Scholarly article on topic 'Associations of proteinuria and the estimated glomerular filtration rate with incident hypertension in young to middle-aged Japanese males'

Associations of proteinuria and the estimated glomerular filtration rate with incident hypertension in young to middle-aged Japanese males Academic research paper on "Clinical medicine"

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{"Dipstick proteinuria" / eGFR / Hypertension / "Japanese males" / "Prospective cohort"}

Abstract of research paper on Clinical medicine, author of scientific article — Naoki Okumura, Takahisa Kondo, Kunihiro Matsushita, Shigeki Osugi, Keiko Shimokata, et al.

Abstract Objective To investigate the independent associations of proteinuria and the estimated glomerular filtration rate (eGFR) with incident hypertension. Methods We investigated 29,181 Japanese males 18–59years old without hypertension in 2000 and examined whether proteinuria and the eGFR predicted incident hypertension independently over 10years. Incident hypertension was defined as a newly detected blood pressure of ≥140/90mmHg and/or the initiation of antihypertensive drugs. Proteinuria and the eGFR were categorized as dipstick negative (reference), trace or ≥1+ and ≥60 (reference), 50–59.9 or <50ml/min/1.73m2, respectively. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of incident hypertension. Results At baseline, 236 (0.8%) and 477 (1.6%) participants had trace and ≥1+ dipstick proteinuria, while 1416 (4.9%) and 129 (0.4%) participants had an eGFR of 50–59.9 and <50ml/min/1.73m2, respectively. The adjusted HRs were significant for proteinuria ≥1+ (HRs 1.20, 95% CI: 1.06–1.35) and an eGFR of <50ml/min/1.73m2 (1.29, 1.03–1.61). When two non-referent categories were combined (dipstick≥trace vs. negative and eGFR<60 vs. ≥60ml/min/1.73m2), the association was more significant for proteinuria (1.15, 1.04–1.27) than for eGFR (0.99, 0.92–1.07). Conclusions Proteinuria and a reduced eGFR are independently associated with future hypertension in young to middle-aged Japanese males.

Academic research paper on topic "Associations of proteinuria and the estimated glomerular filtration rate with incident hypertension in young to middle-aged Japanese males"

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ELSEVIER

Associations of proteinuria and the estimated glomerular filtration rate with incident hypertension in young to middle-aged Japanese males^^

Naoki Okumura a, Takahisa Kondo aÄ* Kunihiro Matsushita a,c, Shigeki Osugia, Keiko Shimokata a, Kyoko Matsudaira a, Kentaro Yamashita a, Kengo Maeda a, Toyoaki Murohara a

a Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan

b Department ofAdvanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School ofMedicine, Nagoya, Japan c Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, USA

ARTICLE INFO ABSTRACT

Objective: To investigate the independent associations of proteinuria and the estimated glomerular filtration rate (eGFR) with incident hypertension.

Methods: We investigated 29,181 Japanese males 18-59 years old without hypertension in 2000 and examined whether proteinuria and the eGFR predicted incident hypertension independently over 10 years. Incident hypertension was defined as a newly detected blood pressure of > 140/90 mm Hg and/or the initiation of antihypertensive drugs. Proteinuria and the eGFR were categorized as dipstick negative (reference), trace or > 1 + and >60 (reference), 50-59.9 or <50 ml/min/1.73 m2, respectively. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of incident hypertension.

Results: At baseline, 236 (0.8%) and 477 (1.6%) participants had trace and > 1 + dipstick proteinuria, while 1416 (4.9%) and 129 (0.4%) participants had an eGFR of 50-59.9 and < 50 ml/min/1.73 m2, respectively. The adjusted HRs were significant for proteinuria > 1 + (HRs 1.20, 95% CI: 1.06-1.35) and an eGFR of <50 ml/min/1.73 m2 (1.29, 1.03-1.61). When two non-referent categories were combined (dipstick > trace vs. negative and eGFR < 60 vs. >60 ml/min/1.73 m2), the association was more significant for proteinuria (1.15,1.04-1.27) than for eGFR (0.99, 0.92-1.07).

Conclusions: Proteinuria and a reduced eGFR are independently associated with future hypertension in young to middle-aged Japanese males.

© 2013 The Authors. Published by Elsevier Inc. All rights reserved.

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Preventive Medicine

journal homepage: www.elsevier.com/locate/ypmed

CrossMark

Available online 14 December 2013

Keywords: Dipstick proteinuria eGFR

Hypertension Japanese males Prospective cohort

Introduction

Hypertension is a highly prevalent disorder that affects more than one quarter of the population worldwide (Kearney et al., 2005) and is a major risk factor for stroke, cardiovascular disease and end-stage renal disease (Arima et al., 2003; Gueyffier, 2003; Klag et al., 1996). Hypertension is even more prevalent in Japan, with an estimated prevalence of ~40% (Kubo et al., 2008). Several factors, such as high sodium intake (1988), obesity (Fox et al., 2007) and physical inactivity (Dickinson et al., 2006), have been identified to be highly associated

☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits noncommercial use, distribution, and reproduction in any medium, provided the original author and source are credited. ☆☆ Funding sources: None.

* Corresponding author at: Department of Advanced Medicine in Cardiopulmonary Disease, Nagoya University Graduate School of Medicine, 65, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan. Fax: +81 52 744 2138.

E-mail address: takahisa@med.nagoya-u.ac.jp (T. Kondo).

with hypertension. However, approximately 90% of adults with hypertension are considered to have essential hypertension, a condition without an overt primary cause (Anderson et al., 1994; Carretero and Oparil, 2000; Nishikawa et al., 2007; Rossi et al., 2006).

The kidney plays a significant role in the regulation ofblood pressure (BP) by controlling blood volume, the levels of electrolytes and the sympathetic nervous system and hormonal systems, such as the renin-an-giotensin-aldosterone system (Brewster and Perazella, 2004; Komukai et al., 2010). Therefore, kidney damage and dysfunction, such as proteinuria and a reduced glomerular filtration rate (GFR), have attracted attention as predictors of hypertension (Brantsma et al., 2006; Forman et al., 2008; Gerber et al., 2006; Gueyffier, 2003; Jessani et al., 2012; Kestenbaum et al., 2008; Palatini et al., 2005; Takase et al., 2012; Wang et al., 2005). However, to the best of our knowledge, only a few studies have investigated the associations of proteinuria and GFR simultaneously with the development of hypertension, and the results were not consistent (Kestenbaum et al., 2008; Takase et al., 2012), leaving uncertainty regarding the respective contributions of these factors to the development of hypertension. Asians, a racial/ethnic group with a

0091-7435/$ - see front matter © 2013 The Authors. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.ypmed.2013.12.009

high prevalence of hypertension (Kearney et al., 2005; Kubo et al., 2008), are particularly understudied regarding this issue.

Therefore, the purpose of the present study was to investigate the independent association of the presence of proteinuria and a reduced eGFR with incident hypertension in a prospective cohort study of young to middle-aged Japanese males with annual BP evaluation.

Materials & methods

Study population

The study subjects included Japanese males who underwent annual medical checkups at their workplaces, all of which were blue-chip companies in Japan (Kondo et al., 2013; Yamashita et al., 2012). Japanese males 16-59 years of age (n = 33,914) were recruited in 2000. We excluded participants with preexisting hypertension (systolic BP > 140 mm Hg, diastolic BP > 90 mm Hg or the use of antihypertensive drugs; n = 4688 at baseline examination) and excluded participants aged < 18 years old (n = 45), with a final sample of 29,181 participants.

Data collection and measurements

Annual medical checkups including blood test and dipstick urine test were conducted through 2010 or until retirement at around 60 years of age. All participants were individually interviewed using a structured questionnaire in the baseline and annual follow-up surveys. The following information was recorded by trained observers: smoking status, alcohol intake, medical history and medications. The smoking status and alcohol intake were classified as current vs. former/never. Weight and height were measured while the subject was wearing light clothing without shoes. The body mass index (BMI) was computed as the weight in kilograms divided by the square of the height in meters. Urine and blood samples were obtained in the morning with overnight fasting. A urinalysis for proteinuria was conducted with Uropaper III (Eiken Chemical Co., Ltd., Tokyo, Japan), and the results were measured using a US-2100 Automated Urine Analyzer (trace (±) corresponds to proteinuria >15 mg/dl, 1 + to >30 mg/dl, 2 + to > 100 mg/dl, 3 + to >300 mg/dl and 4 + to > 1000 mg/dl). The blood analyses were conducted at a single laboratory. The GFR was estimated using the three-variable equation proposed by the Japanese Society of Nephrology (eGFR [ml/min/1.73 m2] = 194 x serum creatinine-1094 x age-0287 x 0.739

[if female]) (Matsuo et al., 2009). In this study, the proteinuria using a dipstick and eGFR were measured at baseline (2000). Diabetes mellitus was defined as a concentration of serum fasting glucose of > 126 mg/dl or the use of glucose-lowering medications.

Blood pressure assessment and incident hypertension

BP was measured annually with the participant in the sitting position after 5 min of rest using an automated sphygmomanometer (BP-203IIIB; Colin Corporation, Tokyo, Japan). The BP was measured two times at intervals of 1 min on the right arm, and the average value was calculated as the baseline BP. When a subject had frequent premature contractions or atrial fibrillation, trained nurses confirmed the BP using a conventional mercury sphygmoma-nometer. Incident hypertension was defined as a newly detected BP of > 140/ 90 mm Hg and/or the initiation of antihypertensive drugs during follow-up.

Statistical analysis

All analyses were performed using the STATA software program version 11 (Stata Corp. College Station, TX, USA). Continuous variables were presented as the medians (interquartile ranges), and differences between the two/three groups were evaluated using the Wilcoxon test/Kruskal-Wallis analysis because not all continuous variables were normally distributed. Categorical variables were presented as numbers (percentages), and comparisons across the groups were made using the chi-square test. Survival curves were calculated according to the Kaplan-Meier method and compared using the log-rank test. Cox proportional hazards models were used to estimate the hazard ratios (HRs) of incident hypertension according to the level of proteinuria and eGFR adjusted for age (continuous), BMI (continuous), serum total cholesterol (continuous), serum uric acid (continuous), diabetes mellitus (category), current smoking (category), current alcohol intake (category) and proteinuria (category) or eGFR (continuous), as appropriate. We used time from baseline as time variable in the Cox models.

We assessed the independent associations of proteinuria and eGFR with incident hypertension after dividing both kidney measures into three categories (dipstick proteinuria: negative, trace and >1 + ; and eGFR: < 50, 50-59.9 and >60 ml/min/1.73 m2). A dipstick negative status and eGFR of >60 ml/min/ 1.73 m2 were used as reference groups. Due to the limited number of individuals with an eGFR of < 50 ml/min/1.73 m2 and dipstick proteinuria > 1+, we also tested dichotomized proteinuria (positive [trace, and > 1 +] vs. negative)

Table 1

Baseline characteristics (dipstick negative, ±, >+ and eGFR > 60,50-59.9, <50 ml/min/1.73 m2): Aichi, Japan, 2000.

Proteinuria

p Value eGFR (ml/min/1.73 m2)

p Value

(n = 29,181) Negative (n = 28,468) Trace (±) (n = 236) (> + ) (n = 477) >60 (n = 27,636) 50-59.9 (n = 1416) <50 (n = 129)

Age (years old) 35 (30-40) 36 (31-43) 39(31-50) 41(33-51) <0.001 36 (30-42) 46 (42-51) 52(48-57) <0.001

Body mass index (kg/m2) 22.3 22.4 22.7 23.3 <0.001 22.3 23.6 23.6 <0.001

(20.6-24.3) (20.6-24.3) (20.8-25.1) (21.0-25.7) (20.6-24.3) (22.0-25.3) (21.8-25.0)

Systolic blood pressure (mm Hg) 114 114 117 118 <0.001 114 116 120 <0.001

(106-121) (106-122) (108-126) (110-128) (106-122) (108-124) (110-129)

Diastolic blood pressure (mm Hg) 68 69 72 74 <0.001 69 74 77 <0.001

(62-76) (63-77) (65-80) (66-81) (63-76) (66-81) (69- 84)

Total cholesterol (mg/dl) 190 190 194 199 <0.001 189 206 210 <0.001

(169-214) (169-214) (168-219) (173-225) (168-213) (185-230) (184-231)

HDL cholesterol (mg/dl) 55 55 54 52 <0.001 55 54 52 <0.001

(47-64) (47-65) (45-63) (45-62) (47-65) (45-63) (44-62)

Triglyceride (mg/dl) 101 100 109 113 <0.001 100 115 121 <0.001

(70-148) (70-148) (78-175) (77-179) (69-147) (81-169) (92-169)

Uric acid (mg/dl) 5.8 5.8 6.0 6.1 <0.001 5.8 6.4 6.9 <0.001

(5.1-6.6) (5.1-6.6) (5.0-6.9) (5.3-7.0) (5.1-6.5) (5.6-7.3) (6.1-7.7)

eGFR (ml/min/1.73 m2) 75.5 75.0 73.1 70.8 <0.001 75.5 56.9 47.1 <0.001

(69.4-82.8) (68.3-82.0) (64.7-80.5) (63.0-78.8) (69.4-82.8) (55.1-58.3) (43.2-49.3)

Fasting blood glucose (mg/dl) 89 90 94 93 <0.001 89 93 94 <0.001

(83-96) (84-96) (86-103) (86-105) (83-96) (87-101) (88-102)

Diabetes (%) 2 2 9 13 <0.001 2 4 9 <0.001

Current smoker (%) 55 55 55 52 0.524 56 42 36 <0.001

Current alcohol intake (%) 72 72 70 66 0.027 72 75 60 0.001

The data are presented as medians (interquartile ranges) for continuous variables and percentages for categorical variables. HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate.

and eGFR (reduced [<60] vs. preserved [>60 ml/min/1.73 m2]), particularly in the subgroup analysis.

A subgroup analysis was conducted according to the baseline BP (optimal [systolic < 120 mm Hg and diastolic < 80 mm Hg] vs. normal or high-normal [systolic is 120-139 mm Hg or diastolic is 80-89 mm Hg]), age (<40 vs. >40 years), BMI (<25 vs. >25 kg/m2), dyslipidemia (serum total cholesterol < 220 vs. >220 mg/dl), diabetes mellitus, current smoking and current alcohol intake. The interaction terms between proteinuria and each subgroup were assessed using likelihood ratio tests in the individual analyses. All reported p values were two-sided, and p < 0.05 was considered to be statistically significant.

Results

Baseline characteristics

The baseline characteristics of the participants according to the level of dipstick proteinuria and eGFR are shown in Table 1. The median age was 35 (30-40) years, and the median eGFR was 75.5 (69.4-82.8) ml/min/1.73 m2. There were 713 participants (2.4%) with proteinuria (dipstick trace: n = 236, proteinuria > + : n = 477). The positive proteinuria group was associated with an older age, lower eGFR and higher prevalence of traditional cardiovascular risk factors, except for current smoking. There were 1545 participants (5.3%) with a reduced eGFR (50-59.9 ml/min/1.73 m2: n = 1416, 45-49.9 ml/min/1.73 m2: n = 118, <45 ml/min/1.73 m2: n = 11). The reduced eGFR group was associated with an older age and higher risk profile of traditional cardiovascular risk factors.

Relationship of proteinuria and eGFR with incident hypertension

During a mean follow-up period of 9.3 years (271,383 person-years), 43.9% of the cohort (12,818 participants) developed hypertension. The number of incident hypertension cases determined by the use of antihypertensive drugs was 2.2% (292 participants) of all incident hypertension cases. The cumulative incidence of hypertension was higher in the positive proteinuria group than in the negative proteinuria group in a Kaplan-Meier analysis (negative: 43.6%; trace: 54.2%; > 1+: 61.0% in 10 years; log-rank test, p < 0.001) (Fig. 1A). Similarly, the cumulative incidence of hypertension was higher in the reduced eGFR group than in the preserved eGFR group (>60 ml/min/1.73 m2: 43.4%; 50-59.9 ml/min/1.73 m2: 52.9%; <50 ml/min/1.73 m2: 62.8% in 10 years; log-rank test, p < 0.001) (Fig. 1B). The median duration since test of proteinuria/reduced eGFR was 5 (2-10) years, and that of reduced eGFR 5 (2-10) years.

The association between the two positive proteinuria categories (trace and > 1 +) and incident hypertension remained significant even after adjusting for age (Table 2). Further adjustment for other potential confounders attenuated the associations; however, the association for proteinuria > 1 + remained significant, even in model 5, which included eGFR (adjusted HR 1.19 [95% CI, 1.06 to 1.34], p < 0.001). Notably, when we compared positive vs. negative proteinuria, the adjusted HR was statistically significant, even in model 5 (1.14 [95% CI, 1.03 to 1.26], p < 0.001). On the other hand, the association between a reduced eGFR (>60 ml/min/1.73 m2) and incident hypertension was more substantially attenuated by the adjustment for age. However, a significant association was observed for an eGFR of < 50 ml/min/1.73 m2 only (vs. > 60 ml/min/1.73 m2) after further adjustment (1.29 [95% CI, 1.03 to 1.61] in model 5, p < 0.001). We did not observe any significant associations between a reduced eGFR (< 60 ml/min/1.73 m2) and incident hypertension in models 3-5 (HR 1.02 [0.95-1.10] in model 3).

Subgroup analysis

We further evaluated the association between positive proteinuria (vs. negative proteinuria) and incident hypertension in several subgroup

o a) o c œ

13 ' o

(%) 75

Log-rank (overall) P<0.001

o in c œ ■E œ

I I !---1 i-

i-—-___j

I I I—j I

Number at risk

2 4 6 8

Analysis time (year)

negative trace

28,468 236 477

26,077 202 383

22,056 149 272

18,794 117 224

16,279 96 176

13,819 83 148

(%) 75 -

Log-rank (overall) P<0.001

I I .I---1___j

Number at risk

- >60 27,636

- 50-59.9 1,416

-<50 129

468 Analysis time (year)

25,373 1,202 87

21,504 921 52

18,369 729 37

15,949 576 26

13,565 467 18

Fig. 1. A. Cumulative incidence of hypertension according to the level of proteinuria estimated using a Kaplan-Meier analysis. Footnote: The blue dotted line indicates subjects without proteinuria. The brown dotted line indicates subjects with dipstick trace proteinuria. The green dotted line indicates subjects with dipstick >+ proteinuria. B. Cumulative incidence of hypertension according to the eGFR estimated using a Kaplan-Meier analysis. Footnote: The blue dotted line indicates subjects with an eGFR of >60 ml/min/1.73 m2. The brown dotted line indicates subjects with an eGFR of 50-59.9 ml/min/1.73 m2. The green dotted line indicates subjects with an eGFR of < 50 ml/min/1.73 m2.eGFR: estimated glomerular filtration rate.

analyses divided by the following parameters: baseline BP, age, BMI, diabetes mellitus, dyslipidemia, current smoking and current alcohol intake. Positive associations between positive proteinuria and incident hypertension were observed in several of the subgroups tested, with few significant interactions. Of importance, the HR was significant among individuals with an optimal BP at baseline (< 120/80 mm Hg) (adjusted HR 1.31 [95% CI, 1.10 to 1.56], p = 0.003) (Fig. 2A). On the other hand, a reduced eGFR of < 60 ml/min/1.73 m2 was not positively associated with the incidence of hypertension in nearly all of the subgroups tested (Fig. 2B). A reduced eGFR of <50 ml/min/1.73 m2 (vs. eGFR > 60 ml/min/1.73 m2) was significantly associated with the incidence of hypertension in several groups, with few interactions (Fig. 2C). We conducted a sensitivity analysis BMI cut off of 23.0 kg/m2, because the Regional Office for Western Pacific Region of WHO (WPRO criteria) proposed a separate classification of obesity for Asia defining adult overweight as a BMI >23.0 kg/m2, and got similar results (data not shown).

Table2

Multivariate-adjusted hazard ratios of incident hypertension according to the level of dipstick proteinuria/eGFR.

Hazard ratio (95% CI)

Model 1 Model 2 Model 3 Model 4 Model 5

Dipstick proteinuria Negative (n = 28,468) Trace (n = 236) >1+ (n = 477) Negative (n = 28,468) Positive (n = 713) eGFR >60 (n = 27,636) 50-59.9 (n = 1416) <50 (n = 129) >60 (n = 27,636) <60 (n = 1545)

Model 1: Crude model.

Model 2: Adjusted for age (continuous).

Model 3: Model 2 + adjusted for BMI (continuous), total cholesterol (continuous), uric acid (continuous), diabetes mellitus (yes/no), current smoking (yes/no) and current alcohol intake

Model 4: Model 3 + adjusted for baseline mean BP (continuous).

Model 5: Model 4 + adjusted for eGFR (continuous) or proteinuria (positive/negative), as appropriate.

Incident hypertension was defined as a newly detected BP of > 140/90 mm Hg and/or the initiation of antihypertensive drugs.

eGFR: estimated glomerular filtration rate, BMI: body mass index, BP: blood pressure.

1.00 (reference) 1.48 (l.24-1.76) 1.79 (l.59-2.0l) 1.00 (reference) 1.68 (l.52-1.85)

1.00 (reference)

1.46 (1.35-1.57)

2.47 (1.99-3.07) 1.00 (reference) 1.58 (1.48-1.70)

1.00 (reference) 1.42 (1.19-1.69) 1.68 (1.49-1.88) 1.00 (reference) 1.59 (1.44-1.75)

1.00 (reference) 1.14(1.06-1.23) 1.71 (1.37-2.13) 1.00 (reference) 1.15 (1.07-1.24)

1.00 (reference) 1.35 (1.13-1.60) 1.49 (1.32-1.67) 1.00 (reference) 1.44 (1.30-1.59)

1.00 (reference) 1.00 (0.93-1.08) 1.55 (1.25-1.94) 1.00 (reference) 1.04(0.96-1.11)

1.00 (reference) 1.05 (0.88-1.25) 1.20 (1.06-1.35) 1.00 (reference) 1.15 (1.04-1.27)

1.00 (reference) 0.97 (0.90-1.05) 1.32 (1.06-1.65) 1.00 (reference) 1.00 (0.93-1.07)

1.00 (reference) 1.04 (0.88-1.24) 1.19 (1.06-1.34) 1.00 (reference) 1.14(1.03-1.26)

1.00 (reference) 0.97 (0.90-1.05) 1.29 (1.03-1.61) 1.00 (reference) 0.99 (0.92-1.07)

Discussion

The present study, which employed annual blood pressure measurement for 10 years, demonstrated that dipstick proteinuria and a reduced eGFR are associated with incident hypertension independently of each other and act as potential confounders in young to middle-aged Japanese males. The observed positive associations were consistent for proteinuria in various clinical subgroups. Similarly, a significant association between the eGFR and the incidence of hypertension was observed in the participants with an eGFR of < 50 ml/min/1.73 m2. When eGFR values of < 60 or > 60 ml/min/1.73 m2 were compared, the associations were not significant after adjusting for age and other potential confounders.

Our results showing a positive association between proteinuria and incident hypertension are in line with those of previous studies (Brantsma et al., 2006; Forman et al., 2008; Gerber et al., 2006; Inoue et al., 2006; Jessani et al., 2012; Wang et al., 2005; Wang et al., 2007) and extend the literature in several aspects. First, we confirmed the presence of this association among a large cohort of Asian males. Second, the association was independent of eGFR. Third, the association remained significant, even in the participants with an optimal BP at baseline. This means that our findings did not change after excluding individuals with latently elevated BP associated with proteinuria, who are likely to develop hypertension. Fourth, we observed a consistent association across several subgroups according to clinical risk factors, such as age, diabetes mellitus and dyslipidemia. Finally, we were able to evaluate the association for a long term of over 10 years.

There are several potential mechanisms linking proteinuria to incident hypertension. Proteinuria exerts a toxic effect on proximal tubular epithelial cells, generating chemotactic factors, such as monocyte che-motactic protein-1 (MCP-1) and reactive oxygen species (ROS) (Morigi et al., 2002; Wang et al., 1999). These factors damage the renal microvas-culature and tubulointerstitium, resulting in the impairment of salt excretion and thus salt-sensitive hypertension (Johnson et al., 2002). Additionally, protein overload in proximal tubular cells leads to the secretion of endothelin-1, which can constrict systemic blood vessels (Dhaun et al., 2012). Furthermore, proteinuria reflects systemic endothelial dysfunction, which is known to be associated with vasoconstriction due to a decreased level of endothelial nitric oxide (NO) (Gkaliagkousi et al., 2009; Higashi and Chayama, 2002; Quyyumi and Patel, 2010; Sander et al., 1999). Therefore, the presence of proteinuria may be a harbinger of future hypertension.

The law stipulates annual medical health examinations for all workers in Japan. Dipstick urine tests have the advantage of being inexpensive, quick and easy to perform therefore, it can be carried out during screening in any countries. Also, to evaluate kidney measures and follow these markers may encourage individuals at risk for hypertension to modify their life style such as sodium intake or physical activity at an early stage of pre-hypertension. Previous studies in Japan have clarified that the detection of proteinuria using dipstick tests in mass screening settings is a strong, independent predictor of end-stage renal disease (Iseki et al., 2003; Iseki et al., 2008). Measuring the level of urinary proteins is important not only for assessing the prognosis and diagnosis of kidney diseases (Matsushita et al., 2010; Herget-Rosenthal et al., 2013), but also managing hypertension and diabetes mellitus, both of which can induce nephropathy (Araki et al., 2007, Ibsen et al., 2005). Our results suggest that the early detection of proteinuria with a simple urine dipstick test may allow clinicians to identify individuals at high risk for developing hypertension. In addition, obtaining information regarding proteinuria may be useful for encouraging persons at high risk of hypertension to modify their lifestyle. However, further studies are needed to evaluate whether these approaches are actually effective, particularly given the modest effect of positive proteinuria and incident hypertension observed in our study.

In contrast to the many studies investigating the association between proteinuria and incident hypertension, the number of epidemio-logical studies reporting an association between a reduced eGFR and future hypertension is limited (Brantsma et al., 2006; Kestenbaum et al., 2008; Takase et al., 2012). Two studies have reported a significant association between a reduced kidney function and the incidence of hypertension (Kestenbaum et al., 2008; Takase et al., 2012). On the other hand, a weaker association with incident hypertension for eGFR than for proteinuria has been reported in the PREVEND (Prevention of REnal and Vascular End stage Disease) Study (Brantsma et al., 2006). Similarly, in our study, the association between an eGFR of <60 compared to > 60 ml/min/1.73 m2 and incident hypertension was weaker than that for positive proteinuria (vs. negative proteinuria). In this study, the eGFR was associated with incident hypertension only when it was lower than 50 ml/min/1.73 m2, a level recommended for referral to a nephrologist by the Japanese Society of Nephrology (Imai et al., 2008). However, the number of participants with an eGFR of <60 ml/min/1.73 m2 in our study was quite small; thus, these results should be interpreted carefully. Further investigations are needed to determine what level of GFR deterioration begins to affect blood pressure.

The potential limitations of our study include the single measurement of eGFR and the use of dipstick proteinuria as a measure of kidney damage. Although the use of the urinary albumin-to-creatinine ratio (UACR) is preferable, as recommended in clinical guidelines, the

presence of dipstick proteinuria has been shown to predict the future risk of albuminuria and is considered useful for screening (Matsushita et al., 2010). Also, we do not have data on causes of proteinuria or kidney dysfunction, although the recent CKD guidelines emphasize the

Optimal BP Normal-high normal BP Age >40 Age <40 BMI >25 BMI <25 Diabetes (+) Diabetes (-) Dyslipidemia (+) Dyslipidemia (-) Smoking (+) Smoking (-) Alcohol (+) Alcohol (-)

Optimal BP Normal-high normal BP Age >40 Age <40 BMI >25 BMI <25 Diabetes (+) Diabetes (-) Dyslipidemia (+) Dyslipidemia (-) Smoking (+) Smoking (-) Alcohol (+) Alcohol (-)

(n=17,592)

(n=11,589)

(n=10,566)

(n=18,615)

(n=5,478)

(n=23,703)

(n=690)

(n=28,491)

(n=6,060)

(n=23,121)

(n=15,981)

(n=13,200)

(n=20,911)

(n=8,270)

Hazard ratio 1.31 (1.10-1.56) 1.09 (0.97-1.23) 1.19 (1.04-1.35) 1.01 (0.87-1.19)

1.04 (0.89-1.23) 1.28 (1.13-1.45) 1.18 (0.88-1.59) 1.13 (1.02-1.26) 0.99 (0.82-1.19) 1.22 (1.09-1.38) 1.12 (0.97-1.29) 1.15 (1.00-1.33) 1.18 (1.05-1.32)

1.05 (0.87-1.26)

Hazard ratio

0.91(0.80-1.04) 1.03(0.94-1.13) 0.94(0.87-1.02) 1.06(0.88-1.27) 1.04(0.92-1.17) 0.96(0.88-1.05) 1.26(0.91-1.75) 0.98(0.91-1.06) 0.93(0.82-1.05) 1.03(0.94-1.13) 0.95(0.85-1.07) 1.00(0.91-1.10) 0.95(0.90-1.07) 1.05(0.91-1.22)

p for interaction 0.079

p for interaction 0.059

Fig. 2. A. Multivariate-adjusted hazard ratios (95% CIs) of incident hypertension in the subgroups (dipstick proteinuria positive vs. negative).Footnote:The HRs were adjusted for age (continuous), BMI (continuous), total cholesterol (continuous), uric acid (continuous), diabetes (yes/no), current smoking (yes/no), current alcohol intake (yes/no), baseline mean BP (continuous) and eGFR (continuous).eGFR: estimated glomerular filtration rate, BMI: body mass index, BP: blood pressure.B. Multivariate-adjusted hazard ratios (95% CIs) of incident hypertension in the subgroups (eGFR< 60 vs. > 60 ml/min/1.73 m2).Footnote:The HRs were adjusted for age (continuous), BMI (continuous), total cholesterol (continuous), uric acid (continuous), diabetes (yes/no), current smoking (yes/no), current alcohol intake (yes/no), baseline mean BP (continuous) and proteinuria (positive/negative).eGFR: estimated glomerular filtration rate, BMI: body mass index, BP: blood pressure.C. Multivariate-adjusted hazard ratios (95% CIs) of incident hypertension in the subgroups (eGFR< 50 vs. > 60 ml/min/ 1.73 m2).Footnote:The HRs were adjusted for age (continuous), BMI (continuous), total cholesterol (continuous), uric acid (continuous), diabetes (yes/no), current smoking (yes/no), current alcohol intake (yes/no), baseline mean BP (continuous) and proteinuria (positive/negative).eGFR: estimated glomerular filtration rate, BMI: body mass index, BP: blood pressure.

Optimal BP Normal-high normal BP Age >40 Age <40 BMI >25 BMI <25 Diabetes (+) Diabetes (-) Dyslipidemia (+) Dyslipidemia (-) Smoking (+) Smoking (-) Alcohol (+) Alcohol (-)

Hazard ratio

1.08(0.85-1.37) 1.15(1.01-1.30) 1.04(0.93-1.17) 1.47(0.90-2.40) 1.24(1.02-1.52) 1.07(0.94-1.23) 1.64(1.16-2.33) 1.12(0.99-1.26) 1.09(0.92-1.29) 1.18(1.02-1.37) 1.01(0.84-1.22) 1.23(1.07-1.42) 1.20(0.90-1.60) 1.57(1.10-2.25)

p for interaction 0.371

Fig. 2 (continued).

importance of causes (KDIGO guideline, 2013). Other potential limitations of this study include the following: our study population consisted of a single race and males only. With a healthy study population, the study might be underpowered to detect an association between reduced eGFR (<60 ml/min/1.73 m2) and incident hypertension. Additionally, as with any observational study, we cannot rule out the possibility of residual unmeasured and unknown confounding factors.

Conclusion

Both proteinuria, as assessed using a dipstick strip, and a reduced eGFR (<50 ml/min/1.73 m2) are associated with incident hypertension independently of each other and known potential confounders. These findings suggest that both kidney damage and kidney dysfunction play important roles in the development of hypertension in young to middle-aged Japanese males.

Conflicts of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

The authors thank the health care providers for their hard work and excellent assistance with this study.

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