + valsartan Ramipril 18 49 67 1.7 NR 3.7 149 NR Mixed NR NR sCr > 2.83mg/dl NR 
   Crossover Ramipril + valsartan Valsartan 18 49 67 1.7 NR 3.7 149 NR Mixed NR NR sCr > 2.83mg/dl NR 
Andersen52 2005 Denmark Parallel-arm Lisinopril + candesartan Lisinopril 75 12 55 75 NR NR 0.02 a 141 83 Diabetic NR NR sCr > 1.47mg/dl NR 
Krimholtz53 2005 UK Parallel-arm Lisonopril + candesartan Lisinpopril + amlodipine 28 47 57 NR 92 0.3 a NR NR Diabetic 30.5 9.3 Cr >1.7mg/dl > 5.5 
Song35 2006 Korea Crossover Ramipril + candesartan Ramipril 25 49 52 NR NR 4.2 134 80 Diabetic 7.4 eGFR < 30ml/min/1.73 m2  > 5.5 
   Crossover Ramipril + candesartan Candesartan 25 49 52 NR NR 4.2 134 80 Diabetic 7.4 eGFR < 30ml/min/1.73 m2 > 5.5 
Atmaca54 2006 Turkey Parallel-arm Lisinopril + losartan Lisinopril 17 12 55 41 NR NR 0.1 a 120 78 Diabetic 7.5 6.2 eGFR < 60ml/min/1.73 m2 NR 
   Parallel-arm Lisinopril + losartan Losartan 17 12 55 41 NR NR 0.1 a 120 79 Diabetic 7.6 6.0 eGFR < 60ml/min/1.73 m2 NR 
Epstein14 2006 USA Parallel-arm Enalapril + eplerenone Enalapril 182 59 61 0.9 74 0.4 a 140 86 Diabetic NR 8.0 eGFR< 70ml/min > 5.0 
   Parallel-arm Enalapril + eplerenone (double dose) Enalapril 177 59 60 0.9 75 0.3 a 143 87 Diabetic NR 8.0 eGFR< 70ml/min >5.0 
Ogawa55 2006 Japan Parallel-arm Imidapril + spironolactone Imidapril + furosemide 30 12 63 NR 0.8 70 0.2 a 155 84 Diabetic 11.1 6.5 NR NR 
Sengul56 2006 Turkey Parallel-arm Lisinopril + telmisartan Lisinopril 95 57 37 0.9 95 0.2 a 140 82 Diabetic 11.1 7.6 sCr > 1.7mg/dl > 5.5 
   Parallel-arm Lisinopril + telmisartan Telmisartan 97 57 39 1.0 94 0.2 a 140 84 Diabetic 11.3 7.6 sCr > 1.7mg/dl >5.5 
Van den Meiracker57 2006 Netherland Parallel-arm ACEI or ARB + spironolactone ACEI or ARB + placebo 59 12 55 NR 1.0 75 0.9 a 146 81 Diabetic NR 8.3 sCr > 3.0mg/dl > 5.0 
Igarashi61 2006 Japan Parallel-arm Enalapril + losartan Double-dose enalapril 26 64 69 0.8 NR 1.8 150 81 Diabetic 14.5 7.2 NR NR 
Chrysostomou72 2006 Australia Parallel-arm Ramipril + irbesartan Ramipril 20 58 75 NR NR 2.6 133 78 Non-diabetic sCr > 2.26mg/dl > 5.0 
   Parallel-arm Ramipril + spironolactone Ramipril 20 63 70 NR NR 2.4 137 78 Nondiabetic sCr > 2.26mg/dl > 5.0 
   Parallel-arm Ramipril + irbesartan + spironolactone Ramipril 21 58 62 NR NR 2.9 131 77 Nondiabetic sCr > 2.26mg/dl > 5.0 
Horita73 2006 Japan Parallel-arm Temocapril + losartan Temocapril 27 12 41 56 0.8 92 0.7 118 73 Non-diabetic Cr clearance < 50ml/min NR 
   Parallel-arm Temocapril + losartan Losartan 29 12 40 55 0.9 91 0.8 123 78 Non-diabetic Cr clearance < 50ml/min NR 
Kanno74 2006 Japan Parallel-arm ACEI + candesartan Candesartan 90 36 60 45 NR NR 1.8 NR NR Nondiabetic sCr > 5.0mg/dl NR 
Bakris79 2007 USA Parallel-arm Ramipril + irbesartan Ramipril 405 66 62 NR NR 0.2 a NR NR Mixed 11.5 NR Renal impairment NR 
Ogawa58 2007 Japan Parallel-arm Temocapril + candesartan Temocapril 80 12 61 48 0.8 NR 0.2 a 154 91 Diabetic 16.8 6.8 sCr > 1.2mg/dl NR 
   Parallel-arm Temocapril + candesartan Candesartan 80 12 62 48 0.7 NR 0.3 a 151 90 Diabetic 16.2 6.9 sCr > 1.2mg/dl NR 
Uresin62 2007 Multinational Parallel-arm Ramipril + aliskiren Ramipril 555 60 60 NR NR NR 156 98 Diabetic NR 7.3 NR NR 
   Parallel-arm Ramipril + aliskiren Aliskiren 559 60 58 NR NR NR 157 98 Diabetic NR 7.3 NR NR 
Nakamura75 2007 Japan Parallel-arm Temocapril + olmesartan Temocapril 16 31 50 1.1 89 2.0 117 68 Nondiabetic NR NR 
   Parallel-arm Temocapril + olmesartan Olmesartan 16 33 56 1.1 89 2.0 118 69 Nondiabetic NR NR 
Joffe36 2007 USA Crossover Enalapril + eplerenone Enalapril 16 1.5 53 69 1.1 97 0.3 148 88 Diabetic 11.8 8.1 sCr > 1.5mg/dl NR 
Menne80 2008 Germany Parallel-arm Lisinopril + valsartan Lisinopril 90 7.5 60 74 NR 113 0.1 a 152 90 Mixed NR NR eGFR < 30ml/min > 5.5 
   Parallel-arm Lisinopril + valsartan Valsartan 86 7.5 58 72 NR 120 0.1 a 152 91 Mixed NR NR eGFR < 30ml/min > 5.5 
Mori-Takeyama76 2008 Japan Parallel-arm Benazepril + candesartan Candesartan 86 36 37 59 0.9 95 1.4 134 83 Nondiabetic NR NR 
Parving15 2008 Multinational Parallel-arm Losartan + aliskiren Losartan 599 61 71 1.2 68 0.5 a 136 78 Diabetic 14.0 8.0 eGFR< 30ml/min/1.73m2 > 5.1 
Tokunaga77 2008 Japan Parallel-arm ARB + spironolactone ARB 64 17 NR NR NR NR NR NR NR Nondiabetic eGFR < 15ml/min/1.73 m2 NR 
Swaminathan37 2008 UK Crossover ACEI or ARB + spironolactone ACEI or ARB + placebo 50 63 74 1.1 NR NR 163 89 Diabetic NR 7.03 Renal impairment NR 
Persson32 2009 Denmark Crossover Irbesartan + aliskiren Irbesartan 32 60 78 NR NR 0.3 a 142 74 Diabetic NR 8.1 eGFR < 40ml/min/1.73 m2 NR 
   Crossover Irbesartan + aliskiren Aliskiren 32 60 78 NR NR 0.3 a 142 74 Diabetic NR 8.1 eGFR < 40ml/min/1.73 m2 NR 
Morales49 2009 Spain Crossover Lisinopril + candesartan Lisinopril 12 1.5 57 58 1.4 58 2.2 139 78 Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
   Crossover Lisinopril + candesartan Eplerenone 12 1.5 57 58 1.4 58 2.2 139 78 Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
Krairittichai63 2009 Thailand Parallel-arm Enalapril + telmisartan Enalapril 80 56 50 1.8 46 2.3 141 76 Diabetic 9.2 7.6 eGFR < 15 ml/min/1.73 m2 > 5.5 
Mehdi59 2009 USA Parallel-arm Lisinopril + losartan Lisinopril + placebo 53 12 51 47 1.6 NR 0.9 a 141 75 Diabetic 15.7 7.9 sCr > 3.0mg/dl (women), sCr > 4.0mg/dl (men) > 5.5 
   Parallel-arm Lisinopril + sproinolactone Lisinopril + placebo 54 12 51 46 1.6 NR 1.0 a 137 73 Diabetic 15.7 7.8 sCr > 3.0mg/dl (women), sCr > 4.0mg/dl (men) > 5.5 
Bianchi78 2010 USA Parallel-arm Ramipril + irbesartan + spironolactone Ramipril 128 36 53 64 NR 64 2.6 156 94 Nondiabetic eGFR < 30ml/min/1.73 m2 > 5.0 
Ohishi81 2010 Japan Parallel-arm Imidapril + valsartan Olmesartan 37 64 86.5 1.7 NR 1.7 NR NR Mixed NR NR sCr > 3.0mg/dl NR 
Titan64 2011 Brazil Parallel-arm Enalapril + losartan Enalapril 56 58 62.5 1.7 52.9 2.9 149 81 Diabetic 17.0 8.4 sCr > 2.5mg/dl > 5.5 
Luno82 2011 Spain Parallel-arm Lisinopril + irbesartan Lisinopril 131b 49 b 65 b NR 1.5 b 45 b 2.6 b 155 b 81 b Diabetic NR 7.0 a eGFR < 30ml/min/1.73 m2 NR 
   Parallel-arm Lisinopril + irbesartan Irbesartan               
Meier50 2011 Switzerland Crossover Lisinopril + losartan Losartan 20 53 50 NR 60 6.6 NR NR Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
   Crossover Lisinopril + losartan Losartan (double dose) 20 53 50 NR 60 6.6 NR NR Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
Slagman43 2011 Netherlands Crossover Lisinopril + vasartan + low sodium Lisinopril + low sodium 52 1.5 51 83 NR 71 1.6 131 76. Nondiabetic eGFR < 30ml/min NR 
   Crossover Lisinopril + vasartan + high sodium Lisinopril + high sodium 52 1.5 51 83 NR 71 1.6 131 76. Nondiabetic eGFR < 30ml/min NR 
    Renin–angiotensin–aldosterone system blockade             Exclusion criteria  
Author Year Country Study design Combined therapy Single therapy Number of patients Duration of follow up (months) Mean age (years) Men (%) Mean serum creatinine (mg/dl) Mean glomerular filtration rate (ml/min or ml/min /1.73 m2Mean albuminuria or proteinuria (g/g or g/day) Mean systolic blood pressure (mm Hg) Mean diastolic blood pressure (mm Hg) Population settings Diabetes duration (years) Mean hemoglobin A1C (%) Kidney function Serum potassium (mEq/l) Jadad score 
Ruilope65 2000 Multinational Parallel-arm Benazepril + valsartan Valsartan 64 1.25 57 71 NR NR 1.8 NR NR Nondiabetic Cr clearance < 20ml/min NR 
   Parallel-arm Benazepril + valsartan (varying dosing regimens) Valsartan 66 1.25 58 68 NR NR 1.7 NR NR Nondiabetic Cr clearance < 20ml/min NR 
Agarwal44 2001 USA Crossover Lisinopril + losartan Lisinopril 16 53 88 2.0 NR 3.6 156 88 Mixed NR NR eGFR < 30ml/min > 5.5 
Russo38 2001 Italy Crossover Enalapril + losartan Enalapril 19 25 40 NR 110 1.5 119 76 Nondiabetic eGFR < 90ml/min/1.73 m2 NR 
   Crossover Enalapril + losartan Losartan 19 25 40 NR 110 1.5 119 76 Nondiabetic eGFR < 90ml/min/1.73 m2 NR 
Tutuncu51 2001 Turkey Parallel-arm Enalapril + losartan Enalapril 22 12 54 NR NR NR 0.1a 117 75 Diabetic 8.1 7.6 Renal impairment NR 
   Parallel-arm Enalapril + losartan Losartan 22 12 58 NR NR NR 0.1 a 117 78 Diabetic 7.6 7.6 Renal impairment NR 
Kincaid-Smith45 2002 Australia Crossover Any ACEI + candesartan Any ACEI 65 NR NR 2.0 NR 2.3 139 82 Mixed NR NR sCr > 3.96mg/dl NR 
Berger39 2002 Germany Crossover ACEI + candesartan ACEI + placebo 12 52 50 1.1 NR NR NR Nondiabetic NR NR 
Ferrari40 2002 Switzerland Crossover Fosinopril + irbesartan Fosinopril 11 1.5 48 64 1.5 77 7.9 143 91 Nondiabetic eGFR < 30ml/min NR 
   Crossover Fosinopril + irbesartan Irbesartan 11 1.5 48 64 1.5 77 7.9 143 91 Nondiabetic eGFR < 30ml/min NR 
Jacobsen26 2002 Denmark Crossover Any ACEI + irbesartan Any ACEI 21 45 81 NR NR 1.9* 156 87 Diabetic 29 NR eGFR < 20ml/min > 4.8 
Rossing27 2002 Denmark Crossover Any ACEI + candesartan Any ACEI 18 58 77 NR NR 1.8* 159 85 Diabetic 13 NR eGFR < 25ml/min > 4.6 
Kuriyama60 2002 Japan Parallel-arm Temocapril + candesartan Candesartan+ amdopidine 17 53 53 2.3 29 4.2 153 91 Diabetic NR 7.7 sCr > 4.0mg/dl NR 
Tylicki66 2002 Poland Parallel-arm Enalapril + losartan Enalapril 32 41 72 1.2 95 2.9 137 88 Nondiabetic sCr > 2.0mg/dl NR 
   Parallel-arm Enalapril + losartan Losartan 32 39 56 1.1 93 2.7 139 89 Nondiabetic sCr > 2.0mg/dl NR 
Luno67 2002 Spain Parallel-arm Lisinopril + candesartan Lisinopril 30 46 70 1.2 90 3.7 135 82 Non-diabetic eGFR < 50ml/min/1.73 m2 > 5.0 
   Parallel-arm Lisinopril + candesartan Candesartan 31 44 61 1.1 100 3.9 134 82 Nondiabetic eGFR < 50ml/min/1.73 m2 > 5.0 
Jacobsen28 2003 Denmark Crossover Enalapril + irbesartan Enalapril 24 42 71 NR NR NR NR NR Diabetic 31 NR eGFR < 30ml/min > 4.8 
Jacobsen29 2003 Denmark Crossover Benazepril + valsartan Benazepril 20 43 72 NR NR 0.4 a 141 81 Diabetic 30 NR eGFR < 30ml/min > 4.8 
   Crossover Benazepril + valsartan Valsartan 20 43 72 NR NR 0.4 a 141 81 Diabetic 30 NR eGFR < 30ml/min > 4.8 
Rossing30 2003 Denmark Crossover Any ACEI + candesartan Any ACEI 20 62 85 NR NR NR NR NR Diabetic 15 NR eGFR < 25ml/min > 4.6 
Kim46 2003 Korea Crossover Ramipril + candesartan Ramipril 43 34 46 NR 60 3.9 NR NR Mixed NR NR eGFR < 25ml/min/1.73 m2 NR 
Song47 2003 Korea Crossover Ramipril + candesartan Ramipril +placebo 34 34 41 NR NR 4.1 NR NR Mixed NR NR eGFR < 25ml/min/1.73 m2 NR 
Campbell41 2003 Italy Crossover Benazepril + valsartan Benazepril 24 49 96 1.7 69 3.3 140 91 Nondiabetic eGFR < 20ml/min/1.73 m2 K > 6 
   Crossover Benazepril + valsartan Valsartan 24 49 96 1.7 69 3.3 140 91 Nondiabetic eGFR < 20ml/min/1.73 m2 K > 6 
Shoji68 2003 Japan Parallel-arm Enalapril + losartan Enalapril 16 12 NR NR NR 79 2.0 NR NR Nondiabetic NR NR 
Segura69 2003 Spain Parallel-arm Benazepril + valsartan Benazepril 24 49 79 NR 70 4.0 152 91 Nondiabetic eGFR < 30ml/min > 5.0 
   Parallel-arm Benazepril + valsartan Valsartan 24 49 79 NR 71 4.4 151 88 Nondiabetic eGFR < 30ml/min > 5.0 
Rutkowski42 2004 Poland Crossover Benazepril + losartan Benazepril 30 36 50 1.2 86 2.1 140 91 Nondiabetic sCr > 2.0mg/dl NR 
   Crossover Benazepril + losartan Losartan 30 36 50 1.2 86 2.1 140 91 Nondiabetic sCr > 2.0mg/dl NR 
Cetinkaya33 2004 Turkey Crossover Enalapril + losartan Enalapril 10 55 55 NR 65 4.8 151 93 Diabetic NR 6.9 NR NR 
   Crossover Enalapril + losartan Losartan 10 55 55 NR 65 4.8 151 93 Diabetic NR 6.9 NR NR 
   Crossover Enalapril + losartan Double-dose monotherapy 10 55 55 NR 65 4.8 151 93 Diabetic NR 6.9 NR NR 
Renke70 2004 Poland Parallel-arm Enalapril + losartan Enalapril 36 41 68 1.2 94 2.9 137 89 Nondiabetic sCr > 2.0mg/dl NR 
   Parallel-arm Enalapril + losartan Losartan 36 39 54 1.1 94 2.7 139 90 Nondiabetic sCr > 2.0mg/dl NR 
Scaglione71 2005 Italy Parallel-arm Ramipril + losartan Ramipril 34 56 52 1.0 72 0.5 161 96 Non-diabetic sCr > 1.3mg/dl (women), sCr > 1.4mg/dl (men) NR 
   Parallel-arm Ramipril + losartan Losartan 34 57 52 1.0 70 0.4 163 93 No-diabetic sCr > 1.3mg/dl (women), sCr > 1.4mg/dl (men) NR 
Matos34 2005 Brazil Crossover Peridopril + irbesartan Peridopril 20 54 25 NR NR 0.9 NR NR Diabetic 11 NR eGFR < 40ml/min/1.73 m2 > 5.0 
   Crossover Peridopril + irbesartan Irbesartan 20 54 25 NR NR 0.9 NR NR Diabetic 11 NR eGFR < 40ml/min/1.73 m2 > 5.0 
Schjoedt31 2005 Denmark Crossover ACEI or ARB + spinolactone ACEI or ARB 22 45 75 NR NR NR NR NR Diabetic 33 NR eGFR < 30ml/min/1.73 m2 > 4.5 
Esnault48 2005 France Crossover Ramipril + valsartan Ramipril 18 49 67 1.7 NR 3.7 149 NR Mixed NR NR sCr > 2.83mg/dl NR 
   Crossover Ramipril + valsartan Valsartan 18 49 67 1.7 NR 3.7 149 NR Mixed NR NR sCr > 2.83mg/dl NR 
Andersen52 2005 Denmark Parallel-arm Lisinopril + candesartan Lisinopril 75 12 55 75 NR NR 0.02 a 141 83 Diabetic NR NR sCr > 1.47mg/dl NR 
Krimholtz53 2005 UK Parallel-arm Lisonopril + candesartan Lisinpopril + amlodipine 28 47 57 NR 92 0.3 a NR NR Diabetic 30.5 9.3 Cr >1.7mg/dl > 5.5 
Song35 2006 Korea Crossover Ramipril + candesartan Ramipril 25 49 52 NR NR 4.2 134 80 Diabetic 7.4 eGFR < 30ml/min/1.73 m2  > 5.5 
   Crossover Ramipril + candesartan Candesartan 25 49 52 NR NR 4.2 134 80 Diabetic 7.4 eGFR < 30ml/min/1.73 m2 > 5.5 
Atmaca54 2006 Turkey Parallel-arm Lisinopril + losartan Lisinopril 17 12 55 41 NR NR 0.1 a 120 78 Diabetic 7.5 6.2 eGFR < 60ml/min/1.73 m2 NR 
   Parallel-arm Lisinopril + losartan Losartan 17 12 55 41 NR NR 0.1 a 120 79 Diabetic 7.6 6.0 eGFR < 60ml/min/1.73 m2 NR 
Epstein14 2006 USA Parallel-arm Enalapril + eplerenone Enalapril 182 59 61 0.9 74 0.4 a 140 86 Diabetic NR 8.0 eGFR< 70ml/min > 5.0 
   Parallel-arm Enalapril + eplerenone (double dose) Enalapril 177 59 60 0.9 75 0.3 a 143 87 Diabetic NR 8.0 eGFR< 70ml/min >5.0 
Ogawa55 2006 Japan Parallel-arm Imidapril + spironolactone Imidapril + furosemide 30 12 63 NR 0.8 70 0.2 a 155 84 Diabetic 11.1 6.5 NR NR 
Sengul56 2006 Turkey Parallel-arm Lisinopril + telmisartan Lisinopril 95 57 37 0.9 95 0.2 a 140 82 Diabetic 11.1 7.6 sCr > 1.7mg/dl > 5.5 
   Parallel-arm Lisinopril + telmisartan Telmisartan 97 57 39 1.0 94 0.2 a 140 84 Diabetic 11.3 7.6 sCr > 1.7mg/dl >5.5 
Van den Meiracker57 2006 Netherland Parallel-arm ACEI or ARB + spironolactone ACEI or ARB + placebo 59 12 55 NR 1.0 75 0.9 a 146 81 Diabetic NR 8.3 sCr > 3.0mg/dl > 5.0 
Igarashi61 2006 Japan Parallel-arm Enalapril + losartan Double-dose enalapril 26 64 69 0.8 NR 1.8 150 81 Diabetic 14.5 7.2 NR NR 
Chrysostomou72 2006 Australia Parallel-arm Ramipril + irbesartan Ramipril 20 58 75 NR NR 2.6 133 78 Non-diabetic sCr > 2.26mg/dl > 5.0 
   Parallel-arm Ramipril + spironolactone Ramipril 20 63 70 NR NR 2.4 137 78 Nondiabetic sCr > 2.26mg/dl > 5.0 
   Parallel-arm Ramipril + irbesartan + spironolactone Ramipril 21 58 62 NR NR 2.9 131 77 Nondiabetic sCr > 2.26mg/dl > 5.0 
Horita73 2006 Japan Parallel-arm Temocapril + losartan Temocapril 27 12 41 56 0.8 92 0.7 118 73 Non-diabetic Cr clearance < 50ml/min NR 
   Parallel-arm Temocapril + losartan Losartan 29 12 40 55 0.9 91 0.8 123 78 Non-diabetic Cr clearance < 50ml/min NR 
Kanno74 2006 Japan Parallel-arm ACEI + candesartan Candesartan 90 36 60 45 NR NR 1.8 NR NR Nondiabetic sCr > 5.0mg/dl NR 
Bakris79 2007 USA Parallel-arm Ramipril + irbesartan Ramipril 405 66 62 NR NR 0.2 a NR NR Mixed 11.5 NR Renal impairment NR 
Ogawa58 2007 Japan Parallel-arm Temocapril + candesartan Temocapril 80 12 61 48 0.8 NR 0.2 a 154 91 Diabetic 16.8 6.8 sCr > 1.2mg/dl NR 
   Parallel-arm Temocapril + candesartan Candesartan 80 12 62 48 0.7 NR 0.3 a 151 90 Diabetic 16.2 6.9 sCr > 1.2mg/dl NR 
Uresin62 2007 Multinational Parallel-arm Ramipril + aliskiren Ramipril 555 60 60 NR NR NR 156 98 Diabetic NR 7.3 NR NR 
   Parallel-arm Ramipril + aliskiren Aliskiren 559 60 58 NR NR NR 157 98 Diabetic NR 7.3 NR NR 
Nakamura75 2007 Japan Parallel-arm Temocapril + olmesartan Temocapril 16 31 50 1.1 89 2.0 117 68 Nondiabetic NR NR 
   Parallel-arm Temocapril + olmesartan Olmesartan 16 33 56 1.1 89 2.0 118 69 Nondiabetic NR NR 
Joffe36 2007 USA Crossover Enalapril + eplerenone Enalapril 16 1.5 53 69 1.1 97 0.3 148 88 Diabetic 11.8 8.1 sCr > 1.5mg/dl NR 
Menne80 2008 Germany Parallel-arm Lisinopril + valsartan Lisinopril 90 7.5 60 74 NR 113 0.1 a 152 90 Mixed NR NR eGFR < 30ml/min > 5.5 
   Parallel-arm Lisinopril + valsartan Valsartan 86 7.5 58 72 NR 120 0.1 a 152 91 Mixed NR NR eGFR < 30ml/min > 5.5 
Mori-Takeyama76 2008 Japan Parallel-arm Benazepril + candesartan Candesartan 86 36 37 59 0.9 95 1.4 134 83 Nondiabetic NR NR 
Parving15 2008 Multinational Parallel-arm Losartan + aliskiren Losartan 599 61 71 1.2 68 0.5 a 136 78 Diabetic 14.0 8.0 eGFR< 30ml/min/1.73m2 > 5.1 
Tokunaga77 2008 Japan Parallel-arm ARB + spironolactone ARB 64 17 NR NR NR NR NR NR NR Nondiabetic eGFR < 15ml/min/1.73 m2 NR 
Swaminathan37 2008 UK Crossover ACEI or ARB + spironolactone ACEI or ARB + placebo 50 63 74 1.1 NR NR 163 89 Diabetic NR 7.03 Renal impairment NR 
Persson32 2009 Denmark Crossover Irbesartan + aliskiren Irbesartan 32 60 78 NR NR 0.3 a 142 74 Diabetic NR 8.1 eGFR < 40ml/min/1.73 m2 NR 
   Crossover Irbesartan + aliskiren Aliskiren 32 60 78 NR NR 0.3 a 142 74 Diabetic NR 8.1 eGFR < 40ml/min/1.73 m2 NR 
Morales49 2009 Spain Crossover Lisinopril + candesartan Lisinopril 12 1.5 57 58 1.4 58 2.2 139 78 Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
   Crossover Lisinopril + candesartan Eplerenone 12 1.5 57 58 1.4 58 2.2 139 78 Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
Krairittichai63 2009 Thailand Parallel-arm Enalapril + telmisartan Enalapril 80 56 50 1.8 46 2.3 141 76 Diabetic 9.2 7.6 eGFR < 15 ml/min/1.73 m2 > 5.5 
Mehdi59 2009 USA Parallel-arm Lisinopril + losartan Lisinopril + placebo 53 12 51 47 1.6 NR 0.9 a 141 75 Diabetic 15.7 7.9 sCr > 3.0mg/dl (women), sCr > 4.0mg/dl (men) > 5.5 
   Parallel-arm Lisinopril + sproinolactone Lisinopril + placebo 54 12 51 46 1.6 NR 1.0 a 137 73 Diabetic 15.7 7.8 sCr > 3.0mg/dl (women), sCr > 4.0mg/dl (men) > 5.5 
Bianchi78 2010 USA Parallel-arm Ramipril + irbesartan + spironolactone Ramipril 128 36 53 64 NR 64 2.6 156 94 Nondiabetic eGFR < 30ml/min/1.73 m2 > 5.0 
Ohishi81 2010 Japan Parallel-arm Imidapril + valsartan Olmesartan 37 64 86.5 1.7 NR 1.7 NR NR Mixed NR NR sCr > 3.0mg/dl NR 
Titan64 2011 Brazil Parallel-arm Enalapril + losartan Enalapril 56 58 62.5 1.7 52.9 2.9 149 81 Diabetic 17.0 8.4 sCr > 2.5mg/dl > 5.5 
Luno82 2011 Spain Parallel-arm Lisinopril + irbesartan Lisinopril 131b 49 b 65 b NR 1.5 b 45 b 2.6 b 155 b 81 b Diabetic NR 7.0 a eGFR < 30ml/min/1.73 m2 NR 
   Parallel-arm Lisinopril + irbesartan Irbesartan               
Meier50 2011 Switzerland Crossover Lisinopril + losartan Losartan 20 53 50 NR 60 6.6 NR NR Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
   Crossover Lisinopril + losartan Losartan (double dose) 20 53 50 NR 60 6.6 NR NR Mixed NR NR eGFR < 15ml/min/1.73 m2 NR 
Slagman43 2011 Netherlands Crossover Lisinopril + vasartan + low sodium Lisinopril + low sodium 52 1.5 51 83 NR 71 1.6 131 76. Nondiabetic eGFR < 30ml/min NR 
   Crossover Lisinopril + vasartan + high sodium Lisinopril + high sodium 52 1.5 51 83 NR 71 1.6 131 76. Nondiabetic eGFR < 30ml/min NR 

Abbreviations: SBP,systolic blood pressure; DBP, diastolic blood pressure, eGFR, estimated glomerular filtration rate; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin-II type-2 receptor blockers; CKD, chronic kidney disease; Cr, creatinine; sCr, serum creatinine; NR, not reported.

aValue represents urinary albumin excretion rate; bValue refers to both study arms.

Effect of combined renin–angiotensin–aldosterone system blockade therapy on kidney-related endpoints.

Thirty study arms reported changes in albuminuria (2,165 patients) and 56 study arms reported changes in proteinuria (2,257 patients), with 10 and 20 study arms reporting changes in albuminuria in grams per gram of creatinine (1,347 patients) and grams per day (818 patients), respectively, and 10 and 46 study arms reporting changes in proteinuria in grams per gram of creatinine (697 patients) and grams per day (1,560 patients), respectively. Meta-analysis showed that combined RAAS blockade therapy was associated with an absolute net decrease in urine albumin excretion of 0.09g/g of creatinine (95% CI, –0.15 to –0.04; P = 0.001; I2 = 72%) and 0.03g/day (95% CI, –0.06 to –0.003; P = 0.03; I2 = 72%), and with an absolute net decrease in urine protein excretion of –0.29g/g of creatinine (95% CI, –0.48 to –0.10; P = 0.003; I2 = 50%) and –0.36g/day (95% CI, –0.48 to –0.25; P < 0.001; I2=50%). Similar results were observed with the use of standardized net changes (Table 1). Of note was that in the 19 study arms of diabetic subjects that reported changes in HbA1C (724 patients), there was no significant net change in HbA1C during the study period (0.06%; 95% CI, –0.12 to 0.25%). Combined RAAS blockade therapy was associated with a 9.4% higher rate of return to normoalbuminuria (95% CI, 4.1 to 14.6%; P < 0.001; I2 = 3.6%) in 12 study arms (1,082 patients), but with a nonsignificantly 2.7% lower rate of progression to overt proteinuria (95% CI, –7.0 to 1.7%; P = 0.23) in 8 study arms (523 patients) relative to monotherapy.

Sixty-nine study arms reported changes in GFR (3,801 patients), with 35 reporting changes in GFR in ml/min (1,522 patients) and 36 study arms reporting changes in GFR in ml/min/1.73 m2) (2,275 patients). Meta-analysis showed that as compared with monotherapy for RAAS blockade, combined RAAS blockade therapy was associated with an absolute net decrease in GFR of 1.79ml/min or ml/min/1.73 m2 (95% CI, –3.05 to –0.54; P = 0.005; I2 = 0%). Similar results were observed with the use of standardized net changes (Table 2). No effect of combined RAAS blockade therapy as compared with monotherapy was observed on the doubling of serum creatinine (Table 3).

Table 2.

Summary effect of combined vs. single RAAS blockade therapy on kidney-related endpoints and blood pressure parameters in patients with chronic kidney disease

     Assessment of heterogeneity Egger test 
Outcome variable No. study arms No. participants Net change* (95% CI) P value I2 index P-value (Chi-square) P value 
Urine albumin excretion        
 Standardized 30 2,165 –0.435 (–0.717, –0.154) 0.002 88.7 <0.001 0.212 
 Absolute (g/g of creatinine)  9 1,287 –0.090 (–0.145,–0.036) 0.001 72.0 <0.001 NA 
 Absolute (g/day) 15  618 –0.032 (–0.061, –0.003) 0.030 72.0 <0.001 NA 
 Absolute (g/g or g/day) 24 1,905 –0.062 (–0.097, –0.028) <0.001 90.0 <0.001 0.898 
Urine protein excretion        
 Standardized 56 2,257 –0.404 (–0.498, –0.309) <0.001 16.6 0.148 0.170 
 Absolute (g/g of creatinine) 10 697 –0.291 (–0.482, –0.099) 0.003 50.0 0.036 NA 
 Absolute (g/day) 45 1,440 –0.363 (–0.478, –0.247) <0.001 50.0 <0.001 NA 
 Absolute (g/g or g/day) 55 2,137 –0.339 (–0.434, –0.243) <0.001 49.6 <0.001 <0.001 
Glomerular filtration rate        
 Standardized 69 3,791 –0.094 (–0.171, –0.017) 0.016 19.8 0.082 0.525 
 Absolute (mL/min or mL/min/1.73m258 2,734 –1.794 (–3.045, –0.544) 0.005 0.790 0.04 
Serum potassium        
 Standardized 61 2,982 0.278 (0.178, 0.377) <0.001 39.2 0.001 0.123 
 Absolute (mEq/L) 54 2,255 0.134 (0.089, 0.179) <0.001 36.2 0.005 0.358 
Systolic blood pressure        
 Standardized 77 5,582 –0.336 (–0.404, –0.268) <0.001 22.7 0.044 0.175 
 Absolute (mmHg) 65 4,365 –3.755 (–4.579, –2.931) <0.001 12.8 0.197 0.584 
Diastolic blood pressure        
 Standardized 76 5,454 –0.279 (–0.363, –0.194) <0.001 47.4 <0.001 0.181 
 Absolute (mmHg) 64 4,237 –2.214 (–3.116, –1.313) <0.001 73.2 <0.001 0.777 
Mean arterial pressure        
 Standardized 17  489 –0.179 (–0.358, –0.001) 0.049 0.677 0.212 
 Absolute (mmHg) 17  489 –1.718 (–3.100, –0.335) 0.015 0.778 0.185 
     Assessment of heterogeneity Egger test 
Outcome variable No. study arms No. participants Net change* (95% CI) P value I2 index P-value (Chi-square) P value 
Urine albumin excretion        
 Standardized 30 2,165 –0.435 (–0.717, –0.154) 0.002 88.7 <0.001 0.212 
 Absolute (g/g of creatinine)  9 1,287 –0.090 (–0.145,–0.036) 0.001 72.0 <0.001 NA 
 Absolute (g/day) 15  618 –0.032 (–0.061, –0.003) 0.030 72.0 <0.001 NA 
 Absolute (g/g or g/day) 24 1,905 –0.062 (–0.097, –0.028) <0.001 90.0 <0.001 0.898 
Urine protein excretion        
 Standardized 56 2,257 –0.404 (–0.498, –0.309) <0.001 16.6 0.148 0.170 
 Absolute (g/g of creatinine) 10 697 –0.291 (–0.482, –0.099) 0.003 50.0 0.036 NA 
 Absolute (g/day) 45 1,440 –0.363 (–0.478, –0.247) <0.001 50.0 <0.001 NA 
 Absolute (g/g or g/day) 55 2,137 –0.339 (–0.434, –0.243) <0.001 49.6 <0.001 <0.001 
Glomerular filtration rate        
 Standardized 69 3,791 –0.094 (–0.171, –0.017) 0.016 19.8 0.082 0.525 
 Absolute (mL/min or mL/min/1.73m258 2,734 –1.794 (–3.045, –0.544) 0.005 0.790 0.04 
Serum potassium        
 Standardized 61 2,982 0.278 (0.178, 0.377) <0.001 39.2 0.001 0.123 
 Absolute (mEq/L) 54 2,255 0.134 (0.089, 0.179) <0.001 36.2 0.005 0.358 
Systolic blood pressure        
 Standardized 77 5,582 –0.336 (–0.404, –0.268) <0.001 22.7 0.044 0.175 
 Absolute (mmHg) 65 4,365 –3.755 (–4.579, –2.931) <0.001 12.8 0.197 0.584 
Diastolic blood pressure        
 Standardized 76 5,454 –0.279 (–0.363, –0.194) <0.001 47.4 <0.001 0.181 
 Absolute (mmHg) 64 4,237 –2.214 (–3.116, –1.313) <0.001 73.2 <0.001 0.777 
Mean arterial pressure        
 Standardized 17  489 –0.179 (–0.358, –0.001) 0.049 0.677 0.212 
 Absolute (mmHg) 17  489 –1.718 (–3.100, –0.335) 0.015 0.778 0.185 

* By random effects model meta-analysis A measure of statistical heterogeneity across study results; an I2 index ≥ 50% indicates medium-to-high heterogeneity.

Table 3.

Summary effect of combined vs. single RAAS blockade therapy on binary outcomes.

Outcome variable Peto fixed-effect model Random-effects model Assessment of heterogeneity Assessment of publication bias 
No. study arm No. participants Odds ratio (95% CI) P value No. study arms No. participants Summary rate difference (95% CI) P value I2 index Chi-square P value Egger test P value 
Doubling of serum creatinine 17 2,998 0.796 (0.523, 1.211) 0.287 17 2,998 –0.7% (–1.9, 0.5) 0.271 18.3 0.240 0.43 
Development of hyperkalemia 35 4,205 2.176 (1.685, 2.810) <0.001 35 4,205 3.4% (1.7, 5.1) <0.001 29.2 0.056 <0.001 
Progression to overt proteinuria  7  491 0.975 (0.534, 1.782) 0.935  8  523 –2.7% (–7.0, 1.7) 0.233 0.604 0.06 
Regression to normoalbuminuria 12 1,082 1.772 (1.320, 2.379) <0.001 12 1,082 9.4% (4.1, 14.6) <0.001 3.6 0.409 0.21 
Achievement of blood pressure goal  9 1,858 1.520 (1.169, 1.977) 0.002  9 1,858 5.0% (2.0, 8.0) 0.001 0.994 0.97 
Addition of other anti-hypertensive drugs 13 1,571 0.608 (0.459, 0.806) 0.001 13 1,571 –4.4% (–8.8, –0.1) 0.045 28.1 0.161 0.09 
Withdrawal of anti-hypertensive drugs  5  882 0.855 (0.488, 1.496) 0.582  5  882 –1.0% (–4.0, 2.1) 0.541 0.983 0.66 
Any adverse effect* 13 2,518 0.901 (0.747, 1.086) 0.275 13 2,518 –1.5% (–5.6, 2.6) 0.477 12.6 0.318 0.38 
Subject drop-out 20 1,965 1.151 (0.739,1.792) 0.533 23 2,107 0.6% (–1.3, 2.4) 0.552 0.498 0.52 
Development of hypotension 22 1,890 3.990 (2.649, 6.009) <0.001 24 2,047 4.6% (2.3, 6.8) <0.001 33.1 0.060 <0.001 
Hospitalization  4  246 2.958 (0.893, 9.803) 0.076  5  326 1.5% (–2.8, 5.9) 0.481 27.0 0.242 0.24 
Mortality  5 1,711 0.384 (0.061, 2.396) 0.305  8 2,410 –0.3% (–0.7, 0.2) 0.279 0.855 0.80 
Outcome variable Peto fixed-effect model Random-effects model Assessment of heterogeneity Assessment of publication bias 
No. study arm No. participants Odds ratio (95% CI) P value No. study arms No. participants Summary rate difference (95% CI) P value I2 index Chi-square P value Egger test P value 
Doubling of serum creatinine 17 2,998 0.796 (0.523, 1.211) 0.287 17 2,998 –0.7% (–1.9, 0.5) 0.271 18.3 0.240 0.43 
Development of hyperkalemia 35 4,205 2.176 (1.685, 2.810) <0.001 35 4,205 3.4% (1.7, 5.1) <0.001 29.2 0.056 <0.001 
Progression to overt proteinuria  7  491 0.975 (0.534, 1.782) 0.935  8  523 –2.7% (–7.0, 1.7) 0.233 0.604 0.06 
Regression to normoalbuminuria 12 1,082 1.772 (1.320, 2.379) <0.001 12 1,082 9.4% (4.1, 14.6) <0.001 3.6 0.409 0.21 
Achievement of blood pressure goal  9 1,858 1.520 (1.169, 1.977) 0.002  9 1,858 5.0% (2.0, 8.0) 0.001 0.994 0.97 
Addition of other anti-hypertensive drugs 13 1,571 0.608 (0.459, 0.806) 0.001 13 1,571 –4.4% (–8.8, –0.1) 0.045 28.1 0.161 0.09 
Withdrawal of anti-hypertensive drugs  5  882 0.855 (0.488, 1.496) 0.582  5  882 –1.0% (–4.0, 2.1) 0.541 0.983 0.66 
Any adverse effect* 13 2,518 0.901 (0.747, 1.086) 0.275 13 2,518 –1.5% (–5.6, 2.6) 0.477 12.6 0.318 0.38 
Subject drop-out 20 1,965 1.151 (0.739,1.792) 0.533 23 2,107 0.6% (–1.3, 2.4) 0.552 0.498 0.52 
Development of hypotension 22 1,890 3.990 (2.649, 6.009) <0.001 24 2,047 4.6% (2.3, 6.8) <0.001 33.1 0.060 <0.001 
Hospitalization  4  246 2.958 (0.893, 9.803) 0.076  5  326 1.5% (–2.8, 5.9) 0.481 27.0 0.242 0.24 
Mortality  5 1,711 0.384 (0.061, 2.396) 0.305  8 2,410 –0.3% (–0.7, 0.2) 0.279 0.855 0.80 

* As defined in the individual studies

Sixty-one study arms reported changes in serum potassium (2,982 patients). By meta-analysis, combined RAAS blockade therapy was associated with an absolute net increase in serum potassium of 0.13 mEq/l (95% CI, 0.09 to 0.18 mEq/l; P < 0.001; I2 = 36%). Similar results were observed using standardized net changes (Table 2). Combined RAAS blockade therapy was associated with a 3.4% higher rate of hyperkalemia (95% CI, 1.7 to 5.1%; P < 0.001; I2 = 29%) relative to monotherapy (Table 3).

Effect of combined renin–angiotensin–aldosterone system blockade therapy on blood pressure parameters.

Seventy-seven study arms reported on changes in SBP (5,582 patients), 76 study arms on changes in DBP (5,454 patients), and 17 study arms (489 patients) on changes in MAP. By meta- analysis, combined RAAS blockade therapy was associated with absolute net decreases in SBP, DBP, and MAP of 3.8mm Hg (95% CI, –4.6 to –2.9mm Hg; P < 0.001; I2 = 13%), 2.2mm Hg (95% CI, –3.1 to –1.3mm Hg; P < 0.001; I2 = 73%), and 1.7mm Hg (95% CI, –3.1 to –0.3mm Hg; P = 0.015; I2 = 0%), respectively. Similar results were observed with the use of standardized net changes (Table 2).

Nine study arms (1,858 patients) reported on the incidence of achieving a BP goal and 13 study arms (1,571 patients) reported on the requirement for additional antihypertensive medications. By meta-analysis, combination therapy produced a 5.0% higher rate of achievement of a BP goal (95% CI, 2.0 to 8.0%; P = 0.001; I2 = 0%) and a 4.4% lower rate of addition of other antihypertensive medications compared to a single-agent regimen (95% CI, –8.8 to –0.1%; P = 0.045; I2 = 28%).

Effect of combined renin–angiotensin–aldosterone system blockade therapy on other endpoints.

Twenty-four study arms reported on the incidence of hypotension (2,047 patients), 13 study arms on the incidence of any adverse effect as defined in the individual trials (2,518 patients), 5 study arms on the incidence of drug withdrawal (882 patients), 23 study arms on dropout rate (2,107 patients), 5 study arms on hospitalization (326 patients), and 8 study arms on all-cause mortality (2,410 patients). By meta-analysis, combined RAAS blockade therapy was not associated with any of these outcomes, with the exception of a 4.6% higher rate of hypotension (95% CI, 2.3 to 6.8%; P < 0.001, I2 = 33%) relative to single therapy (Table 3).

Investigations of heterogeneity.

Figures 3 and 4 show the results of subgroup analyses of standardized net changes in albuminuria, proteinuria, and GFR, and of summary differences in the rates of development of hyperkalemia and hypotension, stratified by study design, population type, baseline BP status, albuminuria/proteinuria level, GFR level, type of drug combination, duration of follow up, measurement methods, and study quality. As shown in Figure 3A, larger standardized net decreases in albuminuria were observed in studies of subjects with a low (< 60ml/min or ml/min/1.73 m2) GFR (P = 0.02). Similarly, as shown in Figure 3B, larger standardized net decreases in proteinuria were observed in studies of nondiabetic compared with diabetic subjects (P = 0.002) and mixed populations (P < 0.001), as well as in studies that enrolled patients with well-controlled hypertension (P = 0.03) and preserved (GFR ≥ 60ml/min or ml/min/1.73 m2) kidney function (P = 0.008).

Figure 3.

Subgroup analyses displaying the effect of combined renin–angiotensin–aldosterone system (RAAS) blockade therapy on standardized net change in albuminuria (A) and standardized net change in proteinuria (B). Where shown, P values refer to subgroup comparisons.

Figure 3.

Subgroup analyses displaying the effect of combined renin–angiotensin–aldosterone system (RAAS) blockade therapy on standardized net change in albuminuria (A) and standardized net change in proteinuria (B). Where shown, P values refer to subgroup comparisons.

Figure 4.

Subgroup analyses displaying the effect of combined renin–angiotensin–aldosterone system (RAAS) blockade therapy on standardized net change in GFR (A), and the summary rate difference in the development of hyperkalemia (B), and hypotension (C). Where shown, P values refer to subgroup comparisons.

Figure 4.

Subgroup analyses displaying the effect of combined renin–angiotensin–aldosterone system (RAAS) blockade therapy on standardized net change in GFR (A), and the summary rate difference in the development of hyperkalemia (B), and hypotension (C). Where shown, P values refer to subgroup comparisons.

As shown in Figure 4A, combined RAAS blockade therapy was associated with larger standardized net decreases in GFR in studies of diabetics as compared with studies of mixed populations (P = 0.01), as well as in studies of subjects with preserved (GFR ≥ 60ml/min or ml/min/1.73 m2) kidney function (P = 0.004), studies that measured rather than calculated GFR (P = 0.03), and studies of good quality (P = 0.0002). As shown in Figure 4B, the highest rates of hyperkalemia were observed in studies that combined an ACEI or ARB with an ARA, although this finding did not reach statistical significance, whereas combination therapy with an ACEI or ARB and a DRI was associated with a higher rate of hyperkalemia than was combination therapy with an ACEI and ARB (P = 0.04). Studies that excluded patients with a baseline serum potassium concentration of > 4.5 and > 5.0 mEq/l were associated with higher rates of hyperkalemia than were studies in which the serum potassium exclusion criterion was not defined (P = 0.02 and P = 0.04, respectively). Furthermore, as shown in Figure 4C, higher rates of hypotension were observed in studies of patients with a low GFR (P < 0.001), studies with a short duration of follow up (1–6 vs. 7–12 months, P = 0.02), and studies combining an ACEI and ARB as compared with studies that combined an ACEI or ARB and ARA (P = 0.009). Regrettably, only one study combining an ACEI or ARB and DRI reported on the development of hypotension, preventing comparison of this with the corresponding effect of other combination therapies.

Funnel plots for the key outcomes of the trials included in the meta-analysis were symmetric and the Egger test was not significant (P > 0.05), suggesting less susceptibility to publication bias (Tables 2 and 3), with the exception of the development of hyperkalemia and hypotension, in which the funnel plots were asymmetric.

DISCUSSION

The present meta-analysis demonstrates that combined RAAS blockade therapy is associated with a significant net improvement in urine albumin/protein excretion and in several BP parameters, including SBP, DBP, and MAP. Combined RAAS blockade therapy is also associated with higher rates of regression to normoalbuminuria and of achievement of BP goals. These beneficial effects were associated with a net decline in GFR, a net increase in serum potassium level, and a higher rate of hyperkalemia and hypotension. Combined RAAS blockade therapy was not associated with higher rates of doubling of serum creatinine, drug withdrawal, development of adverse effects (as defined in the individual studies), patient dropout, hospitalization, or mortality. The overall findings are consistent with results of ONTARGET.17

Chronic kidney disease is a public health problem and an independent risk factor for cardiovascular morbidity and mortality.83,84 A 10-year study of patients with stage 3 CKD demonstrated a cumulative incidence of kidney failure of only 4%, whereas the overall mortality rate rose to 51%.85 Hypertension and proteinuria are well-recognized risk factors for predicting the progression of CKD5 and cardiovascular morbidity and mortality.86,87 Several clinical practice guidelines recommend the use of RAAS blockade therapy for hypertension in patients with CKD, in light of the dual benefit of such therapy on BP and proteinuria.9,10,88,89 Previous meta-analyses of dual RAAS blockade with an ACEI and ARB demonstrated a significant decrease in proteinuria but no clinically meaningful changes in GFR or serum potassium.11–13 These systematic reviews included a smaller number of trials13–39 with total numbers of patients ranging from 425–2,042; these smaller reviews also suffered from potential contamination of the control group in that a variable percentage of study participants were receiving dual RAAS blockade therapy; furthermore, these reviews did not explore more comprehensive measures of efficacy and safety or subgroup analyses.

Our meta-analysis suggests that combined RAAS blockade therapy is associated with a decline in GFR, especially in diabetic patients, patients with preserved kidney function (GFR ≥ 60ml/min or ml/min/1.73 m2), and patients in whom GFR was measured rather than calculated or estimated. We hypothesize that stricter BP goals in studies of diabetic patients might have induced the upward titration of antihypertensive medications. In conjunction with the well-known autonomic sympathetic dysfunction observed in patients with diabetes, this relative lack of strictness increased the likelihood of hypotensive episodes, resulting in acute declines in GFR. By contrast, in studies of patients with impaired kidney function, the use of combined low-dose RAAS blockade therapy and a more cautionary upward titration of these agents might have prevented further declines in GFR. In addition, measured GFR, which is the “gold standard” among measurements of kidney function, is likely to represent a more sensitive marker of hemodynamic changes in response to antihypertensive therapy.

Our meta-analysis demonstrated a clear beneficial effect of combined RAAS blockade therapy in reducing albuminuria and proteinuria. Combined RAAS blockade therapy was also associated with a higher rate of regression to normoalbuminuria. These findings are consistent with the results of prior meta-analyses.11–13 In subgroup analyses, standardized net changes in proteinuria were more pronounced in patients without diabetes, those with well-controlled hypertension, and those with preserved kidney function. We can only speculate as to whether the presence of diabetes, poorly controlled hypertension, and a low GFR are associated with more advanced microvascular endothelial injury, thereby attenuating the benefit of combined RAAS blockade therapy. By contrast, combined RAAS blockade therapy produced a more robust benefit in standardized net changes in abuminuria in patients with a low GFR, a discrepancy that requires further study. Direct comparisons of subgroups within trials would help to address this and other inconsistencies identified in our meta-analysis.

In addition to an improvement in kidney-related endpoints with combined RAAS blockade therapy, we observed a significant improvement in all BP parameters with such therapy, as well as a higher rate of achievement of BP goals (as defined in individual trials) and a lower rate of addition of other antihypertensive medications.

Hypertension is a cause and consequence of CKD, and its treatment is largely inadequate in CKD, especially among patients with diabetes.86 Our subgroup analysis suggests that combined RAAS blockade therapy can help achieve BP goals even in patients with diabetes. Hypotension, however, might have been more clearly recognizable in studies of patients with overt proteinuria and studies with a short duration of follow up (i.e., less than 1 year), which in turn would have impeded the demonstration of a potential benefit of combined RAAS blockade therapy. Importantly, the net increase in serum potassium and higher rate of development of hyperkalemia in patients assigned to combined RAAS blockade therapy are other important safety concerns. This is particularly true for patients with an increased susceptibility to hyperkalemia (e.g., patients with a serum potassium concentration > 4.5 mEq/L or a GFR < 30ml/min, or both, and diabetic patients with hyporeninemic hypoaldosteronism).90

Our data synthesis has several strengths. To our knowledge, this is the largest systematic review of RCTs of patients with CKD to examine the effect of combined vs. single-agent RAAS blockade therapy on kidney-related endpoints, BP parameters, and other clinically important safety endpoints. The results were consistent across a broad range of analyses, including the use of absolute and standardized net changes in the continuous outcomes of interest, as well as the investigations of heterogeneity through the conduct of several informative subgroup analyses. However, several limitations in our analysis should also be noted. We were unable to assess the dosing schedules of combined RAAS blockade therapy, including dosing escalations and maximal dosing schemes, which probably contributed to the heterogeneity of the individual trial-effect estimates in our analysis. Additionally, our observations cannot be generalized to patients with advanced kidney disease (e.g., stage 4 CKD), in which the effect of combined RAAS blockade therapy on both GFR and the development of hyperkalemia remains unknown, as most of the studies in our analysis excluded such patients.

In conclusion, the present meta-analysis of 59 RCTs encompassing 4,975 participants demonstrates that the use of combined RAAS blockade therapy is more effective than monotherapy for RAAS blockade at reducing albuminuria and proteinuria, achieving a higher rate of regression to normoalbuminuria, decreasing BP, and achieving a higher rate of reaching BP goals. However these beneficial effects were compromised by a significant, albeit small, short-term decline in GFR that is of unclear clinical significance, and by higher rates of development of hypotension. The potential long-term benefit of combined RAAS blockade therapy on kidney function in patients with CKD requires further study. In the meantime, combined RAAS blockade therapy should be used judiciously in patients with proteinuric kidney disease, with close monitoring of their BP, kidney function, and serum potassium concentration.

AUTHORS’ CONTRIBUTIONS

Paweena Susantitaphong and Bertrand L. Jaber were responsible for the conception and design of this study, performed the analysis and interpretation of the study data, and wrote the draft of this paper; Paweena Susantitaphong, Ethan M. Balk, S. Eiam-Ong, Nicolas E. Madias, and Bertrand L. Jaber performed critical revision of the paper for important intellectual content; Paweena Susantitaphong, Kamal Sewaralthahab, Ethan M. Balk, Somchai Eiam-Ong, Nicolaos E. Madias, and Bertrand L. Jaber provided final approval of the paper; Bertrand L. Jaber and Ethan M. Balk provided statistical expertise; and Paweena Susantitaphong and Kamal Sewaralthahab collected and assembled the study data.

DISCLOSURE

The authors have no conflicts of interest to declare.

ACKNOWLEDGMENTS

This work was made possible in part through a fellowship to Dr. Susantitaphong funded by the International Society of Nephrology. This work was supported in part by grant UL1 RR025752 from the National Center for Research Resources (NCRR). The content of the work reported in this paper is solely the responsibility of the authors and does not necessarily represent the official views of the NCRR or the U.S. National Institutes of Health. The authors are grateful to Victor F. Seabra, MD, of the Federal University of Sao Paulo, Brazil, for technical assistance in generating the figures for the subgroup analyses.

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