Annals of Internal Medicine

Review

Systematic Review: Blood Pressure Target in Chronic Kidney Disease and Proteinuria as an Effect Modier
Ashish Upadhyay, MD; Amy Earley, BS; Shana M. Haynes, DHSc; and Katrin Uhlig, MD, MS

Background: The optimal blood pressure target in patients with chronic kidney disease (CKD) is unclear. Purpose: To summarize trials comparing lower versus higher blood pressure targets in adult patients with CKD and focus on proteinuria as an effect modifier. Data Sources: MEDLINE and the Cochrane Central Register of Controlled Trials (July 2001 through January 2011) were searched for reports from randomized, controlled trials with no language restriction. Study Selection: Authors screened abstracts to identify reports from trials comparing blood pressure targets in adults with CKD that had more than 50 participants per group; at least 1-year follow-up; and outcomes of death, kidney failure, cardiovascular events, change in kidney function, number of antihypertensive agents, and adverse events. Data Extraction: Reviewers extracted data on study design, methods, sample characteristics, interventions, comparators, outcomes, number of medications, and adverse events and rated study quality and quality of analyses for proteinuria subgroups. Data Synthesis: Three trials with a total of 2272 participants were included. Overall, trials did not show that a blood pressure target of

less than 125/75 to 130/80 mm Hg is more beneficial than a target of less than 140/90 mm Hg. Lower-quality evidence suggests that a low target may be beneficial in subgroups with proteinuria greater than 300 to 1000 mg/d. Participants in the low target groups needed more antihypertensive medications and had a slightly higher rate of adverse events. Limitations: No study included patients with diabetes. Trial duration may have been too short to detect differences in clinically important outcomes, such as death and kidney failure. Ascertainment and reporting of adverse events was not uniform. Conclusion: Available evidence is inconclusive but does not prove that a blood pressure target of less than 130/80 mm Hg improves clinical outcomes more than a target of less than 140/90 mm Hg in adults with CKD. Whether a lower target benefits patients with proteinuria greater than 300 to 1000 mg/d requires further study. Primary Funding Source: Kidney Disease: Improving Global Outcomes (KDIGO).

Ann Intern Med. 2011;154:541-548. www.annals.org For author affiliations, see end of text. This article was published at www.annals.org on 15 March 2011.

he optimal blood pressure target for patients with hypertension and chronic kidney disease (CKD) is unclear. Recent clinical practice guidelines have recommended a lower blood pressure goal of 130/80 mm Hg or less for patients with CKD compared with 140/90 mm Hg or less for those without CKD, because of a higher risk for cardiovascular disease and kidney failure in CKD (13). Because proteinuria amplies both cardiac and renal risks, some guidelines recommend an even lower target for patients with CKD and proteinuria (4 7). This systematic review summarizes trials in adults with CKD that compare the effects of treatment with a lower versus higher blood pressure target on clinically important outcomes and focuses particularly on proteinuria as an effect modier.

1 July 2001 to 4 January 2011 without language restriction. In addition, we identied articles from the systematic search conducted for the 2004 Kidney Disease Outcomes Quality Initiative clinical practice guideline on hypertension and antihypertensive agents in CKD (3), which included articles indexed in MEDLINE from 1966 to July 2002. Appendix Table 1 (available at www.annals.org) provides the search strategy.
Study Selection

All authors screened abstracts to identify randomized, controlled trials (RCTs) and observational follow-up reports of RCTs comparing blood pressure targets in adults with non dialysis-dependent CKD. Trials were eligible if they included participants with CKD (glomerular ltration rate [GFR] 60 mL/min per 1.73 m2, elevated urinary albumin level [30 mg/d, or urinary albumin creatinine

METHODS
We developed and followed a standard protocol for this review that built on the evidence review conducted for the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guideline for management of blood pressure in CKD.
Data Sources and Searches
See also: Web-Only Appendix Tables CME quiz Conversion of graphics into slides
2011 American College of Physicians 541

We searched MEDLINE and the Cochrane Central Register of Controlled Trials for articles indexed from
Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Review

Blood Pressure Target in CKD

ratio 0.03 g/g or dipstick-positive albuminuria], or elevated urinary protein level [300 mg/d, or urinary protein creatinine ratio 0.2 g/g]) (8). Studies had to report at least 1 of the following outcomes: death, kidney failure, clinical cardiovascular events, categorical change in kidney function, rate of change in GFR (GFR slope), and number of antihypertensive agents needed to achieve blood pressure targets. Adverse events of interest were patient withdrawal because of adverse events, decrease in drug dose or discontinuation of therapy, and symptoms related to hypotension. We excluded studies with fewer than 50 participants per group or follow-up shorter than 1 year.
Data Extraction and Quality Assessment

Figure. Summary of evidence search and selection.

MEDLINE and Cochrane search results for articles indexed since July 2001 (n = 6267) Excluded (n = 6139) Articles retrieved for full-text review (n = 130) Excluded (n = 62) Other relevant articles included in the evidence review for the 2004 KDOQI BP guideline (n = 18) Articles selected for the evidence review for the ongoing KDIGO guideline (n = 86) Excluded for not examining BP targets or were in a pediatric population (n = 78) Articles examining BP targets included in the systematic review (n = 8 [from 3 trials])

One of the authors extracted data from each article, and another author conrmed the data extraction. We extracted data on study design, methods, sample characteristics, interventions, comparators, outcomes, number of medications, and adverse events. We graded overall study quality as good, fair, or poor (9 11). Studies were graded by one of the authors, which was conrmed by another author and nalized in a meeting of all authors. Two authors perused the inclusion and exclusion criteria of the trials to assess applicability. We assessed the quality of the subgroup analyses by baseline proteinuria on the basis of recently proposed criteria for reporting and interpreting subgroup analyses (12, 13). Although we examined published articles and articles on study designs, we did not contact investigators for unpublished answers to our quality questions.
Data Synthesis and Statistical Analysis

BP blood pressure; KDIGO Kidney Disease: Improving Global Outcomes; KDOQI Kidney Disease Outcomes Quality Initiative.

Data were summarized in tables and synthesized in narrative form. Given the limited number of trials and the clinical heterogeneity for types of CKD, measures of proteinuria, and outcome denitions, we did not perform quantitative meta-analysis.
Role of the Funding Source

Trial Characteristics

The authors are supported by KDIGO to conduct systematic reviews and provide methods support for developing KDIGO guidelines, including the ongoing guideline on management of blood pressure in CKD. The ndings were presented to the KDIGO guideline Work Group, and the manuscript was condentially shared with the Work Group Chairs, who approved submission but did not provide feedback or comments on the manuscript. The funding source did not participate in the design, conduct, or reporting of the study.

RESULTS
Search Yield

The Figure summarizes the search yield. Eight reports from 3 RCTs with a total of 2272 patients were included in this review (14 21). No articles examined blood pressure targets exclusively in patients with CKD and diabetes.
542 19 April 2011 Annals of Internal Medicine Volume 154 Number 8

The 3 RCTs included in this review are the MDRD (Modication of Diet in Renal Disease) Study (14 16), the AASK (African American Study of Kidney Disease and Hypertension) Trial (17, 18), and the REIN-2 (Ramipril Efcacy in Nephropathy 2) trial (19). The MDRD Study and AASK Trial also have reports on posttrial observational follow-up (20, 21). All trials provide subgroup analyses by baseline proteinuria levels. Trial characteristics are summarized in Table 1. The MDRD Study A included 585 patients with GFRs of 25 to 55 mL/min per 1.73 m2 and Study B included 255 patients with GFRs of 13 to 24 mL/min per 1.73 m2. Patients with diabetes who required insulin were excluded from the study, and only 3% of patients were classied as having diabetic nephropathy. The trial phase had a 2 2 factorial design, and patients were randomly assigned to a low or usual blood pressure target and 1 of 2 types of diet. The use of all antihypertensive agents was allowed, but angiotensin-converting enzyme (ACE) inhibitors, with or without a diuretic, were encouraged as the rst-choice agents and calcium-channel blockers, with or without a diuretic, were encouraged as the second-choice
www.annals.org

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Blood Pressure Target in CKD

Review

Table 1. Characteristics, Methodological Quality, and Applicability of Studies Evaluating BP Targets in Patients With CKD
Characteristic Follow-up, y Cause of CKD Race Applicable CKD stage Inclusion criterion of kidney function (measured GFR or CrCl), mL/min per 1.73 m2 Baseline kidney function (measured GFR), mL/min per 1.73 m2 Applicable proteinuria category Proteinuria exclusion criteria MDRD Study (n 840) Trial: 4 (mean, 2.2) Posttrial: 7 (mean, 6.2) Nondiabetic CKD White: 85% 34 GFR, 1355 AASK Trial (n 1094) Trial: 4 (median, 3.8) Posttrial: 8.812.2 Hypertensive nephrosclerosis Black: 100% 3 GFR, 2065 REIN-2 Trial (n 338) 3 (median, 1.6) ND (excluded T1DM) ND (conducted in Europe) 34 CrCl 70 if proteinuria 3000 mg/d CrCl 45 if proteinuria 10003000 mg/d Low BP target: 36 Usual BP target: 34 10005000 mg/d UPE 1000 mg/d if CrCl 45 mL/min per 1.73 m2 UPE 3000 mg/d if CrCl is 4570 mL/min per 1.73 m2 Mean (SD) UPE: Low BP target: 2800 mg/d (2000) Usual BP target: 2900 mg/d (1900) Mean UPE, by subgroup: UPE 3000 mg/d: UPE, 1800 mg/d UPE 3000 mg/d: UPE, 4900 mg/d

Low BP target: 33 Usual BP target: 32 3001000 mg/d UPE 10 000 mg/d

Low BP target: 46 Usual BP target: 45 300 mg/d UPCR 2.5 g/g

Baseline proteinuria criteria

Median UPE: Low BP target: 390 mg/d Usual BP target: 310 mg/d

BP inclusion criteria, mm Hg Target BP, mm Hg

Achieved BP, mm Hg

Primary outcome

MAP 125 Low BP target: MAP 92 (125/75)* Usual BP target: MAP 107 (140/90)* Low BP target: MAP, 90 (126/77) Usual BP target: MAP, 94 (133/80) Rate of change in GFR

Median UPCR (IQR): Low BP target: 0.08 g/g (0.030.36 g/g) Usual BP target: 0.08 g/g (0.030.37 g/g) Median UPCR (IQR), by subgroup: UPCR 0.22 g/g Low BP target: 0.04 g/g (0.020.08 g/g) Usual BP target: 0.04 g/g (0.020.09 g/g) UPCR 0.22 g/g Low BP target: 0.58 g/g (0.351.08 g/g) Usual BP target: 0.73 g/g (0.421.37 g/g) DBP 95 Low BP target: MAP 92 Usual BP target: MAP 102107 Low BP target: 130/78 Usual BP target: 141/86 Rate of change in GFR and composite of 50% (or 25 mL/min per 1.73 m2) reduction in GFR, ESRD, or death Trial: Good Posttrial: Fair

ND Low BP target: 130/80 Usual BP target: DBP 90 Low BP target: 130/80 Usual BP target: 134/82 ESRD

Study quality

Trial: Good Posttrial: Fair

Good

AASK African American Study of Kidney Disease and Hypertension; BP blood pressure; CKD chronic kidney disease; CrCl creatinine clearance; DBP diastolic blood pressure; ESRD end-stage renal disease; GFR glomerular ltration rate; IQR interquartile range; MAP mean arterial pressure; MDRD Modication of Diet in Renal Disease; ND no data; REIN-2 Ramipril Efcacy in Nephropathy 2; T1DM type 1 diabetes mellitus; UPCR urinary protein creatinine ratio; UPE urinary protein excretion. * In participants aged 61 y, target MAP was 98 mm Hg and 113 mm Hg for the low and usual target groups, respectively.

agents. In the posttrial follow-up observation lasting a mean of 6 years, no specic blood pressure target or antihypertensive agent was recommended. The AASK Trial included black adults with hypertensive nephrosclerosis. Patients with diabetes were excluded from the study. The trial phase had a 3 2 factorial design, and patients were randomly assigned to a low or usual blood pressure target and therapy with 1 of 3 initial antihypertensive agents (ACE inhibitor, -blocker, or dihydropyridine calcium-channel blocker). The trial protocol allowed the sequential addition of furosemide, doxazosin, clonidine, hydralazine, and minoxidil to achieve the randomized blood pressure target. In the 8- to 12-year posttrial follow-up observation, all patients were assigned the blood pressure target of less than 130/80 mm Hg and were treated with either an ACE inhibitor or an angiotensin-receptor blocker. The REIN-2 trial included patients with proteinuria greater than 1000 mg/d for at least 3 months. Patients with
www.annals.org

proteinuria between 1000 and 3000 mg/d were included if their creatinine clearance was less than 45 mL/min per 1.73 m2, and patients with proteinuria greater than 3000 mg/d were included if their creatinine clearance was less than 70 mL/min per 1.73 m2. Patients with type 1 diabetes mellitus were excluded. All patients were treated with the ACE inhibitor ramipril, 5 mg/d, during the trial. The dihydropyridine calcium-channel blocker felodipine, 5 to 10 mg/d, was an add-on therapy in the group assigned to the low blood pressure target. Antihypertensive agents other than ACE inhibitors, angiotensin-IIreceptor blockers, and dihydropyridine calcium-channel blockers were allowed in both groups.
Quality Assessment

Methodological quality of the 3 trials was graded as good. Quality of the follow-up reports was graded as fair because the original trial interventions were not continued
19 April 2011 Annals of Internal Medicine Volume 154 Number 8 543

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Review

Blood Pressure Target in CKD

Table 2. Quality Assessment of Subgroup Analyses by Baseline Proteinuria Levels in Randomized, Controlled Trials of Blood
Pressure Targets in Patients With Chronic Kidney Disease
Assessment Question Trial Was subgroup analysis prespecified in study design? Were proteinuria categories prespecified in study design? Were a priori power calculations done for subgroups? Were baseline characteristics provided for subgroups? Were subgroup results adjusted for baseline variables? Was formal interaction testing for effect modification by baseline proteinuria done? Was the level of statistical significance adjusted for multiple testing? No* No No No Yes Yes No MDRD Study Observational Follow-up No No No No Yes Yes No Trial No* No No Yes Yes Yes No AASK Trial Observational Follow-up No No No Yes Yes Yes No Yes Yes No Yes Yes No No REIN-2 Trial

AASK African American Study of Kidney Disease and Hypertension; MDRD Modication of Diet in Renal Disease; REIN-2 Ramipril Efcacy in Nephropathy 2. * Interaction analyses by baseline proteinuria were specied before the outcome analyses. Proteinuria categories were chosen post hoc before the outcome analyses.

and, in the MDRD Study, the choice of agents and blood pressure targets were not dened. Table 2 shows the quality assessment of the subgroup analyses by baseline proteinuria levels. Published articles reporting results and study design were reviewed for quality assessment (1522).
Trial Results

marizes the results from the proteinuria subgroup and interaction analyses.
Clinical Outcomes

Table 3 summarizes the trial and follow-up results, and Appendix Table 2 (available at www.annals.org) sum-

The MDRD Study, AASK Trial, and REIN-2 trial failed to show benet for clinical outcomes from the low versus usual blood pressure targets. Although the point estimates in the MDRD Study and AASK Trial suggested that the low target might reduce kidney failure, the CIs

Table 3. Results of Efficacy Outcomes in Randomized, Controlled Trials of Blood Pressure Targets (Low Versus Usual) in Adults
With Chronic Kidney Disease
Outcome Trial 50% (or 25 mL/min per 1.73 m2) decrease in GFR, kidney failure, or death* Kidney failure or death MDRD Study Observational Follow-up Trial Risk reduction, 2% (95% CI, 22% to 21%); P 0.85 Risk reduction, 12% (CI, 13% to 32%); P 0.31 Risk reduction, 2% (CI, 31% to 20%); P 0.87 Risk reduction, 6% (CI, 29% to 31%); P 0.72 2 vs. 2; P ND HR, 0.98 (CI, 0.48 to 2.01); P 0.96 2% vs. 3%; P ND 0.26 (CI, 0.21 to 0.64); P 0.25 AASK Trial Observational Follow-up HR, 0.91 (CI, 0.77 to 1.08); P 0.27 HR, 0.85 (CI, 0.71 to 1.02); P 0.08 HR, 0.95 (CI, 0.78 to 1.15); P 0.59 REIN-2 Trial

50% decrease in GFR or kidney failure Kidney failure

Study A: RR, ND; P 0.05 Study B: RR, 0.85 (CI, 0.60 to 1.22); P 0.33 HR, 0.76 (CI, 0.52 to 1.10); P 0.15 2 vs. 1; P ND RR, 1.03 (CI, 0.59 to 1.79) Study A: 1.6 (CI, 0.8 to 3.9); P 0.18 Study B: 0.5 (CI, 0.4 to 1.4); P 0.28

HR, 0.77 (CI, 0.65 to 0.91); P 0.002 HR, 0.68 (CI, 0.57 to 0.82); P 0.001 10 vs. 6; P ND

23% vs. 20%; P 0.99 2 vs. 1; P ND 1% vs. 1%; P ND 0.22 vs. 0.24; P 0.62

Mortality, % Cardiovascular mortality CVD events Rate of annual GFR decline, mL/min per 1.73 m2

AASK African American Study of Kidney Disease and Hypertension; CVD cardiovascular disease; GFR glomerular ltration rate; HR hazard ratio; MDRD Modication of Diet in Renal Disease; ND no data; REIN-2 Ramipril Efcacy in Nephropathy 2; RR risk ratio; SCr serum creatinine. * Doubling of SCr concentration, kidney failure, or death for observational follow-up study. Adjusted analysis. Doubling of SCr concentration or kidney failure for observational follow-up study. Cardiovascular hospitalization. Less in the low target group.
544 19 April 2011 Annals of Internal Medicine Volume 154 Number 8 www.annals.org

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Blood Pressure Target in CKD

Review

around the estimates were wide and included the possibility of either important benet or harm. The only statistically signicant result was in the MDRD Study follow-up, which showed a 23% reduction (95% CI, 18% to 43%) in the hazard for kidney failure in the group assigned to the low target. Data on deaths and cardiovascular disease outcomes were not informative given the lack of ascertainment or low event rates.
Proteinuria Subgroups

ported, but the total number of drug classes used during the trial was 3.0 in the low target group and 2.4 in the usual target group.
Adverse Events

The cut points and measures for proteinuria assessment varied across studies. A total of 11 subgroup results were reported; 7 showed benets for the low blood pressure target in higher proteinuria subgroups (Appendix Table 2). Benet was seen in subgroups with a urinary protein creatinine ratio greater than 0.22 g/g in the AASK Trial (considered to correlate with urinary protein excretion 300 mg/d) and urinary protein excretion greater than 1000 mg/d in the MDRD Study. One subgroup analysis in the follow-up report from the AASK Trial showed that the usual blood pressure target was benecial in patients with a urinary protein creatinine ratio of 0.22 g/g or less for the composite outcome of a 50% decrease in GFR or kidney failure. Inconsistencies between interaction tests and subgroup analyses were found within and across studies (Appendix Table 2). In the MDRD Study, overall results for the rate of decrease in GFR were negative, but the low blood pressure target was benecial in high proteinuria subgroups (1000 mg/d in MDRD Study A and 3000 mg/d in MDRD Study B). The interaction tests by baseline proteinuria were also positive, suggesting benet of the low blood pressure target mainly in people with high proteinuria. In the follow-up report from the MDRD Study, however, the result for kidney failure was favorable for the low blood pressure target. Subgroup analysis showed that the low target was benecial in patients with proteinuria greater than 1000 mg/d, but the interaction test by baseline proteinuria was not statistically signicant, suggesting benet of the low target in all proteinuria levels. In the AASK Trial, the results for the primary composite clinical outcome were negative, whereas the subgroup analysis showed that the low blood pressure target was benecial in patients with urinary protein creatinine ratios greater than 0.22 g/g in both the trial and follow-up. For the other composite outcomes, however, subgroup analyses and corresponding interaction tests favored lower blood pressure targets in the high proteinuria group only during follow-up.
Number of Antihypertensive Agents

In the MDRD Study, participants were asked to report on 24 symptoms attributable to low blood pressure during each follow-up visit. Of the 24 symptoms, only the frequency of feeling faint differed signicantly between the low and usual blood pressure target groups in both studies (Study A and Study B). Feeling faint was reported in 15% of visits per patient in the low target group compared with 12% in the usual target group in Study A (P 0.0012) and 18% of visits per patient in the low target group compared with 12% in the usual target group in Study B (P 0.009). More patients in the low target group also needed a reduction in antihypertensive medications because of persistent symptoms of hypotension (3.2% vs. 0.7% in the usual target group; P 0.01). The incidence of conditions requiring patient withdrawal from the study, however, did not differ between the groups. In the AASK Trial, all participants were asked about shortness of breath, syncope, dizziness, and lightheadedness. In addition, the investigators also reported on the incidence of hyperkalemia, angioedema, edema, cough, and sexual dysfunction. Among all adverse events, only cough was more frequent in the low target group than in the usual target group (55% vs. 47%; P 0.05). This is not explained by the greater use of ACE inhibitors in the low target group, because the 3 2 factorial design ensured similar distribution of drug classes in the 2 groups. In the REIN-2 trial, 6 of 169 participants in the low target group and 3 of 169 participants in the usual target group had treatment-related adverse events that necessitated withdrawal from the trial. A total of 23% of participants in the low target group and 17% in the usual target group had serious adverse events, but specic events were not reported.

DISCUSSION
This systematic review of RCTs in adults with CKD did not nd conclusive evidence favoring a blood pressure target of less than 125/75 to 130/80 mm Hg rather than a target of less than 140/90 mm Hg. After a mean 2- to 4-year follow-up, the main trial results did not show benet for clinical outcomes (14 19). Only the posttrial follow-up report from the MDRD Study showed benet of the lower target for kidney failure after about a 6-year follow-up (21). Subgroup analyses by baseline proteinuria levels in the MDRD Study and AASK Trial, but not in the REIN-2 trial, suggest benet for the lower target in patients with proteinuria greater than 1000 mg/d and urinary protein creatinine ratio greater than 0.22 g/g, respectively (1521). Treatment to a lower target required, on average, 0.3 to 0.6 additional antihypertensive drugs per patient
19 April 2011 Annals of Internal Medicine Volume 154 Number 8 545

In the MDRD Study, the mean number of antihypertensive agents prescribed per patient for the low and usual blood pressure target groups was 1.9 and 1.5, respectively, in Study A and 2.1 and 1.8 in Study B. In the AASK Trial, the mean number of antihypertensive agents was not rewww.annals.org

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Review

Blood Pressure Target in CKD

(14, 17, 20). A slightly higher rate of adverse events was suggested in the low target groups (14, 17, 19). Clinical heterogeneity in study populations and interventions may have resulted in some of the inconsistencies across trials. Trials studied participants with different causes of CKD and used different antihypertensive regimens. Only the AASK Trial had, by design, a balanced use of an ACE inhibitor, a -blocker, and a calcium-channel blocker in each group. The benet for kidney failure in the MDRD Study follow-up may have been confounded by the greater use of ACE inhibitors in the low target group than in the usual target group (51% vs. 32%). The lack of any benet in the higher proteinuria subgroup of the REIN-2 trial was in the setting of all patients receiving an ACE inhibitor and the low target group also receiving the dihydropyridine calcium-channel blocker felodipine. Trial reports were graded as good quality, whereas the reports from posttrial follow-up and subgroup analyses were graded as fair quality. Condence in subgroup ndings is enhanced if the purpose and categories for analysis are prespecied in the study design (12, 13, 2325). The REIN-2 trial was the only study that had prespecied subgroup analysis by baseline proteinuria levels, but it did not report on interaction testing. Cut points and measurement techniques used for proteinuria subgroup analyses varied in all 3 studies. Results were inconsistent between interaction tests and subgroup analyses for the same or different outcomes, both within and across studies. Exploratory subgroup analyses, although important in generating hypothesis for future research, are often underpowered, susceptible to spurious results because of multiple testing, and vulnerable to reporting and publication biases (12, 13). A major limitation of the evidence base is that the 3 trials excluded people with type 1 diabetes mellitus and included very few patients with diabetic kidney disease. In addition, trial duration may have been too short to detect differences for clinically important outcomes, such as death and kidney failure. We captured delayed effects by including reports from the posttrial follow-up, but these were limited by the possibility of confounding from lack of randomization. We also cannot discount publication bias or selective reporting of some outcomes or subgroup analyses, because we did not contact investigators for unpublished data. Studies with small sample sizes and short follow-up were excluded, but they probably would not have changed our conclusions. Ascertainment and reporting of adverse events were also inconsistent across studies. To put our ndings in the context of the current literature, we conducted a separate MEDLINE search to identify reviews on this topic published between 1 January 2008 and 31 December 2010 (search terms are provided in Appendix Table 3, available at www.annals.org). We believe ours is the only review specically in patients with CKD and with a detailed analysis of effect modication by baseline proteinuria. The 2009 Cochrane review by Arguedas
546 19 April 2011 Annals of Internal Medicine Volume 154 Number 8

and colleagues (26) in patients with hypertension included the CKD trials and also found no benet for a target lower than 140/90 mm Hg to 160/100 mm Hg for mortality or morbidity. The reviews by Rosendorff and Black (27) and Roy and colleagues (28) highlight limited evidence for a low blood pressure target in patients with cardiovascular disease and raise concern about impaired coronary perfusion from aggressive lowering of diastolic blood pressure in patients with coronary artery disease or left ventricular hypertrophy. In addition to these reviews, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial provides important supplemental information (29). The ACCORD trial compared systolic blood pressure targets of less than 120 mm Hg and less than 140 mm Hg in more than 4000 patients with diabetes at high risk for cardiovascular outcomes. Most participants had normal kidney function, but approximately 40% had micro- or macroalbuminuria. The main results did not show any difference in the primary composite outcome of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death between the 2 groups, but GFR decreased below 30 mL/min per 1.73 m2 more often and more serious adverse events were attributed to antihypertensive treatment in the low target group. Finally, several recent commentaries and editorials have also highlighted the controversies surrounding the topic of blood pressure targets in CKD (30 35). Future research needs to address the evidence gap for patients with diabetes and CKD. A subgroup analysis of persons with elevated albuminuria in the ACCORD trial would be informative in this regard. For patients without diabetes, the ongoing SPRINT (Systolic Blood Pressure Intervention Trial) (36) and the HALT-CKD (HALT Progression of Polycystic Kidney Disease) study (37) could provide valuable data. SPRINT compares systolic blood pressure targets of less than 120 mm Hg and less than 140 mm Hg in 9000 patients with hypertension and without diabetes; it will be completed by 2018. It is enrolling participants with CKD, cardiovascular diseases, or risk factors for cardiovascular diseases. Similarly, the HALT-PKD study compares the efcacy of blood pressure targets of 95/60 to 110/75 mm Hg and 120/70 to 130/80 mm Hg in patients with autosomal dominant polycystic kidney disease; it will be completed by 2013. Although both SPRINT and the HALT-PKD study excluded participants with heavy proteinuria (urinary albumin creatinine ratio 0.6 g/g for SPRINT and 0.5 to 1.0 g/g for HALTPKD), subgroup analysis in the lower proteinuria range should be considered for these trials to better understand the effect modication by proteinuria. For ACCORD, SPRINT, HALT-PKD, and other future trials, the use of well-established albuminuria, proteinuria, and GFR categories will be helpful to harmonize and compare subgroup results across studies (38). In summary, evidence does not conclusively show that a currently recommended blood pressure target of less than
www.annals.org

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Blood Pressure Target in CKD

Review

130/80 mm Hg improves clinical outcomes more than a conventional target of less than 140/90 mm Hg in adults with CKD. A lower target may be benecial in persons with proteinuria greater than 300 to 1000 mg/d. We suggest that practitioners use discretion in patients with CKD and proteinuria and base the blood pressure target on individualized risk benet assessment and the patients tolerance and preferences. Treatment to a lower target may require greater vigilance to monitor for and avoid possible symptoms and adverse events from hypotension.
From the Tufts Center for Kidney Disease Guideline Development and Implementation, Tufts Medical Center, and Tufts University School of Medicine, Boston, Massachusetts.
Note: A draft of the KDIGO blood pressure guideline will be available

for public review in the next few months. If interested in participating in the review, please register at www.kidney.org/professionals/kdigo /guidelinesignup.cfm.
Disclaimer: The judgments and interpretations in this article are those of the authors and are not those of the KDIGO guideline Work Group. Acknowledgment: The authors thank Andrew Levey, MD, for valuable

suggestions and critical review of a prior version of the manuscript.

Financial Support: The authors are supported by KDIGO to conduct systematic reviews and provide methods support for developing KDIGO guidelines. Potential Conflicts of Interest: Drs. Upadhyay and Uhlig: Grant

(money to institution): KDIGO. Ms. Earley: Employment (money to institution): KDIGO. Dr. Haynes: Employment (money to institution): Tufts Medical Center. Disclosures can also be viewed at www.acponline.org /authors/icmje/ConictOfInterestForms.do?msNumM10-2790.
Requests for Single Reprints: Katrin Uhlig, MD, MS, Tufts Center for Kidney Disease Guideline Development and Implementation, William B. Schwartz Division of Nephrology, 800 Washington Street, #391, Boston, MA 02111; e-mail, kuhlig@tuftsmedicalcenter.org.

Current author addresses and author contributions are available at www .annals.org.

References
1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, et al; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA. 2003;289:2560-72. [PMID: 12748199] 2. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al; Management of Arterial Hypertension of the European Society of Hypertension. 2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2007;25:1105-87. [PMID: 17563527] 3. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43:S1-290. [PMID: 15114537] 4. The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. Arch Intern Med. 1997;157:
www.annals.org

2413-46. [PMID: 9385294] 5. Ogihara T, Kikuchi K, Matsuoka H, Fujita T, Higaki J, Horiuchi M, et al; Japanese Society of Hypertension Committee. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res. 2009;32:3-107. [PMID: 19300436] 6. Harris D, Thomas M, Johnson D, Nicholls K, Gillin A; Caring for Australasians with Renal Impairment (CARI). The CARI guidelines. Prevention of progression of kidney disease. Nephrology (Carlton). 2006;11 Suppl 1:S2-197. [PMID: 16684077] 7. The Renal Association. The UK CKD eGuide to Hypertension. 2010. Accessed at www.renal.org/whatwedo/InformationResources/CKDeGUIDE /Hypertension.aspx on 10 January 2011. 8. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classication, and stratication. Am J Kidney Dis. 2002;39:S1-266. [PMID: 11904577] 9. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009:S1-130. [PMID: 19644521] 10. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1-155. [PMID: 19845597] 11. Balk E, Raman G, Chung M, Ip S, Tatsioni A, Alonso A, et al. Effectiveness of management strategies for renal artery stenosis: a systematic review. Ann Intern Med. 2006;145:901-12. [PMID: 17062633] 12. Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey Smith G. Subgroup analyses in randomised controlled trials: quantifying the risks of false-positives and false-negatives. Health Technol Assess. 2001;5:1-56. [PMID: 11701102] 13. Wang R, Lagakos SW, Ware JH, Hunter DJ, Drazen JM. Statistics in medicinereporting of subgroup analyses in clinical trials. N Engl J Med. 2007; 357:2189-94. [PMID: 18032770] 14. Lazarus JM, Bourgoignie JJ, Buckalew VM, Greene T, Levey AS, Milas NC, et al. Achievement and safety of a low blood pressure goal in chronic renal disease. The Modication of Diet in Renal Disease Study Group. Hypertension. 1997;29:641-50. [PMID: 9040451] 15. Klahr S, Levey AS, Beck GJ, Caggiula AW, Hunsicker L, Kusek JW, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modication of Diet in Renal Disease Study Group. N Engl J Med. 1994;330:877-84. [PMID: 8114857] 16. Peterson JC, Adler S, Burkart JM, Greene T, Hebert LA, Hunsicker LG, et al. Blood pressure control, proteinuria, and the progression of renal disease. The Modication of Diet in Renal Disease Study. Ann Intern Med. 1995;123: 754-62. [PMID: 7574193] 17. Wright JT Jr, Bakris G, Greene T, Agodoa LY, Appel LJ, Charleston J, et al; African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:2421-31. [PMID: 12435255] 18. Norris K, Bourgoigne J, Gassman J, Hebert L, Middleton J, Phillips RA, et al; AASK Study Group. Cardiovascular outcomes in the African American Study of Kidney Disease and Hypertension (AASK) Trial. Am J Kidney Dis. 2006;48:739-51. [PMID: 17059993] 19. Ruggenenti P, Perna A, Loriga G, Ganeva M, Ene-Iordache B, Turturro M, et al; REIN-2 Study Group. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet. 2005;365:939-46. [PMID: 15766995] 20. Appel LJ, Wright JT Jr, Greene T, Agodoa LY, Astor BC, Bakris GL, et al; AASK Collaborative Research Group. Intensive blood-pressure control in hypertensive chronic kidney disease. N Engl J Med. 2010;363:918-29. [PMID: 20818902] 21. Sarnak MJ, Greene T, Wang X, Beck G, Kusek JW, Collins AJ, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modication of diet in renal disease study. Ann Intern Med. 2005;142:342-51. [PMID: 15738453] 22. Beck GJ, Berg RL, Coggins CH, Gassman JJ, Hunsicker LG, Schluchter MD, et al. Design and statistical issues of the Modication of Diet in Renal Disease Trial. The Modication of Diet in Renal Disease Study Group. Control Clin Trials. 1991;12:566-86. [PMID: 1664792] 23. Bria E, Di Maio M, Cuppone F, Nistico ` C, Cognetti F, Giannarelli D.
19 April 2011 Annals of Internal Medicine Volume 154 Number 8 547

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Review

Blood Pressure Target in CKD

J Nephrol. 2010;32:381-2. [PMID: 20814197] 32. Toto RB. Rebuttal: PRO Position. People with chronic kidney disease should have a blood pressure lower than 130/80 mm Hg. Am J Nephrol. 2010;32: 377-8. 33. Toto RB. Debate: PRO Position. People with chronic kidney disease should have a blood pressure lower than 130/80 mm Hg. Am J Nephrol. 2010;32: 370-3. 34. Agarwal R. Rebuttal: CON Position. People with chronic kidney disease should have a blood pressure lower than 130/80 mm Hg. Am J Nephrol. 2010; 32:379-80. 35. Agarwal R. Debate: CON Position. People with chronic kidney disease should have a blood pressure lower than 130/80 mm Hg. Am J Nephrol. 2010; 32:374-6. 36. ClinicalTrials.gov. SPRINT (Systolic Blood Pressure Intervention Trial). Clinical trial. Accessed at www.clinicaltrial.gov/ct2/show/NCT01206062?term SPRINT&rank2 on 25 January 2011. 37. ClinicalTrials.gov. HALT Progression of Polycystic Kidney Disease (HALT PKD). Clinical trial. Accessed at www.clinicaltrial.gov/ct2/show/NCT00283686 ?termHALT-PKD&rank1 on 25 January 2011. 38. Matsushita K, van der Velde M, Astor BC, Woodward M, Levey AS, de Jong PE, et al; Chronic Kidney Disease Prognosis Consortium. Association of estimated glomerular ltration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet. 2010;375:2073-81. [PMID: 20483451]

Should subgroup analysis of randomized clinical trials have a direct impact on clinical practice? [Letter]. J Clin Oncol. 2007;25:605-6. [PMID: 17290074] 24. Rothwell PM. Treating individuals 2. Subgroup analysis in randomised controlled trials: importance, indications, and interpretation. Lancet. 2005;365:17686. [PMID: 15639301] 25. Sleight P. Debate: Subgroup analyses in clinical trials: fun to look at but dont believe them!. Curr Control Trials Cardiovasc Med. 2000;1:25-27. [PMID: 11714402] 26. Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets for hypertension. Cochrane Database Syst Rev. 2009:CD004349. [PMID: 19588353] 27. Rosendorff C, Black HR. Evidence for a lower target blood pressure for people with heart disease. Curr Opin Cardiol. 2009;24:318-24. [PMID: 19395951] 28. Roy M, Mahmood N, Rosendorff C. Evidence for aggressive blood pressurelowering goals in patients with coronary artery disease. Curr Atheroscler Rep. 2010;12:134-9. [PMID: 20425249] 29. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, et al; ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-85. [PMID: 20228401] 30. Lewis JB. Blood pressure control in chronic kidney disease: is less really more? J Am Soc Nephrol. 2010;21:1086-92. [PMID: 20576804] 31. Luft FC. Editorial perspective. The low down on down low [Editorial]. Am

MANUSCRIPT PROCESSING

AND

TURNAROUND

Annals sends about half of submitted manuscripts for peer review and publishes about 10% of submitted material. The 2010 processing and notificaton turnaround time for manuscripts that were rejected without external peer review was within 1 week for more than 95% of submitted manuscripts. The processing and notification turnaround time for manuscripts that were received and rejected after external peer review was within 4 weeks for 50% and within 8 weeks for 98%.

548 19 April 2011 Annals of Internal Medicine Volume 154 Number 8

www.annals.org

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Annals of Internal Medicine

Current Author Addresses: Drs. Upadhyay, Haynes, and Uhlig and Ms.

Earley: Tufts Center for Kidney Disease Guideline Development and Implementation, William B. Schwartz Division of Nephrology, 800 Washington Street, #391, Boston, MA 02111.
Author Contributions: Conception and design: A. Upadhyay, A. Earley, S.M. Haynes, K. Uhlig. Analysis and interpretation of the data: A. Upadhyay, A. Earley, S.M. Haynes, K. Uhlig. Drafting of the article: A. Upadhyay, A. Earley, S.M. Haynes, K. Uhlig. Critical revision of the article for important intellectual content: A. Upadhyay, A. Earley, S.M. Haynes, K. Uhlig. Final approval of the article: A. Upadhyay, A. Earley, S.M. Haynes, K. Uhlig. Obtaining of funding: K. Uhlig. Administrative, technical, or logistic support: A. Upadhyay, A. Earley, S.M. Haynes, K. Uhlig. Collection and assembly of data: A. Upadhyay, A. Earley, S.M. Haynes, K. Uhlig.

www.annals.org

19 April 2011 Annals of Internal Medicine Volume 154 Number 8 W-191

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Appendix Table 1. Search Strategy for Randomized, Controlled Trials of Blood Pressure Targets
1. 2. 3. 4. 5. 6. 7. exp kidney diseases/ exp kidney glomerulus/ exp kidney function tests/ kidney transplantation.mp. or exp Kidney Transplantation/ ((kidney or renal) adj (transplant$ or recipient$)).tw. or/1-5 *bone transplantation/ or *heart transplantation/ or *liver transplantation/ or *lung transplantation/ or *pancreas transplantation/ 8. 6 not 7. 9. (Proteinuria$ or albuminuria$).tw. or exp proteinuria/ or exp albuminuria/ 10. 8 and 9. 11. exp hypertension/ 12. exp hypertension, renal/ 13. hypertens$.af. 14. high blood pressure.af. 15. (eleva$ adj6 blood pressure).tw. 16. or/11-15 17. 8 and 16 18. exp Angiotensin-Converting Enzyme Inhibitors/ 19. Capoten.tw. or 62571-86-2.rn. 20. benazepril.tw. or 86541-75-5.rn. 21. Lotensin.tw. 22. Vasotec.tw. or 84680-54-6.rn. 23. (Prinivil or Zestril).tw. or 83915-83-7.rn. 24. Monopril.tw. or 98048-97-6.rn. 25. Altace.tw. or 87333-19-5.rn. 26. perindopril.tw. or perindopril.af. or 82834-16-0.rn. 27. (quinapril or Accupril).tw. or 82586-55-8.rn. 28. (moexipril or Univasc).tw. or 103775-10-6.rn. 29. (trandolapril or Mavik).tw. or 87679-37-6.rn. 30. moexipril.af. 31. or/18-30 32. exp Receptors, Angiotensin/ 33. (candesartan cilexetil or Atacand).tw. or 139481-59-7.rn. 34. (eprosartan or Teveten).tw. or 133040-01-4.rn. 35. (irbesartan or Avapro).tw. or 138402-11-6.rn. 36. exp Losartan/ or losartan.tw. or Cozaar.tw. or 114798-26-4.rn. 37. (olmesartan medoxomil or Benicar).tw. or 144689-24-7.rn. 38. (telmisartan or Micardis).tw. or 144701-48-4.rn. 39. (valsartan or Diovan).tw. or 137862-53-4.rn. 40. or/32-39 41. (beta-blocker or Acebutalol).tw. or 37517-30-9.rn. 42. Atenolol.tw. or 29122-68-7.rn. 43. Betaxolol.tw. or 63659-18-7.rn. 44. esmolol.tw. or 84057-94-3.rn. 45. nebivolol.tw. or 99200-09-6.rn. 46. metoprolol.tw. or 37350-58-6.rn. 47. Carteolol.tw. or 51781-06-7.rn. 48. penbutolol.tw. or 36507-48-9.rn. 49. pindolol.tw. or 13523-86-9.rn. 50. carvedilol.tw. or 72956-09-3.rn. 51. labetalol.tw. or 36894-69-6.rn. 52. levobunolol.tw. or 47141-42-4.rn. 53. metipranolol.tw. or 22664-55-7.rn. 54. nadolol.tw. or 42200-33-9.rn. 55. propranolol.tw. or 525-66-6.rn. 56. sotalol.tw. or 3930-20-9.rn. 57. timolol.tw. or 26839-75-8.rn. 58. bisoprolol.tw. or 66722-44-9.rn. 59. oxprenolol.tw. or 6452-71-7.rn. 60. or/41-59 61. diuretics.tw. 62. furosemide.tw. or 54-31-9.rn. 63. bumetanide.tw. or 28395-03-1.rn. 64. torsemide.tw. or 56211-40-6.rn. 65. ethacrynic acid.tw. or 58-54-8.rn. 66. hydrochlorothiazide.tw. or 58-93-5.rn. 67. chlorthalidone.tw. or 77-36-1.rn.

Appendix Table 1Continued

68. indapamide.tw. or 26807-65-8.rn. 69. metolazone.tw. or 17560-51-9.rn. 70. amiloride.tw. or 2609-46-3.rn. 71. spironolactone.tw. or 52-01-7.rn. 72. (eplerenone or acetazolamide).tw. or 59-66-5.rn. 73. or/61-72 74. exp Calcium Channel Blockers/ 75. amlodipine.tw. or 88150-42-9.rn. 76. bencyclane.tw. or 2179-37-5.rn. 77. bepridil.tw. or 64706-54-3.rn. 78. diltiazem.tw. or 42399-41-7.rn. 79. felodipine.tw. or 72509-76-3.rn. 80. flunarizine.tw. or 52468-60-7.rn. 81. gallopamil.tw. or 16662-47-8.rn. 82. isradipine.tw. or 75695-93-1.rn. 83. lidoflazine.tw. or 3416-26-0.rn. 84. mibefradil.tw. or 116644-53-2.rn. 85. nicardipine.tw. or 55985-32-5.rn. 86. nifedipine.tw. or 21829-25-4.rn. 87. nimodipine.tw. or 66085-59-4.rn. 88. nisoldipine.tw. or 63675-72-9.rn. 89. nitrendipine.tw. or 39562-70-4.rn. 90. perhexiline.tw. or 6621-47-2.rn. 91. prenylamine.tw. or 390-64-7.rn. 92. verapamil.tw. or 52-53-9.rn. 93. or/74-92 94. 31 or 40 or 60 or 73 or 93 95. 8 and 94 96. 10 and 94 97. 17 or 95 or 96 98. randomized controlled trial.pt. 99. controlled clinical trial.pt. 100. randomized controlled trials/ 101. Random Allocation/ 102. Double-blind Method/ 103. Single-blind Method/ 104. clinical trial.pt. 105. Clinical Trials.mp. or exp Clinical Trials/ 106. (clinic$ adj25 trial$).tw. 107. ((singl$ or doubl$ or trebl$ or tripl$) adj (mask$ or blind$)).tw. 108. Placebos/ 109. placebo$.tw. 110. random$.tw. 111. trial$.tw. 112. (randomized control trial or clinical control trial).sd 113. (latin adj square).tw. 114. Comparative Study.tw. or Comparative Study.pt. 115. exp Evaluation studies/ 116. Follow-Up Studies/ 117. Prospective Studies/ 118. (control$ or prospectiv$ or volunteer$).tw. 119. Cross-Over Studies/ 120. or/98-119 121. 97 and 120 122. Animals/ not humans/ 123. 121 not 122 124. (guidelines or meta analysis or practice guideline or review or review).mp. [mpti, ot, ab, sh, hw, kw, nm] 125. 123 not 124 126. limit 125 to yr2002-2009 127. remove duplicates from 126

W-192 19 April 2011 Annals of Internal Medicine Volume 154 Number 8

www.annals.org

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

Appendix Table 2. Results of Interaction Tests and Subgroup Analyses by Baseline Proteinuria in Trials of Blood Pressure Targets (Low Versus Usual) in Patients With Chronic

www.annals.org
MDRD Study Trial Overall UPCR 0.22 g/g UPCR 0.22 g/g NS NS Favors low target (HR, 0.74 [95% CI, 0.560.99]; P 0.04) NS NS Favors low target (HR, 0.73 [CI, 0.580.93]; P 0.01) Observational Follow-up Proteinuria Category Trial Observational Follow-up Proteinuria Category AASK Study REIN-2 Trial Trial Interaction test NS Favors low target NS NS Overall UPCR 0.22 g/g UPCR 0.22 g/g NS NS NS Favors low target with increased proteinuria (P 0.02) NS NS Favors low target (HR, 0.67 [CI, 0.520.87]; P 0.002) Favors low target (HR, 0.61 [CI, 0.450.85]) Favors low target (HR, 0.62 [CI, 0.401.0]) NS (P 0.08) Interaction test Overall UPCR 0.22 g/g UPCR 0.22 g/g NS Interaction test NS NS NS Favors low target with increased proteinuria (P 0.02) NS Favors usual target (HR, 1.39 [CI, 1.041.87]; P 0.03) Favors low target (HR, 0.76 [CI, 0.580.99]; P 0.04) Favors low target with increased proteinuria (P 0.007) Overall NS NS NS Favors low target NS NS Favors low target (HR, 0.55 [CI, 0.400.80]) Favors low target (HR, 0.53 [CI, 0.350.83]) NS (P 0.09) Overall NS UPE, 10003000 mg/d UPE 3000 mg/d NS NS NS Study A: favors low target Study B: NS Interaction test Overall NS NS NS Interaction test Favors lower target with increased proteinuria (P 0.004) Favors low target Favors low target (P 0.02 in Study A and 0.01 in Study B) UPE, 10003000 mg/d UPE 3000 mg/d Interaction test

Kidney Disease

Outcome

Proteinuria Category

50% (or 25 mL/min per 1.73 m2) decrease in GFR, kidney failure, or death*

Kidney failure or death

Overall UPE 300 mg/d UPE, 3001000 mg/d

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013

UPE, 10003000 mg/d

UPE 3000 mg/d

Interaction test

50% decrease in GFR or kidney failure

Kidney failure

Overall UPE 300 mg/d UPE, 3001000 mg/d UPE, 10003000 mg/d

UPE 3000 mg/d

Rate of GFR decline

Interaction test Overall UPE 250 mg/d UPE, 2501000 mg/d UPE, 10003000 mg/d

UPE 3000 mg/d Interaction test

19 April 2011 Annals of Internal Medicine Volume 154 Number 8 W-193

AASK African American Study of Kidney Disease and Hypertension; CVD cardiovascular disease; GFR glomerular ltration rate; HR hazard ratio; MDRD Modication of Diet in Renal Disease; NS not signicant; REIN-2 Ramipril Efcacy in Nephropathy 2; SCr serum creatinine; UPCR urinary protein creatinine ratio; UPE urinary protein excretion. * Doubling of SCr, kidney failure, or death for observational follow-up study. Estimate from a gure. P no data. Doubling of SCr or kidney failure for observational follow-up study. Annual GFR decrease of 4.0 vs. 5.0 mL/min per 1.73 m2. Estimate from a gure. P no data. Annual GFR decrease of 8.5 vs. 13 mL/min per 1.73 m2 in Study A and 5 vs. 7.5 mL/min per 1.73 m2 in Study B. Estimates from a gure. P no data.

Appendix Table 3. Search Strategy for Recent Reviews of

Blood Pressure Targets in Proteinuria
1. exp Kidney Glomerulus/ 2. exp Kidney disease/ 3. exp Kidney Function Tests/ 4. exp Renal Replacement Therapy/ 5. exp Kidney Transplantation/ 6. exp kidney, artificial/ 7. exp ultrafiltration/ 8. exp sorption, detoxification/ 9. renal.af. or renal.tw. 10. nephro$.af. or nephro$.tw. 11. kidney.af. or kidney.tw. 12. ur?emia.af. or ur?emia.tw. 13. h?emodialysis.af. or h?emodialysis.tw. 14. (hemofiltr$ or haemofiltr$).af. or (hemofiltr$ or haemofiltr$).tw. 15. or/1-14 16. Animals/ not humans.mp. [mpti, ot, ab, nm, hw, ui, tx, kw, ct, sh] 17. 15 not 16 18. exp blood pressure/ 19. 17 and 18 20. limit 19 to (meta analysis or review or review literature or review, academic) 21. limit 20 to yr2008-2010

W-194 19 April 2011 Annals of Internal Medicine Volume 154 Number 8

www.annals.org

Downloaded From: http://annals.org/ by Rizka Mulya on 02/22/2013