Association between Overall Lifestyle Changes and the Incidence of Proteinuria: A Population-based, Cohort Study

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1 ORIGINAL ARTICLE Associatio betwee Overall Lifestyle Chages ad the Icidece of Proteiuria: A Populatio-based, Cohort Study Miako Wakasugi 1, Juichiro Kazama 2, Ichiei Narita 3, Kuitoshi Iseki 3, Shouichi Fujimoto 3, Toshiki Moriyama 3, Kuihiro Yamagata 3, Tsueo Kota 3, Kazuhiko Tsuruya 3, Koichi Asahi 3, Masahide Kodo 3, Issei Kurahashi 4, Yasuo Ohashi 5, Kejiro Kimura 3 ad Tsuyoshi Wataabe 3 Abstract Objective This study aimed to examie the associatio betwee the chages i a overall healthy lifestyle, as quatified by the umber of uhealthy lifestyle factors ad obesity status, ad the icidece of proteiuria i the geeral Japaese populatio. Methods A retrospective cohort study was coducted amog 99,404 (me, 36.9%) participats aged from years of age who uderwet two health check-ups with a 1-year iterval i Japa betwee 2008 ad Ay participats with chroic kidey disease at baselie were excluded. The smokig status, body mass idex, physical activity, alcohol cosumptio, ad healthy eatig habits were combied ito a simple overall healthy lifestyle score ragig from 0 to 5. The chages i overall healthy lifestyle scores from baselie (rage, -5 to +5) ad the icidece of proteiuria, defied by a dipstick urialysis (score 1+), were assessed at the secod check-up. A logistic regressio aalysis was used to examie the associatio betwee the chages i overall healthy lifestyle scores ad the icidece of proteiuria. Results After oe year of follow-up, 3.9% of me ad 2.4% of wome developed proteiuria. Each icrease (or decrease) i the chages i overall healthy lifestyle scores was associated with a reduced (or icreased) risk of proteiuria i both me (odds ratio (OR) 0.87; 95% cofidece iterval (CI), ) ad wome (OR 0.87; 95%CI, ) after adjustig for age, baselie lifestyle scores, hypertesio, diabetes mellitus, ad hypercholesterolemia. Stratified aalyses based o age, the presece or absece of hypertesio, or diabetes mellitus revealed similar results. Coclusio Overall lifestyle chages, eve withi a year, were foud to ifluece the icidece of proteiuria. Key words: CKD, epidemiology, multiple behaviour itervetio, obesity, proteiuria (Iter Med 56: , 2017) (DOI: /iteralmedicie ) Itroductio The prevetio of proteiuria/albumiuria is highly desirable i both cliical ad public health settigs, because proteiuria/albumiuria is a progostic marker of kidey disease, as well as a idepedet risk factor for cardiovascular morbidity ad mortality (1-6). The odds of developig proteiuria/albumiuria are heighteed by poor lifestyle behaviours ad the obesity status both idepedetly ad i com- Divisio of Comprehesive Geriatrics i Commuity, Niigata Uiversity Graduate School of Medical ad Detal Scieces, Japa, Departmets of Nephrology ad Hypertesio, Fukushima Medical Uiversity, Japa, Steerig Committee for Desig of the comprehesive health care system for chroic kidey disease based o the idividual risk assessmet by Specific Health Checkups, Japa, Aalysis LLC, Japa ad Departmet of Itegrated Sciece ad Egieerig for Sustaiable Society, Chuo Uiversity, Japa Received for publicatio July 16, 2016; Accepted for publicatio September 19, 2016 Correspodece to Dr. Miako Wakasugi, miakowa@med.iigata-u.ac.jp 1475

2 Iter Med 56: , 2017 DOI: /iteralmedicie biatio (7-11). Because multiple lifestyle behaviours coexist ad may iteract, studyig the combied impact of lifestyle factors istead of their idividual impact o proteiuria/albumiuria is highly relevat. Furthermore, applyig a simple lifestyle idex is useful for decisio-makers ad political govermets, ad for health professioals, ad it may also motivate people to chage their lifestyles i a healthier directio, particularly if the message is simple. A overall uhealthy lifestyle, quatified as the umber of uhealthy life-related factors ad obesity status, is associated with the icidece of microalbumiuria (10) ad proteiuria (11). A commuity-based prospective cohort study reported that a overall uhealthy lifestyle, icludig curret smokig, obesity (body mass idex (BMI) of 30 kg/m 2 ), ad a poor diet quality as defied by a low Dietary Approaches to Stop Hypertesio (DASH)-type diet score, was sigificatly associated with the icidece of microalbumiuria over a 15-year period, after adjustig for age, sex, family history of kidey disease, educatio, baselie hypertesio, ad diabetes (10). Aother commuity-based cohort study reported that a overall uhealthy lifestyle, icludig curret smokig, obesity (BMI of 25 kg/m 2 ), heavy alcohol cosumptio, lack of physical activity, ad uhealthy eatig habits, was sigificatly associated with the icidece of proteiuria (11). These studies, however, were limited i that they failed to address how chages i lifestyle-related factors are associated with the icidece of proteiuria. Lifestyles chage throughout life, eve i the elderly stages (12). I the above cotext, this study aimed to examie the associatio betwee chages i a overall healthy lifestyle ad the icidece of proteiuria i the geeral Japaese populatio. Study populatio Materials ad Methods This retrospective cohort study used data from the Specific Health Checkups ad Guidace System i Japa (SHC) i 2008 ad The SHC has bee described elsewhere (13, 14). I brief, the participats were idividuals aged from years who uderwet the SHC throughout Japa. The participats aswer a self-admiistered questioaire that covers their medical history, smokig habits, alcohol itake, exercise habits, ad eatig habits. Traied staff measures the height, weight, ad blood pressure of each participat. Serum ad spot urie samples were collected. The preset study icluded participats who uderwet two health check-ups with a 1-year iterval i Japa betwee 2008 ad Ay participats with chroic kidey disease (CKD) at baselie were excluded. CKD was defied as glomerular filtratio rate (GFR) <60 ml/mi/1.73 m 2 as calculated usig the estimated GFR (egfr) formula for Japaese idividuals (15), 1+ proteiuria o urialysis, or both (16). All participats remaied aoymous ad the study complied with the Declaratio of Helsiki ad Ethical Guidelies for Epidemiological Studies published by the Miistry of Educatio, Sciece ad Culture ad the Miistry of Health, Labour ad Welfare of Japa. The study protocol was approved by the ethics committee of Fukushima Medical Uiversity (IRB No. 1485). Chages i overall healthy lifestyle scores ad covariates Overall healthy lifestyle scores were calculated at baselie ad at the oe-year follow-up by addig up the total umber of lifestyle factors for which the participats were at low risk. For each lifestyle factor (smokig, BMI, alcohol itake, exercise habits, ad eatig habits), we created a biary lowrisk variable, i which the participats were give a score of 1 if they met the criteria for low risk, ad 0 if otherwise, i accordace with a previous study (11, 13, 17-27). The apriori defiitio of low risk was based ot oly o the curret literature ad recommeded guidelies, but also o the levels that were cosidered to be realistically obtaiable withi the geeral populatio (11, 13). The overall healthy lifestyle scores raged from 0 (least healthy) to 5 (most healthy). For smokig, a low risk was defied as ot curretly smokig. A optimal body weight was defied as a BMI <25 kg/m 2, the stadard World Health Orgaizatio cutoff for healthy weight. For alcohol, low risk was defied as a average daily alcohol cosumptio of less tha 20 g. For exercise habits, two questios were posed: Are you i the habit of exercisig to a light sweat for more tha 30 miutes at a time, 2 times weekly, for over a year? ad I daily life, do you walk or do ay equivalet amout of physical activity more tha oe hour a day? Those who aswered Yes to both questios were cosidered low risk based o the curret Japaese guidelies (11, 13, 28). Regardig eatig habits, the followig two questios were posed: Do you skip breakfast more tha 3 times per week? ad Do you eat sacks after supper more tha 3 times a week?. Those who aswered No to both questios were cosidered low risk (11, 13). We also calculated chages i overall healthy lifestyle scores durig a oe-year period (rage, -5 to +5) ad classified the participats accordig to score chages ito three categories: improved (icreased from lower to higher scores), deteriorated (decreased from higher to lower scores), ad uchaged (the same scores) (29). Diabetes was defied i accordace with the America Diabetes Associatio guidelies (30) as a fastig plasma glucose (FPG) cocetratio of 126 mg/dl or higher, HbA1c of 6.5% or higher, or self-reported use of ati-hyperglycaemic drugs. The value of haemoglobi A1c (HbA1c) was estimated as a Natioal Glycohemoglobi Stadardizatio Program equivalet value calculated with the followig equatio (31): HbA1c (%) = HbA1c (%) + 0.4%. Hypertesio was defied as the use of atihypertesive medicatio, a systolic blood pressure 140 mmhg ad/or a diastolic blood pressure 90 mmhg, or both. Hypercholesterolemia 1476

3 Iter Med 56: , 2017 DOI: /iteralmedicie Figure 1. Flowchart of the participat selectio. was defied as the use of cholesterol-lowerig medicatio, a low-desity lipoprotei (LDL) cholesterol level 140 mg/dl, or both. Outcome measuremet The primary ed-poit was the icidece of proteiuria, defied as a dipstick urialysis score of 1+ or greater (equivalet to 30 mg/dl) due to the difficulty of discrimiatig betwee egative ad trace positive dipstick readigs (32, 33), at the SHC i Statistical aalyses Data were aalysed separately by sex, ad preseted as the mea (stadard deviatio) for cotiuous variables ad the umber of subjects (percet) for categorical variables. Descriptive statistics of cliical characteristics across the categories of overall healthy lifestyle score at baselie were compared usig the chi-square test for tred for categorical data, ad a aalysis of variace (ANOVA) or the Jockheere-Terpstra test for cotiuous variables. A logistic regressio was used to assess the relatioship betwee chages i overall healthy lifestyle scores ad the icidece of proteiuria after adjustig for a priori idetified potetial covariates. The iitial model tested the mai effect of chages i overall healthy lifestyle scores as a cotiuous variable o the icidece of proteiuria, after adjustig for age (per 10-year icrease) ad overall healthy lifestyle scores at baselie (cotiuous variable). The secod, fully adjusted model added a term for hypertesio (yes/o), diabetes (yes/o), ad hypercholesterolemia (yes/o). To assess the robustess of the mai results, sesitivity aalyses were performed. First, we performed a multiple logistic regressio aalysis with baselie overall healthy lifestyle scores as a categorical variable. For wome, baselie overall healthy lifestyle scores of 0 (least healthy) ad 1 were combied ito oe category because there were few cases. Secod, a age-stratified aalysis was performed, sice the age distributio of the study participats was dispersed. We icluded a cotiuous term for age i the agestratified subgroup aalysis. Baselie overall healthy lifestyle scores of 0-1 for me, ad 0-2 for wome, were treated as oe category, because there were few cases. Third, subgroup aalyses were performed based o the presece or absece of diabetes or hypertesio. Fially, we ra separate models predictig the icidece of proteiuria for each idividual lifestyle factor with the healthy lifestyle factor as a categorical variable. p<0.05 was cosidered to be statistically sigificat, ad all tests were two-tailed. All statistical aalyses were performed with SPSS for Widows statistical package (Versio 18.0; SPSS, Chicago, IL, USA) ad the Stata/MP software program (Versio 12.1; Stata Corp, College Statio, TX, USA). Results Of the 667,218 idividuals aged years who participated i the SHC i 2008, we excluded those for whom serum creatiie (=112,540) measuremets were uavailable (Fig. 1). The serum creatiie level is ot icluded as a madatory item of the SHC, but it is icluded i some areas. Amog these idividuals, 453,660 had ormal real fuctio (egfr 60 ml/mi/1.73 m 2 ) ad egative proteiuria o dipstick examiatio. Amog these idividuals, those with missig iformatio (=252,473) were excluded. Of the idividuals who were ot missig ay iformatio (= 201,187), 127,784 were re-examied i the 2009 SHC pro- 1477

4 Iter Med 56: , 2017 DOI: /iteralmedicie Table 1. Cliical Characteristics of Male Participats by Healthy Lifestyle Scores (=36,703). 0 [=134 (0.4%)] 1 [=1,654 (4.5%)] Healthy lifestyle scores at baselie 2 [=5,967 (16.3%)] 3 [=11,535 (31.4%)] 4 [=12,302 (33.5%)] 5 [=5,111 (13.9%)] Baselie data Age (years) 55.8 (8.8) 57.8 (9.3) 60.8 (8.8) 63.1 (8.4) 64.8 (7.6) 66.7 (6.3) <0.001 History of stroke (%) <0.001 History of heart disease (%) <0.001 History of real failure (%) Comorbidities (%) Hypertesio <0.001 Diabetes Hypercholesterolemia BMI (kg/m 2 ) 27.3 (2.2) 25.5 (3.2) 24.5 (3.3) 23.8 (3.0) 22.8 (2.4) 22.2 (1.8) <0.001 Systolic BP (mmhg) 131 (15) 130 (17) 131 (17) 130 (17) 129 (16) 129 (16) 0.02 Diastolic BP (mmhg) 82 (11) 80 (11) 79 (11) 78 (10) 77 (10) 76 (10) <0.001 HDL cholesterol (mg/dl) 55 (14) 55 (15) 57 (15) 58 (15) 59 (16) 61 (15) <0.001 LDL cholesterol (mg/dl) 125 (33) 121 (32) 121 (31) 121 (29) 121 (28) 121 (27) 0.13 Triglycerides (mg/dl) 147 [103, 217] 134 [93, 202] 118 [84, 171] 106 [76, 151] 97 [70, 136] 88 [65, 122] <0.001 FPG (mg/dl) 106 (23) 103 (26) 101 (22) 100 (21) 100 (20) 99 (19) <0.001 Haemoglobi A 1c(%) 5.9 (0.7) 5.8 (0.9) 5.8 (0.7) 5.7 (0.7) 5.7 (0.7) 5.7 (0.6) 0.01 Serum Cr (mg/dl) 0.77 (0.11) 0.78 (0.11) 0.78 (0.11) 0.78 (0.11) 0.79 (0.10) 0.80 (0.10) <0.001 egfr (ml/mi/1.73 m 2 ) 85 (15) 82 (15) 81 (14) 79 (14) 78 (13) 76 (12) <0.001 Follow-up data Healthy lifestyle scores i 2009 (%) Icidece of proteiuria (%) <0.001 Numbers are mea (stadard deviatio) or proportio. For triglycerides, media ad the 25th ad 75th percetile are show. BMI: body mass idex, BP: blood pressure, HDL: high-desity lipoprotei, LDL: low-desity lipoprotei, FPG: fastig plasma glucose, Cr: creatiie, egfr: estimated glomerular filtratio rate p for tred gram. Agai, those with missig iformatio were excluded (=28,380), thus resultig i a fial sample size of 99,404. Compared with those who met the iclusio criteria, those who were excluded who did ot have CKD i 2008 were more likely to be male, youger, have hypertesio, diabetes, a lower baselie healthy lifestyle score, ad a history of stroke, heart disease, or real disease (Supplemetary Table 1). Tables 1 ad 2 show the cliical characteristics as a fuctio of healthy lifestyle scores by sex. Participats with higher healthy lifestyle scores at baselie were more likely to be older, have a history of stroke, lower BMI, lower triglyceride levels, lower fastig glucose, lower egfr, ad less likely to have hypertesio ad diabetes i both me ad wome. Me with higher healthy lifestyle scores at baselie were more likely to have a history of heart disease ad higher high-desity lipoprotei (HDL)-cholesterol levels, while wome with higher healthy lifestyle scores at baselie were more likely to have a history of real failure. After oe year of follow-up, 23.1% of me ad 18.4% of wome had a higher overall healthy lifestyle score (the improved category), whereas 19.4% of me ad 16.9% of wome had a lower overall healthy lifestyle scores (the deteriorated category); 57.5% of me ad 64.7% of wome had the same scores as those at baselie (the uchaged category). The oset of proteiuria was oted i 1,434 of 36,703 me (3.9%) ad 1,514 of 62,701 wome (2.4%). Overall, a clearly iverse dose-depedet relatioship was observed betwee the baselie overall healthy lifestyle scores ad the icidece of proteiuria i both me ad wome (p<0.001 for tred, Fig. 2). The icidece of proteiuria teded to be higher amog the participats i the deteriorated category, but lower i the improved category, compared with those i the uchaged category. Table 3 shows the results of a logistic regressio aalysis estimatig the odds of the icidece of proteiuria after a oe-year follow-up by sex. These results idicate that havig hypertesio, diabetes, or lower baselie overall healthy life- 1478

5 Iter Med 56: , 2017 DOI: /iteralmedicie Table 2. Cliical Characteristics of Female Participats by Healthy Lifestyle Scores (=62,701). 0 [=26 (0.0%)] 1 [=347 (0.6%)] Healthy lifestyle scores at baselie 2 [=3,363 (5.4%)] 3 [=14,318 (22.8%)] 4 [=31,771 (50.7%)] 5 [=12,876 (20.5%)] Baselie data Age (years) 56.4 (8.4) 56.2 (9.1) 60.0 (8.8) 62.4 (8.1) 63.9 (7.4) 65.9 (5.9) <0.001 History of stroke (%) History of heart disease (%) History of real failure (%) Comorbidities (%) Hypertesio <0.001 Diabetes <0.001 Hypercholesterolemia BMI (kg/m 2 ) 27.2 (1.9) 24.6 (4.2) 25.5 (4.0) 24.4 (3.8) 21.8 (2.7) 21.4 (2.1) <0.001 Systolic BP (mmhg) 127 (16) 127 (17) 128 (18) 128 (17) 127 (17) 127 (17) 0.97 Diastolic BP (mmhg) 75 (12) 75 (10) 76 (11) 75 (10) 74 (10) 74 (10) 0.44 HDL cholesterol (mg/dl) 65 (13) 64 (17) 63 (15) 64 (16) 67 (16) 68 (16) 0.06 LDL cholesterol (mg/dl) 127 (42) 125 (35) 131 (32) 131 (30) 129 (29) 129 (29) 0.42 Triglycerides (mg/dl) 128 [91, 209] 113 [79, 166] 104 [76, 144] 96 [71, 132] 88 [66, 119] 85 [65, 115] <0.001 FPG (mg/dl) 101 (15) 97 (16) 97 (20) 95 (17) 93 (14) 94 (14) Haemoglobi A 1c(%) 5.7 (0.6) 5.6 (0.6) 5.7 (0.6) 5.7 (0.6) 5.7 (0.5) 5.7 (0.5) 0.51 Serum Cr (mg/dl) 0.57 (0.10) 0.58 (0.09) 0.59 (0.09) 0.59 (0.08) 0.60 (0.08) 0.60 (0.08) 0.01 egfr (ml/mi/1.73 m 2 ) 87 (17) 84 (17) 81 (15) 80 (14) 79 (14) 77 (13) <0.001 Follow-up data Healthy lifestyle scores i 2009 (%) Icidece of proteiuria (%) <0.001 Numbers are mea (stadard deviatio) or proportio. For triglycerides, media ad the 25th ad 75th percetile are show. BMI: body mass idex, BP: blood pressure, HDL: high-desity lipoprotei, LDL: low-desity lipoprotei, FPG: fastig plasma glucose, Cr: creatiie, egfr: estimated glomerular filtratio rate p for tred style scores, ad decreases i healthy lifestyle scores were all associated with greater odds of developig proteiuria i both me ad wome. Each icrease i healthy lifestyle factors at baselie was associated with 18% (95% cofidece iterval (CI), 13-22%) ad 24% (95% CI, 18-29%) lower adjusted odds ratios (OR) for icidet proteiuria i me ad wome, respectively. A 1-healthy lifestyle score icrease (or decrease) after oe year was idepedetly associated with a 13% (95% CI, 6-19%) ad 13% (95% CI, 6-20%) reductio (or icrease) i OR for icidet proteiuria i me ad wome, respectively. Logistic regressio aalyses were repeated with baselie overall healthy lifestyle scores as a categorical variable istead of a cotiuous variable, yieldig similar results (Fig. 3). Each icrease (or decrease) i chages i healthy lifestyle scores was associated with a reduced (or icreased) OR for icidet proteiuria i both me (OR, 0.87; 95% CI, ) ad wome (OR, 0.87; 95% CI, ). Whe stratified by age categories, the associatios were geerally similar with those of the etire study populatio, although they were o loger sigificat, except i the female age category of years of age. Stratified aalyses based o the presece or absece of hypertesio revealed that the associatios were geerally similar with those of the etire study populatio. Furthermore, the associatios were cosistet amog the participats without diabetes; amog the participats with diabetes, o sigificat associatio was observed i both me (OR, 0.89; 95% CI, ) ad wome (OR, 0.97; 95% CI, ). We also performed a aalysis usig separate models predictig the icidece of proteiuria for each idividual lifestyle factor with the healthy lifestyle factor as a categorical variable (Table 4). Compared with the category of idividuals with o adherece to healthy lifestyle factors at baselie (Y0) or oe-year follow-up (Y1) ( Neither Y0 Y1 ), improved chages i alcohol cosumptio were sigificatly associated with reduced OR for icidet proteiuria i me (OR, 0.73; 95% CI, ). O the other had, quittig 1479

6 Iter Med 56: , 2017 DOI: /iteralmedicie Figure 2. Icidece of proteiuria as stratified by the baselie scores ad chages i overall healthy lifestyle scores. Chages i the overall healthy lifestyle scores (o-smokig, healthy weight, adequate alcohol drikig, physically active, ad healthy eatig habits) were categorized as improved (icreased from lower to higher scores), deteriorated (decreased from higher to lower scores), ad uchaged (the same scores). Overall, a clearly dose-depedet relatioship was observed betwee the baselie overall healthy lifestyle scores ad the icidece of proteiuria i both me ad wome ( : p<0.001 for tred). Table 3. Predictio of Icidece of Proteiuria by Chages i Healthy Lifestyle Score. Variable Male (=36,703) Female (=62,701) Odds Ratio (95% CI) p value Odds Ratio (95% CI) p value Age, y 1.00 (1.00, 1.01) (1.00, 1.01) 0.11 Hypertesio 1.71 (1.53, 1.91) < (1.43, 1.77) <0.001 Diabetes 1.71 (1.50, 1.96) < (1.41, 1.96) <0.001 Hypercholesterolemia 1.02 (0.91, 1.14) (0.98, 1.20) 0.13 Healthy lifestyle score chage 0.87 (0.81, 0.94) < (0.80, 0.94) Healthy lifestyle score at baselie 0.82 (0.78, 0.87) < (0.71, 0.82) <0.001 Covariates icluded i the model were age, healthy lifestyle score at baselie, hypertesio, diabetes, ad hypercholesterolemia. CI: cofidece iterval smokig was associated with a icreased OR (OR, 2.05; 95% CI, ) i wome, relative to the Neither Y0 Y1 category. The associatios were ot sigificat i positive chages i other idividual lifestyle factors durig the oeyear follow-up period. Relative to the Neither Y0 Y1 category, egative chages i each idividual lifestyle factor durig the oe-year follow-up period ( Yes Y0, No Y1 ) were ot sigificatly associated with a icreased OR for the icidece of proteiuria. Discussio This atiowide, large retrospective cohort study revealed that about oe fifth of all participats improved their overall healthy lifestyle scores ad aother fifth of the participats demostrated a deterioratio i their scores after a oe-year follow-up, suggestig that lifestyle deterioratio was as commo as lifestyle improvemet i the geeral populatio without CKD. Furthermore, this study demostrated that chages i the overall lifestyle scores, eve withi a dura- 1480

7 Iter Med 56: , 2017 DOI: /iteralmedicie Figure 3. Forest plot showig odds ratios with 95% cofidece itervals for the associatio betwee baselie healthy lifestyle scores or chages i healthy lifestyle scores ad the icidece of proteiuria i the subgroups ad the etire study populatio. All aalyses were adjusted for the followig covariates (except for the variables used to defie the subgroup i each case): age, hypertesio, diabetes, ad hypercholesterolemia. C: chages i healthy lifestyle scores, DM: diabetes mellitus, HT: hypertesio, HLS: healthy lifestyle scores tio as short as oe year, were idepedetly associated with the icidece of proteiuria after adjustig for age, baselie lifestyle scores, hypertesio, diabetes mellitus, ad hypercholesterolemia for both me ad wome without CKD at baselie. A 1-healthy lifestyle score icrease (or decrease) after oe year was idepedetly associated with a 13% reductio (or icrease) i OR for icidet proteiuria i both sexes. These fidigs idicate that lifestyle chages, eve withi a year, ca sigificatly ifluece icidet proteiuria. This simple message is therefore cosidered to be iformative for health professioals to motivate people to chage their lifestyle i a healthier directio. Cosistet with previous studies, a sigificat, graded, iverse associatio was observed betwee the overall healthy lifestyle scores at baselie ad icidet proteiuria. However, with regard to the idividual compoets of the healthy lifestyle score, egative ad positive (with the exceptio of alcohol itake i me) chages i each idividual lifestyle factor after oe year were ot sigificatly associated with a icreased OR for the icidece of proteiuria. These results suggest that although the idividual effects of each factor might be weak or isigificat, multiple healthy lifestyle behaviours might have a additive or syergistic positive ifluece o health. Previous observatioal studies support this possibility by showig liear relatioships betwee risk reductio ad the umber of healthy lifestyle behaviours for several diseases, such as coroary heart disease (17, 18), type 2 diabetes mellitus (19), stroke (20), demetia (21), sudde cardiac death (22), ad cacer (23-25), as well as a reductio i total mortality (26). I additio to the additive or syergistic positive ifluece o health, targetig multiple risk behaviours offers the potetial to icrease health beefits. Multiple behaviour itervetio, defied as efforts to treat two or more health be- 1481

8 Iter Med 56: , 2017 DOI: /iteralmedicie Table 4. Odds Ratios (95% CI) ad p Values for Categorically Defied Idividual Healthy Lifestyle Factor Compoets Predictig the Icidece of Proteiuria, with Neither Y0 Y1 as the Referece, i Me ad Wome. Male (=36,703) Female (=62,701) Healthy Lifestyle Score compoet Neither Y0 Y1 No Y0, Yes Y1 Yes Y0, No Y1 Yes Y1, Yes Y1 Neither Y0 Y1 No Y0, Yes Y1 Yes Y0, No Y1 Yes Y1, Yes Y1 Not smokig ref 1.10 (0.81, 1.49); p=0.54 BMI<25 kg/m 2 ref 0.76 (0.57, 1.02); p=0.06 Low alcohol ref 0.73 (0.58, 0.93); p=0.01 Regular exercise ref 0.92 (0.77, 1.09); p=0.35 Healthy eatig habits ref 0.84 (0.66, 1.06); p= (0.63, 1.56); p= (0.64, 1.15); p= (0.68, 1.10); p= (0.70, 1.03); p= (0.84, 1.31); p= (0.71, 0.92); p= (0.64, 0.81); p< (0.79, 1.01); p= (0.80, 1.04); p= (0.65, 0.89); p=0.001 ref 2.05 (1.21, 3.46); p=0.01 ref 0.98 (0.74, 1.30); p=0.88 ref 0.92 (0.50, 1.69); p=0.79 ref 0.95 (0.80, 1.12); p=0.51 ref 0.87 (0.69, 1.09); p= (0.54, 2.69); p= (0.53, 1.02); p= (0.32, 1.37); p= (0.79, 1.14); p= (0.87, 1.33); p= (0.77, 1.35); p= (0.55, 0.70); p< (0.63, 1.34); p= (0.76, 1.00); p= (0.65, 0.90); p=0.001 Covariates icluded i the model were age, hypertesio, diabetes, hypercholesterolemia, smokig status, BMI, alcohol itake, regular exercise, ad healthy eatig habits (except for the variable used to defie the subgroup i each case). CI: cofidece iterval, Y0: year 0 (at baselie), Y1: year 1 (1 year follow-up) haviours either simultaeously or sequetially withi a limited time period, have show substatial ad real effects o behaviour chages. For example, the impact of multiple behaviour itervetio for weight maagemet had three times the effect of sigle behaviour itervetio (34). Smokers treated for two or three behaviours were as effective i beig abstiet at log-term follow-up as those treated for oly smokig (35). Success i chagig oe or more lifestyle behaviours may also icrease oe s cofidece or selfefficacy to improve risk behaviours for which idividuals have little motivatio to alter (36). Although more studies o multiple behaviour itervetio are eeded, we would like to emphasize the desirability of a uified simple approach that promotes commo steps for prevetig several diseases ad coditios icludig proteiuria. The preset study revealed a uexpected associatio betwee quittig smokig ad a icreased OR for the icidece of proteiuria i wome. This fidig is cotradictory to previous reports, which demostrated that cigarette smokig was idepedetly associated with a icreased risk of proteiuria for both me ad wome (7, 37), ad that the discotiuatio of smokig substatially reduced the risk of proteiuria i the healthy middle-aged workig populatio (38). Regardig the reaso for this surprisig result, the possibility of reverse causality could be suggested, i.e., poor health associated with proteiuria might have led to smokig cessatio. Our study is associated with several limitatios. First, proteiuria was measured by a urie dipstick oly oce. However, a previous Japaese cohort study revealed that proteiuria measured by urie dipstick oly oce sigificatly predicted ed-stage kidey disease (1). Thus, the outcome of our study is still meaigful. Secod, the overall healthy lifestyle scores, except for BMI, were determied based o self-reportig ad thus may ot be accurate. We also did ot evaluate utritio, give the lack of iformatio o this aspect. Furthermore, optimal body weight was defied as BMI <25 kg/m 2 i agreemet with previous studies, ad a lower limit of BMI was ot set. Because beig uderweight is associated with the icidece of proteiuria i wome (39), this defiitio may weake the true associatios betwee overall healthy lifestyle scores ad the icidece of proteiuria. Third, we did ot have ay iformatio regardig atihypertesive drug classes, such as agiotesi-covertigezyme ihibitors or agiotesi receptor blockers, that might ifluece the icidece of proteiuria. However, our results were geerally similar with or without hypertesio. Fourth, despite adjustig for potetial cofoudig factors, residual cofoudig factors may still have iflueced these fidigs. For example, we did ot adjust for socioecoomic status because this iformatio was ot available. Fially, the study duratio was relatively short for detectig the icidece of proteiuria i the geeral populatio. Despite this, our study revealed that healthy lifestyle chages could result i sigificat effects o icidet proteiuria, eve withi a short time frame. We believe that the large sample size of this study may have compesated for this limitatio. Despite these limitatios, this study also has stregths worth otig. First, the study was a large-scale retrospective cohort study with participats from throughout Japa. Secod, to the best of our kowledge, this is the first report demostratig the ifluece of chages i overall healthy lifestyle o the icidece of proteiuria i the geeral Japaese populatio. Our fidigs suggest the possibility that multiple behaviour itervetio might be effective i prevetig several chroic diseases, such as CKD. 1482

9 Iter Med 56: , 2017 DOI: /iteralmedicie I coclusio, overall healthy lifestyle chages, eve withi the short spa of a year, ca sigificatly ifluece the icidece of proteiuria. Our data highlight the importace of a overall healthy lifestyle for prevetig proteiuria, ad also highlight the ifluece of lifestyle deterioratio i acceleratig the icidece of proteiuria, eve withi a year. These fidigs therefore suggest that it is ever too late to chage oe s lifestyle. The authors state that they have o Coflict of Iterest (COI). Ackowledgemet This study was supported by a Health ad Labour Scieces Research Grat for Desig of the comprehesive health care system for chroic kidey disease based o the idividual risk assessmet by Specific Health Checkups from the Miistry of Health, Labour ad Welfare of Japa, ad i part by a Grat-i- Aid for Research o Advaced Chroic Kidey Disease, Practical Research Project for Real Diseases from the Japa Agecy for Medical Research ad Developmet, AMED. Refereces 1. 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