Association of dipstick hematuria with all-cause mortality in the general population: results from the specific health check and guidance program in Japan

ABSTRACT

INTRODUCTION

Asymptomatic hematuria and proteinuria are often detected by mass screening in adults [1, 2]. Isolated hematuria seldom develops into renal insufficiency, but 10.6% of persons with isolated hematuria may develop proteinuria during the follow-up period [3]. Hematuria is relatively common, particularly in elderly women, among general screening participants [4, 5]. Hematuria is a risk factor for developing end-stage renal disease (ESRD), although the risk of ESRD is lower than that of developing proteinuria [4, 5]. Further, asymptomatic hematuria is a confirmed risk factor for developing ESRD, even in young adults [6].

Albuminuria (proteinuria) is a significant predictor of both all-cause and cardiovascular mortality [7]. Recent reports suggest that hematuria is also related to mortality and cardiovascular events in a chronic kidney disease (CKD) cohort [8]. Few studies, however, have investigated the relationship between hematuria and mortality among a large screening population.

We evaluated the effects of several baseline confounders on mortality, including obesity, hypertension, dyslipidemia and CKD, in a nationwide general screening cohort [9]. In this nationwide screening program, dipstick urine testing for proteinuria is a mandatory laboratory examination, but dipstick urine testing for hematuria is not. Participants of this screening were 40–74 years of age, and therefore the effects of menstruation, if any, would be minimal. In the present study, we examined the significance of dipstick hematuria in relation to mortality.

MATERIALS AND METHODS

Screened subjects

The specific health check and guidance program, the so-called Tokutei-Kenshin, was started in Japan in 2008. Details of this cohort were published previously [9].

Databases included in this study were obtained from Fukushima, Ibaraki, Toyonaka, Fukuoka, Miyazaki and Okinawa. Data were sent to a data center, the NPO Japan Clinical Research Support Unit, for verification. Outliers were deleted through winsorization and accounted for 0.01–0.1% of the total. Eligible participants visited a preassigned clinic or hospital and responded to a questionnaire regarding past history of stroke, cardiac disease and kidney disease; lifestyle habits such as smoking, alcohol intake and regular exercise such as walking, dietary habits and medications for hypertension, diabetes mellitus (DM) and dyslipidemia. Screening participants are eligible for public support for standard health checks, such as measurement of height, weight, waist circumference, blood pressure, fasting blood glucose, hemoglobin A1c (HbA1c), triglyceride, serum high-density lipoprotein cholesterol, serum low-density lipoprotein cholesterol, glutamyl oxaloacetic transaminase, glutamate pyruvate transaminase, gamma-glutamyl transpeptidase, hemoglobin, uric acid and serum creatinine, and dipstick urine testing for proteinuria, hematuria and glycosuria. Proteinuria was coded as (−), (±), (1+), (2+), and (≥3+) and positive proteinuria was defined as ≥1+. Serum creatinine was measured using the enzymatic method. Glomerular filtration rate (GFR) was calculated using the formula of the Japanese Society of Nephrology [10].

Blood pressure was measured in all the cohorts using a standard sphygmomanometer. Hypertension was defined as ≥140/90 mmHg or on antihypertensive medication. The HbA1c value was estimated as a National Glycohemoglobin Standardization Program equivalent value calculated with the following formula: HbA1c (%) = HbA1c (Japan Diabetes Society) (%) + 0.4%.

National database of death certificates

Upon permission from the Ministry of Health and Welfare, we obtained the database of death certificates between 2008 and 2012 (total registered ∼6 million). The dataset included sex, birth date, place of death, date of death and causes of death by ICD-10. The database was solely used and managed by C.I., and the principal analyses to identify persons that died among the screened subjects were completed by March 2015. Afterward, further analyses were performed using a standard analysis file without any personal identifiers.

Outcomes

The use of two registries allowed us to identify candidates that died after participating in the screening in each district. Identifiers such as sex, birth date, date of death and place of death were used and confirmed at each of the screening centers.

Ethics approval

All procedures performed in studies involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (Fukushima Medical University; IRB approval number #1485, #2771) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

This study was performed according to Ethical Guidelines for Medical and Health Research Involving Human Subjects enacted by MHLW of Japan [http://www.mhlw.go.jp/file/06-Seisakujouhou-10600000-Daijinkanboukouseikagakuka/0000069410.pdf and http://www.mhlw.go.jp/file/06-Seisakujouhou-10600000-Daijinkanboukouseikagakuka/0000080278.pdf]. In the context of the guideline, the investigators shall not necessarily be required to obtain informed consent, but we made public information concerning this study on the web [http://www.fmu.ac.jp/univ/sangaku/data/koukai_2/2771.pdf] and ensured opportunities for the research subjects to refuse utilizing their personal information.

Statistical analysis

Data were analyzed with SAS/STAT software (version 6.03, SAS Institute, Tokyo, Japan). Student’s t-test and the chi-squared test were used to compare the significance of discrete variables. Multivariate logistic analysis was performed after adjusting for age, sex, body mass index (BMI), estimated GFR (eGFR), proteinuria and other pertinent variables. The hazard ratio (HR) and 95% confidence interval (CI) were calculated. A P < 0.05 was considered statistically significant in all analyses.

RESULTS

The baseline characteristics of those tested for dipstick hematuria are summarized in Table 1 (n = 112 115). Although dipstick testing for proteinuria was almost 100%, the results were available for approximately 38.0% of the total number screened (n = 295 297) (Table 1). Proteinuria was more common among those with dipstick-positive hematuria {defined as +1 [hematuria (+)], 10.7%} than those without hematuria [hematuria (−), 5.0%]. Hematuria was positive in 17.5% (n = 19 660) of the total tested. The prevalence of hematuria was 9.5% in men (Table 1) and 22.7% in women (Table 1).

The reasons for testing for hematuria were not clear, but proteinuria tended to be more prevalent among those tested for hematuria: 5.9% of those tested for hematuria and 5.0% of those not tested for hematuria (Supplementary data, Table S1).

We identified 1290 (1.2% of the total) deaths and the characteristics of the subjects are summarized in Table 2. The prevalence of proteinuria, smoking habit, medication for hypertension and DM, and past history of stroke, heart disease and kidney disease were significantly higher among those who died. Figure 1 shows the relationship between the baseline hematuria status and mortality in men and women. In men, hematuria was a significant predictor of death [HR (95% CI) 1.464 (1.147–1.846), P = 0.003], but not in women [HR (95% CI) 0.820 (0.617–1.073), P = 0 151] (Table 3). In the 40- to 54-year age group, hematuria was not a significant risk factor in either men or women (Table 3), whereas it was a significant risk factor in men in the 55- to 74-year age group [HR (95% CI) 1.482 (1.156–1.878), P = 0.002], but not in older women (Table 3).

FIGURE 1

Baseline hematuria status and mortality in men and women.

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The mortality risk by hematuria increased when associated with proteinuria (Table 4, Figure 2) and low eGFR (Table 5, Figure 3). Mortality risks were further examined by classifying the men and women into five groups according to the dipstick hematuria score (Supplementary data, Table S2). The leading cause of death was neoplasm regardless of hematuria, occurring in 51.3% of the total, 50.3% in those hematuria (−) and 56.1% in those hematuria (+). Causes of death are summarized in Supplementary data, Table S3.

FIGURE 2

Mortality by combination of hematuria and proteinuria.

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FIGURE 3

Mortality by combination of hematuria and eGFR.

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Demographics were compared between men and women without hematuria (Supplementary data, Table S4a) and men and women with hematuria (Supplementary data, Table S4b). Regardless of the presence or absence of hematuria, men had higher levels of blood pressure, serum uric acid and prevalence of proteinuria.

DISCUSSION

The findings of the present study indicated that dipstick hematuria was a significant predictor of mortality, particularly in elderly men (≥55 years of age). In women, however, dipstick hematuria was not a significant predictor of mortality, although there was a high prevalence of hematuria [11–13]. Mortality rate is usually lower in women than in men, even among those aged 60–74 years, suggesting the involvement of factors other than the effect of sex hormones. In men, the higher the degree of hematuria based on the dipstick score, the higher the rate of mortality. In subjects with hematuria (≥3+), the HR was ∼1.7. The causes of death did not differ between those hematuria (−) and hematuria (+) (Supplementary data, Table S3).

Patients with urinary tract stones, cancer and autosomal dominant polycystic kidney disease may have dipstick hematuria or even show a high degree of hematuria (macrohematuria) [14]. The mean age of hematuria (+) subjects was higher than that of hematuria (−) subjects, both in men (Table 4) and women (Table 4). Also, mean eGFR values were lower and the prevalence of proteinuria was higher in those with hematuria. These observations may support the notion that people with asymptomatic hematuria have atherosclerosis or chronic inflammation. Hematuria is often observed not only in glomerulonephritis and systemic vasculitis, but also in atheroembolic renal disease [15]. Therefore, it is possible that arteriosclerosis and chronic inflammation are involved in the development of hematuria.

Asymptomatic hematuria is often the first clue indicating IgA nephropathy. Dipstick hematuria is common in IgA nephropathy. Knoop et al. reported that hematuria is a predictor of mortality in IgA nephropathy [16]. Similarly, Lin et al. reported a significant association of microscopic hematuria with mortality in men in a Stage 3–5 CKD cohort [8]. They suggested that moderate hematuria is associated with all-cause mortality and cardiovascular events among nondiabetic patients with Stages 3–5 CKD.

Sex differences in the demographics were detected regardless of the absence (Table 4) or presence of hematuria (Table 4). Smoking and alcohol intake had a significantly higher prevalence in men. A significant association between BMI and the incidence and prevalence of CKD and ESRD was also reported [17]. In Japan, the incidence of ESRD is higher in men than in women [18]. Other modifiable factors, such as lifestyle-related factors, including diet, exercise, smoking and alcohol intake, may explain the sex difference, at least in part. We recently demonstrated the beneficial effects of intervention by dieticians and supportive care by co-medical staff to improve compliance with medical treatment [19].

The reasons for the high prevalence of hematuria in women are not clear. In our cohort, subjects were older than 40 years of age (mean age >60 years). Therefore, the possibility of contamination by menstruation, if any, would be little. The high prevalence of hematuria in women in this age group may be explained, in part, by aging. A 2005 report of dipstick hematuria screening in Hong Kong [13] indicated a prevalence of 5.8% in those 20–40 years of age, 14.2% in those 41–60 years of age, and 18.6% in those 60 years of age and over, which is similar to the finding in our cohort (mean age of 64 years). Hematuria is a common and important complication in patients with atrial fibrillation on oral anticoagulation therapy [20]. Hematuria is common in elderly women based on general screening in Japan [1]. Vivante et al. [6] reported a higher prevalence of hematuria in men than in women, but others have reported the opposite results [1, 21]. Therefore, the prevalence of hematuria may vary depending on the background and age of the examined subjects.

Observational studies of large cohorts revealed a role for hematuria in CKD progression [1, 6], but a role has not been demonstrated in small studies. In general, the absolute risk of asymptomatic hematuria is low [22–24]. Glomerular hematuria may damage tubular function through hemoglobin-mediated nephrotoxicity [25]. Cytotoxic effects of oxidative stress induced by hemoglobin, heme or iron released from red blood cells may account for the tubular injury [26]. The precise mechanisms responsible for hematuria, however, remain unclear. Acute kidney injury is associated with prolonged hospitalization and high mortality, and predisposes individuals to CKD. Currently, there are no effective treatments for acute kidney injury. Recent findings on the effect of phagocytic removal of debris by the tubular epithelial cells and kidney tissue repair in experimental animals may provide a basis for the development of potentially novel therapies for acute kidney injury [27].

A strength of the present study is that subjects were participants of a large nationwide screening program. They were evaluated based on the same clinical and laboratory tests, and the same questionnaire regarding lifestyle-related variables. Identification of those who died during the study period was made using the national death certificate database and confirmed in each district.

There are several limitations to this study. First, the results are based on one measurement obtained in 2008. Dipstick testing results may vary with repeated measurements. We did not use a microscope to confirm the presence of hematuria. The effects of changes in dipstick hematuria, therefore, remain to be studied. Actually, hematuria disappeared during the follow-up in 44.2% of the participants who were hematuria (+) [3]. Second, this screening program is voluntary and therefore self-selected. Therefore, it is possible that some participants had hidden cancer or were being treated for cancer, particularly urogenital cancer [28]. As people age, early detection of malignancies such as urogenital cancers is important. Regarding the type of cancer, the overall tendency did not differ markedly between males and females with or without hematuria, but death by urogenital tumor was frequently observed in men with hematuria [2.6% of hematuria (−) women and 0% of hematuria (+) women, 2.3% of hematuria (−) men and 7.4% of hematuria (+) men]. By using the longitudinal screening data, we could further investigate the role of dipstick hematuria in detecting cancer. Third, there are obvious regional differences in the incidence and prevalence of cardiovascular disease and ESRD. In this study, we screened participants from only 6 of 47 prefectures from the north to the south. Therefore, the database may not be representative of Japan. Fourth, participants in this screening were restricted to those who were middle-aged and older (40–74 years). This policy was based on the assumption of a benefit of early detection and subsequent modification of lifestyle-related diseases such as DM, hypertension, dyslipidemia, cardiovascular disease and probably CKD. Actually, lifestyle changes to nonsmoking, healthy weight, decreased alcohol intake, increased physical activity and healthy eating habit are associated with a low incidence of proteinuria [29]. The relationship of these factors with hematuria, however, is not well studied. Also, the cost of screening for hematuria (in addition to proteinuria), which is largely covered by the Japanese government, is not clear. In this program, positive urine tests for protein and sugar must be reported to examinees, whereas urine occult blood does not have to be reported in some municipalities. Dipstick urine tests were usually performed using Ames dipsticks. As shown in Table 1, there were slight differences in the characteristics of the subjects, except in systolic blood pressure and history of heart disease. Participants tested for hematuria had a higher prevalence of proteinuria (10.7%) than those that were not tested (5.0%). We considered that this may be related to the instructions given by the nurses and/or requests of the screenees themselves.

In conclusion, the present study revealed a significant association of dipstick hematuria with mortality in men among general screening participants in Japan. Dipstick urine tests are simple and inexpensive methods of detecting both ESRD and mortality, and are therefore preferable in developing countries. Further studies are needed to elucidate the relationship between lifestyle-related variables and mortality in men with hematuria. The clinical significance and monitoring frequency of asymptomatic hematuria remain to be determined [30].

SUPPLEMENTARY DATA

Supplementary data are available online at http://ndt.oxfordjournals.org

ACKNOWLEDGEMENTS

This study would not have been possible without the generous support of the public health nurses, the Kokuho Agency in each district. This work was supported by a Health and Labor Sciences Research Grants for ‘Study on the design of the comprehensive health care system for chronic kidney disease (CKD) based on the individual risk assessment by Specific Health Checkup’ from the Ministry of Health, Labor and Welfare of Japan, and a Grant-in-Aid for ‘Research on Advanced Chronic Kidney Disease (REACH-J), Practical Research Project for Renal Disease’ from the Japan Agency for Medical Research and Development, AMED.

CONFLICT OF INTEREST STATEMENT

None declared.

REFERENCES