Original Paper Nephron Clin Pract 2014;126:33–38 DOI: 10.1159/000355639
Received: November 16, 2012 Accepted: August 23, 2013 Published online: January 15, 2014
Hyperuricemia Is a Significant Risk Factor for the Onset of Chronic Kidney Disease Akiko Toda Yuko Ishizaka Mizuki Tani Minoru Yamakado Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital, Tokyo, Japan
Abstract Background: Recent studies have shown that hyperuricemia is an independent risk factor for cardiovascular disease. However, few studies have examined whether hyperuricemia is a risk factor for chronic kidney disease (CKD), so to investigate the significance of hyperuricemia as a risk factor for CKD, we analyzed data collected in annual health check-ups. Methods: The data of 11,048 subjects who underwent an annual health check-up were analyzed in cross-sectional and longitudinal studies. Results: After adjustment for covariate factors, a multivariate logistic regression analysis showed that age, systolic blood pressure, diastolic blood pressure, LDL-cholesterol, triglyceride, HbA1c, and uric acid (hazard ratio: 1.66) were independently and significantly associated with CKD. We also analyzed the data of 1,652 subjects who underwent annual health check-ups for 5 consecutive years. Over that 5-year period, 93 subjects developed CKD. We compared the baseline data of the subjects who developed CKD with the data of those who did not, and we found significant between-group differences in gender, age, HDL-
© 2014 S. Karger AG, Basel 1660–2110/14/1261–0033$39.50/0 E-Mail [email protected] www.karger.com/nec
cholesterol, the estimated glomerular filtration rate, and uric acid. After adjustment for several covariate factors, a multivariate Cox regression analysis showed that only age and hyperuricemia (hazard ratio: 1.36) were independent risk factors for the development of CKD. Conclusions: We found that hyperuricemia is an independent risk factor for the development of CKD. © 2014 S. Karger AG, Basel
Introduction
The clinical issues associated with hyperuricemia are gouty arthritis, gouty tophus, and renal calculus, and it has been thought that only insoluble urate crystal depositions play an important role in the destructive and proinflammatory process. However, the latest evidence indicates that soluble urate in body fluids is also harmful and leads to kidney disease, hypertension and cardiovascular disease [1]. Other recent evidence shows that hyperuricemia is an independent risk factor for cardiovascular disease [2, 3]. Regarding the kidney, several studies have shown that uric acid contributes to the progress of renal diseases, such as cyclosporine nephropathy [4], and IgA nephropAkiko Toda, MD, PhD Center for Multiphasic Health Testing and Service Mitsui Memorial Hospital 1 Kandaizumicho, Chiyoda-ku, Tokyo 101-8643 (Japan) E-Mail toda-tky @ umin.ac.jp
Downloaded by: Fudan University Library 61.129.42.15 - 5/15/2015 7:35:53 PM
Key Words Hyperuricemia · Chronic kidney disease · Risk factors · Annual health check-up
Materials and Methods Study Population All subjects underwent an annual health check-up at The Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital in Tokyo, Japan. The number of healthy subjects who underwent the annual health check-up in 2007 was 10,788 (6,289 men and 4,499 women, men: 53.8 ± 10.7 years old, women: 50.3 ± 12.6 years old). Among these subjects, 1,652 subjects had undergone an annual health check-up for 5 consecutive years from 2002 to 2007 (1,079 men and 573 women, men: 53.3 ± 9.4 years old, women: 51.9 ± 9.3 years old). Almost half of the subjects voluntarily applied for the annual health check-up. For the others, the check-up was arranged by their employer. The subjects whose data were analyzed in this study provided written informed consent, and the study was approved by the Ethics Committees at our institution. Data Analysis Information for each subject was obtained through a self-administered questionnaire and confirmed through an interview with a physician. Blood samples were collected after an overnight fast, and urine samples were taken during hospital visits. HDL-cholesterol, LDLcholesterol, triglycerides, serum insulin, and uric acid (UA) were measured enzymatically. HbA1c was measured by a latex agglutination immunoassay. Creatinine was measured by an enzymatic method using the Accuras Auto CRE test (Shino test, Tokyo, Japan) and calibrated with a Multi-Chem Calibrator A (Wako, Osaka, Japan), which was traceable to an isotope dilution-mass spectrometry method. Urine samples were analyzed using a Clinitek ATLAS XL device combined with an ATLAS Reagent Cartridge PRO 12 instrument. The eGFR was calculated using a version of the modification of diet in renal disease equation modified for Japanese: eGFR (ml/ min/1.73 m2) = 194 × age–0.287 × serum creatinine [mg/dl, the enzymatic method]–1.094 × (0.739 if female) [8].
34
Nephron Clin Pract 2014;126:33–38 DOI: 10.1159/000355639
Table 1. Baseline characteristics of the study population (n =
10,508) Value ± SD or % Men Age, years BMI Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl Triglyceride, mg/dl HbA1c, % HOMA-IR eGFR, ml/min/1.73 m2 Uric acid, mg/dl Hematuria (–) (+/–) (1+) (2+) (3+) Proteinuria (–) (+/–) (1+) (2+) (3+)
58.3 52.1 ± 11.6 22.6 ± 3.2 122.9 ± 19.4 77.5 ± 12.1 60.1 ± 15.0 125.6 ± 30.9 110.7 ± 94.1 5.35 ± 0.6 1.56 ± 1.28 75.3 ± 14.5 5.43 ± 1.37 75.5 11.3 7.4 4.7 1.1 83.0 12.9 3.1 0.8 0.2
HOMA-IR = Homeostasis model assessment-insulin resistance.
Statistical Analysis All statistical analyses were performed using SAS (Dr. SPSS II, SAS Institute Inc., Cary, N.C., USA). The statistical significance of differences in the characteristics of participants was determined using the unpaired t test or a one-way ANOVA. The hazard ratios (HRs; 95% CI) were calculated using a multivariate logistic regression analysis or multivariate Cox regression analysis. p < 0.05 was considered significant.
Results
Study Population Our study population was 10,788 subjects who underwent an annual health check-up in 2007. After excluding subjects taking medication for hyperuricemia, we analyzed the data from 10,508 subjects in a cross-sectional study. Their baseline characteristics are shown in table 1. In accord with the Kidney Disease Outcomes Quality Initiative-Kidney Disease: Improving Global Outcome (K/ Toda/Ishizaka/Tani/Yamakado
Downloaded by: Fudan University Library 61.129.42.15 - 5/15/2015 7:35:53 PM
athy [5]. However, hyperuricemia has not yet been recognized as a prominent risk factor for the onset of renal injury. Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease and cardiovascular disease [6], and the prevention of CKD has become a focus of attention worldwide. To prevent CKD, it is important to clarify its risk factors. However, a decrease in the estimated glomerular filtration rate (eGFR) is one of the causes of hyperuricemia. It is thus difficult to establish whether hyperuricemia is not only a complication of CKD, but also a risk factor for CKD. Some studies have found that hyperuricemia has a harmful effect on kidney function [7], but few studies have investigated whether hyperuricemia is a risk factor for CKD. To determine whether hyperuricemia is a risk factor for CKD, we analyzed data from healthy subjects who underwent annual health check-ups in cross-sectional and longitudinal studies.
Table 2. Clinical characteristics of subjects with and without CKD among the study population
Men, % Age, years BMI Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl Triglyceride, mg/dl HbA1c, % HOMA-IR eGFR, ml/min/1.73 m2 Uric acid, mg/dl
CKD– (n = 9,203) average ± SD
CKD+ (n = 1,305) average ± SD
56.1 51.3 ± 11.6 22.5 ± 3.1 122.4 ± 19.2 77.2 ± 11.9 60.5 ± 15.0 124.8 ± 30.8 109.5 ± 96.7 5.32 ± 0.63 1.53 ± 1.21 78.1 ± 12.8 5.32 ± 1.34
74.7 57.8 ± 10.1 23.4 ± 3.2 125.8 ± 20.6 79.8 ± 12.6 57.1 ± 14.4 131.0 ± 31.2 119.0 ± 73.0 5.51 ± 0.67 1.78 ± 1.64 54.9 ± 7.8 6.22 ± 1.33
p value
Received: November 16, 2012 Accepted: August 23, 2013 Published online: January 15, 2014
Hyperuricemia Is a Significant Risk Factor for the Onset of Chronic Kidney Disease Akiko Toda Yuko Ishizaka Mizuki Tani Minoru Yamakado Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital, Tokyo, Japan
Abstract Background: Recent studies have shown that hyperuricemia is an independent risk factor for cardiovascular disease. However, few studies have examined whether hyperuricemia is a risk factor for chronic kidney disease (CKD), so to investigate the significance of hyperuricemia as a risk factor for CKD, we analyzed data collected in annual health check-ups. Methods: The data of 11,048 subjects who underwent an annual health check-up were analyzed in cross-sectional and longitudinal studies. Results: After adjustment for covariate factors, a multivariate logistic regression analysis showed that age, systolic blood pressure, diastolic blood pressure, LDL-cholesterol, triglyceride, HbA1c, and uric acid (hazard ratio: 1.66) were independently and significantly associated with CKD. We also analyzed the data of 1,652 subjects who underwent annual health check-ups for 5 consecutive years. Over that 5-year period, 93 subjects developed CKD. We compared the baseline data of the subjects who developed CKD with the data of those who did not, and we found significant between-group differences in gender, age, HDL-
© 2014 S. Karger AG, Basel 1660–2110/14/1261–0033$39.50/0 E-Mail [email protected] www.karger.com/nec
cholesterol, the estimated glomerular filtration rate, and uric acid. After adjustment for several covariate factors, a multivariate Cox regression analysis showed that only age and hyperuricemia (hazard ratio: 1.36) were independent risk factors for the development of CKD. Conclusions: We found that hyperuricemia is an independent risk factor for the development of CKD. © 2014 S. Karger AG, Basel
Introduction
The clinical issues associated with hyperuricemia are gouty arthritis, gouty tophus, and renal calculus, and it has been thought that only insoluble urate crystal depositions play an important role in the destructive and proinflammatory process. However, the latest evidence indicates that soluble urate in body fluids is also harmful and leads to kidney disease, hypertension and cardiovascular disease [1]. Other recent evidence shows that hyperuricemia is an independent risk factor for cardiovascular disease [2, 3]. Regarding the kidney, several studies have shown that uric acid contributes to the progress of renal diseases, such as cyclosporine nephropathy [4], and IgA nephropAkiko Toda, MD, PhD Center for Multiphasic Health Testing and Service Mitsui Memorial Hospital 1 Kandaizumicho, Chiyoda-ku, Tokyo 101-8643 (Japan) E-Mail toda-tky @ umin.ac.jp
Downloaded by: Fudan University Library 61.129.42.15 - 5/15/2015 7:35:53 PM
Key Words Hyperuricemia · Chronic kidney disease · Risk factors · Annual health check-up
Materials and Methods Study Population All subjects underwent an annual health check-up at The Center for Multiphasic Health Testing and Services, Mitsui Memorial Hospital in Tokyo, Japan. The number of healthy subjects who underwent the annual health check-up in 2007 was 10,788 (6,289 men and 4,499 women, men: 53.8 ± 10.7 years old, women: 50.3 ± 12.6 years old). Among these subjects, 1,652 subjects had undergone an annual health check-up for 5 consecutive years from 2002 to 2007 (1,079 men and 573 women, men: 53.3 ± 9.4 years old, women: 51.9 ± 9.3 years old). Almost half of the subjects voluntarily applied for the annual health check-up. For the others, the check-up was arranged by their employer. The subjects whose data were analyzed in this study provided written informed consent, and the study was approved by the Ethics Committees at our institution. Data Analysis Information for each subject was obtained through a self-administered questionnaire and confirmed through an interview with a physician. Blood samples were collected after an overnight fast, and urine samples were taken during hospital visits. HDL-cholesterol, LDLcholesterol, triglycerides, serum insulin, and uric acid (UA) were measured enzymatically. HbA1c was measured by a latex agglutination immunoassay. Creatinine was measured by an enzymatic method using the Accuras Auto CRE test (Shino test, Tokyo, Japan) and calibrated with a Multi-Chem Calibrator A (Wako, Osaka, Japan), which was traceable to an isotope dilution-mass spectrometry method. Urine samples were analyzed using a Clinitek ATLAS XL device combined with an ATLAS Reagent Cartridge PRO 12 instrument. The eGFR was calculated using a version of the modification of diet in renal disease equation modified for Japanese: eGFR (ml/ min/1.73 m2) = 194 × age–0.287 × serum creatinine [mg/dl, the enzymatic method]–1.094 × (0.739 if female) [8].
34
Nephron Clin Pract 2014;126:33–38 DOI: 10.1159/000355639
Table 1. Baseline characteristics of the study population (n =
10,508) Value ± SD or % Men Age, years BMI Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl Triglyceride, mg/dl HbA1c, % HOMA-IR eGFR, ml/min/1.73 m2 Uric acid, mg/dl Hematuria (–) (+/–) (1+) (2+) (3+) Proteinuria (–) (+/–) (1+) (2+) (3+)
58.3 52.1 ± 11.6 22.6 ± 3.2 122.9 ± 19.4 77.5 ± 12.1 60.1 ± 15.0 125.6 ± 30.9 110.7 ± 94.1 5.35 ± 0.6 1.56 ± 1.28 75.3 ± 14.5 5.43 ± 1.37 75.5 11.3 7.4 4.7 1.1 83.0 12.9 3.1 0.8 0.2
HOMA-IR = Homeostasis model assessment-insulin resistance.
Statistical Analysis All statistical analyses were performed using SAS (Dr. SPSS II, SAS Institute Inc., Cary, N.C., USA). The statistical significance of differences in the characteristics of participants was determined using the unpaired t test or a one-way ANOVA. The hazard ratios (HRs; 95% CI) were calculated using a multivariate logistic regression analysis or multivariate Cox regression analysis. p < 0.05 was considered significant.
Results
Study Population Our study population was 10,788 subjects who underwent an annual health check-up in 2007. After excluding subjects taking medication for hyperuricemia, we analyzed the data from 10,508 subjects in a cross-sectional study. Their baseline characteristics are shown in table 1. In accord with the Kidney Disease Outcomes Quality Initiative-Kidney Disease: Improving Global Outcome (K/ Toda/Ishizaka/Tani/Yamakado
Downloaded by: Fudan University Library 61.129.42.15 - 5/15/2015 7:35:53 PM
athy [5]. However, hyperuricemia has not yet been recognized as a prominent risk factor for the onset of renal injury. Chronic kidney disease (CKD) is a major risk factor for end-stage renal disease and cardiovascular disease [6], and the prevention of CKD has become a focus of attention worldwide. To prevent CKD, it is important to clarify its risk factors. However, a decrease in the estimated glomerular filtration rate (eGFR) is one of the causes of hyperuricemia. It is thus difficult to establish whether hyperuricemia is not only a complication of CKD, but also a risk factor for CKD. Some studies have found that hyperuricemia has a harmful effect on kidney function [7], but few studies have investigated whether hyperuricemia is a risk factor for CKD. To determine whether hyperuricemia is a risk factor for CKD, we analyzed data from healthy subjects who underwent annual health check-ups in cross-sectional and longitudinal studies.
Table 2. Clinical characteristics of subjects with and without CKD among the study population
Men, % Age, years BMI Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg HDL-cholesterol, mg/dl LDL-cholesterol, mg/dl Triglyceride, mg/dl HbA1c, % HOMA-IR eGFR, ml/min/1.73 m2 Uric acid, mg/dl
CKD– (n = 9,203) average ± SD
CKD+ (n = 1,305) average ± SD
56.1 51.3 ± 11.6 22.5 ± 3.1 122.4 ± 19.2 77.2 ± 11.9 60.5 ± 15.0 124.8 ± 30.8 109.5 ± 96.7 5.32 ± 0.63 1.53 ± 1.21 78.1 ± 12.8 5.32 ± 1.34
74.7 57.8 ± 10.1 23.4 ± 3.2 125.8 ± 20.6 79.8 ± 12.6 57.1 ± 14.4 131.0 ± 31.2 119.0 ± 73.0 5.51 ± 0.67 1.78 ± 1.64 54.9 ± 7.8 6.22 ± 1.33
p value
