Based on Serum Creatinine Levels in Hypertensive Patients

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1 Tohoku J. Exp. Med., 2011, 224, Seasonal Variation in Estimated Glomerular Filtration Rate 137 Seasonal Variation in Estimated Glomerular Filtration Rate Based on Serum Creatinine Levels in Hypertensive Patients Hisashi Masugata, 1 Shoichi Senda, 1 Michio Inukai, 1 Takashi Himoto, 1 Koji Murao, 2 Naohisa Hosomi, 3 Yasuyoshi Iwado, 4 Takahisa Noma, 4 Masakazu Kohno 4 and Fuminori Goda 1 1 Department of Integrated Medicine, Kagawa University, Kagawa, Japan 2 Department of Advanced Medicine and Laboratory Medicine, Kagawa University, Kagawa, Japan 3 Department of Clinical Neuroscience and Therapeutics, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan 4 Department of Cardiorenal and Cerebrovascular Medicine, Kagawa University, Kagawa, Japan Seasonal variations in blood pressures should be kept in mind when controlling blood pressure in hypertensive patients. Seasonal variations in glomerular filtration rate (GFR) also may have a clinical significance. However, it is time-consuming to measure GFR directly. We therefore examined the seasonal variation in estimated glomerular filtration rate (egfr) based on serum creatinine levels in hypertensive patients without CKD (egfr 60 ml/min/1.73 m 2 ) and those with chronic kidney disease (CKD) (egfr < 60 ml/min/1.73 m 2 ). This study included 47 hypertensive patients without CKD (69 ± 11 yrs) and 55 hypertensive patients with CKD (76 ± 8 yrs). The egfr was determined from the equation: egfr = 194 age (serum creatinine) ( if female). Overall, both groups of hypertensive patients demonstrated similar seasonal variations in egfr. Importantly, hypertensive patients without CKD and those with CKD showed the lower egfr in summer (June-August) (71.8 ± 13.2 and 37.2 ± 13.0 ml/min/1.73 m 2, respectively) compared with the egfr in spring (March-May) (77.9 ± 13.0 and 43.0 ± 14.0 ml/min/1.73 m 2, respectively) (p < 0.05). The decrease in egfr from spring to summer was similar for both types of hypertensive patients (without CKD, 6.1 ± 7.0; with CKD, 5.8 ± 5.2 ml/min/1.73 m 2 ). However, the percent change in egfr from spring to summer was greater in hypertensive patients with CKD ( 13.8 ± 9.4 %) than in those without CKD ( 7.7 ± 8.3 %) ( p = 0.001). In conclusion, careful observation regarding renal function is needed for hypertensive patients with CKD during summer. Keywords: chronic kidney disease; creatinine; estimated glomerular filtration rate; hypertension; seasonal variation Tohoku J. Exp. Med., 2011, 224 (2), Tohoku University Medical Press Seasonal variation in arterial blood pressures has been demonstrated (Hata et al. 1982; Woodhouse et al. 1993; Imai et al. 1996; Kristal-Boneh et al. 1997), with blood pressures being higher during the winter than in the summer. From previous studies in older adults (Khaw et al. 1984; Barrett-Connor et al. 1984), a 10-mmHg rise in systolic blood pressure is associated with an approximately 10% increase in the risk of death from stroke and ischemic heart disease. Therefore, seasonal variations in blood pressures should be kept in mind when controlling blood pressure in hypertensive patients. Seasonal variations in glomerular filtration rate also may have a clinical significance. However, there are no data regarding seasonal variations in glomerular filtration rate in hypertensive patients. Renal dysfunction in patients with chronic kidney disease (CKD) has also been established as a risk of cardiovascular events, independent of conventional cardiovascular risk factors, including blood pressure (Go et al. 2004; Ninomiya et al. 2005; Irie et al. 2006; Imai et al. 2008). Therefore, in hypertensive patients, anti-hypertensive drugs (Whitworth et al. 1992; Osawa et al. 2006) and improvement of lifestyle (Orth et al. 2001) are recommended to prevent the onset or progression of CKD. The National Kidney Foundation formed a task force to heighten awareness of cardiovascular disease in CKD, and defined CKD using parameters such as a decrease in glomerular filtration rate < 60 ml/min/1.73 m 2. However, it is time-consuming to measure glomerular filtration rate directly. In Japan, an estimated glomerular filtration rate (egfr) for Japanese patients was proposed by the Japanese Society of Nephrology (Imai et al. 2007) in order to detect the early stages of CKD; however, its clinical usefulness has not Received April 18, 2011; revision accepted for publication May 18, doi: /tjem Correspondence: Hisashi Masugata, M.D., Ph.D., Department of Integrated Medicine, Kagawa University, , Miki-cho, Kita-gun, Kagawa , Japan. masugata@med.kagawa-u.ac.jp 137

2 138 H. Masugata et al. been fully established. Moreover, there are no data regarding seasonal variations of egfr in hypertensive patients, who frequently suffer from CKD. In this study, we investigated and compared the seasonal variations in egfr in hypertensive patients with and without CKD. Methods Subjects and Protocol The study subjects were 102 patients (65 male, 37 female; mean age 73 ± 10 years, range years) who had been diagnosed with hypertension at Kagawa University Hospital and who had regularly visited the outpatient clinic from spring (March, 2010-May, 2010), through winter (December, 2010-February, 2011) during one year. Hypertension was defined as systolic blood pressure 140 mmhg and/or diastolic blood pressure 90 mmhg. Blood pressure was determined using the conventional cuff method. All patients were treated with at least one antihypertensive drug. For at least one year prior to their enrollment in this study, the antihypertensive drugs did not change for any patients. In addition, the antihypertensive drugs did not change for any patients during the one-year observation period for obtaining the blood examination data. Patients with a history of heart failure or obvious heart disease were excluded. None of the patients had a history of atherosclerotic cardiovascular disease or stroke. Blood pressure was measured at an outpatient clinic every one or two months during the one-year observation period for each patient. During this period, a blood examination was performed at each season: namely, spring (March, 2010-May, 2010), summer (June, 2010-August, 2010), autumn (September, 2010-November, 2010), and winter (December, 2010-February, 2011). Blood samples were taken in the morning after an 8-hour overnight fast. Plasma total cholesterol, triglyceride, high-density lipoprotein cholesterol (HDL-C), serum albumin, blood urea nitrogen (BUN), serum creatinine, uric acid, hemoglobin, and hematocrit were measured by standard laboratory techniques. Serum creatinine levels were measured by using enzymatic creatinine assays. This protocol was approved by the Ethics Committee of Kagawa University. Informed consent was obtained from all participants. Estimation of Glomerular Filtration Rate (egfr) The glomerular filtration rate was estimated from the equation for Japanese patients, proposed by a working group of the Japanese Chronic Kidney Disease Initiative (Imai et al. 2007) as follows: egfr = 194 age (serum creatinine) ( if female). The average values of egfr of 4 seasons (spring, summer, autumn, and winter) were used to determine whether the participants had CKD or not. Participants with average values of egfr 60 ml/min/1.73 m 2 were included in the group of hypertensive patients without CKD, and those with average values of egfr < 60 ml/min/1.73 m 2 were included in the group of hypertensive patients with CKD. We evaluated the decrease in egfr from spring to summer by calculating the difference between the egfr values in the summer and spring. Moreover, we assessed the percent change in egfr from spring to summer as follows: Percent changes in egfr from spring to summer = (egfr summer egfr spring )/egfr spring. Statistical Analysis Data are expressed as means ± s.d.. Statistical analysis was performed using the SPSS software package (SPSS, Chicago, IL, USA). Differences between the two groups were checked by the χ 2 test for categorical variables or by the independent t-test for continuous variables. For comparison of mean values of egfr, BUN, creatinine, uric acid, hemoglobin, hematocrit, and blood pressure among Table 1. Clinical Characteristics of the Subjects. Without CKD (egfr 60 ml/min/1.73 m 2 ) With CKD (egfr < 60 ml/min/1.73 m 2 ) p value Number (male/female) 47 (27/20) 55 (38/17) Age (years) 69 ± ± 8 < BMI (kg/m 2 ) 24.0 ± ± 3.8 NS Diabetes (n (%)) 8 (17 %) 16 (29 %) NS Dyslipidemia (n (%)) 25 (53 %) 16 (51 %) NS Total cholesterol (mg/dl) 191 ± ± 30 NS HDL cholesterol (mg/dl) 54 ± ± Triglyceride (mg/dl) 111 ± ± 59 NS Serum albumin (g/dl) 4.3 ± ± Heart rate (beats/min) 71 ± ± 11 NS Anti-hypertensive drugs Diuretics (n (%)) 7 (15 %) 21 (38 %) ARB/ACEI (n (%)) 30 (64 %) 44 (80 %) NS CCB (n (%)) 32 (68 %) 32 (58 %) NS β-blocers (n (%)) 15 (32 %) 12 (22 %) NS α-blockers (n (%)) 4 (9 %) 5 (9 %) NS CKD, chronic kidney disease; BMI, body mass index; HDL, high-density lipoprotein; egfr, estimated glomerular filtration rate; ARB, angiotensin II receptor blockers; ACEI, angiotensin converting enzyme inhibitors; CCB, calcium channel blockers.

3 Seasonal Variation in Estimated Glomerular Filtration Rate 139 the 4 seasons, the one-way analysis of variance (ANOVA) test was used, and post hoc comparisons were made using least square differences test. Values of p < 0.05 were considered to indicate statistical significance. Results Clinical Characteristics of Subjects The clinical and egfr parameters of the subjects are summarized in Table 1. The mean age and serum uric acid level were significantly higher in patients with CKD than in those without CKD. The diastolic blood pressure, HDLcholesterol, serum albumin, and hemoglobin were significantly lower in patients with CKD than in those without CKD. The prevalence of diuretics used as anti-hypertensive drugs was significantly higher in patients with CKD than in those without CKD. Seasonal Variations in BUN, Creatinine, Uric Acid, Hemoglobin, Hematocrit, and Blood Pressure Although the values of BUN, creatinine, hemoglobin, Table 2. Comparison of Seasonal Variations of BUN, Creatinine, Uric Acid, Hemoglobin, Hematocrit, and Blood Pressure between the Two Groups. Without CKD (egfr 60 ml/min/1.73 m 2 ) With CKD (egfr < 60 ml/min/1.73 m 2 ) BUN BUN spring (mg/dl) 19.8 ± ± 10.3 BUN summer (mg/dl) 22.0 ± ± 14.6 BUN autumn (mg/dl) 20.6 ± ± 12.0 BUN winter (mg/dl) 20.9 ± ± 11.7 Creatinine Creatinine spring (mg/dl) 0.93 ± ± 0.62 Creatinine summer (mg/dl) 1.04 ± ± 0.81 Creatinine autumn (mg/dl) 0.95 ± ± 0.67 Creatinine winter (mg/dl) 0.94 ± ± 0.66 Uric acid Uric acid spring (mg/dl) 6.0 ± ± 1.3 Uric acid summer (mg/dl) 6.5 ± ± 1.7* # Uric acid autumn (mg/dl) 6.1 ± ± 1.6 Uric acid winter (mg/dl) 6.0 ± ± 1.3 Hemoglobin Hemoglobin spring (g/dl) 13.4 ± ± 1.7 Hemoglobin summer (g/dl) 13.0 ± ± 1.7 Hemoglobin autumn (g/dl) 13.4 ± ± 1.7 Hemoglobin winter (g/dl) 13.4 ± ± 1.7 Hematocrit Hematocrit spring (%) 40.5 ± ± 4.5 Hematocrit summer (%) 39.0 ± ± 4.8 Hematocrit autumn (%) 40.0 ± ± 5.1 Hematocrit winter (%) 40.9 ± ± 4.8 SBP SBP spring (mmhg) 137 ± ± 20 SBP summer (mmhg) 132 ± ± 18 SBP autumn (mmhg) 138 ± ± 20 SBP winter (mmhg) 136 ± ± 19 DBP DBP spring (mmhg) 75 ± ± 12 DBP summer (mmhg) 72 ± ± 12 DBP autumn (mmhg) 74 ± ± 12 DBP winter (mmhg) 72 ± ± 12 BUN, blood urea nitrogen; SBP, systolic blood pressure; DBP, diastolic blood pressure. *p<0.05 vs Uric acid spring ; # p<0.05 vs Uric acid winter ; p<0.05 vs SBP spring, SBP autumn, and SBP winter.

4 140 H. Masugata et al. Table 3. Comparison of Seasonal Variation of egfr between the Two Groups. Without CKD (egfr 60 ml/min/1.73 m 2 ) With CKD (egfr < 60 ml/min/1.73 m 2 ) egfr spring (ml/min/1.73 m 2 ) 77.9 ± ± 14.0 egfr summer (ml/min/1.73 m 2 ) 71.8 ± 13.2* 37.2 ± 13.0* # egfr autumn (ml/min/1.73 m 2 ) 76.2 ± ± 13.9 egfr winter (ml/min/1.73 m 2 ) 76.4 ± ± 14.2 egfr summer egfr spring (ml/min/1.73 m 2 ) 6.1 ± ± 5.2 % chage in egfr from spring to summer (%) 7.7 ± ± 9.4 egfr, estimated glomerular filtration rate; CKD, chronic kidney disease. *p < 0.05 vs egfr spring ; # p < 0.05 vs egfr winter. Fig. 1. Comparison of seasonal egfr variations in hypertensive patients with and without CKD. The two groups demonstrated similar seasonal variations in egfr. The egfr was the lowest in the summer (June-August) for both groups. The egfr in the summer (June-August) was statistically lower than that in spring (March-May) for both groups (p < 0.05). egfr, estimated glomerular filtration rate. and hematocrit did not show statistically significant differences among the 4 seasons, the value of uric acid increased in summer in patients with CKD ( p = 0.027) (Table 2). Diastolic blood pressure did not differ among the 4 seasons. However, systolic blood pressure decreased in summer in patients with CKD ( p = 0.034). Seasonal Variations in egfr The comparisons of seasonal variations in egfr between hypertensive patients with and without CKD are summarized in Table 3. Because we divided the participants into two groups based on egfr, the mean values of egfr were significantly lower in patients with CKD than in those without CKD during each season ( p < 0.001). Both groups demonstrated similar seasonal variations in egfr (Fig. 1). The egfr was the lowest in the summer (June August) for both groups. The egfr in the summer (June-August) was significantly lower than that in spring (March-May) for both patients without CKD ( p = 0.024) and those with CKD (p = 0.028). The decrease in egfr from spring to summer was similar for both groups (without CKD, 6.1 ± 7.0; with CKD, 5.8 ± 5.2 ml/min/1.73 m 2 ). However, the percent change in egfr from spring to summer was significantly greater in patients with CKD ( 13.8 ± 9.4 %) than the percent change in egfr in those without CKD ( 7.7 ± 8.3 %) (p = 0.001). Thus, the degree of the decrease in egfr was greater in patients with CKD. Influences of Prescribed Antihypertensives and Age on Seasonal Variations in egfr We compared the seasonal variation of egfr between patients with and without the combination of renin-angiotensin system (RAS) inhibitors and diuretics. We found that the seasonal variation of egfr was greater in 25 patients ( 14.0 ± 11.0 %) with the combination of RAS inhibitors and diuretics than in 77 patients ( 8.4 ± 7.1 %) without the combination of RAS inhibitors and diuretics ( p = 0.004). In addition, we compared the seasonal variation of egfr between 53 elderly (age 73 yrs) and 49 young (age < 73 yrs) patients. We found that the seasonal variation of egfr was greater in elderly patients ( 12.2 ± 9.8 %) than in young patients ( 7.2 ± 6.0 %) (p = 0.002).

5 Seasonal Variation in Estimated Glomerular Filtration Rate 141 Discussion The present study has revealed the seasonal variations in egfr in hypertensive patients with and without CKD. The data led us to the following conclusions: (1) egfr is the lowest in the summer for hypertensive patients with and without CKD; (2) although the reduction in egfr from spring to summer is similar for hypertensive patients with and without CKD, the percent change in egfr from spring to summer is greater in hypertensive patients with CKD than in those without CKD. The most striking result in our analysis was that human egfr values appear to decrease in the summer. Although some previous animal studies have demonstrated seasonal variation in the glomerular filtration rate, consensus is still lacking. Nawaz and Shah (1984) reported that the plasma concentrations of endogenous creatinine and urea in sheep were significantly higher because of haemoconcentration during summer, resulting in a lower glomerular filtration rate than in the winter. By contrast, Tsuda et al. (1995) reported that the glomerular filtration rate of sheep was significantly higher in the summer than in the winter. These controversial results may be attributed to the differences in the methodology for assessing glomerular filtration rates. As our human study estimated glomerular filtration rate using the equation proposed by the working group of the Japanese Chronic Kidney Disease Initiative, the seasonal variation in egfr may have mainly reflected the seasonal changes in serum creatinine levels. In this observational study, patients serum creatinine levels may have increased because of dehydration during summer. However, the seasonal changes in serum creatinine levels were not statistically significant (Table 2). In contrast, the systolic blood pressure and uric acid levels were decreased in summer in patients with CKD. Therefore, the seasonal variation in egfr in the present study may be produced in part by dehydration during summer. Moreover, prescribed antihypertensives and age may influence the seasonal variation of egfr. The seasonal variation in egfr demonstrated in the present study suggests that careful observation for dehydration may be needed to prevent a decrease in egfr in hypertensive patients with CKD. Hydration could be a treatment to prevent decrease in egfr in summer. The decrease in egfr in the summer was not enormous, either for hypertensive patients without CKD ( 6.1 ± 7.0 ml/min/1.73 m 2 ) or those with CKD ( 5.8 ± 5.2 ml/min/1.73 m 2 ). However, the baseline egfr in spring was lower in patients with CKD (43.0 ± 14.0 ml/min/1.73 m 2 ) than in those without CKD (77.9 ± 13.0 ml/min/1.73 m 2 ). Therefore, the percent reduction was greater in patients with CKD ( 13.8 ± 9.4 %) than in those without CKD ( 7.7 ± 8.3 %). Patients with CKD showed improvement of egfr in the autumn and winter, and did not show significant deterioration of renal function during the one-year observation. However, a previous study (Sasaki et al. 1975) demonstrated that patients with chronic glomerular nephritis submitted to repeated upright posture exhibited a decrease in the glomerular filtration rate with decreased circulating plasma volume. Therefore, further studies for a longer duration of observation may be needed to determine the effects of decreased egfr in the summer, possibly resulting from haemoconcentration or dehydration, on the prognosis of renal function in hypertensive patients. The limitation of the present study was that we did not assess renal function by 24-hour urine collection. We did not perform direct measurement of GFR by using the clearance of exogenous markers. Therefore, egfr based on serum creatinine levels in the present study may be different from the true seasonal variations in glomerular filtration rate to some degree. In conclusion, egfr is the lowest in the summer for hypertensive patients with CKD and those without CKD. Because the degree of the seasonal variations in egfr is greater in patients with CKD, careful observation regarding renal function is needed for hypertensive patients with CKD during summer. Conflict of Interest The authors declare no conflict of interest. References Barrett-Connor, E., Suarez, L., Khaw, K., Criqui, M.H. & Wingard, D.L. (1984) Ischemic heart disease risk factors after age 50. J. Chronic. Dis., 37, Go, A.S., Chertow, G.M., Fan, D., McCulloch, C.E. & Hsu, C.Y. 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