Ptre HT and Mortalitas

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

Original Investigation

Prehypertension and Incidence of ESRD: A SystematicReview 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 an-

alyses 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 high-range (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)

areincreasing 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: [email protected]).

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 sex- matched 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 cross-sectional 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,

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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 120-129/80-84 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 AssessmentTwo 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, low- and 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).

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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

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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%,12 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 .

Primary Outcomes and Subgroup AnalysesThe 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, 1.19-1.74), 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 (x2 = 6.57; P = 0.01; Fig 3). We found no signi

cant differences in the other subgroups (Table 2).

Sensitivity Analyses

Multiple methods were used to test sensitivity, and the primary results were not in uenced by the use of xed-effect 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.

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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 120-129/80-84 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

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Am J Kidney Dis. 2014;63(1):76-83 79Prehypertension and ESRD

Huang et alFigure 2. Forest plot of comparison: prehypertension versus optimal blood pressure, outcome: end-stage renal disease. Abbrevi-

ations: 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.

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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 pre- hypertension and ESRD detected in our study may be confounded because prehypertension is a stage on the progression to hypertension and only those who

Table 2. Subgroup Analyses of End-Stage Renal Disease in

Prehypertension

Subgroup RR (95% CI) P

Blood pressure range 0.01

Low-range prehypertension 1.44 (1.19-1.74)

High-range prehypertension 2.02 (1.70-2.40)

Sex 0.7

Male 1.62 (1.17-2.24)

Female 1.79 (1.17-2.75)

Race/ethnicity 0.2

Asian 1.44 (1.16-1.79)

Non-Asian 1.71 (1.47-1.98)

Participant's average age 0.2

<50 y 1.44 (1.16-1.79)

50 y 1.71 (1.47-1.98)

Participants with baseline 0.1

CKD excludedYes 1.76 (1.50-2.06)

No 1.43 (1.19-1.73)

Study quality 0.6

Good (score, 7-8) 1.60 (1.40-1.84)Fair (score, 4-6) 1.73 (1.27-2.37)

Abbreviations: CI, confidence interval; CKD, chronic kidney disease; RR, relative risk. develop sustained true hypertension are at risk of developing ESRD.

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 prospective cohort studies with reported multivariate-adjusted RRs. Prehypertension is associated commonly with other cardiovascular risk factors,16,26,27 especially obesity and metabolic syndrome,28,29 which also accelerate the development and progression of CKD.28-30

Whether the mild elevation of BP directly increases the risk of CKD or whether the increased incidence is caused by susceptibility to other concurrent risk factors remains unclear.31,32

In our study, most of the included studies were adjusted adequately for other risk factors. These adjustments reduce the possibility that confounders in uenced the association between prehypertension and ESRD.

Important clinical and public health implications come from these ndings. First, considering the robust evidence of an association between pre- hypertension and long-term risk of ESRD shown in our study, consideration of earlier interventions for prehypertension is preferable to prevent the progression of CKD in the general population. Currently, lifestyle modi cation is the mainstay of treatment for prehypertension in the general population. However, high-risk subpopulations with prehypertension,

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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.

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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

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 within-person 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 CKD-related death, so data for CKD-related mortality were not available for meta-analysis. Therefore, we cannot

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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 impor-tance 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.

ACKNOWLEDGEMENTSSupport: 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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