Asymptomatic trace and overt proteinuria in high-and low-body weight individuals : A preliminary report of community-based epidemiological study

Implication for health policy/practice/research/medical education: The prevalence of trace proteinuria assessed by dipstick urinalysis demonstrated J-shaped relationship against body mass index similarly to overt proteinuria. However, the degree and pattern of associations of trace proteinuria with body mass index may differ from those of overt proteinuria. Please cite this paper as: Nakajima K, Kanda E, Muneyuki T, Suwa K. Asymptomatic trace and overt proteinuria in highand low-body weight individuals: A preliminary report of community-based epidemiological study. J Nephropathol. 2018;7(2):5156. DOI: 10.15171/jnp.2018.14. O ri gi na l A rt ic le ARTICLE INFO


Objectives
It is equivocal whether TrP is also associated with high and low body weight.Therefore, we address this issue in a large community-based epidemiological study, using a database of 20-85-year-old 75 645 Japanese men and women who underwent medical checkups in 2008.

Subjects
The investigation is based on a composite, observational research program that was conducted to investigate the lifestyle and potential factors correlated with metabolic diseases (8).The study contains of data recorded during medical checkups of asymptomatic people living or working in Saitama prefecture, a suburb of Tokyo, Japan.Participants who reported having kidney disease, such as diabetic kidney disease and those with suspected cancer or cirrhosis, were excluded.Consequently, 70 886 subjects (men, 63.9%) were enrolled in the current cross-sectional investigation.

Measurements of clinical parameters
Anthropometric assessments and laboratory tests, comprising ordinary dipstick urinalysis, were conducted in the early morning after an overnight fast.Height and weight were measured objectively using ordinary electronic scales.Body mass index (BMI) was calculated as weight (in kg) divided by height (in m 2 ). Serum variables were measured using standard methods on Hitachi Autoanalyzers (Hitachi, Tokyo, Japan) at Saitama Health Promotion Corporation.Dipstick urinalysis was conducted using Uro-Paper III EIKEN (Eiken Chemical, Tokyo, Japan) with fresh single-spot urine specimens.The results were recorded as none (−), trace (±), or ≥ +1, which are equivalent to semi-quantitative urinary protein concentrations of approximately 0, 15, and ≥ 30 mg/dL, respectively.In this study, TrP and OP were defined as ± and ≥ +1, respectively.Serum creatinine levels were not investigated in all subjects.Nevertheless, because glomerular filtration rate (GFR) is an important confounding factor for proteinuria (1), estimated GFR (eGFR) was calculated applying the following equation for Japanese people (10) and evaluated in limited subjects (n = 31 281): eGFR (mL/min/1.73m 2 ) = 194×Cr -1.094 ×age× -0.287 (if female) ×0.739, where, Cr = serum creatinine concentration (mg/dL).

Ethics approval
The research followed the tenets of the Declaration of Helsinki.The protocol was approved by the Ethics Committees of Kanagawa University of Human Services in 2016.Written informed consent was obtained from all participants.

Statistical analysis
Data are expressed as the mean ± standard deviation (SD) or median (interquartile range).Wilcoxon rank test was used to test the differences between TrP and OP in each BMI category after TrP and OP is numbered as 1 and otherwise as 0. As in our previous study (5), multivariate logistic regression models were used to examine the association between six BMI categories (≤ 18.9, 19.0-20.9,21.0-22.9,23.0-24.9,25.0-26.9,or ≥ 27.0 kg/m 2 ) and TrP or OP with adjustment for relevant confounding factors, yielding odds ratio (OR) and 95% coefficient intervals (CI).

Results
The clinical characteristics of subjects are shown in Table 1.As expected, all of the variables, except high-density lipoprotein cholesterol and eGFR, increased with an increasing BMI category (analysis of variance, all P < 0.001).TrP was much more prevalent (n = 2933, 4.1%) on average than OP (n = 2231, 3.1%, Wilcoxon rank test, P < 0.001).Additionally, proportions of Trp were significantly higher than OP in every BMI category (all P < 0.001), except in obese subjects (BMI ≥ 27.0 kg/m 2 ) (6.0% for TrP and 6.3% for OP, P = 0.36).The prevalence of TrP was higher in subjects with high or low BMI compared with individuals with a BMI of 21.0-22.9kg/m 2 , yielding a J-shaped relationship between the prevalence of TrP and BMI.Similar trends were observed for OP.Other categorical variables increased with an increasing BMI category in a linear manner (χ 2  test, all P < 0.001).Logistic regression analysis showed that, compared with the reference BMI category (21.0-22.9kg/m 2 ), the other BMI categories were significantly associated with TrP independently of relevant confounding factors, with the exception of the BMI category of 19.0-20.9kg/m 2 (Table 2, Model 3).When subjects Trace and overt proteinuria in high-and low-body weight with OP were excluded and the same analysis was conducted (vs.non-proteinuria, n = 65722), similar results were observed.By contrast, OP was also significantly associated with the BMI categories of ≤ 18.9, 25.0-26.9,and ≥ 27.0 kg/m 2 , but not 19.0-20.9nor 23.0-24.9kg/m 2 .Notably, BMI of ≤ 18.9 and ≥ 27.0 kg/m 2 , which reflect both ends of BMI categories, were more strongly associated with OP rather than TrP.Further adjustment for eGFR (Model 4) did not largely change these associations, although the associations between BMI categories and OP were more attenuated than TrP, and associations of both ends of BMI categories with OP remained significant.

Discussion
Current study demonstrated similar results to our previous study (5) regarding the associations between BMI categories and OP.Additionally, current results indicate that TrP was much more prevalent than OP, except in obese individuals, in this general Japanese population, and that both types of proteinuria were significantly associated with high and low body weight.Importantly, TrP was significantly associated with the BMI category of 23.0-24.9kg/m 2 , a category reflecting high-normal body weight for Asian people (11), which suggests that compared with OP, TrP may be a sensitive marker for the effects of increased body weight, even within the normal range, on the kidney.However, the clinical relevance of TrP is still poorly understood, especially compared with microalbuminuria defined as an albumin/creatinine ratio of 30-300 mg/g.Moreover, the relationship between TrP detected by Note: Data are expressed as the mean ± SD or number (percentage).Triglyceride concentrations are expressed as the median (interquartile range).All parameters and categorical values increased significantly with an increasing BMI category, except for HDL-cholesterol and eGFR (analysis of variance/χ 2 test; all, P < 0.001).TrP and OP were defined as ± and ≥ +1, respectively, on dipstick urinalysis.Abbreviations: BMI, body mass index; CVD, cardiovascular disease (including stroke); eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; NGSP, National Glycohemoglobin Standardization Program; OP, overt proteinuria; TrP, trace proteinuria.Trace and overt proteinuria in high-and low-body weight dipstick urinalysis and microalbuminuria is equivocal, although the prevalence of microalbuminuria was high (approximately 60%-90%) in subjects with TrP in urine samples (7,8).It is also unknown whether TrP is sensitive to chronic kidney disease than plausible low-molecular-weight biomarkers including urinary β-trace protein and β2-microglobulin (12,13).
In general, proteinuria, which is often transient, may be caused by a variety of factors, including drugs, infection, exercise, and posture, as well chronic cardiometabolic conditions (14).Therefore, clinicians should take care when assessing the cause of TrP.However, considering that OP might develop several years after the detection of TrP, and macroalbuminuria generally follows microalbuminuria (15), TrP may be a useful surrogate marker for early kidney damage associated with abnormal body weight and its cardiometabolic effects because the measurement of microalbuminuria and other urinary biomarkers for kidney damage is cost-and time-consuming (3).

Conclusions
Current study suggests that TrP is also associated with high and low body weight, seemingly like OP.However, the degree and pattern of associations of TrP with BMI may differ from those of OP.Further in depth studies involving subjects with specific pathophysiologic conditions, including diabetic and hypertensive nephropathy, are needed to examine the fundamental clinical relevance of TrP independently of OP.

Limitations of the study
TrP was evaluated using only dipstick urinalysis in this study.Simultaneous measurements of microalbuminuria and other urinary biomarkers will be needed to warrant the current results.

Table 1 .
Clinical characteristics of subjects according to BMI category

Table 2 .
Odds ratios for TrP or OP according to BMI Category