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Systematic Review: Blood Pressure Target in Chronic Kidney Diseaseand Proteinuria as an Effect ModierAshish 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 bloodpressure targets in adult patients with CKD and focus on protein-uria as an effect modifier.

Data Sources: MEDLINE and the Cochrane Central Register ofControlled Trials (July 2001 through January 2011) were searchedfor reports from randomized, controlled trials with no languagerestriction.

Study Selection: Authors screened abstracts to identify reportsfrom trials comparing blood pressure targets in adults with CKDthat 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 antihypertensiveagents, and adverse events.

Data Extraction: Reviewers extracted data on study design, meth-ods, sample characteristics, interventions, comparators, outcomes,number of medications, and adverse events and rated study qualityand quality of analyses for proteinuria subgroups.

Data Synthesis: Three trials with a total of 2272 participants wereincluded. 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 thata low target may be beneficial in subgroups with proteinuriagreater than 300 to 1000 mg/d. Participants in the low targetgroups needed more antihypertensive medications and had aslightly higher rate of adverse events.

Limitations: No study included patients with diabetes. Trial dura-tion may have been too short to detect differences in clinicallyimportant outcomes, such as death and kidney failure. Ascertain-ment and reporting of adverse events was not uniform.

Conclusion: Available evidence is inconclusive but does not provethat a blood pressure target of less than 130/80 mm Hg improvesclinical outcomes more than a target of less than 140/90 mm Hg inadults with CKD. Whether a lower target benefits patients withproteinuria greater than 300 to 1000 mg/d requires further study.

Primary Funding Source: Kidney Disease: Improving Global Out-comes (KDIGO).

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

The optimal blood pressure target for patients with

hypertension and chronic kidney disease (CKD) is un-clear. Recent clinical practice guidelines have recom-mended a lower blood pressure goal of 130/80 mm Hg orless for patients with CKD compared with 140/90 mm Hg or less for those without CKD, because of a higher risk forcardiovascular disease and kidney failure in CKD (13).Because proteinuria amplies both cardiac and renal risks,some guidelines recommend an even lower target for pa-tients with CKD and proteinuria (47).

This systematic review summarizes trials in adults withCKD that compare the effects of treatment with a lowerversus higher blood pressure target on clinically important

outcomes and focuses particularly on proteinuria as an ef-fect modier.

METHODS We developed and followed a standard protocol for

this review that built on the evidence review conductedfor the Kidney Disease: Improving Global Outcomes(KDIGO) clinical practice guideline for management of blood pressure in CKD.Data Sources and Searches

We searched MEDLINE and the Cochrane CentralRegister of Controlled Trials for articles indexed from

1 July 2001 to 4 January 2011 without language restric-

tion. In addition, we identied articles from the systematicsearch conducted for the 2004 Kidney Disease OutcomesQuality Initiative clinical practice guideline on hyperten-sion and antihypertensive agents in CKD (3), which in-cluded 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 re-ports of RCTs comparing blood pressure targets in adults with nondialysis-dependent CKD. Trials were eligible if

they included participants with CKD (glomerular ltrationrate [GFR] 60 mL/min per 1.73 m2 , elevated urinary albumin level [ 30 mg/d, or urinary albumincreatinine

See also:

Web-OnlyAppendix TablesCME quizConversion of graphics into slides

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ratio 0.03 g/g or dipstick-positive albuminuria], or ele-vated urinary protein level [ 300 mg/d, or urinary pro-teincreatinine ratio 0.2 g/g]) (8). Studies had to reportat 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 pressuretargets. Adverse events of interest were patient withdrawalbecause of adverse events, decrease in drug dose or discon-tinuation of therapy, and symptoms related to hypoten-sion. We excluded studies with fewer than 50 participantsper group or follow-up shorter than 1 year.

Data Extraction and Quality Assessment One of the authors extracted data from each article,

and another author conrmed the data extraction. We ex-tracted data on study design, methods, sample characteris-tics, interventions, comparators, outcomes, number of medications, and adverse events.

We graded overall study quality as good, fair, or poor(911). Studies were graded by one of the authors, which was conrmed by another author and nalized in a meet-ing of all authors. Two authors perused the inclusion andexclusion criteria of the trials to assess applicability.

We assessed the quality of the subgroup analyses by baseline proteinuria on the basis of recently proposed cri-teria for reporting and interpreting subgroup analyses (12,13). Although we examined published articles and articleson study designs, we did not contact investigators for un-published answers to our quality questions.

Data Synthesis and Statistical AnalysisData were summarized in tables and synthesized in

narrative form. Given the limited number of trials and theclinical heterogeneity for types of CKD, measures of pro-teinuria, and outcome denitions, we did not performquantitative meta-analysis.

Role of the Funding SourceThe authors are supported by KDIGO to conduct sys-

tematic reviews and provide methods support for develop-ing KDIGO guidelines, including the ongoing guidelineon management of blood pressure in CKD. The ndings were presented to the KDIGO guideline Work Group, andthe manuscript was condentially shared with the Work Group Chairs, who approved submission but did not pro-vide feedback or comments on the manuscript. The fund-ing source did not participate in the design, conduct, orreporting of the study.

RESULTSSearch Yield

The Figure summarizes the search yield. Eight reportsfrom 3 RCTs with a total of 2272 patients were includedin this review (1421). No articles examined blood pres-sure targets exclusively in patients with CKD and diabetes.

Trial CharacteristicsThe 3 RCTs included in this review are the MDRD

(Modication of Diet in Renal Disease) Study (1416),the AASK (African American Study of Kidney Disease andHypertension) Trial (17, 18), and the REIN-2 (RamiprilEfcacy in Nephropathy 2) trial (19). The MDRD Study and AASK Trial also have reports on posttrial observationalfollow-up (20, 21). All trials provide subgroup analyses by baseline proteinuria levels. Trial characteristics are summa-rized in Table 1.

The MDRD Study A included 585 patients withGFRs of 25 to 55 mL/min per 1.73 m2 and Study Bincluded 255 patients with GFRs of 13 to 24 mL/min per1.73 m2 . Patients with diabetes who required insulin wereexcluded from the study, and only 3% of patients wereclassied as having diabetic nephropathy. The trial phasehad a 2 2 factorial design, and patients were randomly assigned to a low or usual blood pressure target and 1 of 2types of diet. The use of all antihypertensive agents wasallowed, but angiotensin-converting enzyme (ACE) inhib-itors, with or without a diuretic, were encouraged as therst-choice agents and calcium-channel blockers, with or without a diuretic, were encouraged as the second-choice

Figure. Summary of evidence search and selection.

MEDLINE and Cochrane search results for articles indexed since July 2001

(n = 6267)

Articles selected for the evidence reviewfor the ongoing KDIGO guideline

(n

= 86)

Articles retrieved for full-text review(n = 130)

Excluded(n = 6139)

Excluded(n = 62)

Articles examining BP targetsincluded in the systematic review

(n = 8 [from 3 trials])

Excluded for not examining BP targets

or were in apediatric population

(n = 78)

Other relevant articlesincluded in the evidence

review for the 2004KDOQI BP guideline

(n = 18)

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

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agents. In the posttrial follow-up observation lasting a mean of 6 years, no specic blood pressure target or anti-hypertensive agent was recommended.

The AASK Trial included black adults with hyperten-sive nephrosclerosis. Patients with diabetes were excluded

from the study. The trial phase had a 3

2 factorialdesign, and patients were randomly assigned to a low orusual blood pressure target and therapy with 1 of 3 initialantihypertensive agents (ACE inhibitor, -blocker, or di-hydropyridine calcium-channel blocker). The trial protocolallowed the sequential addition of furosemide, doxazosin, clo-nidine, hydralazine, and minoxidil to achieve the randomizedblood pressure target. In the 8- to 12-year posttrial follow-upobservation, all patients were assigned the blood pressure tar-get of less than 130/80 mm Hg and were treated with eitheran 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

proteinuria between 1000 and 3000 mg/d were included if their creatinine clearance was less than 45 mL/min per1.73 m2 , and patients with proteinuria greater than 3000mg/d were included if their creatinine clearance was lessthan 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 di-hydropyridine calcium-channel blocker felodipine, 5 to 10mg/d, was an add-on therapy in the group assigned to thelow blood pressure target. Antihypertensive agents otherthan ACE inhibitors, angiotensin-IIreceptor blockers, anddihydropyridine calcium-channel blockers were allowed inboth groups.

Quality Assessment Methodological quality of the 3 trials was graded as

good. Quality of the follow-up reports was graded as fairbecause the original trial interventions were not continued

Table 1. Characteristics, Methodological Quality, and Applicability of Studies Evaluating BP Targets in Patients With CKD

Characteristic MDRD Study ( n 840) AASK Trial (n 1094) REIN-2 Trial ( n 338)

Follow-up, y Trial: 4 (mean, 2.2) Trial: 4 (median, 3.8) 3 (median, 1.6)Posttrial: 7 (mean, 6.2) Posttrial: 8.812.2

Cause of CKD Nondiabetic CKD Hypertensive nephrosclerosis ND (excluded T1DM)Race White: 85% Black: 100% ND (conducted in Europe)Applicable CKD stage 34 3 34Inclusion criterion of kidney function

(measured GFR or CrCl), mL/min per 1.73 m 2

GFR, 1355 GFR, 2065 CrCl 70 if proteinuria 3000 mg/dCrCl 45 if proteinuria 10003000 mg/d

Baseline kidney function (measuredGFR), mL/min per 1.73 m 2

Low BP target: 33 Low BP target: 46 Low BP target: 36Usual BP target: 32 Usual BP target: 45 Usual BP target: 34

Applicable proteinuria category 3001000 mg/d 300 mg/d 10005000 mg/dProteinuria exclusion criteria UPE 10 000 mg/d UPCR 2.5 g/g UPE 1000 mg/d if CrCl 45 mL/min

per 1.73 m 2

UPE 3000 mg/d if CrCl is 4570mL/min per 1.73 m 2

Baseline proteinuria criteria Median UPE: Median UPCR (IQR): Mean (SD) UPE:Low BP target: 390 mg/d Low BP target: 0.08 g/g (0.030.36 g/g) Low BP target: 2800 mg/d (2000)Usual BP target: 310 mg/d Usual BP target: 0.08 g/g (0.030.37 g/g) Usual BP target: 2900 mg/d (1900)

Median UPCR (IQR), by subgroup: Mean UPE, by subgroup:UPCR 0.22 g/g UPE 3000 mg/d: UPE, 1800 mg/d

Low BP target: 0.04 g/g (0.020.08 g/g) UPE 3000 mg/d: UPE, 4900 mg/dUsual 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)

BP inclusion criteria, mm Hg MAP 125 DBP 95 NDTarget BP, mm Hg Low BP target: MAP 92

( 125/75)*Low BP target: MAP 92 Low BP target: 130/80

Usual BP target: MAP 107( 140/90)*

Usual BP target: MAP 102107 Usual BP target: DBP 90

Achieved BP, mm Hg Low BP target: MAP, 90(126/77)

Low BP target: 130/78 Low BP target: 130/80

Usual BP target: MAP, 94(133/80)

Usual BP target: 141/86 Usual BP target: 134/82

Primary outcome Rate of change in GFR Rate of change in GFR and composite of50% (or 25 mL/min per 1.73 m 2 )

reduction in GFR, ESRD, or death

ESRD

Study quality Trial: Good Trial: Good GoodPosttrial: Fair Posttrial: Fair

AASK African American Study of Kidney Disease and Hypertension; BPblood pressure; CKD chronic kidney disease; CrCl creatinine clearance; DBP diastolicblood 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 proteincreatinine 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.

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and, in the MDRD Study, the choice of agents and blood

pressure targets were not dened.Table 2 shows the quality assessment of the subgroupanalyses by baseline proteinuria levels. Published articlesreporting results and study design were reviewed for quality assessment (1522).Trial Results

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

marizes the results from the proteinuria subgroup and in-

teraction analyses.

Clinical Outcomes 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 es-timates in the MDRD Study and AASK Trial suggestedthat the low target might reduce kidney failure, the CIs

Table 2. Quality Assessment of Subgroup Analyses by Baseline Proteinuria Levels in Randomized, Controlled Trials of BloodPressure Targets in Patients With Chronic Kidney Disease

Assessment Question MDRD Study AASK Trial REIN-2 Trial

Trial ObservationalFollow-up


Was subgroup analysis prespecified in study design? No* No No* No YesWere proteinuria categories prespecified in study design? No No No No YesWere a priori power calculations done for subgroups? No No No No NoWere baseline characteristics provided for subgroups? No No Yes Yes YesWere subgroup results adjusted for baseline variables? Yes Yes Yes Yes YesWas formal interaction testing for effect modification by baseline proteinuria done? Yes Yes Yes Yes NoWas the level of statistical significance adjusted for multiple testing? No No No No No

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.

Table 3. Results of Efficacy Outcomes in Randomized, Controlled Trials of Blood Pressure Targets (Low Versus Usual) in AdultsWith Chronic Kidney Disease

Outcome MDRD Study AASK Trial REIN-2 Trial



50% (or 25 mL/min per 1.73 m 2 ) decrease in GFR,kidney failure, or death*

Risk reduction, 2% (95% CI,22% to 21%); P 0.85

HR, 0.91 (CI, 0.77 to1.08); P 0.27

Kidney fai lure or death Study A: RR, ND; P 0.05 HR, 0.77 (CI, 0.65to 0.91);P 0.002

Risk reduction, 12% (CI,13% to 32%); P 0.31

HR, 0.85 (CI, 0.71 to1.02); P 0.08

Study B: RR, 0.85 (CI, 0.60

to 1.22); P 0.3350% decrease in GFR or kidney

failure Risk reduction, 2% (CI,

31% to 20%); P 0.87HR, 0.95 (CI, 0.78 to

1.15); P 0.59

Kidney failure HR, 0.76 (CI, 0.52 to 1.10);P 0.15

HR, 0.68 (CI, 0.57to 0.82);P 0.001

Risk reduction, 6% (CI,29% to 31%); P 0.72

23% vs. 20%;P 0.99

Mortality, % 2 vs. 1; P ND 10 vs. 6; P ND 2 vs. 2; P ND 2 vs. 1;P ND

Cardiovascular mortality HR, 0.98 (CI, 0.48 to 2.01);P 0.96

1% vs. 1%;P ND

CVD events RR, 1.03 (CI, 0.59 to 1.79) 2% vs. 3%; P ND Rate of annual GFR decline,

mL/min per 1.73 m 2Study A: 1.6 (CI, 0.8 to

3.9); P 0.18 0.26 (CI, 0.21 to 0.64);

P 0.25 0.22 vs. 0.24;

P 0.62Study B: 0.5 (CI, 0.4 to

1.4); P 0.28

AASK African American Study of Kidney Disease and Hypertension; CVD cardiovascular disease; GFR glomerular ltration rate; HR hazard ratio; MDRDModication 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.




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around the estimates were wide and included the possibil-ity of either important benet or harm. The only statisti-cally signicant result was in the MDRD Study follow-up, which showed a 23% reduction (95% CI, 18% to 43%) inthe hazard for kidney failure in the group assigned to thelow target. Data on deaths and cardiovascular disease out-

comes were not informative given the lack of ascertainmentor low event rates.

Proteinuria Subgroups The cut points and measures for proteinuria assess-

ment varied across studies. A total of 11 subgroup results were reported; 7 showed benets for the low blood pres-sure target in higher proteinuria subgroups ( Appendix Ta-ble 2). Benet was seen in subgroups with a urinary pro-teincreatinine ratio greater than 0.22 g/g in the AASK Trial (considered to correlate with urinary protein excre-tion 300 mg/d) and urinary protein excretion greater

than 1000 mg/d in the MDRD Study. One subgroup anal-ysis in the follow-up report from the AASK Trial showedthat the usual blood pressure target was benecial in pa-tients with a urinary proteincreatinine ratio of 0.22 g/g orless for the composite outcome of a 50% decrease in GFR or kidney failure.

Inconsistencies between interaction tests and subgroupanalyses were found within and across studies ( Appendix Table 2). In the MDRD Study, overall results for the rateof decrease in GFR were negative, but the low blood pres-sure target was benecial in high proteinuria subgroups( 1000 mg/d in MDRD Study A and 3000 mg/d inMDRD Study B). The interaction tests by baseline pro-teinuria were also positive, suggesting benet of the low blood pressure target mainly in people with high protein-uria. In the follow-up report from the MDRD Study, how-ever, the result for kidney failure was favorable for the low blood pressure target. Subgroup analysis showed that thelow target was benecial in patients with proteinuria greater than 1000 mg/d, but the interaction test by base-line 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 clinicaloutcome were negative, whereas the subgroup analysisshowed that the low blood pressure target was benecial inpatients with urinary proteincreatinine ratios greater than0.22 g/g in both the trial and follow-up. For the other com-posite outcomes, however, subgroup analyses and correspond-ing interaction tests favored lower blood pressure targets in thehigh proteinuria group only during follow-up.

Number of Antihypertensive Agents In the MDRD Study, the mean number of antihyper-

tensive agents prescribed per patient for the low and usualblood 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 re-

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

Adverse Events In the MDRD Study, participants were asked to re-

port on 24 symptoms attributable to low blood pressureduring each follow-up visit. Of the 24 symptoms, only thefrequency of feeling faint differed signicantly betweenthe low and usual blood pressure target groups in bothstudies (Study A and Study B). Feeling faint was re-ported in 15% of visits per patient in the low target groupcompared 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 groupin Study B (P 0.009). More patients in the low targetgroup also needed a reduction in antihypertensive medica-tions because of persistent symptoms of hypotension

(3.2% vs. 0.7% in the usual target group; P 0.01). Theincidence of conditions requiring patient withdrawal fromthe study, however, did not differ between the groups.

In the AASK Trial, all participants were asked aboutshortness of breath, syncope, dizziness, and lightheaded-ness. In addition, the investigators also reported on theincidence of hyperkalemia, angioedema, edema, cough,and sexual dysfunction. Among all adverse events, only cough was more frequent in the low target group than inthe usual target group (55% vs. 47%; P 0.05). This isnot explained by the greater use of ACE inhibitors in thelow target group, because the 3 2 factorial design en-sured 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 targetgroup had treatment-related adverse events that necessi-tated withdrawal from the trial. A total of 23% of partici-pants in the low target group and 17% in the usual targetgroup had serious adverse events, but specic events werenot reported.

DISCUSSIONThis 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- to4-year follow-up, the main trial results did not show ben-et for clinical outcomes (1419). Only the posttrialfollow-up report from the MDRD Study showed benet of the lower target for kidney failure after about a 6-yearfollow-up (21). Subgroup analyses by baseline proteinuria levels in the MDRD Study and AASK Trial, but not in theREIN-2 trial, suggest benet for the lower target in pa-tients with proteinuria greater than 1000 mg/d and urinary proteincreatinine 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




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(14, 17, 20). A slightly higher rate of adverse events wassuggested in the low target groups (14, 17, 19).

Clinical heterogeneity in study populations and inter-ventions may have resulted in some of the inconsistenciesacross trials. Trials studied participants with differentcauses of CKD and used different antihypertensive regi-

mens. Only the AASK Trial had, by design, a balanced useof an ACE inhibitor, a -blocker, and a calcium-channelblocker in each group. The benet for kidney failure in theMDRD Study follow-up may have been confounded by the greater use of ACE inhibitors in the low target groupthan in the usual target group (51% vs. 32%). The lack of any benet in the higher proteinuria subgroup of theREIN-2 trial was in the setting of all patients receiving an ACE inhibitor and the low target group also receiving thedihydropyridine calcium-channel blocker felodipine.

Trial reports were graded as good quality, whereas thereports from posttrial follow-up and subgroup analyses were graded as fair quality. Condence in subgroup nd-ings is enhanced if the purpose and categories for analysisare prespecied in the study design (12, 13, 2325). TheREIN-2 trial was the only study that had prespecied sub-group analysis by baseline proteinuria levels, but it did notreport on interaction testing. Cut points and measurementtechniques used for proteinuria subgroup analyses varied inall 3 studies. Results were inconsistent between interactiontests and subgroup analyses for the same or different out-comes, both within and across studies. Exploratory sub-group analyses, although important in generating hypoth-esis for future research, are often underpowered,susceptible to spurious results because of multiple test-

ing, 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 andincluded very few patients with diabetic kidney disease. Inaddition, trial duration may have been too short to detectdifferences for clinically important outcomes, such as deathand kidney failure. We captured delayed effects by includ-ing reports from the posttrial follow-up, but these werelimited by the possibility of confounding from lack of ran-domization. We also cannot discount publication bias orselective reporting of some outcomes or subgroup analyses,

because we did not contact investigators for unpublisheddata. Studies with small sample sizes and short follow-up were excluded, but they probably would not have changedour conclusions. Ascertainment and reporting of adverseevents were also inconsistent across studies.

To put our ndings in the context of the current lit-erature, we conducted a separate MEDLINE search toidentify 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 be-lieve ours is the only review specically in patients withCKD and with a detailed analysis of effect modication by baseline proteinuria. The 2009 Cochrane review by Arguedas

and colleagues (26) in patients with hypertension includedthe CKD trials and also found no benet for a target lowerthan 140/90 mm Hg to 160/100 mm Hg for mortality ormorbidity. The reviews by Rosendorff and Black (27) andRoy and colleagues (28) highlight limited evidence for a low blood pressure target in patients with cardiovascular

disease and raise concern about impaired coronary perfu-sion from aggressive lowering of diastolic blood pressure inpatients with coronary artery disease or left ventricularhypertrophy.

In addition to these reviews, the ACCORD (Action toControl Cardiovascular Risk in Diabetes) trial provides im-portant supplemental information (29). The ACCORDtrial compared systolic blood pressure targets of less than120 mm Hg and less than 140 mm Hg in more than 4000patients with diabetes at high risk for cardiovascular out-comes. Most participants had normal kidney function, butapproximately 40% had micro- or macroalbuminuria. Themain results did not show any difference in the primary composite outcome of nonfatal myocardial infarction,nonfatal stroke, or cardiovascular death between the 2groups, but GFR decreased below 30 mL/min per 1.73 m2

more often and more serious adverse events were attributedto antihypertensive treatment in the low target group. Fi-nally, several recent commentaries and editorials have alsohighlighted the controversies surrounding the topic of blood pressure targets in CKD (3035).

Future research needs to address the evidence gap forpatients 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 PressureIntervention Trial) (36) and the HALT-CKD (HALT Pro-gression of Polycystic Kidney Disease) study (37) couldprovide valuable data. SPRINT compares systolic bloodpressure targets of less than 120 mm Hg and less than 140mm Hg in 9000 patients with hypertension and withoutdiabetes; it will be completed by 2018. It is enrolling par-ticipants with CKD, cardiovascular diseases, or risk factorsfor cardiovascular diseases. Similarly, the HALT-PKDstudy 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 dis-

ease; it will be completed by 2013. Although bothSPRINT and the HALT-PKD study excluded participants with heavy proteinuria (urinary albumincreatinine ratio

0.6 g/g for SPRINT and 0.5 to 1.0 g/g for HALT-PKD), subgroup analysis in the lower proteinuria rangeshould be considered for these trials to better understandthe effect modication by proteinuria. For ACCORD,SPRINT, HALT-PKD, and other future trials, the use of well-established albuminuria, proteinuria, and GFR cate-gories will be helpful to harmonize and compare subgroupresults across studies (38).

In summary, evidence does not conclusively show thata currently recommended blood pressure target of less than




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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 sug-gest that practitioners use discretion in patients with CKDand proteinuria and base the blood pressure target on in-

dividualized riskbenet assessment and the patients tol-erance and preferences. Treatment to a lower target may require greater vigilance to monitor for and avoid possiblesymptoms and adverse events from hypotension.

From the Tufts Center for Kidney Disease Guideline Development andImplementation, Tufts Medical Center, and Tufts University School of Medicine, Boston, Massachusetts.

Note: A draft of the KDIGO blood pressure guideline will be availablefor 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 valuablesuggestions and critical review of a prior version of the manuscript.

Financial Support: The authors are supported by KDIGO to conductsystematic reviews and provide methods support for developing KDIGOguidelines.

Potential Conflicts of Interest: Drs. Upadhyay and Uhlig: Grant (money to institution): KDIGO. Ms. Earley: Employment (money to insti-tution): KDIGO. Dr. Haynes: Employment (money to institution): TuftsMedical Center. Disclosures can also be viewed at www.acponline.org /authors/icmje/ConictOfInterestForms.do?msNum M10-2790.

Requests for Single Reprints: Katrin Uhlig, MD, MS, Tufts Center forKidney Disease Guideline Development and Implementation, WilliamB. Schwartz Division of Nephrology, 800 Washington Street, #391,Boston, MA 02111; e-mail, [email protected].

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

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et al; National Heart, Lung, and Blood Institute Joint National Committee onPrevention, 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 Hy-pertension. 2007 Guidelines for the Management of Arterial Hypertension: TheTask Force for the Management of Arterial Hypertension of the European Soci-ety of Hypertension (ESH) and of the European Society of Cardiology (ESC). JHypertens. 2007;25:1105-87. [PMID: 17563527]3. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinicalpractice 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:

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 Hyper-tension Guidelines for the Management of Hypertension (JSH 2009). HypertensRes. 2009;32:3-107. [PMID: 19300436]6. Harris D, Thomas M, Johnson D, Nicholls K, Gillin A; Caring for Austral-asians 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 chronickidney 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, preven-tion, 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 re-cipients. 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. Effectivenessof management strategies for renal artery stenosis: a systematic review. Ann InternMed. 2006;145:901-12. [PMID: 17062633]12. Brookes ST, Whitley E, Peters TJ, Mulheran PA, Egger M, Davey SmithG. 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 inmedicinereporting 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, MilasNC, et al. Achievement and safety of a low blood pressure goal in chronic renaldisease. 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 pro-gression 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 onprogression 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 AmericanStudy 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, TurturroM, et al; REIN-2 Study Group. Blood-pressure control for renoprotection inpatients with non-diabetic chronic renal disease (REIN-2): multicentre, ran-domised 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 hyper-tensive 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. Theeffect 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 InternMed. 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 RenalDisease Trial. The Modication of Diet in Renal Disease Study Group. ControlClin Trials. 1991;12:566-86. [PMID: 1664792]23. Bria E, Di Maio M, Cuppone F, Nistico C, Cognetti F, Giannarelli D.




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Should subgroup analysis of randomized clinical trials have a direct impact onclinical practice? [Letter]. J Clin Oncol. 2007;25:605-6. [PMID: 17290074]24. Rothwell PM. Treating individuals 2. Subgroup analysis in randomised con-trolled trials: importance, indications, and interpretation. Lancet. 2005;365:176-86. [PMID: 15639301]25. Sleight P. Debate: Subgroup analyses in clinical trials: fun to look atbutdont believe them!. Curr Control Trials Cardiovasc Med. 2000;1:25-27.[PMID: 11714402]

26. Arguedas JA, Perez MI, Wright JM. Treatment blood pressure targets forhypertension. Cochrane Database Syst Rev. 2009:CD004349. [PMID:19588353]27. Rosendorff C, Black HR. Evidence for a lower target blood pressure forpeople with heart disease. Curr Opin Cardiol. 2009;24:318-24. [PMID:19395951]28. Roy M, Mahmood N, Rosendorff C. Evidence for aggressive blood pressure-lowering 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-pressurecontrol 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

J Nephrol. 2010;32:381-2. [PMID: 20814197]32. Toto RB. Rebuttal: PRO Position. People with chronic kidney disease shouldhave 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 shouldhave 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 diseaseshould 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&rank 2 on 25 January 2011.37. ClinicalTrials.gov. HALT Progression of Polycystic Kidney Disease (HALTPKD). Clinical trial. Accessed at www.clinicaltrial.gov/ct2/show/NCT00283686?term HALT-PKD&rank 1 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 cardiovas-cular mortality in general population cohorts: a collaborative meta-analysis. Lan-cet. 2010;375:2073-81. [PMID: 20483451]

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Current Author Addresses: Drs. Upadhyay, Haynes, and Uhlig and Ms.Earley: Tufts Center for Kidney Disease Guideline Development andImplementation, 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. Upa-dhyay, 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.

Annals of Internal Medicine

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Appendix Table 1. Search Strategy for Randomized,Controlled Trials of Blood Pressure Targets

1. exp kidney diseases/2. exp kidney glomerulus/3. exp kidney function tests/4. kidney transplantation.mp. or exp Kidney Transplantation/5. ((kidney or renal) adj (transplant$ or recipient$)).tw.6. or/1-57. *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/11-1517. 8 and 1618. 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/18-3032. 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/32-3941. (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/41-5961. 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/61-7274. 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/74-9294. 31 or 40 or 60 or 73 or 9395. 8 and 9496. 10 and 9497. 17 or 95 or 9698. 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).sd113. (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/98-119121. 97 and 120122. Animals/ not humans/123. 121 not 122124. (guidelines or meta analysis or practice guideline or review or

review).mp. [mp ti, ot, ab, sh, hw, kw, nm]125. 123 not 124126. limit 125 to yr 2002-2009127. remove duplicates from 126

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A p p e n d i x T a b l e 2 . R e s u l t s o f I n t e r a c t i o n T e s t s a n d S u b g r o u p A n a l y s e s b y B a s e l i n e P r o t e i n u r i a i n T r i a l s o f B l o o d P r e s s u r e T a r g e t s ( L o w V e r s u s U s u a l ) i n P a t i e n t s W i t h C h r o n i c

K i d n e y D i s e a s e

O u t c o m e

M D R D S t u d y

A A S K S t u d y

R E I N - 2

T r i a l

P r o t e i n u r i a C a t e g o r y

T r i a l

O b s e r v a t i o n a l F o l l o w - u p

P r o t e i n u r i a C a t e g o r y

T r i a l

O b s e r v a t i o n a l F o l l o w - u p

P r o t e i n u r i a

C a t e g o r y

T r i a l

5 0 % ( o r 2 5 m L / m i n

p e r 1 . 7 3 m

2 ) d e c r e a s e

i n G F R

, k i d n e y

f a i l u r e ,

o r d e a t

h *

O v e r a

l l

N S

N S

U P C R 0 . 2 2 g / g

N S

N S

U P C R 0 . 2 2 g / g

F a v o r s

l o w t a r g e t ( H R

, 0 . 7 4

[ 9 5 % C I , 0

. 5 6 0 . 9 9 ] ; P

0 . 0 4 )

F a v o r s

l o w t a r g e t

( H R

, 0 . 7 3 [ C I ,

0 . 5 8 0 . 9

3 ] ;

P

0 . 0 1 )

I n t e r a c t i o n t e s t

F a v o r s

l o w t a r g e t w i t h i n c r e a s e

d

p r o t e i n u r i a

( P

0 . 0 2 )

K i d n e y

f a i l u r e o r

d e a t

h

O v e r a

l l

N S

F a v o r s

l o w t a r g e t

O v e r a

l l

N S

N S

U P E 3 0 0 m g /

d

N S

U P C R 0 . 2 2 g / g

N S

N S

U P E

, 3 0 0 1 0 0 0 m g /

d

N S

U P C R 0 . 2 2 g / g

N S

F a v o r s

l o w t a r g e t

( H R

, 0 . 6 7 [ C I ,

0 . 5 2 0 . 8

7 ] ;

P

0 . 0 0 2 )

U P E

, 1 0 0 0 3

0 0 0 m g

/ d

F a v o r s

l o w t a r g e t

( H R

,

0 . 6 1 [ C I , 0 . 4 5 0 . 8 5 ] )

U P E 3 0 0 0 m g /

d

F a v o r s

l o w t a r g e t

( H R

,

0 . 6 2 [ C I , 0 . 4 0 1 . 0 ] )


N S ( P

0 . 0 8 )


F a v o r s


d


( P

0 . 0 2 )

5 0 % d e c r e a s e i n G F R o r

k i d n e y

f a i l u r e

O v e r a

l l

N S

N S

U P C R 0 . 2 2 g / g

N S

F a v o r s u s u a

l t a r g e t ( H R

, 1 . 3 9

[ C I , 1 . 0 4 1 . 8

7 ] ;

P

0 . 0 3 )

U P C R 0 . 2 2 g / g

N S

F a v o r s

l o w t a r g e t

( H R

, 0 . 7 6 [ C I ,

0 . 5 8 0 . 9

9 ] ;

P

0 . 0 4 )


F a v o r s


d


( P

0 . 0 0 7 )

K i d n e y

f a i l u r e

O v e r a

l l

N S

F a v o r s

l o w t a r g e t

O v e r a

l l

N S

U P E 3 0 0 m g /

d

N S

U P E

, 3 0 0 1 0 0 0 m g /

d

N S

U P E

, 1 0 0 0 3

0 0 0 m g

/ d

F a v o r s

l o w t a r g e t

( H R

,

0 . 5 5 [ C I , 0 . 4 0 0 . 8 0 ] )

U P E

, 1 0 0 0 3

0 0 0

m g /

d

N S

U P E 3 0 0 0 m g /

d

F a v o r s

l o w t a r g e t

( H R

,

0 . 5 3 [ C I , 0 . 3 5 0 . 8 3 ] )

U P E 3 0 0 0 m g /

d

N S


N S ( P

0 . 0 9 )


R a t e o f

G F R d e c l i n e

O v e r a

l l

N S

O v e r a

l l

N S

O v e r a

l l

N S

U P E 2 5 0 m g /

d

N S

U P E

, 2 5 0 1 0 0 0 m g /

d

N S

U P E

, 1 0 0 0 3

0 0 0 m g

/ d

S t u d y A :

f a v o r s

l o w t a r g e t

S t u d y B : N S

U P E

, 1 0 0 0 3

0 0 0

m g /

d

N S

U P E 3 0 0 0 m g /

d

F a v o r s

l o w t a r g e t

U P E 3 0 0 0 m g /

d

N S


F a v o r s

l o w t a r g e t

( P

0 . 0 2

i n S t u d y A a n

d 0 . 0 1 i n

S t u d y B )


F a v o r s

l o w e r t a r g e t w i t h

i n c r e a s e

d p r o t e i n u r i a

( P

0 . 0 0 4 )


A A S K

A f r i c a n A m e r i c a n S t u d y o f K i d n e y D i s e a s e a n d H y p e r t e n s i o n ; C V D

c a r d i o v a s c u l a r d i s e a s e ; G F R

g l o m e r u l a r l t r a t i o n r a t e ; H R

h a z a r d r a t i o ; M D R D

M o d i c a t i o n o f D i e t i n R e n a l D i s e a s e ; N S

n o t

s i g n i c a n t ; R E I N - 2

R a m i p r i l E f c a c y i n N e p h r o p a t h y 2 ; S C r

s e r u m c r e a t i n i n e ; U P C R u r i n a r y p r o t e i n c r e a t i n i n e r a t i o ; U P E

u r i n a r y p r o t e i n e x c r e t i o n .

* D o u b l i n g o f S C r , k i d n e y f a i l u r e , o

r d e a t h f o r o b s e r v a t i o n a l f o l l o w - u p s t u d y .

E s t i m a t e f r o m a g u r e .

P

n o d a t a .

D o u b l i n g o f S C r o r k i d n e y f a i l u r e f o r o b s e r v a t i o n a l f o l l o w - u p s t u d y .

A n n u a l G F R d e c r e a s e o f 4 . 0 v s . 5 . 0

m L / m i n p e r 1 . 7 3 m

2 . E

s t i m a t e f r o m a g u r e .

P

n o d a t a .

A n n u a l G F R d e c r e a s e o f 8 . 5 v s . 1

3 m L / m i n p e r 1 . 7 3 m

2

i n S t u d y A a n d 5 v s . 7 . 5

m L / m i n p e r 1 . 7 3 m

2

i n S t u d y B

. E s t i m a t e s f r o m a g u r e .

P

n o d a t a .

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Appendix Table 3. Search Strategy for Recent Reviews ofBlood 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/1-1416. Animals/ not humans.mp. [mp ti, ot, ab, nm, hw, ui, tx, kw, ct, sh]17. 15 not 1618. exp blood pressure/19. 17 and 1820. limit 19 to (meta analysis or review or review literature or review,

academic)21. limit 20 to yr 2008-2010

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