1

Am J Kidney Dis. 2014;63(1):76-83

Original Investigation
Prehypertension and Incidence of ESRD: A Systematic
Review and Meta-analysis
Yuli Huang, MD,1 Xiaoyan Cai, MD,2 Jianyu Zhang, MD,1 Weiyi Mai, MD, PhD,3
Sheng Wang, MD,1 Yunzhao Hu, MD, PhD,2 Hao Ren, MD,4 and Dingli Xu, MD1
Background: Studies of the association of prehypertension with the incidence of end-stage renal disease
(ESRD) after adjusting for other cardiovascular risk factors have shown controversial results.
Study Design: Systematic review and meta-analysis of prospective cohort studies.
Setting & Population: Adults with prehypertension.
Selection Criteria for Studies: Studies evaluating the association of prehypertension with the incidence of
ESRD identified by searches in PubMed, EMBASE, and Cochrane Library databases and conference pro ceedings, without language restriction.
Predictor: Prehypertension.
Outcomes: The relative risks (RRs) of ESRD were calculated and reported with 95% CIs. Subgroup analyses were conducted according to blood pressure (BP), age, sex, ethnicity, and study characteristics.
Results: Data from 1,003,793 participants were derived from 6 prospective cohort studies. Compared with
optimal BP, prehypertension significantly increased the risk of ESRD (RR, 1.59; 95% CI, 1.39-1.91). In sub group analyses, prehypertension significantly predicted higher ESRD risk across age, sex, ethnicity, and
study characteristics. Even low-range (BP, 120-129/80-84 mm Hg) prehypertension increased the risk of
ESRD compared with optimal BP (RR, 1.44; 95% CI, 1.19-1.74), and the risk increased further with highrange (BP, 130-139/85-89 mm Hg) prehypertension (RR, 2.02; 95% CI, 1.70-2.40). The RR was significantly
higher in the high-range compared with the low-range prehypertensive population (P = 0.01).
Limitations: No access to individual patient-level data.
Conclusions: Prehypertension is associated with incident ESRD. The increased risk is driven largely by
high-range prehypertension.
Am J Kidney Dis. 63(1):76-83. 2013 by the National Kidney Foundation, Inc. Published by Elsevier Inc. All
rights reserved.
INDEX WORDS: Prehypertension; end-stage renal disease; meta-analysis; kidney failure; high-normal blood
pressure; chronic kidney disease (CKD).

he incidences of chronic kidney disease

(CKD) and end-stage renal disease (ESRD)

are
increasing and represent a major worldwide
public health problem.1,2 It has been reported that
CKD affects 10%-15% of the adult population
worldwide.3 People with CKD have decreased life
expectancy, and those

From the 1Department of Cardiology, Nanfang Hospital,

Southern Medical University, Guangzhou; 2Clinical Medicine
Research Institute, the First People s Hospital of Shunde (the
Af liated Hospital at Shunde, Southern Medical University),
Foshan; 3Department of Cardiology, the First Af liated Hospital
of Sun Yat-sen University; and 4Department of Nephrology,
Nanfang Hospital, Southern Medical University, Guangzhou,
People s Republic of China.
Received April 24, 2013. Accepted in revised form July 31,
2013. Originally published online September 30, 2013.
Address correspondence to Dingli Xu, MD, Department of
Cardiology, Nanfang Hospital, Southern Medical University,
1838 North Guangzhou Avenue, Guangzhou 510515, China
(e-mail: dinglixu@ mmu.com) or Hao Ren, MD, Department of
Nephrology, Nanfang Hospital, Southern Medical University,
Guangzhou 510515, China (e-mail: renhao67@aliyun.com).
'

'

2013 by the National Kidney Foundation, Inc. Published by

Elsevier Inc. All rights reserved.
0272-6386/36.00
http://dx.doi.org/10.1053/j.aj d.2013.07.024 with ESRD

who are receiving hemodialysis have a 20-fold

higher mortality rate than that of age- and sexmatched individuals with normal kidney
function.4 Accordingly, identi cation and
treatment of risk factors for CKD should be a
public health priority.
Prehypertension, which is de ned in the
Seventh Report of the Joint National Committee
on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC7), is
associated with a risk of developing hypertension
and also is related to cardiovascular disease
morbidity and mortality.5 Data from crosssectional studies also have shown that
prehypertension, particularly high-range normal
blood pressure (BP), is associated with CKD and
ESRD.- However, it is dif cult to establish the
detrimental effects of prehypertension on the
kidneys from cross-sectional studies because
kidney diseases per se can elevate BP. Some
prospective cohort studies have indicated that
prehypertension is related to the incidence of
ESRD,10,11 whereas other studies have shown that
the association is not statistically signi cant.12-15
The differences in results among these studies
may be explained by the incidence rate of ESRD
being low; thus, small and short-term studies fail
to show this association. Furthermore,

Am J Kidney Dis. 2014;63(1):76-83

Prehypertension and ESRD

arguments against using the term prehypertension also include the fact that there is inhomogeneity within this
category; the risk of progression to hypertension and development of cardiovascular disease is higher in
individuals with BP of 130-139/85- 89 mm Hg (high-range prehypertension) than in those with BP of 120129/80-84 mm Hg (low-range prehypertension).16 This inhomogeneity also may be present in the association
between prehypertension and CKD.12,13
Given these inconsistent results, a systematic review and meta-analysis of prospective cohort studies that
examined the association of prehypertension with ESRD risk may help clarify this issue. The objective of the
present study was to evaluate the association of prehypertension with the incidence of ESRD.

METHODS
Search Strategy and Selection Criteria
Electronic databases (PubMed, EMBASE, and the Cochrane Library) were searched for cohort studies to January 28, 2013, using the terms
"prehypertension," "prehypertensive," "pre- hypertension," "pre-hypertensive," "blood pressure," "borderline hypertension" and "chronic kidney
disease," "chronic kidney failure," "chronic kidney insuf ciency," "chronic kidney dysfunction," "chronic renal failure," "chronic renal insuf
ciency," "chronic renal dysfunction," "end-stage kidney disease" or "end- stage renal disease," and "risk factors." Terms were explored when
possible within each database. There were no language or publication form restrictions. In addition, reference lists of potentially relevant
studies were searched manually. The detailed search syntax for the database PubMed is shown in Item S1 (provided as online supplementary
material).The syntax for other databases was similar but was adapted when necessary.
Studies were included if they met the following criteria: (1) prospective cohort study involving participants 18 years or older; (2) baseline
evaluation of BP and other cardiovascular risk factors, for example, age, diabetes mellitus, body mass index, dyslipidemia, and smoking; (3)
follow-up of 1 year or longer with assessment of ESRD; and (4) reporting of multivariate-adjusted relative risks (RRs) and 95% con dence
intervals (CIs) for events associated with prehypertension (BP, 120-139/80-89 mm Hg) versus reference (optimal BP, <120/80 mm Hg), or
reported RRs and 95% CIs for low- (BP, 120-129/80-84 mm Hg) and high-range prehypertension (BP, 130-139/85-89 mm Hg) versus
reference, respectively.
Studies were excluded if: (1) enrollment depended on having a particular condition or risk factor (eg, if enrollment in a study was limited to
only patients with diabetes or CKD or coronary artery disease), (2) the study reported only age- and sex-adjusted RRs, and (3) data were
derived from the same cohort or from a secondary analysis or combined analysis of other cohort studies.
If duplicate studies were from the same cohort and offered the same outcome messages, only the latest published study was included.

Data Extraction and Quality Assessment

Two investigators (Y.H. and X.C.) independently used the mentioned search strategy to identify potentially relevant articles. The
investigators obtained the full reports of potentially relevant studies and reviewed each using prede ned eligibility criteria; abstracted data for
study and participant characteristics, follow-up

duration, and outcome assessment; and transferred this information to specially designed pretested paper forms.
The quality of each study was evaluated following the guidelines developed by the US Preventive Task Force and a modi ed checklist.17-19
This checklist assessed: (1) the designation of the prospective study, (2) maintenance of comparable groups, (3) adequate adjustment for
potential confounders (at least 5 of 6 factors among age, sex, diabetes mellitus, body mass index or other measure of overweight/obesity,
cholesterol level, and smoking), (4) documented rate of loss to follow-up, (5) outcome assessed blinded to baseline status, (6) clear de nition
of exposures (prehypertension) and outcomes, (7) temporality (BP measured at baseline, not at the time of outcome assessment), and (8)
follow-up of at least 2 years. Studies were graded as good quality if they met 7-8 criteria, fair if they met 4-6 criteria, and poor if they met fewer
than 4 criteria.

Data Synthesis and Analysis

The primary outcome was risk of ESRD morbidity. Subgroup analyses of primary outcomes were conducted according to level of BP (low- vs
high-range prehypertension), sex (men vs women), participant age (average <50 vs 50 years), ethnicity (Asian vs non-Asian), exclusion of
participants with baseline CKD (yes vs no), and adequate adjustment for risk factors (yes vs no).
Multivariate-adjusted outcome data (expressed as RRs and 95% CIs) were used for analysis. We logarithmically transformed these values
in every study and calculated the corresponding standard errors (SEs) to stabilize the variance and normalize the distribution. The statistical
analysis used the inverse variance approach to combine log RRs and SEs.
When multivariate-adjusted RRs and 95% CIs for events associated with prehypertension were available, these study data were used
directly in the pooled meta-analysis calculations. For studies that published RRs and 95% CIs of speci c subgroups (eg, men and women, lowand high-range prehypertension, or age-speci c subgroups) but did not report an estimated overall risk, subgroup data were used to calculate
the overall RRs and 95% CIs for entry into the meta-analysis calculations.
We used x2 and /2 statistics to test heterogeneity (25%, 50%, and 75% represented low, moderate, and high heterogeneity, respectively).20
Results of studies were pooled by using xedeffects models, if appropriate, after consideration of heterogeneity among trials. Otherwise, a
random-effects model was used. We assessed publication bias by inspecting funnel plots for each outcome in which the natural logarithm of
the RR was plotted against SE, as well as Egger's test (linear regression method) and Begg's test (rank correlation method).
We also conducted sensitivity analyses in which the pooled RR was recalculated by omitting one study at a time. P values were 2 tailed,
and statistical signi cance was set at 0.05. All analyses were performed with RevMan software (version 5.1 for Windows; The Nordic Cochrane
Centre, The Cochrane Collaboration) and Stata, version 12.0 (StataCorp LP).
Am J Kidney Dis. 2014;63(1):76-83

Prehypertension and ESRD

RESULTS
Selected Studies and Characteristics
Two independent reviewers determined that of the initial 2,358 study report abstracts reviewed, 22 quali ed for
full review (Fig 1). The primary analysis included data for 1,003,793 participants derived from 6 prospective
cohort studies that reported an association between prehypertension and the incidence of ESRD.10-15 Of the 6
studies, 2 were from Asia10,14 and 4 were from the United States and Europe

Am J Kidney Dis. 2014;63(1):76-83

Huang et al

Figure 1. Flow of selection for studies through review. Abbreviations: BP, blood pressure; Cls, confidence intervals; CKD,
chronic kidney disease; ESRD, end-stage renal disease; RRs, relative risks.

(Table

1).11-13,15

The proportion of Asians was 25.6%, the prevalence of prehypertension was 34.5%14 to
46.7%, and follow-up was 8.314 to 26 years.11 One study enrolled only men,12 and all other studies enrolled both
sexes. According to the prede ned quality assessment criteria, 4 studies were graded as good11,12,14,15 and 2 studies
did not meet our criteria for adequate adjustment of potential confounders and were graded as fair.10,13 Details of
the quality assessment are presented in Table S 1 .
12

Primary Outcomes and Subgroup Analyses

The data have high homogeneity (J2 = 5%; P = 0.4); therefore, xed-effects models were used for the analyses.
Overall, prehypertension was associated with increased risk of ESRD (RR, 1.59; 95% CI, 1.39-1.91; P < 0.001;
Fig 2). There was no evidence of publication bias identi ed by visual inspection of the funnel plot (Fig S1) or

'

'

indicated by Begg s test (P = 0.9) and Egger s test (P = 0.8).

In subgroup analyses, prehypertension signi cantly predicted higher ESRD risk across subgroups with

'

analyses conducted according to BP range; participant s age, sex, and ethnicity; and study quality (Table 2).
Even low-range prehypertension increased the risk of ESRD compared with optimal BP (RR, 1.44; 95% CI, 1.191.74), and the risk increased further with high-range prehypertension (RR, 2.02; 95% CI, 1.70-2.40). The RR was
higher in the high-versus low-range prehypertensive populations (
cant differences in the other subgroups (Table 2).

x2 = 6.57; P = 0.01; Fig 3). We found no signi

Sensitivity Analyses
Multiple methods were used to test sensitivity, and the primary results were not in uenced by the use of xedeffect models compared with random-effect models, odds ratios compared with RRs, or recalculation by omitting
one study at a time.

DISCUSSION
After controlling for multiple cardiovascular risk factors, a robust and statistically signi cant association
between prehypertension and long-term risk of ESRD was found in this meta-analysis. Results were consistent
across age, sex, trial characteristics, and ethnicity.
6

Am J Kidney Dis. 2014;63(1):76-83

Huang et al

Since the JNC 7 proposal, the term prehypertension has been contentious.21 The term has not been adopted
by other national and international hypertension guidelines, which have elected to keep the older BP classi
cation systems.16 For example, the 2007 report from the Task Force for the Management of Arterial Hypertension
of the European Society of Hypertension and European Society of Cardiology preferred to classify BP of 120129/80-84 mm Hg as normal and BP of 130-139/85-89 mm Hg as high-normal. 22 One of the most important
arguments against using the term prehypertension is that the risks of progression to hypertension and
development of cardiovascular events differ between patients with BP in the 130- 139/85-89

mm Hg range

and those with BP in the 120-129/80-84

mm Hg range. Our study had suf - cient power to show that the risk
of ESRD is increased even with fairly mild elevations of BP. In particular, we found that individuals with low-range
pre- hypertension were 44% more likely to develop ESRD than those with optimal BP, and this risk was
increased further in high-range prehypertension (RR, 2.02). Therefore, our ndings reaf rm the importance of the
de nition of prehypertension. However, our results further show the great heterogeneity of the prehypertension
subcategory. This information is important to health professionals and those engaged in the primary prevention
of CKD.
Our study was supported by the recently reported Ohasama Study from Japan, which demonstrated a signi
cant association between prehypertension and the development of CKD in a general population (de ned as
estimated glomerular ltration rate < 60 mL/min/1.73 m2 or the presence of proteinuria).23 However, during a
mean follow-up of 9.9 years in a study of 3,313 Iranian adults without

Am J Kidney Dis. 2014;63(1):76-83

Am J Kidney Dis. 2014;63(1):76-83

Prehypertension and ESRD

79

Huang et al
Figure 2. Forest plot of comparison: prehypertension versus optimal blood pressure, outcome: end-stage renal disease. Abbreviations: BP, blood pressure; CI, confidence interval; CNHS, China National Hypertension Survey; HUNT I, the first Health Study in
Nord-Trondelag; MRFIT, Multiple Risk Factor Intervention Trial; NA, not available; OKIDS, the Okinawa Dialysis Study.

Am J Kidney Dis. 2014;63(1):76-83

CKD, Tohidi et al24 determined that people with

prehypertension, even those with high normal
BP, did not have a signi cantly increased risk of
developing CKD (de ned as estimated glomerular
ltration rate < 60 ml./min/1.73 m2) than those
with optimal BP. The differences in results of
these studies may be due to the different cohort
samples, follow-up durations, and de nitions of
CKD.
Because most of the included studies lacked
longitudinal BP follow-up, the association of prehypertension and ESRD detected in our study
may be confounded because prehypertension is
a stage on the progression to hypertension and
only those who

This possibility would diminish the bene t of

treating prehypertension or concluding that the
association of prehypertension with ESRD is
strong evidence for lower target BPs. However,
data from the Hisayama Study demonstrated that
pre- hypertension was associated signi cantly
with renal arteriosclerosis by kidney biopsy after
adjustment for other cardiovascular risk factors
(odds ratio, 5.99; 95% CI, 2.20-15.97),25
supporting a potential pathophysiologic
relationship between prehypertension and
progression to ESRD.

The main strengths of this meta-analysis were

the very large sample of participants ( >1 million)
and that results were consistent across age, sex,
trial characteristics, and ethnicity. Furthermore,
inclusion criteria in our study were restricted to
Table 2. Subgroup Analyses of End-Stage Renal Disease
prospective cohort studies with reported
in
multivariate-adjusted RRs. Prehypertension is
Prehypertension
associated commonly with other cardiovascular
Subgroup
RR (95% CI)
P
risk factors,16,26,27 especially obesity and
28,29
which also accelerate
Blood pressure range
0.01 metabolic syndrome,
the development and progression of CKD.28-30
Low-range prehypertension
1.44 (1.19-1.74)
Whether the mild elevation of BP directly
High-range prehypertension
2.02 (1.70-2.40)
increases the risk of CKD or whether the
Sex
0.7 increased incidence is caused by susceptibility to
other concurrent risk factors remains unclear.31,32
Male
1.62 (1.17-2.24)
In our study, most of the included studies were
Female
1.79 (1.17-2.75)
adjusted adequately for other risk factors. These
Race/ethnicity
0.2
adjustments
reduce
the possibility
that
Asian
1.44 (1.16-1.79)
confounders in uenced the association between
Non-Asian
1.71 (1.47-1.98)
prehypertension and ESRD.
Participant's average age

<50 y

0.2
1.44 (1.16-1.79)
1.71 (1.47-1.98)

Important
clinical
and
public
health
implications
come
from
these
ndings.
First,
Participants with baseline
0.1
considering
the
robust
evidence
of
an
association
CKD excluded
between pre- hypertension and long-term risk of
Yes
1.76 (1.50-2.06)
ESRD shown in our study, consideration of earlier
No
1.43 (1.19-1.73)
interventions for prehypertension is preferable to
Study quality
0.6
prevent the progression of CKD in the general
Good (score, 7-8)
1.60 (1.40-1.84)
population. Currently, lifestyle modi cation is the
Fair (score, 4-6)
1.73 (1.27-2.37)
mainstay of treatment for prehypertension in the
Abbreviations: CI, confidence interval; CKD, chronic
general
population.
However,
high-risk
kidney disease; RR, relative risk. develop sustained
subpopulations with prehypertension,
true hypertension are at risk of developing ESRD.
50 y

10

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Prehypertension and
ESRD

Figure 3. Forest plot of comparison: subgroup analyses of primary outcomes conducted according to the level of blood
pressure (BP; low-range prehypertension vs high-range prehypertension). Abbreviations: CI, confidence interval; MRFIT,
Multiple Risk Factor Intervention Trial; NA, not available; OKIDS, the Okinawa Dialysis Study.

11

Am J Kidney Dis. 2014;63(1):76-83

especially high-range prehypertension, may be

an important study population for future
controlled trials of pharmacologic treatment.
Second, the BP target for patients with CKD is
not consistent among different guidelines. The
JNC 7 recommends that in patients with diabetes
or kidney disease, the BP goal is <130/80 mm
Hg.5 However, the KDIGO (Kidney Disease:
Improving Global Outcomes) Clinical Practice
Guideline for Management of Blood Pressure in
Chronic Kidney Disease recommends no optimal
single BP target for all patients with CKD, but
encourages individualized treatment based on
age, severity of albuminuria, and comorbid
conditions.33 Available evidence with regard to
whether adults with CKD with a BP target

<130/80

mm Hg have better clinical outcomes

than those with a BP target <140/90 mm Hg is

inconclusive.34 Given the low incidence rates of
ESRD, prior interventional studies may not be
adequately powered or may have follow-up that
is too short to detect the difference in ESRD
incidence. However, in our study, meta-analysis
of large-sample, long-term follow-up, prospective
studies documented a robust and statistically
signi cant association between pre- hypertension
and the incidence of ESRD, especially for
individuals with high-range prehypertension.
Thus, controlled trials with large samples and
long follow-up periods are required to determine
the lower BP target in patients with CKD,
especially patients with other risk factors such as
severe proteinuria.

This meta-analysis has some limitations.

First, we had no access to individual patient-level

Am J Kidney Dis. 2014;63(1):76-83

data. However, most included studies were

adjusted adequately for potential confounders
and were of high quality, reducing the likelihood
that other cardiovascular risk factors in uenced
the association between prehypertension and
ESRD.
Second,
the
determination
of
prehypertension in most studies was based on
single-day
measurements,
albeit
multiple
readings
were
taken.
Because
BP
measurements are subject to random withinperson variation, use of a single-day baseline BP
could have led to misclassication of BP levels
and dilution bias between pre- hypertension and
the incidence of ESRD. Furthermore, the lack of
longitudinal BP follow-up also is a limitation to
distinguish
whether
the
association
of
prehypertension with ESRD is due primarily to
the future progression to true hypertension.
Nevertheless, based on the snapshot BP
measurement,
results
indicate
that
prehypertension is associated with an increased
incidence of ESRD. Third, most included studies
lacked data for baseline kidney function and
proteinuria.10,13-15 In these studies, it is unknown
whether CKD was already present in individuals
who
subsequently
developed
ESRD.
Nevertheless, results of our subgroup analysis
did not differ signi cantly according to whether
participants with baseline CKD were excluded.
Therefore, use of these ndings in evaluating the
BP of individuals at high risk of ESRD was not
affected. Finally, although 4 of the 6 included
studies de ned ESRD as dialysis or kidney
transplantation or death due to kidney failure,
only one study reported the risk ratio of CKDrelated death, so data for CKD-related mortality
were not available for meta-analysis. Therefore,
we cannot

12

Huang et al

assess whether the competing risk of death affected the incidence of the ESRD outcome.
In conclusion, prehypertension is associated with increased long-term risk of ESRD. The increased
risk is driven largely by higher BPs within the pre- hypertensive range. This nding reaf rms the importance of the de nition of prehypertension, as well as the heterogeneity of the prehypertension
subcategory. This information is important to health professionals and those engaged in the prevention
of CKD.

ACKNOWLEDGEMENTS
Support: The project was supported by the Medical Scienti c Research Grant of Health Ministry of Guangdong province, China
(Nos. B2011310, A2012663, and B2012343), Cardiovascular Medicine Research Fund of Guangdong, China (Nos. 2009X20 and
2011X38), and Scienti c Research Fund of Foshan, Guangdong, China (Nos. 201208227 and 201208210).
Financial Disclosure: The authors declare that they have no other relevant nancial interests.

SUPPLEMENTARY MATERIAL
Table S1: Quality assessment of the included studies.
Figure S1: Funnel plot of prehypertension versus optimal blood pressure.
Item S1: Literature search strategy for PubMed.
Note: The supplementary material accompanying this article (http://dx.doi.org/10.1053/j.ajkd.2013.07.024) is available at
www.ajkd.org

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