Article in press - uncorrected proof

Clin Chem Lab Med 2010;48(12):17731776 2010 by Walter de Gruyter Berlin New York. DOI 10.1515/CCLM.2010.347

Short Communication

Association between coffee consumption and the estimated glomerular filtration rate in the general Japanese population: preliminary data regarding C-reactive protein concentrations

Kazuhiko Kotani1,2,*, Naoki Sakane1, Toshiyuki Yamada2 and Nobuyuki Taniguchi2

1

Keywords: C-reactive protein; chronic kidney disease; coffee consumption; glomerular filtration rate; sugar intake.

Division of Preventive Medicine, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan 2 Department of Clinical Laboratory Medicine, Jichi Medical University, Shimotsuke-City, Tochigi, Japan

Abstract
Background: Cardiometabolic disorders including cardiovascular disease (CVD) where the relevance of regular coffee consumption is debatable, has been linked with the development of chronic kidney disease (CKD). A more recent study suggests that coffee consumption is associated with normal or increased kidney function as assessed by the estimated glomerular filtration rate (eGFR). The present study investigated whether the association between coffee and the eGFR was independent of chronic inflammation, and whether adding sugar to coffee could affect the eGFR. Methods: A total of 114 age- and gender-matched Japanese individuals (females/maless68/46, mean ages59.5 years), without CVD and severe CKD, were studied. Clinical variables, such as body mass index, blood pressure, blood glucose, lipids and high-sensitivity C-reactive protein (hsCRP), in addition to eGFR wthe Modification of Diet in Renal Disease (MDRD) study equationx, were measured. Results: Coffee drinkers had higher eGFR values w73.9"16.5 (SD) mL/min/1.73 m2x than non-coffee drinkers (68.6"11.7). The difference remained significant (Fs5.04, ps0.027), independently of clinical variables, including hsCRP. The eGFR values among coffee drinkers were similar between the subjects with and without use of sugar. Conclusions: The association of coffee drinking habits to eGFR may occur independently of inflammation as assessed by hsCRP. The use of sugar may have no effect on GFR. Further research is needed to clarify this phenomenon. Clin Chem Lab Med 2010;48:17736.
*Corresponding author: Kazuhiko Kotani, PhD, MD, Division of Preventive Medicine, Clinical Research Institute, National Hospital Organization Kyoto Medical Center, 11 Fukakusa Mukaihata-cho, Fushimi-ku, Kyoto 612-8555, Japan Phone: q81-285-58-7386, Fax: q81-285-44-9947, E-mail: kazukotani@jichi.ac.jp Received January 3, 2010; accepted June 18, 2010; previously published online August 24, 2010

Coffee drinking is widespread throughout the world. Although Japan has no traditional habit of coffee consumption, presently over half of Japanese people drink coffee regularly, with most drinking filtered coffee (1). Therefore, elucidating the impact of coffee consumption on health/ disease can be important, although the impact is debatable (2). Recent studies have reported beneficial effects of coffee drinking on the development of insulin resistance and type 2 diabetes, as well as cardiovascular disease (CVD), although these findings are not always consistent (2, 3). Chronic systemic low-grade inflammation, as expressed by C-reactive protein (CRP), is involved in the physiology and pathology of cardiometabolic disorders (4), and some factors such as coffee drinking are anti-inflammatory (5). Therefore, suppression of inflammation by coffee may contribute to the beneficial effects of coffee drinking on cardiometabolic disorders. In addition, the manner in which coffee is consumed (i.e., adding sugar to coffee) may result in inconsistent findings concerning the association of coffee with cardiometabolic disorders (2, 3). Interestingly, a more recent study has suggested that coffee consumption may be associated with normal or increased kidney function as assessed by the estimated glomerular filtration rate (eGFR) in a Japanese population (6). This association should be confirmed from many viewpoints, since chronic kidney disease (CKD) and its association with CVD is also a great public concern (7). The present study investigated whether the association of eGFR with coffee was independent of circulating CRP concentrations and whether the use of sugar with coffee affected the eGFR values among Japanese subjects. The prevalence of regular coffee consumption largely differs by age in Japan, with older people drinking coffee less frequently than younger and middle-aged people (5). This can complicate the statistical analyses due, for example, to insufficient control of the effect of age on results. The present study was controlled for both age and gender. A total of 114 community-dwelling non-smoking subjects (women/ mens68/46; mean ages59.5 years, range 4070 years), with no features of CVD, severe CKD wdefined as an eGFR F40 mL/min/1.73 m2 (8)x, diabetes mellitus wdefined as a fasting plasma glucose F7.0 mmol/L (9)x, hematological

2010/002

Article in press - uncorrected proof

1774 Kotani et al.: Coffee drinking and eGFR

Table 1 Clinical characteristics between the groups of subjects who did or did not consume coffee regularly. Variables Age, years Men/women, number Body mass index, kg/m2 Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Glucose, mmol/L Total cholesterol, mmol/L Triglycerides, mmol/L HDL-cholesterol, mmol/L High-sensitivity CRP, mg/L eGFR, mL/min/1.73 m2 Non-drinkers 59.5"8.7 23/34 24.3"2.7 136.7"19.5 75.3"10.7 5.44"0.74 4.85"0.95 1.07 (0.881.36) 1.55"0.39 0.12 (0.070.19) 68.6"11.7 Drinkers 59.5"8.7 23/34 24.2"2.9 134.8"18.0 76.5"12.9 5.20"0.60 5.14"0.81 0.98 (0.761.24) 1.70"0.41 0.09 (0.070.14) 73.9"16.5 p-Value Matching factor Matching factor 0.983 0.598 0.571 0.064 0.087 0.291 0.042a 0.054 0.050a

Values are expressed as the mean"standard deviation in parametrically distributed variables or as the median (interquartile range) in nonparametrically distributed variables. Triglycerides and high-sensitivity CRP were analyzed after the log-transformation because of the skewed distribution. Significance between the groups using the t-test: apF0.05. HDL, high-density lipoprotein; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate.

disorders and acute infectious disease such as the common cold, were randomly selected from a database of communitybased health check-up screening subjects. The study was approved by the Ethics Committees of National Hospital Organization Kyoto Medical Center, and each subject gave informed consent. Coffee drinking, defined as the consumption of at least one or more cups/day, and if present, adding sugar to coffee, were self-reported. Body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure, plasma glucose, serum total cholesterol, triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) were measured using standard methods. Blood samples were obtained from each subject after an overnight fast, and without coffee consumption. Serum high-sensitivity CRP (hsCRP) was measured using an ELISA kit (Assay Pro, Assay-Pro LLC., St. Charles, MO, USA). After a 1000-fold dilution of serum, the concentrations in all samples fell within the assay range of 0.25 16 mg/L. The eGFR was calculated using the following formula wthe Modification of Diet in Renal Disease (MDRD) study group equationx: 0.741=175=serum creatininey1.154= agey0.203 (=0.742 if the subject was female) (8). Creatinine was measured using the enzymatic method traceable to the isotopic dilution mass spectrometry method (regent: Wako Pure Chemical Ind. Ltd., Tokyo, Japan; analyzer: Hitachi 7600-110 chemistry autoanalyzer, Hitachi High-Technologies Co. Ltd., Tokyo, Japan) (10). One cup of coffee (approximately 150200 mL) contains approximately 300400 mg of total polyphenols (11), and the maximum serum concentration of polyphenols following food intake is approximately 0.002 mg/mL per 100 mg of food polyphenols (12). Creatinine measurements based on Trinders reagents (13) may be interfered by phenols in the blood. Experimentally, we added 00.1 mg/mL (a final concentration) of polyphenols (i.e., water-soluble chlorogenic acid: a representative polyphenol) to serum samples in which the creatinine concentrations were already known, and measured using our creatinine method. Creatinine concentrations did not appear to change with respect to stepwise-diluted amounts of polyphenols (data not shown). Therefore, we concluded that coffee

drinking in the present study did not affect creatinine measurements. Data were expressed as the mean"standard deviation (SD), or the median plus interquartile range. Differences between the groups were compared using the t-test. A general linear model for eGFR (as a dependent variable) was used to examine the influence of coffee drinking (as a fixed variable), with adjustments of the clinical variables, including hsCRP. Statistical analyses were performed with the Statistical Package for Social Science (SPSS) version 11.0 for Windows software program (SPSS Inc., Chicago, IL, USA). A pF0.05 was considered statistically significant. Coffee drinkers showed significantly higher eGFR concentrations compared with non-coffee drinkers (Table 1). The group of coffee drinkers exhibited significantly higher HDLC concentrations than the group of non-drinkers. Coffee drinkers tended to have lower hsCRP concentrations compared with non-drinkers (ps0.054). After adjusting for all clinical variables including hsCRP, the influence of coffee drinking on eGFR remained independently significant, while age and BMI were also found to significantly influence eGFR (Table 2). Even when age and gender were excluded from the adjustments, the influence of coffee drinking on eGFR remained independently significant (Fs4.354, ps0.040), while BMI and SBP significantly influenced the eGFR (data not shown). Among coffee drinkers, the eGFR was not significantly different between the subjects that consumed coffee with (ns27, 72.3"18.3 mL/min/1.73 m2) or without (ns25, 73.9"13.9; ps0.735) sugar. Similarly, after adjusting for all clinical variables including hsCRP, no significant influence of adding sugar on eGFR was observed (Fs1.435, ps0.238; data not shown). The present shows that Japanese coffee drinkers might have higher eGFR compared with non-coffee drinkers. This supports a recent study that has demonstrated a significant relationship between coffee drinking and normal or increased eGFR (10). Although the present study did not assess the amount of coffee consumed, Japanese individuals generally consume smaller amounts of coffee (5). It is interesting to

Article in press - uncorrected proof

Kotani et al.: Coffee drinking and eGFR 1775

Table 2 The influence of coffee consumption on eGFR (mL/min/ 1.73 m2). Variables Age, years Gender Body mass index, kg/m2 Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Glucose, mmol/L Total cholesterol, mmol/L Triglycerides, mmol/L HDL-cholesterol, mmol/L High-sensitivity CRP, mg/L Coffee drinking habits, absence/presence F-value 7.570 1.141 8.314 0.828 0.036 0.025 0.329 0.353 0.004 0.179 5.042 p-Value 0.007a 0.288 0.005a 0.365 0.849 0.875 0.568 0.554 0.954 0.673 0.027b

Triglycerides and high-sensitivity CRP were analyzed after the logtransformation because of the skewed distribution. The significance level according to a general linear model analysis for eGFR (as a dependent variable) and coffee drinking habits (as a fixed variable) with adjustments on the other clinical variables (as covariables): a pF0.01, bpF0.05. eGRP, estimated glomerular filtration rate; HDL, high-density lipoprotein; CRP, C-reactive protein.

hol, and this variable did not significantly change the results as shown in Table 2 (alcohol drinking habits, Fs0.022, ps0.883; coffee drinking habits, Fs4.993, ps0.028; all data not shown). In our study population, alcohol consumption habits did not appear to greatly affect eGFR. Limitations of the current study included a relatively small sample size. Although a single eGFR measurement has been a common approach in many epidemiological studies, we acknowledge that this is a weakness in assessing CKD. These limitations will also be addressed in future studies. Collectively, Japanese coffee drinkers may have significantly higher eGFR compared to non-coffee drinkers, independent of hsCRP, and eGFR might not be affected by the addition of sugar to coffee. The present study has provided some insight into these considerations, but additional research is required to clarify this phenomenon.

Acknowledgements
This study was supported in part by a Grant-in-Aid for the Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (K.K, N.S) and the Foundation for the Development of the Community, Japan.

note that the association in our study between coffee and eGFR was detected even with minimal coffee consumption (e.g., one or two cups/day). A more important finding was that this association might not be strongly mediated by chronic inflammation, reflective of hsCRP. This finding will promote the mechanistic understanding of the association between coffee and eGFR, although the possibility of coffee-induced anti-inflammation cannot be completely ruled out by this study alone. The components of coffee are diverse (6), and the caffeine-related actions (i.e., antagonized adenosine receptors, inhibited phosphodiesterases) and the antioxidant- and micronutrientrelated coffee functions may help explain the observed associations. Moreover, the addition of sugar to coffee did not affect the eGFR. This finding may also add some insight to previous findings regarding eGFR (6). A small amount of sugar may not have any effect on eGFR. The mechanistic influence of coffee itself on eGFR should be explored in further detail. In this study, coffee drinkers had significantly higher HDL-C. HDL-C has been reported to not be influenced by coffee drinking (14). Therefore, the residual confounding factors which were not measured in our present study can be considered to impact the mechanisms involved in the association between coffee and eGFR. For example, besides exercise and nutritional factors, the socio-economic status and educational level should be included in future studies. In addition, alcohol consumption may be confounding, due to the reported significant effects of alcohol on eGFR (15). We included the data on self-reported alcohol drinking habits (absence or presence of one or more go/day, regardless of alcohol type; 23 g of ethanol is contained in one go, which is the Japanese traditional unit) into the analysis, which was adjusted for all clinical variables (as in Table 2). There were subjects who did (ns35) and did not consume (ns79) alco-

Conflict of interest statement

Authors conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research support played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication. Research funding: None declared. Employment or leadership: None declared. Honorarium: None declared.

References
1. Iso H, Date C, Wakai K, Fukui M, Tamakoshi A. The relationship between green tea and total caffeine intake and risk for selfreported type 2 diabetes among Japanese adults. Ann Intern Med 2006;144:55462. 2. van Dam RM. Coffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer. Appl Physiol Nutr Metab 2008;33:126983. 3. van Dam RM, Hu FB. Coffee consumption and risk of type 2 diabetes: a systematic review. J Am Med Assoc 2005;294:97104. 4. Buckley DI, Fu R, Freeman M, Rogers K, Helfand M. C-reactive protein as a risk factor for coronary heart disease: a systematic review and meta-analyses for the U.S. Preventive Services Task Force. Ann Intern Med 2009;151:48395. 5. Kotani K, Tsuzaki K, Sano Y, Maekawa M, Fujiwara S, Hamada T, et al. The relationship between usual coffee consumption and serum C-reactive protein level in a Japanese female population. Clin Chem Lab Med 2008;46:14347. 6. Nakajima K, Hirose K, Ebata M, Morita K, Munakata H. Association between habitual coffee consumption and normal or increased estimated glomerular filtration rate in apparently healthy adults. Br J Nutr 2010;103:14952. 7. Hage FG, Venkataraman R, Zoghbi GJ, Perry GJ, DeMattos AM,

Article in press - uncorrected proof

1776 Kotani et al.: Coffee drinking and eGFR

8.

9.

10.

11.

Iskandrian AE. The scope of coronary heart disease in patients with chronic kidney disease. J Am Coll Cardiol 2009;53:2129 40. Imai E, Horio M, Nitta K, Yamagata K, Iseki K, Hara S, et al. Estimation of glomerular filtration rate by the MDRD study equation modified for Japanese patients with chronic kidney disease. Clin Exp Nephrol 2007;11:4150. Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (American Diabetes Association). Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26:31607. Flegar-Mestric Z, Perkov S, Simonovic B, Juretic D. Applica bility of common reference intervals for serum creatinine concentrations to the Croatian population. Clin Chem Lab Med 2010;48:2315. Fukushima Y, Ohie T, Yonekawa Y, Yonemoto K, Aizawa H,

12.

13.

14.

15.

Mori Y, et al. Coffee and green tea as a large source of antioxidant polyphenols in the Japanese population. J Agric Food Chem 2009;57:12539. Miura K, Kitadate K. The function of the next generation of polyphenol oligonol. Jpn J Complement Altern Med 2008; 5:16371 (in Japanese with English abstract). Trinder P. Determination of blood glucose using an oxidaseperoxidase system with a non-carcinogenic chromogen. J Clin Pathol 1969;22:15861. Jee SH, He J, Appel LJ, Whelton PK, Suh I, Klag MJ. Coffee consumption and serum lipids: a meta-analysis of randomized controlled clinical trials. Am J Epidemiol 2001;153:35362. Chung FM, Yang YH, Shieh TY, Shin SJ, Tsai JC, Lee YJ. Effect of alcohol consumption on estimated glomerular filtration rate and creatinine clearance rate. Nephrol Dial Transplant 2005;20:16106.

Copyright of Clinical Chemistry & Laboratory Medicine is the property of De Gruyter and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.